Neurology and Clinical Neuroscience

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

NEUROLOGY AND CLINICAL NEUROSCIENCE

ISBN-13: 978-0-323-03354-1 ISBN-10: 0-323-03354-7

Copyright © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data Neurology and clinical neuroscience / editor, Anthony H.V. Schapira; associate editors, Edward Byrne . . . [et al.]. p. ; cm. ISBN 0-323-03354-7 1. Neurology—Textbooks. 2. Neurosciences—Textbooks. 3. Nervous system—Diseases—Textbooks. I. Schapira, Anthony H. V. (Anthony Henry Vernon). II. Byrne, Edward, M.D. [DNLM: 1. Nervous System Diseases. 2. Neurology. WL 140 N49269 2007] RC346.N4514 2007 616.8—dc22 2006046665

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To my wife, Laura, and my daughter, Sarah

CONTRIBUTORS

Rasheed A. Afinowi, MBBS, MSc

Clinical Research Fellow, Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom Intracranial Hemorrhage: Aneurysmal, Idiopathic, and Hypertensive

Rexford S. Ahima, MD, PhD

Doris-Eva Bamiou, MD, MSc, MPhil

Honorary Senior Lecturer, Institute of Child Health, University College London; Consultant in Audiological Medicine, National Hospital for Neurology and Neurosurgery, London, United Kingdom Vestibular System Disorders

Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine; Endocrinologist, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Neurology of Endocrinology

Christopher Bass, MA, MD, FRCPsych

Marta Altieri MD, PhD

Michel Baulac, MD

Department of Neurological Sciences, 1st Faculty of Medicine and Surgery, University of Roma La Sapienza, Rome, Italy Cerebral Venous Thrombosis

Hortensia Alvarez, MD

Neuroradiologist, Diagnostic and Therapeutic Vascular, Neuroradiology, Bicetre Hospital, Kremlin Bicetre, France Arteriovenous Malformations of the Brain and Spinal Cord

Shalini A. Amukotuwa, MBBS(Hons), BMedSci

Departmental Research Fellow, Department of Neurosciences, St. Vincent’s Hospital, Melbourne, Victoria, Australia Spinal Disease: Neoplastic, Degenerative, and Infective Spinal Cord Diseases and Spinal Cord Compression

Yaacov Anziska, MD

Associate in Neurology, Columbia University College of Physicians and Surgeons; Resident in Clinical Neurophysiology, NewYork–Presbyterian Hospital, New York, New York Metabolic, Immune-Mediated, and Toxic Neuropathies

Honarary Senior Clinical Lecturer in Psychiatry, University Department of Psychiatry, Warneford Hospital; Consultant in Liaison Psychiatry, John Radcliffe Hospital, Oxford, United Kingdom Conversion and Dissociation Syndromes Professor of Neurology and Head, Epileptology Unit, Clinique Paul Castaigne, Hôpital de la Pitié-Salpêtrière, Paris, France Clinical Spectrum [Epilepsy]

Antonio Belli, MD, FRCS(SN)

Neurologist, Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom Intracranial Hemorrhage: Aneurysmal, Idiopathic, and Hypertensive

Paul Bentley, MA, MRCP

Specialist Registrar–Neurology, St. Mary’s Hospital, London, United Kingdom Prothrombotic States and Related Conditions

Italo Biaggioni, MD

Professor of Medicine and Pharmacology, Vanderbilt School of Medicine, Nashville, Tennessee Orthostatic Hypotension

Marcelo E. Bigal, MD, PhD

Gregory J. Artz, MD

Fellow, Department of Neurotology, Michigan Ear Institute, Farmington Hills, Michigan Auditory System Disorders

Assistant Professor of Neurology, Albert Einstein College of Medicine of Yeshiva University; Director of Research, Montefiore Headache Center, Bronx, New York; Director of Research, The New England Center for Headache, Stamford, Connecticut Chronic Daily Headache

Messoud Ashina, MD, PhD, DMedSci

Rolfe Birch, MChir, FRCS, FRCS(Eng)

Associated Professor of Neurology, University of Copenhagen School of Medicine; Staff Neurologist, Danish Headache Center—University of Copenhagen, Copenhagen, Denmark Tension-Type Headache

Professor in Neurological Orthopaedic Surgery, University College London, London; Head, Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, United Kingdom Tumors of the Peripheral Nerve

vii

viii

Contributors

Bastiaan R. Bloem, MD, PhD

Neurologist, University Medical Center, Nijmegen, The Netherlands Gait Disturbances and Falls

Georgina Burke, BSc, MBBS, MRCP

Specialist Registrar–Neurology, Wessex Neurological Centre, Southampton General Hospital, Southampton, United Kingdom Neuromuscular Junction Disorders

Bradley F. Boeve, MD

Associate Professor of Neurology, Mayo Clinic College of Medicine; Consultant, Divisions of Behavioral Neurology and Movement Disorders and Mayo Sleep Disorders Center, Mayo Clinic, Rochester, Minnesota Dementia with Lewy Bodies

Jean Lud Cadet, MD

Lysa Boissé, MD, MSc

John N. Caviness, MD

Resident in Neurology, Queen’s University/Kingston General Hospital, Kingston, Ontario, Canada Neurological Disorders Associated with Human Immunodeficiency Virus Infection

Karen I. Bolla, PhD

Chief, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland Environmental Toxins Professor of Neurology, Mayo Clinic College of Medicine; Consultant, Division of Movement Disorders, Mayo Clinic Scottsdale, Scottsdale, Arizona Huntington Disease

Associate Professor of Neurology, Psychiatry and Behavior Sciences, and Environmental Health Sciences, Neurology, Johns Hopkins School of Public Health; Director of Neuropsychology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Environmental Toxins

Stephen D. Cederbaum, MD

John G. F. Boughey, MBChB, MRCP

Professor of Physiology, Faculty of Medicine, Université Aix-Marseille; Head, Department of Clinical Neurophysiology, Hôpital de la Timone; Director, U751 Epilepsy and Cognition, INSERM, Marseille, France Developmental Defects and Pathophysiology [Epilepsy]

Behavioral Neurology Fellow, Department of Neurology, Mayo Clinic, Jacksonville, Florida Alzheimer’s Disease

Professor of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California Urea Cycle Disorders

Patrick Chauvel, MD

Kevin B. Boylan, MD

Assistant Professor, Department of Neurology, Mayo Medical School; Mayo Clinic, Jacksonville, Florida Amyotrophic Lateral Sclerosis

Robert Brenner, MD, FRCP

Consultant Neurologist, Department of Academic Neuroscience, Royal Free Hospital, London, United Kingdom Investigations in Multiple Sclerosis

Edward B. Bromfield, MD, MEd

Associate Professor of Neurology, Harvard Medical School; Chief, Division of Epilepsy and Sleep, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Drug Treatment [Epilepsy]

Patrick F. Chinnery, MBBS(Hons), PhD, MRCPath, FRCP

Professor of Neurogenetics, The University of Newcastle upon Tyne; Honorary Consultant Neurologist, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom Metabolic Myopathies (Including Mitochondrial Disorders)

Soke Miang Chng, MD

Neuroradiologist, Diagnostic and Therapeutic Vascular Neuroradiology, Bicetre Hospital, Kremlin Bicetre, France Arterionenous Malformations of the Brain and Spinal Cord

Mark J. Cook, MD

Professor of Clinical Neurology, Columbia University College of Physicians and Surgeons; Director, Department of Neurology, Harlem Hospital Center, New York, New York Neurology of Drug and Alcohol Addictions

Professor of Neurology, University of Melbourne School of Medicine, Parkville; Director, Department of Neurology, St. Vincent’s Hospital, Melbourne, Victoria, Australia Disorders of Taste and Smell; Spine and Spinal Cord: Developmental Disorders; Spinal Disease: Neoplastic, Degenerative, and Infective Spinal Cord Diseases and Spinal Cord Compression

Camilla Buckley, BM, BCh, MRCP, DPhil

John R. Crawford, PhD

John C. M. Brust, MD

Lecturer in Clinical Neurology, Department of Clinical Neurology, University of Oxford; Honorary Specialist Registrar, Neurosciences Group, Radcliffe Infirmary, Oxford, United Kingdom Neuromuscular Junction Disorders

Professor, School of Psychology, University of Aberdeen, Aberdeen, UK; Consultant Clinical Neuropsychologist, Grampian University Hospitals NHS Trust, Aberdeen, United Kingdom Executive Function and Its Assessment

contributors

Eric A. Crombez, MD

Assistant Professor, Department of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California Urea Cycle Disorders

Jeffrey L. Cummings, MD

The Augustus S. Rose Professor of Neurology, David Geffen School of Medicine at UCLA; Director, UCLA Alzheimer’s Disease Center; Director, Deane F. Johnson Center for Neurotherapeutics, UCLA Medical Center, Los Angeles, California Affective Disorders

Marinos C. Dalakas, MD

Chief, Neuromuscular Diseases Section, National Institutes of Health, Bethesda, Maryland; Professor of Neurology, University of Athens Medical School; Chief, Section of Neuroimmunology and Neuromuscular Diseases, Department of Pathophysiology, University Hospital, Athens, Greece Inflammatory Myopathies

Josep Dalmau, MD, PhD

Associate Professor of Neurology, University of Pennsylvania School of Medicine; Neurologist, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Paraneoplastic Disorders of the Nervous System

Pe¯teris Da¯ rzin¸sˇ , BMBS, PhD, FRACP, FRCPC

Associate Professor in Geriatric Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University; Consultant Physician, Rehabilitation and Aged Services Program, Southern Health; Monash Ageing Research Centre, Kingston Centre—Monash University, Melbourne, Victoria, Australia Delirium

Bruce Day, MBBS, FRACP

Honorary Lecturer, Department of Medicine, Monash University; Director of Neurophysiology, Alfred Hospital, Melbourne, Victoria, Australia The Persistent Vegetative State (Prolonged Postcoma Unresponsiveness) and Posthypoxic Brain Injury

H. Gordon Deen, MD

Associate Professor of Neurosurgery, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant in Neurosurgery, Mayo Clinic Jacksonville, Jacksonville, Florida Head Trauma

Rajas Deshpande, MD, DM

Senior Consultant and Head, Neurology Department, Aditya Birla Memorial Hospital, Therzaon, India Clinical Spectrum: Definition and Natural Progression [Multiple Sclerosis and Demyelinating Disorders]

ix

Günther Deuschl, MD

Professor of Neurology, University of Kiel; Head of Department, Klinik für Neurologie, Universitats Klinikum Schleswig-Holstein, Campus Kiel, Germany Tremor

David W. Dodick, MD

Professor of Neurology, Mayo Clinic College of Medicine; Neurology Consultant, Mayo Clinic, Scottsdale, Arizona Other Secondary Headache Disorders

Erika D. Driver-Dunckley, MD

Clinical Instructor, Mayo Clinic College of Medicine, Scottsdale; Senior Associate Consultant, Mayo Clinic Hospital, Phoenix, Arizona Huntington Disease

James Evans, MD

Assistant Professor, Department of Neurosurgery, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Trigeminal Neuralgia and Other Facial Pain

Steven K. Feske, MD

Associate Professor of Neurology, Harvard Medical School; Chief, Division of Stroke and Neurovascular Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Neurology of Pregnancy and the Puerperium

John K. Fink, MD

Professor, Department of Neurology, University of Michigan Medical School; Physician-Scientist, Geriatric Research, Education, and Clinical Center, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan Hereditary Spastic Paraplegias

April L. Fitzsimmons, MD

Clinical Fellow, Department of Neurology, Harvard Medical School; Fellow in Neuro-oncology, Brigham and Women’s Hospital, Boston, Massachusetts Tumors of the Spinal Cord

Deborah I. Friedman, MD

Associate Professor of Ophthalmology and Neurology, University of Rochester School of Medicine and Dentistry; Attending Physician, Strong Memorial Hospital, Rochester, New York Idiopathic Intracranial Headache

Ilan S. Freedman, MBBS

Orthopaedic Registrar, Department of Orthopaedic Surgery, Western and Alfred Hospitals, Melbourne, Victoria, Australia Spinal Trauma

Simon C. Gandevia, MD, PhD, DSc

Professor, University of New South Wales School of Medical Sciences, Sydney; Deputy Director, Prince of Wales Medical Research Institute, Randwick, New South Wales, Australia Organization: Pyramidal and Extrapyramidal System [Motor System and Motor Diseases]

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Contributors

Felix Geser, MD, PhD

Richard Greenwood, MB, BCh, MD, FRCP

Nir Giladi, MD

Amparo Gutierrez, MD

Visiting Scholar, Center of Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Primary Autonomic Failure

Senior Lecturer, Sackler School of Medicine, Tel Aviv University; Director, Movement Disorders Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Gait Disturbances and Falls

Recognised Teacher, Institute of Neurology, University of London; Consultant Neurologist, Acute Brain Injury Service, National Hospital for Neurology and Neurosurgery, and Regional Neurological Rehabilitation Unit, Homerton University Hospital NHS Trust, London, United Kingdom Rehabilitation of Stroke Associate Professor of Clinical Neurology, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana Anatomy and Physiology of Muscle and Nerve

M. John Gill, BSc, MB, ChB, MSc

Maxime Guye, MD, PhD

Professor, Departments of Medicine, Microbiology, and Infectious Disease, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada Neurological Disorders Associated with Human Immunodeficiency Virus Infection

Neurophysiology and Neuropsychology Laboratory, Faculty of Medicine, Université de la Méditerranée; Neurologist, Clinical Neurophysiology Service, CHU la Timone, and Center for Biological and Medical Magnetic Resonance (CNRS UMR 6612), CHU la Timone, Marseille, France Developmental Defects and Pathophysiology [Epilepsy]

Peter J. Goadsby MD, PhD, DSc

Glenda M. Halliday, PhD

Professor, Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom TACs and SUNCT

Graeme M. Gonzales, MD

Department of Neurology, University of Melbourne, Parkville, Victoria, Australia Disorders of Taste and Smell

Neill R. Graff-Radford, MBBCh, FRCP(Lond)

Professor of Neurology, Mayo College of Medicine; Mayo Clinic Jacksonville, Jacksonville, Florida Alzheimer’s Disease

Elizabeth Graham, FRCP, FRCOphth

Consultant Medical Ophthalmologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Retinal Disease

Robin Grant, MBChB, MD, FRCP(Glasg), FRCP(Edin)

Honorary Senior Lecturer in Neurology, Division of Clinical Neurosciences, University of Edinburgh Faculty of Medicine; Consultant Neurologist, Western General Hospital, Edinburgh, United Kingdom Neurological Complications of Treatments

John E. Greenlee, MD

Professor and Interim Chair, Department of Neurology, University of Utah School of Medicine; Neurologist, Veterans Administration Medical Center, Salt Lake City, Utah Bacterial Meningitis (Including Lyme Disease, TB, and Syphilis)

Professor of Medicine, University of New South Wales School of Medical Sciences; National Health and Medical Research Council Principal Research Fellow, Prince of Wales Medical Research Institute, Sydney, New South Wales, Australia Organization: Pyramidal and Extrapyramidal System

Cynthia L. Harden, MD

Associate Professor of Neurology, Weill Medical College of Cornell University, New York, New York Management of Status Epilepticus

Jeffrey M. Hausdorff, BSE, MSME, PhD

Senior Lecturer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Lecturer in Medicine, Harvard Medical School, Boston, Massachusetts; Director, Laboratory of Gait and Neurodynamics, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Gait Disturbances and Falls

Robert C. Hermann, Jr., MD

Clinical Professor of Medicine and Neurology and Director, Neurology EMG Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas Peripheral Nerve Injury

Rhonda O. Holmes, BSpPathol

Senior Clinician, Neurosciences, and Speech Pathologist, Austin Health, Heidelberg, Victoria, Australia Motor Speech and Swallowing Disorders

Alan C. Jackson, MD, FRCPC

Professor of Medicine (Neurology) and Microbiology and Immunology, Queen’s University Faculty of Medicine; Attending Staff, Department of Medicine (Neurology), Kingston General Hospital, Kingston, Ontario, Canada Viral Meningitis and Encephalitis

contributors

Malaka B. Jackson, MD

John B. Kerrison, MD

Kim Jeffs, MBBS, FRACP

Joshua C. Kershen, MD

Endocrinology Fellow, Division of Pediatric Endocrinology, University of Pennsylvania/Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Neurology of Endocrinology

Honorary Fellow, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne; Consultant Geriatrician, The Northern Hospital, Epping; Research Fellow, Northern Clinical Research Centre, The Northern Hospital, Melbourne, Victoria, Australia Delirium

Richard T. Johnson, MD, FRCP

Distinguished Service Professor of Neurology, Microbiology, and Neuroscience, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; Neurologist, Johns Hopkins Hospital, Baltimore, Maryland Acute Disseminated Encephalomyelitis and Progressive Multifocal Leukoencephalopathy

Heinz Jungbluth, MD, PhD

Clinical Research Fellow, Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital; Consultant Paediatric Neurologist, Evelina Children’s Hospital, St. Thomas’ Hospital, London, United Kingdom Congenital Myopathies

Padmaja Kandula, MD

Assistant Attending Neurologist, Weill Medical College of Cornell University, New York, New York Management of Status Epilepticus

Raju Kapoor, DM, FRCP

Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Pathophysiology of Multiple Sclerosis: Demyelination and Axonal Injury

Horacio Kaufmann, MD

The Alex and Shirley Aidekman Professor of Neurology, Mount Sinai School of Medicine; Director, Autonomic Disorders Research and Treatment Program, Mount Sinai Medical Center, New York, New York Orthostatic Hypotension

Andrew H. Kaye, MBBS, MD, FRACS

Professor and Head, Department of Surgery, University of Melbourne, Parkville; Director of Neurosurgery, Royal Melbourne Hospital, Parkville, Victoria, Australia Hydrocephalus Including Normal-Pressure Hydrocephalus

Noojan J. Kazemi, MBBS

Research Fellow, University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, Australia Hydrocephalus Including Normal-Pressure Hydrocephalus

xi

Charleston Neuroscience Institute; St. Francis Hospital and Trident Hospital; Retina Consultants of Charleston, Charleston, South Carolina Genetic Causes of Blindness

Assistant Professor, Department of Neurology, Tufts University School of Medicine; Neurologist, Tufts-New England Medical Center, Boston, Massachusetts Infective Neuropathies

Desmond Kidd, MD, FRCP

Honorary Senior Lecture, Royal Free and University College School of Medicine; Consultant Neurologist, Royal Free Hospital, London, United Kingdom Examination of the Visual System

Glynda Kinsella, DiplPhysiol, MSc, PhD

Associate Professor of Psychological Science, La Trobe University; Clinical Neuropsychologist, Caulfield General Medical Centre, Melbourne, Victoria, Australia Principles of Neuropsychometric Assessment; Executive Function and Its Assessment

Laurence J. Kinsella, MD, FAAN

Professor of Neurology, Saint Louis University School of Medicine; Chief, Neurology and Neurophysiology, Forest Park Hospital, St. Louis, Missouri Vitamin Deficiencies

Neil Kitchen, MD, FRCS(SN)

Consultant Neurosurgeon and Associate Clinical Director, National Hospital for Neurology and Neurosurgery, London, United Kingdom Intracranial Hemorrhage: Aneurysmal, Idiopathic, and Hypertensive

Autumn M. Klein, MD, PhD

Instructor in Neurology, Harvard Medical School; Fellow in Clinical Neurophysiology, Division of Epilepsy and Sleep, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Neurology of Pregnancy and the Puerperium

Andrew J. Kornberg, MD

Professor of Paediatrics, Faculty of Medicine, Dentistry and Health Science, University of Melbourne; Director, Department of Neurology, Royal Children’s Hospital; Attending, St. Vincent’s Hospital, Parkville, Victoria, Australia Spine and Spinal Cord: Developmental Disorders

Thomas Kossmann, MD, FRACS

Professor and Director, Department of Trauma Surgery, and Director, National Trauma Research Institute, The Alfred Hospital/Monash University, Melbourne, Victoria, Australia Spinal Trauma

xii

Contributors

John W. Krakauer, MD

Assistant Professor of Neurology, Columbia University College of Physicians and Surgeons; Assistant Attending Neurologist, NewYork–Presbyterian Hospital, New York, New York Ischemic Stroke: Mechanisms, Evaluation, and Treatment

Richard B. Lipton, MD

Professor of Neurology, and Epidemiology and Population Health and Vice-Chair, Department of Neurology, Albert Einstein College of Medicine of Yeshiva University; Director, Montefiore Headache Center, Bronx, New York Chronic Daily Headache

Marcelo Kremenchutzky, MD

Assistant Professor, Department of Clinical Neurological Sciences, University of Western Ontario; Neurologist, London Health Sciences Centre, London, Ontario, Canada Clinical Spectrum: Definition and Natural Progression [Multiple Sclerosis and Demyelinating Disorders]

Jan D. Lünemann, MD

Brian C. Kung, MD

Hanns Lochmüller, MD

Resident, Otolaryngology—Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Examination of Hearing and Balance

University of Munich Hospital, Neurology Clinic and Outpatient Service, Friedrich-Baur Institute, Munich, Germany Muscular Dystrophies

Richard P. Lango, MD

James R. Lupski, MD, PhD

Instructor in Neurology, Department of Neurology/Neuroimmunology, University of Rochester School of Medicine and Dentistry; Fellow in Neurology, Strong Memorial Hospital, Rochester, New York Treatment of Multiple Sclerosis

The Rockfeller University Christopher H. Browne Center for Immunology and Immune Diseases, Laboratory of Viral Immunobiology, New York, New York Epidemiology and Genetics of Multiple Sclerosis

Cullen Professor of Molecular and Human Genetics and Professor of Pediatrics, Baylor College of Medicine; Attending Pediatrician and Consulting Medical Geneticist, Texas Children’s Hospital and Ben Taub General Hospital, Houston, Texas Inherited Neuropathies

Pierre Lasjaunias, MD, PhD

Neuroradiologist, Bicetre Hospital, Kremlin Bicetre, France Arteriovenous Malformations of the Brain and Spinal Cord

Ramon C. Leiguarda, MD

Professor of Neurology, University of Buenos Aires School of Medicine; Chairman, Department of Cognitive Neurology, Institute of Neurological Research–Fleni, Buenos Aires, Argentina Apraxia

Peter J. Lennarson, MD

Neurologic Surgeon, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska Coma and Brain Death

Gian-Luigi Lenzi, MD, FRCP

Professor, Department of Neurological Sciences, 1st University of Roma La Sapienza, Rome, Italy Cerebral Venous Thrombosis

Francois Lette, MD

Senior Associate Consultant, Division of Executive and International Medicine, Mayo Clinic, Jacksonville, Florida Parasitic and Fungal Infections

Bernardo Liberato, MD

Director, Neurovascular Service, Hospital Copa D’Or, Rio de Janeiro, Brazil Ischemic Stroke: Mechanisms, Evaluation, and Treatment

Linda M. Luxon, BSc, MBBS, FRCP

Professor of Audiological Medicine, University of London; UCL Institute of Child Health, Great Ormond Street Hospital for Children; Consultant Audiological Physician and Lead Clinician, Department of Neuro-Otology, National Hospital for Neurology and Neurosurgery, London, United Kingdom Vestibular System Disorders

John M. Lynch, MB, MRCPI

Clinical Research Fellow, National Hospital for Neurology and Neurosurgery, London, United Kingdom Genetics [Epilepsy]

Richard A. L. Macdonnell, MD, FRACP

Associate Professor, Faculty of Medicine, University of Melbourne, Melbourne; Deputy Director of Neurology, Austin Health, Heidelberg, Victoria, Australia Motor Speech and Swallowing Disorders

Eric T. MacKenzie, PhD

Director of Research, University of Caen; Staff, University Medical Center, Caen, France Anatomy and Physiology of Cerebral and Spinal Cord Circulation

Boby Varkey Maramattom, MD, DM

Consultant, Division of Critical Care Neurology, Department of Neurology, Lourdes Hospital, Kochi, Kerala, India Neurology of Pulmonology and Acid-Base Disturbance

contributors

Gad A. Marshall, MD

Clinical Instructor in Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California Affective Disorders

xiii

Francesco Muntoni, MD

Professor of Pediatric Neurology, Department of Pediatrics, Hammersmith Hospital Campus, Imperial College, London, United Kingdom Congenital Myopathies

Roland Martin, MD

National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Bethesda, Maryland; Universita Autonoma de Barcelona/Hospital Universitari Vall d’Hebron, Unitat de Neuroimmunologia Clínica, Barcelona, Spain Epidemiology and Genetics of Multiple Sclerosis

Kaye Murray, MBChB, BMedSci

Research Registrar, National CJD Surveillance Unit, University of Edinburgh; Specialist Registrar in Neurology, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom Prion Diseases

John H. Menkes, MD

Professor Emeritus of Neurology and Pediatrics, David Geffen School of Medicine at UCLA; Director Emeritus of Pediatric Neurology, Cedars Sinai Medical Center, Los Angeles, California Wilson Disease

Alessio Mercurio, MD

Department of Neurological Sciences, 1st University of Roma La Sapienza, Rome, Italy Cerebral Venous Thrombosis

Geoffrey Miller, MA, MB, ChB, MPhil, MD, FRCP, FRACP

Professor of Pediatrics and Neurology, Department of Pediatrics, Yale University School of Medicine; Clinical Director, Pediatric Neurology Service, Yale–New Haven Children’s Hospital, New Haven, Connecticut Neurology of Cerebral Palsy

Neil R. Miller, MD

Professor of Ophthalmology, Neurology, and Neurosurgery and Frank B. Walsh Professor of Neuro-Ophthalmology, Johns Hopkins University School of Medicine; Full-Time Faculty Member, Johns Hopkins Hospital, Baltimore, Maryland Optic Neuropathies

Bahram Mokri, MD

Professor of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota Low CSF Headache

Maria Cristina Morganti-Kossmann, PhD

Assistant Professor and Associate Director, Basic Research, National Trauma Research Institute, The Alfred Hospital/Monash University, Melbourne, Victoria, Australia Spinal Trauma

Hugo W. Moser, MD

Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Director, Neurogenetics Research Center, Kennedy Krieger Institute, Baltimore, Maryland Leukodystrophies

Sakkubai Naidu, MD

Professor of Pediatrics and Neurology, Johns Hopkins University School of Medicine; Director, Neurogenetics Unit, Kennedy Krieger Institute, Baltimore, Maryland Leukodystrophies

Peter J. Nestor, MBBS, PhD, FRACP

Senior Research Associate, University of Cambridge; Honorary Consultant Neurologist, Addenbrooke’s Hospital, Cambridge, United Kingdom Disorders of Memory

Nancy J. Newman, MD

Leo Delle Jolley Professor of Ophthalmology, Professor of Ophthalmology and Neurology, and Instructor in Neurological Surgery, Emory University School of Medicine, Atlanta; Lecturer in Ophthalmology, Harvard Medical School, Boston; Director of NeuroOphthalmology, Emory Eye Center, Atlanta, Georgia Genetic Causes of Blindness

Fiona L. M. Norwood, MD

Consultant Neurologist, King’s Neuroscience Centre, King’s College Hospital, London, United Kingdom Channelopathies of Muscle (Including Myotonic Dystrophy)

Wolfgang H. Oertel, MD

Professor of Neurology, Philipps University School of Medicine, Marburg, Germany Restless Legs Syndrome

Michael D. Osborne, MD

Assistant Professor in Physical Medicine and Rehabilitation and Assistant Professor in Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant, Mayo Clinic, Jacksonville, Florida Neurorehabilitation

Michael L. Oshinsky, PhD

Assistant Professor of Neurology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Headache Pathogenesis

xiv

Contributors

Eoin P. O’Sullivan, MD

Consultant Ophthalmologist, Mayday University Hospital, Croydon, United Kingdom Retinal Disease

Mark A. Paine, MBBS, FRACP

Jan Raethjen, MD

Lecturer, University of Kiel; PD, Klinik für Neurologie, Universitäts Klinikum Schleswig-Holstein, Campus Kiel, Germany Tremor

Consultant Neurologist, Department of Clinical Neurosciences, St Vincent’s Hospital, and Neuroophthalmology Unit and Vestibular Investigation Unit, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia Primary Myelopathies (Degenerative, Infective, Metabolic)

Jeremy Rees, PhD, FRCP

Carlos A. Pardo-Villamizar, MD

Sylvain Rheims, MD

Assistant Professor of Neurology and Pathology, Division of Neuroimmunology and Neuroinfections Disorders, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland Neurosarcoidosis and Behçet Disease

Juan M. Pascual, MD, PhD

Associate Professor of Neurology and Physiology, University of Texas Southwestern Medical School; Attending Neurologist and Pediatrician, University of Texas Southwestern Medical Center Hospitals and Children’s Medical Center, Dallas, Texas Encephalopathies

Milena K. Pavlova, MD

Instructor in Neurology, Harvard Medical School; Medical Director, Sleep Disorders Center, Division of Epilepsy and Sleep, Brigham and Women’s Hospital/Faulkner Department of Neurology, Boston, Massachusetts Primary Disorders of Sleep

Ronald F. Pfeiffer, MD

Professor and Vice Chair, Department of Neurology, University of Tennessee School of Medicine, Memphis, Tennessee Bladder and Sexual Function and Dysfunction; Neurology of Gastroenterology and Hepatology

Werner Poewe, MD

Chairman, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria Parkinson Plus Disorders

Christopher Power, MD, FRCPC

Professor of Medicine, Microbiology, and Immunology, University of Alberta Faculty of Medicine; CINR Investigator/AllFMK Scholar, University of Alberta, Edmonton, Alberta, Canada Neurological Disorders Associated with Human Immunodeficiency Virus Infection

Gary Price, MBChB, MSc, MRCPsych

Clinical Research Fellow in Neuropsychiatry, Institute of Neurology, University College London; Honorary Specialist Registrar, National Hospital for Neurology and Neurosurgery, London, United Kingdom Schizophrenia and Schizophrenia-like Psychosis

Senior Lecturer in Medical Neuro-oncology and Honorary Consultant Neurologist, Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom Tumors of the Brain Hospices Civils de Lyon, Lyon, France Assessment and Management Principles [Epilepsy]

George P. A. Rice, MD, FRCPC

Professor, Department of Clinical Neurological Sciences, University of Western Ontario; Multiple Sclerosis Clinic Director, London Health Sciences Centre, London, Ontario, Canada Clinical Spectrum: Definition and Natural Progression [Multiple Sclerosis and Demyelinating Disorders]

Nicole J. Rinehart, MClin Psych, PhD, MAPS

Senior Lecturer, Centre for Developmental Psychiatry and Psychology, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, Victoria, Australia Autism and Attention Deficit/Hyperactivity Disorder

Thomas D. Rizzo, Jr., MD

Assistant Professor in Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota; Chair, Department of Physical Medicine and Rehabilitation, Mayo Clinic, Jacksonville, Florida Neurorehabilitation

Mary M. Robertson, MBChB, MD, DPM, MRCPCH, FRCP, FRCPsych

Emeritus Professor of Neuropsychiatry and UCL Visiting Professor, St. George’s Hospital Medical School; Honorary Consultant Neuropsychiatrist and St. George’s Hospital Senior Visiting Fellow, Institute of Neurology, London, United Kingdom; UCL Honorary Medical Advisor, Tourette Syndrome (UK) Association Tourette’s Syndrome, Tics, and Obsessive-Compulsive Disorders

Georges Rodesch, MD

Neuroradiologist, Diagnostic and Therapeutic Vascular Neuroradiology, Foch Hospital, Suresnes, France Arteriovenous Malformations of the Brain and Spinal Cord

Timothy A. Roehrs, PhD

Professor, Department, Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine; Director of Research, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan The Physiology of Sleep

contributors

Gustavo C. Roman, MD

Professor of Medicine/Neurology, University of Texas School of Medicine at San Antonio, San Antonio, Texas Vascular Dementia

xv

Thomas D. Sabin

Professor and Vice-Chair, Department of Neurology, Tufts University School of Medicine; Acting Chief of Neurology, Tufts-New England Medical Center, Boston, Massachusetts Infective Neuropathies

Maria A. Ron, PhD, FRCP, FRCPsych

Professor in Neuropsychiatry, Institute of Neurology, University College London; Consultant Psychiatrist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Schizophrenia and Schizophrenia-like Psychosis

Michael R. Rose, MD, FRCP

Mohammad Salajegheh, MD

Clinical Associate, Neuromuscular Diseases Section, National Institutes of Health, Bethesda, Maryland Inflammatory Myopathies

Michael M. Saling, PhD

Honorary Senior Lecturer, Department of Neurosciences, King’s College Medical School; Consultant Neurologist, King’s Neuroscience Centre, King’s College Hospital, London, United Kingdom Channelopathies of Muscle (Including Myotonic Dystrophy)

Associate Professor, Department of Psychology, School of Behavioral Science, University of Melbourne, Melbourne; Director of Neuropsychology, Austin and Heidelberg Repatriation Hospitals, Melbourne, Victoria, Australia Disorders of Language

Richard B. Rosenbaum, MD

Martin A. Samuels, MD, DSc(hon), FAAN, MACP

Clinical Professor of Neurology, Department of Neurology, Oregon Health Sciences University School of Medicine and The Oregon Clinic, Portland, Oregon Neurology of Rheumatology, Immunology, and Transplantation

Jeffrey V. Rosenfeld, MBBS, MD, MS, FRACS, FRCS(Edin), FACS

Professor and Head, Department of Surgery, Central and Eastern Clinical School, Monash University; Director, Department of Neurosurgery, The Alfred Hospital, Melbourne, Victoria, Australia Coma and Brain Death

Myrna R. Rosenfeld, MD, PhD

Associate Professor of Neurology, University of Pennsylvania School of Medicine; Division Chief, Neurooncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Paraneoplastic Disorders of the Nervous System

Thomas Roth, PhD

Professor, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine; Divison Head, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan The Physiology of Sleep

Devon I. Rubin, MD

Assistant Professor, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant, Department of Neurology, Mayo Clinic, Jacksonville, Florida Peripheral Nerve Injury

Philippe Ryvlin, MD, PhD

Professor of Neurology, Université Claude Bernard Lyon 1; Praticien Hospitalier, Hospices Civils de Lyon, Lyon, France Assessment and Management Principles [Epilepsy]

Professor of Neurology, Harvard Medical School; Neurologist-in-Chief and Chairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Neurology of Cardiology, Cardiac Surgery, and Vascular Medicine; Neurology of Hematology; The Neurology of Common Electrolyte Disorders

Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci

Chairman and Professor, Department of Clinical Neurosciences, Royal Free and University College Medical School; and Professor of Neurology, National Hospital for Neurology and Neurosurgery and Institute of Neurology, London, United Kingdom Parkinson’s Disease

Anette Schrag, MD, PhD

Senior Lecturer and Honorary Consultant Neurologist, Department of Clinical Neurosciences, Royal Free and University College Medical School, London, United Kingdom Tourette’s Syndrome, Tics, and Obsessive-Compulsive Disorders

Todd J. Schwedt, MD

Assistant Professor of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri Other Secondary Headache Disorders

Steven R. Schwid D, MD

Associate Professor of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York Treatment of Multiple Sclerosis

Neil J. Scolding, PhD, FRCP

Professor of Clinical Neurosciences, Department of Neurology, University of Bristol Institute of Clinical Neurosciences; Consultant Neurologist, Frenchay Hospital, Bristol, United Kingdom The Neurological Vasculitides

xvi

Contributors

Julian L. Seifter, MD

Associate Professor of Medicine, Harvard Medical School; Division of Nephrology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts The Neurology of Common Electrolyte Disorders

Jon Sen, BSc(Hon), MB, BS, MSc

Research fellow, Institue of Neurology, Queen Square, London, United Kingdom Intracranial Hemorrhage: Aneursymal, Idiopathic, and Hypertensive

Caroline A. Sewry, BSc, PhD, FRCPath

Professor of Muscle Pathology, Dubowitz Neuromuscular Centre, Imperial College Faculty of Medicine, Hammersmith Hospital, London; Centre for Inherited Neuromuscular Disorders, Department of Histopathology, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom Congenital Myopathies

Pankaj Sharma, MD, PhD, MRCP, DHMSA

Honorary Senior Lecturer in Neurology, Imperial College London; Consultant Neurologist, Hammersmith Hospital Acute Stroke Unit, Charing Cross Hospital, London, United Kingdom Prothrombotic States and Related Conditions

Hiroshi Shibasaki, MD, PhD

Emeritus Professor, Kyoto University Graduate School of Medicine; Consultant, Takeda General Hospital, Kyoto, Japan Myoclonus

Stephen D. Silberstein, MD, FACP

Professor of Neurology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Migraine

Karin Stiasny-Kolster, MD

Department of Neurology, Philipps University School of Medicine, Marburg, Germany Restless Legs Syndrome

Alan Stiles, DMD

Clinical Instructor, Department of Oral and Maxillofacial Surgery, Jefferson Medical College of Thomas Jefferson University; Clinical Staff, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Trigeminal Neuralgia and Other Facial Pain

Elsdon Storey, MBBS, DPhil, FRACP

Professor of Neuroscience, Monash University–Alfred Hospital Campus School of Medicine; Head, Neurology Unit, Alfred Hospital, Melbourne, Victoria, Australia Principles of Neuropsychometric Assessment; The Neglect Syndrome; Executive Function and Its Assessment; Hydrocephalus Including Normal-Pressure Hydrocephalus

Austin J. Sumner, MD

Chairman, Neurology, Louisiana State University Health Sciences Center, New Orleans, Louisiana Anatomy and Physiology of Muscle and Nerve

Kinga Szigeti, MD

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Inherited Neuropathies

Valerie S. Tay, MBBS(Hons), FRACP

Neurology Fellow, Royal Children’s Hospital and St. Vincent’s Hospital, Melbourne, Victoria, Australia Spine and Spinal Cord: Developmental Disorders

Zelalem Temesgen, MD

Assistant Professor of Medicine, Mayo Clinic College of Medicine; Consultant, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota Parasitic and Fungal Infections

Zoë Terpening, BPsych Marco Sinisi, MD

Neurosurgeon, Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, United Kingdom Tumors of the Peripheral Nerve

Intern Clinical Neuropsychologist, Department of Clinical Psychology, University of Sydney; Intern Clinical Neuropsychologist, Neuropsychology Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Higher Visuoperceptual Disorders and Disorders of Spatial Cognition (Excluding Hemi-inattention/Neglect)

Sanjay M. Sisodiya, PhD, FRCP

Pierre Thomas, MD, PhD

Reader in Neurology, Institute of Neurology, University College London; Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Genetics [Epilepsy]

Kenneth J. Smith, BSc, PhD

Professor of Neurophysiology, Department of Clinical Neurosciences, King’s College London, London, United Kingdom Pathophysiology of Multiple Sclerosis: Demyelination and Axonal Injury

Professor of Neurology, Université de Nice-Sofia-Antipolis; Praticien Hospitalier, Hôpital Pasteur, Nice, France Assessment and Management Principles [Epilepsy]

Bruce J. Tonge, MBBS, MD, DPM, MRCPsych, FRANZCP, CertChildPsych, RANZCP

Professor, Centre for Developmental Psychiatry and Psychology, School of Psychology, Psychiatry, and Psychological Medicine, Monash University, Melbourne, Victoria, Australia Autism and Attention Deficit/Hyperactivity Disorder

contributors

Omar Touzani, PhD

Lecturer, University of Caen; Staff, University Medical Center, Caen, France Anatomy and Physiology of Cerebral and Spinal Cord Circulation

Douglass M. Turnbull, MBBS, MD, PhD, FRCP

Professor of Neurology, The University of Newcastle upon Tyne; Honorary Consultant Neurologist, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom Metabolic Myopathies (Including Myochondrial Disorders)

Ryan J. Uitti, MD

Professor of Neurology, Mayo Medical School, Rochester, Minnesota; Chair, Department of Neurology, Mayo Clinic, Jacksonville, Florida Inherited Ataxias

Dennis Velakoulis, MBBS, FRANZCP

Clinical Director, Melbourne Neuropsychiatry Centre, University of Melbourne; Director, Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia Clinical Assessment of Mental Status

Angela Vincent, MBBS, MSc, FRCPathol

Professor of Neuroimmunology, University of Oxford; Honorary Consultant in Immunology, Neurosciences Group, John Radcliffe Hospital, Oxford, United Kingdom Neuromuscular Junction Disorders

Maggie C. Walter, MD

Privat-Docent, University of Munich Medical Center, Neurology Clinic and Outpatient Service, Friedrich-Baur Institute, Munich, Germany Muscular Dystrophies

Mark Walterfang, MBBS, FRANZCP

Research Fellow, Melbourne Neuropsychiatry Centre, University of Melbourne; Consultant Neuropsychiatrist, Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia Clinical Assessment of Mental Status

xvii

John D. G. Watson, DPhil, MB, BS, BSC, FRACP

Associate Professor of Medicine, University of Sydney Faculty of Medicine, Sydney; Visiting Neurologist, Sydney Adventist Hospital, Wahroonga, and Hornsby Ku-Ring-Gai Hospital, Sydney, New South Wales, Australia Higher Visuoperceptual Disorders and Disorders of Spatial Cognition (Excluding Hemi-inattention/Neglect)

Louis H. Weimer, MD

Associate Clinical Professor of Neurology, Columbia University College of Physicians and Surgeons and Neurological Institute of New York; Associate Attending, NewYork–Presbyterian Hospital, New York, New York Metabolic, Immune-Mediated, and Toxic Neuropathies

Patrick Y. Wen, MD

Associate Professor of Neurology, Harvard Medical School; Director, Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Tumors of the Spinal Cord

Gregor K. Wenning, MD, PhD

Head, Clinical Neurobiology Unit, and Head, Autonomic Function Unit; Senior Fellow, Movement Disorder Unit; Vice-Chairman, European MSA Study Group; Department of Neurology, University Hospital/Medical University, Innsbruck, Austria Primary Autonomic Failure; Parkinson Plus Disorders

Nathaniel Robb Whaley, MD

Neurology Resident, Mayo Clinic, Jacksonville, Florida Inherited Ataxias

William N. Whiteley, MD, MRCP

Clinical Research Fellow, Division of Clinical Neurosciences, University of Edinburgh; Specialist Registrar in Medical Neurology, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom Neurological Complications of Treatments

Nick S. Ward, MBBS, MD, MRCP

Lecturer, Institute of Neurology, University College London; Wellcome Advanced Fellow, Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery and Institute of Neurology, London, United Kingdom Rehabilitation of Stroke

Thomas T. Warner, MD, PhD, FRCP

Reader in Clinical Neurosciences, Royal Free and University College Medical School; Consultant Neurologist, Royal Free Hospital; Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Dystonia

Robert G. Will, MA, MD, MBBCh, FRCP

Professor of Clinical Neurology, University of Edinburgh; Consultant Neurologist, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom Prion Diseases

Thomas O. Willcox, Jr., MD

Associate Professor, Department of Otolaryngology–Head and Neck Surgery, Jefferson Medical College of Thomas Jefferson University; Attending Surgeon, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Examination of Hearing and Balance; Auditory System Disorders

xviii

Contributors

Adrian J. Williams, MBBS, FRCP, AASM

Consultant Physician and Director, Lang Fox Respiratory Unit and Sleep Disorders Centre, Guy’s and St. Thomas’ Foundation NHS Trust, London, United Kingdom Sleep Apnea

John W. Winkelman, MD, PhD

Associate Professor in Psychiatry, Harvard Medical School; Medical Director, Sleep Health Center, Brigham and Women’s Hospital, Boston, Massachusetts Primary Disorders of Sleep

Bryan K. Woodruff, MD

Clinical Instructor, Mayo Clinic College of Medicine, Scottsdale; Senior Associate Consultant, Mayo Clinic Hospital, Phoenix, Arizona Frontotemporal Dementia

P R E FA C E

Many have regarded the practice of clinical neurology as an arcane art, and non-neurologists often are daunted by the prospect of managing neurological cases. In large part, this perception of neurology is a legacy from not so long ago, when few if any investigations were available and diagnosis rested on meticulous documentation and evaluation of clinical features. Although neurology remains quintessentially a clinical art, it has benefited greatly from advances in both the investigational and the basic neurosciences. The advent of imaging with CT, MRI, MRS, PET, SPECT, and other technologies has transformed clinical practice, improving our understanding of diseases and their diagnosis and management. Progress in the molecular sciences has had a particular impact on neurology. A substantial proportion of neurological disorders are the consequence of inheritance. The identification of the genetic basis of various neurological diseases, including neurodegenerative and neuromuscular disorders, migraine, and stroke, has provided insight into pathogenesis and has further refined diagnosis and management. These and other advances have made neurology and the neurosciences the most exciting and probably the most rapidly evolving sector of medicine today. Neurologists already are blessed with a number of outstanding textbooks in either single or multiple volumes. What then was the driver to bring this newcomer—Neurology and Clinical Neuroscience—into the field? The primary intention was to provide a comprehensive and up-to-date review of clinical neurology for both experienced practitioners and neurologists-in-training. Integral to this approach was a desire to include as much clinical neuroscience as was relevant and appropriate so that the clinician could understand the basis for the rapid progress in management of specific diseases, especially regarding application of advances in the molecular neurosciences to neurological disease. An important and novel aspect of the book is its emphasis on illustrations in full color, ensuring both clarity and readability. The organization of this book does not range far from the formula that has proved successful for neurology texts over several decades: A review of consciousness, cognition, and the special senses is an appropriate place to begin, because much of neurology rests on a sound understanding of these concepts. Sleep medicine, neuropsychiatry, neuro-ophthalmology, neurootology, and disorders of the autonomic nervous system are essential components of neurological practice. Into these sections we have introduced chapters on assessment to aid or remind neurologists of the techniques involved in clinical evaluation. Other sections that follow the main topic areas of clin-

ical neurology practice include the cerebrovascular, demyelinating, infective, inflammatory, and neurodegenerative diseases; neuromuscular disorders; headache; and epilepsy. Neuro-oncology has become an important component of neurological practice, both as a result of the direct effects of tumors of the nervous system and also because of the consequences of treatment of these and other tumors on brain, spinal cord, and peripheral nerve function. This area has therefore been covered in some detail. A substantial part of the work of a clinical neurologist is the assessment, diagnosis, and management of neurological disease in general medical practice. We have included a comprehensive section on this topic, in acknowledgment of this fundamentally important area. In the preparation of this book, it has been my privilege to work with some of the foremost leaders in the field of clinical neurology. The eminent section editors, Ed Byrne, Billi DiMauro, Richard Frackowiak, Richard Johnson, Yoshikuni Mizuno, Martin Samuels, Stephen Silberstein, Elsdon Storey, and Zbigniew Wszolek have worked tirelessly to ensure the success of this book. Their input into its composition and content has been invaluable. The contributing authors represent an outstanding collection of experts in their respective fields. It is with great gratitude that I thank them for their hard work and congratulate them on their excellent contributions. We, the editors, are greatly indebted to them and hope that they feel the final product justifies their efforts and our cajoling! Three special people deserve particular thanks and recognition for their contributions to the successful production of this book. The first is Susan Pioli, Director of Medical Publishing for Butterworth Heinemann for many years and now head of Neurology for Elsevier. Her support for this text was essential, and it is true to say that she was the midwife at its birth, ensuring its safe and successful entry into this world. Her knowledge of the field and her longstanding friendships and contacts within neurology have been invaluable. It has been a privilege, an education, and a delight to work with her. Heather Krehling has been the ringmaster, coordinating the receipt and production of manuscripts, gently cajoling and always hyper-efficient. The monumental task of assembling the materials for the numerous chapters of this book was a responsibility she discharged with brilliance, humor, and charm. It is a great credit to her. Finally, I thank Rebecca Gaertner of Elsevier for her wonderful help and support in seeing this project through to a successful conclusion. TONY SCHAPIRA

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1

CHAPTER

CLINICAL ASSESSMENT MENTAL STATUS ●

●

●

OF

●

Dennis Velakoulis and Mark Walterfang

Since the mid-1980s, the relationship between the clinical neurosciences of neurology, neuropsychology, and psychiatry has been the subject of several important textbooks that seek to cross these disciplinary boundaries.1-6 Lishman7 succinctly described the overlap between neurology and psychiatry as a “delicate balance . . . between our knowledge and understanding of the brain and our knowledge and understanding of people.” Neuropsychology, as a relative newcomer to this field, has added a third element to this balance, and the advent of new investigative imaging modalities and molecular biology technologies has further assisted in “closing the great divide.”8 At the heart of these converging relationships lies an increasing appreciation that a thorough assessment and formulation of individual patients is incomplete without reference to the knowledge and skills of other disciplines. The logical conclusion to this convergence is that disciplinary hybrids such as neuropsychiatry, behavioral neurology, and cognitive neuropsychology may be better replaced by the broader concept of a clinical neuroscience. Although the core expertise of each discipline may differ, the clinical assessment always includes the documentation of a detailed history and the performance of an examination that is driven by a process of hypothesis testing. The major difference in assessment between disciplines is determined by their specific expertise, whether it be the neurological examination, the psychiatric mental state examination, or a detailed neuropsychological assessment. An element common to all is the assessment of cognition, which in neurological practice has been termed the mental status examination.9 In psychiatric practice, the term mental state/status examination refers to a broader assessment of the patient’s mental state and incorporates the cognitive assessment. Because most neurologists and psychiatrists are restricted to bedside assessments of patients and have limited access to neuropsychological expertise, all possible information must be incorporated into decisions regarding the patient’s cognitive abilities. The clinical skill of cognitive assessment extends far beyond the administration of a test and the generation of a score. A common error among junior clinicians is to base diagnosis on a test score and ignore the richness of cognitive information available from the remainder of their interaction with the patient. This chapter takes a broad approach to cognitive assessment as a process that should incorporate all information available to the clinician from the moment a referral is initiated through

2

cognitive testing to the process of feedback to the patient. Neuropsychological assessment, although seen as the “gold standard” of cognitive assessment, is not always available because of limited service resources, cost, or geographical issues. Even if neuropsychological expertise is available, it may be limited by the patient’s inability or refusal to undertake formal testing. In such situations, clinical needs may still necessitate an assessment of the patient’s cognitive state, and the clinician needs to form a judgment on the basis of all available information.

NEUROCOGNITIVE HISTORY General Principles The neurocognitive history begins from the moment the patient is referred. The information provided in a referral may include the following: ■ Mode of referral: urgency, triggers for referral ■ Presenting symptoms ■ Longitudinal course: acute, subacute, gradual, fluctuating,

progressive ■ Medical or psychiatric history ■ Investigations with positive or negative findings ■ The referral question

The neurocognitive history begins with the events precipitating the referral or assessment, particularly the first symptom of change, an understanding of gross functional capacity, and a sense of the longitudinal course of symptoms. From this basic “sketch” of an individual’s function, more specific questions can be directed toward specific cognitive domains; the presence or absence of neurobehavioral symptoms or signs; an individual’s capacity to function in social, occupational, and interpersonal roles; and relevant previous and related history.

Informant History Although the key informant is usually a relative or caretaker, the clinician should seek information from as wide a range of sources as possible. Key informants may include a nursing

chapter 1 clinical assessment of mental status home worker, neighbor, friend, or primary care physician. Such information may be crucial if the validity of the patient’s history is limited by impairments in insight regarding the nature of their deficits. The patient and the informant should be interviewed separately, if possible. Informants are most likely to provide a full and frank history when interviewed alone. Caretakers may not wish to disclose the extent of their concerns with the patient present, for fear of distressing him or her. This is especially relevant if caretakers have not discussed their concerns with the patient or if the content of their concerns is experienced as a betrayal of trust, which in extreme circumstances may put the caretaker at risk.

3

of such a critical event may provide useful information about the type of disturbance and its onset but, perhaps more important, the nature guides future management through emphasis of issues such as safety, competence, and suitability of placement. A similar situation can occur when a patient’s environment is radically changed, such as a residential shift from a highly structured environment to a less structured one, or the loss of a crucial source of support, such as with the illness or death of a spouse. A gradually developing impairment may, however, manifest abruptly when it reaches a critical threshold for caretakers or relatives whose capacity to accommodate the deficits of the patient has been exhausted.

Evolution of Symptoms Patient History The content of the history provided by the patient is meaningful, because many patients are aware of their difficulties to a degree and may proffer a straightforward problem list. Equally revealing is the patient who is seemingly unaware of any difficulties and denies problems as a result of cognitive impairments or psychiatric disturbance. Most patients respond well to an open-ended question about their presentation, such as “What is your understanding of why you are seeing me today?” In some circumstances, it is also appropriate to reveal the concerns of others: for example, “I understand that you have been having difficulties with your memory recently.” The process of the provision of historical information may be equally revealing. Patients may betray language difficulties through word-finding problems, psychosis through thought disorder, depressed mood through a lengthy latency in response time, or executive impairment through an empty or concrete account of events.

Integration of Neurobehavioral and Neurocognitive History Neurobehavioral disturbances such as depression or psychosis are often the initial presenting feature in patients with neurocognitive impairment. Conversely, patients who initially present with the neurocognitive features of dementia may later exhibit psychotic symptoms; disinhibited, stereotypical, or inappropriate behavior; or mood and anxiety disturbance.10 Psychiatric disorders with associated behavioral disturbance may themselves manifest with neurocognitive impairments, such as the difficulties with sustained attention, memory, and processing speed seen in major depression11 or the working memory impairments seen in schizophrenia.12 Neurobehavioral impairment may herald future neurocognitive impairment, and vice versa. For example, frontotemporal dementias commonly manifest with neurobehavioral disturbance,13 and late-life depression may herald Alzheimer’s disease.14

Assessment Trigger Assessment may be triggered by a critical event such as a patient’s putting himself or herself at risk or endangering others or such as significant interpersonal conflict. The nature

The longitudinal course of illness is most commonly established through informants, and a complete history may need to be obtained from a number of sources. The nature of the onset of symptoms and the context in which they occur may be diagnostically discriminatory. For example, delirium usually manifests rapidly over a couple of days in the context of significant medical insult, whereas neurocognitive impairment associated with a central nervous system (CNS) neoplasm usually manifests over a few months, frequently in concert with other neurological symptoms. Many caretakers of patients with a dementing illness report subtle and insidious changes occurring for a year or more before assessment. Exceptions to this may occur, such as a subacute delirium or a rapidly progressive dementia. The longitudinal course may allow diagnostic differentiation particularly within the dementias. Alzheimer’s disease and frontotemporal dementias usually show gradual progression, whereas the time course of vascular dementia is often, but not always, stepwise. Rapid cognitive decline is suggestive of a prion dementia or a potentially reversible cause such as vasculitis or neoplasia. The sequence of symptoms can be similarly informative. Depressed mood and neurovegetative disturbance for 3 months before the onset of memory problems are likely to indicate a depressive “pseudodementia.” An initial presentation of apathy, disinhibition, or stereotypical behaviors before memory or language impairment are suggestive of a frontotemporal dementia, whereas impaired new learning as the first symptom would be more suggestive of an Alzheimer’s-type dementia. The age at symptom onset may narrow the list of differential diagnoses. Cognitive impairment in early adult life may be associated with adult-onset forms of inherited metabolic disorders, such as leukodystrophies, but are more frequently associated with potentially reversible causes of impairment, such as CNS infections, inflammatory disorders, or neoplasia. When impairment manifests in the fourth through sixth decades, early-onset dementias, such as frontotemporal dementia or familial Alzheimer’s disease, or the early manifestation of undiagnosed vascular disease should be considered. In later decades, most such illnesses are vascular or degenerative. Finally, the presence of fluctuations in the mental state and functioning may provide clues to etiology. Fluctuations in the level of arousal and orientation over days are seen in delirium. Late afternoon and early evening deteriorations may reflect the “sundowning” seen in dementias, whereas episodes of undiagnosed confusion occurring over a number of months may point to a diagnosis of Lewy body dementia.

4

Section

I

C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s

T A B L E 1–1. Evaluation of Functional Impairment Personal function: eating, toileting, bathing, dressing, grooming Home function: cooking, cleaning, household maintenance Interpersonal: relationships with spouse and family, friends, colleagues Occupational: performance, punctuality, promotion/demotion, conflict Financial: management of cash and change, bill paying, financial planning Transport: driving, public transport, geographical orientation Leisure: hobbies, pastimes

Gross Functional Capacity Patients and caretakers do not always have a specific complaint of “cognitive impairment.” Functional impairment as noticed by caretakers, relatives, or colleagues is commonly a precipitant for assessment. A thorough history of the pattern and nature of functional impairment provides valuable diagnostic information and may help treatment planning (Table 1–1).

Attention and Orientation Attention is not a unitary construct. Sustained, directed attention is the ability to attend to a specific stimulus without being distracted by extraneous internal or environmental stimuli. Other aspects of attention include the ability to share attention between simultaneous tasks (divided attention), the ability to switch attention between tasks, and the ability to attend to stimuli at different spatial locations. Disturbance of sustained, directed attention is most commonly reported in delirium (see Chapter 11) but may also be present with anxiety or mood disturbance, executive dysfunction (see Chapter 7), or dementias. Orientation is a more complex function involving the capacity to attend to stimuli and to process and retain information regarding locale and point in time. The following questions are useful guides to areas for evaluation: ■ Can the patient attend to, and persevere with, most tasks, or

■

Neurocognitive Baseline An understanding of an individual’s premorbid neurocognitive function allows an estimate of the degree and rate of decline. In impaired individuals with superior premorbid intellect, cross-sectional assessment may be within accepted norms for age. Commonly used screening instruments such as the MiniMental State Examination (MMSE) have a significant ceiling effect (see Chapter 2 on neuropsychological assessment) and are likely to be insensitive to this decline.15 Conversely, individuals with long-standing premorbid intellectual impairment may be incorrectly classified as suffering a degenerative process such as dementia, when in fact their neurocognitive function is stable. Baseline function can be estimated grossly from the patient’s maximal educational and occupational attainment and from mental state features such as vocabulary and capacity for abstract thinking. A number of assessment tools for estimating premorbid intellectual function have been devised and rely on the stability of semantic language functions independent of disease or age. The most well-known and widely used is the National Adult Reading Test.16 This probes reading ability for irregular words, which has been shown to be relatively preserved in many disorders.17 Other similar tools include the Wechsler Test of Adult Reading18 and the Cambridge Contextual Reading Test.19 This issue is also addressed in Chapter 2 on neuropsychological assessment.

FUNCTION IN NEUROCOGNITIVE DOMAINS For the purposes of history taking, neurocognitive function is usefully categorized into the domains of attention, language, visuospatial function, memory, and executive function. Very few neurocognitive functions are discrete, however, and most functions are distributed across more than one domain: for example, remembering a list of three items relies on receptive and expressive speech, in addition to memory. The presence of any impairments in hearing and vision should be established as early as possible in an interview.

■ ■ ■

does the patient demonstrate difficulties completing a task or take much longer than would be expected (a measure of sustained, directed attention)? Can the patient attend to the television or to reading of a newspaper article, a magazine, or a book (sustained, directed attention)? Can the patient ignore distractions? Can the patient converse while doing something else (a measure of divided attention)? Is the patient aware of the time of day or day of the week, and does he or she act accordingly with regard to mealtimes or daily tasks?

Language Language is the basic tool of human communication and a basic component of many cognitive abilities. Language functions are commonly ascribed to the dominant hemisphere, and because cerebral dominance for language is closely allied to handedness, it is useful to be aware of the patient’s handedness before language function is assessed. Most of the conditions that produce disorders of language affect the left hemisphere and are commonly of vascular, traumatic, neoplastic, or degenerative origin. Disorders of language are separated into aphasia (partial or total inability to articulate ideas or comprehend spoken or written language), alexia (inability to read), and agraphia (inability to write). An understanding of the large group of aphasias has been complicated by various nomenclatures, although the most recognized is that originally proposed by Benson and Geschwind,20 which divides the group into Broca’s, Wernicke’s, global, conduction, anomic, and transcortical aphasias. This is discussed in more detail in Chapter 3. The following questions are useful guides to areas for evaluation: ■ Has the patient had any difficulties with speech, such as in

finding the right word or using the wrong word? ■ Can the patient pronounce words correctly, or does he or

she make errors in pronunciation? Are these errors consistent? ■ Has there been a change in the patient’s grammar or sentence construction?

chapter 1 clinical assessment of mental status ■ Has there been any reduction in the patient’s quantity or

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fluency of speech or in how much detail he or she provides in relating events? Has the patient had difficulties in understanding or following conversation? Does the patient miss the “gist” of the conversation? Does he or she misunderstand jokes or puns? Does the patient’s speech jump about from idea to idea or drift off the topic? Has there been a change in the amount, legibility, quality, sophistication, or size of the patient’s handwriting?

Visuospatial Functions Visuospatial functions allow persons to orient themselves in space, enable safe locomotion, facilitate interaction with other individuals and objects, and allow for the expression and understanding of visual symbols of communication. Such functions are often related to pathology affecting the parietal cortex, which also contains contralateral motor and sensory representations of the body soma. Many disorders or diseases that disturb visuospatial functions are associated with significant motor or sensory impairment. Visuospatial disturbance is common in dementias of all types, but it is most commonly seen with Alzheimer’s-type dementia. It is the presenting and dominant feature in the posterior variant, posterior cortical atrophy. Vascular or other acquired focal lesions of the parietal regions may also manifest with visuospatial difficulties. Aspects of visuoperceptual disturbance are discussed further in Chapter 5. The following questions are useful guides to areas for evaluation: ■ Is the patient able to dress himself or herself appropriately?

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Does he or she wear items of clothing the wrong way around, inside out, or fitted incorrectly? Of importance, however, is that often a dressing apraxia may result from visuoperceptual disturbances or spatial inattention. Can the patient find his or her way around the house, to the shops, and in unfamiliar environments when directions are provided? Can the patient still use everyday objects—eating utensils, grooming items (toothbrush, comb), or tools of his or her trade—appropriately? Can the patient tell the time from an analog clock or watch? Can the patient use more complicated household items, such as an oven, washing machine, television, video recorder, or compact disc player? Disturbances of these functions may also arise from various forms of apraxia. Does the patient ever get left and right mixed up? Does the patient seem to ignore one side of his or her body when bathing, shaving, or dressing or one side of his or her environment when eating, walking/driving, or interacting socially?

Memory Anterograde episodic memory is a general term for the registration, acquisition, storage, and subsequent retrieval of new information. Anterograde episodic memory impairment is perhaps the most common manifestation of neurocognitive disturbance. Anterograde episodic memory consists of several stages, beginning with the reception and registration of the

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information by a sensory modality, followed by the holding of the information temporarily in working memory (defined as the current content of consciousness); then storage in a more permanent form, which is enhanced by association with other already stored information and augmented by practice or rehearsal; and, finally, the process of retrieval. Each of these steps requires the integrity of the preceding steps, and any interruption in this hierarchy may disrupt anterograde episodic memory function. A detailed discussion of the various memory systems and their disorders is presented in Chapter 4. Patients with dementia, particularly Alzheimer’s disease and vascular dementias, usually present to clinicians with memory disturbance before the onset of other neurocognitive or neurobehavioral disturbances. Memory impairment occurs commonly in brain disorders acquired from such causes as traumatic injury, postinfection states, and chronic exposure to CNS toxins such as alcohol. The following questions are useful guides to areas for evaluation: ■ Can the patient recall recent conversations and accurately

relate recent family news? ■ Is the patient able to describe or relate recent world or local

events that may have been heard on the radio, seen on television, or read in the newspaper? ■ Has the patient missed birthdays, anniversaries, or other special events? ■ Does the patient tend to relate events or occasions from the more distant past when questioned about, or discussing in conversation, more recent events? ■ Has the patient had difficulties recalling the names of people, places, or things?

Executive Function Executive functions are a group of complex functions that are based on the interaction with and executive control of basic processes such as attention, memory, and language. The prefrontal lobes and connected subcortical structures are crucial to the integrity of executive function, personality, and behavior. Cognitive functions that have been attributed to these networks include adaptive behavior, abstract conceptual ability, set-shifting/mental flexibility, problem-solving, planning, initiation, sequencing of behavior, and personality factors such as drive, motivation, and inhibition. Patients with the dysexecutive syndrome fail to anticipate changes, show poor planning ability, and do not learn from their errors. They are poor at selfguided learning and goal-setting, in that they perform normally on externally driven tasks but are poor at self-motivated tasks. Such patients are sensitive to interference from irrelevant stimuli, and may display both motor and cognitive perseveration. A more detailed overview of executive function and dysfunction can be found in Chapter 7. Disorders that commonly manifest with executive dysfunction include frontotemporal dementias, traumatic brain injury, chronic alcohol abuse, and focal disease caused by vascular lesions or neoplasms. Of importance, but not as well recognized, is that patients with schizophrenia may exhibit subtle but often disabling disturbances of executive dysfunction. The following questions are useful guides to areas for evaluation:

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■ Has the patient shown a “personality change”? ■ Has there been any decline in appropriate social judgment,

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such as inappropriate familiarity with strangers or disinhibited sexual or aggressive behavior? Of note is that not all patients with executive dysfunction display these features. Has there been any change in the patient’s degree of motivation or drive? Has the patient developed a set of purposeless repetitive behaviors? Can the patient plan and organize daily activities appropriately, or has he or she begun to struggle to keep work, home, or social life running smoothly? Is the patient making sound judgments, or have there been “out of character” decisions recently?

FUNCTION IN NEUROBEHAVIORAL DOMAINS A thorough neurobehavioral assessment is essential for the neurocognitive history, because a number of disorders cause both psychological and cognitive dysfunction, and neurological diseases may manifest initially with psychological disturbance. Failing to recognize neurobehavioral disturbance can delay correct diagnosis, increase caregiver burden, and cause unnecessary, although relievable, suffering for patients and their families. The neurobehavioral assessment is largely synonymous with the psychiatric “mental state examination.” In contrast to the traditional medical view of the history as a description of symptoms and the examination as a description of signs, the mental state examination includes elements of both the history and the phenomena observed by the examiner. The mental state examination includes descriptions of the patient, his or her behavior, and a summary of his or her responses to questions regarding mental phenomena. Like the cognitive assessment, mental state assessment should not be confined to only the part of the interview in which symptoms are being elicited. The patient who denies hallucinations but frequently and suddenly looks askance while muttering or overtly vocalizing can reasonably be inferred to be responding to hallucinations.

Appearance and Behavior There is much to be gained by careful observation of the patient’s appearance, especially if the interviewer has obtained a good sense of the patient’s premorbid state. The patient’s personal grooming, dress, and general state of health provide important information about functional abilities. Even the state of the patient’s hands may reveal important information. The dry, chaffed hands of a repetitive washer, the nicotine-stained fingers of a patient with schizophrenia, and the tremor of a patient with alcohol dependence are some examples. Patients with chronic schizophrenia may be disheveled and dress unusually, with many layers of clothes or with seemingly little regard for their appearance. They may look around the room in a suspicious manner and on occasion may look for monitoring devices. Depressed patients may sit stooped, with slowing of their movements, or may be restless and agitated, rubbing and wringing their hands. Patients with a pseudodementia may find the interview too difficult and resort to frequent “I don’t know” answers. Anxious patients are visibly anxious, sweaty, and restless. Patients with a dysexecutive syndrome may make inappropriate sexual suggestions or be impul-

sive. The presence of abnormal movements or postures during the interview may be more informative than when the patient is being examined formally. The patient’s interactions with the examiner, administrative staff, or nursing staff may provide invaluable information.

Speech In addition to the language disturbances just described, the examiner should note the rate and quantity of speech. Often the reaction of the examiner to the patient’s speech provides diagnostic clues. The slowed, labored speech of the patient with depression may make the interview long and tedious, whereas the rapid, pressured speech of the manic patient may leave the examiner feeling frustrated and exhausted. The disordered speech of the patient with schizophrenia leaves an interviewer perplexed.

Mood Mood is the sustained level of emotional tone, whereas affect refers to the patient’s emotional behavior. The emotional response of the examiner to the patient provides a further indicator of the patient’s emotional state. Patients with disorders of mood such as major depressive disorder often show impairments in attention and psychomotor speed.21,22 Bipolar disorder is associated with impairments in attention, verbal memory, and executive function. High rates of comorbid mood disturbance are associated with Parkinson’s disease,23 Huntington’s disease,24 and multiple sclerosis.25 Late-onset depression is being increasingly seen as a prodrome to the dementias.14 Inquiries about a patient’s mood state may include the following: “How have you been feeling recently?” “Do you have periods of time when you are always down?” In patients with speech disorders, responding to such questioning may not be possible, and close informants can be asked directly, “Does he/she seem unhappier to you than usual?” Informants are able to comment on the reactivity of mood, inasmuch as depressed patients are often unable to “brighten up.” Patients who are depressed may describe themselves as feeling sad, unhappy, hopeless, useless, blue, or “flat.” This mood state is often accompanied by disturbances in sleep, appetite, concentration, and motivation. The depressed patient conveys sadness and misery or presents as anxious and irritable. Commonly used tools for rating the severity of depressive symptoms include the patient-rated Beck Depression Inventory26 and the clinician-rated Hamilton Depression Rating Scale.27 Patients with elevated mood states display euphoria, elation, and irritability in association with overactivity, accelerated thoughts, disinhibited behavior, reduced sleep, and grandiose ideas. Examiners who find themselves regularly suppressing a smile or giggle in interviews with patients should always ask themselves whether the patient’s mood is elevated. Reduced intensity and narrowing of affective responses is termed blunting of affect and is a key feature of schizophrenia.

Anxiety Anxiety, a normal and adaptive component of human psychological function that allows for the identification of danger or

chapter 1 clinical assessment of mental status threat, may become inappropriate and/or excessive. Anxiety disorders include panic disorder, characterized by panic attacks (discrete, relatively brief periods of intense anxiety accompanied by somatic symptoms of sympathetic drive), agoraphobia (recurrent fear of inability to escape from situations such as being in a crowd or an enclosed area), social anxiety (fear of social situations), specific phobia (of a discrete object, such as heights or water), and generalized anxiety, which leads to diffuse anxiety on most days.28 Pathological anxiety states have been associated with stroke,29 Huntington’s30 and Parkinson’s diseases,31 temporal lobe epilepsy,32 and thyrotoxicosis.33 A history of anxiety can be sought through inquiries about increasing or frequent worrying, its source, and the presence of concomitant physiological signs such as sweating, tachycardia, shortness of breath, and tremor and whether the degree of worry seems excessive to the patient or caretaker. An anxiety disorder with a strong relationship to neurological disorders is obsessive-compulsive disorder, which is associated with intrusive recurrent thoughts (obsessions) and repetitive behaviors or mental acts (compulsions such as counting, checking, or cleaning). Obsessive-compulsive disorder has been strongly associated with Gilles de la Tourette syndrome34 and with the pediatric neuropsychiatric disorder pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS).35 Symptoms of obsessive-compulsive disorder can be ascertained by questions about compulsive behaviors, such as “Do you find yourself checking/cleaning things more than once or more often than you need to?”, and obsessions, such as “Do you have recurrent, intrusive thoughts/ideas/images/impulses?” Severe anxiety states can lead to depersonalization and derealization. These conditions can be difficult for patients to describe, but descriptions can be elicited by asking the following questions: “Have you ever had the sense that the world around you is different or changed?” (derealization) “Have you ever felt detached from the world around you or as if you are an observer of yourself?” (depersonalization) Both these states may be described by patients in the prodrome of complex partial seizures, although are most commonly seen in patients with anxiety or panic disorders. Patients with panic disorder describe symptoms lasting many minutes with a buildup of anxiety symptoms such as a sense of fear, palpitations, hyperventilation, and perioral numbness. The symptoms associated with complex partial seizures are usually stereotyped and much briefer than those seen in panic disorder.

Thought Content and Form In a number of neurological disorders, patients may develop abnormalities in their beliefs about themselves or the environment around them. Thought content can be seen as a spectrum from normal, reality-based thinking to delusions, which are fixed false ideas out of keeping with the patient’s cultural background or education.28 Delusions are categorized by the nature of their content, such as persecutory, grandiose, somatic, and erotomanic delusions or delusions of jealousy or reference. Delusions are classically associated with schizophrenia but are seen in patients with Huntington’s disease, temporal lobe

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epilepsy, leukodystrophies, systemic lupus erythematosus, and most forms of dementia.36 Persecutory delusions are commonly seen in delirium and substance intoxication. Organic delusions are particularly associated with diseases affecting the limbic system.37 In schizophrenia, delusions tend to be very well systematized (generally static and supported by an extensive belief system) and often have a bizarre nature, whereas in neurological disorders they are often poorly systematized and are predominantly persecutory.38 Informants may provide the most valid and reliable history about delusional ideas, although they may be unaware of them if the patient has not voiced his or her beliefs. It is useful to directly but gently inquire about delusional ideas, using questions such as “Sometimes people feel that they are being watched, that others are planning to hurt them, or that they have special abilities that other people don’t. Have you ever felt like that?” Mood or anxiety disorders are associated with altered thought content. Depression is associated with thoughts such as “Everything seems black,” “I will not get better,” or “Life is not worth living” or with suicidal ideas. Mania is associated with thoughts such as “I am immortal,” whereas anxious patients may express thoughts such as “Something terrible is going to happen.” Suicidal ideation or other thoughts involving harm should always be carefully asked about and documented, including ideas, plans, and intent. When patients clearly express all three, the patient can be seen to be at grave risk of acting on these ideas and usually requires hospitalization. Thought form refers to the structure of thought and is necessarily conveyed through speech. The form of thought may be fragmented and interspersed with pauses in the delirious patient. Thoughts that progressively veer away from the question (tangentiality) or that do not follow logically from each other (loosening of associations) are almost pathognomonic of schizophrenia. The manic patient with flight of ideas displays a flow of thought that is rapid and determined by factors other than the logical flow of ideas, such as the sounds of words (clanging).

Perception Perceptual experience occurs on a continuum, with “true” perception of stimuli at one end and frank hallucinations at the other.39 Hallucinations are defined as percept-like experiences in the absence of an external stimulus that are spontaneous and unwilled and cannot be readily controlled.40 Illusions, which are distortions or elaborations of a normal stimulus, also belong to this continuum. Hallucinations can be well formed and complex or poorly formed and simple,41 and they are categorized according to sensory modality. Complex and elaborate auditory hallucinations are the hallmark of schizophrenia but can occur in severe affective psychotic states. Poorly formed, fragmented auditory hallucinations may be present in organic states such as delirium. Special note should be made of complex visual hallucinations, which are often a feature of organic states. Examples include the Charles Bonnet syndrome and peduncular hallucinosis, where lesions to the visual pathways and to their terminations or ascending inhibitory afferent pathways, respectively, can result in strikingly vivid formed scenes, complex patterns, or groups of miniature figures or animals.42

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Olfactory, gustatory, and tactile hallucinations are not commonly experienced in psychiatric illness and should alert the clinician to the possibility of neurological conditions such as complex partial seizures or neoplasia. For patients who are reluctant or unable to discuss their experiences, questioning caretakers about behavior that might represent a reaction to perceptual disturbance, such as responding to voices or gaze movements in response to visual phenomena, may prove useful.

Vegetative Function Vegetative functions such as sleep, appetite, and sexual drive are often disturbed in patients with neurobehavioral disturbances, particularly disturbances of mood.43 Patients may complain of appetite disturbance with weight loss or gain; sleep disturbance with insomnia in initial, middle, or terminal sleep phases (the last known as early morning wakening, a characteristic of severe depression); altered libido; disturbances in energy and motivation; and impaired capacity to enjoy usual pursuits.

Insight and Judgment A patient’s lack of insight into illness may reduce the validity of a history, such as the patient’s self-report of memory complaints44 or of adherence to prescribed treatments.45 Insight has been traditionally viewed in both psychological and cognitive frames. In the psychological frame, insight relates to acceptance of illness and the need for its treatment. Insight is impeded by denial of illness, which occurs to varying degrees and reflects psychological coping mechanisms that allow the patient to deal with the fear, hopelessness, or shame associated with sickness and its treatment.46 Cognitive models focus on the neurocognitive capacity of an individual to internalize, retain, and cognitively process the awareness of symptoms, attribute these to an illness, and appreciate the likely effects of accepting or refusing treatment.47 Cognitive models of insight were devised from the strong association of disorders in which disrupted frontalexecutive function is the cognitive hallmark, such as frontotemporal dementia and schizophrenia, with poor insight.45,48 An apparent change in insight is likely to reflect an organic process, inasmuch as the psychological mechanisms that relate to insight tend to be personality based and thus relatively stable.49 The concept of insight overlaps with the neurological symptom of anosognosia, a lack of awareness of neurological deficit, first described by Babinski50 and most commonly seen in right hemisphere stroke. Although it most commonly characterizes a lack of awareness of hemiparesis, anosognosia can also occur for amnesia, apraxia, aphasia, cortical blindness, and prosopagnosia.51 The observation that most lesions associated with anosognosia involve the parietal lobes or related connections reinforces the role of the parietal lobe in awareness of illness and, in particular, the role of the right inferior parietal cortex in attention.52 A patient’s insight can be inquired about with open-ended questions such as “Why do you think you have come to see me today?” and “In what way does this problem affect you?” More direct, closed-ended questioning such as “What would happen if you stopped your tablets?” is appropriate afterward.

OTHER ABNORMAL BEHAVIORS A range of other neurobehavioral disturbances may alert the clinician to the possibility of associated cognitive or neurological impairment. Apathy, disinhibition, and stereotypies can prove diagnostically challenging because they may initially mimic other disorders. These behaviors are often seen in frontotemporal dementia, itself a mimicker of other neurobehavioral disorders, and are elements of the three behavioral subtypes of these disorders53 (see also Chapter 7). Apathy may manifest as apparent depression, disinhibition as mood elevation, and stereotypies as compulsive behaviors or dyskinesias. Utilization behavior and echo phenomena (echopraxia, echolalia) are uncommon but important neurobehavioral syndromes that may be easily missed or ignored. Finally, catatonia constitutes a medical emergency for which the underlying cause must be determined quickly to ensure appropriate treatment.

Apathy Apathy is best defined as a state of reduced or absent motivation.54 In practice, apathy manifests as a reduction in the initiation of goal-directed behavior. Apathy is most common in disorders that disrupt the frontal-subcortical circuit, considered to be the substrate for motivated behavior. This circuit includes the anterior cingulate cortex, nucleus accumbens, globus pallidus, and thalamus.55 Disruption to these circuits with consequent apathy is seen in frontal-subcortical dementias such as Parkinson’s disease, Huntington’s disease,56,57 and frontotemporal dementia; traumatic brain injury58; schizophrenia59; and vascular insult.60 Apathy in many of these syndromes may respond to stimulant medication,61 and in schizophrenia, atypical antipsychotic agents may reduce apathy through increased dopamine release in the frontal cortex.62 On history, the differentiation of apathy from depression can be difficult, although patients with pure apathy often blandly deny feeling depressed and do not transmit a depressed affect. The other cardinal features of depression, such as neurovegetative disturbance, are often absent. Family and caretakers may become angry or resentful at a patient whose worsening apathy is perceived as a voluntary withdrawal. The distinction between apathy and depression is important, so that an apathetic patient with frontotemporal dementia does not receive an incorrect diagnosis of depression, which leads to delays in appropriate management, or, conversely, so that patient with a reversible clinical depression does not remain untreated.63

Disinhibition Inhibition is the capacity to cognitively “cancel” a thought, response, or activity that is considered unintended, unwanted, or inappropriate. Social disinhibition is associated with insults to the nondominant inferior frontal cortex64 and linked subcortical structures. Lesions to these regions result in release of motor, affective, instinctive, or cognitive behaviors such as hyperactivity, elevated mood, hyperorality and hypersexuality, and accelerated or grandiose thinking.65 Disorders that produce disinhibition include focal vascular, neoplastic or traumatic lesions,66 and frontotemporal dementia.67 Cognitive disinhibition of automatic responses to stimuli is associated with lesions

chapter 1 clinical assessment of mental status of the anterior cingulate cortex and impaired performance on tasks such as the Stroop test. (See also Chapter 7.) Many patients may not be able to relate disinhibited behavior but can be questioned about behaviors that they “wouldn’t usually do,” such as excessive spending, substance use, social or sexual inappropriateness, or risk-taking behavior. Understandably, caretakers are usually able to relate a history of such behaviors, particularly if it represents a change from previous behavior.

Stereotypies Stereotypies are repetitive, rhythmical, and invariant motor behaviors, without an apparent purpose or function, that can vary from simple motor behaviors such as rocking or hand waving to extraordinarily complex acts and rituals.68 They are one of the defining features of autism and are common in patients with mental retardation.69 Stereotypies are seen in adults with lesions or disorders affecting the frontostriatal circuit running between the dorsolateral frontal cortex and the head of the caudate nucleus.70 Frontotemporal dementias commonly manifest with stereotypic behaviors resulting from degeneration of the dorsolateral prefrontal cortex.71 Stimulant medications can produce complex stereotypies through a dopaminergic effect on the basal ganglia.72 Other repetitive motor behaviors such as compulsive behaviors and tics are seen in patients with Gilles de la Tourette syndrome and obsessive-compulsive disorder, both of which are considered to be associated with basal ganglia pathology.72,73 Of importance is that stereotypies, compulsions, complex tics, mannerisms (unusual or pathological styles of performing goal-directed activities, such as a bizarre gait and unusual ways of greeting people), and habits can often be difficult to distinguish purely on the basis of subjective observation. The context and history of the motor phenomena provide important diagnostic information.

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dromes such as latah.79 Echolalia has been described in patients with dysphasia and left hemispheric lesions.80

Catatonia Catatonia is a disorder associated with a number of behavioral, motor, and cognitive phenomena. Catatonic patients may be mute or akinetic; exhibit stereotypic and manneristic movements; adopt unusual postures; or exhibit negativism, waxy flexibility, mitmachen (automatic motion obedience), and gegenhalten (an increase in muscle tone in response to passive movement). Echopraxia, echolalia, and palilalia (perseverative repetition of a syllable or word) may also be present. Catatonia may be associated with psychotic illnesses such as schizophrenia or bipolar disorder, or it may be secondary to metabolic encephalopathies or primary neurological conditions, including post-encephalitic states, brain tumors, and seizure disorders. The distinction between primary psychiatric and secondary catatonias is one extreme example of the need to make a diagnosis regarding the cause of the patient’s mental state on the basis of the informant history, background history, and the physical examination alone.

RELEVANT HISTORY Medical History

Utilization behavior refers to the phenomenon in which patients grasp and purposively use objects within their reach, even though this action may be inappropriate or out of context.74,75 It reflects an inability to inhibit an automatic action cued by an environmental stimulus. It has been described in patients with lesions affecting the prefrontal/subcortical circuits.75,76 Examples given by Lhermitte75 included “pouring” from an empty jug into a glass, using a knife and fork on a plate without food, and lighting multiple cigarettes for the examine while the first remains unsmoked. An awareness of utilization behavior is important because it may be misinterpreted as odd, eccentric, or even antisocial behavior by the inexperienced examiner.

A history of traumatic brain injury, epilepsy, stroke, meningitis, encephalitis, or cerebral hemorrhage points toward the likelihood of neurocognitive or neurobehavioral disturbance. Systemic diseases with CNS involvement, such as autoimmune disorders, syphilis, and malignancy, may be revealed through the medical history. A history of infection with or risk factors for human immunodeficiency virus (HIV) should always be inquired about because of the wide-ranging effects of HIVrelated illness on cognition, mood, and behavior. Smoking, diabetes, hypertension, and hypercholesterolemia increase the risk of strokes and may provide clues to the presence of vascular CNS disease. The effects of therapeutic drugs on the CNS must always be considered. Dopaminergic agents used in the treatment of Parkinson’s disease may cause psychosis,81 and anticholinergic agents impair cognition.82 Treatments used for systemic disorders may produce neurobehavioral states, as is seen in the depression associated with β-interferon used for viral hepatitis83 and the mania secondary to corticosteroid use for autoimmune disorders.84 Polypharmacy, particularly in the elderly, increases the likelihood of medication neurotoxicity.85 The possibility of drug withdrawal states warrants specific inquiry about the use of benzodiazepines, sedatives, hypnotics, and alcohol.

Echolalia and Echopraxia

Psychiatric History

Echo phenomena are the unsolicited and stereotyped repetition of another person’s speech (echolalia) or actions (echopraxia). These phenomena are commonly observed in patients with schizophrenia, especially during acute illness or in catatonic states. They have been well described in patients with neurodevelopmental disorders, including Gilles de la Tourette syndrome and autism,77,78 and with various complex startle syn-

A psychiatric history allows the clinician to differentiate between a relapse of an established disorder and new-onset disease. The neurocognitive deficits of chronic schizophrenia may manifest as a dementing illness86; “hypofrontal” disinhibition and poor judgment may be the presenting symptoms of mania87; and patients with depression may present with a “pseudodementia.”88

Utilization Behavior

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Family History Because of the strong genetic basis for many neurobehavioral and neurocognitive disorders, a detailed family history is essential. This should include age; cause of death; history of neurological, neurobehavioral, or systemic disease; and a history of consanguinity. In some jurisdictions, cases of disorders such as Creutzfeldt-Jakob disease must be reported to the appropriate authority, such as the Centers for Disease Control and Prevention, and it may be possible to consult disease registers to confirm a family history, inasmuch as about 10% of cases of Creutzfeldt-Jakob disease are dominantly inherited.

Substance Use History A thorough longitudinal alcohol history is essential for the verification of Korsakoff’s amnesia, alcoholic dementia, delirium tremens, and alcoholic hallucinosis, A smoking history should be obtained, including total exposure and past or current related illnesses. Stimulants such as amphetamines may produce neurobehavioral symptoms such as delusions and hallucinations,89 chronic marijuana usage may lead to psychosis and cognitive impairment,90 and inhalant solvent abuse has been associated with acute and chronic cognitive impairment, depression, and psychosis.91

NEUROBEHAVIORAL RATING SCALES The use of validated scales allows a rapid snapshot of neurobehavioral disturbance and the longitudinal monitoring of illness progression and treatment response within a patient. Although most physicians are familiar with cognitive screening tools such as the MMSE, noncognitive neurobehavioral scales are not yet in widespread use. The use of validated scales such as the Neuropsychiatric Inventory (NPI) and Neurobehavioral Rating Scale (NRS) is slowly moving from research to clinical settings.

Neuropsychiatric Inventory The NPI92 is a semistructured clinician interview of caretakers in which the severity and frequency of disturbance in 12 symptom domains is rated (Table 1–2). The NPI shows good interrater and test-retest reliability.92 It has been modified and validated for use in nursing homes (NPI-NH)93 and in various non-English versions.94-97 Scoring in subscales of the NPI has been shown to correlate strongly with those in other wellvalidated symptomatic scales, such as the Behavioral Patho-

T A B L E 1–2. Symptom Domains Rated by the Neuropsychiatric Inventory Hallucinations Delusions Agitation/aggression Depression Anxiety Elation/euphoria

Apathy/indifference Disinhibition Irritability/lability Aberrant motor behavior Nighttime behavior* Appetite/eating change*

*Additional domains in the Neuropsychiatric Inventory for nursing homes.

logic Rating Scale for Alzheimer’s Disease (BEHAVE-AD) and Hamilton Rating Scale for Depression.98 The performance characteristics of the NPI have been established in a range of neurological conditions, including Alzheimer’s disease,99 Parkinson’s disease,100 frontotemporal dementia,101 progressive supranuclear palsy,102 corticobasal degeneration,103 mild cognitive impairment,104 Tourette disorder,105 subcortical vascular ischemia,106 multiple sclerosis,107 and Huntington’s disease.30 The NPI has a key role alongside cognitive scales in monitoring the noncognitive improvements with cholinesterase inhibitor treatment of various dementias, and it has been shown to reliably detect improvement in individuals treated with donepezil,108 galantamine,109 and rivastigmine.110

Neurobehavioral Rating Scale The NRS is a 27-item, multidimensional instrument designed to measure neurobehavioral disturbance after traumatic brain injury.111 Based on the Brief Psychiatric Rating Scale,112 the NRS is a brief structured patient interview that takes 15 to 20 minutes to complete. It includes ratings of neurobehavioral symptoms, basic tests of cognition, and questions about the patient’s current level of function. The NRS has demonstrable utility in assessing a number of different organic neurobehavioral states, including traumatic brain injury,113-116 dementia,117,118 Parkinson’s disease,119 HIV-related dementia,120 and the post-endarterectomy state.121 As with the NPI, translations of the NRS into other languages have been made and are of proven validity.121

NEUROCOGNITIVE EXAMINATION Many clinicians assess cognitive function by using standardized instruments such as the MMSE,122 which offer a brief, validated, and easily communicable approach. However, because most commonly used instruments have limitations, an understanding of the how to assess separate cognitive domains allows the clinician to tailor the examination to an individual presentation. The necessity of performing a formal neurocognitive examination warrants emphasis, because in the absence of a thorough and structured assessment, it is possible to miss a clear deficit. For example, patients who perform well verbally may mask significant impairments in other cognitive domains, such as memory or visuoperceptual function. Few neurologists would consider their assessment complete without a physical neurological examination of the patient or a careful history of the presenting symptoms. Although a complete neurocognitive assessment may be unnecessary for all patients, it is similarly a key component of the clinical assessment in a number of circumstances. This section describes an approach to a largely qualitative bedside cognitive assessment and serves as an introduction to the subject. More details regarding the examination of each domain and the disorders that such an examination may reveal can be found in subsequent chapters.

Principles of Cognitive Assessment When to undertake neurocognitive examination A neurocognitive examination should be undertaken whenever the reported complaint is a cognitive one, in clinical cir-

chapter 1 clinical assessment of mental status cumstances in which cognitive impairment occurs frequently (postsurgically, in cerebrovascular disease, in neoplasia, or in trauma), or when there is an unexplained history of personality, functional, or behavioral change. In many countries, standardized cognitive assessment is mandatory before the prescription of cholinesterase inhibitors for dementia.

General observation Much can be gained from general observation of both patient and informant and from the physical examination. A patient’s grooming and state of hygiene can be indicators of impoverished motivation and drive or of hemineglect. Alterations in gross motor activity, such as agitation or retardation, and the presence focal movements such as tremor, tics, or choreiform movements should be noted. The state of a patient’s sensorium can be ascertained by his or her capacity to sustain attention during the interview process and his or her capacity to filter out extraneous stimuli. Memory impairments may become obvious during clinical interview if a patient is unable to provide a history of recent events or the illness, as may a history that is poorly elaborated or impoverished. Impairments in insight into illness may be apparent at the outset if a patient denies any abnormality, if the history is discrepant with that obtained from an informant, or if a patient is unable to make the link between subjective complaints (such as impaired memory) and functional decline (such as driving difficulties or home safety concerns).

Setting The examiner should ensure that enough time is allowed for the examination; that the environment is quiet, well-lit, and nondistracting; and that the patient’s usual sensory aids such

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as glasses or hearing aids are available. At the outset of examination, the role of the caregiver in this aspect of the assessment should be clearly defined. Many patients manage cognitive difficulties through reference to or reliance on a spouse or caretaker. It is important that this is not replicated in the assessment situation, in which a caretaker might subtly assist the patient during neurocognitive testing. When necessary, the participation of appropriately trained interpreters, who do not “help” the patient and who are skilled in the translation of linguistically difficult or culturally specific items, is invaluable. Finally, due consideration should be given to the patient’s level of fatigue and cooperation. Patients who have completed a long clinical history and physical examination may not be able to perform optimally during neurocognitive assessment, and it may be necessary to schedule a second session at which the assessment can be completed.

Quantitative versus qualitative data When quantitative screening or assessment instruments are used to gauge cognition in patients, it is important for the clinician to look beyond the quantitative result in making a diagnosis. For example, a score of 22 of 30 on the MMSE is below most accepted cutoffs for dementia, but it may not point definitively to organic cognitive impairment. Such a score may be seen, for example, in individuals of limited education, in patients sedated by medication, or in patients with psychiatric illness such as major depression or schizophrenia. The quality of a patient’s performance is as important as the numeric measure in many or most quantitative tests; examples include perseveration displayed on a serial subtraction task or in a copying or clock-drawing task (Fig. 1–1). Further details of the quantitative aspects of neuropsychological testing may be found in Chapter 2

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Figure 1–1. Perseveration in a copying task and in a clock-drawing task.

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Examination of Attention and Orientation Testing of orientation to time is more sensitive to cerebral dysfunction than testing of orientation to place, and impaired orientation to person should raise the possibility of a psychogenic fugue state. Successful completion of tests of orientation requires intact memory and expressive language; that is, these are not “pure” tests of attention. When time orientation is tested, orientation to the approximate time of day (within 1 hour), should be assessed as well as that to the day of the week, month, and year, and is perhaps the most reliable and sensitive. Disorientation as to the exact date has a very high base rate in the normal population and is rarely clinically useful. Marked disorientation to time is most com-mon in patients with delirium or Korsakoff’s amnesia. Orientation is often preserved in early dementia. Attention has traditionally been tested by serial subtraction tasks and reverse spelling of words, such the serial sevens and “WORLD” backwards tasks in the MMSE. Such tasks are dependent on working memory, as well as on calculation and spelling, respectively, both of which are strongly related to educational background and both of which may be disrupted by focal lesions that do not otherwise impair attention.123 Reciting an overlearned sequence such as days of the week or months of the year in reverse order requires sustained attention and intact working memory; this test is very sensitive to disturbance of attentional processes and is generally understood across cultures and languages. Repeating a spoken sequence of digits, starting with two digits and increasing the length of the sequence with each correct attempt, is also a sensitive marker of attention, particularly when the patient needs to repeat the sequence in reverse, which is more difficult and places a greater load on working memory. Most subjects correctly complete 7 ± 2 digits forward and 5 ± 1 in reverse. Digit span testing depends on intact working memory, the frontal lobe–mediated brief store of visual or auditory information in current consciousness (e.g., remembering a telephone number before writing it down). Continuous performance tasks, which require the patient to respond when a particular stimulus is presented (e.g., the letter “A” in a list of random letters read by the examiner9) are minimally dependent on working memory but are good measures of sustained, directed attention. Finally, it is important for the clinician to be aware that attentional impairment may impair performance in other parts of the cognitive examination. If attention is markedly impaired, poor results on testing in other domains may not necessarily indicate that function in those domains is also impaired (Table 1–3).

Examination of Language As with attentional disturbance, impaired language can affect many other aspects of the neurocognitive examination and

T A B L E 1–3. Tests of Attentional Function Serial sevens/WORLD backwards Orientation to time/place Overlearned sequences (days of week, months of year) Digit span: forward and reverse Continuous performance task

hence should be tested early. A significant subjective understanding of the patient’s capacity for language can be gained during the clinical interview with regard to the degree of spontaneous speech, articulation, capacity for word-finding, and comprehension (Table 1–4). Comprehension of language is often aided by nonverbal communication, and patients with language disturbance may be able to respond appropriately to verbal communication by relying on nonverbal cues. Comprehension should be tested in a variety of tasks of different degrees of difficulty to detect subtle impairment and, ideally, should be tested in both written and verbal form. Where expressive speech is not possible, motor rather than verbal responses indicating comprehension should be sought. At its most simple, it can be tested by yes/no responses to simple/rhetorical questions (“Is today Friday?”) and also to more difficult ones (e.g., “If the lion and the tiger have a fight, and the lion is eaten by the tiger, is the tiger still alive?”) Comprehension is also frequently tested with multistage commands, such as the paper-folding item in the MMSE, but these too are dependent on working memory. Reading comprehension can be tested by asking the patient to read through a short paragraph from a newspaper or magazine article. Repetition should similarly be tested with a graded series of tasks of increasing linguistic complexity and may be impaired in isolation in the presence of intact comprehension or expression. Initially starting with monosyllabic or oligosyllabic words, the examiner should progress to simple phrases and to more complex sentences, such as the commonly used “No ifs, ands, or buts” phrase and more difficult-to-articulate phrases, such as “The orchestra played, and the audience applauded.” Naming to confrontation is commonly impaired in aphasias, and such impairment is commonly associated with wordfinding difficulties in spontaneous speech. Anomia, the inability to name objects, can be objectively tested with a confrontation naming task. When this test is conducted at the bedside, objects from various categories should be used (colors, body parts, room objects, parts of objects), and it is important to use uncommon items (“knuckle” on the hand, “winder” of a watch), as well as common items such as pens, shoes, and watches, because many aphasic patients reveal their anomia only when confronted with uncommon items. As with poor performances in other domains, naming difficulties may also arise from other causes, such as visual agnosia. Reading is the language task in which performance is most determined by educational status, and poor literacy is not uncommon in many patient populations. The capacities to read aloud and to understand written language are potentially dissociable and should be tested separately. Patients should be asked to read simple and then complex words, particularly comparing the pronunciation of orthographically regular (sounded as spelled) words such as “shed” to irregular words such as “rough,” as well as phrases such as “Close your eyes.” Writing should be tested to detect agraphia, which frequently accompanies aphasia. Agraphia is diagnosed when basic language errors, gross spelling errors, or paragraphias (word or syllable substitutions) are present. The patient should be asked to write sentences both spontaneously and in response to dictation, with the latter ideally containing a number of orthographically irregular words and/or homonyms (“The boy’s aunt made a large pie out of steak and dough”). Further details of language assessment can be found in Chapter 3.

chapter 1 clinical assessment of mental status T A B L E 1–4. Tests of Language Function Comprehension: single-/multiple-stage verbal and written commands, newspaper article Repetition: words, phrases, sentences Naming: colors, body parts, objects Reading: simple and complex words, phrases Writing: spontaneous and dictated sentences

Examination of Visuoperceptual/ Visuoconstructional Function and Calculation Visual and constructional impairments are often present with parieto-occipital lesions, particularly of the nondominant hemisphere, which, in combination with lesions of prefrontal regions, is important for spatially directed attention.124 When ventral occipitotemporal regions are affected, visual recognition is impaired, particularly for objects, written words (pure alexia), colors, or faces (prosopagnosia). Dorsal lesions result in impairment of visuospatial organization. A detailed exposition of disorders of visual perception may be found in Chapter 5. When a patient is unable to maintain attention to one side of his or her spatial field or body soma, visual and somatosensory neglect, respectively, are said to occur and are typically seen with nondominant parietal lesions. Lesions in the dominant parietal region may result in Gerstmann’s syndrome, which, in addition to agraphia, manifests with calculation dysfunction (acalculia), right/left disorientation, and naming inability for fingers (finger agnosia). A disorder of skilled movement, apraxia, occurs when lesions in a network that includes the inferior dominant parietal region result in the loss of the ability to perform the “formulas for movement” stored in this region of the brain (ideomotor apraxia) or the capacity to perform a series of actions such as putting a letter in an envelope, sealing it, and stamping it in the correct sequence (ideational apraxia). Visuospatial organization is commonly tested by tasks of figure drawing or copying, such as figure copying or clock drawing, although the latter taps into many cognitive functions and can be considered as a cognitive screening test in its own right.125 A gradient from simple to complex figures should be used, and patients can also be asked to spontaneously draw figures such as a house or a tree. Many different ways to conduct and score clock drawing tasks have been published, although most require subjects to correctly place all numbers on the clock and appropriately place hands demonstrating a time in response to command. Most constructional tests are sensitive for visual neglect, which can also be tested by line bisection tasks. Orobuccal and limb praxis should be tested separately because they are controlled by different neural pathways. Dominant and nondominant sides should be tested separately. Patients should be asked to demonstrate a movement such as using a comb and to imitate the examiner’s movements. The latter can be done in a systematized manner by using the interlocking finger test.126 Calculation should be specifically tested by means of simple arithmetic in addition to functional real-life examples but is often tapped by the serial sevens test (Table 1–5).123

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T A B L E 1–5. Tests of Visuoconstructional Function, Prascis, and Calculation Spatial organization: figure copying and clock drawing Neglect: figure copying, clock drawing, somatosensory testing, line bisection Praxis: left and right limb demonstrations and imitations, orobuccal demonstrations, finger postures Calculation: simple arithmetic, shopping tasks

Examination of Memory “Memory disturbance” is most commonly used to refer to a disorder of episodic, declarative memory (memory for things that can be stated). This manifests as difficulty in recalling personally experienced material from the past and/or learning new information, and it is often found in dementing disorders such as Alzheimer’s disease and in amnestic disorders such as Korsakoff’s syndrome. Declarative memory has traditionally been divided into immediate, recent, and remote memory. Immediate memory is now more commonly described as working memory and refers to the very brief storage of the auditory and visual contents of current consciousness in the dominant perisylvian language areas of the cortex and the nondominant parietal cortex, respectively, and under frontal executive control. Recent memory is the term traditionally used by physicians to describe the capacity for new learning of verbal and visual material. The consolidation of recent memories is a function of the hippocampus, related structures in the medial temporal zones, and hippocampal outflow through the fornices to the mammillary bodies and thalamus. Remote memory is a time-based distinction, but the term may be used to imply that the relevant memories are consolidated and no longer hippocampally dependent. Remote memory is made up of autobiographical, episodic memory (memory for events) and semantic memory (memory for knowledge and words, dependent on anterior temporal neocortex). The nosology of the various memory systems and their disorders is covered in detail in Chapter 4. Working memory is usually tested by items such as digit span or by the immediate recall of a word list. Recent memory is generally tested with delayed recall of a word list, name and address, or a short story. Patients with a primary deficit in registration or encoding of memory (e.g., as in Alzheimer’s disease) demonstrate rapid forgetting and limited spontaneous recall and do not benefit from the provision of clues. Patients with lesions affecting dorsal prefrontal circuits have poor or inefficient retrieval of normally registered memory and show limited spontaneous recall but may benefit from cueing.127 Nonverbal memory should be tested through the reproduction of a visual figure after a delay. Ideally, these figures are constructions that do not lend themselves to a verbal description, as then patients can use intact verbal memory as a “workaround.” Testing for nonverbal recall is not included in the MMSE, but it is featured in other brief tools such as the Neuropsychiatry Unit Cognitive Screening Instrument (NUCOG)128 and is illustrated in Figure 1–2. Remote memory is tested by the patient’s recall of personal history and his or her general fund of knowledge. The latter may

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Drawing reproduction.

Figure 1–2. Testing for nonverbal recall.

Stimuli

Copies

Recall

T A B L E 1–6 Tests of Memory Function Working memory: digit span, immediate verbal recall Recent memory: recall of word list, name and address, short story, visual shapes (with cueing) Remote memory: autobiographical data, general knowledge, word meanings

be difficult to test in a standardized manner, inasmuch as commonly used questions about political leaders or historical events are strongly education- and culture-dependent (Table 1–6).

Examination of Executive Function Control of executive functions is commonly ascribed to the prefrontal lobes and related subcortical structures, although this involves a deliberate simplification. Executive dysfunction may be seen in focal prefrontal lesions, frontotemporal dementias, or neurobehavioral syndromes such as schizophrenia and major depression, among other disorders. The basal ganglia and thalamus are connected to the frontal lobes through defined circuits, and lesions of these structures or circuits can manifest with executive impairment.129 A fuller account of executive functioning and the various features of the dysexecutive syndrome can be found in Chapter 7. Set-shifting/sequencing is the ability of the patient to shift efficiently from one cognitive set to another and to inhibit no longer appropriate responses, and its impairment manifests as perseveration.130,131 The neural substrate for set-shifting involves the dorsolateral prefrontal cortex and its connections to basal ganglia and thalamus.132 The initiation of cognitive

strategies is an integral but often overlooked element of the cognitive examination and is often the core deficit underlying apathy syndromes, particularly after occurrence of medial frontal lesions that affect the anterior cingulate region.65 Abstract thinking appears to be a function of the lateral frontal zones, and impairment of abstract thinking manifests as concreteness of thinking. The orbitomedial frontal zones are involved in the processing of emotion and in judgment and planning; lesions to this region, particularly on the nondominant side, manifest as disinhibition and poor judgment.65 The capacity to integrate abstractive and emotional functions, perhaps best illustrated in the appreciation of humor, relates to right frontal regions.133 Although impairments in set shifting can be observed behaviorally, they can be directly tested with tasks of motor or written sequencing. Motor sequencing is tested with the fist-edge-palm task, which is particularly impaired in patients with dominant frontal lesions but also at the extremes of age.134 Written sequences of alternating letters or shapes can also be used.135 Initiation can be assessed with tests of verbal fluency by initial letter (words beginning with a particular letter) in a limited time span. Most adults score 16 to 18 ± 4 words in 1 minute. Although abstract thinking is commonly tested with proverbs, these are notoriously culturally, educationally, and age sensitive and are best replaced by questions regarding similarities (e.g., “What is the similarity between a desk and a chair?” or “What is the difference between a painting and poetry?”). Capacity to inhibit, as well as manage, interference can be tested with a “go–no-go” task where the patient is asked to provide a response to one particular examiner’s instruction, while not responding to a second, but related, instruction, such as “Tap on the table when I tap it once, but don’t tap the table when I tap it twice” (Table 1–7).

chapter 1 clinical assessment of mental status T A B L E 1–7. Tests of Executive Function Set-shifting: motor and written sequencing Initiation: verbal (category and word) fluency Abstraction: proverbs, similarities Inhibition: go–no-go task

Cortical Release Signs Although they are technically not a part of the mental status examination, a brief discussion of cortical release signs or primitive reflexes is warranted. These signs include the grasp, palmomental/pollicomental, snout, and pout reflexes.74 The presence and nature of such signs in schizophrenia may be an index of severity of neurodevelopmental disturbance and may aid in assessing prognosis, expected outcome, development of medication side effects such as tardive dyskinesia, and treatment planning.136,137 In geriatric psychiatry, cortical release signs are valuable aids to illness staging138,139 and outcome prediction140 and may be diagnostic aids in particular subtypes such as frontotemporal dementia.141,142 Although the palmomental reflex is relatively nonspecific, the grasp reflex is virtually never present in healthy elderly subjects143-147 and should be considered an indicator of CNS disease in this population.

STANDARDIZED COGNITIVE ASSESSMENT INSTRUMENTS Standardized cognitive assessment instruments are collections of cognitive testing items that have been validated against “gold standards” of neuropsychological testing or clinical or neuropathological diagnosis. These tools, which are designed to be rapidly administered during clinical assessments, are recommended in populations in which the rate and severity of impairment is relatively high—that is, in which a high prior probability maximizes positive predictive value. The ultimate goal of cognitive assessment has been to develop the ideal cognitive screening or assessment instrument, and this search is reflected in the plethora of published tools.

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patients, with low to moderate correlations between scores on this task and those on standard neuropsychological tests of memory.148 The MMSE does not assess long-delay recall, which can result in false-negative findings in the evaluation of relatively mild memory disorder and may fail to reveal amnesia.149 The “WORLD backwards” and serial sevens forms are not equivalent, and it has been recommended that they be replaced by the “months backwards” task.150 A significant concern with the structure of the MMSE is the lack of specific items that test executive function and spatial recall, and the American Neuropsychiatric Association has recommended that clinicians “supplement it with specific measures of spatial functions, delayed memory, and executive abilities.”151 Finally, a patient’s age and level of education significantly affect MMSE scores, and this needs to be taken into account when scores are interpreted.152,153 In response to these limitations, the more comprehensive Modified Mini-Mental State Examination has been developed and is being increasingly used in epidemiological and community-based surveys.154

Neurobehavioral Cognitive Status Examination The Neurobehavioral Cognitive Status Examination (NCSE), now known as the Cognistat, was developed for use in neurosurgical patients and involves the “screen and metric” approach in 11 cognitive domains155: level of consciousness, orientation, attention, comprehension, repetition, naming, construction, memory, calculation, similarities, and judgment. The resultant profile provides a “pattern” of distribution of cognitive dysfunction across the relevant domains. The Cognistat has shown utility in a number of neurocognitive conditions, particularly dementias, but has proved less useful in populations with neurobehavioral or neuropsychiatric disorders. The Cognistat assesses some aspects of executive function but does not test sequencing, inhibition, or verbal fluency. It appears to be a reasonably sensitive tool for the detection of dementia, but at a significant cost to its specificity,156 and is subject to the same effects of age and education as is the MMSE.157 The screen and metric approach has been criticized for sacrificing sensitivity for expediency, resulting in false-negative results in some populations.158 The Cognistat takes significantly longer to complete than the MMSE.

Mini-Mental State Examination and the Modified Mini-Mental State Examination

Addenbrooke’s Cognitive Examination

The MMSE is the most widely used of a substantial number of available screening tests122 and is a popular clinical measure that has validated versions available in many languages. The MMSE consists of a variety of tasks, yields a summed score with a maximum of 30 points, and can generally be administered in less than 10 minutes. The tasks have been grouped into seven categories, each rationally representing a different function: orientation to time, orientation to place, registration, attention and calculation, spontaneous recall, language (naming, repetition, reading, and spontaneous writing), and visual construction. The traditional cutoff score for dementia in mixed samples is less than 24, but this requires adjustment depending on the desired sensitivity versus specificity (see Chapter 2). The MMSE has significant content limitations. There is substantial variability in the recall of three words in healthy elderly

Addenbrooke’s Cognitive Examination (ACE) was developed by Mathuranath and coworkers in Cambridge159 and was reported to be able to reliably differentiate frontotemporal from Alzheimer’s dementia, although this property has been questioned.160 It has shown utility in parkinsonian syndromes161 and in differentiating early dementia from affective disorders.162 Addenbrooke’s Cognitive Examination provides a total score out of 100 and includes all items from the MMSE, which allows the clinician to generate both scores. It provides unequal scores on scales of orientation, attention/concentration, verbal fluency, language, and visuospatial function. Calculating a ratio of scores in these areas may aid in the differentiation of dementia subtypes. A revised version of Addenbrooke’s Cognitive Examination is currently being developed by the Cambridge group.

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Frontal Assessment Battery In view of the generally low inclusion rates of executive function testing in most screening tools, a further option is to use a dedicated executive battery such as the Frontal Assessment Battery, which has shown good correlation with neuropsychological measures of cognitive function and discriminant validity for patients with frontal lobe disorders.163 The Frontal Assessment Battery may for be used to supplement the MMSE, because of its lack of executive function testing.

COGNITIVE ASSESSMENT BEYOND THE BEDSIDE The testing methods, items, and screening instruments described in this chapter are all bedside methods of ascertaining neurocognitive function. The “gold standard” of cognitive assessment is the “formal” neuropsychological assessment, in which validated tools backed by normative and illness data are used. Neuropsychological assessment is a valuable but scarce and time-intensive resource. Not all patients with cognitive impairment require or tolerate neuropsychological testing. Hence, although all neurological services should have access to appropriately trained neuropsychologists, it is up to the neurologist to determine which patients need formal assessment and the nature of the question asked of the neuropsychologist. A referral to “Please provide a cognitive assessment” is the equivalent of the inadequate “Please provide a neurological/ psychiatric opinion.” The more information made available and the more specific the referral question, the more relevant will be the opinion; for example, “How does this patient’s current function differ from their estimated baseline?”; “Can the pattern of this patient’s cognitive dysfunction differentiate between a developmental or acquired disorder?”; or “Is this patient’s pattern of impairment indicative of a frontotemporal rather than Alzheimer’s dementia?” Aspects of neuropsychological testing are covered in greater detail in the following chapter.

ASSESSING THE “UNASSESSABLE” PATIENT On occasion, a patient refuses to participate in cognitive testing. Such patients include the insightful patient with early dementia who becomes anxious and distraught and develops a “catastrophic reaction” if asked questions that are clearly probing his or her memory. In other situations, patients may berate the examiner for asking “silly questions”: “Do you think I’m stupid?” “What are you, a schoolteacher?” “Why don’t you ask that other doctor I saw before?” The clinical imperative for cognitive assessment may still be as relevant as it is for the compliant patient. It is in these situations that the skill and expertise of the clinician are paramount. When faced with such a situation, the junior clinician may give up and state that “the patient is not assessable.” The experienced clinician may be able to rescue the interview through gently reassuring the patient and moving on to more familiar and less threatening territory such as the patient’s family, his or her interests, or day-to-day activities. Through skillful questioning about a favorite football team’s recent fortunes or grandchildren’s names and ages, the clinician may build up a clear picture of memory difficulties. Similarly, asking the patient to draw the floor plan of his or her house may provide important cognitive information. The clinician’s inventiveness and flexibility can be developed only

through the experience of clinical contact with a variety of patients.

THE NEUROCOGNITIVE FORMULATION The aim of the neurocognitive formulation is to piece together a “story” from all the information available. Although this chapter has focused on the neurocognitive history and the mental status examination, the physical examination and the results of investigations must contribute to the formulation. The process of assembling the formulation allows the clinician to integrate the developmental, educational, social, and genetic aspects of the patient’s presentation into a framework that provides not only a diagnosis but also a comprehensive management and treatment plan.

Case Example Mr. Jones, a 50-year-old executive with two teenaged children, presented for neurological assessment after a recent minor head injury in a car accident, on a background of 18 months of personality and functional change. Mr. Jones’ major complaint was of feeling rundown and lethargic, which had led his local doctor to prescribe antidepressants. His wife had noted that, for the last 18 months, he had been lacking motivation, had been forgetful, and had been allocated work duties well below his level of seniority. The family history revealed that Mr. Jones’ father had recently received a diagnosis of Parkinson’s disease after a 10-year history of gradual cognitive decline. Mr. Jones had been educated to tertiary level. There was no medical, psychiatric, or substance use history. On mental state examination, he manifested psychomotor retardation with poor grooming and a relative lack of concern regarding the recent events in his life. He did not describe depressed mood or communicate a depressed affect. He was oriented and performed well on attentional and memory testing. There were no abnormalities of visuoconstruction, praxis, left/right orientation, or calculation. He performed normally on language tasks. He had difficulty with a three-step motor sequencing task, could name only five animals in 1 minute (Fig. 1–3) and gave concrete responses on a task of similarities. He scored 29 out of 30 on the MMSE. Neurological examination findings were normal except for bilateral grasp reflexes. The neurocognitive history revealed personality and functional change, decreased motivation, slowing, and blandness of affect in a man with a family history of a dementia. Bedside cognitive testing yielded a normal MMSE score, but he performed poorly on tasks of executive function. The neurological finding of bilateral grasp reflexes was considered abnormal. A provisional diagnosis of a frontotemporal dementia was made, and investigations were ordered. Magnetic resonance imaging showed bilateral frontal atrophy out of keeping with his age, together with mild enlargement of the frontal horns of the ventricles; cerebral single photon emission computed tomography revealed bilateral frontal hypoperfusion. Neuropsychological testing confirmed the executive deficits and provided a baseline of cognitive performance for future reference. Several significant issues needed to be addressed in the ensuing months, including the possibility of a genetic condition and its implications for his young family, his ability to work and drive, and the effect of an early dementia on his family.

chapter 1 clinical assessment of mental status ■

0 – 15

15 – 20

antelope

owl

30 – 45

45⫹

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Figure 1–3. Verbal fluency by semantic category (animals) in 15-second epochs: impaired in a case of frontotemporal dementia.

hippo

eagle zebra

“I don’t know the names of many animals”.

CONCLUSION

Suggested Reading

The assessment of neurocognitive function extends far beyond the administration of cognitive tests and should include relevant aspects of history from a breadth of informants, as well as from the patient, and examination findings. A diagnosis is rarely made on the basis of a deficit in cognition alone. Even if the only positive finding is a single deficit in one cognitive domain, the clinician must always bear in mind Lishman’s “delicate balance”7 when discussing his or her formulation with the patients and caretakers and planning management and treatment appropriately.

Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New York: Oxford University Press, 2003. Mitchell AJ: Neuropsychiatry and Behavioral Neurology Explained. Philadelphia: Elsevier, 2004. Price BH, Adams RD, Coyle JT: Neurology and psychiatry. Closing the great divide. Neurology 2000; 54:8. Schiffer RB, Rao SM, Fogel BS: Neuropsychiatry, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2003. Yudovsky SC, Hales RE: American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. Washington, DC: American Psychiatric Publishing, 2003.

References

K E Y

P O I N T S

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The assessment of a patient with suspected cognitive impairment incorporates information obtained from a variety of sources, including the mental status examination.

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A neurocognitive history contains information from patients and informants regarding the evolution of illness, history, and associated functional and behavioral changes.

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The mental status examination should cover a broad range of cognitive domains, including attention, memory, language, executive function, and visuospatial tasks. It should be informed by observation and assessment from first contact to the end of the interaction with the patient, and it includes the use of a structured assessment.

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The neurocognitive formulation is the synthesis of the history and mental status examination findings with physical examination findings. Diagnosis is based on the overall clinical picture, and should not be made on the basis of test scores alone. The neurocognitive formulation informs diagnosis, further investigation, and management options.

1. Andrewes D: Neuropsychology: From Theory to Practice. East Sussex, UK: Psychology Press Ltd., 2001. 2. Mesulam M-M: Behavioral Neurology. Philadelphia: FA Davis, 1985. 3. Cummings J: Clinical Neuropsychiatry. Orlando, FL: Grune & Stratton, 1985. 4. Lishman WA: Organic Psychiatry: The Psychological Consequences of Cerebral Disorder. Oxford, UK: Blackwell Science, 1998. 5. Schiffer RB, Rao SM, Fogel BS: Neuropsychiatry. Philadelphia: Lippincott Williams & Wilkins, 2003. 6. Yudovsky SC, Hales RE: American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. Washington, DC: American Psychiatric Publishing, 2003. 7. Lishman AW: Neuropsychiatry: a delicate balance. Psychosomatics 1992; 33(1):4-9. 8. Price BH, Adams RD, Coyle JT: Neurology and psychiatry. Closing the great divide. Neurology 2000; 54:8. 9. Strub R, Black F: The Mental Status Examination in Neurology. Philadelphia: FA Davis, 2000. 10. Finkel S: Behavioral and psychological symptoms of dementia: a current focus for clinicians, researchers, and caregivers. J Clin Psychiatry 2001; 62(Suppl 21):3-6. 11. Marvel C, Paradiso S: Cognitive and neurological impairment in mood disorders. Psychiatr Clin North Am 2004; 27:19-36.

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12. Flashman L, Green M: Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment. Psychiatr Clin North Am 2004; 27:1-18. 13. Chow T: Frontotemporal dementias: clinical features and management. Semin Clin Neuropsychiatry 2003; 8:58-70. 14. Schweitzer I, Tuckwell V, O’Brien J, et al: Is late onset depression a prodrome to dementia? Int J Geriatr Psychiatry 2002; 17:995-1005. 15. Tombaugh T, McIntyre N: The Mini-Mental State Examination: a comprehensive review. J Am Geriatr Soc 1992; 40: 922-935. 16. Nelson H, O’Connell A: Dementia: the estimation of premorbid intelligence levels using the new adult reading test. Cortex 1978; 14:234-244. 17. Cummings J, Houlihan J, Hill M: The pattern of reading deterioration in dementia of the Alzheimer type: observations and implications. Brain Lang 1986; 29:315-323. 18. Wilkinson G: WRAT3 Administration Manual. Wilmington, DE: Wide Range, 1993. 19. Beardsall L, Huppert F: Improvement in NART word reading in demented and normal older persons using the Cambridge contextual reading test. J Clin Exp Neuropsychol 1994; 16:232-242. 20. Alexander M, Benson D: The aphasias and related disturbances. In Joynt RJ, Griggs RC, eds: Clinical Neurology. Philadelphia, Lippincott: 1998, pp 1-58. 21. Shenal B, Harrison D, Demaree H: The neuropsychology of depression: a literature review and preliminary model. Neuropsychol Rev 2003; 13:33-42. 22. Rogers M, Kasai K, Koji M, et al: Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neurosci Res 2004; 50:1-11. 23. Tandberg E, Larsen J, Aarsland D, et al: The occurrence of depression in Parkinson’s disease. A community-based study. Arch Neurol 1996; 53:175-179. 24. Folstein S, Abbott M, Chase G, et al: The association of affective disorder with Huntington’s disease in a case series and in families. Psychol Med 1983; 13:537-542. 25. Feinstein A: The Clinical Neuropsychiatry of Multiple Sclerosis. Cambridge, UK: Cambridge University Press, 1999. 26. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561-571. 27. Hamilton MA: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56-62. 28. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press, 1994. 29. Castillo C, Schultz S, Robinson R: Clinical correlates of earlyonset and late-onset post-stroke generalized anxiety. Am J Psychiatry 1995; 152:1174-1179. 30. Paulsen J, Ready R, Hamilton J, et al: Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry 2001; 71:310-314. 31. Richard I, Schiffer R, Kurlan R: Anxiety and Parkinson’s disease. Mov Disord 1996; 8:501-506. 32. Young G, Chandarana P, Blume W, et al: Mesial temporal lobe seizures presenting as anxiety disorders. J Neuropsychiatry Clin Neurosci 1995; 7:352-357. 33. Simon N, Blacker D, Korbly N, et al: Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review. J Affect Disord 2002; 69:209-217. 34. George M, Trimble M, Ring H, et al: Obsessions in obsessivecompulsive disorder with and without Gilles de la Tourette’s syndrome. Am J Psychiatry 1993; 150:93-97. 35. Snider L, Swedo S: PANDAS: current status and directions for research. Mol Psychiatry 2004; 9:900-907. 36. Cummings J: Organic psychosis. Psychosomatics 1988; 29:16-26.

37. Cummings J: Organic delusions: phenomenology, anatomical correlates and review. Br J Psychiatry 1985; 146:184187. 38. Cutting J: The phenomenology of acute organic psychosis. Comparison with acute schizophrenia. Br J Psychiatry 1987; 151:324-332. 39. van Os J: Is there a continuum of psychotic experiences in the general population? Epidemiol Psichiatr Soc 2003; 12:242-252. 40. Bentall R, Slade P: Reality testing and auditory hallucinations: a signal detection analysis. Br J Clin Psychol 1985; 24:159-169. 41. Assad G, Shapiro B: Hallucinations: theoretical and clinical overview. Am J Psychiatry 1986; 143:1088-1097. 42. Santhouse AM, Howard RJ, Ffytche DH: Visual hallucinatory syndromes and the anatomy of the visual brain. Brain 2000; 123(Pt 10):2055-2064. 43. Goldberg D, Bridges K, Duncan-Jones P, et al: Dimensions of neuroses seen in primary-care settings. Psychol Med 1987; 17:461-470. 44. Harwood D, Sultzer D, Wheatley M: Impaired insight in Alzheimer’s disease: association with cognitive deficits, psychiatric symptoms, and behavioural disturbances. Neuropsychiatry Neuropsychol Behav Neurol 2000; 13:83-88. 45. Lacro J, Dunn L, Dolder C, et al: Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002; 63:892-909. 46. Johnson S, Orrell M: Insight, psychosis and ethnicity: a casenote study. Psychol Med 1996; 26:1081-1084. 47. David A: “To see ourselves as others see us.” Aubrey Lewis’ insight. Br J Psychiatry 1999; 175:210-216. 48. David A: Insight and psychosis. Br J Psychiatry 1990; 156: 798-808. 49. McGlashan T: Recovery from mental illness and long-term outcome. J Nerv Ment Dis 1987; 175:681-685. 50. Babinski J: Contribution à l’étude des troubles mentaux dans l’hémiplégie organique cérébrale (anosognosie). Revue Neurologique 1914; 22:845-848. 51. Vuilleumier P: Anosognosia: the neurology of beliefs and uncertainties. Cortex 2004; 40:9-17. 52. Heilman K, Watson R: Mechanisms underlying the unilateral neglect syndrome. Adv Neurol 1977; 18:93-105. 53. Hodges J, Miller B: Frontotemporal dementia (Pick’s disease). In Hodges J, ed: Early-Onset Dementia: A Multidisciplinary Approach. Oxford, UK: Oxford University Press, 2001, pp 284-303. 54. Marin R: Differential diagnosis and classification of apathy. Am J Psychiatry 1990; 147:22-30. 55. Mega M, Cummings J: Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci 1994; 6:358-370. 56. Burns A, Folstein S, Brandt J, et al: Clinical assessment of irritability, aggression and apathy in Huntington’s and Alzheimer’s disease. J Nerv Ment Dis 1990; 178:20-26. 57. Starkstein S, Mayberg H, Preziosi T, et al: Reliability, validity and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1992; 4:134-139. 58. Andersson S, Krogstad J, Finset A: Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 1999; 29:447-456. 59. Roth R, Flashman L, Saykin A, et al: Apathy in schizophrenia: reduced frontal lobe volume and neuropsychological deficits. Am J Psychiatry 2004; 161:157-159. 60. Phillips S, Sangalang V, Sterns G: Basal forebrain infarction. A clinicopathologic correlation. Arch Neurol 1987; 44:11341138.

chapter 1 clinical assessment of mental status 61. Marin R, Fogel B, Hawkins J, et al: Apathy: a treatable syndrome. J Neuropsychiatry Clin Neurosci 1995; 7:23-30. 62. Hertel P, Nomikos G, Iurlo M, et al: Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain. Psychopharmacology (Berlin) 1996; 124:74-86. 63. Levy M, Cummings J, Fairbanks L, et al: Apathy is not depression. J Neuropsychiatry Clin Neurosci 1998; 10:314-319. 64. Aron A, Robbins T, Poldrack R: Inhibition and the right inferior frontal cortex. Trends Cogn Sci 2004; 8:170-177. 65. Starkstein S, Robinson R: Mechanism of disinhibition after brain lesions. J Nerv Ment Dis 1997; 185:108-114. 66. Starkstein S, Boston J, Robinson R: Mechanisms of mania after brain injury: 12 case reports and review of the literature. J Nerv Ment Dis 1988; 176:87-100. 67. Neary D, Snowden J, Northen B, et al: Dementia of frontal lobe type. J Neurol Neurosurg Psychiatry 1988; 51:353-361. 68. Cooper S, Dourish C: Neurobiology of Stereotyped Behaviour. London: Oxford University Press, 1990. 69. Lewis M, Gluck J, Bodfish J, et al: Neurobiological basis of stereotyped movement disorder in animals and humans. In Sprague R, Newell K, eds: Stereotypy: Brain-Behavior Relationships. Washington, DC, American Psychological Association Press, 1996, pp 37-67. 70. Stuss D, Benson D: Neuropsychological studies of the frontal lobes. Psychol Bull 1984; 95:3-24. 71. Grossman M: Frontotemporal dementia: a review. J Int Neuropsychol Soc 2002; 8:566-583. 72. Graybiel A, Canales J: The neurobiology of repetitive behaviors: clues to the neurobiology of Tourette syndrome. In Cohen D, Goetz C, Jankovic J, eds: Tourette Syndrome. Philadelphia: Williams & Wilkins, 2001, pp 123-131. 73. Cummings J: Anatomic and behavioral aspects of frontalsubcortical circuits. Ann N Y Acad Sci 1995; 769:1-13. 74. Walterfang M, Velakoulis D: Cortical release signs in psychiatry. Aust N Z J Psychiatry 2005; 39:317-327. 75. Lhermitte F: “Utilization behaviour” and its relation to lesion of the frontal lobes. Brain 1983; 106:237-255. 76. Rudd R, Maruff P, MacCuspie-Moore C, et al: Stimulus relevance in eliciting utilisation behaviour. Case study in a patient with a caudate lesion. Cogn Neuropsychiatry 1998; 3:287-298. 77. Harris JC: Developmental Neuropsychiatry. Assessment, Diagnosis and Treatment of Developmental Disorders. New York: Oxford University Press, 1998. 78. Coffey CE, Brumback RA, eds: Pediatric Neuropsychiatry. Washington, DC: American Psychiatric Press, 1998. 79. Tanner CM, Chamberland J: Latah in Jakarta, Indonesia. Move Disord 2001; 16:526-529. 80. Schuler A: Echolalia. Issues and clinical applications. J Speech Hear Disord 1979; 44:411-434. 81. Wint D, Okun M, Fernandez H: Psychosis in Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17:127-136. 82. Katzenschlager R, Sampaio C, Costa J, et al: Anticholinergics for symptomatic management of Parkinson’s disease. Cochrane Database Syst Rev 2003; (2):CD003735. 83. Loftis J, Hauser P: The phenomenology and treatment of interferon-induced depression. J Affect Disord 2004; 82:175190. 84. Brown E, Khan D, Nejtek V: The psychiatric side effects of corticosteroids. Ann Allergy Asthma Immunol 1999; 83:495503. 85. Inouye S: Prevention of delirium in hospitalized older patients: risk factors and targeted intervention strategies. Ann Med 2000; 32:257-263. 86. Lawson W, Waldman I, Weinberger D: Schizophrenic dementia. Clinical and computed axial tomography correlates. J Nerv Ment Dis 1988; 176:207-212.

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87. Shulman K: Disinhibition syndromes, secondary mania and bipolar disorder in old age. J Affect Disord 1997; 46:175182. 88. Dobie D: Depression, dementia and pseudodementia. Semin Clin Neuropsychiatry 2002; 7:170-186. 89. Harris D, Batki S: Stimulant psychosis: symptom profile and acute clinical course. Am J Addict 2000; 9:28-37. 90. Kalant H: Adverse effects of cannabis on health: an update of the literature since 1996. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:849-863. 91. Westermeyer J: The psychiatrist and solvent-inhalant abuse: recognition, assessment and treatment. Am J Psychiatry 1987; 144:903-907. 92. Cummings J, Mega M, Gray K, et al: The Neuropsychiatric Inventory: a comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314. 93. Wood S, Cummings J, Hsu M, et al: The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000; 8:75-83. 94. Choi S, Na D, Kwon H: The Korean version of the Neuropsychiatric Inventory: a scoring tool for neuropsychiatric disturbance in dementia patients. J Korean Med Sci 2000; 15:609-615. 95. Leung V, Lam L, Chiu H: Validation study of the Chinese version of the Neuropsychiatric Inventory (CNPI). Int J Geriatr Psychiatry 2001; 16:789-793. 96. Vilalta-Franch J, Lozano-Gallego M, Hernandez-Ferrandiz M, et al: The Neuropsychiatric Inventory: psychometric properties of its adaptation into Spanish. Rev Neurol 1999; 29: 15-19. 97. Politis A, Mayer L, Passa M, et al: Validity and reliability of the newly translated Hellenic Neuropsychiatric Inventory (H-NPI) applied to Greek outpatients with Alzheimer’s disease: a study of disturbing behaviors among referrals to a memory clinic. Int J Geriatr Psychiatry 2004; 19:203208. 98. Reisberg B, Auer S, Monteiro I: Behavioral pathology in Alzheimer’s disease (BEHAVE-AD) rating scale. Int Psychogeriatr 1996; 8(Suppl 3):301-308. 99. Mega M, Cummings J, Fiorello T, et al: The spectrum of behavioural changes in Alzheimer’s disease. Neurology 1996; 46:130-135. 100. Aarsland D, Cummings J, Larsen J: Neuropsychiatric differences between Parkinson’s disease with dementia and Alzheimer’s disease. Int J Geriatr Psychiatry 2001; 16:184191. 101. Mourik J, Rosso S, Niermeijer M, et al: Frontotemporal dementia: behavioral symptoms and caregiver distress. Dement Geriatr Cogn Disord 2004; 18:299-306. 102. Litvan I, Mega M, Cummings J, et al: Neuropsychiatric aspects of progressive supranuclear palsy. Neurology 1996; 47:1184-1188. 103. Litvan I, Cummings J, Mega M: Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiatry 1998; 65:717-721. 104. Lyketsos C, Lopez O, Jones B, et al: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002; 288:1475-1483. 105. Kulisevsky J, Litvan I, Berthier M, et al: Neuropsychiatric assessment of Gilles de la Tourette patients: comparative study with other hyperkinetic and hypokinetic movement disorders. Mov Disord 2001; 16:1098-1104. 106. Aharon-Peretz J, Kliot D, Tomer D: Behavioral differences between white matter lacunar dementia and Alzheimer’s disease: a comparison on the neuropsychiatric inventory. Dement Geriatr Cogn Disord 2000; 11:294-298.

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107. Diaz-Olavarrieta C, Cummings J, Velazquez J, et al: Neuropsychiatric manifestations of multiple sclerosis. J Neuropsychiatry Clin Neurosci 1999; 11:51-57. 108. Holmes C, Wilkinson D, Dean C, et al: The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 2004; 63:214-219. 109. Monsch A, Giannakopoulos P: Effects of galantamine on behavioural and psychological disturbances and caregiver burden in patients with Alzheimer’s disease. Curr Med Res Opin 2004; 20:931-938. 110. Aupperle P, Koumaras B, Chen M, et al: Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer’s disease: results of a 52-week open-label study. Curr Med Res Opin 2004; 20:1605-1612. 111. Levin H, High W, Goethe K, et al: The Neurobehavioural Rating Scale: assessment of the behavioural sequelae of head injury by the clinician. J Neurol Neurosurg Psychiatry 1987; 50:183-193. 112. Overall J, Gorham D: The brief psychiatric rating scale. Psychol Reports 1962; 10:799-812. 113. Vanier M, Mazaux J, Lambert J, et al: Assessment of neuropsychologic impairments after head injury: interrater reliability and factorial and criterion validity of the Neurobehavioral Rating Scale–Revised. Arch Phys Med Rehabil 2000; 81:796-806. 114. Merchant R, Bullock M, Carmack C, et al: A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. Ann N Y Acad Sci 1999; 890:42-50. 115. Rapoport M, McCauley S, Levin H, et al: The role of injury severity in neurobehavioral outcome 3 months after traumatic brain injury. Neuropsychiatry Neuropsychol Behav Neurol 2002; 15:123-132. 116. Vilkki J, Ahola K, Holst P, et al: Prediction of psychosocial recovery after head injury with cognitive tests and neurobehavioral ratings. J Clin Exp Neuropsychol 1994; 16:325338. 117. Sultzer D, Berisford M, Gunay I: The Neurobehavioral Rating Scale: reliability in patients with dementia. J Psychiatr Res 1995; 29:185-191. 118. Pollock B, Mulsant B, Rosen J, et al: Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry 2002; 159:460-465. 119. Mathias J: Neurobehavioral functioning of persons with Parkinson’s disease. Appl Neuropsychol 2003; 10:57-68. 120. Hilton G, Sisson R, Freeman E: The Neurobehavioral Rating Scale: an interrater reliability study in the HIV seropositive population. J Neurosci Nurs 1990; 22:36-42. 121. Rabee H, Saadani M, Iqbal K, et al: Neurobehavioral effects of carotid endarterectomy. Saudi Med J 2001; 22:433-437. 122. Folstein M, Folstein S, McHugh P: “Mini Mental State.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198. 123. Manning R: The serial sevens test. Arch Intern Med 1982; 142:1192. 124. Critchley M: The Parietal Lobes. New York: Hafner, 1966. 125. Shulman K: Clock drawing: is it the ideal cognitive test? Int J Geriatr Psychiatry 2000; 15:548-561. 126. Moo L, Slotnick S, Tesoro M, et al: Interlocking finger test: a bedside screen for parietal lobe dysfunction. J Neurol Neurosurg Psychiatry 2003; 74:530-532. 127. Tulving E, Kapur S, Craik F, et al: Hemispheric encoding/ retrieval asymmetry in episodic memory: positron emission tomography findings [Review]. Proc Natl Acad Sci U S A 1994; 91:2016-2020.

128. Walterfang M, Velakoulis D, Gibbs A, et al: The NUCOG: construction and piloting of a cognitive screening instrument in a neuropsychiatric unit. Australas Psychiatry 2003; 11: 325-329. 129. Marburg D: The effect of lesions in the centromedian nucleus of the thalamus on the monkey’s performance in delayed alternation and object reversal tasks. Int J Neurosci 1973; 5:207-214. 130. Ridley R: The psychology of perseverative and stereotyped behaviour. Prog Neurobiol 1994; 44:221-231. 131. Hotz G, Helm-Estabrooks N: Perseveration. Part I: a review. Brain Inj 1995; 9:151-159. 132. Nagahama Y, Okada T, Katsumi Y, et al: Dissociable mechanisms of attentional control within the human prefrontal cortex. Cereb Cortex 2001; 11:85-92. 133. Shammi P, Stuss D: Humour appreciation: a role of the right frontal lobe. Brain 1999; 122:657-666. 134. Luria A: The Working Brain. New York: Basic Books, 1973. 135. Luria A: Frontal lobe syndromes. In Vinken P, Bruyn G, eds: Handbook of Clinical Neurology, vol 2. New York: Elsevier, 1969, pp 725-757. 136. Barnes T, Crichton P, Nelson H, et al: Primitive (developmental) reflexes, tardive dyskinesia and intellectual impairment in schizophrenia. Schizophr Res 1995; 16:47-52. 137. Youssef H, Waddington J: Primitive (developmental) reflexes and diffuse cerebral dysfunction in schizophrenia and bipolar affective disorder: over-representation in patients with tardive dyskinesia. Biol Psychiatry 1988; 23:791-796. 138. Franssen E, Reisberg B, Kluger A, et al: Cognitionindependent neurologic symptoms in normal aging and probable Alzheimer’s disease. Arch Neurol 1991; 48:148154. 139. Benesch C, McDaniel K, Cox C, et al: End-stage Alzheimer’s disease: Glasgow Coma Scale and the neurologic examination. Arch Neurol 1993; 50:1309-1315. 140. Burns A, Jacoby R, Levy R: Neurological signs in Alzheimer’s disease. Age Ageing 1991; 20:45-51. 141. Gregory C, Orrell M, Sahakian B, et al: Can frontotemporal dementia and Alzheimer’s disease be differentiated using a brief battery of tests? Int J Geriatr Psychiatry 1997; 12:375383. 142. Sjögren M, Wallin A, Edman A: Symptomatological characteristics distinguish between frontotemporal dementia and vascular dementia with a dominant frontal lobe syndrome. Int J Geriatr Psychiatry 1997; 12:656-661. 143. Di Legge S, Di Piero V, Altieri M, et al: Usefulness of primitive reflexes in demented and non-demented cerebrovascular patients in daily clinical practice. Eur Neurol 2001; 45:104110. 144. Hogan D, Ebly E: Primitive reflexes and dementia: results from the Canadian Study of Health and Aging. Age Ageing 1995; 24:375-381. 145. Jacobs L, Gossman M: Three primitive reflexes in normal adults. Neurology 1980; 30:184-188. 146. Jenkyn L, Reeves A, Warren T, et al: Neurologic signs in senescence. Arch Neurol 1985; 42:1154-1157. 147. Kobayashi S, Yamaguchi S, Okada K, et al: Primitive reflexes and MRI findings, cerebral blood flow in normal elderly. Gerontology 1990; 36:199-205. 148. Cullum M, Thompson L, Smernoff E: Three word recall as a measure of memory. J Clin Exp Neuropsychol 1993; 15: 321-329. 149. Benedict R, Brandt J: Limitations of the Mini-Mental State Examination for the detection of amnesia. J Geriatr Psychiatry Neurol 1993; 5:233-237. 150. Galasko D, Klauber MR, Hofstetter CR, et al: The Mini-Mental State Examination in the early diagnosis of Alzheimer’s disease. Arch Neurol 1990; 47:49-52.

chapter 1 clinical assessment of mental status 151. Malloy P, Cummings J, Coffey C, et al: Cognitive screening instruments in neuropsychiatry: a report of the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 1997; 9:189-197. 152. O’Connor D, Pillott P: The influence of education, social class and sex on Mini-Mental State scores. Psychol Med 1989; 19:771-776. 153. Mungas D, Marshall S, Weldon M, et al: Age and education correction of Mini-Mental State Examination for English and Spanish speaking elderly. Neurology 1996; 46:700-706. 154. Teng EL, Chui H: The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987; 48:314-318. 155. Kiernan R, Mueller J, Langston J, et al: The Neurobehavioral Cognitive Status Examination: a brief but quantitative approach to cognitive assessment. Ann Intern Med 1987; 107:481-485. 156. Drane D, Osato S: Using the Neurobehavioral Cognitive Status Examination as a screening measure for older adults. Arch Clin Neuropsychol 1997; 12:139-143. 157. Drane DL, Yuspeh RL, Huthwaite JS, et al: Healthy older adult performance on a modified version of the Cognistat

158.

159. 160. 161. 162.

163.

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(NCSE): demographic issues and preliminary normative data. J Clin Exp Neuropsychol 2003; 25:133-144. Oehlert M, Hass S, Freeman M, et al: The Neurobehavioral Cognitive Status Examination: accuracy of the “screenmetric” approach in a clinical sample. J Clin Psychol 1997; 53:733-737. Mathuranath P, Nestor P, Berrios G, et al: A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000; 55:1613-1620. Bier J, Ventura M, Donckels V, et al: Is the Addenbrooke’s Cognitive Examination effective to detect frontotemporal dementia? J Neurol 2004; 251:428-431. Bak T, Rogers T, Crawford L, et al: Cognitive bedside assessment in atypical parkinsonian syndromes. J Neurol Neurosurg Psychiatry 2005; 76:420-422. Dudas R, Berrios G, Hodges J: The Addenbrooke’s Cognitive Examination (ACE) in the differential diagnosis of early dementias versus affective disorder. Am J Geriatr Psychiatry 2005; 13:218-226. Dubois B, Slachevsky A, Litvan I, et al: The FAB: a frontal assessment battery at bedside. Neurology 2000; 55:16211626.

CHAPTER

PRINCIPLES

2

OF NEUROPSYCHOMETRIC ASSESSMENT ●

●

●

●

Elsdon Storey and Glynda Kinsella

It might legitimately be asked why this chapter was written by both a neurologist and a neuropsychologist. The answer, in part, is that a neurologist who has worked closely with neuropsychologists is perhaps in the best position to interpret the discipline to his or her colleagues; neuropsychology is often a “black box” to neurologists, to a greater extent than neuropsychologists themselves may realize. This can lead to uncritical acceptance of neuropsychologists’ conclusions without the productive interaction that characterizes, for example, neuroradiological review sessions. At the other extreme, the real added value of expert neuropsychological assessment may be discounted by those unconvinced of its validity. In any event, the value of neuropsychological assessment is considerably increased when the neurologist requesting it understands its strengths, limitations and pitfalls, and the sort of data on which its conclusions are based.

are pure tests of a single domain, and almost all can be performed poorly for several reasons. For example, inability to copy the Rey Complex Figure might result from impairments of volition, comprehension, planning, or praxis, as well as from some form of the most obvious cause of visual impairment. Assignment of particular tests to particular domains is therefore to some extent arbitrary; many tests are capable of being assigned to more than one domain. The interested reader is referred to Lezak and colleagues (2004) and Spreen and Strauss (1998) for details of individual tests. Multidimensional tests, such as the Mini-Mental State Examination (MMSE), may be subjected to factor analysis. This type of analysis identifies groupings of test items that correlate with each other and may well assess aspects of the same domain. In this way, the range of domains assessed by such a test may be identified.

COGNITIVE DOMAINS AND NEUROPSYCHOLOGICAL TESTS

Prerequisites for Meaningful Testing

Cognitive Domains Cognitive domains are constructs (intellectual conceptualizations to explain observed phenomena, such as gravity) invoked to provide a coherent framework for analysis and testing of cognitive functions. The various cognitive processes in each domain are more or less related and are more or less independent of processes in other domains. Although these domains do not have strict, entirely separable neuroanatomical substrates, they do each depend on particular (but potentially overlapping) neural networks.1 In view of the way in which cognitive domains are delineated, it is not surprising that there is some variation in their stated number and properties, but commonly recognized ones with their potential neural substrates are listed in Table 2–1.

Neuropsychological Assessment of Individual Cognitive Domains In practice, although many neuropsychological tests assess predominantly one domain, very few in routine clinical use

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Adequate testing within some domains requires that some others are sufficiently intact. For example, a patient whose sustained, focused attention (concentration) is severely compromised by a delirium is unable to register a word list adequately. Consequently, delayed recall is impaired, even in the absence of a true amnesia or its usual structural correlates. A patient with sufficiently impaired comprehension may perform poorly on the Wisconsin Card Sorting Test because the instructions were not understood, rather than because hypothesis generation was compromised. These considerations give rise to the concept of a pyramid of cognitive domains, with valid testing at each level dependent on the adequacy of lower level performance2 (Fig. 2–1). In addition to intact attention and comprehension, patient performance may be compromised by poor motivation—for example, as a result of depression or in the setting of potential secondary gain—or by anxiety. Neurological impairments (e.g., poor vision, ataxia), psychiatric comorbid conditions, preexisting cognitive impairments (e.g., mental retardation), specific learning difficulties or lack of education (e.g., resulting in illiteracy), and lack of mastery of the testing language can all interfere with valid testing and must be carefully considered by the neuropsychologist in interpreting test results.3

chapter 2 principles of neuropsychometric assessment

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T A B L E 2–1. Commonly Assessed Cognitive Domains and Their Potential Neural Substrate Domain

Main Neural Substrate

Attention

Ascending reticular activating system, superior colliculus, thalamus, parietal lobe, anterior cingulate cortex, and the frontal lobe Classical speech zones, typically in the left dominant hemisphere, including Wernicke’s and Broca’s areas, and the angular gyrus Hippocampal-entorhinal cortex complex Frontal regions Left parietal cortex Ventral visual system: occipital regions to anterior pole of temporal lobe

Language Memory Object recognition (visual) Spatial processing Executive functioning

Posterior parietal cortex, frontal eye fields, dorsal visual system Inferotemporal/midtemporal and polar temporal cortex Frontal-subcortical circuits, including dorsolateral prefrontal, orbital frontal, and anterior cingulate circuits

Executive function Memories (various types) Visuoperceptual function, Praxis Comprehension (language) Attention (Consciousness) ■

Figure 2–1. The pyramid of cognitive domains. An unconscious or inattentive patient is not able to comprehend test instructions, even though the relevant linguistic networks may be intact. A patient with severely impaired comprehension may not understand the test instructions for praxis, for example, and so forth.

BASIC PRINCIPLES OF PSYCHOMETRICS Test Reliability For a neuropsychological test (or any other test) to be clinically useful, it must be both reliable and valid. A reliable test is one for which differences in scores reflect true differences in what is being measured, rather than random variation (“noise”) or systematic bias (e.g., consistent differences between test scores at different centers). The reliability coefficient of a test is the proportion of total test result variability that is attributable to true differences in test results. It may also be conceptualized as the variability that would remain after multiple administrations of a test resulted in random variations that canceled each other out, with no systematic bias assumed. (An analogy familiar to neurologists would be electronic averaging in evoked potentials.) Reliability coefficients of standard neuropsychological tests typically vary from about 0.70 (acceptable) to 0.95 (high). Reliability may be assessed in a number of ways. Test-retest reliability accounts for both random variability resulting from the test itself and systematic bias resulting from practice effects, although it cannot enable the clinician to easily distinguish between the two. It presupposes a stable test popu-

lation, which may be an unattainable ideal over longer periods of time, inasmuch as acute pathological conditions such as results of strokes and traumatic injuries tend to improve and degenerative conditions tend to worsen. The internal consistency of a multi-item test can be gauged by split-half reliability, whereby scores from half the test items are compared with scores from the other half (but this leaves moot how the division is performed), or by calculating the mean reliability coefficient obtained from all possible split-half comparisons. The latter strategy generates a statistic called Cronbach’s a. Sometimes, alternative (parallel) versions of tests are constructed, often in order to facilitate serial testing in an effort to avoid practice effects. The reliabilities of the different versions can then be compared, in a process very similar to split-half reliability testing. The difficulty, of course, is in knowing whether the two versions really are equivalent, so that variance between the two represents unreliability rather than differences in difficulty or in the variable or variables actually being measured. Interrater reliability accounts for the variation in test scores resulting from administration by different testers. This is clearly important particularly in multicenter studies and is an essential property for semiquantitative clinical rating scales. The importance of test reliability underlies the importance of test administration with standardized materials in a standardized manner and a conducive environment, and by appropriately trained personnel (e.g., not by an intern in a noisy ward).

Test Validity A valid test measures what it is purported to measure. Whereas an unreliable test cannot be valid (as score variations reflecting true differences in the intended measured variable are concealed by noise or systematic bias), reliability itself is no guarantee of validity. Consideration of the following test of semantic knowledge illustrates this point: 1. 2. 3. 4.

What is 2 + 3? Which city is the capital of the USA? How many seconds are in a minute? What was the maiden name of Charcot’s maternal grandmother?

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All readers presumably score 75% on this test, which is therefore absolutely reliable but quite invalid as a test of semantic knowledge. Validity can be gauged in a number of ways. Criterion validity reflects the utility of the test in decision making. Perhaps the ideal form of criterion validity is predictive validity, in which test results are used to make a decision or prediction, such as in which patients amnestic mild cognitive impairment will convert to Alzheimer’s disease, and the validity of the decision is subsequently established on follow-up. Such studies tend to be long and expensive, however, and so other methods of assessing validity are often required. Concurrent validity, another form of criterion validity often used instead, involves comparing test results with a nontest parameter of relevance, such as sustained, directed attention in children with their class disciplinary records. Ecological validity, a related concept, reflects the predictive value of the test for performance in real-world situations. For example, neuropsychological tests of visual attention and executive function, but not of other domains, have been found to have reasonable ecological validity for predicting driving safety, in comparison with the “gold standard” of on-road testing.4 Construct validity assesses whether, for example, a test purportedly of a particular cognitive domain is correlated with other established tests of that particular domain and functions as tests of that domain are expected to function. Content validity concerns checking the test items against the boundaries and content of the domain (or portion of the domain) to be assessed. Face validity exists when, to a layperson (such as the subject undergoing testing), a test seems to measure what it is purported to measure. Thus, a driving simulator has good face validity as a test of on-road safety, whereas an overlapping figures test of figure/ground discrimination may not, even though it may actually be relevant to perceptual tasks during driving. More detailed discussions of reliability and validity were given by Mitrushina and associates (2005), Halligan and colleagues (2003), or Murphy and Davidshofer (2004).

Symptom Validity Testing Symptom validity testing is rather different and is used as a method to reveal nonorganic deficits (e.g., malingering). It relies on the fact that patients with no residual ability in a domain, who are forced to respond to items randomly or by guessing, can nevertheless sometimes be correct by chance. Performance at statistically significantly worse than chance levels can be explained only by some retention of ability in that domain, with that ability being used (consciously or unconsciously) to produce incorrect answers. This forced-choice/ statistical analysis concept should already be familiar to neurologists, as it underlies much of psychophysically correct sensory testing. (A fine example is the University of Pennsylvania Smell Identification Test [UPSIT] for evaluation of olfaction.5) Other methods for detecting nonorganic deficits also exist; they depend on recognition of deviation from the usual patterns of cognitive impairment (e.g., recognition memory’s being worse than spontaneous recall) or discrepancy between scores on explicit tests of a domain and behavior or other tests implicitly dependent on that domain (e.g., dysfluency appearing only when “language” is tested). This subject is covered in more detail elsewhere.6

Ceiling and Floor Effects Two further difficulties may limit the use of neuropsychological measures: lack of discrimination across the range of abilities expected and practice effects on repeated testing. An ideal test would reveal a linear decline in ability in the tested domain, from the supremely gifted to the profoundly impaired. In practice, this is rarely, if ever, achieved. Some tests discriminate well between patients with different severities of obvious impairment but are problematic in attempts to detect subtle disorders and fail to stratify the normal population appropriately. This is known as a ceiling effect. On the other hand, some tests sensitive to subtle declines and capable of stratifying the normal population, are too difficult for patients with more profound deficits. Real differences in their residual abilities may be missed. This is a floor effect. Some tests have both ceiling and floor effects, leading to a sigmoid curve of scores versus ability. If patients with Alzheimer’s disease are assumed to decline at a constant rate, then on average, over time, the MMSE shows both ceiling and floor effects (Fig. 2–2).

Practice Effects Practice effects arise when the act of taking a test more than once results in an improvement in the subject’s true score. Repeated assessments over time are often desirable, to determine whether a deficit is static or declining or to monitor treatment or recovery. Such serial assessment is virtually impossible with some tests because of practice effects. For example, once the patient has been exposed to the Wisconsin Card Sorting Test and has learned that the examiner periodically changes the correct sorting rule without divulging this to the patient, much of the challenge and novelty of this test is lost. Repeated exposure to a test, particularly over a short period, may result in overt learning. This probably accounts for the initial rise in MMSE and Alzheimer’s Disease Assessment Scale, Cognitive subscale (ADAS-Cog) scores in the placebo recipients in trials of cholinesterase inhibitors in Alzheimer’s disease, for example (Fig. 2–3). The use of alternative forms, such as the Crawford version of the Rey Auditory Verbal Learning Test, may overcome some of these difficulties,7 but not all alternative versions of tests really are equivalent (e.g., the Taylor alternative version of the complex figure is easier to recall than the original Rey Complex Figure itself; see Chapter 12 in Mitrushina et al [2005]). Furthermore, learning may be implicit (procedural), in such a way that patients become more proficient at a type of test with practice in the absence of conscious remembering. This may improve scores even on true alternative versions.

Comparison with Appropriate Normative Data For tests to be useful in making clinical predictions about an individual, particularly on the first assessment, it is essential that individuals’ scores be compared with appropriate normative data. Many test scores in normal populations show systematic variation with demographic variables, such as age, years of education, and gender, and these must be accounted for before interpretation is possible. This may be done by using either stratified norms or regression equations with the

chapter 2 principles of neuropsychometric assessment

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NATURAL HISTORY OF AD

Early diagnosis

Severe

Mild-moderate

30 Cognitive symptoms 25 Loss of functional independence

MMSE

20 15

Behavioral problems

10

Nursing home placements

5

Death

0

2

1

3

4

5

6

7

8

9

Years ■

Figure 2–2. The Mini-Mental State Examination (MMSE) shows both ceiling effects (flatter segment of

Mean (±SEM) change in ADAS-cog/11 from baseline

graph, upper left) and floor effects (flatter segment of graph, to right) in comparison with its sensitivity to change in the middle stages of Alzheimer’s disease (AD). (From Gauthier S, ed: Clinical Diagnosis and Management of Alzheimer’s Disease. London, UK: Martin Dunitz, 1996.)

Double-blind

Open-extension

Improvement

–4 –3 –2 –1 0 1 2 3 Deterioration Baseline

3

6 Time (months)

9

relevant variables factored in. It is essential that the “normal” population sampled to provide the normative data is relevant to the patient being tested. For example, a stratification category of native English speakers “>60 years” with an average of 16 years of education is hardly an appropriate normative population against which to compare an 89-year-old patient with only 5 years of education who learned English as an adult immigrant. The selection of appropriate norms is covered in detail in the handbook by Mitrushina and associates (2005). Testing patients whose language of preference is not that of the test (and the examiner) is particularly plagued with pitfalls: Direct translation on the spot introduces too much random variability. Versions in the target language must first be validated and norms established in that population, allowing for differences in word usage and familiarity. In the case of nonverbal tests, it must be shown that scores are equivalent in the different target groups. Even a carefully translated test may end up measuring something different from the original version.8

12

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Figure 2–3. Alzheimer’s Disease Assessment Scale, Cognitive subscale (ADAS-Cog) scores in a trial of an acetylcholinesterase inhibitor in Alzheimer’s disease. Diamonds represent scores of patients receiving placebo in the double-blind phase and inhibitor in the extension phase; squares represent scores of patients taking the inhibitor. A drop in score (negative values) represents an improvement on this test on which 0/70 is a perfect score. Note the improvement of about −1/2 at 6 weeks in the placebo recipients’ scores. In large part, this probably represents a practice effect. (From Coyle J, Kershaw P: Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer’s disease. Biol Psychiatry 2001; 49: 289-299. Copyright 2001. Reprinted with permission from the Society of Biological Psychiatry.)

These considerations can considerably restrict test choice in assessment in these patients. The effects of culture are even more insidious. Even populations with a common language and broadly similar cultures, such as Americans and Australians, cannot always be directly compared. For example, the Boston Naming Test, a commonly used confrontational naming assessment instrument, contains pictures of a pretzel and a beaver. Older Australians, without experience of either, tend to call the first a snake and the second a platypus!

Reporting of Test Scores Once appropriate norms are identified, the test scores have to be reported in an intelligible manner. This is commonly done in terms of standard deviations from the mean for the appropriate normative sample, by using Z scores, T scores, or IQ scores. A Z score of −11/2 would indicate a score 11/2 standard

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deviations (SD) below average, whereas one of +2 would indicate a score 2 SD above average. T scores have the mean set at 50 and 1 SD set at 10. Hence, a T score of 70 is 2 SD above average. IQ scores have the mean set at 100, and 1 SD set at 15. Hence, an IQ score of 85 is 1 SD below average. Of course, reporting scores in terms of SD assumes that the measured variable is normally distributed in the population. This is not the case with, for example, the Boston Naming Test or the Rey Complex Figure Test copy, for which results from the normal population are positively skewed (see Mitrushina et al [2005]). Reporting by percentiles—the percentage of the normative population whose scores fall below that score level—avoids this difficulty: If a score is below the second percentile, it would indicate impairment, regardless of the distribution of test scores. On the other hand, for tests with a normal distribution of scores, reporting by percentiles does tend to overemphasize unimportant differences near the mean and underemphasize more extreme deviations. For example, the real difference between the first and the 10th percentile levels is likely to be much more important (and larger) than the real difference between the 41st and 50th percentiles. However, other tests have their own idiosyncratic scoring systems (e.g., MMSE: maximum score 30/30; ADAS-Cog: maximum score 0/70). Neuropsychologists also frequently report scores by bands with descriptive labels (such as superior, above average, borderline, etc.). The relationship between some of these various scoring methods for a test with normally distributed scores is shown in Figure 2–4.

Low average

Borderline impaired

Impaired

11/3 2.5␴

2.0␴

1.5␴

2nd

The concepts of sensitivity, specificity, and, more particularly for decision making, positive and negative predictive value and likelihood ratio are as important for neuropsychological tests as for any other form of diagnostic testing in medicine. Their definitions are provided in Table 2–2. The important effect of base rate (prevalence) on these values must also be remembered. For example, the base rate of Alzheimer’s disease in 75year-old patients with memory complaints is much higher than that in 45-year-olds worried that they are not staying on top of their jobs, so that poor performance on a brief verbal memory test has a much higher positive predictive value in the older population.

Cutoffs and Receiver Operating Characteristic Curves When a test cutoff point is set (as is often done for the MMSE or the Modified Mini-Mental State Examination, to distinguish demented from nondemented subjects), there is a trade-off between sensitivity and specificity. This may be formalized as a receiver operating characteristic (ROC) curve, on which sensitivity is plotted against 1 − specificity for each proposed cutoff point. The optimal cutoff point for the purpose (e.g., individual diagnosis, requiring high specificity, or community screening, requiring high sensitivity) can then be ascertained from this

High average

Average

2/3

1.0␴

10

20

M

0.5␴

Standard deviations

25th

30

40

50

60

1.0␴

75th

70

Very superior

Superior

11/3

2/3

0.5␴

9th

1

Decision Theory

1.5␴ 91st

80

2.0␴

2.5␴

98th

90

99

Percentiles

–2.5

–2.0

–1.5

–1.0

–0.5

M

0.5

1.0

1.5

2.0

2.5

55

60

65

70

75

137.5

Z-Score (SD)

25

30

35

40

45

50 T-Score

62.5

70

80

90

100

110

120

130

12

14

16

IQ Scores (WAIS III)

1

4

6

8

10 Subtest Scores (WAIS III)

■

Figure 2–4. The relationship between various ways of reporting test scores and the normal distribution. SD, standard deviation; WAIS III, Wechsler Adult Intelligent Scale–Third Edition. (Adapted from The Psychological Corporation. Methods of expressing test scores. Test Service Notebook, April 1955, No. 1 48. Reproduced with permission of publisher, Harcourt Assessment, Inc.)

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chapter 2 principles of neuropsychometric assessment 1.0

T A B L E 2–2. Definitions of Important Test Parameters

0.8

0.6 Sensitivity

a = true positive scores b = false positive scores c = false negative scores d = true negative scores Prevalence = (a + c)/(a + b + c + d) Sensitivity = a/(a + c) Specificity = d/(b + d) Positive predictive value = a/(a + b) Negative predictive value = d/(c + d) Likelihood ratio (positive) = posttest odds/pretest odds = sensitivity/{1 − specificity} = {a/(a + c)}/{1 − [d/(b + d)]}

27

0.4 AUC = 0.959, CSF-CBF index AUC = 0.850, CSF tau level

graph. For example, Monsch and colleagues (1995) used ROC analysis to determine that the optimal cutoff score for the MMSE in a geriatric outpatient service is 25/26.9 The utility of different measures of the same parameter can also be compared (e.g., see Fig. 2–5), or the effects of adding another test of the same parameter studied; the test or combination that has the greatest area under the ROC curve is the most accurate discriminator.

MEASURING DEFICITS AND CHANGES Methods of Establishing a Baseline Most patients have not previously undergone neuropsychological assessment when they are referred, and so there is no established personal baseline against which they can be compared when they are assessed. There are several approaches to this problem. Using demographically stratified norms (see section on Comparison with Appropriate Normative Data) is helpful, and there are even demographic formulas available in some countries, including the United States, to enable estimation of premorbid IQ.10 However, these still involve comparison with a group, which may not be completely appropriate for a given individual. A second approach is to estimate premorbid ability from performance on a cognitive task known to be (relatively) resistant to cognitive decline, such as semantic knowledge. The National Adult Reading Test (of pronunciation of irregularly spelled words)11 and its U.S. variants, as well as the vocabulary subtest of the Wechsler Adult Intelligence Scale and its successors, have been used for this purpose. A large variation between Z scores in different domains might suggest that the lower scores are the result of deterioration and that the higher scores (the patient’s best performance), qualified by all available qualitative information about the patient’s premorbid achievements and abilities, provide a reasonable estimate of the patient’s overall cognitive ability. For example, sometimes an individual’s occupational history is helpful: some otherwise normal older individuals may have difficulty copying a cube, but such difficulty in a former architect, draftsperson, or mathematics teacher would indeed be cause for concern. This best performance approach is discussed by Lezak and colleagues (2004, pp 97-99). The pitfalls in relying on the best test score in the absence of such further qualifying information have been illustrated by Mortensen and associates (1991).12

0.2

AUC = 0.871, CBF ratio in posterior cingulate AUC = 0.590, CBF ratio in temporoparietal region

0.0 0.0 ■

0.2

0.4 0.6 1 – specificity

0.8

1.0

Figure 2–5. Receiver operating characteristic curves of the power of four diagnostic indexes to discriminate between patients with mild cognitive impairment that did (in 22 patients) or did not (in 8 patients) progress to Alzheimer’s disease. AUC, area under the curve; CBF, cerebral blood flow; CSF, cerebrospinal fluid. (From Okamura N, Arai H, Maruyama M, et al: Combined analysis of CSF tau levels and [(123)I]iodoamphetamine SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimer’s disease. Am J Psychiatry 2002; 159:474-476. Reprinted with permission from the American Journal of Psychiatry. Copyright 2002 American Psychiatric Association.)

Measuring Change Sometimes, despite the previously mentioned inferential methods for obtaining a baseline, there is still doubt as to whether deterioration has occurred. Repeated assessments can help to identify progressive deterioration in such circumstances, even if there was uncertainty about score interpretation at the initial assessment. However, this raises the question of how true deterioration can be distinguished from random fluctuations in test scores. One simple way of determining whether a change in test score is significant is the standard deviation method, in which it is assumed that any score change of more than 1 SD is significant. Although this often does reveal truly significant changes, it is less accurate in doing so than are a number of more sophisticated methods.13 In part, this potential inaccuracy arises from the random error component of the actual test scores themselves. Even if a test does not display practice effects, or if truly parallel (alternative) forms are available, only part of a patient’s actual test score consists of the true score, whereas part consists of random variability. The reliability coefficient (rxx) of a test is a measure of the proportion of the total variance of a test score that results from variance in the true score. If a subject took such a test multiple times, the average score would approximate the true score. The extent to which a single observed total score represents that patient’s true score can be estimated with the standard error of measurement (SEM), which increases as the total test variance (σx) increases and

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decreases as the reliability coefficient (rxx) increases (indicating a decrease in that portion of the total variance due— to— random variance), according to the formula SEM − σx √1 − rxx . This means that confidence intervals (e.g., 95%) can be placed on an individual score, or two scores obtained on separate occasions can be compared to determine whether they are likely to represent a true change. Reliable change indices (RCIs), calculated from data on normal subjects or—better—from populations containing individuals identified as undergoing significant change according to an external “gold standard” (e.g., reaching criterion for diagnosis of dementia) have been devised that account for measurement error, practice effects, and regression to the mean.13 Regression equation-based measures have also been developed.13 Overall, these perform more satisfactorily, although none is ideal.

STRATEGIES IN NEUROPSYCHOLOGICAL ASSESSMENT Neuropsychological assessment would be extremely protracted and exhausting (and thereby inaccurate) for both tester and patient, not to mention prohibitively expensive, if all domains were assessed in all possible detail. Some strategy for keeping time and costs to acceptable levels is therefore required. One possibility is to use a standard battery, such as the HalsteadReitan or Luria-Nebraska battery.14,15 The difficulty with this approach is that testing may occupy several hours, but the particular referral problems are still insufficiently clarified at the end. Another approach is hypothesis driven, on the basis of referral details and the history from the patient. This makes intrinsic sense to physicians: a patient complaining of diplopia and unsteadiness of gait will rightly be given a more thorough neurological examination than will a patient complaining of dyspnea, pleuritic chest pain, and productive cough. Many assessors use a combination of screening tests across the range of cognitive domains, concentrating on those that seem most relevant (e.g., episodic memory in Alzheimer’s disease). This flexible approach may be modified in midsession: As pointed out in the Cognitive Domains and Neuropsychological Tests section, an abnormal performance may well have a number of possible causes, each of which must then be assessed. Often, the Wechsler Adult Intelligence Scale–Third Edition and the Wechsler Memory Scale–Third Edition, or a selection of items from these, are used for screening. Although the Wechsler Adult Intelligence Scale was designed to assess the range of abilities in the normal population rather than to investigate patients with particular cognitive deficits, test administration is very well standardized, and the normative data are extensive (although not stratified by educational level); therefore, these tests are an attractive option for this purpose. Their merits and pitfalls are discussed by Lezak and colleagues (2004, pp 648-660). Some multidomain bedside screening mental status tests used by nonneuropsychologists, such as the Mattis Dementia Rating Scale16 and the Cognistat (formerly called the Neurobehavioral Cognitive State Examination),17 are designed on a “tripwire” (“screen + metric”) basis, with a challenging item given first and, only if the screening item is failed, easier ones then given to establish the degree of impairment in that domain. This approach can save time for both examiner and patient.

Computerized versions of some individual tests are in widespread use (e.g., the Continuous Performance Test and the Wisconsin Card Sorting Test). In view of the duration and expense of neuropsychological assessment, however, it is not surprising that attempts have been made to computerize the entire testing process. An example is the Cambridge Neuropsychological Test Automated Battery.18 The drawbacks of this approach, however, include not only the loss of flexibility, and therefore the ability to perform hypothesis-generated testing, but also the loss of the potentially very valuable information derived from consideration of referral details, the history from patient and informant, and observation during the test procedure. Consideration of all these features by a trained practitioner is the basis of neuropsychological assessment, as distinct from the more limited neuropsychological testing. An experienced neuropsychologist is able to detect evidence of impulsivity, poor or fluctuating attention, poor planning, and so forth. These observations are particularly important when assessing patients with the dysexecutive syndrome (see Chapter 7: Executive Function and its Assessment), in whom the manner of test performance is often more revealing than the result. Furthermore, anxiety, fatigue, and depression adversely affect performance on many neuropsychological tests; detection of and allowance for or minimization of these process factors are important parts of the neuropsychologist-patient interaction. In interpreting neuropsychological test results, as with any other collection of test results, the neuropsychologist must remember that if abnormality is defined statistically, and if enough tests are performed, some are expected to yield “abnormal” results by chance. Formal adjustment of the statistical threshold of abnormality (a Bonferroni correction) is possible but cannot be applied blindly in a situation in which the tests are not necessarily fully independent. Conversely, even mild abnormalities on several different measures of a particular domain greatly increase the likelihood that function is impaired in that domain. The corollary is that reliance on a single test to define abnormality within a domain is unsound.

OPTIMAL USE OF NEUROPSYCHOLOGY In earlier years in the field of neuropsychology, much effort was devoted to separating “organic” from “nonorganic” causes of deficit. With the enormous advances in neuroimaging since the 1970s, the emphasis has shifted somewhat. Neuropsychology is supremely useful for determining whether a patient is impaired in a particular domain or domains (e.g., “Does my HIV [human immunodeficiency virus]–positive patient have early features of AIDS [acquired immunodeficiency syndrome]–dementia complex?”). It may identify mild impairments in the absence of obvious neuroimaging changes (e.g., after traumatic brain injury or in some patients with mild cognitive impairment). It is also useful for determining the pattern of involvement across cognitive domains. The latter information can suggest particular diagnoses or refine the differential diagnosis (e.g., “This pattern of deficits is most consistent with semantic dementia”), and can also suggest likely problem areas—and, as important, areas of retained strength—that can be used to inform rehabilitation and compensatory strategies. Although neuropsychological tests are typically not tests of decision-making capacity per se, useful inferences regarding the possible or likely presence of problems in this area can be

chapter 2 principles of neuropsychometric assessment drawn. Neuropsychological assessment can be employed preoperatively (e.g., for epilepsy or tumor surgery) to document the extent of cognitive problems and again postoperatively to determine whether worsening (or new deficits) have resulted from the procedure. Serial assessments can be performed to monitor the progression of a condition (e.g., mild cognitive impairment) or the effectiveness of treatment (e.g., central nervous system vasculitis). Lastly, through variations of symptom validity testing, and by studying the pattern of failures on easier versus harder tasks, conscious or unconscious simulation of deficit can be detected. For a neuropsychology referral to yield the most useful information, the right question must be asked, accompanied by the appropriate background information. A note such as “?Dementia—please do the needful” is hardly adequate! The relevant symptoms with their duration, a list of past medical and psychiatric problems (especially substance abuse, anxiety, depression, and sleep apnea), and a full list of current medications are required. The neuropsychologist starts by taking an extensive history, but ready availability of documented background information saves time and false starts.

SUMMARY Psychometric testing, as a component of neuropsychological assessment, is a rigorous, scientifically based discipline. For results to be valid and useful, however, the most suitable tests and normative data must be selected. Administration by experienced clinicians trained to note qualitative as well as quantitative abnormalities, and to detect interference from process factors, contributes greatly to the value of such testing. Resources are often scarce, but careful selection of patients for referral and proper referral information ensures their optimal use.

K E Y

P O I N T S

●

Neuropsychological assessment involves consideration of referral information, history from the patient and (if possible) informant, observed personality, behavioral and emotional features, and quantitative and qualitative aspects of neuropsychological testing.

●

As with any test, neuropsychological tests must be reliable; that is, random variability must be low. This requirement underlines the importance of training and standardization in test administration.

●

Neuropsychological tests must also be valid; that is, they must actually measure what they are purported to measure.

●

Appropriate normative data are an essential prerequisite for test interpretation. Correction for the effects of demographic variables (e.g., age, education) is often necessary. Translation of tests across languages or cultures is potentially problematic.

●

Although individual tests are often considered as measures of one cognitive domain, poor performance on almost all tests in current routine clinical practice can occur for

29

multiple reasons. Conversely, poor performance on multiple tests of a single domain increases the reliability of a judgment that there is impairment within that domain. ●

Neuropsychological assessment is particularly useful in detecting mild cognitive changes in the absence of obvious neuroimaging abnormalities or other neurological features and in determining whether these are likely to have an organic basis, in the differential diagnosis (based on the pattern of deficits) of conditions causing cognitive impairment, in identifying cognitive strengths and weaknesses to guide rehabilitation and compensatory strategies, in providing inferential information on competency and employability issues, and in following changes in cognition as a result of disease or its treatment.

Suggested Reading Halligan PW, Kischka U, Marshall JC. Handbook of Clinical Neuropsychology. Oxford, UK: Oxford University Press, 2003. Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment, 4th ed. New York: Oxford University Press, 2004. Mitrushina M, Boone KB, Razani J, et al. Handbook of Normative Data for Neuropsychological Assessment, 2nd ed. New York: Oxford University Press, 2005. Murphy KR, Davidshofer CO. Psychological Testing: Principles and Applications, 6th ed. Englewood Cliffs, NJ: Prentice Hall, 2004. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary, 2nd ed. New York: Oxford University Press, 1998.

References 1. Mesulam MM: From sensation to cognition. Brain 1998; 121:1013-1052. 2. Crowe SF: Neuropsychological Effects of the Psychiatric Disorders. Amsterdam: Harwood Press, 1998, p 11. 3. Groth-Marnat G: Neuropsychological Assessment in Clinical Practice. New York: John Wiley & Sons, 2000, p 95. 4. Whelihan WM, DiCarlo M, Paul RH: The relationship of neuropsychological functioning to driving competence in older persons with early cognitive decline. Arch Clin Neuropsychol 2005; 20:217-228. 5. Doty RL, Shaman P, Kimmelman CP, et al: University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984; 94:176-178. 6. Rodgers R, ed: Clinical Assessment of Malingering and Deception, 2nd ed. New York: Guilford Press, 1997. 7. Crawford JR, Steward LE, Moore JW: Demonstration of savings on the AVLT and development of a parallel form. J Clin Exp Neuropsychol 1989; 11:975-981. 8. Ferraro FR, ed: Minority and Cross-Cultural Aspects of Neuropsychological Assessment. Studies on Neuropsychology, Development, and Cognition. Lisse, The Netherlands: Swets and Zeitlinger, 2002. 9. Monsch AU, Fold NS, Ermini-Fünfschilling DE, et al: Improving the diagnostic accuracy of the Mini-Mental State Examination. Acta Neurol Scand 1995; 92:145-150. 10. Barona A, Chastain R: An improved estimate of premorbid IQ for blacks and whites on the WAIS-R. Int J Clin Neuropsychol 1986; 8:169-173.

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11. Nelson HE, Willison JR: The National Adult Reading Test (NART): Test Manual, 2nd ed. Windsor, UK: NEFR Nelson, 1991. 12. Mortensen EL, Gade A, Reinisch JM: “Best Performance Method” in clinical neuropsychology. J Clin Exp Neuropsychol 1991; 13:361-371. 13. Frerichs RJ, Tuokko HA: A comparison of methods for measuring cognitive change in older adults. Arch Clin Neuropsychol 2005; 20:321-333. 14. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Applications, 2nd ed. Tucson: Neuropsychology Press, 1993.

15. Golden CJ, Purisch AD, Hammeke TA: Luria-Nebraska Neuropsychological Battery: Forms I and II. Los Angeles: Western Psychological Press, 1991. 16. Mattis S: Dementia Rating Scale (DRS). Odessa, FL: Psychological Assessment Resources, 1988. 17. Kiernan RJ, Mueller J, Langston JW: Cognistat (Neurobehavioral Cognitive Status Examination). Lutz, FL: Psychological Assessment Resources, 1995. 18. Robbins TW, James M, Owen AM, et al: Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 1994; 5:266-281.

CHAPTER

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LANGUAGE ●

Michael M. Saling

There are two main schools of thought in the history of neurogenic language disorders, both of which have relevance to modern aphasiology. The first, the Wernicke-LichtheimGeschwind tradition, emphasized that primary language functions are represented in discrete regions of cortex (“centers”) and that the activities of these loci are integrated through connecting fiber tracts. The Wernicke-Lichtheim scheme consisted of a center for motor images of words, located in the posterior third of the inferior frontal convolution (Broca’s area), as well as a center for acoustic images of words (Wernicke’s area). A fiber tract (arcuate fasciculus) joined the two centers, with the flow of information running from posterior to anterior. A third center for concepts was located in the extrasylvian cortex, with an outflow to Broca’s area and input from Wernicke’s area. There was an output from Broca’s area to the motor cortex and an input to Wernicke’s area from the auditory cortex. This simple scheme systematized the main perisylvian and transcortical aphasia syndromes observed before 1885 and predicted the existence of a syndrome as yet unobserved at that time: conduction aphasia. The WernickeLichtheim model was later refined by members of the Boston School, principally Frank Benson and Norman Geschwind, with the addition of three new syndromes, and the inclusion of the inferior parietal lobule as language cortex (see Benson and Ardila, 1996). The second main stream is represented by neurologists such as Hughlings Jackson, Sigmund Freud, and Aleksandr Luria who conceived of language as represented in broader hierarchical cortical zones or gradients, organized around the centers of the Wernicke-Lichtheim model. The role of connecting tracts was deemphasized. Luria’s aphasiology preserves the anteroposterior schema of the Wernicke-Lichtheim model but redefines localization of language as hierarchical and distributed. Modern clinical aphasiology is based on the classical syndromes described in the Wernicke-Lichtheim tradition and their modifications. Concepts of their localization, however, have come to be shaped further by ongoing clinicopathological observation and functional neuroimaging, and current views on the localization of language are not too distant from those of the Jackson-Freud-Luria tradition. Linguistic ideas have also become part and parcel of modern aphasiology. A glossary of important linguistic terms and concepts is given in Table 3–1.

LANGUAGE PRODUCTION At a clinical level, language disorders are more easily recognized and identified in language production, either spoken or written, than in disturbances of comprehension. Production consists of three broad stages: conceptualization, formulation, and overt execution. The first two of these stages are described in detail in the following sections. From a neuroanatomical perspective, conceptualization (the development of an intention to speak, and a decision about what will be said) depends on the dorsolateral prefrontal cortex. Formulation (the conversion of ideas into the structure of spoken language) depends on Broca’s region. Execution is the production of physical speech and depends on all of the motor mechanisms associated with speech (see Duffy, 2005).

Conceptualization This is a largely prelinguistic phase that involves the development of an intention to speak and a decision as to what will be said. Development of an intention and a decision about the message to be conveyed is often referred to as macroplanning. From that point on, the message must be reshaped into a particular set of logical relationships (propositions) that can be expressed in terms of the syntactic and semantic structure of language. This is often referred to as microplanning. Propositions form a link between thought and its expression in language. It is noteworthy that this concept was anticipated by the British neurologist Hughlings Jackson, who regarded it as essential for understanding the relationship between thought and speech in aphasia. Conceptualization depends on connectivity between extrasylvian association cortex and the classical perisylvian language axis, a concept borne out by functional neuroimaging (see Blank, Scott, Murphy, et al, 2002).

Formulation This phase deals with the conversion of propositions into actual sentences (sentence encoding). It is governed directly by the rules of syntax and semantics and consists of two important components. The first involves the selection of appropriate open class of lexical items (see Table 3–1) to convey the

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T A B L E 3–1. Essential Linguistics Concepts Phonological

Lexical

Morphological

Phonology is the study of the structure and patterning of the sounds of language. Many of the clinical features of language disorders are phonological. The units of analysis are phonemes, which can be defined as the basic meaningdistinguishing sounds (essentially consonant and vowel sounds) of the language. Whereas phonology is concerned with the patterning of sounds within a word, and is therefore a sublexical discipline, lexicology is concerned with the whole word as a single entity. At a lexical level, there is a dichotomy that is fundamental to the understanding of aphasic disorders, because aphasic variants affect the two classes of words differentially. The open class, so-called because it is conceptually unlimited and new items are steadily added as vocabularies increase, consists principally of nouns, verbs, adverbs, and adjectives—that is, words that refer to specific objects, actions, and attributes and that convey substantive content. The closed class, which is conceptually limited and does not increase in size as vocabularies increase, consists of articles (e.g., “a,” “the,” “that”), conjunctions (e.g., “and,” “but”), pronouns (e.g., “you,” “they”), and prepositions (e.g., “up,” “along,” “below”). The distinction between open- and closed-class words parallels the distinction between the meaning of a sentence (semantics) and the form or sequential structure of a sentence (syntax). Morphology concerns the internal structure of words. The aspect of morphology that is most important for understanding language disturbances is word formation, or the construction of a new word from an existing word by adding an affix. This can be derivational, whereby an adjective such as “good” is converted to a noun such as “goodness,” or inflectional, whereby a word is changed to suit the grammar of a sentence; for example, “run” might become “running,” or “pencil” might become “pencils.” Because the suffixes “-ing” and “-s” cannot stand alone, they are referred to as bound morphemes.

intended meaning. The linguistic concept of selection is of central importance in aphasic disorders. Selection implies the possibility of choice among alternatives, and errors in selection manifest clinically as paraphasias. A paraphasia has two essential features: (1) It is an error of selection resulting in the substitution of a word or part of a word with a frequently incorrect or inappropriate alternative, and (2) it is unintended. Selection processes occur at the phonemic and the semantic levels (see Table 3–1). In neuroanatomical terms, selection processes are heavily, but not exclusively, dependent on posterior perisylvian association cortices. The second component of formulation involves the genesis of correctly ordered positional slots into which the words of the sentence are inserted. These sequentially ordered schemas are often called sentence frames, and their construction is contributed to and defined by closed class (function) words and bound morphemes (see Table 3–1) Sentence frames are constructed according to the rules of syntax (see Table 3–1). The functional neuroanatomy of syntactic processing is complex, involving a network of left perisylvian structures, and it appears that Broca’s area is a key nodal structure within this network. Disorders of syntax, including Broca’s

T A B L E 3–2. The Fluent-Nonfluent Distinction

Anatomical Fundamental disorder Syndrome

Nonfluent Production

Fluent Production

Anterior (prerolandic) language areas Sequential organization (conceptualization, formulation) Perisylvian Aphemia Broca’s aphasia Extrasylvian Transcortical motor aphasia

Posterior (postrolandic) language areas Selection Perisylvian Pure word deafness Wernicke’s aphasia Conduction aphasia Extrasylvian Transcortical sensory aphasia Anomic aphasia

Note: Mixed transcortical aphasia and global aphasia are associated with clinically nonfluent production but also involve an underlying selection disorder.

aphasia, occur most prominently with lesions involving the anterior aspects of the perisylvian language zone.

Fluency The division of language disturbances into fluent and nonfluent is the most fundamental and clinically appreciable dichotomy in diagnostic aphasiology. The major aphasia syndromes are encompassed within the distinction of fluent versus nonfluent (see Table 3–2). Fluent language output in an aphasic patient is defined by the use of sentences that are syntactically intact but are semantically compromised because of a selection disorder. The following example, taken from a description of a severe form of fluent dysphasia, namely jargonaphasia (a variant of Wernicke’s aphasia), illustrates this point:1 “This guy has got to this thing, this thing made out in order to slash immediately to all of the windpails. . . . This is going right over me from there, that’s up to is 5 station stuff from manatime, and with that put it all in and build it all up so it will all be spent with him conversing his condessing.” The sequential relationships between grammatical entities in the passage are preserved. It is the closed class entities that are primarily affected by errors in selection, resulting in phrases that are devoid of meaning, and jargonistic substitutions (neologistic paraphasias) such as “manatime,” and “condessing.” Prosodic features are characteristically retained. Prosodic features are rhythmic and emphatic aspects of language production that allow the listener to appreciate whether the speaker is, for example, asking a question or making a statement. Nonfluent aphasic output, in contrast, is characterized by a dissolution of syntactic structure; in particular, the production of closed class words is affected. The following are examples of nonfluent language: 1. A soldier talking about a bullet wound to his head on the battlefront: “Well . . . well . . . front . . . well . . . advance . . . well . . . bullet . . . well . . . nothing much . . . hospital . . . operation . . . well . . . speech . . . speech . . . speech. . . .”2

chapter 3 disorders of language 2. In response to the question “Have you played no games?”: “Played games, yes, played one, daytime, garden.”3 3. Explaining a readmission to hospital: “Ah . . . Monday . . . ah, Dad and Paul and Dad . . . hospital. Two . . . ah, doctors . . . and ah . . . thirty minutes.”4 In contrast to the fluent output, these utterances are devoid of syntactic structure, exemplified by the lack of closed class words, and the relative excess of open class words. This pattern constitutes agrammatism. Nevertheless, there is appropriate selection of open class words (nouns and verbs), and as a consequence nonfluent output does not entirely have the “empty” character of fluent output. The length of phrases is heavily reduced in agrammatic disorders.

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Unintended substitutions also occur in writing (paragraphias). Like paraphasias, they can be literal or they can involve semantic substitutions (see Table 3–3).

Circumlocutions Circumlocutions are compensatory phenomena, produced in response to a word retrieval failure. Patients with fluent aphasias, particularly anomic aphasia, use an expanded expression or phrase as a substitute for the intended word. For example, “eyelashes” may be expressed as “eye butterflies,” or “skiing” as “walking on water.” Circumlocutory language produces a rambling, wordy quality to the patient’s conversation.

Empty Speech Paraphasia and Other Deviations Paraphasias Paraphasias are defined as unintended utterances. In essence, there is a failure of selection at the phonemic level, producing a phonemic (literal) paraphasia (e.g., “I drove home in my lar”) or at a word (lexical) level (e.g., “I drove home in my wagon”), producing a verbal paraphasia (Table 3–3). Paraphasias are said to be neologistic when the unintended word is heavily contaminated with extraneous phonemes and, as a result, contains juxtapositions of sublexical fragments that are not characteristic of the language (phonemic neologisms) and are nonsensical in context. For example:5 EXAMINER: Are you feeling better than this morning? PATIENT: Not too melsise, I don’t think. EXAMINER: Pardon me? PATIENT: I motsumsirs, orie. Morphemic neologisms occur when valid morphemes are assembled in a manner that does not produce an acceptable word (e.g., “man-a-time”).

T A B L E 3–3. Paraphasias and Other Selection Errors Type

Examples

Phonemic (literal)

“glear” instead of “clear” “spink” instead of “sphinx” “gedrees” instead of “degrees” “tums” instead of “tongs” “trep”→“tretz”→“fretful”→“pretzel”

Conduit d’approche (successive phonemic approximations to a target word) Verbal Formal (similar form, different meaning) Morphemic (assembled from legal morphemes) Semantic (substituted word belongs to the same general category) Circumlocutions (word substituted with a phrase of the same meaning)

“dare” instead of “pear” “man-a-time,”* “summer-ly” “train” instead of “car” “Taj Mahal” instead of “pyramid” “cloth” instead of “blanket” “seahorse” instead of “unicorn” “drinking container” instead of “cup”

*Morphemic assemblies that do not produce acceptable words are called neologisms.

When lengthy sentences with very few open class (substantive) words are produced, the output is devoid of content and is referred to as “empty.” For example: “Well you know . . . that thing . . . that thing we were going to do . . . well, okay, then. . . . and that’s it.”

Paragrammatism Paragrammatism consists of errors in grammatical usage, such as unusual word order or juxtaposition of function words. It is observed in fluent aphasias and is not to be confused with agrammatism (described previously), which occurs in nonfluent aphasia. For example: “I couldn’t is that where I went.”

APHASIA SYNDROMES Contrary to earlier views, more recent tractography findings indicate that the arcuate fasciculus consists of two components. The first is a direct tract connecting the posterior segments of the inferior and middle temporal gyri with Broca’s area (Brodmann’s areas 44 and 45), as well as with parts of the middle frontal gyrus and inferior precentral gyrus. The second component is an indirect tract with anterior and posterior segments. The posterior segment connects Wernicke’s area with the inferior parietal lobule (Brodmann’s areas 39 and 40), whereas the anterior segment connects the inferior parietal lobule with frontal language cortex (see Catani et al, 2005). Structures connected by the arcuate fasciculus are somewhat more extensive than classical views suggested, and this broader concept of the perisylvian region accommodates the clinicopathological studies of fundamental language disorders since the 1950s more successfully. Furthermore, it suggests that the arcuate fasciculus might be important in uniting perisylvian and extrasylvian language regions. Aphasias caused by anterior (prerolandic) lesions are associated with nonfluent language production, whereas those caused by posterior lesions (postrolandic) are associated with fluent disorders. There are two major nonfluent aphasias: Broca’s aphasia, in which repetition is disturbed, and transcortical motor aphasia (TMA), in which repetition is normal. The fluent aphasias are Wernicke’s and conduction aphasias, in which repetition is disturbed, and anomic and transcortical sensory aphasias (TSA), in which repetition is preserved (Table 3–4) (see LaPointe, 2005). In addition, there are two aphasias in which the dysfluency typical of anterior dysphasias is combined with the impaired comprehension typical of posterior dysphasias: global aphasia and mixed transcortical aphasia.

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T A B L E 3–4. Classification of Aphasia by Fluency and Comprehension Impaired Repetition

Normal Repetition

Nonfluent Broca’s* Global†

Transcortical motor Mixed transcortical

Fluent Conduction* Wernicke’s†

Anomic Transcortical sensory

*Comprehension preserved. † Comprehension impaired.

Nonfluent Production with Impaired Repetition: Speech Dyspraxia and Broca’s Aphasia Speech Dyspraxia (Aphemia) The syndrome of speech dyspraxia occurs quite separately from the other anterior aphasias. There is, however, a widely recognized dictum in aphasiology that lesions restricted to Broca’s area do not necessarily cause Broca’s aphasia. Embolic infarctions of Brodmann’s areas 44 and 45, often involving subjacent white matter and extension into the anterior insula, cause a wide spectrum of acute effects ranging from subtle hesitancy to mutism. Recovery is rapid—within days, weeks, or months— and in some cases, minimal residual dysfluency may be the only detectable language feature. Dyspraxia of facial, oropharyngeal, lingual, and respiratory functions is an associated feature that might persist beyond the resolution of language deficits, manifesting, in many cases, with some features reminiscent of the syndrome of speech dyspraxia. The chronic picture is “deficits in the smoothness with which vocalization of one phoneme in a series can be ceased and changed to the next, in precise control of the respiratory component of vocalization, and/or in precise positioning of the oral cavity to produce desired phonemes . . . better explained by inadequacy in skilled execution of movements, an apraxia in speaking . . . but not an associated disorder in language usage.”6 This resembles Luria’s idea of efferent motor aphasia, in which the primary disorder relates to skilled sequential movements or kinetic melodies in which the patient is able to position the articulators correctly but is not capable of moving smoothly from one articulatory position to the next.7 Originally, Pierre Paul Broca used the term aphemia to refer to this condition. There appears to be a revival in the use of this term in relation to progressive speech disturbances. Michael Alexander’s group at Boston University has taken the view that aphemia is a distinctive syndrome arising from small lesions in the left inferior frontal gyrus (pars opercularis), inferior precentral gyrus, and underlying white matter.8 The main features of speech dyspraxia are shown in Table 3–5.

Functional neuroanatomy of speech dyspraxia It is now recognized that articulatory function depends on a hierarchically organized network of structures involving cerebellum, thalamus, striatum, anterior insula, and sensorimotor cortex. Current concepts of Broca’s area, particularly the

T A B L E 3–5. Main Features of Speech Dyspraxia (Aphemia) Effortful articulatory approximations and attempts at self-correction Dysprosody Articulatory inconsistency Difficulty initiating speech, sometimes with unproductive articulatory groping Often preserved articulation of automatic speech Preserved syntax and semantics

posterior portion (Brodmann’s area 44) abutting on the precentral sulcus (Brodmann’s area 6), include the view that it mediates the encoding of phonological word forms into articulatory plans. This places it at the apex of the articulatory hierarchy. Broca’s area also shows increased activity during syntactic processing, although lesions restricted to this area cause impairments in speaking rather than language,6 a view dramatically foreshadowed by the neurologist Pierre Marie in 1906 with a paper titled “The Third Frontal Convolution Does Not Play Any Special Role in the Function of Language” (see Harrington). Functional neuroimaging findings have raised the possibility that Broca’s area represents a bridge between articulation and language production.

The Syndrome of Broca’s Aphasia The term Broca’s aphasia is applied to a syndrome that occurs after more extensive infarction in the territory of the superior division of the middle cerebral artery. A core clinical feature is the production of sentences that lack syntactic structure. In its milder forms, affected patients produce simplified phrase structures, with a loss of the prosodic (melodic) aspects of speech. In its more severe forms, speech becomes telegraphic with strikingly effortful articulation. The effort involved in articulation results in highly economical phrases, usually restricted to nouns and verbs (e.g., “money. . . . send”). Loss of fluency in Broca’s syndrome is the combined effect of an impairment at the linguistic level (agrammatism) and an impairment of articulatory programming (speech dyspraxia). Agrammatism, or a dissolution of grammatical form, is characterized by greatly reduced use of open class words (articles, conjunctions, prepositions) and of morphemic structure (affixes), with relative preservation of words that convey substantive content (open class words such as nouns and verbs). The writing disturbance in Broca’s aphasia parallels spoken language in that it is sparse, effortful, clumsy, agrammatic, and paragraphic. Repetition is impaired and reflects essentially the same pattern of nonfluency as is that in spontaneous language. Written language is also agrammatic, with graphemic and graphomotor errors. Comprehension in Broca’s aphasia is not unscathed, but it nevertheless serves the patient comparatively well in daily life, and comprehension deficits are not a particularly noticeable feature of the clinical encounter. Some authorities have argued that there is a unitary impairment that produces both expressive agrammatism and syntactic comprehension deficits. There are cases, however, in which expressive agrammatism and comprehension dissociate, which suggests that there are separate mechanisms for elaborating syntactic form in language production and for appreciating syntactic

chapter 3 disorders of language form in heard or read language and that these mechanisms can be separately impaired. Gesture and communicative pragmatics (i.e., all of the nonverbal behaviors that accompany language appropriate the communicative context) are usually preserved. The syndrome of Broca’s aphasia can be observed as a later consequence of infarction. The initial clinical picture resembles a global aphasia. After weeks or months, there is a gradual emergence of the dyspraxic and agrammatic features, and these evolve slowly toward the long-standing features of the syndrome of Broca’s aphasia (see Mohr,6 page 230).

Functional neuroanatomy of Broca’s aphasia Broca’s aphasia is typically produced by fairly large lesions in the territory of the superior division of the left middle cerebral artery. Right hemiparesis, particularly involving the face and arm, is typically present as a neighborhood sign. Broca’s area, the anterior insula, and the basal ganglia are often all damaged, and the lesion usually also includes the middle frontal gyrus and the anterior parietal lobe. Involvement of Broca’s area alone is not a sufficient condition for the emergence of the syndrome of Broca’s aphasia. Neuroimaging findings have suggested that damage to Broca’s area impairs the production of all forms of speech (propositional and nonpropositional; see Blank et al, 2002). Propositional speech refers to newly formulated language output that conveys an idea, as opposed to nonpropositional speech, which is more automatic in nature and conveys nonideational content such as feeling states. At a clinical level, it is well accepted that propositional speech is most severely affected and that automatic nonpropositional aspects of speech are often preserved. Grammatical output depends on the interaction between Broca’s area and other cortical regions. Functional neuroimaging in normal subjects demonstrates that the middle frontal gyrus is commonly activated by language tasks that activate Broca’s area, which suggests that this region should also be included in a language production network (see Blank et al., 2002). Tractography of the arcuate fasciculus suggest that this pathway terminates in the middle frontal and inferior precentral gyri (Fig. 3–1), as well as in classically defined Broca’s area (see Catani et al., 2005).

Anterior segment

Geschwind's territory

Broca's territory

Posterior segment Long segment

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Nonfluent Production with Normal Repetition: Transcortical Motor Aphasia Like all actions, language output, whether in the form of speech or writing, must be planned. Planning is a complex and multilevel process, ranging from the intention to produce propositional output (conceptualization) to the specification of appropriate syntactic structure and semantic forms (formulation) and then to the specification of phonology and articulatory patterns (overt execution). Cognitive capacity for planning is limited and dependent on normal frontal lobe function. The cardinal clinical manifestations of TMA can be conceptualized as a pathological disruption in planning of language output.

The Syndrome of Transcortical Motor Aphasia TMA is a nonfluent aphasia. The quantity and complexity of speech and of written output are reduced, but repetition, writing in response to dictation, reading, confrontation naming, and comprehension are well preserved. This pattern reflects the notion that TMA is a disorder of spontaneous, selfinitiated language output, with facilitation of output when external supports are provided. There is general agreement that there are two variants of TMA.10 The first often manifests initially as mutism, which resolves to poorly initiated and nonfluent output, characterized more by an articulatory disturbance than by a language disturbance. Output is normal during repetition. Comprehension and naming are also well preserved. There is some debate as to whether this form of TMA is a true aphasia. It occurs with infarcts in the territory of the left anterior cerebral artery, particularly with involvement of the supplementary motor area. It also occurs after resection of the left supplementary motor area. This variant of TMA has been ascribed to isolation of the supplementary motor area from frontal perisylvian language mechanisms. In this view, isolation of the supplementary motor area results in impaired motor programming before the overt execution of language output.11 The second variant of TMA is characterized by very sparse language production, which gives the impression of a reduced intention or motivation to speak. What speech is produced is well articulated but with impoverished syntax and narrative. Nevertheless, repetition is normal, even for long and complex sentences. Although patients with this form of TMA do not initiate routine series (e.g., naming the months of the year, nursery rhymes) on request, they freely complete the series after the examiner has provided the first few elements. Similarly, they are able to fill in sentence frames provided by the examiner (e.g., and the sun is ”). Luria “the day is referred to this condition as dynamic aphasia.7 He believed that the underlying impairment was an inability to elaborate the linear scheme of sentences or, in current terms, an inability to elaborate propositions. Luria’s description of the production difficulties of this group of patients is instructive:12 “As a rule, these patients answer simple questions relatively easily, frequently prefacing their reply with an echolalic*

Wernicke's territory ■

Figure 3–1. Terminations of the arcuate fasciculus suggested by tractography. (From Catani M, Jones DK, Ffytche DH: Perisylvian language networks of the human brain. Ann Neurol 2005; 57:8-16, Fig. 3. Copyright © 2006 Wiley-Liss, Inc., A Wiley Company. Reprinted with permission of John Wiley & Sons, Inc.)

*Echolalia is the patient’s tendency to echo what the examiner says but to change the grammar to suit himself or herself. For example, in response to the examiner’s question “How are you feeling?” the patient may reply, “How am I feeling?” Logoclonia is the tendency to repeat the final syllable of a word. For example, “telephone . . . phone . . . phone.”

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repetition of the question, but they have difficulty as soon as they are asked to read a text and relate it to the examiner, or to compose a story from a picture given to them, and they are completely helpless if they have to write an essay on any freely chosen subject. In these cases they state that their thoughts will not move, that nothing enters their head, and they usually abandon the task or do nothing more than reproduce some habitual verbal stereotype, usually taken from their past experience.” The dynamic variant of TMA occurs with damage to the left frontal cortex anterior or superior to Broca’s area, involving the middle or superior frontal gyrus or both.

Fluent Production with Impaired Repetition and Comprehension: Wernicke’s Aphasia and Pure Word Deafness The Syndrome of Wernicke’s Aphasia The disturbance associated with Karl Wernicke’s name is perhaps the prototypic fluent aphasia. Nevertheless, disagreements about the exact features of Wernicke’s aphasia continue, and it should be recognized that there are a number of variants, which range from a lexical agnosia (pure word deafness) to jargonaphasia. From a diagnostic perspective, this condition is sometimes confused with psychiatric disturbances or even delirium in a busy emergency room. The following is a list of core features accepted in current practice: ■ Output is fluent, often empty of substantive meaning, with ■

■

■

■

an excess of closed class words and circumlocutions. Paraphasias are common. These may be phonemic (literal) or semantic, but the former is held to be the most frequent type. Paraphasias may be so severe that jargon is produced (jargonaphasia). Similar output features are seen in writing, which, however, displays preserved penmanship. Patients appear to be unaware of or unconcerned about their highly disturbed and often nonsensical output, in contrast to the frustration shown by those with Broca’s aphasia. Comprehension is severely impaired, predominantly because of a difficulty in discriminating between phonemes. The profundity of the comprehension impairment makes this the most disabling feature of Wernicke’s aphasia. As a consequence of the comprehension difficulty, output during attempts at conversation is seldom related to the conversational context. Some patients respond on the basis of incidental nonlinguistic cues. Repetition of words and sentences is impaired.

The following is an example of the fluent output disorder of a patient with severe Wernicke’s aphasia, illustrating runs of paragrammatism:13 I feel very well. My hearing, writing been doing very well; things that I couldn’t hear from; in other words, I used to be able to work cigarettes I didn’t know how. The pay I didn’t know how. I can write, cheesterfeela for over twenty years I can write it. Chesterfeel, I know all about it, I can write it.

Neuroanatomy of Wernicke’s Aphasia Wernicke’s aphasia is caused by lesions in the posterior segment of the superior temporal gyrus. Persistent and very severe forms, such as jargonaphasia, involve the supramarginal gyrus as well. Because Wernicke’s area falls within the territory of the inferior division of the middle cerebral artery, it is seldom accompanied by hemiparesis as a neighborhood sign. It may, however, be accompanied by a right superior quadrantanopia as a result of damage to the temporal portion of the optic radiation in subjacent white matter.

Pure Word Deafness The hallmark of this condition is an inability to recognize the phonology of language, despite normal hearing and normal ability to recognize nonlanguage sounds. The fundamental disturbance is at a phonemic rather than a lexical level, as evidenced by normal comprehension of written language. Repetition and writing in response to dictation are impossible. Spontaneous writing, however, is intact. Pure word deafness is, in effect, a phonemic agnosia. Pure word deafness is caused by damage to the region of the posterior insula and temporal isthmus. The condition is also encountered in epileptic aphasia (Landau-Kleffner syndrome).

Fluent Production with Normal Comprehension and Impaired Repetition: Conduction Aphasia The syndrome of conduction aphasia is perhaps the most controversial of the aphasias. It was postulated as a theoretical possibility from the Wernicke-Lichtheim model. In essence, Wernicke assumed that if the pathway connecting Broca’s and Wernicke’s areas were to be interrupted, speech would be fluent but paraphasic, and comprehension would be preserved, but the patient would be unable to repeat what he or she heard. This disconnection concept was challenged, principally by Sigmund Freud, who held that conduction aphasia, to the extent that this syndrome actually existed, was more likely to be the result of cortical damage and that its exact character would depend on the proximity of the lesion to either Broca’s or Wernicke’s areas. This notion has been revisited in light of tractography studies of the arcuate fasciculus (see Catani et al, 2005). Conduction aphasia is fundamentally a disorder of repetition. The breakdown in repetition has two underlying causes, giving rise to two variants of the syndrome: reproduction conduction aphasia and repetition conduction aphasia. Reproduction conduction aphasia is a specific disorder of phonological processing in which the processes by which the perceived phonemic representation of a word is converted into articulatory sequences are impaired. Repetition conduction aphasia, or acousticomnestic aphasia in Luria’s classification,7 is considered to be a disorder in a particular aspect of short-term memory: namely, reduced capacity to pass information from a short-term acoustic store to the output system. From a cognitive perspective, both forms of the syndrome involve a breakdown in a privileged communication channel. From a neuroanatomical perspective, the notion that this channel is necessarily the arcuate fasciculus, a deep white matter pathway

chapter 3 disorders of language that was initially thought to connect Broca’s and Wernicke’s areas, has been remarkably persistent in neurological thinking, but the clinicoanatomical literature indicates that there is no reason to believe that arcuate fasciculus interruption is a more feasible explanation for conduction aphasia than are lesions in the perisylvian language cortex.

The Syndrome of Conduction Aphasia The core clinical features of reproduction conduction aphasia are as follows: ■ Output is fluent, with phonemic paraphasias and with

normal or near normal comprehension. ■ Against this background, repetition of words, phrases, and

sentences, as well as writing in response to dictation, is very impaired and is hampered by prominent phonemic paraphasias. Phonemic paraphasias are also seen in naming and reading. ■ Characteristic attempts are made to correct the phonemic selection errors by successive approximations, or conduit d’approche (see Table 3–3). This phenomenon suggests that the representation of phonological knowledge is intact in conduction aphasia and that the impairment lies in the integration of phonology with articulatory processing. Repetition conduction aphasia is easily recognized on neuropsychological evaluation from a severe inability to repeat sentences, against a background of fluent spontaneous output and normal comprehension. Because of the absence of overt language symptoms, these cases rarely come to medical attention. In contrast to reproduction conduction aphasia, language is devoid of paraphasic errors. Affected patients usually exhibit a severely reduced digit span. The following example of fluent output in a conduction aphasic illustrates the profuse phonemic paraphasias and conduit d’approche:13 EXAMINER: Tell me what’s going on in this picture. PATIENT: Oh . . . he’s on top o’ the ss . . . ss . . . swirl . . . it’s a . . . ss . . . sss . . . ss . . . sweel . . . sstool . . . stool.

Neuroanatomy of Conduction Aphasia Most cases with conduction aphasia have lesions centered on the supramarginal gyrus. The lesion can include white matter deep to the supramarginal gyrus, involving the posterior end of the arcuate fasciculus. Whether involvement of the posterior arcuate fasciculus is a necessary condition is debatable. Anterior transection of the arcuate fasciculus does not produce conduction aphasia. Lesions in the insular cortex, including subinsular white matter, are also an important cause of conduction aphasia. It is recognized that conduction aphasia can occur with pure suprasylvian or pure subsylvian lesions (see Benson and Ardila, 1996).

Fluent Production with Normal Repetition and Impaired Comprehension: Transcortical Sensory Aphasia TSA is a rather controversial condition. It is similar to all posterior aphasias in the sense that it manifests as a fluent language disturbance, which ranges from severely paraphasic and

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circumlocutory speech to relatively normal output with occasional semantic paraphasias. The hallmark of TSA is impaired comprehension but well-preserved repetition. Patients with TSA are able to repeat long and complex sentences that they cannot comprehend. The pattern of cognitive breakdown in TSA is variable, which suggests that this is not a single entity. Location of the causative lesion is also not certain and might be more widely distributed than classical aphasiologists suspected. Computed tomographic evidence suggests that lesions producing TSA tend to overlap in the inferior region of the temporo-parieto-occipital junctional cortex, as well as occipitotemporal cortex and underlying white matter. This inferior and medial distribution implicates the posterior cerebral artery.14 Other affected patients have lesions that are more superolateral, lying in the posterior watershed region between the posterior and middle cerebral arteries.14 TSA is also associated with degenerative conditions, such as the posterior cortical atrophy variant of Alzheimer’s disease.15 TSA is noted for its frequent association with other posterior focal neighborhood signs, such as Gerstmann’s syndrome, agnosia, alexia, constructional impairments, and ideational apraxia, in both focal and degenerative etiologies.

Fluent Production, Normal Repetition, and Preserved Comprehension: Anomic Aphasia The main feature of anomic aphasia is a supramodal wordfinding difficulty, with little effect on comprehension. Supramodal implies that the anomia is present regardless of the sense modality through which the item to be named is presented. Language production is fluent, but it is devoid of substantive content, circumlocutory, and paraphasic. Repetition is normal, which means that anomic aphasia is a transcortical disorder, and it has been suggested that it is on a continuum with TSA. Norman Geschwind’s adaptation of the Wernicke-Lichtheim model attributed the role of name retrieval to the angular gyrus, which is widely recognized as a zone of convergence for visual, auditory, and tactile information and a repository for semantic information. It is anatomically well placed as a nodal structure for the activation of semantically specified concepts. It is richly interconnected with the posterior temporal region, where activated concepts are converted to phonemic form. Angular gyrus lesions produce the features of anomic aphasia, but it is recognized that dysnomic features can arise from multiple loci and are therefore poorly localizing. In the author’s own experience, however, extra-angular lesions seldom produce the prominent fluent and circumlocutory output disturbance of anomic aphasia. For example (in which the patient attempts to convey that he suffered a stroke after aortic surgery):13 EXAMINER: Can you tell me about your illness? PATIENT: I had a. . . . I had a one or two three . . . There’s one . . . I had a . . . a . . . I know the exact part of it. EXAMINER: And it was after the operation? PATIENT: Right, about a day later, while I was under whatchmacall. . . . EXAMINER: Anesthesia? PATIENT: Under where they put you, just two or three people, an’ you stay in there for a couple o’ days.

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Nonfluent Production, Normal Repetition, and Impaired Comprehension: Mixed Transcortical Aphasia The syndrome of mixed transcortical aphasia was initially described in 1948 by Kurt Goldstein, although the condition had been anticipated by the classical aphasiologists. There is a severe reduction in the quantity of spontaneous output; comprehension is also severely impaired, but repetition remains intact. This pattern of impairment was ascribed to isolation of the speech area, a concept that was later to be confirmed by Geschwind in his classic study of a case of carbon monoxide poisoning. Repetition is made possible by the integrity of the perisylvian language axis: namely, Broca’s and Wernicke’s areas and the connections between them. Broca’s and Wernicke’s areas are, however, disconnected from anterior and posterior association cortices that mediate the ideational basis of language. Functional neuroimaging findings support the notion of a widely distributed left-lateralized extrasylvian neocortical system involved in the formulation of propositional language before its conversion to articulated speech (see Blank et al., 2002). Echolalia is a prominent component of mixed transcortical aphasia and, like intact repetition, can be thought of as reflecting the preservation of the automatic aspects of language, devoid of an ideational context. The lesions producing mixed transcortical aphasia tend to be multifocal or diffuse and include hypoxic insults, large watershed infarctions or a combination of focal watershed and pial infarction, and degenerative processes. The mixed transcortical aphasia syndrome also occurs in thalamic infarction.

PRIMARY PROGRESSIVE APHASIA Primary progressive aphasia refers to a gradually evolving aphasia, in the absence of other cognitive disorders. It is often the first symptom of neurodegenerative conditions such as one of the forms of frontotemporal dementia (see Chapter 73). The term primary progressive aphasia is applied when the speech and language symptoms have progressed for about 2 years in the absence of any other cognitive or behavioral changes.16 Even when the underlying dementia begins to manifest, the aphasic disturbance remains the most prominent and disabling symptom. Although some studies suggest that 50% to 60% of primary progressive aphasia cases have a fluent disturbance, at least two variants (fluent and nonfluent forms) are currently acknowledged. A third logopenic variant (characterized by slow and halting word production in the context of highly simplified but grammatically correct sentences) has also been proposed. Mesulam16 estimated that the underlying neuropathology in about 60% of patients with primary progressive aphasia is neuronal loss, gliosis, and spongiform change. Some cases are caused by frontotemporal dementia with parkinsonism linked to chromosome 17 (see Chapter 74), a genetic tauopathy. A further 20% have Pick’s disease, and fewer than 20% have Alzheimer’s disease.

Fluent Progressive Aphasia: Semantic Dementia In semantic dementia, spontaneous language is fluent, dysnomic, and possibly circumlocutory, but production and

comprehension of syntax are normal. The hallmark feature is a loss of word meaning, underpinned by a degradation of semantic function. On confrontation testing, for example, patients not only are anomic but also are unable to give any of the attributes of the object. The intended word is often replaced by a superordinate category (e.g., “flower” instead of “daisy”), which reflects an early loss of subordinate knowledge. Speech itself is normal in terms of rate of production and articulation. Published consensus criteria for the diagnosis of frontotemporal dementia link semantic dementia with disorders of object and face recognition (visual agnosia and prosopagnosia, respectively) as additional manifestations of semantic loss.17 This is controversial with regard to the definition of primary progressive aphasia mentioned previously.16 The earliest cerebral change in this variant is left anterolateral temporal atrophy. Semantic dementia is considered to be one of the clinical variants of frontotemporal dementia.

Nonfluent Progressive Aphasia The nonfluent progressive aphasia variant manifests with nonfluent speech, agrammatism, and difficulties in comprehending complex syntactic structures but also with preserved semantic function, at least at a single-word level. Articulation is labored. Cases of progressive aphemia or of speech apraxia but without a true aphasia have also been described. The distinction between nonfluent progressive aphasia and progressive aphemia parallels the distinction between Broca’s aphasia and aphemia. Most patients with nonfluent progressive aphasia and pure progressive aphemia have been shown to have Pick’s disease, with more restricted atrophy in the latter group.18 Both conditions are regarded as frontotemporal dementia variants17 and may represent a clinical spectrum reflecting varying degrees of damage to the anterior insular, inferior premotor cortex, and pars opercularis.

An Intermediate Variant: Logopenic Progressive Aphasia The logopenic progressive aphasia variant does not meet the criteria for semantic dementia or nonfluent progressive aphasia. Rate of speech output is reduced, with hesitancies suggestive of a word-finding difficulty and with impaired repetition. Articulation is normal. Grammar is simplified but correct. Semantic function is preserved, but syntactic comprehension is impaired. Logopenic progressive aphasia is associated with left temporoparietal atrophy. Together with a high frequency of the apolipoprotein E ε4 haplotype in this group, this anatomical distribution of atrophy suggests that logopenic progressive aphasia might be an atypical-onset form of Alzheimer’s disease. Further definition of primary progressive aphasia variants is likely to continue (see Grossman, 2002). Because primary progressive aphasia is an evolving language disorder, distinctions between the variants might be stage related. On the basis of a longitudinal study, Kertesz and colleagues suggested that although the aphemic, logopenic, agrammatic, and semantic distinctions are useful, there is some tendency for outcomes to converge as the dementia progresses.19

chapter 3 disorders of language ACQUIRED DISORDERS OF READING: THE ALEXIAS Fundamental Concepts: The Dual-Route Model In nonideographic writing systems—in which individual symbols do not themselves stand for concepts or ideas—all phonemes of the language have corresponding written representations, known as graphemes. Learning to read depends on acquiring knowledge of the phonemic equivalents of the graphemic system: that is, the rules of grapheme-phoneme correspondence. In sensory terms, this involves an integration between visual and auditory processing systems. Beginning and unskilled readers depend heavily on grapheme-phoneme correspondence and therefore on phonological pathways. This gives rise to the phenomenon of letter-by-letter synthesis: reading by sounding out each grapheme in turn before synthesizing the individual sounds into the word itself. This approach is considered to be sublexical because it depends on sequential identification of individual components of the word. It allows the individual to read any string that conforms to the phonological structure of the language and can therefore be “sounded out.” This would include all words with regular grapheme-phoneme correspondence, such as “cat,” “glint,” and “slap,” as well as pseudowords such as “rint,” “glaint,” or “lume.” But this does not allow the individual to read orthographically irregular words (written differently from the way they sound) such as “yacht,” “psalm,” or “thyme.” Words such as these can be read correctly only through a purely visual route; an attempt at using a phonological (grapheme-to-phoneme conversion) pathway would result in a mispronunciation. With increasing reading proficiency, all words come to be recognized visually (lexical or whole-word reading), but the sublexical route must still be recruited for pseudowords. This dual-route model is fundamental to understanding the acquired alexias.

The Dual-Route Model and Reading Disorders: Deep and Surface Alexias Deep alexia and surface alexia are psycholinguistic “syndromes.” They do not necessarily correspond to particular loci of cerebral damage, but they are useful in systematizing patterns of reading impairment and relating these patterns to putative mechanisms of disruption.

Deep Alexia The main features of deep alexia are as follows: ■ Normal reading of familiar and highly imageable words,

regardless of whether they have regular (“desk”) or irregular (“yacht”) grapheme-phoneme correspondence. ■ Inability to read pseudowords correctly according to the usual grapheme-phoneme conversion rules of the language. ■ Visual reading errors (e.g., “patience” for “patients”) and semantic reading errors (e.g., “ship” for “boat,” “cash” for “money”) are common. This pattern is brought about by a loss of the phonological or grapheme-phoneme conversion route. The patient is left with a residual ability to recognize familiar words but cannot recruit a phonological strategy to tackle unfamiliar words or pseudowords, which are, in effect, profoundly unfamiliar.

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T A B L E 3–6. Central Alexia Syndromes Psycholinguistic Syndrome Deep alexia Surface alexia

Deficit Loss of grapheme-tophoneme conversion Loss of visual word form access to semantic system

Closest Equivalent Neurological Syndrome, or Lesion Location Alexia with agraphia Aphasic alexia Left temporoparietal Generalized atrophy Primary progressive aphasias

Deep alexia is seen in patients with severe aphasias and with widespread damage in a frontoparietal distribution.

Surface Alexia Patients with surface alexia are able to read orthographically regular words (“rush,” “tint,” “same”) and pseudowords (“glant,” “sint,” “glame”) but are unable to read irregular words (“gaoled,” “subtle,” “colonel”). Pronunciation is regularized (e.g., “denni” for “deny”). This feature cannot be detected in languages with uniform, unambiguous grapheme-phoneme conversion rules (e.g., Spanish), but it is readily demonstrable in English. Reading is effortful, taking appreciably more time for long words than short words (word length effect). There is inability to recognize words at a glance. Word meaning is accessed only after the word has been pronounced. If an error in pronunciation occurs, the meaning is deemed to be that of the unintended word. For example, if the word “pretty” is read as “pity,” its meaning is judged to be “compassion.” This constellation of features implies preservation of the phonological route but loss of visual access to the semantic system. Deep alexia and surface alexia are regarded as central alexias, because they represent a loss of access by visual representations of word forms to central phonemic and semantic mechanisms (Table 3–6).

Neurological Classification of Alexias There is an alternative, nonpsycholinguistic classification system for the alexias. Although some syndromes are essentially the same in both (e.g., pure alexia), there really is no equivalent syndrome in the other classification system for others (see Benson and Ardila, 1996, for suggested correlations between the two classification systems).

Alexia without Agraphia (Pure Alexia) Patients with pure alexia read by sequentially identifying the letters of the word (letter by letter reading). This is a slow and laborious process, and at least in the subacute phase, silent reading is not possible. Speed of reading depends on the number of letters in the word (word length effect); therefore, wholeword recognition is not possible. All other language functions are well preserved, giving rise to the term pure alexia. Writing is also intact, but the patient is not able to read what he or she has written. The classical lesion in pure alexia is infarction of

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the medial surface of the left occipital lobe and splenium of the corpus callosum. It is now accepted that splenial involvement is not a necessary condition for the emergence of pure alexia. Pure alexia tends to evolve acutely from an inability to identify individual letters to recovery of letter identification and letter-by-letter reading and, in some cases, recovery of silent reading. Alexia without agraphia is regarded as a peripheral alexia because the deficit occurs at the level of visual processing without involving the more central mechanisms of grapheme-phoneme conversion or semantic processing.

Alexia with Agraphia Strictly speaking, alexia with agraphia is diagnosed when reading and writing are impaired against a background of otherwise normal language functions. This pattern, however, is rare. The nature of the reading and writing impairment is variable. Alexia with agraphia is caused by lesions in the temporoparietal cortex and is often accompanied by mild features of Wernicke’s aphasia. In pure forms of alexia with agraphia, residual reading depends on whole-word recognition, and it therefore resembles the psycholinguistic syndrome of deep alexia.

Aphasic Alexia (Co-occurring with Broca’s or Wernicke’s Aphasia) With severe Broca’s aphasia there is a profound disruption of grapheme-to-phoneme conversion, and residual reading occurs at the level of whole-word reading. This brings about a striking impairment of reading comprehension despite relatively wellpreserved comprehension of speech. Like alexia with agraphia, alexia in Broca’s aphasia resembles the psycholinguistic syndrome of deep alexia. It is sometimes referred to in the neurological classification of alexias as the third alexia. Wernicke’s aphasia causes impairments for spoken and written language. The comprehension impairment for speech tends to recover more rapidly than does reading comprehension, and the evolving clinical picture is one of alexia with agraphia.

ACQUIRED NEUROGENIC AGRAPHIA Speech and writing are the two major output modalities for language. It is often assumed that language disorders in speech are paralleled by an equivalent pattern in writing, and, as a consequence, the agraphias have come to be overshadowed by the aphasias. Aphasic agraphias certainly can reflect the production disorder of the aphasic syndrome, but this is not always the case, and there is often overlap between writing disorders in fluent and nonfluent aphasias. Classical agraphic syndromology is therefore somewhat less satisfactory than classical aphasiology. Most classifications have recognized agraphias associated with aphasic syndromes (aphasic agraphias), those associated with fundamental visuospatial disorders (e.g., neglect), and those associated with upper limb motor disorders and dyspraxic disorders. Benson and Ardila (1996) proposed a dichotomous classification, into aphasic and mechanical agraphias (Table 3–7). The mechanical agraphias raise the question as to whether writing impairments of nonsymbolic origin (such as dystonic, paretic, or apractic forms) should be regarded as true agraphias, which is, again, reminiscent of the question of whether speech dyspraxia should be regarded as aphasic or dysarthric. Perhaps

T A B L E 3–7. Classification of the Agraphias Aphasic Agraphias Agraphia in Broca’s aphasia Agraphia in Wernicke’s aphasia Agraphia in conduction aphasia Agraphia in other aphasias Mechanical Agraphias Motor agraphia Paretic agraphia Dyskinetic agraphia Hypokinetic agraphia Hyperkinetic agraphia Dystonic agraphia Pure agraphia Apractic agraphia Spatial agraphia Based on Benson DF, Ardila A: Aphasia: A Clinical Perspective. New York: Oxford University Press, 1996, p 214, Table 12.1.

the term agraphia should be reserved for language-based disturbances in writing and graphomotor impairment for nonlinguistic disturbances. Table 3–8 lists the main characteristics of some of the aphasic agraphias, and Table 3–9 lists characteristics of the higher-level mechanical agraphias.

Neurocognitive Classification of Agraphias Neuropsychological studies have resulted in an alternative classification of the agraphias, analogous to the psycholinguistic classification of the alexias. The distinction is made between central and peripheral agraphias, with matching of the concepts of central and peripheral alexias. Spatial and apractic agraphia can be regarded as peripheral because they do not involve fundamental language mechanisms. Table 3–10 summarizes the central agraphias.

T A B L E 3–8. Characteristics of Aphasic Agraphia: Comparison with Spoken Output Spoken Output

Written Output

Agraphia in Broca’s Aphasia Sparse output Effortful Poor articulation Short phrase length Dysprosody Agrammatism (lack of closed class words) Poor spelling

Sparse output Effortful Clumsy calligraphy Abbreviated output (No written equivalent) Agrammatism (lack of closed class words) Poor spelling

Agraphia in Wernicke’s Aphasia Normal vocal characteristics Noneffortful speech Good articulation Normal phrase length Normal prosody Lack of open class (substantive) words Paraphasias

Normal graphic characteristics Noneffortful writing Well-formed letters Normal sentence length (No written equivalent) Lack of open class (substantive) words Paragraphias

Adapted from Benson DF, Ardila A: Aphasia: A Clinical Perspective. New York: Oxford University Press, 1996, pp 218-219, Tables 12.3 and 12.4.

chapter 3 disorders of language

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T A B L E 3–9. Apractic and Spatial Agraphias Apractic Agraphia Fundamentally, a loss of ability to form normal graphemes Profuse written spelling errors, despite a retained ability to spell orally Profuse iterations, repairs, and other distortions Writing difficulty evident in spontaneous writing, writing in response to dictation, and copying Can occur in isolation from speech difficulties or upper limb apraxia and can therefore be regarded as a “pure” apraxia; this, however, is rare Usually occurs in association with ideomotor dyspraxia or other inferior parietal signs Spatial Agraphia Loss of ability to utilize spatial constraints and organization in writing Letters are reiterated Spatial delimiters between words are not used correctly (“Th esunis shi ning” instead of “The sun is shining”) Progressive enlargement of margins, heavily slanted writing, and other forms of malpositioning of writing Impairments seen in automatized (for example, signature) and nonautomatized forms of writing Occurs in association with other spatial impairments, typically in right hemisphere lesions

T A B L E 3–10. Central Agraphias Syndrome

Linguistic Impairment

Neuroanatomy

Lexical agraphia (analogous to surface dyslexia)

Loss of whole word processing Inability to spell irregular or ambiguous words, with preserved spelling of regular words and graphemically legal nonwords Graphemic regularization (for example, “grayshus” instead of “gracious”) Loss of sublexical processing Impairment of phoneme-to-grapheme conversion Inability to spell nonwords, with preserved ability to spell regular and irregular familiar words Inability to write nonwords or words with low imageability Semantic paragraphias with no visual similarity to the target (for example, “travel” instead of “car”)

Dominant angular gyrus, with sparing of immediate perisylvian region

Phonological agraphia (analogous to phonological dyslexia) Deep agraphia (analogous to deep dyslexia)

Dominant supramarginal gyrus and insula

Large supramarginal or insula lesions

Suggested Reading

K E Y

P O I N T S

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Aphasias can be divided into fluent and nonfluent types. This basic dichotomy can be refined further, depending on whether repetition and comprehension are impaired, to describe eight basic aphasic syndromes.

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Several types of focal degenerative pathologies can manifest as primary progressive aphasias, without significant involvement of other cognitive domains over at least the first 2 years of the illness. These are of two broad types: fluent primary progressive aphasia (a feature of the syndrome of semantic dementia) and nonfluent primary progressive aphasia.

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Two different classification systems for acquired dyslexias are in current use: one based on the two-pathway (wholeword and phonetic) psycholinguistic model and the other based on classical lesional behavioral neurological observations. Although there is no direct correspondence, both systems account for a distinction between central disorders (of language) and peripheral disorders (of visual processing of letters and words).

Benson DF, Ardila A: Aphasia: A Clinical Perspective. New York: Oxford University Press, 1996. Blank SC, Scott SK, Murphy K, et al: Speech production: Wernicke, Broca, and beyond. Brain 2002; 125:1829-1838. Catani M, Jones DK, Ffytche DH: Perisylvian language networks of the human brain. Ann Neurol 2005; 57:8-16. Duffy JR: Motor Speech Disorders: Substrates, Differential Diagnoses, and Management. 2nd ed. St. Louis: Mosby, 2005. Grossman M: Progressive aphasic syndromes: clinical and theoretical advances. Curr Opin Neurol 2002; 15:409-413. LaPointe LL, ed: Aphasia and Related Neurogenic Language Disorders, 3rd ed. New York: Thieme, 2005.

References 1. Brown JW: Case reports of semantic jargon. In Brown JW, ed: Jargonaphasia. New York: Academic Press, 1981, p 171. 2. Luria AR: Language and Cognition. New York: Wiley & Sons, 1982, p 224. 3. Head H: Aphasia and Kindred Disorders of Speech, vol 2. London: Cambridge University Press, 1926, p 229. 4. Goodglass H: Agrammatism. In Whitaker H, ed: Studies in Neurolinguistics, vol 2. New York: Academic Press, 1976, p 238.

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5. Kertesz A: The anatomy of jargon. In Brown JW, ed: Jargonaphasia. New York: Academic Press, 1981, p 91. 6. Mohr JP: Broca’s area and Broca’s aphasia. In Whitaker H, ed: Studies in Neurolinguistics, vol 1. New York: Academic Press, 1976, p 221. 7. Kagan A, Saling MM: An Introduction to Luria’s Aphasiology: Theory and Application. Baltimore: Paul H. Brookes, 1992. 8. Schiff HB, Alexander MP, Naeser MA, Galaburda AM: Aphemia: Clinical-anatomic correlations. Arch Neurol 1983; 40:720727. 9. Harrington A: Medicine, Mind, and the Double Brain. Princeton, NJ: Princeton University Press, 1987, p 261. 10. Ardila A, Lopez MV: Transcortical motor aphasia: one or two aphasias? Brain Lang 1984; 22:350-353. 11. Cimino-Knight AM, Hollingsworth AL, Gonzalez-Rothi LJ: The transcortical aphasias. In LaPointe LL, ed: Aphasia and Related Neurogenic Language Disorders 3rd ed. New York: Thieme, 2004, pp 169–185. 12. Luria AR: Human Brain and Psychological Processes. New York: Harper & Row, 1966, pp 358-359.

13. Goodglass H, Wingfield A: Word-finding deficits in aphasia: brain-behavior relations and clinical symptomatology. In Goodglass H, Wingfield A, eds: Anomia: Neuroanatomical and Cognitive Correlates. San Diego, CA: Academic Press, 1997, p 7. 14. Kertesz A, Sheppard A, McKenzie R: Localization in transcortical sensory aphasia. Arch Neurol 1982; 39:475-478. 15. Benson DF, Davis RJ, Snyder BD: Posterior cortical atrophy. Arch Neurol 1988; 45:789-793. 16. Mesulam MM: Primary progressive aphasia. Ann Neurol 2001; 49:425-432. 17. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554. 18. Hodges JR, Davies RR, Xuereb JH, et al: Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56:399-406. 19. Kertesz A, Davidson W, McCabe P, et al: Primary progressive aphasia: diagnosis, varieties, evolution. J Int Neuropsychol Soc 2003; 9:710-719.

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MEMORY ●

Peter J. Nestor

DEFINITIONS AND TERMINOLOGY Declarative and Nondeclarative Memory In general, when patients speak of memory complaints, they are referring to the recollection of information for which there is conscious awareness. In neuropsychological terminology, this is called declarative, or explicit, memory. The corollary is nondeclarative, or implicit, memory, which refers to phenomena such as motor skill learning, priming and classical conditioning (Table 4–1). For instance, with appropriate training, a tennis player can be seen to “learn,” as evidenced by improved performance; however, in the course of a rally, the player is not consciously recollecting the motor sequence required to execute each shot. Priming refers to a situation in which prior exposure leads to altered performance and can be shown experimentally in language tasks such as naming and lexical decision making. For example, imagine being presented with words on a computer screen and being asked to read them as soon as they appear; the latency between exposure and response (reaction time) is shorter if a related, as opposed to a nonrelated, item is presented immediately before the test item (e.g., a subject will respond faster to the word tiger if it is preceded by lion rather than house). Highlighting the dissociation between declarative and nondeclarative memory is the fact that patients with Alzheimer’s disease have marked declarative deficits and yet may respond even faster with priming (hyperpriming) than control subjects. Although nondeclarative memory is crucial for many functions, it is not what patients usually mean when they report memory symptoms and is not discussed further.

Episodic and Semantic Memory Declarative memory is further subdivided into context-specific and non–context-specific types known as episodic and semantic memory, respectively. Episodic memories are unique in that they are recollections of an individual’s own past experiences, and therefore each is specific in time and space. In contrast, semantic memory refers to knowledge of universal facts and does not require evocation of the circumstances in which such information was acquired. Furthermore, factual knowledge is typically not learned from a single episode but rather is encoun-

tered in many contexts over time. To illustrate these definitions, an individual is retrieving semantic memories when he or she recalls that Paris is the capital of France and is home to the Louvre and Eiffel Tower. When the individual recollects specific events from his or her own visit to Paris, this virtual reconstruction of the event constitutes an episodic memory—regardless of how fragmentary the events recalled may have become. This ability to travel mentally in time is sometimes referred to as autonoetic (self-understanding) consciousness, which emphasizes the critical position of self-awareness in the recollective process. It is characteristically multimodal (e.g., visual scenes, sounds, verbal narrative). Declarative memory is also considered in terms of encoding, storage, and retrieval. In other words, a neurophysiological change takes place during learning (encoding); this change must leave some enduring trace (storage), and there must be a mechanism by which this trace can be reactivated, at will, to lead to the subjective experience of remembering (retrieval). Often, these processes cannot be disentangled in the clinic; for instance, a patient with no recall of new information on formal neuropsychological testing may have a deficit at any or all of these stages. Nevertheless, neuropsychological tests can, to some extent, tease these stages apart by varying task demands. For example, a patient who requires an excessive number of learning trials to reach a criterion and yet retains a lot of this information after a delay can be considered as having an encoding problem. This profile is often indicative of an attention disorder rather than a true amnesic syndrome. Storage problems may be suggested by an accelerated decay in recall performance between two time points (e.g., immediately and 30 minutes after encoding). However, it is important to realize that a degree of decay is seen under normal circumstances; therefore, interpretation requires comparison with demographically matched norms. Retrieval deficits can be investigated by comparing free recall (“What did I ask you to remember?”) with recognition memory (“Which of these did I show you earlier?”). Recognition is typically tested by either forced-choice questions—in which target answers and foils (incorrect alternatives) are presented simultaneously in pairs and the patient has to choose those that he or she has seen before—or by asking for yes/no responses as targets and foils are presented in a random sequence. Because the patient is presented the previously studied material, retrieval demands are minimized, and

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hence a retrieval deficit is suggested where there is disproportionate impairment of free recall in comparison with recognition memory. Recognition is, however, an easier task than is free recall, and so this dissociation also needs to be assessed by comparison with control norms. It is likely that the neural systems responsible for these processes partially overlap, in that some brain areas such as the hippocampus may be necessary for all aspects, whereas other areas may be differentially engaged at a specific stage. For example, functional activation studies of changes in cerebral blood flow suggest greater engagement of the left and right prefrontal cortices during encoding and retrieval, respectively.1

Amnesia Amnesia is the generic term for loss of memory. An inability to establish new memories after the pathological event is called anterograde amnesia, whereas the inability to recall memories that had been established before the pathological event is called retrograde amnesia (Fig. 4–1). The fact that the distinction

T A B L E 4–1. Classification of Memory Types

Memory performance

Nondeclarative (implicit) memory Motor skill learning Priming Classical conditioning Working memory Declarative (explicit) memory Episodic memory Semantic memory

between anterograde and retrograde is referenced to the pathological insult is important. Students often think erroneously that retrograde amnesia refers to memory loss for past events, whereby “past” is loosely defined as any time before the clinical consultation. This leads to the absurd situation of testing for retrograde deficits by asking the patient what they did “yesterday,” which makes the distinction from anterograde deficits meaningless, as it becomes referenced to the everchanging present. Patients with dense amnesia, especially in the acute phase, may confabulate: that is, fill in memory gaps with false statements. The episodic/semantic memory distinction is inconsistently defined with regard to the term amnesia. In popular usage, the term amnesic syndrome denotes severe loss of episodic memory with preservation of working memory and general semantic memory (i.e., word meanings, object knowledge). The most sensitive marker is loss of autonoetic awareness. A patient may produce what sounds like a specific episodic memory (e.g., “When I was ten, I fell off a horse and broke my arm”) but, when asked to elaborate, is unable to do so in a manner that offers convincing evidence of mental time travel, rather than mere repetition of an overlearned statement. The situation becomes more ambiguous with regard to factual semantic knowledge (public events, famous people), including personal semantic facts (e.g., names of schools attended, name of employers). Variable degrees of impairment in factual semantic knowledge are usual in amnesia, and this information can be objectively dated in time (in contrast to an individual’s episodic recollections, which are more difficult to date or verify). As a consequence, evidence for temporal gradients in memory impairment is typically compiled from these datable facts. For instance, a patient with a new-onset pathological process who knows that the Berlin Wall was pulled

Key Anterograde, with temporally graded retrograde, amnesia Focal anterograde amnesia Focal (organic) retrograde amnesia Focal (non-organic) retrograde amnesia Global amnesia

Time Remote past

Present Pathological insult Retrograde amnesia

■

Anterograde amnesia

Figure 4–1. Schematic representation of different profiles of amnesia.

chapter 4 disorders of memory down, that apartheid ended, and that Iraq invaded Kuwait but does not remember a tsunami killing hundreds of thousands, the World Trade Center being destroyed, or Princess Diana dying has evidence for a retrograde amnesia extending back to the early to mid-1990s. It should be noted that the distinction between episodic and semantic memory—the degree of “semanticization”—becomes blurred at this point, inasmuch as some facts may be recalled from the specific context in which they were encountered—as so-called “flashbulb” memories. In addition, the frequency of exposure to particular facts varies between individuals. For example, the average American has most likely had many more encounters with stories about the World Trade Center than with stories about the Berlin Wall, and this will bias successful recollection towards the more recent, semantically reinforced event.

Working Memory An important concept to distinguish from both episodic and semantic memory is working memory, frequently referred to by experimental psychologists as short-term memory. This refers to information that, at any given moment, is held “online” by the brain—that is, in consciousness—and that is not recollected after a distraction period (unless incidental episodic encoding of the material has also taken place). This faculty is exemplified by the ability to keep a telephone number in the mind in the interval between looking it up the telephone directory and dialing the number. Models of working memory posit auditory-verbal and visuospatial components that are coordinated and manipulated by a central executive system.2 A highly distributed network of cortical and subcortical areas supports working memory, although the dorsolateral prefrontal cortex appears to be particularly important for the executive component. It is therefore unsurprising that working memory is most vulnerable to diffuse insults such as those found in metabolic encephalopathies and closed head injury. It can be dissociated from the long-term declarative memory systems described previously; patients with even the densest amnesia can still have intact working memory. It is important for clinicians to understand the difference between this true short-term memory system and what patients (and many clinicians) may colloquially refer to as short-term memory. The latter, incorrect usage indicates memory for recently experienced events or exposures and therefore actually refers to recently acquired episodic memory.

NEUROBIOLOGY OF LEARNING AND MEMORY Cellular Mechanisms From a theoretical perspective, a neural system responsible for learning must be adaptive; in its most elementary form, a sensory event leads to an alteration in behavior at a later time. Put another way, biological events corresponding to learning must take place at the initial experience, and some outcome from these events must remain stable over time. In everyday experience, evidence for this adaptation is illustrated through the sense of familiarity experienced when a related sensory stimulus is subsequently encountered. However, in neurobiological terms, this process can be generalized to any alteration

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of behavior that is a consequence of a prior experience. Therefore, learning and memory in the broadest sense can encompass phenomena that are far removed from the recollection of an individual’s previous life events, such as the habituation of a blink reflex in response to a recurring visual stimulus. The relevance of this to the neurobiology of memory is that these more fundamental phenomena—forms of nondeclarative memory—are much more accessible to direct experimentation, not least because they can be studied in organisms with much simpler nervous systems. Important insights into the neural basis of learning and memory have been gleaned from studies in organisms as diverse as invertebrates, such as the Drosophila fruit fly and the Aplysia sea slug, and mammalian species, including nonhuman primates. These models indicate that activity-dependent changes can occur in the efficacy of synaptic transmission; in other words, certain physiological stimuli can give rise to synaptic plasticity. This plasticity is often referred to as a Hebbian synapse, after Donald Hebb, who postulated in 1949 that if a given neuron is repeatedly involved in provoking a second neuron to fire, then the efficiency with which this process takes place will increase. Support for Hebb’s postulate was subsequently explored and developed in a large body of neurophysiological experimentation. The basic observation is that after a brief repetitive stimulation, the amplitude of the excitatory postsynaptic potential is enhanced, and this enhancement can be shown to persist for hours or days. This phenomenon is referred to as long-term potentiation (LTP) and is initially facilitated through modifications to existing proteins at the synapse. A further level of complexity in the dynamics of synaptic transmission is that with certain neurons and stimulation protocols, the converse process, long-term depression (LTD), may occur. Clearly, long-term memory as it is known in humans requires neural changes that persist over much longer periods. By studying very simple nervous systems such as that of Aplysia, neuroscientists have demonstrated, in behaving organisms, that synaptic plasticity in response to classical conditioning gives rise to changes in gene expression and consequently to alterations in protein synthesis. Glutamate is the principal excitatory neurotransmitter in the central nervous system, and LTP has been demonstrated to occur through agonism of ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. LTP can be induced by agonism of NMDA receptors, whereas maintenance of LTP, including modulation of gene expression, occurs through AMPA receptors. The relevance of this to clinical practice is that perturbation of glutamate transmission has become a target for pharmacological intervention to enhance mnemonic function. It is already recognized that certain manipulations can impair function; for instance, the NMDA antagonist, ketamine, causes dosedependent impairments in episodic memory. Another excitatory neurotransmitter implicated in some forms of LTP is acetylcholine. Loss of cholinergic neurons in the basal forebrain is a recognized feature of Alzheimer’s disease, in which memory impairment is the most salient feature. Cholinesterase inhibitor therapy for Alzheimer’s disease is now standard; unfortunately, although these agents offer some symptomatic benefit for attention deficits and behavioral disturbances, their ability to improve memory performance is, at best, modest. These observations suggest that the transmission properties of existing synapses can be modified by usage, but it is notable that the “hard wiring” of the nervous system is also dynamic.

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The dendritic spines, the sites of synaptic connections in the neuronal dendritic arbor, also display plasticity over time, which suggests that the neural networks themselves may be adaptive.3 Technical developments, enabling dendritic spines to be labeled and studied in real time, have shown that changes in structure, including the generation of new dendritic spine protrusions, can be triggered by LTP-inducing activity. Conversely, some LTD-inducing stimuli have been shown to cause loss of dendritic spines. It must be acknowledged, however, that although these morphological and physiological findings suggest mechanisms by which learning and memory may be supported, the precise relevance of these specific processes to memory in vivo is far from established in the mature brain. For further reading on these topics and other current issues in the neuroscience of memory, the excellent essays by Dudai (2002) are recommended.

The Topography of Memory Experimental manipulations of individual synapses are also considerably removed from an understanding of what constitutes a “memory trace”; this shorthand term is often used to indicate the neural representation of an individual memory. Lesions studies indicate that several brain regions have a critical role in supporting declarative memory. Amnesia characteristically arises with lesions to limbic areas that are subsumed within the anatomical network, often referred to as either the circuit of Papez or the Delay and Brion system. This network includes the mesial temporal lobe (including hippocampus and adjacent entorhinal cortex), the fornix, the diencephalon, and the posterior cingulate region (see Fixed Memory Disorders section, Strategic Lesions subsection). Between synaptic plasticity and the topographical anatomy of regions implicated in amnesia, the precise nature of the memory trace remains difficult to delineate. As already discussed, the information that constitutes episodic memory comprises multiple sensory modalities. The prevailing hypothesis is that structures such as the hippocampus do not “store” this information, but rather act to bind the disparate components that constitute a memory trace. To illustrate this model,

consider an episodic memory of a specific conversation comprising, for simplicity, an auditory component (the dialogue) and a visual component (the scene). At the time of encoding, visual and auditory inputs contemporaneously activate a neural network in the isocortex, including auditory and visual association cortex, as well as the mesial temporal lobe. The temporospatial firing pattern that represents the memory trace can then be subsequently re-activated via the hippocampus. The traditional view (Fig. 4–2) is that with time, this neural representation gradually becomes independent of the hippocampus: so-called consolidation. This is the explanation for the Ribot effect, a temporal gradient in retrograde amnesia in which amnesia is most dense for the time immediately before the pathological insult and is progressively less dense for earlier periods. This view is almost certainly an oversimplification; many amnesic patients do not exhibit a Ribot effect but, rather, a flat profile of memory loss extending back over their whole life. Furthermore, when it is found, the temporal gradient often extends back over several decades, which suggests that consolidation is an implausible entity in evolutionary terms, inasmuch as it implies that in old age, the brain is still consolidating memories from early adult life.4 Another hotly debated topic is whether the distinction between semantic and episodic memory is meaningful in biological terms. Evidence for two separable memory systems comes from the observation that individuals with episodic memory amnesia have preservation of general semantic knowledge. Furthermore, neuropsychological studies have shown that patients with hippocampal amnesia, including those with damage sustained in infancy,5 can acquire new semantic knowledge in spite of the amnesia. This suggests that semantic memory, including its acquisition, can be supported independently of the hippocampus. The opposing view is that the acquisition of both semantic and episodic memory is dependent on a unitary system. Evidence for this comes from the observation that although acquisition of semantic knowledge may occur in patients with hippocampal amnesia, it is not completely normal.6 Whereas each episodic memory is unique in time and space, semantic facts are experienced in multiple contexts. This means that there is an enormous encoding advantage for the latter, which may explain the dissociation.

Isocortical neural network

Hippocampus

Encoding

Retrieval (Early

■

Years

Remote)

Figure 4–2. Schematic representation of the “classical” model of memory consolidation. At encoding, the sensory percept activates a network of isocortical neurons in concert with the hippocampus. Reactivation of this “memory trace” (corresponding to conscious retrieval of the memory) initially requires hippocampal input; however, in time, the memory trace maybe be reactivated independently of the hippocampus. Although this model can account for some features of the amnesic syndrome in some cases, there are many inconsistencies and controversies. In summary, the concept of memory consolidation remains a hotly debated subject.

chapter 4 disorders of memory In addition to the interaction of the hippocampus and isocortical sensory association areas in sustaining declarative memory, the amygdala and prefrontal cortex merit mention. The amygdala is involved in emotional processes, such as recognition of fear in other’s faces, but with regard to memory, it is thought to reinforce encoding of emotionally salient events. Clearly, people do not recollect their entire life experience as a bland, continuous narrative. The fact that some experiences are forgotten but others are remembered is related in part to their differing emotional significance, and it is thought that encoding of emotionally significant events is facilitated by an interaction of the amygdala with other mesial temporal structures.7 The prefrontal cortex is thought to have a “meta” role in mnemonic processing, being involved in focusing attention for encoding, forming retrieval strategies, and monitoring output.8 For instance, when a person is asked to produce a list of animals, performance is enhanced if the list is clustered into semantic categories (“category clustering”) such as zoo animals, farm animals, and domestic animals. The prefrontal cortex is specifically engaged in this type of processing, but not in storing the memories per se. Consequently, frontal lesions can cause deficits in free recall with relative preservation of recognition, because the latter does not require an active retrieval strategy.

ASSESSMENT OF MEMORY Clinical Assessment Wherever possible, a history should be obtained from a close relative of the patient to cross-reference to the patient’s account. After the clinician explains the procedure to the patient and obtains his or her consent, the informant should be seen alone, to allow frank discussion without fear of embarrassment. A common mistake in assessing patients with memory symptoms is failure to examine memory adequately. There is often insufficient time in a general clinic to test delayed recall over a long interval; however, new learning can be informally assessed by giving the patient some material to encode and then testing recall and recognition after a 5-minute distraction period filled with other elements of the examination. A seven-item name and address recall can be assessed without any special equipment; this test yields indices of encoding, recall, and recognition (Fig. 4–3). Asking the patient to copy abstract designs, followed by testing of spontaneous recall and recognition, can help assess nonverbal memory.

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Remote autobiographical memory is best evaluated in the clinic by probing for facts about the patient’s life, such as place of birth, schools attended, occupational history, residences, marriages, children, and grandchildren. This provides personal semantic facts that can be checked against the informant’s account. Remote episodic memory can be assessed by asking for specific anecdotes from different life periods (e.g., “Tell me something that happened to you at secondary school”). This, of course, raises the problem of how the veracity of these memories is confirmed, particularly as even a spouse may be unable to confirm some events. When possible, prompts to events that include the informant can circumvent this problem (e.g., “Tell me something that happened on your wedding day”; “Tell me about a family holiday when the children were young”). In pragmatic terms, false memories seldom pose a problem because the usual response with organic memory impairment is failure to produce any memory (real or otherwise). In a clinical setting, in contrast, memory impairment in confabulators is typically apparent without the use of such probes. Semantic memory for facts can be tested by knowledge of famous people and events, but these must be tailored to the expected knowledge of the local population. For instance, in a U.K. clinic, the clinician might ask, “Who is the prime minister?” “Who was the woman prime minister?” “Which member of the Royal family died in a car accident in Paris?” “Which members of the Beatles are still alive and which are not?” and so forth. Family informants offer a ready-made, reasonably well-matched source for gauging control performance. General semantic knowledge can be assessed by category fluency tasks (naming as many animals as possible in 1 minute), picture naming, definition (“What is a caterpillar?”), naming according to definition (“What is the large gray animal with a trunk called?”), object knowledge (asking patient to demonstrate use of a stethoscope, corkscrew, stapler, and so forth). The important detail in testing general semantic memory is to ensure that a range of low-frequency items is included; asking the patient to name a “watch” and a “pen,” as in the Mini-Mental State Examination, will only identify very advanced impairments.

Neuropsychological Assessment The neuropsychologist also documents the patient’s history, including the demographic information necessary for test interpretation (age, education, handedness). Memory performance also needs to be interpreted in the context of general cog■

Figure 4–3. Bedside test of name and address recall. Scoring: Each encoding trial (T1 to T3) is scored on a 7-point scale (1 point for each item). Delayed recall (DR) is tested after five minutes. Recognition can be assessed by presenting the name and address on paper with two foils of similar structure. (See Mathuranath PS, Nestor PJ, Berrios GE, et al: A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000; 55:1613-1620.)

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T A B L E 4–2. Selected Neuropsychological Tests of Memory Test New Learning Rey Auditory Verbal Learning Test (RAVLT) California Verbal Learning Test (CVLT) Story Recall (Logical Memory) Recognition Memory Test (RMT) Doors and People Test

Description

Word list encoding, free recall, and recognition Word list semantic clustering, encoding, free recall and recognition Story free recall ± recognition Face and word recognition

Rey-Osterrieth Complex Figure*

Verbal and nonverbal recall and recognition Nonverbal recall ± recognition

Paired Associates Learning (PAL)

Object/spatial location recall

Rivermead Behavioural Memory Test (RBMT)

Various tests including some “real-life” memory tasks

Remote Memory Autobiographical Memory Interview (AMI) Galton-Crovitz cue-word test

General Semantic Memory Category fluency

Personal semantics and episodes from childhood, early adulthood, and recent past Specific autobiographical episodes generated to word prompts

Boston Naming Test

Generation of exemplars to a target category Picture naming

Graded Naming Test

Picture naming

Pyramids and Palm Trees Test

Word and picture forced-choice associative knowledge

Reference or Source

Rey A: L’Examen Clinique en Psychologie. Paris: Presses Universitaires de France, 1964 Delis DC, Kaplan E, Kramer J, et al: California Verbal Learning Test (CVLT-II) Second Edition—Adult Version. San Antonio, TX: The Psychological Corporation, 2000 Wechsler D: Wechsler Memory Scale—Revised. San Antonio, TX: The Psychological Corporation, 1987. Warrington, EK: Recognition Memory Test. Windsor, UK: NFER-Nelson, 1984 Baddeley A, Emslie H, Nimmo-Smith I: Doors and people. Oxford, UK: Thames Valley Test Company, 1994 Osterrieth PA: Le Test de Copie d’Une Figure Complex [Complex Figure Copy Test]. Arch Psychol 1944; 30:206-356. Cambridge Neuropsychological Test Automated Battery. Cambridge, UK: Cambridge Cognition, Ltd. Wilson BA, Cockburn J, Baddeley A: Rivermead Behavioural Memory Test (RBMT-II). Oxford, UK: Thames Valley Test Company, 2003 Kopelman M, Wilson B, Baddeley A: The Autobiographical Memory Interview (AMI). Oxford, UK: Thames Valley Test Company, 1990 Crovitz HF, Schiffman H: Frequency of episodic memories as a function of their age. Bull Psychonom Soc 1974; 4:517-518

Kaplan E, Goodglass H, Weintraub S: Boston Naming Test. Philadelphia: Lea & Febiger (Also published by Psychcorp and LWW.), 1983 McKenna P, Warrington EK: The Graded Naming Test. Windsor, UK: NFER-Nelson, 1993 Howard D, Patterson K: Pyramids and Palm Trees Test. Oxford, UK: Thames Valley Test Company, 1992

Factual Semantic Memory Variations on tests of famous people, news events, etc.† *See Figure 4-9 † These tests are typically used to assess the temporal extent of amnesia; however, because knowledge of such events varies greatly between communities, these tests are typically devised by individual neuropsychology laboratories.

nitive abilities; thus, the assessment is never restricted to memory alone. A vast array of tests are available that probe various aspects of memory: encoding, retrieval, and recognition; verbal and nonverbal memory; remote memory; and so on. Some of the memory tests in common usage are listed in Table 4–2. Reliable interpretation of neuropsychological performance requires that the tests be administered under standardized conditions by an appropriately trained examiner. Ad hoc incorporation of neuropsychological tests into the bedside examination is therefore best avoided.

SYNDROMES OF MEMORY DISTURBANCE Transient Memory Disorders Transient Global Amnesia Transient global amnesia (TGA) is a syndrome of sudden onset, occurring in late middle or old age. An affected patient is

characteristically densely amnesic and appears confused, repeatedly asking questions such as “Where am I?” or “What are we doing?” The event typically lasts for several hours, and during this time there is both anterograde and retrograde amnesia, although knowledge of personal identity is maintained. After the acute attack resolves, the patient is left with a period of amnesia for the time of the episode. The cause is uncertain, with suggested possibilities including a vascular transient ischemic attack, a seizure, or migraine. In single photon emission computed tomography images, transient perfusion defects in the mesial temporal lobe are evident during the episode,9 which highlights the presence of hippocampal dysfunction even if not identifying the underlying cause. Although TGA has an acute onset, it is seldom confused with more dangerous causes of acute amnesia such as viral limbic encephalitis, because the patient is otherwise alert, well and, more often than not, already in the recovery phase by the time of assessment. TGA typically occurs only once, and although cases of recurrent TGA are described, repeated episodes should alert the clinician to the possibility of transient epileptic amnesia (TEA).

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Transient Epileptic Amnesia

Trauma

Temporal lobe epilepsy is an increasingly recognized cause of transient memory impairment in middle-aged and elderly persons. The diagnosis is most secure when amnesic attacks are associated with a history of temporal lobe epilepsy or electroencephalographic evidence of temporal lobe discharges— which may be evident only on a during-sleep recording—and when the frequency of episodes is unequivocally improved by anticonvulsant therapy. Typical attacks of TEA differ in several ways from those of TGA, although the syndromes may be impossible to differentiate on the basis of the retrospective clinical account of an individual episode. The most useful distinguishing features of TEA are that the amnesic attacks are often briefer than those of TGA (less than 1 hour) and may occur on waking from sleep.10 In contrast to TGA, the patient may remember that he or she was unable to remember during the episode. It is not clear whether TEA results from an ictal or postictal state. In addition to discrete attacks of TEA, some patients with temporal lobe epilepsy appear to have accelerated forgetting of new episodic memories. These patients do not have evidence of an anterograde amnesia over the half-hour period usually employed to test delayed recall during neuropsychological assessment. However, episodic memory recall over longer periods appears to be impaired.11 Typically, the problem becomes apparent to the patient when the patient is discussing specific events with family members, such as the details of a particular outing, or while he or she is looking at holiday photographs. Although the family members confirm that the patient appeared normal at the time the particular event took place, the patient subsequently claims no recollection of the episode. It is speculated that subclinical temporal spike activity—particularly during sleep—may interfere with longterm consolidation of these memories.

After regaining consciousness from severe closed head injury, patients typically have a variable retrograde amnesia in combination with anterograde amnesia, called post-traumatic amnesia. This type of amnesia is conventionally defined as the period from regaining consciousness to when a continuous memory record is reestablished. If the period of amnesia is brief (hours), the prognosis for a full recovery is generally good. Although those with prolonged post-traumatic amnesia appear to have significant memory impairment, they do not have a pure amnesic syndrome in the strict sense, inasmuch as there are also deficits in attention and concentration. The marked distractibility seen in such cases is more akin to that seen with a diffuse encephalopathy.

Migraine On occasion, migraine sufferers present with memory symptoms similar to those described in the previous section on TEA, but no evidence can be found to support a diagnosis of epilepsy. In such circumstances, it is impossible to be certain of a causal relationship, but a speculative trial of migraine prophylaxis may be worthwhile.

Drugs Severe alcohol intoxication is a well-known cause of brief amnesic periods. However, in this author’s experience, these “alcoholic blackouts” never come to specialists’ attention as a diagnostic problem. More relevant to clinical practice is that a multitude of prescribed drugs are associated with symptoms of memory impairment. Patients affected by these medications do not have amnesia as such, but they complain of poor memory in the context of feeling “spaced out,” “like a zombie,” or “unable to think”; these symptoms are indicative of an attention deficit. Commonly implicated agents include benzodiazepines, antidepressants, anticonvulsants, neuroleptics, and anticholinergics. Obtaining a detailed drug history is especially important for patients with organic memory impairment, particularly in the context of a degenerative etiology such as Alzheimer’s disease, because these compounds exacerbate the existing deficits.

Electroconvulsive Therapy Electroconvulsive therapy for treatment of severe depression is associated with a brief retrograde and anterograde amnesia but is not generally thought to cause ongoing memory impairment after the event. The severity of memory impairment is minimized by applying a unilateral, as opposed to bilateral, stimulus.

Fixed Memory Disorders Strategic Lesions Mesial temporal lobe Lesions that damage the hippocampus and adjacent areas provide the archetypal substrate for amnesia. Possibly the most famous (or notorious, depending on one’s perspective) case in 20th century neuropsychology is that of H.M., a man who underwent bilateral mesial temporal lobectomy to control intractable epilepsy in the 1950s and was found postoperatively to have profound episodic memory impairment.12 Since H.M., numerous cases of hippocampal amnesia have been studied. Such cases typically have dense anterograde amnesia with variable retrograde amnesia. The degree of retrograde amnesia is approximately proportional to the extent of mesial temporal lobe lesions, whereas damage restricted to the cornu ammonis 1 field of the hippocampus may be associated with an almost pure anterograde amnesia.13 The hippocampus is particularly susceptible to anoxic damage; hence, bilateral focal hippocampal lesions are typically seen after resuscitation from cardiac arrest, carbon monoxide poisoning, and other states of hypoxemia or hypotension that cause inadequate cerebral perfusion. The blood supply of the hippocampus is predominantly via temporal branches of the posterior cerebral artery and, consequently, emboli to the vertebrobasilar system can also cause bilateral infarction. Unilateral infarcts (Fig. 4–4) from the same source tend to cause material-specific deficits; left- and right-sided lesions cause disproportionate verbal and visual memory deficits, respectively. The latter are usually evident in spatial memory tasks, although there is controversy regarding whether a lesion restricted to the right hippocampus is sufficient to cause the deficit. There is evidence to suggest that right parahippocampal damage may play a crucial role.14 Unilateral infarcts of the hippocampal head can also arise from anterior choroidal artery

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Diencephalon (Thalamus and mamiliary body)

Fornix

Basal forebrain

Mesial temporal lobe (Hippocampus and entorhinal cortex) ■

Figure 4–5. Lesion sites associated with amnesia in humans.

Basal forebrain

■

Figure 4–4. Right-sided mesial temporal lobe infarct (related to atrial fibrillation) in a patient with a material-specific nonverbal memory deficit.

occlusion. Aside from vascular disease, the other major causes of focal mesial temporal lobe damage are viral and immune system–mediated limbic encephalitides (see sections on Immune System–Mediated Limbic Encephalitis and Viral Limbic Encephalitis).

Fornix The fornix is the principal projection from the mesial temporal lobe to the mamillary body and thalamus. Most reports describe a relatively pure, anterograde amnesia. Iatrogenic lesions caused by surgical division in the course of removing colloid cysts from the third ventricle,15 as well as tumors and trauma, are recognized causes.

Diencephalon The fornix, both directly and via the mamillary body, projects to the rostral thalamic nuclei and particularly to the anterior thalamic nucleus. Lesions in this region can cause dense anterograde and retrograde amnesia. Posteromedial central branches from the posterior cerebral arteries supply the anterior nuclei, and hence infarction caused by emboli in the vertebrobasilar system can cause bilateral lesions. This bilateral vulnerability is further increased because the central artery of Percheron, which arises from one or other posterior cerebral artery, divides to supply both mesial thalami; thus, a single vessel occlusion can lead to bilateral infarction. Bilateral lesions can also result from anoxic damage (deep watershed infarcts). As with mesial temporal lesions, unilateral thalamic lesions are associated with material-specific deficits. It is difficult to prove that amnesia may be caused by focal mamillary body lesions, but this seems the most parsimonious explanation in some cases.16 Patients with diencephalic amnesia may also have a degree of executive impairment, caused by disruption of frontostriatal networks.

Cases in which lesions in the region of the septal nuclei, the diagonal band of Broca, the nucleus basalis of Meynert, the substantia innominata, and the nucleus accumbens are associated with amnesia have been described. It is speculated that this may be a consequence of damage to cholinergic projections originating in the diagonal band of Broca and projecting to the hippocampus,17 although the specific anatomical mechanism is far from certain. Although this area lies in close proximity to the diencephalon, several reports indicate that the latter may be spared in such cases. The typical pathological process is rupture of an aneurysm in the anterior communicating artery.

Retrosplenial cortex As the name suggests, the retrosplenial cortex lies immediately adjacent to the splenium of the corpus callosum (Fig. 4–5). This cause of amnesia is rare, because focal lesions of the retrosplenial cortex are seldom encountered. Nevertheless, there have been several case reports in which amnesia was associated with damage to this area. Material-specific deficits are typical with unilateral lesions.18 Interestingly, the neural connections of the retrosplenial cortex are to the mesial temporal lobe and the dorsolateral prefrontal cortex, which place it in what is potentially a pivotal point in relation to structures involved in episodic memory processing. The usual pathological process is hemorrhage related to an underlying vascular malformation. Tumors of the splenium itself have also been reported to cause amnesia,19 and it may be that this is a consequence of retrosplenial cortex compression; however, the fornix lies subjacent to the ventrorostral surface of the splenium, so that damage to this structure may also be relevant to the genesis of the amnesic syndrome.

Korsakoff’s Psychosis Korsakoff’s psychosis (or syndrome) is a severe, diencephalic amnesia caused by thiamine deficiency. It is typically seen in alcoholic patients with very poor diets, but it is important to remember that the critical factor is the dietary deficiency, rather than the alcohol. Thus, Korsakoff’s psychosis may occur in any disorder in which there is failure to maintain thiamine intake, such as gastrointestinal disorders (including gastric

chapter 4 disorders of memory T A B L E 4–3. Checklist of Emergency Management of Management and Investigation of Acute Amnesia 1. Start thiamine (>400 mg daily) with multi–vitamin B supplement and IV acyclovir. 2. Check blood biochemistry (including Mg) and hematology, and arrange cerebral imaging (MRI if possible). Is there: Temporal lobe hemorrhagic necrosis? (HSVE) High signal in hippocampi? (autoimmune and paraneoplastic limbic encephalitis) 3. CSF for biochemistry, cell counts, and HSV PCR assay Is there evidence of HSVE? 4. Is there evidence of EEG? Nonconvulsive status epilepticus Period complexes (HSVE) 5. Antineuronal antibody, VGKC-Ab, paraneoplastic screen (including FDG-PET if standard test results negative). 6. Trial of immunomodulation therapy if HSVE and Korsakoff’s psychosis are definitely ruled out. CSF, cerebrospinal fluid; EEG, electroencephalogram; FDG-PET, fluorodeoxyglucose–positron emission tomography; HSV, herpes simplex virus; HSVE, herpes simplex virus encephalitis; IV, intravenous; Mg, magnesium; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; VGKC-Ab, voltagegated potassium channel antibodies.

restriction surgery) and hyperemesis gravidarum. It usually follows from Wernicke’s encephalopathy, which consists of the classic triad of ataxia, ophthalmoplegia, and delirium, although presentation with delirium alone is common. It is therefore also referred to as Wernicke-Korsakoff syndrome. Korsakoff’s psychosis can be prevented at this encephalopathic stage by highdose parenteral thiamine (given in combination with empirical multi–vitamin B group supplements, because multiple deficiencies may be present). Thiamine levels can be assessed by assay of erythrocyte transketolase activity, but this is seldom appropriate, because empirical therapy is straightforward and should not be delayed. Wernicke’s encephalopathy can be precipitated by glucose infusion in incipient thiamine deficiency. Of importance is that Mg2+ is a cofactor for thiamine activity, and patients may be resistant to thiamine therapy until concomitant magnesium deficiency is corrected.20 Unfortunately, if the patient has amnesia without delirium, which suggests that Korsakoff’s psychosis has already ensued, the prognosis for recovery is very poor. Nevertheless, suspected Korsakoff’s psychosis and limbic encephalitides (see next section) represent the most urgent management problems among the memory disorders, and thiamine deficiency should always be considered in cases with acute or subacute amnesia (Table 4–3). Korsakoff’s psychosis typically causes a severe global amnesia. Anterograde amnesia is profound and accompanied by a severe retrograde amnesia. If the retrograde amnesia is temporally graded (worse for more recent retrograde memories) rather than complete, it usually spares only very remote memory. Typically, there is an associated dysexecutive syndrome. Neuronal loss is found in the mamillary body, the mediodorsal nucleus, and anterior thalamic nucleus; damage to the anterior thalamic nucleus appears most specific for Korsakoff’s psychosis–related amnesia.21

Immune System–Mediated Limbic Encephalitis Paraneoplastic limbic encephalitis causes the subacute onset of amnesia, typically over days to weeks. Like other paraneo-

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plastic neurological syndromes, antibodies raised in response to the tumor are thought to cross-react with neuronal epitopes. Patients typically present with memory impairment in association with confusion and, not infrequently, seizures. Because of these additional features, it is difficult to make appropriate generalizations about the type of memory deficit, but marked impairment of free recall of new information is typical. The electroencephalogram may show focal temporal lobe discharges. Magnetic resonance imaging (MRI) in the acute phase may reveal high signal in the hippocampi on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. The presence of antineuronal antibodies in serum—most commonly anti-Hu—is supportive, but a negative result should not deter a search for malignancy if suspicion is high, particularly if there is a cerebrospinal fluid (CSF) pleocytosis.22 A twopronged management strategy offers the best chance of improvement: treatment of the acute neurological disorder and definitive management of the tumor. Anecdotal reports suggest that immunomodulatory therapy (steroids, gamma globulin, or plasmapheresis) may be helpful in some cases and should be tried. The most commonly associated malignancy is small-cell lung cancer, with gonad, breast, and non-Hodgkin lymphoma also likely possibilities. Imaging of chest, abdomen, pelvis, and breasts should be performed. Paraneoplastic phenomena are often associated with very early tumors; therefore, if these investigations yield negative results, a full-body fluorodeoxyglucose positron emission tomographic scan to look for metabolic hot spots can increase yield. Cases in which hippocampal atrophy ensues have a poor prognosis for recovery. However, some patients with hippocampi that appear preserved on MRI may recover memory, although prognosis for such recovery is unpredictable (Fig. 4–6).23 Nonparaneoplastic limbic encephalitis has a clinical onset and memory symptoms that may be indistinguishable from those of paraneoplastic limbic encephalitis.24 Temporal lobe seizures and confusion may also occur. The key feature is the presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the serum, as are found in neuromyotonia, a condition that may coexist with the limbic encephalitis. Imaging studies indicate abnormal signal in the hippocampus on MRI scanning (Fig. 4–7), whereas the CSF is usually acellular.22 Anecdotal reports suggest that immunomodulatory therapy can improve amnesia and that the VGKC-Ab titer may be correlated with disease activity.

Viral Limbic Encephalitis Limbic encephalitis also occurs with herpes simplex virus encephalitis (HSVE); typically, herpes simplex virus (HSV) type 1 is the causative organism, although HSV type 2 can produce the same illness. The clinical features are similar to those of immune system–mediated limbic encephalitis, with memory impairment, confusion, and seizures, although the presentation is typically more fulminant. There is a significant mortality rate, and memory sequelae are common in survivors. HSVE is a medical emergency, in that the best chance for full recovery is with early treatment. Empirical acyclovir should be commenced in all suspected cases as first-line management (i.e., before the diagnostic workup is started; see Table 4–3). Cerebral imaging with MRI, to look for signal changes and hemorrhage in the rostral temporal lobes, often provides supportive evidence. If MRI is unavailable, computed tomography can be

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Figure 4–6. Two cases of limbic encephalitis and underlying small cell lung cancer—one with preserved hippocampi (left) whose amnesia responded to therapy and the other with severe hippocampal destruction (right) whose amnesia persisted. (From Bak TH, Antoun N, Balan KK, et al: Memory lost, memory regained: neuropsychological findings and neuroimaging in two cases of paraneoplastic limbic encephalitis with radically different outcomes. J Neurol Neurosurg Psychiatry 2001; 71:40-47. Reproduced by permission from the BMJ Publishing Group.)

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Figure 4–7. High signal intensity (arrows) in hippocampi on coronal magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) in voltage-gated potassium channel antibodies (VGKC-Ab)–associated limbic encephalitis. (From Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody– associated encephalopathy: a potentially immunotherapy response form of limbic encephalitis. Brain 2004; 127(3):701-712. Reproduced by permission of Oxford University Press.)

utilized, although it is considerably less sensitive.25 Periodic temporal lobe discharges on electroencephalography also provide good supportive evidence. The CSF study shows a lymphocytic pleocytosis, but a very high erythrocyte count— suggestive of a traumatic tap—may also result from cortical hemorrhagic necrosis. Definitive diagnosis is usually established by demonstration of a positive CSF polymerase chain reaction assay for HSV. In the acute phase, memory assessment is usually superfluous because patients are typically delirious, often requiring sedation and mechanical ventilation. Various combinations of semantic and episodic memory impairments are seen in survivors, depending on the precise location and extent of cerebral damage. Mesial temporal damage is associated with anterograde amnesia, and because the distribution of pathological process is often asymmetrical, material-specific deficits are common. Variable degrees of retrograde amnesia may occur in association with the anterograde memory deficit, and HSVE can occasionally give rise to a relatively focal retrograde amnesia.26 This phenomenon appears to occur when there is disproportionate temporal isocortical damage (as opposed to hippocampal and entorhinal lesions). Temporal isocortical damage can also cause semantic memory impairments. Unlike semantic dementia (see later discussion), these are often quite patchy, giving rise to what are referred to as category-specific deficits.27 Semantic knowledge can be considered in categories defined by their semantic relatedness. For instance, varieties of land animals, breeds of dogs, varieties of birds, body parts, tools, and musical instruments can all be considered as belonging to definable semantic categories and tested for accordingly. The commonest reported category-specific deficit is the dissociation of synthetic artifacts from living creatures, but various other

chapter 4 disorders of memory permutations are also described. Category-specific deficits are of research interest because they offer insights into the neural structuring of semantic memory. The basic principle is that as the degree of similarity between semantic exemplars increases, so too does the overlap in the neural networks that represent the items. The attributes of an item give rise to a stable neural representation—or “attractor” in computational models—that identifies it as a specific, nameable entity. For semantically related items (e.g., land animals), these attractors share common features and thus may share common vulnerability if part of the network is damaged. See Rogers and Plaut (2002) for a detailed review of lesion evidence, computational models and proposed theories of category-specific deficits.28

Progressive Memory Disorders Alzheimer’s Disease Alzheimer’s disease is the commonest cause of memory impairment. In established Alzheimer’s disease, the diagnosis is usually straightforward: Patients have severe impairment of episodic memory with variable degrees of impairment in other cognitive domains, including semantic and working memory. However, the insidious onset and slowly progressive nature of the impairment make early diagnosis more difficult because, in contrast to the disorders already discussed, patients do not start out with a dense amnesia. It is increasingly recognized that relatively isolated episodic memory impairment can precede full-blown dementia by several years.29 Because the clinical diagnostic criteria for Alzheimer’s disease include impairment in multiple cognitive domains, early symptomatic cases that have not crossed this threshold cannot be labeled “Alzheimer’s disease” if the consensus diagnostic criteria are strictly applied.30 This had led to the introduction of the term amnestic mild cognitive impairment (MCIa) to describe isolated impairment of episodic memory.31 In spite of the current vogue for “diagnosing” MCIa, it must be emphasized that this term does not denote a pathological entity but rather a degree of severity. If symptomatic Alzheimer’s disease begins with isolated episodic memory impairment, why not revise the diagnostic criteria so that MCIa is called Alzheimer’s disease? The problem is that in the clinic, the more subtle the cognitive impairment, the less certain it is that symptoms will progress. Many patients with what appears to be isolated memory impairment may have a psychiatric illness or simply have “a bad memory” that will not worsen over time. Annual progression rates from the MCIa stage to probable Alzheimer’s disease are usually reported to be in the vicinity of 15% per annum. However, there is considerable variability in progression rates between cohorts, which most likely relates to differences in clinical features at baseline; within the designation of MCIa, there is scope for inclusion of cases that vary from minimal impairment to being on the cusp of a consensus classification of Alzheimer’s disease. Therefore, it is not surprising that MCIa patients who exhibit features suggestive of Alzheimer’s disease—such as subtle non-mnestic cognitive deficits, hippocampal atrophy visible on MRI, and temporoparietal hypometabolism evident on positron emission tomography—are at highest risk of early deterioration to dementia. The key to clinical assessment is to disentangle “sinister” memory symptoms from more benign lapses. To this end, three factors in the clinical assessment are essential. The first is

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always to document history from an informant who knows the patient well. Although the patient usually acknowledges memory lapses, sinister lapses are particularly evident to the informant. In contrast, patients with nonsinister memory symptoms often complain vociferously of the problem, but an informant states that the symptoms have little or no effect. The second is to note the quality of the symptoms. Attention lapses, which can be exacerbated by stress or depression, occur in the normal population and cause people to misplace their keys, forget why they just opened the refrigerator (the “fridge door” effect), miss prearranged appointments, and so on. On the other hand, forgetting an appointment or passing on a phone message but then subsequently having no clear recollection of the appointment’s being made or the conversation’s occurring in the first place is a far more ominous symptom. Likewise, getting temporarily lost in an unfamiliar place is of little significance, whereas forgetting how to get about in one’s usual neighborhood is a more serious matter. Another helpful way to examine these issues objectively is to take a detailed autobiographical history. Many patients with early Alzheimer’s disease present very well if allowed to take the lead in the consultation. However, patients can be taken out of their “comfort zone” by being asked for specific details of major life events (e.g., schools attended, full employment history, residences, marriages, birth details of children and grandchildren), and their answers can often expose major problems that would otherwise be missed. The final assessment is to examine memory formally, both in the clinic and with formal neuropsychological measures. In the early stages, patients with organic memory impairment resulting from Alzheimer’s disease exhibit good registration of new information but profound deficits in delayed free recall. Of note is that the widely used Mini-Mental State Examination contains little to expose this deficit. The only delayed-recall task is threeitem word recall, which is usually conducted after a delay of only a few seconds. Intelligent patients can often hold this information in working memory; hence, a perfect score on the Mini-Mental State Examination does not exclude the possibility of a significant episodic memory deficit. The cause of the episodic memory deficit in Alzheimer’s disease is complex. Early neurofibrillary tangle deposition (one of the hallmarks of Alzheimer’s disease) in the mesial temporal lobe suggests that memory impairment may be underpinned by damage to this area. However, although structural imaging may reveal hippocampal atrophy in many individuals (Fig. 4–8), there is considerable overlap in this feature between Alzheimer’s disease and healthy aging. Likewise, although cholinergic depletion is well recognized in Alzheimer’s disease, pathological32 and cholinergic ligand-based functional imaging studies33 suggest that this is not a major feature of the very early stage of the disease. Positron emission tomography suggests that the deficit may result from the combined effect of a degeneration of the functional network, including the mesial temporal lobe, diencephalon, and retrosplenial/posterior cingulate cortex.34

Dementia with Lewy Bodies Dementia with Lewy bodies (DLB) is probably the second commonest cause of dementia in elderly persons, after Alzheimer’s disease. It is characterized by fluctuating confusion, hallucinations (typically of the formed visual type), spontaneous extrapyramidal features, and a neuropsychological profile of prominent working memory and visuoperceptual deficits.35

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Figure 4–8. Hippocampal atrophy (arrows) in a man with mild

Figure 4–9. Rey-Osterrieth Complex Figure Copy Test.

Alzheimer’s disease (Mini-Mental State Examination score = 22/30).

Nevertheless, the presenting complaint is often stated to be “memory problems.” The key difference from Alzheimer’s disease is that for the degree of episodic memory impairment, there is disproportionate impairment of the aforementioned domains. The memory impairment itself is also qualitatively different from that seen in Alzheimer’s disease and, indeed, from amnesic syndromes in general. In keeping with the working memory deficit, patients have marked deficits in encoding. For instance, in three-trial learning of a sevenelement name and address, many patients with very mild Alzheimer’s disease can repeat all seven elements after the first trial and, if not, performance generally improves over the subsequent trials. In contrast, DLB patients tend to have marked impairment of registration after the first trial and little or no improvement over subsequent trials. However, whereas delayed recall in early Alzheimer’s disease is markedly impaired in spite of good registration (e.g., learning trial scores are 6/7, 7/7, and 7/7; delayed-recall score is 0/7), many patients with DLB recall a large proportion of what they managed to encode (e.g., learning trial scores are 3/7, 4/7, and 4/7; delayed-recall score is 3/7). DLB is associated with a marked cholinergic deficit and, although cholinesterase inhibitors were introduced primarily for Alzheimer’s disease, it appears from anecdotal reports and small trials that they are more useful in improving cognition in DLB.36 In addition to the positive effects that these drugs have on the neuropsychiatric features of DLB, they seem particularly helpful in improving working memory and the related encoding deficit.

Frontotemporal Dementia There are three clinical presentations of frontotemporal dementia: a neuropsychiatric syndrome, nonfluent progressive aphasia, and semantic dementia.37 Of these, semantic dementia is of most interest with respect to impainment of declarative memory.38 As the name suggests, these patients have progressive semantic memory impairment (factual knowledge, word meanings, and object knowledge), which gives rise to

comprehension deficits and fluent aphasia. Unlike post-HSVE cases, significant category-specific deficits in semantic knowledge are rarely encountered, possibly because HSVE is more likely to result in a patchy distribution of cortical damage. In fascinating contrast to amnesic syndromes, patients with semantic dementia have relative preservation of episodic memory, as evinced by their often remarkably rich ability to recount anecdotes from the recent past. An important caveat for the neuropsychological assessment of episodic memory in semantic dementia is that the semantic knowledge deficit confounds performance on verbal memory tasks. Word-list learning or story recall is aided under normal circumstances by the ability to make semantic associations; if semantic knowledge is degraded, then word-list learning is analogous to normal subjects’ learning a list of unfamiliar foreign-language words. Nevertheless, because degeneration is usually maximal in the left temporal lobe, a degree of verbal episodic memory impairment is difficult to rule out. However, on nonverbal tests that minimize semantic associative knowledge (e.g., the Rey-Osterrieth Complex Figure Copy Test [Fig. 4–9]), delayed recall scores are often within the normal range. The remote memory profile also provides an interesting contrast to that seen in classic amnesic syndromes. Recent episodic memory (dating back weeks to months) is relatively preserved in comparison with memory from more remote time periods,39 a finding that is also true of semantic facts that can be dated to a specific time period (such as knowledge of famous people and events).40 These findings suggest that remote autobiographical memories may actually be supported by similar mechanisms to those involved in semantic memory. The distribution of degenerative change in semantic dementia is typically asymmetrical and involves the anterior temporal lobes (especially the poles and inferior surfaces) (Fig. 4–10). The preservation of episodic memory was initially thought result from sparing of the hippocampi; however, volumetric MRI has shown that hippocampal atrophy in semantic dementia is at least as severe as that seen in Alzheimer’s disease, which suggests that the amnesia in the latter may be more a consequence of damage to other areas. A final contentious issue in semantic dementia is whether the asymmetrical atrophy of the

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antidepressant therapy may be indicated, but longitudinal follow-up is the only way to reach a definitive diagnosis.

Hysterical Amnesia

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Figure 4–10. Focal atrophy of the temporal lobe (arrow) in semantic dementia.

temporal lobes can give rise to material-specific semantic memory deficits. Some authors have suggested that patients with greater right-sided atrophy have more problems with nonverbal semantics41 (such as prosopagnosia for famous faces). The alternative view is that semantic knowledge is bilaterally distributed but naming is lateralized to the left. Consequently, verbal semantics are more impaired with greater degrees of left temporal atrophy, because this weights word-processing ability.

Memory Impairment in Psychiatric Disorders Anxiety and Depression Symptoms of episodic memory impairment are very common with anxiety and depression, and disentangling these from early Alzheimer’s disease represents one the greatest diagnostic challenges in the assessment of memory disorders. This is further compounded by the fact that the anxiety itself may be driven by fear of Alzheimer’s disease in a patient with a positive family history. As already discussed in the Alzheimer’s disease section, the quality of memory symptoms can be a helpful discriminator. Exacerbation of normal attention lapses (the already mentioned “fridge door” effect) is typical in anxiety and depression. A discrepancy between the severity of self-rated versus informant-related memory deficits and a discrepancy between selfreported memory deficits and retained functional abilities are also useful for diagnosis. Normal neuropsychological performance is also reassuring; however, many patients in this category have impairments in free recall, which may be related to both compromised attention at encoding and anxiety-induced interference with retrieval strategies. Independent evidence of anxiety or affective symptoms offers only circumstantial evidence to support the diagnosis of “nonorganic” memory symptoms, because there is also an increased prevalence of anxiety and depression among patients with incipient dementia. In summary, it is sometimes impossible to discriminate between the memory impairment of anxiety or depression and that of incipient Alzheimer’s disease. In such circumstances, a trial of

Neuropsychological performance is only a semiobjective measure, inasmuch as valid results depend on the motivation and cooperation of the patient. Thus, there is scope for patients to elaborate their deficits, if that is their wont. As with any deficit in which elaboration of the signs is suspected, the examiner must be alert to the possibility that the patient may be exaggerating a truly organic deficit for fear of not being taken seriously. Nevertheless, a few profiles should alert the examiner that test performance may not necessarily be indicative of an organic disorder. For instance, apparent marked impairment on encoding, with no learning curve over successive learning trials but followed by good recall after delay, raises suspicions. Likewise, clinicians occasionally encounter patients who display reasonable free recall and yet perform far worse when the same material is presented in a recognition memory format. In such circumstances, the remainder of the neuropsychological assessment can offer further clues; many tests (e.g., naming) are graded in difficulty, and therefore finding that a patient is struggling with easy items but managing difficult items may be helpful. True hysterical amnesia is a fairly uncommon disorder but one that most commonly manifests with a characteristic profile: focal retrograde amnesia. The patient presents with a dense amnesia for a discrete period, with apparently normal memory for events from before and after the amnesic period and normal performance on tests of new learning. Alternatively, there may be a complete retrograde amnesia, including loss of personal identity. Psychological precipitants for this so-called psychogenic fugue state, such as marital problems, criminal fraud, and bereavement, are often reported. One caveat is that cases of organic focal retrograde amnesia are also described, particularly in connection with focal temporal isocortical damage (such as after HSVE or severe head injury).42 Nevertheless, in organic cases, the border zone between preservation and loss in remote memory is often rather blurred. Furthermore, in organic cases, anterograde memory is usually not entirely normal, particular in the early stages. In other words, focal retrograde amnesia tends to be relative in organic disorders but appears absolute in hysterical amnesia.43

K E Y

P O I N T S

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Conscious long-term memory in humans is divided into memory for specific events (episodic memory) and memory for general knowledge and facts (semantic memory).

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Working memory is a short-term memory system that allows the mind to keep information in continuous consciousness (“on line”). It is important for clinicians to understand how this system differs from long-term memory in order to accurately classify deficits.

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The term amnesia refers to a severe inability to establish and/or recall long-term memories, with preservation of working memory.

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Most patients who seek medical advice for symptoms of memory failure do not have frank amnesia but, nevertheless, may have organic impairment in long-term memory. Accurate diagnosis in such cases is facilitated by (1) taking a corroborative history from an informant and (2) having a problem-oriented, structured plan for memory examination.

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Acute or rapidly evolving amnesia is a medical emergency for which the clinician must have a clear understanding of the differential diagnosis, because immediate empirical therapy offers the best hope of avoiding long-term disability.

Suggested Reading Dudai Y: Memory from A to Z. Keywords, Concepts and Beyond. Oxford, UK: Oxford University Press, 2002. Kopelman MD: Disorders of memory. Brain 2002; 125:2152-2190. Nestor PJ, Scheltens P, Hodges JR: Advances in the early detection of Alzheimer’s disease. Nat Med 2004; 5:S34-S41. Rogers TT, Plaut DC: Connectionist perspectives on categoryspecific deficits. In Forde E, Humphreys G, eds: Category Specificity in Brain and Mind. Brighton, UK: Psychology Press, 2002, pp 251-289. Squire LR, Zola SM: Episodic memory, semantic memory, and amnesia. Hippocampus 1998; 8:205-211. Tulving E, Craik FM, eds: The Oxford Handbook of Memory. New York: Oxford University Press, 2000.

References 1. Tulving E, Kapur S, Craik FI, et al: Hemispheric encoding/retrieval asymmetry in episodic memory: positron emission tomography findings. Proc Natl Acad Sci U S A 1994; 91:2016-2020. 2. Baddeley A: Working memory. Science 1992; 255:556-559. 3. Hayashi Y, Majewska AK: Dendritic spine geometry: functional implication and regulation. Neuron 2005; 46:529-532. 4. Nadel L, Moscovitch M: Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 1997; 7:217-227. 5. Vargha-Khadem F, Gadian DG, Watkins KE, et al: Differential effects of early hippocampal pathology on episodic and semantic memory. Science 1997; 277:376-380. 6. Manns JR, Hopkins RO, Squire LR: Semantic memory and the human hippocampus. Neuron 2003; 38:127-133. 7. Kensinger EA, Schacter DL: Emotional content and realitymonitoring ability: fMRI evidence for the influences of encoding processes. Neuropsychologia 2005; 43:1429-1443. 8. Moscovitch M: Memory and working-with-memory: a component process model based on modules and central systems. J Cogn Neurosci 1992; 4:257-267. 9. Jovin TG, Vitti RA, McCluskey LF: Evolution of temporal lobe hypoperfusion in transient global amnesia: a serial single photon emission computed tomography study. J Neuroimaging 2000; 10:238-241. 10. Zeman AZ, Boniface SJ, Hodges JR: Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry 1998; 64:435-443. 11. Blake RV, Wroe SJ, Breen EK, et al: Accelerated forgetting in patients with epilepsy: evidence for an impairment in memory consolidation. Brain 2000; 123(Pt 3):472-483.

12. Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957; 20:11-21. 13. Zola-Morgan S, Squire LR, Amaral DG: Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 1986; 6:2950-2967. 14. Bohbot VD, Kalina M, Stepankova K, et al: Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex. Neuropsychologia 1998; 36:1217-1238. 15. Hodges JR, Carpenter K: Anterograde amnesia with fornix damage following removal of IIIrd ventricle colloid cyst. J Neurol Neurosurg Psychiatry 1991; 54:633-638. 16. Dusoir H, Kapur N, Byrnes DP, et al: The role of diencephalic pathology in human memory disorder. Evidence from a penetrating paranasal brain injury. Brain 1990; 113(Pt 6):16951706. 17. Abe K, Inokawa M, Kashiwagi A, et al: Amnesia after a discrete basal forebrain lesion. J Neurol Neurosurg Psychiatry 1998; 65:126-130. 18. McDonald CR, Crosson B, Valenstein E, et al: Verbal encoding deficits in a patient with a left retrosplenial lesion. Neurocase 2001; 7:407-417. 19. Rudge P, Warrington EK: Selective impairment of memory and visual perception in splenial tumours. Brain 1991; 114:349360. 20. McLean J, Manchip S: Wernicke’s encephalopathy induced by magnesium depletion. Lancet 1999; 353:1768. 21. Harding A, Halliday G, Caine D, et al: Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 2000; 123(Pt 1):141-154. 22. Darnell RB, Posner JB: A new cause of limbic encephalopathy. Brain 2005; 128:1745-1746. 23. Bak TH, Antoun N, Balan KK, et al: Memory lost, memory regained: neuropsychological findings and neuroimaging in two cases of paraneoplastic limbic encephalitis with radically different outcomes. J Neurol Neurosurg Psychiatry 2001; 71:40-47. 24. Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody–associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127:701-712. 25. Jha S, Patel R, Yadav RK, et al: Clinical spectrum, pitfalls in diagnosis and therapeutic implications in herpes simplex encephalitis. J Assoc Physicians India 2004; 52:24-26. 26. O’Connor M, Butters N, Miliotis P, et al: The dissociation of anterograde and retrograde amnesia in a patient with herpes encephalitis. J Clin Exp Neuropsychol 1992; 14:159178. 27. Warrington EK, Shallice T: Category specific semantic impairments. Brain 1984; 107:829-854. 28. Rogers TT, Plaut DC: Connectionist perspectives on categoryspecific deficits. In Forde E, Humphreys G, eds: Category Specificity in Brain and Mind. Brighton, UK: Psychology Press, 2002, pp 251-289. 29. Amieva H, Jacqmin-Gadda H, Orgogozo JM, et al: The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study. Brain 2005; 128:10931101. 30. McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease. Neurology 1984; 34:939944. 31. Petersen RC, Stevens JC, Ganguli M, et al: Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1133-1142.

chapter 4 disorders of memory 32. DeKosky ST, Ikonomovic MD, Styren SD, et al: Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002; 51:145-155. 33. Rinne JO, Kaasinen V, Jarvenpaa T, et al: Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74:113-115. 34. Nestor PJ, Fryer TD, Smielewski P, et al: Limbic hypometabolism in Alzheimer’s disease and mild cognitive impairment. Ann Neurol 2003; 54:343-351. 35. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1113-1124. 36. Grace J, Daniel S, Stevens T, et al: Long-Term use of rivastigmine in patients with dementia with Lewy bodies: an open-label trial. Int Psychogeriatr 2001; 13:199205. 37. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554.

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38. Hodges JR, Patterson K, Oxbury S, et al: Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 1992; 115:1783-1806. 39. Nestor PJ, Graham KS, Bozeat S, et al: Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia. Neuropsychologia 2002; 40:633654. 40. Hodges JR, Graham KS: A reversal of the temporal gradient for famous person knowledge in semantic dementia: implications for the neural organisation of long-term memory. Neuropsychologia 1998; 36:803-825. 41. Snowden JS, Thompson JC, Neary D: Knowledge of famous faces and names in semantic dementia. Brain 2004; 127:860872. 42. Kapur N, Ellison D, Smith MP, et al: Focal retrograde amnesia following bilateral temporal lobe pathology. A neuropsychological and magnetic resonance study. Brain 1992; 115(Pt 1): 73-85. 43. Kopelman MD: Focal retrograde amnesia and the attribution of causality: An exceptional critical view. Cogn Neuropsychol 2000; 17:585-621.

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HIGHER VISUOPERCEPTUAL DISORDERS AND DISORDERS OF SPATIAL COGNITION ●

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Zoë Terpening and John D. G. Watson

At least one third of the primate brain is devoted to visual perception and visual processing.1 A vast amount has been learned about the visual system in the past 100 years or so, from both laboratory studies and studies of clinical and healthy populations. This research has identified multiple areas in the cerebral cortex (not just the occipital lobe) that receive visual input (Figs. 5–1 through 5–3). There is both parallel and distributed processing of visual stimuli. One of the most famous depictions are the diagrams of Van Essen and colleagues,2 which map the macaque cerebral cortex (Fig. 5–1). The term higher visuoperceptual disorders carries the implication of abnormalities at the level of the thalamus and above, with the majority of cases arising from diseases of the cerebral hemispheres. Many disorders of higher visuoperceptual function have been described, some of them in syndromic fashion, and include Balint’s syndrome, cerebral akinetopsia (rare), cerebral dyschromatopsia (somewhat more common), disorders of face recognition (prosopagnosia), environmental disorientation (which overlaps with spatial disorientation: see also Chapter 6), and visual agnosias. Even one of the rarer language disorders may be thought of as a primary visual disturbance: alexia without agraphia (see Chapter 3). Higher-order visual complaints are often one of the first indications of a number of other neurological illnesses such as prion diseases. All these entities are of interest in their own right and may lead to significant morbidity. They are commonly not initially recognized, which causes further distress and difficulty for the patients, their families, and those who interact with them on a daily basis, such as work colleagues and health professionals.

EPIDEMIOLOGY Many of the diseases that underlie these abnormalities are age related—in particular, the dementias and cerebrovascular disease—so these entities are more frequent in older persons and are increasingly commonly encountered as the population ages. Within the neurodegenerative disorders, using Alzheimer’s disease as the prototype, estimates for the prevalence of higher-order visual disturbances are as high as 57%,

mainly because of a high prevalence of visual agnosia. The severity of the dementia is strongly correlated with the complexity of the presenting visual disturbance.3 The effects of these higher visuoperceptual disorders are amplified by other disorders of perception that may be present in older people, including visual loss because of anterior visual pathway disease (e.g., cataract, macular degeneration) and impairments of hearing and mobility. Studies have suggested that of people between the ages of 75 and 79, at least 12% have some visual impairment, rising to 23% in the 85- to 89-yearold age range.4 By 90 years of age, at least one in three people will have some visual deficit.4,5

THE TWO-SYSTEMS APPROACH TO HIGHER VISUOSPATIAL FUNCTIONING Higher visual processing attempts to achieve two primary objectives: the identification of visual stimuli and their localization in space. These two goals of visual analysis are often abbreviated as “what” and “where” (Fig. 5–4). Research has demonstrated that these two goals are achieved relatively independently through two anatomically separated systems known as the ventral (what) and dorsal (where) visual processing pathways.6-8 The fundamental concept is that there is a dorsal stream of information concerned with an object’s location and a ventral stream concerned with its identity. Because this distinction is so widespread in the literature, it must be considered, but even the proponents of this dualistic model freely admit that it is an oversimplification of the true situation, given that strong interactions occur between the two networks. We use this dichotomy in the current chapter to help distinguish higher visual disorders that are primarily deficits of visuoperception from those that are largely visuospatial in nature.

ANATOMY AND PHYSIOLOGY In general, higher visuoperceptual and visuospatial disorders reflect damage to one or several multiple brain regions includ-

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Disorders of the Temporal Vision–Related Cortex (Ventral Processing Stream) Damage to the cortical regions of the ventral processing stream results in a variety of disturbances of visual form and color perception (Table 5–1). These can include dyschromatopsia and alexia without agraphia. Most commonly, however, damage to these regions results in a form of visual agnosia, a clinical syndrome characterized by an inability to recognize a visually presented object despite the presence of adequate cognition, visual acuity, attention, and language skills.11,12 Agnosias are commonly subdivided on the basis of a distinction made by Lissauer,13 who posited in 1890 that the process of recognition has two distinct stages: apperception and association. Apperception is the ability to form a conscious percept of a sensory impression (e.g., an object), which can be thought of as the construction of different visual attributes of

Figure 5–1. Flattened map of cortical areas in the macaque. The locations of multiple visual areas are shown in colors that indicate whether they are in the occipital lobe (purple, blue, and reddish hues), parietal lobe (yellow, orange, and light brown hues), temporal lobe (green hues) or frontal lobe (dark brown hues). Note how much of the cerebral cortex is devoted to processing of visual information. The scale applies only to the flattened map; the brain drawings are much smaller. The abbreviations and numbers refer to discrete areas of cortex—refer to the original publication for a full explanation. (From Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991; 1(1): 1-47. Reproduced by permission of Oxford University Press.)

CA3 CA1

ing (but not restricted to) the occipital lobes, temporal lobes, parietal lobes, and underlying white matter. In many of the described syndromes, the right hemisphere appears to be more affected than the left, with many investigators proposing that much of the bilateral activation on higher visual tasks results from the transcallosal influence of the right hemisphere.9,10 The precise nature of the damage for each particular disorder is discussed in the following sections.

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the stimulus into a whole percept. Patients who present with these difficulties are said to have the syndrome of apperceptive agnosia, sometimes referred to as apperceptive visual object agnosia.12 Association, on the other hand, refers to the imparting of meaning to the percept, achieved through the use of matching or linking the percept to a previous experience or knowledge.13 Patients with association difficulties, who are said to have the syndrome of associative visual agnosia, often have difficulty accessing the memory of an object’s name or its meaning from the visual stimulus, despite a more or less correctly perceived visual percept, and demonstrably intact knowledge (if accessed via other modalities) of the object’s name and semantic attributes. Visual agnosias are often further classified on the basis of the categorical impairment such as prosopagnosia (agnosia for faces), environmental agnosia (agnosia for topographical orientation), and color agnosia.

Dyschromatopsia and Color Anomia Dyschromatopsia is a rare acquired inability to discriminate colors by hue.14 Dyschromatopsia is most often associated with damage to the inferior part of the occipital lobes, in the fusiform gyrus. This corresponds to the area identified in functional experiments as the human color area (V4).15,16 Patients usually have difficulty in tasks such as sorting sets of colored

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Figure 5–2. Hierarchy of visual areas in the macaque. This diagram shows over 30 visual cortical areas, shaded similarly to Figure 5–1, two subcortical visual stages— the retinal ganglion cell layer (RGC) and the lateral geniculate nucleus (LGN), plus several non-visual areas such as area 7b of the somatosensory cortex, area 36 and the hippocampal complex (HC). These areas are connected by extensive linkages, most of which have been demonstrated to be reciprocal pathways. The patterns of connections help to illustrate two fundamental principles of organization: hierarchical connections and parallel processing. (From Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991; 1:1-47.)

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T A B L E 5–1. Summary of Clinical Presentation and Location of Lesion in the Temporo-Occipital Vision Disorders Condition

Description

Location of Lesion

Dyschromatopsia Color agnosia (and anomia)

Inability to distinguish colors by hue Inability to name colors despite being able to match and sort items by color Inability to read despite preserved ability to write

Inferior occipital lobe, occipitotemporal lobe

Inability to recognize familiar objects despite intact visual acuity, contrast sensitivity, and often color perception and stereopsis Sensory percept stripped of meaning Inability to recognize familiar faces Inability to recognize familiar environments

Bilateral occiptotemporal lobes

Alexia without agraphia or pure alexia Apperceptive (object) Associative agnosia Prosopagnosia Environmental agnosia

counters. Hemidyschromatopsia may be more common; reflecting the location of damage, there is often an associated superior quadrantanopia on the same side. Color anomia is a disorder in which patients present with an inability to name colors but are still able to sort colored counters and differentiate between colors despite failure to name them.17

Occipitotemporal lobes

Bilateral occiptotemporal lobes Bilateral (but right > left) occipitotemporal lobes Right occipitotemporal lobes

Alexia Without Agraphia Alexia without agraphia (or pure alexia) is an acquired reading disorder in which the patient is unable to read, despite preservation of other aspects of language such as spelling and writing.18 Pure alexia is usually caused by an occlusion of distal

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C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s monly manifests as an inability to separate the object from a confounding background (figure-ground discrimination) or to interpolate the contours of a fragmented object (visual closure). Patients with severe visual object agnosia are normally unable to name objects presented to them visually, such as an empty glass, but can usually do so with the assistance of additional cues such as being allowed to hold it or hearing the noise when a spoon is tapped on the side of the glass. Causative lesions are typically bilateral, in the occipitotemporal lobes. Isolated, severe cases of visual object agnosia are rare, and almost all have followed carbon monoxide or mercury poisoning. However, lesser degrees of visual object agnosia are commonly encountered, particularly in Alzheimer’s disease, and may also result from tumors, hypoxic/hypotensive brain damage, or stroke, usually in the posterior cerebral artery territory.

Associative Agnosia

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Figure 5–3. Borders of multiple visual areas in humans revealed by functional magnetic resonance imaging. Several functionally defined visual areas (V1, V2, etc.) are displayed on the flattened cortex of the right hemisphere, viewed from behind. The positive sign denotes areas that correspond with the upper visual field, and the negative sign the lower visual field (although there is controversy relating to the properties of the ventrally placed color area, V4). The brightness of the areas represents the significance of the responses. Note that there are many visually responding areas that are not yet further typified. (From Sereno MI, Dale AM, Reppas JB, et al: Borders of multiple visual areas in human revealed by functional magnetic resonance imaging. Science 1995; 268:889-893.)

(posterior) branches of the left posterior cerebral artery. The resultant damage is believed to interrupt the transfer of neural information from the visual cortex to the language cortex. Stroke is one of the most common causes of pure alexia, but more rarely it may result from closed head injury, tumor, occipital lobectomy, arteriovenous malformations, and Alzheimer’s disease. Further details are given in Chapter 3, Disorders of Language.

Apperceptive Visual Agnosia: Visual Object Agnosia Visual object agnosia is an inability to recognize familiar objects from their visual shape attributes despite preservation of visual acuity, contrast sensitivity, and often color perception and stereopsis. This failure of object recognition can be attributed to impaired perception, which may be severe enough to prevent matching or copying of simple shapes, but more com-

Those patients with associative agnosia have apparently preserved sensory capability and may retain the ability to match and copy common objects but still fail to recognize them. Such cases led Teuber19 in 1968 to describe this as “a normal percept that has somehow been stripped of its meaning.” Some patients may have their problem limited to a specific class of objects, of which the best known is prosopagnosia—the failure to discriminate and recognize faces. Other object classes with which specific difficulties have been reported include animals or animal species, plants, foods, clothing, makes of cars, colors, or places. Some examples are discussed in the following paragraphs. The cerebral lesions are in areas similar to those causing apperceptive agnosia but have occasionally been linked to more diffuse cerebral damage such as hypoxic/ischemic brain damage or carbon monoxide poisoning and progressive multifocal leukoencephalopathy.

Associative Visual Agnosia for Familiar Faces: Prosopagnosia Prosopagnosia is characterized by an inability to identify familiar faces. Patients may correctly identify the emotion but still fail to identify the face. Given that differences between faces are subtle, the patient with prosopagnosia has difficulty telling them apart but might be able to do so if there is a highly salient feature such as a birthmark or beard. The patient is often able to recognize familiar people from other attributes, such as gait, clothes, or voice. The particular attributes of faces and the task of their recognition are much debated in the literature, but it seems likely that face recognition requires some abilities that do not overlap with other visual recognition abilities. A number of studies have been made of the ability to recognize faces in the normal, upright orientation in a type of gestalt perception, compared with recognizing faces that are upside-down. The latter is a very much harder task for normal subjects and involves different (feature-by-feature rather than whole-object) visual processing. It is intriguing that some prosopagnosics do not have this face inversion effect and, paradoxically, may perform better with inverted faces, suggesting a specific deficit in whole-object processing.20 Prosopagnosia is usually caused by more anterior lesions in the inferior occipitotemporal cortex (the anterior aspects of the lingual and fusiform gyri).21,22 In most cases, bilateral damage

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Figure 5–4. Network analysis of cortical visual pathways represented graphically for object and spatial visual networks in the right hemisphere. The magnitude of the direct effect (which can vary between −1 and +1) is proportional to the arrow width for each path, with values given in the scale below. Positive path coefficients are shown in solid arrows, and negative in dashed arrows. Paths where the coefficient was at or near zero are shown as dotted lines. The relative location of the brain regions is distorted somewhat to maintain figure clarity. (From McIntosh AR, Grady CL, Ungerleider LG, et al: Network analysis of cortical visual pathways mapped with PET. J Neurosci 1994; 14:655666.)

is described, but some cases have occurred with just a rightsided lesion. This damage is most commonly a result of stroke, tumors, demyelination, or degenerative atrophy. Many face recognition studies on normal subjects have been carried out using functional brain imaging techniques. Haxby and colleagues8 provided some of the key experiments, initially with positron emission topography and then with functional magnetic resonance imaging. Figure 5–5 is an example of the type of stimulus used for these experiments. Figure 5–6 shows the activation along the inferior occipitotemporal cortex in such a face-matching experiment.23

Associative Visual Agnosia: Environmental or Topographical Agnosia Environmental agnosia, also referred to as topographical disorientation, is an inability to recognize the features or landmarks of a familiar place or region, such as one’s town or even one’s home. Environmental agnosia is associated with lesions in the right medial occipitotemporal region. Unlike the other agnosias, formal testing is not usually required for diagnosis; although disorders such as visual hemineglect may affect navigational tasks, they rarely manifest the profound disorientation observed in this disorder (see Table 5–1).

Disorders of the Parietal Vision–Related Cortex (Dorsal Processing Stream) Damage to the parietal vision–related cortex commonly results in impairments of the perception, location, and manipulation of items in space (Table 5–2). These can include hemispatial neglect, Balint’s syndrome, impaired spatial relations, and akinetopsia.

Hemispatial Neglect Hemispatial neglect is said to be present when patients fail to respond, report, or act on meaningful stimuli that are presented to the side contralateral to a brain lesion. This deficit cannot be attributed to sensory or motor deficits and usually

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Figure 5–5. Stimuli used in the prior positron emission tomography study and current functional magnetic resonance imaging study. A sample stimulus item used in the face-matching task is shown at left; the sensorimotor control stimulus is shown at right. For the face-matching task, the subject indicated whether the right or left test face was the same individual as shown in the upper sample stimulus (right in this case). For the sensorimotor control condition, the subject responded to the left or right, in alternating order, on each presentation of this stimulus. (From Haxby JV, Horwitz B, Ungerleider LG, et al: The functional organization of human extrastriate cortex: a PET-rCBF study of selective attention to faces and locations. J Neurosci 1994; 14:6336-6353.)

results from unilateral lesions of the posterior parietal region, although other critical regions have also been identified. This disorder is discussed in detail in Chapter 6.

Balint’s Syndrome Patients with Balint’s syndrome usually present with a triad of features—optic ataxia, oculomotor gaze apraxia, and simultanagnosia/visual inattention—as a result of bilateral damage to the parieto-occipital regions. Causes include strokes, tumor, trauma, Creutzfeldt-Jakob disease, diffuse cerebral hypotension/hypoxia, Alzheimer’s disease (especially its posterior cortical atrophy variant),24-26 and human immunodeficiency

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T A B L E 5–2. Summary of Clinical Presentation and Location of Lesions in Parieto-occipital Vision Disorders Condition

Description

Location of Lesion

Hemispheric neglect

Patients fail to respond to, report, or act on meaningful stimuli that are presented to the side opposite a brain lesion Triad of symptoms of optic ataxia, oculomotor apraxia, and visuospatial inattention (simultanagnosia) Inability to guide limbs visually Inability to execute purposeful eye movements Inability to perceive entire picture or integrate separate parts Impaired spatial relations in which patients misestimate size, distance, shape, and orientation. Inability to detect motion

Unilateral parietal lobe (usually greater on right)

Balint’s syndrome Optic ataxia Oculomotor apraxia Simultanagnosia Impaired spatial relations Akinetopsia

Bilateral damage to the parieto-occipital region Bilateral parieto-occipital region Bilateral parieto-occipital region Bilateral parieto-occipital region Bilateral parieto-occipital region Damage to the human visual motion area (V5/MT)

arm’s length). The second component of Balint’s syndrome is oculomotor gaze apraxia, also called psychic paresis of gaze, which is a defect of volitional pursuit movements and saccadic movements to visual targets, not attributable to visual inattention, in the presence of preserved spontaneous and reflexive saccades. Completing the triad is visual inattention (or simultanagnosia), which is a reduced ability to detect more than one visual object at the same time, regardless of size. The most common complaints that might flag such a diagnosis included persistent complaints of bumping into things, “tunnel vision,” and reading difficulties. Impaired spatial relations are also found in this syndrome, including difficulty in estimating the size, distance, orientation, and shape of objects.

Environmentally Impaired Spatial Relations Commonly a result of biparieto-occipital lesions, these patients present with a disordered perception of spatial relations. They often report walking into furniture and misreaching for objects because they cannot judge the distance to the item.

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Figure 5–6. Whole-head reconstruction of S5 showing right sagittal cut-away view with statistical results reconstructed from posterior coronal EPI images. Regions with larger signal intensities during the face-matching task relative to control are shown. The focal signal increase in the ventral pathway is located in the inferior occipital sulcus and the fusiform gyrus. (From Clark VP, Keil K, Maisog JM, et al: Functional magnetic resonance imaging of human visual cortex during face matching: a comparison with positron emission tomography. Neuroimage 1996; 4:1-15.)

virus–associated encephalitis. Optic ataxia refers to the inaccurate reaching for a stationary object in extrapersonal space, and although it usually manifests concurrently with oculomotor gaze apraxia and simultanagnosia, it may exist independently. The differential diagnosis includes cerebellar ataxia and proprioceptive deficits. The distinction can usually be made by comparing the reaching inaccuracy to an object in the patient’s own space (e.g., his or her nose) with that to an item that is specifically extrapersonal (e.g., the examiner’s finger held at

Akinetopsia Akinetopsia is an inability to detect motion, so that a moving object such as a car will appear to “jump” from one stationary position to another. Compared with the other higher visuospatial disorders, cases of cerebral akinetopsia are very rare. The human visual motion area (V5/MT) has been identified to lie in the lateral cortex at the junction of the occipital, parietal, and temporal lobes (Fig. 5–7).27 The only two cases of akinetopsia from bilateral lesions have been well described in the literature.28,29

DIAGNOSIS As with much of clinical medicine, and in particular clinical neurology, a detailed history is of paramount importance in achieving an accurate diagnosis of higher visuoperceptual and visuospatial spatial disorders. Indeed, despite the descriptions of the classical, “pure” syndromes in the previous section, such isolated deficits are distinctly uncommon, and patients more usually present with elements of two or more of these syn-

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Figure 5–7. The human visual motion area (V5/MT) has been identified to lie in the lateral cortex at the junction of the occipital, parietal, and temporal lobes. (From Watson JDG, Myers R, Frackowiak RSJ, et al: Area V5 of the human brain: evidence from a combined study using positron emission tomography and magnetic resonance imaging. Cereb Cortex 1993; 3(1):79-94. Reproduced by premission of Oxford University Press.)

dromes. Many patients may be dismissed as having psychiatric conditions. A number of patients in our experience have been seen by optometrists and ophthalmologists and have been told that there was nothing wrong with their eyes, without the possibility of an organic process affecting the brain being considered. A clinical neurological examination should be performed, particularly directed at the visual system. With a little time and care, confrontation visual field testing can be most informative about the nature of any visual field defect, particularly in cases of quadrantanopia or hemianopia. (It is worth noting that standard implementations of automatic computerized visual field testing may not be very helpful in some instances.) Color recognition and naming are easy to test. Object recognition (describing visually presented objects, matching objects in arrays, copying drawings of objects, identifying overlapping or fragmented objects, displaying verbal knowledge of objects, naming by tactile or auditory information) can be tested at the bedside

or in the clinic, and one can also attempt a simple but systematic assessment of prosopagnosia (descriptions of faces, recognition and naming of faces, facial matching, verbal knowledge of familiar and famous people, identifying people through other modalities such as voice, gait, or perfume smell). With access to a clinical neuropsychology service, especially with research facilities, such patients can be more readily assessed in greater detail (see screening battery in the following section for more specific tests for each disorder). Cerebral imaging may be useful, including computed tomography and particularly magnetic resonance imaging. This may show generalized or focal atrophy, evidence of nonfocal and/or discrete cerebral ischemic changes, space occupying lesions such as tumors or abscesses, or even the characteristic appearances of Creutzfeldt-Jakob disease (especially on diffusion-weighted images). Other forms of cerebral imaging that may help include single-photon emission computed tomography and positron emission tomography scans,

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T A B L E 5–3. Neuropsychological Tests Used to Assess Visuoperceptual, Visuospatial, and Visuoconstructional Abilities Visuoperceptual

Visuospatial

Visuoconstructional

Benton Visual Form Discrimination Test Hooper Visual Organization Test Embedded Figures Test Visual Object and Space Perception Battery Benton Facial Recognition Test

Line Bisection Test Mesulam’s Cancellation Test Benton Judgment of Line Orientation Visual Object and Space Perception Battery

Clock drawing test (Addenbrooke’s Cognitive Examination) Rey-Osterrieth Complex Figure Test Block Design Test (Wechsler Adult Intellegence Scale)

although the latter are often not as accessible or affordable. Patients with such disorders may from time to time also undergo electroencephalograms and visual evoked responses, but in our experience these are not often helpful.

Diagnostic Pitfalls It is always helpful to bear in mind a hierarchy of neurological function when testing perception. An integrative higher visual disorder is difficult to diagnose reliably unless attention, cognition, language, and elementary vision are reasonably intact. Delirious patients often present with false localizing cortical signs (easy to recognize when the delirium is florid but much harder when there is a “quiet delirium”). If a patient presents with concurrent depression or advanced dementia, it may be difficult to diagnose an agnosia reliably without careful consideration of the potential confounding effects of these disorders on visuoperceptual testing. It is also important to remember that many of these disorders should be demonstrably limited to the visual sensory modality. For example, a patient presenting with visual object agnosia should be unable to recognize an object by sight but able to recognize the object when other cues such as touch or sound are introduced. If the clinician fails to assess this second step in diagnosis when the patient is unable to name visually presented objects, it might be incorrectly concluded that the patient has an anomia, resulting in the underlying problem being missed. In our experience, a common pitfall in diagnosis, perhaps surprising given the importance of visual function in day-today life, is that a patient’s complaints and/or disability may not be immediately recognized as essentially visuospatial in nature. This is compounded by the commonly observed fact that patients with visual field deficits may be unaware of them. For example, in the history taking, difficulties with dressing are often mentioned by the patient, family members, or nursing staff. This loosely named “dressing apraxia” may also be observed as a sign if the patient is in the hospital. Dressing difficulties may be sought by asking the patient to put on an item of clothing for the upper body, such as a shirt, blouse, or pullover, that has been turned inside out. Such difficulties are often not apraxic at all but instead arise from visuospatial impairments such as neglect.

variety of normed tests. These can be classified according to whether they focus on visuoperceptional, visuospatial, or visuoconstructional impairments (Tables 5–3 and 5–4).

Assessment Strategies for the Non–neuropsychologist While a neurologist frequently requests a neuropsychological assessment to assess visual impairments formally, in the context usually of a dementia, there are simple ways to screen for suspected disorders within the course of a neurological examination.30 The commonly used screening instrument for dementia, the Folstein Mini-Mental State Examination (MMSE), is inadequate for an assessment of this type. The only test items in this or in similar screening examinations that are especially relevant to higher visuoperceptual and visuospatial disorders are the copying of the interlocking pentagons and cube, the drawing of a clock face, the naming of objects such as the watch and pencil, the reading and subsequent carrying out of a simple command, and the writing of a sentence (although the last is more relevant to language testing). One can also examine for neglect phenomena (see Chapter 6) by asking the patient to copy diagrams, bisect lines, draw and copy a clock, and search for a target or targets in an array of shapes or letters (Fig. 5–8). The more complex copying of the Rey-Osterrieth figure is extremely sensitive to higher visuoperceptual and visuospatial disorders (Figs. 5–9 and 5–10). It has the advantage of a scoring system, with norms being widely available. Object recognition can be tested by having people name and describe visually presented objects, match objects out of an array, and copy and spontaneously draw objects. The patient’s verbal knowledge of named objects and ability to name objects by touch or other sensory inputs rather than sight should also be checked, to ensure that difficulties with visual recognition are not merely manifestations of a broader dissolution of semantic knowledge about the objects, rather than a visual agnosia. These functions can be more formally assessed by a number of neuropsychological tests.

TREATMENT AND ASSISTANCE A Screening Battery for Detecting and Diagnosing Disorders of Higher Visual Function Neuropsychologists have a wide range of specialized tools for assessing particular aspects of higher visual disorders, with a

The first important task of the clinician in this situation is to make a diagnosis or institute steps that will lead to a diagnosis; the condition must be recognized for what it is, delineated, labeled appropriately, and explained to the patient, family members, and others. If investigations demonstrate a

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T A B L E 5–4. Screening Battery for Higher Visual Disorders for the Neurologist Disorder

Practical Screening Batteries for the Differential Diagnosis

Dyschromatopsia

Ask the patient to name colors presented to them. Those with dyschromatopsia will fail this task. Ask the patient to read Ishihara color plates. Patients with the more severe cases of dyschromatopsia will have difficulty on this task. Ask the patient to match colored counters (Farnsworth tests). Patients will generally have difficulty with this task if they have dyschromatopsia. Ask the patient to name colors presented to them. They should be unable to do this. Ask the patient to match colored counters. Unlike patients with dyschromatopsia, they will be able to complete the task. Ask the patient “What color is the sky?” and similar questions. The patient will be able to give the correct answer. Ask the patient to color in a picture giving them colored pens. If the patient colors with appropriate colors (e.g., a tree trunk as brown) he is more likely suffering from color anomia. If unable to do so, the differential diagnosis includes color agnosia. Ask the patient to read a paragraph from a magazine or newspaper, progressing down to single words and letters; if impaired, proceed to Step 2. Ask the patient to trace the letters and try to identify each of them. Someone with alexia without agraphia should be able to identify them by tracing. Hold up an object such as glasses or a stopwatch and ask patients to name the object. Those with visual agnosia will be unable to do so. Ask the patient to mime an object’s use (e.g., a toothbrush or hammer). He will generally be unable to mime the object’s use. Give the object to the patient to hold, and ask the patient to name it. Those with visual agnosia will be able to name the object with the help of perceptual cues. Formal neuropsychological testing is usually required to determine the specific type of visual agnosia. Ask the patient to identify pictures of famous people from a magazine or other pictures. A patient with prosopagnosia will have difficulty naming famous people. If the patient is able to name family members, ask a spouse or family member to wear an unusual item such as large glasses and a hat and return to the room without speaking. Failure to identify the family member is strongly suggestive of prosopagnosia. Family members report disorientation and confusion in familiar places or areas. Exclude hemispatial neglect. Ask the patient to copy a simple drawing of a house or tree. A patient with true hemispatial neglect will generally fail to draw a particular side of the picture or will only draw one part of the object. Ask the patient to search for a target or targets in an array of shapes or letters. Patients with hemispatial neglect will miss targets in the affected part of their visual field. Simultagnosia: Ask the patient to describe what is going on in a complex picture or copy a complex drawing (such as the Rey figure). A person with simultagnosia will tend to focus on one small area and is generally unable to integrate the parts of the picture into the whole. Optic ataxia: Ask the patient to reach out or point to a target object in space. A patient with optic ataxia will be unable to do this accurately, a form of visual disorientation. Oculomotor apraxia: Observe the patient’s gaze while the patient is asked to make voluntary eye movements in different directions. Ask the patient to draw a clock face with the hands at a particular time. A patient with impaired spatial relations will have difficulty arranging the hands, circle, and numbers. One must always remember impaired semantic function (such as in Alzheimer disease or focal lobar atrophy of the temporal lobes) can affect such tasks as drawing a clock in a similar way. Ask the patient to complete a simple maze task. Patients with impaired spatial relations will have trouble staying within the lines and completing the task. Patient reports seeing the world in “snapshots” or as if strobe lighting is present. Ask the patient about difficulties in crossing the road, anticipating speeds of cars, and so on.

Color anomia/color agnosia Color agnosia

Alexia without agraphia

Visual agnosia

Prosopagnosia

Environmental agnosia Hemispatial neglect

Balint’s syndrome

Impaired spatial relations

Akinetopsia

treatable cause (e.g., a tumor), then correct treatment should be implemented.

Driving The next responsibility is to arrange appropriate driving assessment. Driving may already be quite dangerous for such people, and early recognition of this is very important. Unfortunately, advice to cease driving is often met by considerable resistance from patients, including the elderly (and sometimes their non-driving partners). Being able to drive is a

badge of independent adulthood and a central part of modern life, particularly in Western countries. In our experience the patient and/or spouse or other close relative may report problems such as not being able to reverse properly, hitting objects such as other cars when parking or driving into and out of garages, failing to stop at the end of the garage, and more general spatial difficulties while driving. In cases of doubt or dispute, an on-road driving test (where available), conducted by a specially trained occupational therapist in a dual control car, may be useful in identifying and documenting such difficulties.

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Figure 5–8. A copy of pentagons (A) and a cube (B) and drawings of a clock face (C) by a 59-year-old man with moderate Alzheimer’s disease and posterior cortical atrophy.

Compensatory Techniques for Patients With Visual Agnosias Patients with visual object agnosia benefit by complementing visual with tactile/auditory stimuli where possible. For patients with prosopagnosia, strategies for helping the individual to identify people by nonfacial cues such as presence or lack of a beard, the voice, clothing, and environment combined with instructions to family and hospital staff to identify themselves in conversation can be particularly helpful for the patient. Agnosia for more specific items, such as clothing or cars, can be overcome to some extent by simple practical strategies such as labeling all the patient’s clothes or getting them to memorize the car’s location or license plate. These strategies may help patients remain independent. Topographical disorientation can be more difficult to ameliorate, but helping the patient to understand the safety issues involved, such as trying not to travel or drive alone and using verbal instructions for travel, and practical solutions, such as marking

routes that are commonly traveled around the house using colored dots, can often help. Agencies that help and train or retrain the blind and vision impaired may offer practical assistance and should always be involved in the care of such patients.

CONCLUSIONS The identification and diagnosis of higher visuoperceptual and visuospatial disorders can be challenging and arduous tasks, given the overlapping symptomatology of many of the entities. “Pure” (classical) cases are rarely seen, and it is more important to untangle the myriad of complaints reported by such patients to establish the range of impaired and preserved functions than it is to attempt to pigeonhole them into a particular syndrome. This allows the clinician to implement compensatory strategies or contact with support agencies that can improve the patient’s quality of life.

chapter 5 higher visuoperceptual disorders

B

A ■

Figure 5–9. A copy of the Rey complex figure (A) and drawing of a house (B) by a patient with simultagnosia. He is unable to combine the parts to form the whole and produces a segmented drawing, unable to locate and integrate each part in space. In B the parts of the house are, from left to right, a wall, the roof, a door, another roof with a driveway immediately below.

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One of the most important issues in Western society in general and for the aging population in particular is early recognition of difficulties in driving.

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Many patients with higher visuoperceptual disorders and disorders of spatial cognition, even those with apparently relatively mild problems, are probably not safe drivers.

Suggested Reading Farah MJ: Visual Agnosia, 2nd ed. Cambridge: MIT Press/Bradford Books, 2004. Heilman KM, Valenstein E (eds): Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003. Barton JJS, Rizzo M (eds): Vision and the Brain, Parts 1 and 2. Neurologic Clinics, Vol. 21, parts 2 and 3. Philadelphia: WB Saunders, 2003.

References

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Figure 5–10 A copy of the Rey complex figure in a patient presenting with higher visual impairments who produces what appears to be an almost mirror image of the original figure.

K E Y

P O I N T S

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These disorders are not as uncommon as is commonly believed, and they lead to intriguing cognitive difficulties and practical problems, although pure, classical cases are rare.

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These disorders may not be recognized initially for what they are, and they are often misdiagnosed by primary care practitioners, optometrists, and ophthalmologists. People with such disorders may be referred to psychiatrists before the final diagnosis is reached.

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Underlying diseases include dementias (particularly of the Alzheimer and Lewy body types), cerebrovascular disease, tumors, and encephalitis.

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Apart from treating the underlying condition (e.g., tumor), there are not many specific therapies available. Often, one must resort to teaching the patient compensatory strategies, but even these can sometimes be unhelpful.

1. Sereno MI, Dale AM, Reppas JB, et al: Borders of multiple visual areas in human revealed by functional magnetic resonance imaging. Science 1995; 268:889-893. 2. Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991; 1:1-47. 3. Mendez MF, Mendez MA, Martin R, et al: Complex visual disturbances in Alzheimer’s disease. Neurology 1990; 40:439-443. 4. Evans R, Fletcher AE, Wormald RPL, et al: Prevalence of visual impairment in people aged 75 years and older in Britain: results from the MRC trial of assessment and management of older people in the community. Br J Ophthalmol 2002; 86:795800. 5. Taylor HR, Keeffe JE, Vu HT, et al: Vision loss in Australia. Med J Aust 2005; 182:565-568. 6. Ungerleider LG, Haxby JV: “What” and “where” in the human brain. Curr Opin Neurobiol 1994; 4:157-165. 7. Haxby JV, Grady CL, Horwitz B, et al: Dissociation of object and spatial visual processing pathways in human extrastriate cortex. Proc Natl Acad Sci U S A 1991; 88:1621-1625. 8. Haxby, J. V, Horwitz, B, Ungerleider, L. G, et al: The functional organization of human extrastriate cortex: a PET-rCBF study of selective attention to faces and locations. J Neurosci 1994; 14:6336-6353. 9. Horwitz B, Soncrant TT, Haxby JV: Covariance analysis of functional interactions in the brain using metabolic and blood flow data. In Gonzalez-Lima F, Finkenstaedt T, Scheich H (eds): Advances in Metabolic Mapping Techniques for Brain Imaging of Behavioral and Learning Functions. Dordrecht: Kluwer, 1992, pp 189-217. 10. McIntosh AR, Grady CL, Ungerleider LG, et al: Network analysis of cortical visual pathways mapped with PET. J Neurosci 1994; 14:655-666. 11. Bauer RM, Demery JA: Agnosia. In Heilman KM, Valenstein E (eds): Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 236-295. 12. Farah MJ: Visual Agnosia: Disorders of Object Recognition and What They Tell Us About Normal Vision. Cambridge: MIT Press, 1990. 13. Lissauer H: Ein fall von seelenblindheit nebst einem Beitrage zur Theori derselben [A case of visual agnosia with a contribution to theory]. Arch Psychiatr Nervenkrankheiten 1890; 21:222-270.

chapter 5 higher visuoperceptual disorders 14. Heilman KM, Valenstein E: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003. 15. Lueck CJ, Zeki S, Friston KJ, et al: The colour centre in the cerebral cortex of man. Nature 1989; 340:386-389. 16. Zeki S, Watson JDG, Lueck CJ, et al: A direct demonstration of functional specialization in human visual cortex. J Neurosci 1991; 11:641-649. 17. Denes G, Semenza C, Stoppa E, et al: Unilateral spatial neglect and recovery from hemiplegia: a follow-up study. Brain 1982; 105:543-552. 18. Warrington EK, Shallice T: Word-form dyslexia. Brain 1980; 103:99-112. 19. Teuber HL: Alteration of perception and memory in man. In Weiskrantz L (ed): Analysis of Behavioral Change. New York: Harper and Row, 1968. 20. Farah MJ, Tanaka JW, Drain HM: What causes the face inversion effect? J Exp Psychol Hum Percept Perform 1995; 21:628634. 21. Damasio AR, Damasio H, Van Hoesen GW: Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology 1982; 32:331-341. 22. Farah M, Levinson KL, Klein KL: Face perception and withincategory discrimination in prosopagnosia. Neuropsychologia 1995; 33:661-674.

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23. Clark VP, Keil K, Maisog JM, et al: Functional magnetic resonance imaging (fMRI) of human visual cortex during face matching: a comparison with positron emission tomography (PET), Neuroimage 1996; 4:1-15. 24. Mendez MF, Ghajarania M, Perryman KM: Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer’s disease. Dementia Geriatr Cogn Disord 2002; 14:33-40. 25. Benson DF, Davis RJ: Snyder BD. Posterior cortical atrophy. Arch Neurol 1988; 45:789-793. 26. Caine D: Posterior cortical atrophy: a review of the literature. Neurocase 2004; 10:382-385. 27. Watson JDG, Myers R, Frackowiak RSJ, et al: Area V5 of the human brain: evidence from a combined study using positron emission tomography and magnetic resonance imaging. Cereb Cortex 1993; 3:79-94. 28. Zihl J, von Cramon D, Mai N: Selective disturbance of movement vision after bilateral brain damage. Brain 1983; 106:313340. 29. Vaina LM: Functional segregation of color and motion processing in the human visual cortex: clinical evidence. Cereb Cortex 1994; 45:555-572. 30. Hodges JR: Cognitive Assessment for Clinicians. Oxford: Oxford University Press, 1994.

6

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THE NEGLECT SYNDROME ●

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Elsdon Storey

There are few more dramatic sights in clinical neurology than a patient ignoring one half of his or her environment, including one half of a meal, or insisting that a paretic left arm is entirely normal, while that held by the examiner must belong to someone else. These examples of severe neglect syndromes, manifest by spatial neglect, and personal neglect with anosognosia (denial of deficit), respectively, are uncommon and a suitable subject for medical literature.1 However, lesser degrees of the neglect syndrome are common, especially in right hemisphere stroke, and have an adverse effect on prospects for rehabilitation and function. Therefore, any practicing neurologist likely to encounter patients with acute or subacute hemispherical lesions—the typical cause of the neglect syndrome— must be aware of its possible manifestations and must be able to confirm their presence at the patient’s bedside. The neglect syndrome is a constellation of related lateralized deficits, including neglect of sensory stimuli; extinction of awareness of one sensory stimulus by another when both are delivered simultaneously; neglect of one half of an object or of space (recognizing that different reference points for “left” exist in this context); neglect of part of a person’s own body; failure to move a (nonparetic) body part as rapidly or persistently as its contralateral equivalent; and failure to recognize that the function of one part of the body is, indeed impaired.2 Although many of these features tend to occur together in individual patients, they are potentially dissociable, and each patient must have his or her own distinctive pattern of impaired and retained abilities elucidated and documented, to facilitate further monitoring, care, and rehabilitation. The neglect syndrome has proved to be a fruitful field for experimental neuropsychology and neuroimaging, and there has been considerable interest in practical techniques to ameliorate its effects, such as prism adaptation. This chapter attempts a broad overview of the area, concentrating on the clinical importance, phenomenology, and examination of neglect.

TERMINOLOGY AND PHENOMENOLOGY The various components of the neglect syndrome each have their own descriptive terms; because patients may exhibit a wide range of combinations of these individual deficits, it would be as inappropriate to lump these together as “neglect” as it would be to refer to all disorders of central language processes

as “aphasia” without further qualification. The reader interested in a more detailed exposition of each of the elements of the neglect syndrome is referred to Heilman and colleagues (2003). The following classification is somewhat arbitrary—for example, neglect dyslexia might conceivably also be regarded as a motor disorder, and spatial neglect might legitimately be considered “sensory”—but some form of organization, even imperfect, is probably useful in considering the wide range of deficits subsumed under “neglect”.

Sensory Aspects of the Neglect Syndrome Sensory Neglect Sensory neglect is said to exist when the patient is not consciously aware of or able to respond to a sensory stimulus contralateral to the lesion, in the absence of a deficit in the relevant sensory pathways or its cortical projections sufficient to prevent apprehension of the stimulus. This defect can be unimodal, but it may affect vision, touch, hearing, and even olfaction together. It can, of course, be difficult to determine whether a patient has neglect or a primary sensory disturbance. However, as pointed out by Heilman and colleagues (2003),2 the bilateral nature of the central auditory pathways makes the diagnosis of auditory neglect easy: A patient with unilateral deafness will hear a sound applied to their deaf side in their good ear if the sound is loud enough, and unilateral cortical lesions typically do not cause deafness. Complete hemianesthesia is uncommon with hemispherical lesions, apart from those involving the thalamus. A patient with a thalamus-sparing cortical lesion who has hemianesthesia probably actually has sensory neglect. The olfactory pathways are uncrossed. Hemianopia, particularly hemianopia plus neglect, is the most difficult to distinguish from hemineglect alone.2,3 Patients with hemianopia without neglect are often aware of and compensate for their deficit, deliberately scanning into their area of field loss, but even the use of examination techniques such as supramaximal stimuli (e.g., bright torch in a dark room) may leave room for doubt.

Extinction Extinction (or sensory extinction to double simultaneous stimulation) is said to be present when the patient does respond to sensory stimulation on the contralesional side but then fails to

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do so when another stimulus is applied simultaneously. The extinguishing stimulus is typically similar to that being extinguished and is usually applied to the corresponding contralateral area, but transmodal extinction (e.g., of a left-sided tactile stimulus by a right-sided visual stimulus) can occur, as can extinction of one stimulus by a second ipsilateral stimulus. When this occurs, the rightward stimulus typically extinguishes that further to the left: this allocentric effect can be seen in the ipsilesional as well as the contralesional receptive field. Extinction, too, may be unimodal or multimodal.

point). For example, patients with neglect of somatocentric hemispace who turn their heads and eyes to the right bring their left visual field into the right side of space, as defined in relation to a somatocentric reference point. This improves their detection of left-sided visual stimuli (defined in relation to a retinocentric reference point) and may help the clinical distinction from hemianopia. A patient with left environmentalcentered neglect who lies on his or her left side would neglect stimuli toward the feet. Spatial neglect also occurs for only peripersonal (near) space (i.e., what can be reached) and, less commonly, for far space, or for both together. A related concept is that of spatial neglect for object-centered (allocentric) space. This refers to a tendency to ignore the left sides of objects, regardless of where they are in retinocentric, somatocentric, or environmental space (Fig. 6–1).4 In addition to neglecting half their environment, such patients may also display neglect dyslexia, in which there is a tendency to ignore the left parts of words (e.g., misreading “consequence” as “sequence”) or of lines. This is an unlikely occurrence in hemianopia without neglect.

Allesthesia Allesthesia refers to the tendency of a patient, without other evidence of right-left confusion, to report contralesional (leftsided) stimuli as having occurred on the ipsilesional (right) side. Thus, when the examiner stimulates the left leg, the patient may be able to point to and move the left leg correctly when asked but reports that the right leg was touched.

Spatial Aspects of the Neglect Syndrome

Representational Neglect

Spatial Neglect

Representational neglect refers to the neglect of the left side of mental images. This disorder first became widely recognized as a result of a thought experiment in which patients imagined themselves standing in the Piazza del Duomo in Milan.5 If they imagined themselves standing on the steps of the cathedral, they could recall the buildings on their right in greater detail than those on the left. If they then imagined themselves standing at the opposite end of the square looking back at the cathedral, they could now recall those buildings previously on their

Spatial neglect refers to decreased awareness of contralesional hemispace. However, what constitutes “hemispace” depends on the frame of reference. Patients may neglect the left side of retinocentric space (i.e., the left side of wherever they are looking), the left side of cephalocentric or somatocentric space (referable to the direction of the head or body), or the left side of environmental space (in relation to an environmental fixed

a.

b.

A ■

B

Figure 6–1. Left, A patient with object-centered neglect fails to copy the left side of the upright tower (A). When the tower is tilted so that some of the left side of the tower now lies on the right side of the picture (and vice versa), the patient still copies only the left side of the tower (B). Right, A patient with left spatial neglect does not cancel lines to the left of the array (a). When the array is separated into two, the patient fails to cancel lines to the left of each array (b), although those to the left of the right-sided array were previously detected before the array was split. (Left, A and B, from Halligan PW, Marshall JC: Towards a principled explanation of unilateral neglect. Cogn Neuropsychol 1994; 11:167-206. Right, a and b, from Driver J, Halligan PW: Can visual neglect operate in object-centered coordinates? An affirmative single case study. Cogn Neuropsychol 1991; 8:475-496.)

chapter 6 the neglect syndrome left (but now on their right) in greater detail than those previously on their right (but now on their left).

Body Image Aspects of the Neglect Syndrome Personal Neglect Personal neglect (or hemiasomatognosia), in its severest form, refers to a patient’s failure to recognize that the contralesional portion of the body belongs to him or her. Such patients may fail to dress, apply makeup to, or shave one side. Milder forms of personal neglect may be suspected when a patient refers to the affected limb in the third person: “It doesn’t work” rather than “my arm doesn’t work.”

Anosognosia and Anosodiaphoria The reader might intuitively suspect that anosognosia (denial of deficit, such as hemiparesis), or the less severe but similar anosodiaphoria (lack of appropriate concern regarding an admitted deficit) is related to personal neglect; however, anosognosia can certainly exist in the absence of personal neglect.6 Of course, neither anosognosia alone nor anisodiaphoria alone is necessarily part of a neglect syndrome: both can occur in other circumstances (e.g., denial of cortical blindness in Anton’s syndrome, la belle indifference in conversion disorders).

Motor Aspects of the Neglect Syndrome Motor neglect, in a broad sense, refers to a situation in which patients fail to perform an appropriate movement, despite awareness of the imperative stimulus and preservation of the requisite power. It is usually implicit that the disorder does not just affect skilled movements, inasmuch as this could then be classed as an apraxia. Heilman and colleagues classified these deficits as action-intentional disorders and recognize four types: akinesia, motor extinction, hypokinesia, and motor impersistence.2 Akinesia refers to failure of initiation of movement. If this failure of initiation is in response to an external stimulus, it may be also be termed motor neglect (in a narrower sense). Akinesia may vary, depending on in which part of peripersonal space the movement occurs and on in which direction the movement is made. For example, akinesia of the left hand may be less severe if movements are attempted in right hemispace (e.g., with the hands crossed), and the ipsilesional (right) hand may move less freely to the left side. Ingenious experiments, designed to separate motor from sensory/hemispatial neglect, have been reported. Perhaps one of the simplest is the crossed response task, in which a stimulus in the right hemifield requires movement of the left arm, and that in the left hemifield requires movement of the right arm.2 Motor extinction is analogous to sensory extinction: a limb that can move normally in isolation moves less well when the opposite limb is moved at the same time. Hypokinesia refers to a normally executed movement with an abnormally long delay from stimulus to movement onset (reaction time). This delay may be long enough to be obvious clinically. Inability to sustain a motor act constitutes motor impersistence. This may be directional (e.g., inability to keep looking in the contralesional but not ipsilesional direction) or may affect the contralesional arm or whichever arm is in contralesional hemispace.

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How Separable Are the Various Components of the Neglect Syndrome? The neglect syndrome has long been recognized to consist of various combinations of the constituent deficits outlined previously. Formal double dissociations have been recorded between a number of the components (e.g., different measures of hemispatial neglect; hemispatial neglect and extinction).7,8 The best evidence for the heterogeneity of the syndrome probably comes from the large study of Buxbaum and coworkers, who found most possible combinations of personal neglect, peripersonal spatial neglect, sensory neglect/extinction (“perceptual neglect”), and motor neglect in their sample of 166 patients with right hemisphere stroke.9 Pure personal neglect was rare, but pure peripersonal spatial neglect, pure sensory neglect, and pure motor neglect were each not uncommon. Of course, their “purity” depends on which tests are chosen for each, together with their psychometric characteristics, but the double dissociations observed still stand.

EXAMINATION FOR THE NEGLECT SYNDROME It is apparent from the preceding section that no one test is adequate for ruling out the neglect syndrome. At the same time, a relatively brief bedside assessment readily detects most clinically significant neglect syndromes. Several batteries of appropriate tests have been developed.10,11 The following outline is condensed predominantly from Heilman and colleagues (2003), to which the reader is referred for further details.

Sensory Aspects The patient should be stimulated on the left side, right side, and on both sides together, in random order, with visual, tactile, and auditory stimuli and asked to state or indicate on which side or sides the stimulus occurred. Verbal misreporting of left as right, despite absence of left-right confusion on other measures (e.g., the patient can point to and/or move the appropriate side as requested), suggests allesthesia. As pointed out previously, auditory neglect or extinction is clearly separable from unilateral deafness, or unilateral involvement of auditory cortex, and nonthalamic lesions typically do not cause complete hemianesthesia, but it can be more difficult to separate visual hemineglect from hemianopia. Confrontational field testing should then be performed with the head turned to the right and to the left: a true hemianopic defect should remain retinocentric, but visual neglect may improve with the head’s turning to the right. Stronger stimuli should also be employed (e.g., a torch, the spot of a laser pointer on the wall in a darkened room, or, at least, targets larger than a hat pin). Sometimes, however, it is difficult to be certain of with what the clinician is dealing.3 Visual extinction of the more central stimulus by that further to the right may be demonstrable in the intact field.3

Spatial Aspects Gross degrees of spatial neglect are evident on observation: the patient disregards the left side of the environment. Asking the patient to report 10 objects around their room (provided that

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Figure 6–2. Patients with left-sided neglect may omit elements to their left when drawing or copying (A, B), although this method is less sensitive than other methods such as object cancellation (C) or line bisection (D). As a practical test of environmental neglect, patients may be asked to list 10 items around them, while the examiner plots their location from the perspective of the patient (E). (From Parton A, Malhotra P, Husain M: Hemispatial neglect. J Neurol Neurosurg Psychiatry 2004; 75:13-21.)

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the bed is not against the left wall) and marking these with regard to a patient-centered reference frame can be a useful measure of less severe spatial neglect (Fig. 6–2E).3 Persistent head and/or eye deviation to the right may also offer a clue to lesser degrees of neglect, which may be elicited by a number of pencil and paper tests. Object drawing/copying tests (see Fig. 6–2A and B) are traditionally used but are not particularly sensitive by themselves,12 are difficult to quantify, and may be confounded by other visuoconstructional problems. A number of cancellation tests have been devised. Those with dense, random arrays with many different types of distractor items, such as the Bells Test,13 or Mesulam’s shape cancellation test (Fig. 6–3; see also Fig. 6–2C),14 seem to be the most sensitive.2,3 A starting point toward the right of the array is probably the most sensitive measure,12 and the location of the first item canceled should be noted. The left-minus-right omission score is also noted: a cutoff point of greater than 2 has been used on the Bells Test, for example.12 Line bisection tests are also easily carried out at the bedside; normal subjects tend to bisect a 20-cm line slightly toward the left, whereas those with left spatial neglect tend to bisect toward the right (see Fig. 6–2D). (They bisect short lines [e.g., 2 to 5 cm] toward the left—the so-called crossover effect—but although this is of great theoretical interest, it is not of practical importance to the clinician, provided that these short lines are avoided.) If the average rightward deviation from the true center points of two successively centrally presented horizontal 20-cm lines is used, a cutoff point of greater than 6.5 mm has been suggested.12 Occasional patients (actually almost 25% in the study of Azouvi et al)12 bisect even the longer lines toward the left: so-called ipsilateral neglect. Although line bisection tasks are less sensitive than cancellation tasks, patients with neglect may show abnormalities on just one or the other, which makes assessment with both necessary. In fact, line bisection may be more related to extinction than to the form of neglect elicited by cancellation tasks, and they may have different anatomical substrates (see “Anatomy of the Neglect Syndrome” section).15

Representational neglect, which does not depend on visuomotor control, may be elicited by asking the patient to describe the landmarks that he or she would see while walking down a well-known thoroughfare—familiar to both the patient and the examiner—in one direction and then in the other.

Body Image Aspects Personal neglect, if severe, may be evident in the patient’s failure to dress or groom one side, in fact, or after they are asked

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Figure 6–3. Mesulam’s object cancellation task, an example of a dense, random array cancellation task with distractors. The subject is shown a separate drawing of the target object (the open “sun” crossed by a diagonal slash). The sheet is aligned with the patient’s midline. The position of the first target circled should be noted. (From Mesulam M-M: Principles of Behavioral Neurology: Tests of Directed Attention and Memory. Philadelphia: FA Davis, 1985.)

chapter 6 the neglect syndrome to demonstrate how they would do so. This has been formalized as the comb and razor/compact test.16 Personal neglect may also be detected by asking the patient to reach his or her left arm with the right arm. This may be rated from 0 (normal) to 3 (no attempt to reach the left arm) according to a published scale.17 Another graded test (the Fluff Test) involves placement of Velcro-backed stickers or cotton balls on a blindfolded patient, and asking the patient to find and remove them.9,18 In the author’s opinion, severe directional akinesia might confound these tests, and should be ruled out separately. Severe anosognosia may be evident in general conversation with the patient, but milder forms are best detected with simple structured scales. In one such test,2 the hemiparetic patient is first asked, “Why did you come to the hospital?” If the patient does not mention the hemiparesis, he or she is asked whether he or she has any other problems. Failure to mention hemiparesis at this stage constitutes grade 1. Such patients are then asked, “Are you weak anywhere?” Failure to acknowledge their hemiparesis at this stage constitutes grade 2. The examiner then picks up the hemiparetic arm and moves it into the ipsilesional space. Denial of weakness when the patient is asked constitutes grade 3. Such a patient is then asked to move the arm. Continued denial of weakness under these circumstances constitutes grade 4.2 Other scales are similar in concept.9

Motor Aspects Spontaneous (endokinetic) akinesia of the contralesional side, out of proportion to weakness, may be evident on observation. The oculomotor equivalent—a gaze preference toward the ipsilesional side—should also be noted if present. Testing arm movements with the patient’s arms crossed and uncrossed, in response to visual cues in the right hemifield (e.g., downward movement of the examiner’s finger triggers movement of the patient’s limb on the left; upward movement, of that on the right) allows distinction of sensory from motor neglect and differentiation of hemispatial from contralateral exogenously evoked akinesia. Visual saccades toward or away from the examiner’s finger in the right hemifield may be tested similarly. Marked hypokinesia, if present, can be observed during this testing as well. Motor extinction can be elicited with an adaptation of the sensory extinction test, in which the patient has to report which side was stimulated and must move that side. Patients with motor extinction, unlike those with sensory extinction, are able to report simultaneous bilateral stimulation but are able to move appropriately after only a unilateral stimulus. Motor impersistence can be tested by asking the patient to hold a limb posture for 20 seconds. This should be checked in both arms, each tested in both contralesional and ipsilesional space. A more formalized motor impersistence battery is available, if required.19

ANATOMICAL SUBSTRATE, AND THEORIES OF CAUSATION Anatomy of the Neglect Syndrome It is well known that in right-handed individuals, left-sided neglect is more frequent and severe with right hemisphere lesions than is right-sided neglect with left hemisphere lesions. Most left-handed patients also display this pattern; only rare left-

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Figure 6–4. Traditional lesion localization in the neglect syndrome. The computed tomography–defined lesions of 10 patients with the neglect syndrome are superimposed. Note the concentration at the temporoparietal junction. (From Heilman KM, Watson RT, Valenstein E: Neglect and related disorders. In Heilman KM, Valenstein E, eds: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 296-346.)

handed patients showing severe right-sided neglect with left hemisphere lesions: so-called crossed neglect. However, severe right-sided neglect may also occur with bilateral lesions.20 In keeping with this, the author has encountered right-sided neglect in patients with probable Alzheimer’s disease. Neglect has traditionally been considered to arise from right parietal damage, and lesions of the inferior parietal lobule and the adjacent section of the superior temporal gyrus are indeed most commonly implicated in modern imaging studies (Fig. 6–4).8 However, it is now clear from both animal and human studies that neglect can arise from lesions of the inferolateral frontal lobe, cingulate gyrus, thalamus, neostriatum, (unilateral) mesencephalic reticular formation,2,21 and even the posterior limb of the internal capsule or the parahippocampal gyrus8 on occasions. It is reasonable to consider these areas as forming an attentional network, disruption of any component of which might result in the neglect syndrome (see Heilman et al, 2003, and Mesulam, 2000, for detailed discussions). Because the neglect syndrome has a number of possible component deficits, some of which have been shown to be doubly dissociable (able to occur independently of each other), the question arises as to whether the various components might have different anatomical substrates. This issue remains unsettled, but there is at least some evidence that visual extinction (and the possibly related impairment of line bisection) is correlated with damage to the inferior parietal lobule or even the parieto-occipital junction, whereas spatial neglect as defined by abnormal performance on cancellation tasks correlated with more anterior lesions, involving the posterior portion of the superior temporal gyrus, or the parietotemporal junction (Fig. 6–5).7,8 Studies of transcranial magnetic stimulation to produce transient focal deficits in normal subjects have supported this view (see Milner and McIntosh, 2005). It is also, at first sight, appealing to speculate that motor aspects of the neglect syndrome, such as hypokinesia, might relate to damage to frontal or striatal components of the

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Rightward shift in line bisection

Figure 6–5. Lesion overlap in 13 patients with neglect (defined by behavioral findings of hemispatial neglect and confirmed on a cancellation task) who also showed rightward deviation on a line bisection task, in comparison with that on 9 otherwise similar patients with neglect who did not show deviation on line bisection. The lesions in those with abnormal line bisection extend further posteriorly. (From Rorden C, Fruhmann Berger M, Karnath H-O: Disturbed line bisection is associated with posterior brain lesions. Brain Res Cogn Brain Res 2005 [ePublication ahead of print].)

Unbiased line bisection

attentional network, whereas sensory aspects, such as sensory neglect and extinction, might arise particularly from parietotemporal damage. However, patients with neglect caused by frontal lesions may be indistinguishable from those with parietal lesions on standard tests of sensory neglect,22 and one transcranial magnetic stimulation study confirmed the importance of sensory aspects to the neglect syndrome observed with frontal damage.23 As both areas are strongly reciprocally connected, and subserve sensory-motor integration, it is not surprising that a strict sensory/motor dichotomy has not been confirmed and that attempts to separate frontal from parietal neglect syndromes on the basis of clinical phenomena at the bedside are likely to be unavailing.

A

Pathophysiology of Sensory Neglect As pointed out previously, the neglect syndrome has multiple, potentially dissociable components and has been a fertile area for cognitive and experimental neuropsychologists. This brief discussion of potential pathomechanisms covers only sensory neglect: readers are referred to the Suggested Readings list for detailed expositions of possible mechanisms underlying these and other components of the syndrome. An obvious suggestion is that sensory neglect actually arises from impaired sensory input. However, patients with obviously impaired sensory input (e.g., hemianesthesia) are often only too well aware of their deficit, whereas unattended stimuli in patients with sensory neglect still elucidate cortical evoked potentials. Perhaps most convincingly, there is now overwhelming evidence for preconscious (implicit) sensory processing of the neglected stimuli. For example, a subject asked to count four indented circles could see only the two on the right, unless the indentations were oriented to form an implied rectangle, in which case all four were reported (Fig. 6–6).24 Furthermore, patients with visual neglect are still able to use left-sided visual information at a preconscious level to guide reaching and grasping movements (see Milner and McIntosh, 2005).

B ■

Figure 6–6. Preconscious processing in visual neglect. When asked to count the number of incomplete circles, a patient with left neglect reported 4 for A and two for B. The implied rectangle (Kanisza’s figure) in A was presumably processed as a single stimulus; although incidental to the task, this preconscious processing demonstrates that the two circles on the left in B were not missed because of sensory impairment. (From Mattingley JB, Davis G, Driver J: Preattentive filling-in of visual surfaces in parietal extinction. Science 1997; 275:671-674. Copyright 1997. AAAS. Reprinted with permission from AAAS.)

Another explanation relates to the role of attention in determining which of the many stimuli with which humans are constantly bombarded are noticed and which are deemed irrelevant and screened out before they reach consciousness. Mesulam proposed that the left hemisphere tends to endow the right side

chapter 6 the neglect syndrome of the environment, or the right side of whatever is being attended (i.e., egocentric or object-centered right), with salience and is biased toward producing rightward-directed attentional shifts, whereas the effects of the unopposed right hemisphere are larger and more symmetrical (slightly favoring the left side).21 Posner and associates had emphasized the role of the right parietal region in disengaging attention from rightsided objects to enable a subsequent leftward shift.25 There is no fundamental conflict between the directional bias and impaired disengagement hypotheses, although there is some evidence that impaired disengagement is not solely responsible for the observed deficits.26 More recently, the attentional network concept has been elaborated to encompass different roles for roles of a ventral network—composed of the temporoparietal junction and ventrolateral frontal lobe—whose role is to detect novel sensory stimuli, and a dorsal network— composed of the superior parietal lobule and the frontal eye fields—that is responsible for goal-directed stimulus and response selection. Only lesions of the ventral network typically result in neglect, elaborated in part through functional disruption of the dorsal network (Fig. 6–7). Recovery is associated with increased activity in the dorsal network, suggesting a “topdown” rather than “bottom-up” compensatory strategy (i.e., a redirection of attention rather than a recapturing of attention by exogenous stimuli).27

THE FREQUENCY AND IMPORTANCE OF NEGLECT The neglect syndrome is typically a result of a focal, lateralized brain lesion. Such lesions are typically structural and acute or subacute (e.g., strokes or rapidly growing tumors), but the syndrome may also occur with focal epilepsy. Diffuse processes, such as those occurring with toxic-metabolic encephalopathies or diffuse axonal injury from trauma, rarely cause neglect.21 In view of the heterogeneity of stroke topographies, the multifaceted nature of the neglect syndrome, the varying methods (with varying sensitivities) used for its detection, and the varying times after stroke at which studies have been conducted, it is not surprising that the literature contains widely differing estimates of the prevalence of the neglect syndrome in stroke. Indeed, a systematic review in 1999 concluded that although the greater frequency of the neglect syndrome after right than after left hemisphere lesions was supported, an accurate estimate of the frequency and recovery rates of the neglect syndrome could not be reached.28 Since then, several large studies have addressed these issues. Using a standardized (but not exhaustive) test battery, Azouvi and associates found moderate to severe behavioral neglect in 25 (36%) of 69 subacute patients (an average of about 3 months after right hemisphere stroke onset), whereas 177 (86%) of 206 such patients displayed some degree of neglect on at least one pencil and paper measure.12 A study by the same group of 78 additional patients with subacute left hemisphere lesions (but without major impairment of comprehension) showed that for each test in the battery, right-sided neglect was less severe. Than was left-sided neglect after right-sided lesions, and only 25-50% as frequent.29 Patients with left hemisphere lesions also tended to show abnormalities on fewer tests within the battery; 44% displayed abnormalities on at least one measure.29 One report of 1281 patients with acute stroke, who

FEF

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Figure 6–7. A, Anatomical regions involved in the dorsal attentional network (blue) involved in goal-directed stimulus and response selection (“top-down”), and in the ventral attentional network (orange) involved in detection of salient sensory events, and in the reorienting of the dorsal network to these, especially if unattended (“bottom-up”). The darkened area represents a hypothetical cortical lesion causing neglect. FEF, frontal eye field; IFg-MFg, inferior frontal gyrus–middle frontal gyrus; IPL-STG, inferior parietal lobule–superior temporal gyrus; IPS-SPL, intraparietal sulcus–superior parietal lobule; TPJ, temporoparietal junction; VFC, ventral frontal cortex. B, A hypothesis for the involvement of both attentional networks in neglect, given a lesion only affecting the ventral network, based on functional magnetic resonance imaging data. Damage to the right ventral circuit (either to the ventral frontal cortex, as shown here, or to the ventral temporoparietal junction) leads to impaired ability to redirect the right dorsal network to new targets (i.e., the “circuit breaker” or disengagement signal function of the ventral network on the dorsal is lost). This decreased activity in structurally intact areas sets up an imbalance between the left and right dorsal systems, as well as the left and right ventral systems, with decreased activity on the right and increased on the left, leading to neglect. Functional improvement in the chronic stage correlates with increased activity of the (intact) dorsal parietal cortex on the right, with decreased activity of that on the left (not shown). L FEF, left frontal eye field; L IPS, left intraparietal sulcus; L TPJ, left temporoparietal junction; L VFC, left ventral frontal cortex; R FEF, right frontal eye field; R IPS, right intraparietal sulcus; R TPJ, right temporoparietal junction; R VFC, right ventral frontal cortex. (From Corbetta M, Kincade MJ, Lewis C, et al: Neural basis and recovery of spatial attention deficits in spatial neglect. Nat Neurosci 2005; 8:1603-1610. Copyright 2005. Reprinted by permission of Macmillan Publishers Ltd.)

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were assessed only for tactile extinction and “visual inattention” on describing a standard scene (the Cookie Theft picture from the Boston Diagnostic Aphasia Examination) revealed that 43% of patients with right hemisphere lesions and 20% of those with left hemisphere lesions displayed abnormalities on one or both measures.30 Subacutely (at 3 months), the respective figures were 17% and 5%. (These percentages are doubtless lower than those reported by the other cited studies as a result of the limited assessment of the neglect syndrome in this study.) Further analysis showed that cortical involvement, right-sided involvement, and increasing age were associated with lesser degrees of improvement by 3 months, whereas handedness and gender had no effect.30 A similar estimate of recovery was derived from an earlier study employing life table analyses, which showed that only 7 (21%) of 34 patients with obvious behavioral neglect in the acute period still displayed such neglect at 3 months.31 The median duration of obvious leftsided sensory neglect was 9 weeks; less florid features such as extinction (median, 43 weeks) and motor impersistence (median, 54 weeks) improved more gradually.31 The presence of the neglect syndrome is an adverse factor for recovery. Patients with right hemisphere strokes recover more slowly than those with left hemisphere strokes; the difference appears to relate to the presence of neglect rather than to poorer motor strength recovery.32 Although this study did not demonstrate the intuitively expected correlation of outcome with anosognosia, others have done so since.33,34 Indeed, one of the study groups found that limited recovery and failure to regain functional independence were correlated with the severity of neglect and the presence of anosognosia in the acute period, as well as with increasing age,34 whereas the other group found no effect of hemispatial neglect (defined on a cancellation task) and personal neglect once anosognosia was allowed for.33 The adverse effect of anosognosia is hardly surprising: It is difficult for patients to cooperate enthusiastically with a rehabilitation program or use strategies to overcome a deficit that they do not believe they have. Chronic neglect increases burden of care; one study of 80 patients with subacute or chronic right hemisphere lesions showed that 37 (48%) displayed neglect on at least one of five measures and that neglect severity rather than lesion size was predictive of increased functional impairment and caregiver burden.9 Neglect can also pose safety concerns, such as in crossing roads or standing next to a hot stove in the kitchen. Education of caregivers is therefore an important aspect of rehabilitation for persistent neglect.

studies reported improvements, whereas others reported worsening of neglect. It has been postulated that the effects of dopaminergic agonists depend on whether the lesion includes damage to the striatum, with the unintended effect of increased disparity in striatal activation in such patients, resulting in increased neglect. (See also Heilman et al, 2003, for additional discussion of dopaminergic agonist treatment.)

Cognitive Training for Remediation of Visual Attention Deficits Remediation of visual attention deficits through a cognitive training (“top-down”) approach has resulted in improvement in some aspects of the neglect syndrome. For example, subjects may be taught to scan back to a red line at the left margin of a text, in order not to ignore the start of each line. Unfortunately, the benefits do not seem to generalize readily to other activities, and maintenance of improvement has not been adequately addressed.35

Treatment of Spatial Representation Deficits

Various rehabilitation strategies have been tried for the neglect syndrome, and the existing literature has been the subject of two 2002 reviews.35,36 Treatment strategies may be divided into those targeting arousal deficits, those directed at deficient visual attention, and those seeking to improve spatial representation deficits.35 (See Pierce and Buxbaum, 2002, for further details of the treatments outlined as follows, together with their outcomes.)

Treatments targeting spatial representation deficits include hemispherical activation approaches (e.g., moving the contralesional limb) and constraint approaches (e.g., immobilizing the unaffected ipsilesional limb or obscuring the ipsilesional visual field in each eye with hemifield patches on glasses). There is some evidence in favor of these approaches, but it is hardly overwhelming.35 A number of other “bottom-up” approaches, aimed at inducing preconscious shifts in spatial representations, have also been explored. An example is leftward trunk rotation therapy, in which more of the left visual field is brought within right-sided peripersonal space. Application of vibration to the left posterior side of the neck produces a similar illusion. Cold water caloric irrigation of the contralesional ear might be thought to act by producing the illusion of head rotation to the right (with compensatory slow eye movement to the left and nystagmus toward the right) but may actually act through the vestibular system’s contribution to spatial representations. Unfortunately, the treatment is uncomfortable, and the effects last only 10 to 15 minutes. Similarly, opticokinetic nystagmus with quick phases induced to the right (i.e., stripes moving to the left) might be considered to produce the illusion of rightward movement. The benefits, however, are reported not to outlast the stimulus. Perhaps the most exciting therapy is prism adaptation, a cheap and noninvasive treatment in which the patient wears Fresnel prisms, which cause a 10-degree apparent rightward shift of viewed objects (Fig. 6–8).37 The benefits generalize to nonvisual aspects of the neglect syndrome, such as tactile extinction38 and, in an initial study, were apparently long-lasting (at least weeks).39 The effects may also extend to patients with chronic neglect syndromes.40 This is potentially an exciting advance in neurorehabilitation, and the results of the first randomized controlled trials should be available in the near future.15

Treatment of Arousal Deficits

CONCLUSION

Dopaminergic agonists (e.g., bromocriptine) have been used to overcome arousal deficits, with contradictory results: Some

The neglect syndrome is common, readily detectable at the patient’s bedside, and has an important effect on rehabilitation

TREATMENT OF THE NEGLECT SYNDROME

chapter 6 the neglect syndrome Optical effect of rightward prism induced shift

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Start of prism adaptation period

End of prism adaptation period

Post-adaptation (after effect)

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Figure 6–8. Adaptation to a rightward displacement in subject’s vision produced by a prism. The adaptation process requires the subject to reach repeatedly for the target. Although error caused by the apparent object placement (second panel) quickly diminishes (third panel), about 50 repetitions have to be performed for full adaptation. After removal of the prisms, the after effect (fourth panel) disappears after a few minutes in normal subjects. The effects on the neglect syndrome, however, persist for longer. (From Parton A, Malhotra P, Husain M: Hemispatial neglect. J Neurol Neurosurg Psychiatry 2004; 75:13-21.)

and recovery of function. However, it is probably underrecognized, at least in its less florid forms, partly because of its diverse manifestations. Examination for these disorders should form part of the assessment of any patient with an acute or subacute hemispherical lesion, especially if it is right-sided. An impressive body of experimental work is now beginning to generate ideas for rationally based rehabilitative therapies, of which prism adaptation shows considerable early promise.

K E Y

P O I N T S

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The neglect syndrome is most typically observed with acute or subacute hemispherical lesions, particularly those affecting the right hemisphere. Disruption anywhere within the attentional network may be responsible, but lesions of the temporoparietal junction and inferolateral frontal lobe are particularly likely to produce neglect.

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The neglect syndrome consists of various combinations of deficits affecting the patient’s conscious detection of contralesional sensory stimuli, awareness of contralesional space (hemispace), whether imagined or real; awareness of the patient’s own body parts contralateral to the lesion; and ability to move contralesional body parts or within contralesional space, not adequately explained by elementary sensory or motor deficits such as hemianopia, hemianesthesia, or hemiparesis.

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These various component deficits can usually be identified at the bedside with a limited range of simple examination techniques, although no one test alone is adequate for this purpose.

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The neglect syndrome has an important adverse effect on rehabilitation and recovery from stroke, and although its most florid manifestations more usually than not resolve within 3 months, it may persist.

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A number of hypotheses have been advanced to explain aspects of the neglect syndrome. Although the resulting debates continue, several rational therapeutic approaches have been suggested as a result. Of these, prism adaptation has shown the greatest initial promise.

Suggested Reading Heilman KM., Watson RT, Valenstein E: Neglect and related disorders. In Heilman KM, Valenstein E, eds: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 296-346. Mesulam M-M: Attentional networks, confusional states and neglect syndromes. In Mesulam M-M, ed: Principles of Behavioral and Cognitive Neurology, 2nd ed. New York: Oxford University Press, 2000, pp 193-256. Milner AD, McIntosh RD: The neurological basis of visual neglect. Curr Opin Neurol 2005; 18:748-753.

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Parton A, Malhotra P, Husain M: Hemispatial neglect [Review]. J Neurol Neurosurg Psychiatry 2004; 75:13-21. Pierce SR, Buxbaum LJ: Treatments of unilateral neglect: A review. Arch Phys Med Rehabil 2002; 83:256-268.

References 1. Sacks O: The Man Who Mistook His Wife for a Hat. London: Duckworth, 1985. 2. Heilman KM, Watson RT, Valenstein E: Neglect and related disorders. In Heilman KM, Valenstein E, eds: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 296-346. 3. Parton A, Malhotra P, Husain M: Hemispatial neglect [Review]. J Neurol Neurosurg Psychiatry 2004; 75:13-21. 4. Driver J, Halligan PW: Can visual neglect operate in objectcentered coordinates? An affirmative single case study. Cogn Neuropsychol 1991; 8:475-496. 5. Bisiach E, Luzzatti C: Unilateral neglect of representational space. Cortex 1978; 14:129-133. 6. Adair JC, Na DL, Schwartz RL, et al: Anosognosia for hemiplegia: test of the personal neglect hypothesis. Neurology 1995; 45:2195-199. 7. Mort DJ, Malhotra P, Mannan SK, et al: The anatomy of visual neglect. Brain 2003; 126:1986-1997. 8. Rorden C, Fruhmann Berger M, Karnath H-O. Disturbed line bisection is associated with posterior brain lesions. Brain Res Cogn Brain Res 2005 [ePublication available ahead of print]. 9. Buxbaum LJ, Ferraro MK, Veramonti T, et al: Hemispatial neglect: subtypes, neuroanatomy and disability. Neurology 2004; 62:749-756. 10. Azouvi P, Marchal F, Samuel C, et al: Functional consequences and awareness of unilateral neglect: study of an evaluation scale. Neuropsychol Rehab 1996; 6:133-150. 11. Wilson B, Cockburn J, Halligan P: Behavioural Inattention Test. Bury St. Edmunds, UK: Thames Valley Test Co., 1987. 12. Azouvi P, Samuel C, Louis-Dreyfus A, et al: Sensitivity of clinical and behavioral tests of spatial neglect after right hemisphere stroke. J Neurol Neurosurg Psychiatry 2002; 73: 160-166. 13. Gauthier L, Dehaut F, Joanette Y: The Bells Test: a quantitative and qualitative test for visual neglect. Int J Clin Neuropsychol 1989; 11:49-54. 14. Mesulam M-M: Principles of Behavioral Neurology: Tests of Directed Attention and Memory. Philadelphia: FA Davis, 1985. 15. Milner AD, McIntosh RD: The neurological basis of visual neglect. Curr Opin Neurol 2005; 18:748-753. 16. Breschin N, Robertson IH: Personal versus extrapersonal neglect: a group study of their dissociation using a reliable clinical test. Cortex 1997; 33:379-384. 17. Bisiach E, Perani D, Vallar G, et al: Unilateral neglect: personal and extra-personal. Neuropsychologia 1986; 24:759-767. 18. Cocchini G, Beschin N, Jehkonen M: The Fluff Test: a simple task to assess body representational neglect. Neuropsychol Rehab 2001; 11:17-31. 19. Benton AL, Sivan AB, Hamsher K deS, et al: Contributions to Neuropsychological Assessment: A Clinical Manual, 2nd ed. New York: Oxford University Press, 1994. 20. Weintraub S, Daffner KR, Ahern G, et al: Right-sided hemispatial neglect and bilateral cerebral lesions. J Neurol Neurosurg Psychiatry 1996; 60:342-344.

21. Mesulam M-M: Attentional networks, confusional states and neglect syndromes. In Mesulam M-M, ed: Principles of Behavioral and Cognitive Neurology, 2nd ed. New York: Oxford University Press, 2000. 22. Husain M, Mattingley JB, Rorden C, et al: Distinguishing sensory and motor biases in parietal and frontal neglect. Brain 2000; 123:1643-1659. 23. Brighina F, Bisiach E, Piazza A, et al: Perceptual and response bias in visuospatial neglect due to frontal and parietal repetitive transcranial magnetic stimulation in normal subjects. Neuroreport 2002; 13:2571-2575. 24. Mattingley JB, Davis G, Driver J: Preattentive filling-in of visual surfaces in parietal extinction. Science 1997; 275:671674. 25. Posner MI, Walker JA, Friedrich JF, et al: Effects of parietal injury on covert orienting of attention. J Neurosci 1984; 4: 1863-1874. 26. Mark VW, Kooistra CA, Heilman KM: Hemispatial neglect affected by non-neglected stimuli. Neurology 1988; 38:12071211. 27. Corbetta M, Kincade MJ, Lewis C, et al: Neural basis and recovery of spatial attention deficits in spatial neglect. Nat Neurosci 2005; 8:1603-1610. 28. Bowen A, McKenna K, Tallis RC: Reasons for variability in the reported rate of occurrence of unilateral spatial neglect after stroke. Stroke 1999; 30:1196-1202. 29. Beis J-M, Keller C, Morin ST, et al: Right spatial neglect after left hemisphere stroke: qualitative and quantitative study. Neurology 2004; 63:1600-1605. 30. Ringman JM, Saver JL, Woolson RF, et al: Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort. Neurology 2004; 63:468-474. 31. Hier DB, Mondlock J, Caplan LR: Recovery of behavioral abnormalities after right hemisphere stroke. Neurology 1983; 33:345-350. 32. Denes G, Semenza C, Stoppa E, et al: Unilateral spatial neglect and recovery from hemiplegia. Brain 1982; 105:543-552. 33. Pedersen PM, Jørgenson HS, Nakayama H, et al: Hemineglect in acute stroke—incidence and prognostic implications: the Copenhagen Stroke Study. Am J Phys Med Rehab 1997; 76:122127. 34. Stone SP, Patel P, Greenwood RJ, et al: Measuring visual neglect in acute stroke and predicting its recovery: the visual neglect recovery index. J Neurol Neurosurg Psychiatry 1992; 55:431-436. 35. Pierce SR, Buxbaum LJ: Treatments of unilateral neglect: a review. Arch Phys Med Rehabil 2002; 83:256-268. 36. Bowen A, Lincoln NB, Dewey M: Cognitive rehabilitation for spatial neglect following stroke. Cochrane Database Syst Rev 2002; (2):CD003586. 37. Rossetti Y, Rode G, Pisella L, et al: Prism adaptation to a rightward optical deviation rehabilitates left hemispatial neglect. Nature 1998; 395:166-169. 38. Maravita A, McNeil J, Malhotra P, et al: Prism adaptation can improve contralesional tactile perception in neglect. Neurology 2003; 60:1829-1831. 39. Frassinetti F, Angeli V, Meneghello F, et al: Long-lasting amelioration of visuospatial neglect by prism adaptation. Brain 2002; 125:608-623. 40. McIntosh RD, Rossetti Y, Milner AD: Prism adaptation improves chronic visual and haptic neglect: a single case study. Cortex 2002; 38:309-320.

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Glynda Kinsella, Elsdon Storey, and John R. Crawford

EXECUTIVE FUNCTION The dysexecutive syndrome has long been exemplified by the classic case of Phineas Gage, whose prefrontal damage from a railway construction accident in 1848 completely altered his personality and work performance.1 A more contemporary exemplar, with the advantage of modern neuroimaging and neuropsychological assessment, is that of E.V.R., reported by Eslinger and Damasio.2 E.V.R. was a successful young accountant who underwent surgical removal of a large orbitofrontal meningioma. His postoperative course illustrates the potentially far-reaching and devastating consequences of executive function impairment: “Post-operatively, E.V.R. was assessed to be in the ‘above average’ range on the Wechsler Adult Intelligence Scale, and at 3 months post-surgery he returned to accounting. However . . . he needed prompting to get up and go to work. He lost all sense of a schedule and employers complained about tardiness and disorganization, although basic skills, manners, and temper were appropriate. Similar difficulties led to a deterioration of his marital life . . . . Unable to hold a job and separated from his family . . . . Employment problems continued . . . . Deciding where to dine might take hours . . . . He would drive to each restaurant to see how busy it was . . . .” This case example provides many of the hallmark features of executive dysfunction and graphically demonstrates the dissonance between preservation of basic cognitive and behavioral skills and grossly impaired regulation of these skills: this is the essence of executive dysfunction.

Characterization of Executive Function Executive function can be understood as the skills that allow humans to solve problems; adapt effectively and flexibly to their environment; and plan, perform, and evaluate goal-directed intentions, such as making a timely financial investment. Correspondingly, executive dysfunction can lead to deficits in the generation and initiation of appropriate behavior, limitations in cognitive flexibility and reasoning skills, and impairments in social judgement.3-10 The breadth of coverage in these descriptions immediately signals the complexity of the processes involved and, not surprisingly, the difficulty that researchers

have encountered in formulating adequate and comprehensive explanatory models of these behaviors. Notwithstanding this challenge, executive function continues to be a focus of interest for both researchers and clinicians, because the concept provides a description of humans’ adaptability to their environment and assistance in developing expectations and predictions of relevance to (1) differential diagnosis in clinical evaluations (for example, in delineating the syndromes of the frontotemporal dementias; see Chapter 74); (2) anticipating dysfunctional behavior of patients in everyday settings11; and (3) estimating decision-making capacity in everyday roles (for example, capacity for handling financial responsibilities12). Understandably, assessment of executive function has become a core component of most neuropsychological assessments.13

Neuropsychological Models of Executive Function Neuropsychological approaches to conceptualizing a model of executive function are varied. Banich4 provided a helpful roadmap to several of the approaches, including working memory, the supervisory attentional system, script knowledge, and goal-directed behavior. A brief description of two of the major theories follows.

Working Memory Baddeley’s working memory model14 (Fig. 7–1) consists of multiple specialized and interlinked components of cognition that allow humans to (1) mentally represent their immediate environment, (2) retain information on-line (available in consciousness in an on-going manner) to enable acquisition of new knowledge, and (3) formulate and act on current goals, through both an attentional control system—the central executive— and several specialized temporary storage systems, which are slave systems to the central executive, such as the articulatory loop and the visuospatial scratch pad.15 Working memory provides on-line cognition (manipulation of data in consciousness) that allows a reasoned response to complex tasks. Research since the 1990s has consistently supported the proposition that the central executive can be fractionated, or, as Baddeley persuasively commented, skills can be governed by an “executive committee” rather than a “homunculus.”16 There have been various attempts at defining the breadth and nature

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(simultaneous) Dual tasking (divided attention)

Attentional switching

Figure 7–1. Diagram of the working memory model of executive functioning. LTM, long-term memory.

Central executive

Fluid systems

Crystalized systems

Visuospatial sketch pad

Visual semantics

Episodic buffer

Phonological loop

Episodic LTM

Language

of executive functions.16-18 However, most taxonomies include focusing attention and inhibiting distraction, coordinating and dividing attention, switching attention, planning, and activating and generating representations drawn from long-term memory via an episodic buffer. Impairments in working memory can result in many of the core features of executive dysfunction, such as inability to maintain task focus as a result of susceptibility to distraction, or inability to perform two or more tasks simultaneously (multitasking). (An example of such multitasking would be simultaneously monitoring young children playing in a swimming pool and cooking a meal, while speaking on a mobile phone.) Working memory, therefore, can provide a comprehensive account of many features of executive dysfunction. Furthermore, the executive aspects of working memory have been closely associated with the prefrontal regions, especially the dorsolateral prefrontal cortex.19

attentional system was conceptualized as a unitary construct, but more recently, Stuss and Alexander argued for a multicomponent supervisory attentional system within which specific processes interlink with specific neural substrates of the frontal cortical-subcortical neural network.10 Furthermore, Stuss and Alexander cautioned against a simple conceptualization of supervisory attentional control. They emphasized that there are many types and levels of attentional control of behavior (e.g., Fig. 7–2) and that the concept of a simple frontal/ posterior dissociation related to control/automatic processes would not adequately capture the complexity of linkage of the system to particular neural substrates. They thereby concurred with other authorities that executive function fractionates into various subordinate roles important for goal-directed behavior. Although varied, existing theories of executive function are not necessarily mutually exclusive. Within most models, there is recognition of a multicomponent executive function system

Supervisory Attentional System Within this model, the emphasis is on the role of attentional control (executive function) in everyday actions. Shallice20,21 provided a two-layer model of an attention system that influences behavior: contention scheduling (automatic processing) and the supervisory attentional system (controlled processing). Contention scheduling allows fast automatic execution of welllearned action sequences. This may be sufficient for many everyday tasks, but it is also prone to error as it operates under minimal conscious supervision. For example, making a cup of coffee can become relatively automatic, but sometimes when a person is tired or distracted, he or she may unintentionally pour milk into the coffee pot instead of into the cup. In contrast, the supervisory attentional system is activated when conscious effort is required: for example, in situations of novelty or crisis or when new skills are learned. An impaired supervisory attentional system and an unmonitored contention scheduling system can account for many of the qualitative features of executive dysfunction, such as perseveration (failing to cease an ongoing behavior when it is no longer appropriate). Contention scheduling and the supervisory attentional system have been proposed to be operated by distinct neural substrates. Specifically, the supervisory attentional system is associated with the prefrontal cortex.22 Initially, the supervisory

Stuss and Benson—prefrontal hierarchies

Level 3

Self-awareness/metacognition (frontopolar) Social integration through principles and values (orbital)

Goal selection Level 2

Planning and anticipation Monitoring of current behavior (dorsolateral)

Sequencing (dorsolateral) Level 1 ■

Drive (medial frontal)

Figure 7–2. Diagrammatic representation of model of executive function. (From: Stuss DT, Alexander MP, Benson DF. Frontal Lobe Functions. In Trimble MR, Cummings JL, eds: Contemporary Behavioral Neurology. Boston: Butterworth Heinemann, 1996, pp 169-187.)

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Dorsolateral prefrontal cortex

Lateral orbital cortex

Anterior cingulate cortex

Caudate (dorsolateral)

Caudate (ventromedial)

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Globus pallidus (lateral dorsomedial)

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Thalamus (VA and MD)

Thalamus (MD)

subserving multiple roles. Furthermore, although executive function disorders are more commonly observed with frontal system dysfunction, most researchers argue that it would be overly simplistic to reduce executive function to a concept of frontal lobe disorder; instead, executive skills undoubtedly rely on networks of interactive systems.10

Neuroanatomical Substrates of Executive Functioning Functional imaging studies have confirmed that complex behaviors such as executive functions are subserved by networks of interconnected brain regions rather than by discrete cortical areas (Fig. 7–3), and a series of parallel frontalsubcortical circuits that link specific regions of the frontal cortex to the striatum, globus pallidus, and thalamus have been described.23,24 Miller and Cummings provided an extensive model of five defined frontal-subcortical circuits,25 of which the dorsolateral prefrontal, orbital frontal, and anterior cingulate circuits are purported to subserve cognitive and behavioral aspects of executive function.26 A corollary of this network structure is that interruption of such circuits outside the frontal cortex leads to many of the classic features of “frontal” dysfunction. For example, infarcts in the caudate head may disturb planning and sequencing, with disinhibition or apathy, depending on which part of the caudate—and therefore which circuit—is disrupted (e.g., see Mendez et al27). Progressive supranuclear palsy is another example of a disorder whose pathological effect is subcortical rather than on the prefrontal cortex and yet that is characterized by a prominent dysexecutive syndrome on the basis of disruption of these circuits.28

Orbitofrontal Circuit The orbitofrontal circuit is important for inhibition, and changes in this control mechanism can, in a variety of ways, affect the behavioral response to environmental and social demands.24,26 Affected patients have been described as acting impulsively, exhibiting emotional and socially inappropriate behavior, and being liable to increased distractibility.29 In severe instances, dysfunction can result in the phenomenon of utilization behavior, in which patients become devastatingly stimulus-bound to environmental cues.30 The orbitofrontal

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Figure 7–3. Diagram of the three principal circuits involving prefrontal cortex: organization of three frontal subcortical circuits in which lesions produce alterations of cognition and emotion. MD, medial dorsal; VA, ventral anterior. (From Baddeley A: Fractionating the central executive. In Stuss DT, Knight RT, eds: Principles of Frontal Lobe Function. New York: Oxford University Press, 2002, pp 246-260.)

network serves as a braking mechanism to stop automatic responding and allows for a flexible approach to environmental manipulation.

Anterior Cingulate Circuit The anterior cingulate circuit is medial in location and has been implicated in resistance to interference (including cognitive inhibition of automatic responses) and in response initiation.31 Cummings24 described the characteristic syndrome as that of apathy, the most extreme form being of akinetic mutism: a profound indifference to the environment in which patients lack any internally generated activity or behavior (see Chapter 9).

Dorsolateral Prefrontal Circuit Impairment of the dorsolateral prefrontal circuit is argued to contribute to many of the observed cognitive features of executive dysfunction that affect cognitive flexibility or attentional switching and the formulation of novel ideas and responses. Deficits include impairments in self-generated behavioral (motor or cognitive) planning, maintenance of cognitive set and set switching,9 and manipulation of working memory information on-line.32 Patients with dorsolateral lesions are frequently described as displaying impaired mental flexibility and poor reasoning.

Information Flow to the Frontal Cortex A complementary view of executive functioning and the prefrontal cortex is that the dorsolateral prefrontal cortex sits at the apex of information flow from the external milieu (the subject’s interaction with the external environment), after that information has been processed through unimodal and then multimodal association cortices, and is able to modulate and select responses to this information. The orbitofrontal and mesial prefrontal cortices, in contrast, receive information on the subject’s internal milieu, including needs and drives, and modulate and select responses to these stimuli.33,34 Therefore, although there is continuing debate on a comprehensive taxonomy of executive processes, most researchers

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agree that executive function is a fractionated functional system that relies on differentiated underlying neural regions and pathways.

FORMAL ASSESSMENT OF EXECUTIVE FUNCTION Common Problems Affecting Executive Function Tests Most clinicians are familiar with the frustrating situation in which patients with executive dysfunction have a significant discrepancy between the reasonably average results of formal testing procedures and major difficulties in real-life behavior.6 Sometimes this may relate to the following aspects of the testing process.

Clinical Tests Can Be Multifactorial Many traditional measures of executive function (e.g., the Wisconsin Card Sorting Test [WCST]) are multifactorial (i.e., they assess a number of different aspects of executive function and other cognitive domains), which renders them liable to be sensitive to executive dysfunction but poor in isolating why failure occurs. That is, test specificity is low, and a patient may fail the test for multiple reasons.

Repeated Testing Can Lead to Marked Practice Effects All executive function tests suffer from practice effects. Although parallel test versions may be available to obviate direct learning effects of the test material (for example, alternate letters in verbal fluency), procedural learning (implicit learning that can improve performance simply by performance of a task more than once) is common in executive function tests. This may reflect the fact that the tasks are designed to be novel and cognitively engaging and the fact that the participant will actively attempt to rehearse strategies to make the task easier. With repeated exposure, a previously novel task therefore becomes automatic.35 This represents a major difficulty in longitudinal studies.

Testing in the Office Is Not the Same as Real-Life Situations In formal testing procedures, most typically conducted within a quiet office environment, distractions are minimized, and tasks are often carefully structured to increase the reliability of the test. However, these artificial constraints may substitute for the patient’s defective executive system.36 Furthermore, test procedures can be relatively brief episodes, so that persistent and sustained attention to a task is rarely assessed thoroughly, and demand for multitasking is low.6,13,37 Unfortunately, these constraints of office testing can prevent the demonstration of the essential features of executive dysfunction. To improve the ecological validity of the assessment, formalized versions of real-world activities in which patients are assessed in naturalistic settings (e.g., Shallice and Burgess’s shopping center

task9) have been devised; although these approaches have yielded highly informative results for guiding rehabilitation,38 they are generally impractical for a busy hospital-based assessment clinic.

Assessment of the Affective, Social, and Judgmental Changes of Executive Dysfunction Are Not Well Covered by Existing Tests Alterations in emotional and social behavior are important components of the executive syndrome, to the extent that Stuss and Alexander argued that social behavioral changes represent the most disabling aspect of the disorder.10 Performance on many tests can be undermined by apathy, disinhibition, or other features of lack of emotional control. However, formalized approaches to the documentation of these key characteristics are limited, although research measures of social cognition, such as the faux pas test,39 or of judgment, such as the gambling game,40 show promise.

Level of Premorbid Ability Is Important when Executive Function Is Assessed It is important to evaluate executive function within the context of the estimated overall premorbid ability of the individual; that is, a below-average score on a test of executive function may be significant if the patient was of above-average premorbid ability, but it would be less suspect if previous general ability was estimated to lie in the below-average range. Furthermore, researchers41,42 have noted that tests of executive function are frequently correlated with general cognitive ability in healthy populations, and this should be considered when individual performances in tests of executive skills are evaluated. In response to these various criticisms, the examiner using executive function tests must carefully observe the quality of performance on the selected tests as much as record the overall level of performance achieved on the outcome measures.

Standard Neuropsychological Tests Commonly Used in Assessing Executive Function Test Batteries or Individual Tests for Executive Function? There are now several test batteries of executive function, including the Behavioural Assessment of the Dysexecutive Syndrome (BADS),43 the Behavioral Dyscontrol Scale,44 and the Delis-Kaplan Executive Function Scale (D-KEFS).45 The DKEFS is especially useful because of its reasonably large normative sample and the provision of multiple standardized tests in which the same outcome scale is used for comparison purposes. These batteries should be considered for use, because they allow comprehensive assessment of executive function; however, in many clinical examinations, time is limited and administration of a full test battery cannot be easily accommodated. Consequently, the neuropsychologist is faced with the decision of individual test selection. Consideration of the cognitive and neural models of executive function, and of reports of the patient’s particular difficul-

chapter 7 executive function and its assessment ties, is essential to guide the examiner in determining which aspects of the fractionated roles of executive function are critical in the assessment. The following sections summarize some of the neuropsychological tests commonly used to assess executive function. The listing is by no means exhaustive, and for more information on these and other related tests, the reader is referred to Lezak and colleagues (2004). The listing of the tests within separate domains of executive function is also debatable16,17 and is provided simply as a guide to the reader. As stated earlier, neuropsychological tests of executive function tend to be multifactorial, which precludes a simple description of the underlying properties of the tests.

Focusing Attention and Inhibiting Distraction An important feature of executive function is the ability to maintain attention on task and to resist interference from distracting events or thoughts. The Stroop Test46-49 provides a classic paradigm for assessing capacity to resist interference from an automatic process (in this instance, reading words: the names of colors) on a more effortful process (identifying the colors of the ink in which the words are printed). There are multiple versions of this test (including the Color-Word interference subtest from the D-KEFS), but in the basic task, participants are timed in (1) reading aloud words that are the names of colors; (2) naming ink patches of color; and (3) naming the color of the ink in which incongruent-color words are printed: for example, stating “blue” when the word “red” is printed in blue letters.46 The increased time taken to complete this final interference trial provides an index of the capacities to focus attention on the appropriate stimulus and to inhibit distraction from the more automatic response of reading the color word (cognitive inhibition). Excessive slowing or an increase in errors on the interference trial provides indication of diminished ability to inhibit inappropriate responses (Fig. 7–4). The test is relatively quick to administer (most versions take approximately 8 minutes), and scoring is by time or error on each trial. A substantial amount of cognitive neuropsychological research50 and a number of neuroimaging studies have confirmed the role of executive function and of the prefrontal

blue yellow red green

blue yellow

green

red

red yellow red ■

green red

blue yellow

green yellow blue red

green

blue

blue yellow green

Figure 7–4. Interference trial of the Stroop test (Victoria version). (From Spreen O, Strauss E: A Compendium of Neuropsychological Tests: Administration, Norms and Commentary, 2nd ed. New York: Oxford University Press, 1998.)

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regions of the brain—specifically, the anterior cingulate/ mesiofrontal circuit—in task performance.51,52 Satisfactory test-retest reliability has been reported for different test versions;6,53 for example, Houx and associates reported high test-retest reliability (r = .80) within a multicenter study of 5804 older adults.35 However, practice effects, as observed in most executive measures, are apparent. Houx and associates reported that speed of performance on the interference trial improved by approximately 5 seconds between baseline and reassessment 2 weeks later, and they argued that procedural learning in the Stroop test has to be taken into account when the course of executive function in patients is monitored over time. Impaired visual acuity or severe color blindness precludes use of the test, but it has been found to be sensitive to executive dysfunction in a range of clinical populations, including patients with traumatic brain injury54 and mildly and moderately demented patients.55 In both of these populations and in patients with Huntington’s disease,56 however, increasing severity of disorder results in increased generalized slowing of response, so that the specific Stroop effect diminishes.55,57 More recent versions of the test have increased its complexity by adding an additional switching trial to the basic color naming, word reading, and color-word interference trials.54,5845,54 In the switching trial, participants are required to name the color of the ink as per the traditional color-word interference trial but to switch to reading the color word of any items enclosed by a rectangle, randomly positioned throughout the trial. This addition provides increased sensitivity for the identification of mild impairment in executive function.

Set-Shifting and Cognitive Flexibility The ability to shift attention readily between different cognitive tasks (cognitive flexibility) is an important feature of adaptive behavior.16,58 One of the most popular tests of set-shifting is the Trail Making Test (TMT)59,60 which consists of two parts: the Trail Making Test Part A (TMT-A) and the Trail Making Test Part B (TMT-B). The TMT-A is a timed trial that requires participants to draw lines to interconnect 25 consecutively numbered circles. The TMT-B is also timed and requires participants to interconnect consecutive numbers and letters, alternating between the two sequences (i.e., 1-A-2-B-3-C-4-D . . . . L-13). Scoring is based on time to complete each trial (errors being reflected in the time score) and derived scores of (1) the difference in time to complete the two sections (TMT-B score minus TMT-A score) and (2) the ratio of TMT-B score to TMTA score. The derived scores provide the advantage of removing the individual variance in speed of response before set-shifting capacity is calculated. These derived scores, as well as time taken to complete TMT-B, have frequently been used as indices of cognitive flexibility or set-shifting.61-66 The derived scores have been shown in some reports of TMT performance to provide better correlations with other measures of cognitive flexibility,61 and neuroimaging research has provided support for the critical role of the dorsolateral and medial frontal cortices in the regulation of cognitive flexibility and set-shifting, as required in the TMT.67 The TMT is quick to administer (approximately 4 to 6 minutes), but additional difficulties in visual scanning and motor control can compromise performance. To address this, the TMT subtest in the D-KEFS includes three extra conditions

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that allow the contributions of visual sequencing and motor speed to be evaluated more thoroughly.45 Because the TMT is predicated on familiarity with the English alphabet, the Color Trails Test68 was developed to provide a nonalphabetical parallel form for use in cross-cultural studies or clinical settings, although only limited normative data are available.69,70 Satisfactory test-retest reliability is reported for the TMT, with many reported coefficients higher than .80 and all exceeding .60.6,53 However, practice effects are again noticeable, especially on the TMT-A, and need to be considered when performance over time is evaluated. A large normative study of 911 participants aged 18 to 89 years has provided useful information on the TMT-A and TMT-B and on the effects of age and education on test performance,71 and this can be supplemented by normative information on the derived scores from a smaller study.72 The TMT has been demonstrated to be sensitive to cognitive impairment in a range of clinical conditions, including Parkinson’s disease,73,74 Alzheimer’s disease,75,76 and other dementias.77-81 The WCST82,83 is the most extensively characterized test of executive function. Although multifactorial, it is frequently described as a task of attentional set-shifting.17,84 The test requires the client to sort a set of cards on the basis of several different characteristics: color, form, and number. Clients are not given instructions on how to sort the cards but must infer the correct method of sorting from the examiner’s mention of “Correct” or “Incorrect” in response to their previous sorting attempts (Fig. 7–5). After a series of consecutive successful sorts, the sorting principle changes without notice, and the participant must both discern that the rule has changed and discover the new criterion for sorting. Scoring includes the

number of correct categories achieved and the number of perseverative errors (an error of sorting within a category that was formerly correct but is no longer appropriate: that is, a failure in ability to switch response according to task demands). The WCST has a number of drawbacks for consideration in the clinic.85 First, administration time is lengthy (approximately 30 to 45 minutes). In response to this limitation, a short form of the WCST has been developed (Modified Wisconsin Card Sorting Test86). A further limitation is that although the WCST was initially reported to be sensitive to dysfunction of the dorsolateral prefrontal cortex, especially on the left,87,88 researchers have more recently criticized the test for failing to discriminate between frontal and nonfrontal brain injury patients.89-91 This lack of specificity may result from the complexity of the task; failure on the WCST can arise as a result of a range of different deficits.29 A further problem for clinical use of the WCST is that performance is particularly prone to practice effects once the subject gains an appreciation of its principles; on the basis of results from a 3-year study of cognitive disorder in Huntington’s disease, Snowden and colleagues suggested that the WCST has limited use in longitudinal studies, although its use in cross-sectional studies remains important.56 Nevertheless, the WCST has been found to be a modest predictor of everyday functional ability after discharge from acute rehabilitation.92

Coordinating the Performance of Multiple Tasks (Dual Tasking) Performing two tasks simultaneously requires dividing attention between the two tasks, coordination of attention, and

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A

Figure 7–5. The Wisconsin Card Sorting Test (WCST). A. Matching by shape, but not number or color. B. Matching by color, but not number or shape.

red blue green yellow

B

chapter 7 executive function and its assessment ongoing monitoring of the effectiveness of performance.93 This skill, termed dual-tasking, provides another avenue to assessment of executive attention.14,17 A commonly used paradigm in dual-task research requires verbal performance of digit span at the same time as a paper and pencil tracking task; dual-task capacity is indexed by comparing performance level in each single task with performance of both tasks under dual-task conditions.93 Within such a paradigm, dual-task impairment has distinguished normal older adults from those with early Alzheimers’s disease94 and from older adults with nonspecific cognitive impairment.95 In a study of patients with severe head injury, Alderman found that a large dualtask decrement was associated with a poor response to behavioral intervention.96 However, as yet, dual-task paradigms have been restricted to clinical research procedures, and their adoption into routine clinical assessment will be dependent on the development of standardized tests and normative databases. In this regard, a new battery of dual-task measures may prove useful.97

Strategically Activating Information from Long-Term Memory and Manipulating Information Online Extensive neuropsychological research has linked verbal fluency performance to executive functioning.98 Verbal fluency tasks require generation of words, usually for 60 to 90 seconds, based on either phonemic (letter fluency) or semantic (category fluency) criteria. A nonverbal analog, design fluency, has been developed and is included in the D-KEFS battery.44 Probably the best known verbal fluency task is the Controlled Oral Word Association test,99 consisting of three 1-minute trials of generating words beginning with the letters F, A, and S (or C, F, and L or with P, R and W). Scoring is based on total words generated within the time limit and is adjusted for age, gender, and education. Phonemic fluency has been argued to be an effortful task, requiring recruitment of executive function, because retrieving words on the basis of orthographic criteria (spelling) is unusual: People normally retrieve words on the basis of their meaning.100 In contrast, semantic fluency is considered less effortful, although patients with early Alzheimer’s disease have been reported to demonstrate more difficulty with semantic fluency than with phonemic fluency, presumably as a function of impaired semantic memory caused by early involvement of the temporal neocortex.101 However, contrary to early conceptualizations concerning differential performance on phonemic and semantic fluency,102 Henry and Crawford demonstrated through meta-analysis that both forms of fluency are equivalent in sensitivity to frontal lesions, which suggests that both draw on resources of executive processes, including initiation, efficient organization of verbal retrieval and recall, and selfmonitoring.103 However, semantic fluency is also sensitive to temporal lobe lesions, which suggests that impaired semantic fluency may be a result of either executive or temporal dysfunction. Research has also confirmed that set-shifting ability contributes to verbal fluency by allowing active strategic search of relevant retrieval cues for generating words (e.g., “ship, sailor, sea . . .”; “soap, shower, shampoo . . .”),104-106 and this has pro-

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moted additional scoring measures: the number of subcategory switches and the cluster size of individual groups of words. Qualitative aspects, such as production of socially inappropriate words or rule breaking by producing proper nouns despite being able to state that these are not allowed, are important additional observations. (The latter is an example of what Walsh termed “the curious dichotomy between knowing and doing” that typifies dysexecutive behavior.107) Neuroimaging studies identify significant activation of the left dorsolateral prefrontal cortex (or its associated network) and the left thalamic nucleus during verbal fluency tasks.108,109 A variety of populations with frontal damage, including patients with many varieties of cortical and subcortical dementia, demonstrate reduced fluency,110 although the underlying neuropsychological impairment causing the reduced fluency varies.111 An advantage of verbal fluency tests is that they are quick to administer (approximately 3 to 8 minutes). However, several variables need to be considered when performance on verbal fluency tasks is interpreted, including (1) the presence of aphasia and (2) premorbid verbal ability112 and educational and vocational achievements,46 which are correlated with fluency performance.

Planning and Hypothesis Generation A further group of tests, such as the Zoo Map test from the BADS,43 require planning and capacity for maintaining goaldirected behavior through dependence on rule adherence. Another of a number of such instruments is the Tower of London task, which requires participants to solve increasingly more difficult spatial problems by planning several moves ahead to resolve the problems in the minimum number of moves.20 The participant is provided with a starting array of different colored beads placed on three pegs (initial position). The task is to move the beads, according to certain rules, across the pegs to achieve a target configuration; the target configurations become increasingly complex, requiring an increasing number of bead moves (Fig. 7–6). Performance is measured in accuracy, latency to initial move, and total time to completion. A computerized version of the task also exists.113 Patients with frontostriatal dysfunction tend to make more rule-breaking errors and perform poorly on the task, often being unable to find solutions to the more complex problems.9,114,115 Although the Tower of London task has been used frequently in research on executive dysfunction, concerns about its reliability116 may limit its use in clinical settings. However, there is some evidence that difficulty in thinking ahead (forming plans of action/goaldirected behavior) during the test may reflect everyday behavioral problems.9

Self-Reports and Informant Reports of Everyday and Emotional Behavior Collateral information in the assessment of executive functioning is vital, because significant executive dysfunction invariably impairs the capacity of affected patients to gauge the effects of their actions on other people, and awareness of social performance in everyday life is frequently observed to be diminished.13 Systematic reports gathered from friends and relatives

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( 2 moves)

Initial position

( 4 moves)

( 5 moves)

Goal position

Goal position

Goal position

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Figure 7–6. The Tower of London Test.

Tower of London Test

assist in clarifying the impact of executive dysfunction on everyday functioning and behavior. To this end, the Dysexecutive Questionnaire43 has been developed as a 20-item self-report and informant report on the difficulties related to executive dysfunction in everyday life. Preliminary analysis identified three factors in the questionnaire (behavior, cognition, and emotion), and a moderately high correlation was established between tests of executive functions (BADS43) and the factor scores derived from informant (family) ratings. Although some other groups were unable to replicate these relationships,117,118 Chan subsequently identified a five-factor structure within a healthy community sample and reported correlations between these Dysexecutive Questionnaire factors and tests of executive function.119 These results were supported and extended in a later study of patients with traumatic brain injury.120 The Dysexecutive Questionnaire, when completed by a health professional, has also been reported to be sensitive to executive dysfunction that follows traumatic brain injury (although it is less accurate when completed by family or patient rating), and it has been suggested that it can be used effectively as a screening instrument to identify executive disorder, through this method of administration.121 Another assessment based on a structured interview of an informant is the Neuropsychiatric Inventory.122 This 10-domain scale was initially developed to fractionate and quantify psychopathology in dementia, but it includes areas of behavior that are relevant to executive dysfunction. The Neuropsychiatric Inventory domains concern delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior. Its originators reported that the inventory was both reliable and valid.122 A self-administered informant-report version (Neuropsychiatric Inventory -Q123) is available. Two recent caregiver-rated questionnaires, designed specifically to assess frontal behavioral change, are the 24-item Frontal Behavioral Inventory124 and the 46-item Frontal Systems Behavioral Scale.125 The items in the Frontal Behavioral Inventory were selected to reflect the core symptoms of frontal lobe–related dementias, whereas the Frontal Systems Behavioral Scale covers the three principal frontal behavioral syndromes: apathy (mesial), disinhibition (orbitofrontal), and (cognitive) executive dysfunction (dorsolateral). Good reliability has been reported for both scales, although an advantage of the Frontal Systems Behavioral Scale is availability of large-scale norms (436 persons; age range, 18 to 95 years), and the availability of self- and family informant–rating versions.125

QUALITATIVE OBSERVATIONS AND BEDSIDE TESTS Qualitative Observations The non-neuropsychologically trained clinician can nevertheless make important qualitative observations about patients with the dysexecutive syndrome. Social inappropriateness in the form of intrusiveness or suggestive comments may be evident. In the dementia clinic in which one of the authors works, this is often displayed or evident only to an examiner of the opposite gender; thus, there is an advantage in the team approach. Apathy is often confused with depression, but it lacks the transmitted affect of despair. A related phenomenon is decreased verbal output, characterized by minimally elaborated answers to questions, with associated lack of spontaneous propositional speech. Apparent indifference (blunted unconcern) displayed while family informants relate a torrid tale of deterioration in behavior, performance, and interpersonal relationships is an important observation, although it is also wise to interview informants separately from the patient. Stereotyped motor behavior or purposeless motor activity may also be evident. Utilization behavior, as a manifestation of stimulus boundedness, may be evident spontaneously or specifically sought.

Bedside Testing Individual Bedside Tests A range of behaviors characteristic of frontal system disorders can provide insight into the features of executive dysfunction. Motor perseveration may be evident in copying drawings of repeating patterns (e.g., “+ 0 + + 0 + + + 0 . . .”), and motor impersistence—often initially evident as a failure to keep eyes closed during sensory testing—can be quantitated.126 Impairment of sequencing can be sought through motor control tests such as Luria’s fist/edge/palm test.127 Sometimes patients may even say the correct sequence aloud while performing it incorrectly: another example of the “curious dichotomy between knowing and doing.”107 Cognitive inhibition may be demonstrated on the antisaccade test,128 as well as on the conflicting tapping test (“tap once when I tap twice, and tap twice when I tap once”) and the go–no-go test (“tap once when I tap once, but don’t tap at all when I tap twice”).127 In each case, the patient should be

chapter 7 executive function and its assessment able to repeat the instructions correctly after having performed the maneuvers incorrectly, to ensure that failure was not attributable merely to impairments of comprehension or memory. It is traditional to test “abstraction” using proverb interpretation. Although this has been formalized as the Gorham proverb test,129 it is problematic because known proverbs may well elicit known interpretations (i.e., they may actually test semantic memory), whereas unknown proverbs may have a number of possible interpretations, which inhibits response. The California Proverbs test45 was intended to overcome this through the use of a multiple-choice format with proverbs of graded unfamiliarity, but tests of word similarities (e.g., “clock”/“thermometer,” “bicycle”/“train,” “poem”/“statue,” and “bridge”/“tunnel”) and differences (“dwarf”/“child,” “river”/ “canal,” “laziness”/“idleness,” “character”/“reputation”)6 are easier to apply in the clinic or at the bedside. Judgment is sometimes assessed by asking patients what they would do in a hypothetical situation, such as if they found water flooding into their kitchen. The difficulty with this approach is that patients may know and give the “correct” answer but do something quite different in practice. An informal adaptation of Shallice’s and Evans’s Cognitive Estimation test,130 which also has several American versions,6 is an examination of practical judgment. For example, patients might be asked how fast a racehorse can gallop (any answer of more than 40 miles/65 km per hour is incorrect), how tall the tallest building in the city is, how many slices are in a loaf of bread, or what the length of the average man’s spine is.

ably always abnormal.134,135 Release signs are more likely to be significant (if still nonlocalizing) in younger patients (younger than 50 years). This subject has been reviewed in depth.135

CONCLUSION Executive function fractionates into subskills, and different executive tests measure different components of executive function. Therefore, within any clinical assessment, more than one test of executive function is required, and the choice of tests must be guided not only by the cognitive and neural model to be used to interpret executive function but also by the presenting complaint of the patient. In many cases, qualitative features of test performance may be critical in the delineation of executive disorder. The challenge for clinical assessment of executive dysfunction in office-based settings continues to be finding a relationship between office-based test performance and performance in everyday activities.

K E Y

Executive function refers to components of cognition that allow humans to form relevant goals, plan how to achieve them, and successfully carry out the intended actions.

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Executive function is a complex cognitive domain, consisting of a number of subcomponents. Several theories successfully account for many aspects of executive dysfunction: prominent theories include those of working memory, developed by Baddeley, and the supervisory attentional system, originally set out by Shallice. Such theories are not mutually exclusive, however.

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Although the terms prefrontal or frontal function and executive function are often used interchangeably, executive functions depend on the integrity of neural networks encompassing structures beyond the prefrontal cortex. Damage to these other structures (e.g., caudate nuclei) can also result in executive dysfunction.

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At least three such networks that include prefrontal cortex have been identified, involving dorsolateral, orbitofrontal, and mesial frontal cortices. Disruption of these networks results in major deficits in planning/sequencing/set-shifting, response inhibition/impulse control, and motivation/drive, respectively. Patients frequently exhibit a combination of two or more of these syndromes.

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Standard neuropsychological assessment in a managed environment can often be surprisingly unrevealing, and even classic “executive” tasks can be insensitive to orbitofrontal or mesial frontal damage. Informant history and behavioral observations form an important part of the assessment in patients with dysexecutive syndromes.

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Non-neuropsychologically trained clinicians can make important behavioral observations and use various bedside techniques to qualitatively examine aspects of executive functioning.

Release Signs (Primitive Reflexes) Release signs, or primitive reflexes (e.g., palmomental, glabellar tap, snout and grasp reflexes), are sometimes sought as evidence of “frontal” involvement. They are thought to represent reappearance of infantile reflexes as a result of loss of inhibition from higher centers, but they have relatively poor localizing value,132 although asymmetrical release signs (palmomental/grasp) are more likely in asymmetrical disease (e.g., strokes) than in diffuse degenerations. Also, about 16% of normal elderly persons have at least one primitive reflex; the palmomental is the least specific for dementia and a grasp response the most specific.133 Even normal elderly individuals do not have three or more, however, and a grasp reflex is prob-

P O I N T S

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The Frontal Assessment Battery A number of such bedside tests, comprising similarities, phonemic verbal fluency (generation of words beginning with “S”), Luria’s fist/edge/palm test, conflicting tapping, and the grasp response have been assembled into the Frontal Assessment Battery.131 This takes less than 10 minutes to perform, and instructions and scoring details are given in the appendix to the original article. The Frontal Assessment Battery demonstrated high interrater reliability of .87, good internal consistency, good concurrent validity against other measures thought to be sensitive to (but not specific for) executive dysfunction (including the WCST), and 89% accuracy in distinguishing patients with “frontal” disorders from controls. Its specificity for patients with executive dysfunction as distinct from other types of cognitive deficits has not, however, yet been established.

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Suggested Reading Crawford JR, Henry JD: Assessment of executive dysfunction. In Halligan PW, Wade N, eds: The Effectiveness of Rehabilitation for Cognitive Deficits. London: Oxford University Press. 2005, 233-245. Lezak MD, Howieson DB, Loring DW: Neuropsychological Assessment, 4th ed. Oxford, UK: Oxford University Press, 2004. Miller BL, Cummings JL, eds: The Human Frontal Lobes— Functions and Disorders. New York: Guilford Press, 1999. Stuss DT, Knight RT, eds: Principles of Frontal Lobe Function. New York: Oxford University Press, 2002.

References 1. Macmillan M: An Odd Kind of Fame: Stories of Phineas Gage. Cambridge, MA: MIT Press, 2000. 2. Eslinger PJ, Damasio AR: Severe disturbance of higher cognition following bilateral frontal lobe ablation. Neurology 1985; 35:1731-1741. 3. Andrewes DG: Neuropsychology: From Theory to Practice. East Sussex, UK: Psychology Press, 2001. 4. Banich M: Cognitive Neuroscience and Neuropsychology, 2nd ed. Boston: Houghton Mifflin, 2004, pp 365-392. 5. Bechara A, Damasio H, Damasio AR: Emotion, Decision Making and the Orbitofrontal Cortex. Cereb Cortex 2000; 10:295-307. 6. Lezak MD, Howieson DB, Loring DW: Neuropsychological Assessment, 4th ed. Oxford, UK: Oxford University Press, 2004. 7. Luria AR: The Working Brain. Harmondsworth, UK: Harper & Row, 1973. 8. Robbins TW: Dissociating executive functions of the prefrontal cortex. Phil Trans R Soc Lond B 1996; 351:1463-1471. 9. Shallice T, Burgess P: Deficits in strategy application following frontal lobe damage in man. Brain 1991; 114:727-741. 10. Stuss DT, Alexander MP: Executive functions and the frontal lobes: a conceptual view. Psychol Res 2000; 63:289-298. 11. Cahn-Weiner DA, Ready RE, Malloy PF: Neuropsychological predictors of everyday memory and everyday functioning in patients with mild Alzheimer’s disease. J Geriatr Psychiatry Neurol 2003; 16:84-89. 12. Griffith HR, Belue K, Sicola A, et al: Impaired financial abilities in mild cognitive impairment. Neurology 2003; 60:449457. 13. Manchester D, Priestley N, Jackson H: The assessment of executive functions: coming out of the office (a review). Brain Injury 2004; 18:1067-1081. 14. Baddeley AD: Is working memory still working? Am Psychol 2001; 56:849-864. 15. Baddeley AD, Logie R: Working memory: the multiplecomponent model. In Miyake A, Shah P, eds: Models of Working Memory. New York: Cambridge University Press, 1999, pp 28-61. 16. Baddeley AD: Exploring the central executive. Q J Exp Psychol A 1996; 49:5-28. 17. Miyake A, Friedman NP, Emerson MJ, et al: The unity and diversity of executive functions and their contributions to complex “frontal lobe” tasks: a latent variable analysis. Cogn Psychol 2000; 41:49-100. 18. Rabbitt PMA, ed: Methodology of Frontal and Executive Functions. Hove, UK: Psychology Press, 1997. 19. D’Esposito M, Postle BR: The Neural Baiss of Working Memory Storage, Rehearsal, and Contral Processes: Evidence from Patient and Functional Magnetic Resonance Imaging Studies. In Squire L, Schacter D, eds: Neuropsychology of Memory 3rd edn. New York: Guilford Press, 2002, pp 215-224.

20. Shallice T: Specific impairments of planning. Philos Trans R Soc Lond B 1982; 298:199-209. 21. Cooper R, Shallice T: Contention scheduling and the control of routine activities. Cogn Neuropsychol 2000; 17:297338. 22. Stuss DT, Shallice T, Alexander MP, et al: A multidisciplinary approach to anterior attentional functions. Ann N Y Acad Sci 1995; 769:191-212. 23. Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 9:357-381. 24. Cummings JL: Fronto-subcortical circuits and human behaviour. Arch Neurol 1993; 50:873-880. 25. Miller BL, Cummings JL: The Human Frontal Lobes: Functions and Disorders. New York: Guilford Press, 1998. 26. Tekin S, Cummings JL: Frontal-subcortical neuronal circuits and clinical neuropsychiatry. An update. J Psychosom Res 2002; 53:647-654. 27. Mendez MF, Adams NL, Lewandowski KS: Neurobehavioral changes associated with caudate lesions. Neurology 1989; 39:349-354. 28. Zakzanis KK, Leach L, Kaplan E: Neuropsychological Differential Diagnosis. Lisse, The Netherlands: Swets & Zeitlinger, 1999, pp 73-82 and 173-193. 29. Royall DR, Lauterbach EC, Cummings JL, et al: Executive control function: a review of its promise and challenges for clinical research. J Neuropsychiatry Clin Neurosci 2002; 14:377-405. 30. Lhermitte F, Pillon B, Serdaru M: Human autonomy and the frontal lobes. Part I: Imitation and utilization behavior: a neuropsychological study of 75 patients. Ann Neurol 1986; 19:326-334. 31. Nathaniel-James DA, Fletcher P, et al: The functional anatomy of verbal initiation and suppression using the Hayling test. Neuropsychologia 1997; 35:559-566. 32. D’Esposito M, Postle BR, Rypma B: Prefrontal cortical contributions to working memory: evidence from event related fMRI studies. Exp Brain Res 2000; 133:3-11. 33. Damasio AR: Descartes’ Error: Emotion, Reason, and the Human Brain. New York: GP Putnam, 1994. 34. Gilbert SJ, Frith CD, Burgess PW: Involvement of rostral prefrontal cortex in selection between stimulus-oriented and stimulus-independent thought. Eur J Neurosci 2005; 21:1423-1431. 35. Houx PJ, Shepherd J, Blauw G-J, et al: Testing cognitive function in elderly populations: the PROSPER study. J Neurol Neurosurg Psychiatry 2005; 73:385-389. 36. Lezak M: The problem of assessing executive functions. Int J Psychol 1982; 17:281-297. 37. Burgess PW: Theory and methodology in executive function and research. In Rabbitt P, ed: Methodology of Frontal and Executive Function. Hove, UK: Psychology Press, 1997, pp 81-116. 38. Alderman N, Burgess PW, Knight C, et al: Ecological validity of a simplified version of the multiple errands shopping test. J Int Neuropsychol Soc 2003; 9:31-44. 39. Stone VE, Baron-Cohen S, Knight RT: Frontal lobe contributions to theory of mind. J Cogn Neurosci 1998; 10:640656. 40. Rahman S, Sahakian BJ, Hodges JR, et al: Specific cognitive deficits in mild frontal variant frontotemporal dementia. Brain 1999; 122:1469-1493. 41. Crawford JR, Obonsawin MC, Bremner M: Frontal lobe impairment in schizophrenia: Relationship to intellectual functioning. Psychol Med 1993; 23:787-790. 42. Obonsawin MC, Crawford JR, Page J, et al: Performance on tests of frontal lobe function reflect general intellectual ability. Neuropsychologia 2002; 40:970-977.

chapter 7 executive function and its assessment 43. Wilson BA, Alderman N, Burgess P, et al: Behavioural Assessment of the Dysexecutive Syndrome. Bury St. Edmunds, UK: Thames Valley Test Company, 1996. 44. Grigsby J, Kaye K, Shetterly SM, et al: Prevalence of disorders of executive cognitive functioning among the elderly: findings from the San Luis Valley Health and Aging Study. Neuroepidemiology 2002; 21:213-220. 45. Delis D, Kaplan E, Kramer J: Delis-Kaplan Executive Function Scale. San Antonio, TX: Psychological Corporation, 2001. 46. Stroop JR: Studies of interference in serial verbal reaction. J Exp Psychol 1935; 18:643-662. 47. Dodrill CB: A neuropsychological battery for epilepsy. Epilepsia 1978; 19:611-623. 48. Golden C: Stroop Color and Word Test Manual (Cat. 30150M). Chicago: Stoelting, 1978. 49. Trennery MR, Crosson B, DeBoe J, et al: Stroop Neuropsychological Screening Test. Tampa, FL: Psychological Assessment Resources, 1989. 50. Stuss DT, Floden D, Alexander MP, et al: Stroop performance in focal lesion patients: dissociation of processes and frontal lobe lesion location. Neuropsychologia 2001; 39:771-786. 51. Cabeza R, Nyberg L: Imaging cognition II: an empirical review of 275 PET and fMRI studies. J Cogn Neurosci 2000; 12:1-47. 52. Peterson BS, Skudlarski P, Getenby JC, et al: An fMRI study of Stroop Word-Color Interference: evidence for anterior cingulate subregions subserving multiple distributed attentional systems. Biol Psychiatry 1999; 45:1237-1258. 53. Spreen O, Strauss E: A Compendium of Neuropsychological Tests: Administration, Norms and Commentary, 2nd ed. New York: Oxford University Press, 1998. 54. Bohnen N, Jolles J, Twijnstra A: Modification of the Stroop Color Word Test improves differentiation between patients with mild head injury and matched controls. Clin Neuropsychol 1992; 6:178-184. 55. Bondi MW, Serody AB, Chan AS, et al: Cognitive and neuropathologic correlates of Stroop Color-Word Test Performance in Alzheimer’s disease. Neuropsychology 2002; 16:335-343. 56. Snowden J, Craufurd D, Griffiths H, et al: Longitudinal evaluation of cognitive disorder in Huntington’s disease. J Int Neuropsychol Soc 2001; 7:33-44. 57. Ponsford J, Kinsella G: Attentional deficits following closed head injury. J Clin Exp Neuropsychol 1992; 14:822838. 58. Burgess PW, Veitch EJ, Costello AdeL, et al: The cognitive and neuroanatomical correlates of multitasking. Neuropsychologia 2000; 38:848-863. 59. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation, 2nd ed. Tucson, AZ: Neuropsychology Press, 1993. 60. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery: research findings and clinical application. In Kaufman AS, ed: Specific Learning Disabilities and Difficulties in Children and Adolescents: Psychological Assessment and Evaluation. New York: Cambridge University Press, 2001, pp 309-346. 61. Arbuthnott K, Frank J: Trail Making Test Part B as a measure of executive control: validation using a set-switching paradigm. J Clin Exp Neuropsychol 2000; 22:518-528. 62. Korrte KB, Horner MD, Windham WK: The Trail Making Test Part B: cognitive flexibility or ability to maintain set? Appl Neuropsychol 2002; 9:106-109. 63. Crowe SF: The differential contribution of mental tracking, cognitive flexibility, visual search, and motor speed to performance on Parts A and B of the Trail Making Test. J Clin Psychol 1998; 54:585-591.

93

64. Lamberty GJ, Putnam SH, Chatel DM, et al: Derived Trail Making Test indices: a preliminary report. Neuropsychiatry Neuropsychol Behav Neurol 1994; 7:230-234. 65. Ratti MT, Bo P, Giardini A, et al: Chronic alcoholism and the frontal lobe: which executive functions are impaired? Acta Neurol Scand 2002; 105:276-281. 66. Stuss DT, Bisschop SM, Alexander MP, et al: The Trail Making Test: a study in focal lesion patients. Psychol Assess 2001; 13:230-239. 67. Moll J, De Oliveiro-Souza R, Moll FT, et al: The cerebral correlates of set-shifting. An fMRI study of the Trail Making Test. Arq Neuropsiquiatr 2002; 60:900-905. 68. Maj M, D’Elia L, Satz P, et al: Evaluation of two new neuropsychological tests designed to minimise cultural bias in the assessment of HIV-1 seropositive persons: a WHO study. Arch Clin Neuropsychol 1993; 8:123-135. 69. Ponton MO, Gonzalez JJ, Hernandez I, et al: Factor analysis of the Neuropsychological Screening Battery for Hispanics (NeSBHIS). Appl Neuropsychol 2000; 7:32-39. 70. Lee TM, Chan CC: Are trail making and color trails tests of equivalent constructs? J Clin Exp Neuropsychol 2000; 22:529534. 71. Tombaugh TN: Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 2004; 19:203-214. 72. Hester RL, Kinsella GJ, Ong B, et al: 2005 Demographic influences on baseline and derived scores from the Trail Making Test in healthy older Australian adults. Clin Neuropsychol 19:45-54. 73. Goldman WP, Baty JD, Buckles VD, et al: Cognitive and motor functioning in Parkinson disease: subjects with and without questionable dementia. Arch Neurol 1998; 55:674680. 74. Pillon B, Gouider-Khouja N, Deweer B, et al: Neuropsychological pattern of striatonigral degeneration: comparison with Parkinson’s disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1995; 58:174-179. 75. Chen P, Ratcliffe G, Belle SH, et al: Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 2000; 55:1847-1853. 76. Chen P, Ratcliffe G, Belle SH, et al: Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001; 58:853858. 77. Hestad K, Aukrust P, Ellertsen B, et al: Neuropsychological deficits in HIV-1 seropositive and seronegative intravenous drug users (IVDUs): a follow-up study. J Int Neuropsychol Soc 1996; 2:126-133. 78. Heun R, Papassotiropoulos A, Jennssen F: The validity of psychometric instruments for detection of dementia in the elderly general population. Int J Geriatr Psychiatry 1998; 13:368-380. 79. Lunn S, Skydsbjerg M, Schulsinger H, et al: A preliminary report on the neuropsychologic sequelae of human immunodeficiency virus. Arch Gen Psychiatry 1991; 48:139-142. 80. Paul R, Moser D, Cohen R, et al: Dementia severity and pattern of cognitive performance in vascular dementia. Appl Neuropsychol 2001; 8:211-217. 81. Selnes OA, Jacobson L, Machado AM, et al: Normative data for a brief neuropsychological screening battery. Multicenter AIDS Cohort Study. Percept Mot Skills 1991; 73:539-550. 82. Grant DA, Berg EA: A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J Exp Psychol 1948; 38:404411. 83. Heaton RK, Chelune GJ, Talley JL, et al: Wisconsin Card Sorting Test. Manual Revised and Expanded. Odessa, FL: Psychological Assessment Resources, 1993.

94

Section

I

C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s

84. Perry RJ, Hodges JR: Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer’s disease. Neurology 2000; 54:2277-2284. 85. Parker DM, Crawford JR: Assessment of frontal lobe function. In Crawford JR, Parker DM, McKinlay WW, eds: A Handbook of Neuropsychological Assessment. London: Erlbaum, 1992, pp 267-291. 86. Nelson HE: A modified card sorting test sensitive to frontal lobe damage. Cortex 1976; 12:313-324. 87. Drewe EA: The effect of type and area of brain lesions on Wisconsin Card Sorting Test performance. Cortex 1974; 10:159170. 88. Milner B: Effects of different brain lesions on card sorting. Arch Neurol 1963; 9:90-100. 89. Anderson CV, Bigler ED, Blatter DD: Frontal lobe lesions, diffuse damage, and neuropsychological functioning in traumatically brain-injured patients. J Clin Exp Neuropsychol 1995; 17:900-908. 90. Axelrod BN, Goldman RS, Heaton RK, et al: Discriminability of the Wisconsin Card Sorting Test using the standardization sample. J Clin Exp Neuropsychol 1996; 18:338-342. 91. Mountain MA, Snow WG: Wisconsin Card Sorting Test as a measure of frontal pathology: a review. Clin Neuropsychol 1993; 7:108-118. 92. Hanks RA, Rapport LJ, Millis SR, et al: Measures of executive functioning as predictors of functional ability and social integration in a rehabilitation sample. Arch Phys Med Rehabil 1999; 80:1030-1037. 93. Logie RH, Cocchini G, Della Sala S, et al: Is there a specific executive capacity for dual task coordination? Evidence from Alzheimer’s disease. Neuropsychology 2004; 18:504-513. 94. Baddeley AD, Baddeley HA, Bucks RS, et al: Attentional control in Alzheimer’s disease. Brain 2001; 124:1492-1508. 95. Holtzer R, Burright RG, Donovick PJ: The sensitivity of dualtask performance to cognitive status in aging. J Int Neuropsychol Soc 2004; 10:230-238. 96. Alderman N: Central executive deficit and response to operant conditioning methods. Neuropsychol Rehabil 1996; 6:161186. 97. Wilson BA, Evans JJ, Greenfield E, et al: Test of Divided Attention. London: Thames Valley Test Company, 2005. 98. Henry JD, Crawford JR: A meta-analytic review of verbal fluency performance following focal cortical lesions. Neuropsychology 2004; 18:284-295. 99. Benton AL, Hamsher KdeS: Multilingual Aphasia Examination. Iowa City: AJA Associates, 1989. 100. Crowe SF: Dissociation of two frontal lobe syndromes by a test of verbal fluency. J Clin Exp Neuropsychol 1992; 14:327339. 101. Salmon DP, Heindel WC, Lange KL: Differential decline in word generation from phonemic and semantic categories during the course of Alzheimer’s disease: implications for the integrity of semantic memory. J Int Neuropsychol Soc 1999; 5:692-703. 102. Perret E: The left frontal lobe of man and the suppression of habitual responses in verbal categorical behaviour. Neuropsychologia 1974; 12:323-330. 103. Henry JD, Crawford JR: Verbal fluency deficits in Parkinson’s disease: a meta-analysis. J Int Neuropsychol Soc 2004; 10:608-622. 104. Baldo J, Shimamura AP, Delis DC, et al: Verbal and design fluency in patients with frontal lobe lesions. J Int Neuropsychol Soc 2001; 7:586-596. 105. Rende B, Ramsberger G, Miyake A: Commonalities and differences in the working memory components underlying letter and category fluency tasks: a dual-task investigation. Neuropsychology 2002; 16:309-321.

106. Troyer AK, Moscovitch M, Winocur G: Clustering and switching as two components of verbal fluency: evidence from younger and older healthy adults. Neuropsychology 1997; 11:138-146. 107. Walsh K: Understanding Brain Damage, 2nd ed. Edinburgh: Churchill Livingstone, 1991. 108. Brannen JH, Badie B, Moritz CH, et al: Reliability of functional MR imaging with word-generation tasks for mapping Broca’s area. AJNR Am J Neuroradiol 2001; 22:1711-1718. 109. Paulescu E, Goldacre B, Scifo P, et al: Functional heterogeneity of left inferior frontal cortex as revealed by fMRI. Neuroreport 1997; 8:2011-2016. 110. Stuss DT, Alexander MP, Hamer LP, et al: The effects of focal anterior and posterior brain lesions on verbal fluency. J Int Neuropsychol Soc 1998; 4:265-278. 111. Henry JD, Crawford JR, Phillips LH: Verbal fluency performance in dementia of the Alzheimer’s type: a meta-analysis. Neuropsychologia 2004; 42:1212-1222. 112. Crawford JR, Moore JW, Cameron IM: Verbal fluency: a NARTbased equation for the estimation of premorbid performance. Br J Clin Psychol 1992; 31:327-329. 113. Robbins TW, James M, Owen AM, et al: A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. J Int Neuropsychol Soc 1998; 4:474-490. 114. Lewis SJ, Cools R, Robbins TW, et al: Using executive heterogeneity to explore the nature of working memory deficits in Parkinson’s disease. Neuropsychologia 2003; 41:645654. 115. Owen AM: Cognitive dysfunction in Parkinson’s disease: the role of fronto-striatal circuitry. Neuroscientist 2004; 10:525557. 116. Humes G, Welsh MC, Retzlaff P, et al: Towers of Hanoi and London: reliability and validity of two executive function tasks. Assessment 1997; 4:249-257. 117. Bogod NM, Mateer CA, McDonald SWS: Self-awareness after traumatic brain injury: a comparison of measures and their relationship to executive functions. J Int Neuropsychol Soc 2003; 9:450-458. 118. Norris G, Tate RL: The Behavioural Assessment of the Dysexecutive Syndrome (BADS): ecological, concurrent, and construct validity. Neuropsychol Rehabil 2000; 10:33-45. 119. Chan RC: Dysexecutive symptoms among a non-clinical sample: a study with the use of the Dysexecutive Questionnaire. Br J Psychol 2001; 92:551-565. 120. Chan RCK, Manly T: The application of “dysexecutive syndrome” measures across cultures: performance and checklist assessment in neurologically healthy and traumatically braininjured Hong Kong Chinese volunteers. J Int Neuropsychol Soc 2002; 8:771-780. 121. Bennett PC, Ong B, Ponsford J: Measuring executive dysfunction in an acute rehabilitation setting: Using the Dysexecutive Questionnaire (DEX). J Int Neuropsychol Soc 2005; 11:376-385. 122. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314. 123. Kaufer DI, Cummings JL, Ketchel P, et al: Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 2000; 12:233239. 124. Kertesz A, Nadkarni N, Davidson W, et al: The Frontal Behavioral Inventory in the differential diagnosis of frontotemporal dementia. J Int Neuropsychol Soc 2000; 6:460-468. 125. Grace J, Malloy PF: Frontal Systems Behavior Scale. Professional manual. Odessa, FL: Psychological Assessment Resources, 2001.

chapter 7 executive function and its assessment 126. Benton AL, Sivan AB, Hamsher KdeS, et al: Contributions to Neuropsychological Assessment, 2nd ed. New York: Oxford University Press, 1994, pp 137-149. 127. Christensen A-L: Luria’s Neuropsychological Investigation, 2nd ed. Copenhagen: Munksgaard, 1979, p 44. 128. Currie J, Ramsden B, McArthur C, et al: Validation of a clinical antisaccade eye movement test in the assessment of dementia. Arch Neurol 1991; 48:644-648. 129. Gorham DR: A proverbs test for clinical and experimental use. Psychol Rep Monogr 1956; 2:1-12. 130. Shallice T, Evans ME: The involvement of the frontal lobes in cognitive estimation. Cortex 1978; 14:294-303. 131. Dubois B, Slachevsky A, Litvan I, et al: The FAB: a frontal assessment battery at bedside. Neurology 2000; 55:16211626.

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132. Jenkyn L, Walsh D, Culver C, et al: Clinical signs in diffuse cerebral dysfunction. J Neurol Neurosurg Psychiatry 1977; 40:956-966. 133. Hogan DB, Ebly EM: Primitive reflexes and dementia: results from the Canadian Study of Health and Aging. Age Ageing 1995; 24:375-381. 134. Di Legge S, Di Piero V, Altieri M, et al: Usefulness of primitive reflexes in demented and non-demented cerebrovascular patients in daily clinical practice. Eur Neurol 2000; 45:104110. 135. Walterfang M, Velakoulis D: Cortical release signs in psychiatry. Aust N Z J Psychiatry 2005; 39:317-327.

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Jeffrey V. Rosenfeld and Peter J. Lennarson

Assessing the level of consciousness and diagnosing the cause of coma are fundamental aspects of medical practice. Consciousness consists of two main components: the level of alertness or arousal and the content of thought. Impairment of arousal is a continuum from drowsiness to stupor and then to coma. In stupor, the patient awakens briefly in response to stimulation and then slips back into a sleeplike state. There is no verbal response. Coma is the inability of the patient to be aroused (i.e., to obey commands, speak, or open the eyes in response to painful stimuli). This is obviously different from a sleep state from which the individual can be aroused. Stupor and coma of recent onset are medical emergencies. Speedy diagnosis and treatment are imperative for achieving the optimal outcome; however, a discussion of the treatment of the many causes of coma is beyond the scope of this chapter. The term brain death implies that the functions of the human brain have irreversibly ceased while other body organ functions continue. Brain death is an important diagnosis because, when made, life support can be validly terminated, allowing the reassignment of resources to patients who can benefit from them. Second, establishing a diagnosis of brain death might expand the number of organs available for transplantation, inasmuch as families of brain-dead patients could be approached with regard to their interest in organ donation. Raising this possibility of organ donation with a family is critical, because even if a patient has declared his or her intentions regarding organ donation before death, the final decision rests with the next of kin in many jurisdictions. The many important ethical issues surrounding brain death are also explored in this chapter; the physician should be cognizant of these so as to offer appropriate advice to the family and to treat the patient with dignity.

CONSCIOUSNESS An appreciation of the phenomenon of consciousness should precede a discussion of coma or “unconsciousness.” Many aspects of consciousness still remain a cardinal mystery of the human being. The essence of consciousness is an awareness of the environment and of the self. This awareness at least involves perception and memory, but the prerequisites for consciousness are alertness and attention. Primary consciousness is the state of having mental images of the present (the “remembered present”). Higher order consciousness is the ability to be aware of being conscious and is accompanied by memories of

the past and the ability to plan for the future. It requires semantic ability, which is the ability to attach meaning to a symbol, and also the ability to manipulate those symbols. Higher order primates may have higher order consciousness to a limited degree. Qualia are the high-order perceptions of qualities, such as the warmth of warm or the redness of red, that are experienced in the normal conscious state.1 Free will, conscience, metamemory (knowledge and beliefs about the functioning of one’s own memory systems), the analysis of one’s own thoughts, and imagination are all integral components of human higher order consciousness that remain mysterious. Much of the planning and execution that humans perform is unconscious or preconscious in the “zombie mode.” An example is sensory processing and gating. The automatisms of complex partial seizures are an extended pathological example of this. Penfield (1937) showed that electrical stimulation of the cortex could alter the content of consciousness and produce “experiential responses” that the patient usually realized were unreal. The “déjà vu” phenomenon is a natural example of this. The neural correlates of consciousness are slowly yielding to the study of individual and group neuronal electrical activity, through the use of surface cortical electrodes and implanted microelectrodes, and to functional brain imaging. Although there is a modularity to brain function, it is the integration of all the modules that is necessary for consciousness. There also seems to be competition between different cortical areas and neurons to choose the best fit for a set of perceptual inputs. There are “essential nodes” for particular perceptions such as face recognition or color perception. Clearly, multiple nodes and regions of the brain, functioning in concert, are necessary for consciousness to exist.2,3 Both the cerebral cortex and subcortical structures such as the thalamus are involved in consciousness. Dandy described temporary loss of consciousness after removal of both frontal lobes with sacrifice of the anterior cerebral arteries at the genu of the corpus callosum and speculated that the striatal damage was responsible for the coma.4 The reticular nucleus that surrounds the thalamus acts as a switch or “gate” to particular thalamic nuclei. It results in different patterns of activity of the thalamic nuclei and therefore in different weighting of sensory input. The intralaminar nucleus of the thalamus sets thresholds for the cortical response to the thalamic input. Thalamic gating is also influenced by feedback from the prefrontal

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cortex.5 The filtering of sensory information is done at a preconscious level so that attention is selectively directed, although it can also be altered at will. Moruzzi and Magoun6 in 1949 produced electroencephalographic arousal by stimulating the brainstem reticular formation rostral to the mid-pons. They termed this system, including its rostral projection, the ascending reticular activating system (ARAS). This is an alerting or arousal system that also indirectly influences sensory processing in the cerebral cortex. It projects rostrally through the midline, intralaminar nucleus, and other nuclei of the thalamus, and via these structures to the cerebral cortex. Attention enables an awake and alert individual to select a task or a stimulus to process from a number of alternatives and to select a cognitive strategy to carry it out.5 The ARAS is thought to facilitate this process by enhancing the perception of differences between competing stimuli. The anterior cingulate gyrus is involved in a wide range of attentional and discriminatory activity and is involved in higher order motor control of many tasks. The parietal cortex is involved in attention in the visual field and the pulvinar of the thalamus is involved in selecting information for attention. The dorsolateral prefrontal cortex is also involved in attention, intention, and working memory; working memory is the term applied to the holding and manipulation of the current content of consciousness. The hippocampal system—including the fornices, the mammillary bodies and mammillothalamic tracts, the amygdala, the anterior thalamic nuclei, the medial dorsal thalamic nuclei, and the entorhinal cortex—are all involved with establishing new anterograde episodic memory. The amygdala, hippocampus, and associated limbic and nonlimbic structures are involved in the generation of internal feelings, emotions, and motivation.5 Various brainstem and basal nuclei form ascending and descending neural systems that influence large areas of the brain by releasing particular neurotransmitters. The cholinergic nuclei, such as the basal forebrain nuclei, the pedunculopontine nucleus, and the laterodorsal tegmental nuclei, play a role in alertness and arousal. Acetylcholine is probably an important neurotransmitter for memory function. The noradrenergic locus ceruleus and lateral tegmental nuclei of the pons assist in responding to sudden contrasting or adverse stimuli, and the locus ceruleus projection to the forebrain and visual cortex is involved in attention. The majority of the cell bodies of the dopaminergic system are in the ventral brainstem tegmentum and are involved in motor function and cognition. The dopaminergic nigrostriatal projection is also involved in motor function and attention. The serotonergic system of the midline raphe nuclei of the tegmentum, largely inhibitory in nature, has a stabilizing effect on information processing, is involved in sleep, and modulates the sleep-wake cycle. The g -amino butyric acid (GABA) inhibitory neurons are widely dispersed throughout the central nervous system and are involved with the selection of sensory information. Barbiturates increase GABAergic activity in the ARAS. Glutamate and aspartate are the excitatory neurotransmitters that play a key role in cortical interplay.5 The N-methyl-D-aspartate (NMDA) receptor may be the main target for the action of general anesthetic agents that produce a pharmacological coma. The corollary, that the NMDA receptor is essential for consciousness, constitutes the Flohr hypothesis, about which there is considerable debate.7 Clearly, many other peptides and receptors are also involved in cortical function and consciousness.

Single neurons in the human entorhinal cortex have very specific responses (e.g., only to faces or only to different types of animal), and some temporal lobe neurons function at a different hierarchical level by responding to the extensively processed perception or imagining of an object and not to the raw retinal input.2 Different components of consciousness therefore seem to exist from the level of individual neurons to that of different brain regions and, indeed, that of the whole brain. Edelman (2004) proposed a theory called neural Darwinism, or neuronal group selection, to explain consciousness, as opposed to an instructive model in which the brain has computer-like properties with a set of programs and algorithms. The three tenets of neural Darwinism are that (1) developmental selection leads to a highly diverse group of circuits, (2) experiential selection leads to changes in the connection strength of synapses, and (3) reentrant mapping occurs, in which brain maps are coordinated in space and time through reentrant signaling across reciprocal connections. This coordination leads to widespread synchronization of widely dispersed neuronal groups, which integrates information such as the color and orientation of visual objects and which Edelman proposed is central to the understanding of consciousness. This is a possible solution to the binding problem, which is the seamless reintegration of separately processed aspects of a sensory percept at a preconscious level. According to neural Darwinism, the brain is a selectional system. Other examples of such systems in nature are evolution and the immune system. Another important characteristic of the brain is degeneracy, in which different elements of the brain can perform the same function and one element can carry out different functions in different neuronal networks at different times. This creates great diversity of brain function. There is no need in the theory of neural Darwinism for a homunculus in the head directing the brain and being the seat of consciousness.1 The principal neural structures of consciousness according to Edelman’s (2004) theory are the cerebral cortex, the thalamus, and the reentrant loops between the two, which he called the dynamic thalamocortical core. He proposed that this neural activity generates the qualia of consciousness. The gamma, or 40-Hz, rhythm of the electroencephalogram (EEG) is believed to be produced by thalamocortical circuits during attention and sensory processing tasks. Attention is directed partly by the reticular nucleus of the thalamus and partly by the relationship of the basal ganglia to the frontal and parietal cortices. Higher order consciousness is based in part on episodic memory, which depends on the hippocampi, and in part on semantic and linguistic ability, which depend on the language cortices of Broca and Wernicke and associated areas (for further reading, see Edelman, 2004; Jasper et al, 1998; John, 2002; Metzinger, 2002; Young et al, 1998; Zeman, 2001).

COMA The Etiology of Coma The fundamental causes of coma are structural, including the mechanical deformation or disruption of neural tissue and ischemia, and metabolic or toxic derangement of neural tissue, inducing hypoxia. A detailed list of the causes is presented in

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T A B L E 8–1. Etiology of Coma Toxic/Metabolic Causes Metabolic and endocrine derangements Hypothermia or hyperthermia Hypoglycemia Diabetic ketoacidosis Hyperosmolar nonketotic coma Renal failure: uremia Hepatic failure: hyperammonemia Reye’s syndrome Hyponatremia/hypernatremia Hypocalcemia Panhypopituitarism Myxedema Adrenal cortical failure (addisonian crisis) Porphyria Hypertensive encephalopathy Nutritional Wernicke’s encephalopathy (thiamine deficiency) Vitamin B12 deficiency Burn encephalopathy Septicemic/toxic shock Hypoxic brain injury Asphyxiation Drowning Anoxemic anoxia (low PaO2) (e.g., as in cardiac arrest) Anemic anoxia (e.g., as in hemorrhagic shock) Toxic brain damage Alcohol, carbon monoxide, cyclosporine, etc. Drug overdose Opiates, barbiturates, benzodiazepines, etc. Inflammatory: vasculitis/infectious processes Meningitis (bacterial) Encephalitis Postinfectious encephalomyelitis (ADEM) Lupus cerebritis and other vasculitides Neurosarcoidosis Neoplastic Leptomeningeal carcinomatosis Dementing processes (end-stage, although PVS is more usual) Epilepsy Status epilepticus (including nonconvulsive status epilepticus) Postictal state Structural Causes Traumatic brain injury Diffuse axonal injury Epidural hematoma Subdural hematoma Intracerebral hematoma Penetrating brain injury Intracranial hemorrhage Subarachnoid hemorrhage Subarachnoid hemorrhage (spontaneous) Aneurysm rupture Arteriovenous malformation rupture Tumor hemorrhage Hemorrhage (spontaneous) Intracerebral, cerebellar, or brainstem Infarction Cerebral, cerebellar, or brainstem Intracranial infection Subdural empyema Focal encephalitis (herpes simplex) Cerebral abscess Brain tumor Primary neoplasm Secondary neoplasm Hydrocephalus Obstructive Communicating ADEM, acute disseminated encephalomyelitis; PaO2, partial pressure of arterial oxygen; PVS, persistent vegetative state.

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Figure 8–1. Computed tomographic scan showing the trajectory of small metal shrapnel fragments across both thalami and internal capsules of a young man who was a victim of a bomb blast. The entry point was just above and behind the right ear, and one fragment was lodged beneath the temporal bone on the left side. He remained deeply comatose after this injury, breathing spontaneously but with minimal response of his limbs to pain and with no eye opening.

Table 8–1. A detailed history from bystanders or relatives is vital in determining the cause of the coma.

The Anatomy and Pathophysiology of Coma Diffuse lesions of both cerebral hemispheres (cortical and subcortical white matter) may cause coma. Bilateral diencephalic damage (especially to the paramedian dorsal thalamus) may also cause coma (Fig. 8–1). The extension of the thalamic lesions into the midbrain tegmentum has an even greater propensity for causing coma or severe neurological deficit, apathy, and impaired attention. Damage to the paramedian gray matter anywhere from the posterior hypothalamus to the tegmentum of the lower pons causes coma.8,9 When the respiratory centers in the lower medulla are damaged, apnea ensues. The testing of brainstem reflexes and for apnea is the clinical means of confirming the destruction of theses critical areas. The irreversible destruction of critical brainstem areas usually follows catastrophic supratentorial events that cause brain herniation and subsequent compression and ischemia of the brainstem. The sequence of cardiovascular changes resulting from progressive mechanical compression and/or ischemia of the brainstem begins with vagal stimulation, which causes decreases in heart rate, mean arterial pressure, and cardiac output. As the pons becomes ischemic, sympathetic stimulation occurs, which results in hypertension with persistence of the bradycardia (Cushing’s reflex). As the medulla becomes ischemic, there

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is unopposed sympathetic stimulation with tachycardia, increased mean arterial pressure, and increased cardiac output. This sequence has been called an “autonomic storm” and has not been well recognized in intensive care unit patients, partly because it may have occurred by the time the patient is admitted to intensive care unit and may be affected by treatment or the presence of other injuries.10

Clinical Assessment of the Comatose Patient A full neurological and general examination of the patient must be undertaken. Some of the pertinent components of the examination are described as follows.5,9

Assessment of the Conscious State The Glasgow Coma Scale (GCS) was devised to provide a simple, reliable, and reproducible method of assessment of conscious state so as to avoid misinterpretation and blurring of terms such as stupor, semicoma, and confusion.11 It has become a universally accepted scale for neurological observation, prognostication, and grading severity and has been found to have good interrater reliability. It was originally a 14-point scale but has been extended to 15 points by splitting limb flexion into two tiers: flexion-withdrawal and flexion-abnormal. Abnormal flexion is defined as any two elements of stereotyped flexion posture, extreme wrist flexion, adduction of the upper arm, and fisting of the fingers over the thumb.12,13 The 15-point scale is the preferred scale for research studies. The GCS is scored on the best response in each of the three categories: eye opening, vocalization, and limb movement (Table 8–2). Testing nail bed pressure with a pencil is the recommended method of applying a painful stimulus. Patients who do not open their eyes, do not speak, and are not obeying commands are said to be comatose. Many clinicians regard a maximum GCS score of 8 as the cutoff for coma. Some limitations to the usefulness of the GCS do exist, however. For example, periorbital swelling and endotracheal intubation, both common conditions in the trauma patient, prevent the accurate assessment of eye opening and verbal response, respectively. Some centers record a “T” next to the score when the patient is intubated and the verbal score cannot be assessed. The GCS is commonly used to monitor neurological progress, and a drop in the GCS of 2 points or more is a sensitive measure of neurological deterioration and necessitates action to halt the progression. Age and depth of coma are the principal predictors of poor outcome or death after traumatic brain injury. Repeated GCS assessments and the recognition of confounding factors are required for any confidence in prediction of outcome. The conscious state is more difficult to assess in infants and young children, and special pediatric coma scales have been devised.14 The Paediatric Glasgow Coma Scale is a simple system based on the GCS with age-related norms for verbal and motor responses (see Table 8–2).15 A rapid and simple assessment of conscious state is the “AVPU” system, in which the examiner assesses the level of response on a four-tiered scale: A is alertness, V is any response to vocal stimuli (what response? opens eyes? moves? vocalizes? any of the above?), P is response only to painful stimuli, and U is unresponsiveness to all stimuli. This scale is used in the primary survey of trauma patients as taught on the Advanced

T A B L E 8–2. Glasgow Coma Scale and Paediatric Glasgow Coma Scale Glasgow Coma Scale (Adult): 15 Points (Teasdale and Jennett14) Response

Paediatric Glasgow Coma Scale: 14 Points (Simpson and Reilly16) Score

Response

Score

Eye Opening Spontaneous To sound To pain Nil

4 3 2 1

Eye Opening Spontaneous To sound To pain Nil

4 3 2 1

Best Verbal Response Oriented Confused conversation Inappropriate words Incomprehensible sounds Nil

5 4 3 2 1

Best Verbal Response Oriented Words Vocal sounds Cries Nil

5 4 3 2 1

Best Motor Response* Obeys commands Localizes pain Flexion-withdrawal Flexion-abnormal Extension None

6 5 4 3 2 1

Best Motor Response Obeys commands Localizes pain Flexion Extension Nil

5 4 3 2 1

Maximum Score

15

Maximum Score

14

*Teasdale and Jennett’s 14-point scale, which was described in 1974,11 has a total of 5 points for the best motor score because there is only one tier for flexion, rather than two tiers, as in the 15-point scale, which is currently used in most centers.

Trauma Life Support Course of the American College of Surgeons. The GCS may also be used in the primary survey and is used in the secondary trauma survey, which includes a comprehensive general examination.

Respiratory Pattern 1. Normal pattern. 2. Cheyne-Stokes: periodic increase and decrease of rate and depth, followed by an expiratory pause and then a repeated pattern; seen with diencephalic pathology and bilateral hemisphere dysfunction (nonspecific). 3. Hyperventilation: raises suspicion of hypoxia or metabolic coma with acidosis, such as with ethylene glycol, methanol, salicylates, and lactic acidosis. Central neurogenic hyperventilation may occur with midbrain damage. 4. Cluster breathing: periods of rapid irregular breathing separated by periods of apnea; is similar to Cheyne-Stokes respiration but without the crescendo/decrescendo pattern or regularity of the latter. This is seen with high medullary or low pontine lesions. 5. Apneustic breathing: deep inspiration followed by breath holding, then long slow expiration at a rate of 6 breaths per minute; implies pontine damage (e.g., basilar artery occlusion). It is a rare pattern. 6. Ataxic (Biot’s) breathing: irregular and disorganized breathing; occurs with medullary dysfunction and is usually preterminal.

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1.

The blood pressure, pulse, capillary return, core temperature, and the state of hydration should all be ascertained. Eyes deviate to the side of lesion • Left frontal lobe lesion

Pupil Examination Pupillary size, shape, and reaction are integral components of the assessment of conscious state. The light reflex is the most useful in distinguishing metabolic from structural causes of coma. 1. Equal-sized and reactive pupils in a comatose patient indicate a metabolic or toxic cause, with the exceptions of anoxia, anticholinergics, glutethimide, and botulinum toxin, which cause fixed, dilated pupils. Narcotics cause small pupils (miosis) that react sluggishly. 2. Unequal-sized pupils imply a structural lesion of the brain or cranial nerves. One caveat is that direct ocular trauma may produce a mydriasis. A pupil that dilates after a cerebral insult is indicative of changing intracranial pathology with increasing tension on the ipsilateral oculomotor nerve resulting from uncal herniation through the tentorial hiatus. Dilated nonreactive pupils from the time of an injury imply irreparable brain damage or bilateral optic nerve injury. The miosis of Horner’s syndrome implies disruption of the sympathetic nervous system input to the pupil and may follow carotid occlusion or dissection, among other causes. 3. Bilateral pinpoint pupils occur with pontine lesions that leave the parasympathetic nerves unopposed. 4. Bilaterally fixed and dilated pupils (7 to 10 mm) occurs with medullary injury, with post-tonsillar or central herniation, after anoxia, or with hypothermia (<32° C). 5. Bilateral nonreactive pupils at the midposition(4 to 6 mm) occurs with an extensive midbrain lesion.

2.

Eyes deviate away from the lesion • Left pontine lesion • Left medial thalamic lesion

3.

Eyes deviate downward • Midbrain pretectal lesion • Thalamic lesion • Metabolic/toxic cause 4.

Left III nerve palsy • Patient looking straight ahead 5.

Right VI nerve palsy • Patient looking to the right side 6.

Eye Motion: Extraocular Muscle Function

(Fig. 8–2)

Deviation of the Ocular Axes

Left hypertropia • III or IV nuclear or nerve injury • Lesion of medial longitudinal fasciculus

Bilateral conjugate deviation ■ Frontal lobe lesion (frontal center for contralateral gaze):

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Figure 8–2. Eye motion: extraocular muscle dysfunction.

the eyes look toward the side of the lesion. ■ Pontine lesion: the eyes look away from the side of the lesion. ■ Medial thalamic lesion: the eyes look away from the side of the lesion. ■ Downward deviation: thalamic or midbrain pretectal lesions, metabolic cause (especially barbiturates).

second and a pause of 2 to 3 seconds in each direction. This may indicate bilateral cerebral dysfunction.

Unilateral outward deviation with dilated pupil (nerve III palsy) Unilateral inward deviation (nerve VI palsy) Skew deviation: nerve III or IV nuclear or nerve injury, or an infratentorial lesion, especially of the dorsal midbrain.

Internuclear ophthalmoplegia is caused by a lesion of the medial longitudinal fasciculus. The eye on the side of the lesion does not adduct on spontaneous or reflex-induced eye movement.

Spontaneous Eye Movement

Reflex Eye Movement

Ocular bobbing with rapid downward movement of the eyes and a slow return occurs with pontine lesions. Random conjugate eye movements are nonspecific for lesion location. In the uncommon periodic alternating gaze (“ping-pong gaze”), the eyes deviate side to side with a frequency of three to five per

Internuclear Ophthalmoplegia

Oculocephalic reflex (doll’s-eye reflex) In the awake patient, the eyes follow the movement of the head or, if the movement is performed slowly, there is contraversive conjugate eye movement if the eyes fixate on a stationary

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target. In the comatose patient with intact brainstem and cranial nerves, the reflex is preserved and the eyes move in the opposite direction when the head is turned laterally or the neck flexed and extended; that is, the conjugate eye movement is contraversive. When the brainstem is damaged, the reflex is lost, and the eyes follow the head movement. Cervical spine injury should be ruled out before this test is performed.

1

Oculovestibular reflex (iced water calorics) The head of the bed is elevated 30 degrees (to place the “horizontal” semicircular canals in the true vertical position), and one ear is irrigated with 50 to 100 mL of iced water. A comatose patient with an intact brainstem has tonic conjugate eye movement to the side of the cold stimulus which may be delayed up to one minute or more. There is no fast component (the nystagmus), which is present in the conscious subject. Absence of response results from brain death, neuromuscular blockade, metabolic causes, and massive infratentorial pathology. Nystagmus without tonic deviation occurs in psychogenic coma. Tympanic membrane rupture or external auditory canal obstruction by blood or debris should be ruled out before this test is performed.

2 3

5 4

Optokinetic nystagmus Optokinetic nystagmus is a rhythmic involuntary conjugate ocular movement in response to the movement of full visual field images, either rotation of an image before the subject, such as a drum with vertical black stripes on a white background, or rocking of a mirror back and forth in front of the patient’s eyes. There is a biphasic response with an initial slow phase provoked by, and in the direction of, the stimulus. This is followed by a fast corrective phase. Optokinetic nystagmus may be elicited in patients feigning coma.

Motor Examination Decorticate posturing is abnormal flexion of the upper limbs (adduction of the arm and slow flexion of the elbow, wrist, and fingers) and extensor posturing of the lower limbs (extension, internal rotation, and plantar flexion). It occurs with large cortical or subcortical lesions. The corticospinal pathway is interrupted above the level of the midbrain. Decerebrate posturing occurs with a brainstem injury at the level of the midbrain or below. There is said to be disinhibition of the vestibulospinal tract and pontine reticular formation by removal of inhibition of the medullary reticular formation (i.e., the “transection” is at the intercollicular level between the red nuclei and the vestibular nuclei in the classical lesion). There is abnormal extension of the upper and lower limbs with extended adducted and hyperpronated arms and extended and internally rotated legs, plantar-flexed and inverted feet, plantarflexed toes, variably clenched teeth, and opisthotonos. Flexed arms with flaccid legs may occur with a lesion in the pontine tegmentum. Flaccid arms with appropriate leg movements may occur after anoxic brain injury.

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Figure 8–3. Schematic diagram showing the various types of brain herniation. 1, Subfalcine or cingulate herniation, in this case caused by an adjacent tumor. Note the midline shift of the septum pellucidum resulting from the mass lesion in the adjacent portion of the brain. 2, Transtentorial uncal herniation with midbrain compression, in this case caused by an acute epidural hematoma. 3, Central herniation with vertical descent of the brainstem. 4, Cerebellar tonsillar herniation through the foramen magnum with compression of the medulla. 5, Upward cerebellar herniation with upper brainstem compression.

disturb the conscious state by direct or indirect pressure on the diencephalon and brainstem. Indirect pressure means displacement of tissue at a distance from the mass. Coning is the name given to progressive cerebral herniation with secondary compression of the brainstem and resultant deepening coma. Computed tomography (CT) and magnetic resonance imaging have helped significantly to elucidate the anatomy of herniation. Plum and Posner (1982) in their classic treatise described progressive and predictable stages of herniation with cephalad-caudal progression. There are five types of supratentorial and infratentorial herniation (Fig. 8–3), described as follows.

Supratentorial Herniation Central (Transtentorial) Herniation

Herniation Syndromes (Coning) Cerebral herniation is the displacement of cerebral tissue as a result of intracranial mass lesions. This displacement may

The classic description is of a sequential rostral-caudal failure from diencephalon to the midbrain, the pons, and finally the medulla. Central herniation is often caused by a tumor in the frontal, parietal, or occipital lobes that reaches the point of

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T A B L E 8–3. Stages of Central Herniation Diencephalon Stage Consciousness

Respiration Pupils Oculomotor

Motor

Midbrain–Upper Pons Stage Respiration Pupils Oculomotor

Motor Lower Pons–Medulla Stage Respiration Pupils Oculomotor Motor

May be caused by displacement or ischemia of the diencephalon This stage is reversible Altered alertness is first sign Usually lethargy is present Some patients have agitation Later stupor, then coma Sighs, yawns, occasional pauses Small (1-3 mm), reacting Conjugate or slightly divergent roving eyes Doll’s-eye reflex present Parinaud’s syndrome with impaired upward gaze may be present Conjugate ipsilateral response to cold water calorics Early: appropriate response to painful stimulus Contralateral hemiparesis may worsen Bilateral Babinski reflex; later, grasp reflexes Decorticate (contralateral to the lesion initially) Prognosis is very poor when midbrain signs have developed; <5% having a good outcome if treatment is undertaken Cheyne-Stokes respiration → sustained tachypnea Moderately dilated: midposition (3-5 mm), fixed Doll’s-eye reflex impaired May be disconjugate May be internuclear ophthalmoplegia with medial moving eye moving less than the laterally moving eye) Response to calorics impaired Decorticate → bilaterally decerebrate Regular, shallow, and rapid (20-40/minute) Midposition (3-5 mm), fixed No doll’s-eye reflex Response to calorics absent Flaccid, bilateral Babinski reflex May be lower limb flexion in response to pain

Medullary Stage (Terminal Stage) Respiration Slow, irregular; sighs, gasps, occasional hyperpnea alternating with apnea Pupils Widely dilated and fixed Adapted from Greenberg MS: Coma. In Greenberg MS, ed: Handbook of Neurosurgery, 5th ed. New York: Thieme, 2001, pp 118-127. Also see Plum and Posner (1982).

decompensation. The diencephalon may herniate through the tentorial incisura, damaging the pituitary stalk and causing diabetes insipidus. Vertical downward shift of the brainstem may be a critical factor in the development of the features of central herniation.16 The brainstem may become ischemic as a consequence of shearing of perforating arteries from the basilar artery. Resultant hemorrhages in brainstem are called Duret hemorrhages. CT may show a downward displacement of the pineal gland and effacement of the perimesencephalic (ambient) cisterns. The posterior cerebral arteries may be kinked at the tentorial edge as they pass onto the inferior surface of the occipital lobe, which results in occipital infarction and cortical blindness. This may further increase the intracranial pressure. The clinical stages of central herniation are outlined in Table 8–3. It is difficult to discern these various stages (and those of the other types of coning) in many patients because of the speed of deterioration, the tendency of the stages to merge, and the mixed and complex pathology that may affect the supratentorial and infratentorial compartments, and because patients often receive early intervention with paralysis, endotracheal intubation, and ventilation that obscures or retards the clinical progression. Nevertheless, it is useful to think conceptually in these terms in contemplating the patient’s condition and the appropriate treatment.

Uncal herniation The uncus of the temporal lobe herniates over the free edge of the tentorium, compressing the midbrain and the oculomotor nerve. This is usually caused by a rapidly expanding middle cranial fossa epidural, subdural, or intratemporal lobe hematoma. The earliest sign of uncal herniation is the ipsilateral dilation of the pupil. A depressed state of consciousness is not a reliable early sign, but the patient may be confused or agitated. Once the brainstem is compromised, the conscious state may deteriorate rapidly to a deep coma. The mass lesion causing the uncal herniation usually causes a contralateral hemiparesis, but as the pressure increases, the opposite cerebral peduncle is compressed against the tentorium, which causes an ipsilateral hemiparesis (Kernohan’s sign). This is recognized at autopsy as Kernohan’s notch. As in central herniation, the posterior cerebral arteries may be compressed against the edge of the tentorium, which may cause occipital lobe infarcts. The early CT findings of uncal herniation are early unilateral encroachment on the suprasellar cistern and later brainstem displacement and flattening, flattening of the contralateral cerebral peduncle, and rotation of the midbrain. Contralateral hydrocephalus may occur. The clinical stages of uncal herniation are outlined in Table 8–4. The distinction between uncal and central herniation is difficult when the compression has reached the midbrain and

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T A B L E 8–4. The Stages of Uncal Herniation Early Third Nerve Stage Pupils Unilateral dilating pupil, ipsilateral to lesion in 85% of patients; often sluggish Oculomotor Doll’s-eye reflex normal or disconjugate (failure of adduction of ipsilateral eye) Caloric reflex may be disconjugate Respiration Normal Motor Appropriate response to pain Contralateral Babinski reflex may be present Late Third Nerve Stage Consciousness Stupor → coma Pupil Fully dilated (unilateral) Oculomotor Complete third nerve palsy with pupil dilatation (>6 mm) and ophthalmoplegia Respiration Hyperventilation sustained; in rare cases, Cheyne-Stokes respiration Motor Usually contralateral weakness If opposite cerebral peduncle is compressed against the tent, an ipsilateral hemiparesis (Kernohan’s sign) and then bilateral decerebrate posture develop Midbrain–Upper Pons Stage Pupils Contralateral pupil dilates initially to midposition (5-6 mm) Oculomotor Palsy Respirations Sustained hyperpnea Motor Bilateral decerebrate rigidity Adapted from Greenberg MS: Coma. In Greenberg MS, ed: Handbook of Neurosurgery, 5th ed. New York: Thieme, 2001, pp 118-127. Also see Plum and Posner (1982).

below. Prediction of the location of the pathology on the basis of the type of herniation syndrome is unreliable, inasmuch as central and uncal herniation may occur together. Decrease in consciousness occurs early in the sequence of central herniation but later in the sequence of uncal herniation. Cushing’s reflex, consisting of hypertension, bradycardia, and respiratory irregularity, which is a feature of medullary compression, is often absent with slowly progressive supratentorial mass lesions. The cause of the coma and the third nerve palsy in cases of presumed uncal herniation is not always uncal compression, because the degree of uncal herniation on imaging or at autopsy may not be correlated with clinical state. The anatomy varies among patients, and in some cases, there is no uncal herniation or it is the contralateral pupil that dilates first, so that the mechanism of the third nerve palsy is likely to be central (i.e., intrinsic to the midbrain) in these cases. Horizontal displacement of the central supratentorial structures may also contribute to or cause the depressed conscious state (see Investigation of Coma).17

Cingulate or subfalcine herniation The cingulate gyrus herniates beneath the falcine edge. This is usually asymptomatic but may be a prelude to transtentorial herniation. Anterior cerebral artery territory infarction may occur if the anterior cerebral arteries are displaced and kinked by the subfalcine herniation.

as a prelude to tumor excision. The superior cerebellar arteries may be occluded, which causes cerebellar infarction; the cerebral aqueduct may be compressed, which causes hydrocephalus; and cortical blindness may result from kinking of the posterior cerebral arteries. Failure of upward gaze or conjugate downward deviation of the eyes may occur.

Tonsillar herniation The tonsils of the cerebellum herniate, or “cone,” through the foramen magnum with compression of the medulla. Respiratory arrest and death may follow. It is caused by supratentorial and infratentorial mass lesions and may be precipitated by lumbar puncture in a patient with noncommunicating (obstructive) hydrocephalus, because of the increasing pressure differential between the intracranial and intraspinal compartments. Patients who present with initial symptoms of occipital headache, diplopia, vertigo, bilateral limb weakness, and ataxia have a posterior fossa lesion and are likely to deteriorate rapidly. Bilateral motor signs at the onset, small pupils, ophthalmoplegia, multiple cranial nerve palsies, and abnormal breathing patterns are other features. Direct pontine compression by a posterior fossa mass lesion contributes to the clinical features of infratentorial herniation to a variable degree with signs such as loss of eye movements, loss of corneal reflexes, miosis, and decerebrate posturing.

Differential Diagnosis of Coma Infratentorial Herniation Upward cerebellar herniation In this type of herniation, the cerebellar vermis ascends through the tentorial incisura. This is sometimes seen with large cerebellar mass lesions and is exacerbated or precipitated by supratentorial ventricular drainage or shunting performed

The differential diagnosis of coma includes (1) the “locked-in” syndrome, which may occur with ventral pontine infarction (see Chapter 9); (2) psychiatric disorder with catatonia or hysterical conversion reaction; (3) neuromuscular weakness with unreversed neuromuscular blockade, which may be encountered in the intensive care unit; (4) myasthenia gravis; and (5) Guillain-Barré syndrome.

chapter 8 coma and brain death The Investigation of Coma The order and scope of the investigation of the patient in coma depends on the likely cause, the urgency of the situation, and the resources available. A detailed description is beyond the scope of this chapter. Some of the relevant investigations are electrolyte measurements, liver function tests, toxicology screen, blood glucose measurement, blood gas measurement, and full blood examination. CT should be performed urgently to establish the presence of a structural lesion, determine whether there are any radiological signs of brain herniation or midline shift, and determine whether urgent neurosurgical intervention is required. Midline shift is the degree of horizontal shift of midline cerebral structures as seen on axial images and is correlated with the conscious state. Anteriorly, the midline is the septum pellucidum between the two frontal horns of the lateral ventricles. Posteriorly, it is the pineal gland, which can be identified on CT if it is calcified. A patient with midline shift is generally alert with 0- to 3-mm shift, drowsy with 3- to 4-mm shift, stuporous with 6- to 8-mm shift, and comatose with 8- to 13-mm shift (Fig. 8–4).17 This correlation of the extent of midline shift with level of consciousness is variable and also depends on the rapidity over which the shift occurred. In our experience, the rapid development of a large midline shift (>2 cm) usually results in a poor outcome or death. A slowly enlarging mass may produce

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marked midline shift without disturbing the conscious state. The location, as well as the size, of the mass lesion is also an important factor. A large frontal tumor may not cause significant shift, whereas a smaller temporal lobe mass might. Magnetic resonance imaging is also very helpful when the patient is more stable, because more information about the cause of the coma can be obtained. Other investigations that directly concern the neurologist are as follows:

Lumbar Puncture If papilledema is present, a CT scan should always be obtained before lumbar puncture is performed. The finding of an intracranial mass lesion and/or obstructive hydrocephalus is a contraindication to lumbar puncture, because of the risk of cerebellar tonsillar herniation. Absence of papilledema, however, does not rule out the presence of hydrocephalus, inasmuch as papilledema may take 6 to 24 hours or longer to develop. Signs of brain herniation and coagulopathy are also contraindications. Lumbar puncture, when feasible, is an important diagnostic tool for detection of central nervous system infection, inflammation, subarachnoid hemorrhage, and free tumor cells. Patients with communicating hydrocephalus may undergo lumbar puncture without undue risk.

Electroencephalogram The EEG slows in traumatic coma; the amount of slowing is proportional to the depth of coma. There may be some lag before the slowing occurs. There is also a loss of electroencephalographic reactivity to external stimuli, such as noise or eye opening, and a loss of spontaneous variability of the EEG patterns. The prognosis may be better when this reactivity is not completely lost and when there are periodic sleep patterns (“spindle pattern coma”). Burst suppression is the worst pattern short of electrical silence and, unless it is drug induced (e.g., by barbiturates), it is a preterminal finding.18 Alpha coma is widespread alpha (8- to 12-Hz) activity in the presence of coma. This is present over the entire scalp and does not vary with external stimuli. This is in contrast to normal alpha rhythm, which is seen over the occipital lobes of relaxed subjects with their eyes closed and is abolished by their becoming alert. Patients with alpha coma usually have a poor prognosis. The grades of electroencephalographic abnormality have been correlated with prognosis.19,20 The use of phase and coherence data improves the accuracy of the EEG. The EEG is easily perturbed by drugs, and so the clinician must be very careful in interpreting the EEG findings in the intensive care environment.18 Subclinical seizure activity may continue after the cessation of clinical seizures and is a possible cause of persistent coma. This seizure activity may be identified through continuous electroencephalographic monitoring with a single channel with two electrodes, one of which is usually a reference electrode. Repeated or continuous multiple-lead EEGs are obtained routinely in some intensive care units. ■

Figure 8–4. Computed tomographic scan showing a severe

Power Spectral Analysis

degree of midline shift caused by a small acute subdural hematoma and underlying severe hemisphere swelling after a traumatic brain injury. The patient was deeply comatose with dilated and fixed pupils.

Real-time power spectral analysis of the EEG is achieved with a fast Fourier transform algorithm, resolves the EEG into its individual frequency components, and can be displayed over

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time.21 Power spectral analysis simplifies the interpretation of the EEG, but a display of the EEG is still necessary to detect seizures. Power spectral analysis has some predictive value; variable spectral patterns are associated with a better prognosis. An unvarying pattern with the frequency component in the delta range (1 to 3 Hz) carries a poor prognosis.22,23 The overall trend in background frequency mirrors the course of the patient over a number of days. Evoked potentials have less variability over time than does power spectral analysis and therefore are more useful.

Evoked Potentials Evoked potentials measure the response of the cerebral hemispheres or brainstem to a sensory stimulus. Signal-averaging techniques are necessary to eliminate the background and preserve the repeated stimuli at fixed intervals. They have some value in prognostication after brain injury. Loss of wave I of the brainstem auditory evoked potentials (BAEPs) after head injury occurs if the inner ear is damaged, and therefore this loss cannot be used for prognostication in these cases. The absence of BAEPs is predictive of a poor outcome. However, the BAEPs may be normal and the outcome poor after traumatic brain injury because the integrity of the cerebral hemispheres is not measured by BAEPs. Somatosensory evoked potentials (SSEPs) have better prognostic value than BAEPs because they test the integrity of the brainstem and the cerebral hemispheres. The absence of any activity beyond wave P15 is highly predictive of death. P15 is the SSEP wave thought to arise from the caudal medulla. N20 is the first cortical peak and is thought to arise from the postcentral gyrus. The presence of SSEP activity beyond 50 to 70 milliseconds appears essential for functional survival. Activity occurring beyond 70 milliseconds has particular prognostic value for quality outcome after anoxic or traumatic brain injury. However, elderly patients may do poorly despite the prediction for a good outcome on the basis of the SSEP. The SSEPs often deteriorate over time after traumatic brain injury and may be absent with high doses of barbiturates.18 Testing for visual evoked responses is not often performed in the comatose patient but may be used to assess the integrity of the visual pathways.

BRAIN DEATH Concepts of human death have evolved over the centuries. The ancient Greeks believed the heart was the essence of life and that absence of the heartbeat was the principal sign of death. Maimonides, the famous Jewish physician and philosopher in the 12th century, believed that breathing, not heartbeat, was the essence of life and that cessation of breathing defined death. He recognized that the decapitated body was dead: Even though there were muscle spasms, there was no central control. He believed the central control of locomotion was also as essential to life as breathing.24 The modern concept of brain death was developed in the 1950s with the advent of mechanical ventilation because patients with irreparable brain damage and apnea could have their heartbeat temporarily sustained. Mollaret and Goulon25 used the term le coma dépassé (a “state beyond coma”) to describe patients in profound coma, although they did not assert that those patients were dead. There were further reports of the same condition with varying causes, and in 1968

an ad hoc committee of the Harvard Medical School formulated criteria asserting that patients with irreversible apnea, areflexia, and complete unresponsiveness from devastating brain injury were legally dead.26 These concepts and the tests for brain death were further refined over two decades, and the declaration of brain death became a widely accepted practice in industrialized nations by the mid-1990s.24 Current opinion holds that death is a process rather than a single event and that the time of death is an arbitrary point on a continuum. Organs and tissues cease to function and eventually die at different times, depending on the cause of death. Most commonly, the death of the patient follows a cardiac arrest, with the brain dying subsequently: first the cortex and then the brainstem. Less commonly, respiratory arrest comes first, followed by brain death and then cardiac arrest within 15 to 30 minutes. Sometimes the brain dies first, followed by respiratory arrest and eventually by anoxic cardiac arrest. The arrest may be postponed many days by maintaining the patient’s oxygenation, ventilation, fluid input, and blood pressure by artificial means, but these patients are accepted as being already dead because there is brainstem death. This seemingly ambiguous state of having a patient with a beating heart, circulation, urine output, and metabolism but with a dead brain is a technological artifact that lengthens the completed process of death of the entire body. Cardiac arrest is not enough, in its own right, to declare death of the patient, because a person can be resuscitated or the heartbeat recommenced during cardiac surgery. It is the death of the brainstem in this situation that determines the death of the patient.

The Whole Brain Formulation Bernat24 defined death as the permanent cessation of function of the “organism as a whole,” which includes the coordination and integration of organ subsystems, the generation of vital functions, and the set of physiological homeostatic mechanisms. It is the “whole brain” that subserves all the clinical functions of the organism. The cerebral cortex directs higher mental function, the diencephalon is responsible for gating and initial processing of sensory input, the hypothalamus regulates homeostatic functions, and vital functions such as heart rate and respiratory drive are controlled by the brainstem. Therefore, permanent cessation of function of the whole brain is required for this formulation. Some subsystems may still be functioning under this definition of death, but they are uncoordinated and meaningless to that individual. Likewise, pockets of functioning neurons after death do not contribute to overall brain function or to the person’s function as a whole. This whole brain definition is favored by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research and is accepted by the Law Reform Commission of Canada, many states of the United States, and several European countries.24 Machado27 proposed a new standard of human death that was based on the concept that consciousness is the key human attribute and provides the highest level of control in the hierarchy of integrating functions in the human being. There must be an irreversible destruction of the anatomical and functional substrata of consciousness throughout the whole brain to diagnose brain death in this formulation. There should be unresponsiveness, no arousal to any stimuli, and no cognitive and affective functions. This definition subtly distinguishes it from

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the standard whole brain formulation.27 This concept has not replaced the current formulation.

some people and cultures do not recognize the concept of brain death.32

The Higher Brain Formulation

The Legal or Statutory Definition of Brain Death

The neocortex is essential for consciousness and cognition, which are essential human attributes. The cerebral cortex, not the lower centers or brainstem, subserves awareness, memory, and personal identity. Permanent loss of the neocortex is necessary and sufficient to determine death in the higher brain formulation of death. Continued functioning of the brainstem and diencephalon are irrelevant to the determination of brain death by this definition. This concept was first proposed in 1975 by Veatch28,29 and supported by others.30 According to this definition, patients in a permanent vegetative state (permanent postcoma unresponsiveness) and anencephalic infants are dead. However, there are major conceptual and practical problems with this definition. Patients with loss of neocortex are still breathing spontaneously, and most societies would therefore not declare these individuals dead. There is a “slippery slope” argument to neocortical death in that there are various degrees of cortical and subcortical death, and patients with advanced dementias may manifest a similar situation, although no one would argue that these individuals are brain dead. How would the clinician distinguish these cases? The established diagnosis of permanent vegetative state requires several assessments over a considerable time, but a diagnosis of death cannot be made in this way. The higher brain formulation determines a loss of personhood, not death. Personhood has a spiritual and psychosocial dimension, in contradistinction to the biological dimension of death.24

In 1970, Kansas became the first state to incorporate brain death in a statutory definition of death. By 1993, more than 90% of states in the United States and the majority of industrialized nations had enacted legislation recognizing brain death. The American Bar Association drafted a model statute that stated in 1975, “For all legal purposes, a human body with irreversible cessation of total brain function, according to the usual and customary standards of medical practice, shall be considered dead.”24 This statute does not specify that death can be determined by the irreversible cessation of spontaneous respiratory and circulatory functions in the majority of cases. In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research developed a model statute called the Uniform Determination of Death Act: “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brainstem, is dead. A determination of death must be made in accordance with acceptable medical standards.”33 Bernat and associates34 proposed a modification to this statement so that the primary definition was that an individual who has sustained irreversible cessation of all functions of the entire brain, including the brainstem, is dead and that this can be determined (1) in the absence of cardiopulmonary support by prolonged absence of respiratory and circulatory function or (2) in the presence of artificial cardiopulmonary support by the tests of brain function.34

The Brainstem Formulation Brain death in the United Kingdom requires the determination of permanent cessation of brainstem function. This concept was developed in the United Kingdom by Pallis8 (see also Pallis, 1983). He recognized that most of the bedside tests for brain death were tests of brainstem function. The term brainstem death indicates that the whole brain is dead, because even if the cortex or basal ganglia, were alive they would not be able to function without a functioning reticular activating system and the body’s vital functions could not be maintained. In other words, brainstem death is equivalent to brain death. This concept is stated in the U.K. Royal Colleges memorandum of 1979.31 The one conceptual flaw in this determination is the rare possibility of a patient’s being “locked-in” with a functioning cerebral cortex and no clinical evidence of brainstem function, which is not an issue with the whole brain formulation. Typically, patients locked because of pontine tegmental pathology differ from patients with brainstem death in that they still have respiratory movements and often have preserved eye opening or vertical eye movements to command. The EEG may also identify this condition, which is discussed further in Chapter 9. (For further reading, see Pallis, 1983.)

The Circulatory Formulation It held by some conservative theologians, and has been stated by authorities in Japan, Israel, Denmark, and the Islamic countries, that death occurs only when the circulation ceases. Thus,

The Diagnosis of Brain Death From a philosophical standpoint, the development of diagnostic bedside tests for death is dependent on the acceptance of the definition of what constitutes death, followed by the development of criteria for the determination of death. These tests then must be validated.

The United Kingdom Guidelines for Brain Death The criteria for the diagnosis of brain death were published by the U.K. Conference of the Medical Royal Colleges in 197635,36 and were further confirmed in a memorandum of the U.K. Conference of the Medical Royal Colleges in 1979,31 in which it was stated that death could be declared once the criteria were satisfied. The diagnosis of brain death is clinical and does not require any confirmatory laboratory or imaging tests. Four preconditions must be met in order to proceed with the clinical tests to confirm brainstem death: 1. The patient is in deep coma. 2. The patient is apneic and therefore on a ventilator. 3. There is irrecoverable structural brain damage. Traumatic brain injury and massive intracranial hemorrhage are the common causes, but anoxic brain injury, intracranial infection, and brain tumor are other causes. Some time may be required to correct physiological derangements such as hypotension, hypoxia, and raised intracranial pressure (if possible) before this criterion can be established.

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4. Reversible causes of brainstem depression or a state mimicking it must be ruled out. Examples of these are neuromuscular blocking agents, depressant drugs such as barbiturates, hypothermia, and gross metabolic derangement.

the diagnostic criteria for clinical diagnosis of brain death. These are outlined in detail in Table 8–6.

The diagnosis of brain death is not usually made for at least 6 hours or, when the cause is anoxic damage or drug overdose, for at least 24 hours. Our practice has been to wait for at least 24 hours in many cases of traumatic brain injury, partly to give the patient’s relatives a chance to accept the diagnosis and the consequences. The confirmatory tests for brainstem death are simple to perform and should be carried out by two independent senior medical practitioners no less than half an hour apart. (The Australia and New Zealand Intensive Care Society recommends that the two examinations be done at least 2 hours apart.37) The U.K. criteria specify that one examiner be a consultant and the other a senior registrar or consultant. These tests are outlined in Table 8–5. They are essentially tests of brainstem reflexes and are entirely clinical. The time of death is arbitrarily determined at the completion of the second examination. The Royal College of Physicians reviewed the U.K. criteria in 1995 and endorsed the original recommendations.38 Physicians in Australia follow the U.K. criteria.

1. Clinical and neuroimaging evidence of an acute central nervous system catastrophe that is compatible with the clinical diagnosis of brain death. 2. Exclusion of complicating medical conditions that may confound clinical assessment (no severe electrolyte, acid base, or endocrine disturbance). 3. No drug intoxication or poisoning. 4. Core temperature = 32° C (90° F).

The United States Guidelines for Brain Death The U.S. guidelines for brain death were presented by the medical consultants on the diagnosis of death to the President’s Commission for the Study of the Ethical Problems in Medicine and Biomedical and Behavioral Research in 1981.33,39 These guidelines were updated and clarified in 1995 by the Quality Standards Committee of the American Academy of Neurology40 and have achieved wide acceptance in the United States. Brain death is defined as the irreversible loss of function of the brain, including the brainstem. In summary, there are three parts to

Prerequisites

Cardinal Findings The three cardinal findings in brain death are coma, absence of brainstem reflexes, and apnea. The examination of brainstem reflexes and testing for apnea are similar to the U.K. criteria, but the guidelines in Table 8–6 should be referred to for the details.

Apnea Testing Pitfalls in the diagnosis of brain death in the U.S. guidelines are stated as follows: 1. 2. 3. 4.

Severe facial trauma. Preexisting pupil abnormalities. Drug toxicity. Sleep apnea or severe pulmonary disease resulting in chronic retention of CO2.

Clinical Observations Compatible with the Diagnosis of Brain Death The U.S. guidelines state that the following manifestations are occasionally seen and should not be misinterpreted as evidence for brainstem function:

T A B L E 8–5. Confirmatory Tests for Brainstem Death: The United Kingdom Guidelines The Five United Kingdom Criteria No pupillary reflex; pupils fixed and fully dilated No corneal reflex No facial muscle movement in response to facial or peripheral pain (e.g., supraorbital margin pressure over the supraorbital nerve) and no coughing or gag on movement of the endotracheal tube or to suction of the trachea (carinal reflex) Absent caloric vestibulo-ocular reflex; the external auditory canals are clear of wax; when at least 20 mL of ice-cold water is administered by syringe into the external canal on each side, no nystagmus results Apnea test* is performed when the other test results are confirmed: There is no respiratory effort after achieving a PaCO2 of 50 mm Hg (6.65 kPa). In practice, 6 to 8 minutes is often enough even to get above 50 mm Hg. The American Codes recommend 60 mm Hg (8.0 kPa), as does the Australia and New Zealand Intensive Care Society, which also requires a pH of <7.3.37 Additional Criteria Absent oculocephalic (doll’s-eye) reflex. The unconscious patient with an intact brainstem probably has an intact oculocephalic reflex. Cervical fracture or instability should be excluded. The head is turned slowly from side to side, and the axis of the eyes remains pointing straight ahead. This reflex is absent if there is brainstem death and the axis of the eyes follows the position of the head. This reflex can also be elicited with a flexion/extension movement of the head. (Author comment: this test is a less powerful vestibular stimulus than ice-cold calorics, and although a positive result rules out brain death, a negative result cannot substitute for a test with ice-cold calorics.) *Apnea Test It is important that this test be done carefully and according to the instructions so that an attempt is made to maintain the blood oxygen level. The PaCO2 should be ≥40 mm Hg (5.3 kPa) before the ventilator is stopped, because the rise of CO2 is often slow. The patient should be preoxygenated with 100% oxygen for 10 minutes before disconnection, and >6 L/minute of oxygen flow should continue to pass down the endotracheal tube via a catheter while the ventilator is disconnected. Special advice may be required for patients with chronic respiratory disease who are less responsive to raised PaCO2 and depend on hypoxia for their respiratory drive.31,35,36 PaCO2, arterial partial pressure of carbon dioxide.

chapter 8 coma and brain death T A B L E 8–6.

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Diagnostic Criteria for Clinical Diagnosis of Brain Death: The United States Guidelines

1. Spontaneous movements of the limbs other than pathologic flexion or extension responses. 2. Respiration-like movements (shoulder elevation and adduction, back arching, intercostal expansion without significant tidal volumes). 3. Sweating, blushing, tachycardia. 4. Normal blood pressure without pressor support or sudden increases in blood pressure. 5. Absence of diabetes insipidus. 6. Deep tendon reflexes, superficial abdominal reflexes. 7. The Babinski reflex.40 Spinal reflexes may persist after brainstem death is diagnosed and may include movements of the body in response to light peripheral stimulation or to flexion of the neck or rotation of the body. These tend to occur at the time of the apnea test, during preparation for transport, at the time of abdominal incision for organ transplantation, and in the morgue. These movements involve withdrawal of the lower limbs, raising of

the arms independently of each other, abduction or adduction of the arms, head rotation, back arching, and even attempts to sit to 40 to 60 degrees. These are called Lazarus signs and are usually single events. Deep tendon reflexes, abdominal reflexes, and the Babinski sign may persist. There may also be skin flushing, shivering, sweating, and myoclonic twitching of limb muscles (see Wijdicks, 2001). There is also the maintenance of blood pressure and even some hypertensive response during donor nephrectomy, which may in part result from adrenal medullary stimulation by a reflex spinal arc.37,41 Patients with brain death develop gross vascular regulatory disturbance and a diffuse metabolic cellular injury that leads inexorably to organ failure and eventual cardiac arrest.10 The vascular regulatory disturbance results initially from extreme sympathetic stimulation and, in a second phase, from a failure of sympathetic outflow, which leads to hypotension and reduced cardiac output. This results in impaired autoregulation with vasodilation at the organ level. The cellular injury with a global mitochondrial dysfunction may result part from the

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A ■

B Figure 8–5. Cerebral angiography of a patient with brain death. Note the filling of the external carotid arterial branches (B) but the cutoff of the internal carotid artery at the level of the skull base (A).

hormonal deficiency (e.g., triiodothyronine) from loss of hypothalamic control.10 Myocardial and renal ischemia commonly result. Neurogenic pulmonary edema and coagulopathy may also occur. Patients with a high chance of proceeding to brain death frequently develop hypotension, and cardiac arrest may occur despite active support.10 However, brain death does not always rapidly lead to somatic death. If hemodynamic parameters in patients with brain death are maintained with norepinephrine/epinephrine, cardiac standstill usually occurs within 48 hours, but this period can be extended to a mean of 23 days with the addition of arginine vasopressin.42 Anterior pituitary dysfunction occurs variably after brain death with falls in triiodothyronine, thyroxine, cortisol, prolactin and folliclestimulating hormone levels. However, thyroid-stimulating hormone and adrenocorticotropic hormone levels may remain normal. Posterior pituitary failure causing diabetes insipidus is common after brain death.10 Hypothalamic failure results in hypothermia. What is the validity of the criteria for the diagnosis of brain death? There has never been a case reported in which a person has recovered when the U.K. criteria were satisfied.43 Some intensive care staff and relatives are confused by the presence of spinal reflexes in the patient who is brain dead. These may increase as the brain-dead patient is maintained on mechanical ventilation. Some explanation to these staff and relatives is required. The diagnosis of brain death is now widely accepted in industrialized countries by both hospital staff and the lay public.

The Confirmatory Laboratory Tests for Brain Death These investigations are not a substitute for clinical examination except if the full clinical examination cannot be carried

out, as in gross facial trauma, and should not precede it. They are used to confirm the diagnosis. The U.S. guidelines state that these confirmatory laboratory tests are desirable for patients in whom specific components of the clinical testing cannot be reliably performed or evaluated. In order of sensitivity, these tests as stated in the U.S. guidelines are conventional angiography, electroencephalography, transcranial Doppler ultrasonography, radionuclide brain scan, and SSEPs.40

Cerebral angiography and radionuclide brain scan (Figs. 8–5 and 8–6) Blood flow tests such as angiography or radionuclide brain scans show no entry of contrast material or isotope into the brain when either is injected systemically into the brain-dead patient. These tests can usually be performed rapidly and are being used in some centers, in cases in which the clinical diagnosis cannot be confirmed, and in some children. Blood flow studies obviate the need for awaiting the elimination of sedatives such as barbiturates, which can linger for days and delay the diagnosis of brain death, and can be performed in patients with metabolic causes of brain death, in whom the etiology of brain death is unclear.44 The confirmation of diagnosis with imaging is of value in optimizing the timing of organ harvesting, but the use of these confirmatory tests is somewhat controversial and is not universally practiced. Cerebral angiography has been considered the final determinant for confirming the diagnosis of brain death. Blood flow must be absent from the anterior and posterior circulations. The blood flow in the internal carotid stops abruptly in the petrous carotid at the skull base. The carotid siphon does not fill. The vertebral artery flow stops at the atlanto-occipital junction. The external carotid flow remains patent and fills early. A

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Figure 8–6. Technetium-99m hexamethyl–propylene amine oxime radionuclide scan of a patient with brain death. Note the absence of radionuclide uptake in the cerebral hemispheres and in the posterior fossa.

criticism of the technique is that a subintimal injection may produce a false block to the artery, but this is unlikely in more than one vessel and should not alter a diagnosis made on the basis of a four-vessel angiogram. Correct positioning of the head and correct rate of contrast material injection are important points of technique that, if not adhered to, may introduce some contrast material into cerebral vessels, producing artifactual cerebral blood flow. The contrast material may injure transplantable organs or may reduce remaining cerebral blood flow. The angiogram should be obtained twice at an interval of 20 minutes to make sure the first result is not artifactual. Intracranial blood flow may still be present if the study is done very early after the diagnosis of brain death, particularly if the mechanism did not involve raised intracranial pressure. In cases in which the supratentorial intracranial pressure is raised, the posterior circulation may be present but the carotid flow is absent, because the pressure from the supratentorial compartment has not yet been completely transmitted to the infratentorial compartment.44-46 A radionuclide brain scan showing the brainstem and supratentorial circulation is an alternative to cerebral angiography in diagnosis of brain death.47 The radionuclide test for brain death is reliable, safe, and rapid. Intravenous injection of technetium 99m (Tc-99m) hexamethylpropylene-amine oxime or iodine 123 iodoamphetamine, which cross the blood-brain barrier, results in their accumulation by functioning brain cells, in which they are held for several hours. There is no uptake of these agents when there is widespread neuronal death. These agents are preferred to the blood pool radionuclides (Tc-99m pertechnetate, Tc-99m diethylenetriaminepentaacetic acid, and Tc-99m glucoheptonate), which do not cross the blood-brain barrier, may not demonstrate the state of blood

flow in the posterior fossa on standard scans, and appear to produce more artifact. However, the addition of single photon emission computed tomography can give precise regional information and show whether there is any preservation of posterior fossa blood flow.44 Absence of uptake produces a characteristic “hollow skull” or “empty light bulb” appearance (see Wijdicks, 2001).

Electroencephalography An EEG is not necessary for making the diagnosis of brain death. It is optional39 but is still used in many countries as a confirmatory test of brain death. A 16- to 18- channel instrument should be used for at least 30 minutes of recording. Electrical activity above 2 μV is absent at a sensitivity of 2 μV/mm with the low filter setting at less than 1 Hz and the high filter setting at 70 Hz. The sensitivity and specificity are about 90%. However, if brainstem death is used for diagnosis of brain death, the absence of electrical activity on an EEG is not very helpful because it reflects cortical activity rather than brainstem activity and may show some activity even though all the criteria for brainstem death have been met. The electroencephalographic findings are therefore irrelevant when brainstem death is used to signify brain death8 (see Wijdicks, 2001). It can also be difficult to achieve a flat trace with all the electronic devices around the patient and if high-gain amplification is used. Nonetheless, a flat trace may help the patient’s relatives accept the diagnosis of brain death.

Evoked potentials Both BAEPs and SSEPs can be used as confirmatory tests for brain death, but they have a rather poor predictive value. An

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intact auditory nerve (wave I) is required for BAEP interpretation. In addition, BAEPs are not well correlated with the severity of brain injury. Absence of waves II to V indicates profound brainstem dysfunction; however, some waves may be present in patients who are brain dead, with absence of brainstem reflexes (see Wijdicks, 2001). The median nerve SSEP cortical wave (N20) is typically absent bilaterally in brain death, but it is also absent in 15% to 20% of patients who are comatose but not brain dead. Nevertheless, bilaterally absent SSEPs have an extremely high positive predictive value for failure to recover beyond permanent vegetative state (see Chapter 9). Similar uncertainties arise from the absence of the N18 wave, which is possibly generated in the cuneate nucleus (see Wijdicks, 2001). A single-wave SSEP with a mean latency of 9 milliseconds may be recorded at the level of C2 in patients with brain death. This potential may arise near the cervicomedullary junction and may indicate residual medullary function, but this does not negate the diagnosis of brain death. Erb’s point potentials must be present for the absence of cortical potentials to be interpretable. The evoked potentials may also be contaminated by potentials that are time locked to the stimulus but generated by extracranial sources.

vessels in brain-dead patients. Magnetic resonance spectroscopy reveals high lactate and choline levels and decreased N-acetyl aspartate levels44 (also see Wijdicks, 2001).

Ultrasonography

The tests for brain death in young children and neonates have not been as thoroughly validated as in adults. The diagnosis of brain death in children should not be made in the first 7 days after birth. Confirmatory tests, in addition to the clinical tests, are required in children up to 12 months of age. From 7 days to 2 months of age, two isoelectric EEGs or two radionuclide studies showing absence of intracranial uptake, 48 hours apart, are recommended. From 2 to 12 months of age, this interval need be only 24 hours. In children older than 12 months, the adult criteria can be used with up to 12 hours of observation without the need for electroencephalographic confirmation.50,51 There remains controversy in determination of brain death in the infant younger than 2 months because the clinical test results are difficult to interpret: the blood pressure and the duration and severity of the insult are often uncertain, and the degree of brain damage is difficult to determine on imaging.52 The determination of brain death in the infant is of relevance only for organ donation. Cessation of treatment for the neonate or infant with irreparable brain damage and ahopeless prognosis is common practice. There is controversy as to whether anencephalic newborns are brain dead and can proceed to multiple-organ donation.24 These infants have no cerebral hemispheres but do have a variably functioning brainstem and therefore, according to the definitions and concepts of brain death described previously, are technically not brain dead. Approximately 65% of anencephalic fetuses die in utero, and most anencephalic liveborn infants die in the first few days. Only about 5% are still alive at 1 week.53 Few of these infants die of brain death; most succumb to respiratory failure, cardiac arrhythmia, or sepsis. Our opinion (and that of Bernat24) is that it is not ethically acceptable to take the organs if these infants are still alive. These infants should be declared dead before their organs can be procured.

Transcranial Doppler ultrasonography is a noninvasive, quick bedside test. The characteristic features of brain death on transcranial Doppler ultrasonography are an oscillating movement of the blood column within arteries, short systolic spikes, and an absence of signal in patients in whom it was previously found to be present. Specificity and sensitivity have been found to be as high as 100% and 90% to 99%, respectively. The anterior and posterior circulations and the extracranial vessels must be studied on both sides to minimize false-positive findings. Patients with a large craniotomy or ventricular drains do not undergo this evaluation44 (also see Wijdicks, 2001). The World Federation of Neurology published a consensus opinion for the use of ultrasonography for the diagnosis of brain death.49

Computed tomography CT is performed with and without contrast material and may show the cause of the coma. After injection of contrast material, there is no increase in brain attenuation in the brain parenchyma of patients with brain death, nor is there any significant opacification of the vessels of the circle of Willis. Identification of contrast material in the extracranial soft tissue, the cervical great vessels, or the kidneys should be seen in order to confirm that enough contrast material has been administered. CT angiography can be used to show an absence of flow in the intracranial vessels. Xenon inhalation has been added to CT to detect cerebral blood flow; in the patient with brain death, there is minimal (<1 to 5 mL/100 g/minute) or no cerebral blood flow.44

Magnetic resonance imaging It is not often practicable to obtain magnetic resonance imaging in patients with brain death. Such imaging reveals transtentorial and tonsillar herniation, lack of intracranial flow void, poor gray-white differentiation, and marked contrast enhancement of the nose and scalp. Magnetic resonance angiography, similar to conventional angiography, shows no flow in the intracranial

The Differential Diagnosis of Brain Death Disorders that mimic brain death include hypothermia, acute poisoning, and acute metabolic encephalopathies. It should be possible to rule out these conditions after a detailed assessment of the patient. In rare cases, the coning process or pathology such as hemorrhage spares the medulla, and there is retained respiratory and cardiovascular function in the absence of other brainstem reflexes. Such patients have “isolated medulla oblongata” and do not meet criteria for brain death (see Wijdicks, 2001). The related neurological disorders akinetic mutism, persistent or permanent vegetative state (postcoma unresponsiveness), and the “locked-in” syndrome caused by pontine tegmental disruption have some of the features of brain death, but respiration is preserved. These conditions are discussed further in Chapter 9.

Brain Death in Neonates and Children

Maternal Brain Death and Live Birth It is possible to keep a brain-dead pregnant women alive on a ventilator many weeks until her fetus is mature enough for

chapter 8 coma and brain death delivery. Is it ethically acceptable to do this in order to save the child? In this situation, there is a conflict of interest between the mother and the fetus. Usually the mother’s interests are placed before those of the fetus, so that abortion is permitted if the mother’s health is in jeopardy. However, in this case, the mother is dead; therefore, even though there is indignity to the mother, delay in determination of maternal death and burial, prolonged emotional trauma for the family, and financial costs, it is ethically justified for the interests of the fetus to be placed first. This applies only if the obstetrician believes there is a reasonable chance that the fetus will reach maturity. The closer to term the fetus is, the more likely there will be a healthy delivery. The father should be able make the final decision on the basis of all the information provided. The mother’s wishes, if stated in advance, also need to be considered.24

Research and Teaching with Brain-Dead Patients Brain-dead patients provide an opportunity for clinicians to perform potentially toxic or injurious experiments or for trainees to practice invasive procedures such as intubation or central venous cannulation. Is it ethically acceptable to do this? The procedures or experiments should not interfere with organ donation or autopsy. The trainees may be helping others by improving their skills, and this may outweigh any disadvantage. Although these procedures have often been done without consent in the past, this practice, on balance, is not ethically acceptable. Consent should be obtained for any procedures, even on a brain-dead patient. The research team should not be involved in the brain death determination. LaPuma54 has formulated ethical guidelines for experimentation that, in summary, are as follows: The dignity and humanity of the body should not be violated. The experiment should be well designed and brief. The patient must be declared brain dead. Voluntary and knowledgeable consent must be given by the next of kin. There should be a clear medical importance to the experiment that will yield valuable information, such as a safe or efficacious treatment for a lethal disease. The institutional ethics review board must sanction the research. The investigators pay for the extra time that the patient spends in the intensive care unit.24,54

Religious and Family Attitudes toward Brain Death Although a religious definition of death may depend on the loss of the soul from the body, this concept is not suitable for medical purposes.24 Judeo-Christian religions have generally accepted the concept of brain death. However, some Catholic and Orthodox Jewish scholars have not accepted it, arguing that brain death is not equivalent to death determined by cardiopulmonary criteria because brain life is not equivalent to human life.24 There is differing opinion among rabbis; some say that according to ancient Jewish law (the Halachah), death can be determined only by prolonged cessation of the breathing and heartbeat, which represent life itself, the only exception being decapitation. Other rabbis have argued that brain death is consistent with Halachic law because brain death is the functional equivalent of decapitation.24 Muslims assert that they do not have the right to determine the timing of death— that is, when to terminate support. The Third International

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Conference of Islamic Jurists considered brain death to be death of a person. Legal death and Sharia principles apply when the following signs are established (see Wijdicks, 2001, page 136): 1. Complete stoppage of the heart and breathing that doctors decide is irretrievable. 2. Complete stoppage of all the vital functions of the brain that the doctors decide is irreversible. It is clearly challenging for religious scholars to apply religious beliefs, precepts, and ancient laws to the modern medical environment, in which technological advance has created artificial and unique conditions. The family may firmly believe that, on religious grounds, brain death is not the true death of their relative and that the ventilator should not be turned off. If this objection is not based on emotional or psychological difficulty in accepting the diagnosis and prognosis, the physician should accept the family’s objections. This does not exclude the withdrawal of some support, such as vasopressor agents, in which case asystole will occur within hours or days. Some states, such as New Jersey, have enacted laws to provide personal religious exemption for the family that does not accept the diagnosis of brain death and desires that ventilation be continued.24 Conflicts between intensive care medical and nursing staff and the family of the brain-dead patient about when to stop artificial ventilation or extubate are common. It is difficult for many families to accept the death of their relative while ventilation and the heartbeat continue. The physicians and nursing staff have an ethical duty to explain clearly to the family what brain death indicates and how it is determined. The facts to emphasize are that cardiorespiratory arrest would have occurred if the ventilator had not been continued, that the patient is legally and biologically dead, and that no patient has ever survived after a diagnosis of brain death. Some families still object because of lack of understanding or a belief that the doctors are wrong. This situation is clearly delicate, but the physician should remain sensitive and compassionate in this situation and allow the ventilator to continue, but the physician can withdraw other aggressive support such as vasopressor drugs.

The Management of Brain Death The family must be fully informed of the likely outcome, and the doctor should try to establish that the relatives are making decisions on the basis of the patient’s wishes rather than their own. It is best if the patient has made known a directive about brain death, as well as his or her wishes regarding organ donation, before death, but this does not often happen.55

Diabetes Insipidus The development of diabetes insipidus often precedes brain death. The hypothalamopituitary axis fails, resulting in a deficiency of antidiuretic hormone secretion. There is polyuria (>250 mL/hour), hypernatremia, hyperosmolality, and dilute urine (urine specific gravity <1.005). 1-Deamino(8-D-arginine) vasopressin, 2 to 4 μg, can be given intravenously regularly or as an infusion to correct diabetes insipidus it if organ donation is contemplated.

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Organ Procurement The demand for organ donors has been a main driver for the acceptance and legalization of brain death. Families consenting to organ donation may derive considerable benefit in knowing that some good has come from the tragedy of the death of their loved one. However, there is a common fear held by family members that the diagnosis of brain death will be made prematurely and that organs will be procured while the patient is still alive. There should be no perception by the family of a conflict of interest by the staff. The family should be given sufficient time to accept the diagnosis of brain death before any discussion of organ donation. It is essential that the staff members who raise the issue of organ donation with the family are independent of the physicians treating the patient and that they not approach the family until the diagnosis of brain death is made by the treating physicians. The next of kin has the right to refuse the organ donation even if the patient has declared previously that he or she wishes to be a donor. It must be made very clear to the family that there can be no organ donation procedure unless the diagnosis of brain death is absolutely confirmed and that even if the family chooses not to proceed with organ donation, the ventilation and support will still cease. If the organ donation does not proceed, the patient is extubated after the second set of brain death tests. It is considered ethically acceptable to continue intravenous fluids and to maintain the blood pressure and ventilation of the patient who is declared brain dead until the organs are procured, as long as the delay is not excessive. A model policy on organ donation has been developed by the Australia and New Zealand Intensive Care Society.37

K E Y

P O I N T S

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Consciousness is an awareness of the environment and of the self. The components of consciousness are alertness and thought content, which consists of primary consciousness, which is the “remembered present,” and higher order consciousness, which is an awareness of the self.

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Coma is the inability of the patient to be aroused—that is, to obey commands, speak, or open the eyes in response to painful stimulus—and is generally represented by a Glasgow Coma Scale (GCS) score of 8 or less.

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Coma is caused by mechanical deformation or disruption of neural tissue, ischemia and/or hypoxia of neural tissue, and metabolic or toxic derangement of neural tissue. Central and uncal herniation, vertical descent of the diencephalon and brainstem, horizontal shift of midline supratentorial structures, and direct compression of the brainstem are the mechanical deformations that cause coma.

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The “whole brain” or brainstem formulations of brain death are the usually accepted clinical and philosophical concepts of brain death in the many countries that permit this diagnosis to be made.

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The diagnosis of brain death is clinical and does not require any confirmatory laboratory tests. The four necessary preconditions that must be met in order to proceed with

confirmation of brainstem death are that the patient be in deep coma, that the patient be apneic and therefore on a ventilator, that there be irrecoverable structural brain damage, and that reversible causes of brainstem depression have been excluded. ●

The clinician should be aware of the legal and ethical dimensions of brain death and organ transplantation so that the patient is treated with dignity and the patient’s family is treated with respect.

Suggested Reading Edelman GM: Wider than the Sky. The Phenomenal Gift of Consciousness. New Haven, CT: Yale University Press, 2004. Jasper HH, Descarries L, Castellucci VF, et al, eds: Advances in Neurology, Vol 77: Consciousness: At the Frontiers of Neuroscience. Philadelphia, Lippincott Raven, 1998. John ER: The neurophysics of consciousness. Brain Res Rev 2002; 39:1-28. Metzinger T, ed: Neural Correlates of Consciousness. Empirical and Conceptual Questions. A Bradford Book. Cambridge, MA: MIT Press, 2002. Pallis C: ABC of Brainstem Death. London: British Medical Journal Publishers, 1983. Penfield W: The cerebral cortex and consciousness. The Harvey Lectures 1937, 35-39. In: Wilkins RH (Ed). Neurosurgical Classics. 1992. pp 226-241. American Association of Neurological Surgeons. Plum F, Posner JB: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia: FA Davis, 1982. Wijdicks EFM: Brain Death. Philadelphia: Lippincott, Williams & Wilkins, 2001. Young GB, Ropper AH, Bolton CF: Coma and Impaired Consciousness. A Clinical Perspective. New York: McGraw-Hill, 1998. Zeman A: Consciousness [Invited review]. Brain 2001; 124:12631289.

References 1. Edelman GM: Wider than the Sky. The Phenomenal Gift of Consciousness. New Haven, CT: Yale University Press, 2004. 2. Crick F, Koch C, Kreiman G, Fried I: Consciousness and neurosurgery. Neurosurgery 2004; 55:273-282. 3. Valatx JL: Disorders of consciousness: anatomical and physiological mechanisms. Adv Tech Standards Neurosurg 2004; 29:3-22. 4. Dandy W: The location of the conscious center in the brain: The corpus striatum. Bull Johns Hopkins Hosp 1946; 79:3458. 5. Young GB: Consciousness. In Young GB, Ropper AH, Bolton CF, eds: Coma and Impaired Consciousness. A Clinical Perspective. New York: McGraw-Hill, 1998, pp 3-37. 6. Moruzzi G, Magoun HW: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949; 1:455. 7. Franks NP, Lieb WR: The role of NMDA receptors in consciousness: what can we learn from anesthetic mechanisms? In Metzinger T, ed: Neural Correlates of Consciousness. Empirical and Conceptual Questions. A Bradford Book. Cambridge, MA: MIT Press, 2002, pp 265-269.

chapter 8 coma and brain death 8. Pallis C: Further thoughts on brainstem death. Anaesth Intensive Care 1995; 23:20-23. 9. Plum F, Posner JB: The Diagnosis of Stupor and coma, 3rd ed. Philadelphia: FA Davis, 1982. 10. Power BM, Van Heerden PV: The physiological changes associated with brain death—current concepts and implications for treatment of the brain dead donor. Anaesth Intensive Care 1995; 23:26-36. 11. Teasdale G, Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81-84. 12. Jennett B, Teasdale G, Galbraith J, et al: Severe head injuries in three countries. J Neurol Neurosurg Psychiatry 1977; 40:291-298. 13. Teasdale G, Jennett B: Assessment and prognosis of coma after head injury. Acta Neurochir (Vienna) 1976; 34:45-55. 14. Simpson DA, Cockington, RA, Hanieh A, et al: Head injuries in young children: the value of the Paediatric Coma Scale. Review of literature and report on a study. Childs Nerv Syst 1991; 7:183-190. 15. Simpson DA, Reilly PL: Paediatric Coma Scale [Letter]. Lancet 1982; 2:450. 16. Ropper AH: Transtentorial herniation. In Young GB, Ropper AH, Bolton CF, eds: Coma and Impaired Consciousness. A Clinical Perspective. New York: McGraw-Hill, 1998, pp 119-129. 17. Ropper AH: Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med 1986; 314:953-958. 18. Moulton RJ: Electrical function monitoring. In Reilly PL, Bullock R, eds: Head Injury. Pathophysiology and Management of Severe Closed Head Injury. London: Chapman & Hall, 1997, pp 229-240. 19. Synek VM: EEG abnormality grades and subdivisions of prognostic importance in traumatic and anoxic coma in adults. Clin Electroencephalogr 1988; 19:160-166. 20. Synek VM: Revised EEG coma scale in diffuse acute head injuries in adults. Clin Exp Neurol 1990; 27:99-111. 21. Bickford RG: Computer analysis of background activity. In Remond A, ed: Electroencephalography Informatics: A Didactic Review of Methods and Applications of Electroencephalography Data Processing. Amsterdam: Elsevier, 1977, pp 215-232. 22. Bricolo A, Turazzi S, Faccioli F, et al: Clinical application of compressed spectral array in long-term EEG monitoring of comatose patients. Electroencephalogr Clin Neurophysiol 1978; 45:211-225. 23. Sironi VA, Ravagnati L, Signoroni G, et al: Diagnostic and prognostic value of EEG compressed spectral analysis in post-traumatic coma. In Villani RJ, Papo I, Giovanelli M et al, eds: Advances in Neurotraumatology. Amsterdam: Excerpta Medica, 1982, pp 328-330. 24. Bernat JL: Brain death. In Bernat JL, ed: Ethical Issues in Neurology. Newton, MA: Butterworth-Heinemann, 1994, pp 113143. 25. Mollaret P, Goulon M: Le coma dépassé. Rev Neurol 1959; 101:3-15. 26. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. J Am Med Assoc 1968; 205:337340. 27. Machado C: Is the concept of brain death secure? In Zeman A, Emanuel L, eds: Ethical Dilemmas in Neurology. London: WB Saunders, 2000, pp 193-212. 28. Veatch RM: Defining death: the role of brain function [Editorial]. JAMA 1979; 242:2001-2002. 29. Veatch RM: The whole-brain oriented concept of death: an outmoded philosophical formulation. J Thanatol 1975; 3:13-30. 30. Shann F: A personal comment: whole brain death versus cortical death. Anaesth Intensive Care 1995; 23:14-15.

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31. Conference of Medical Royal Colleges and their Faculties in the UK: Memorandum on the diagnosis of death. BMJ 1979; 1:322. 32. Pallis C: The position in the USA and elsewhere. ABC of brain stem death. BMJ 1983; 286:209-210. 33. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Defining Death. Medical, Ethical and Legal Issues in the Determination of Death. Washington, DC: U.S. Government Printing Office, 1981, p 160. 34. Bernat JL, Culver CM, Gert B: On the definition and criterion of death. Ann Intern Med 1981; 94:389-394. 35. Conference of Medical Royal Colleges and their Faculties of the UK: Diagnosis of death. Statement issued by the honorary secretary of the Conference of Medical Royal Colleges and their Faculties in the United Kingdom on 11 Oct 1976. BMJ 1976; 1:322. 36. Conference of Medical Royal Colleges and their Faculties of the UK: Diagnosis of brain death. BMJ 1976; 2:1187-1188. 37. Pearson IY: Australia and New Zealand Intensive Care Society Statement and Guidelines on brain death and model policy on organ donation. Anaesth Intensive Care 1995; 23:104-108. 38. Royal College of Physicians. Criteria for the diagnosis of brainstem death. J R Coll Physicians 1995; 29:381-382. 39. Guidelines for the determination of death. Report of the medical consultants on the diagnosis of death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. JAMA 1981; 246:2184-2186. 40. Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee the American Academy of Neurology. Neurology 1995; 45:1012-1014. 41. Wetzel R, Setzer N, Stiff JL, et al: Hemodynamic responses in brain dead organ donor patients. Anesth Analg 1985; 64:125128. 42. Yoshioka T, Sugimoto H, Uenishi M, et al: Prolonged hemodynamic maintenance by the combined administration of vasopressin and epinephrine in brain death. Neurosurgery 1986; 18:565-567. 43. Pallis C: Brain stem death. In Braakman R, ed: Handbook of Clinical Neurology, Volume 13: Head Injury. Amsterdam: Elsevier, 1990, pp 441-496. 44. Monsein LH: The imaging of brain death. Anaesth Intensive Care 1995; 23:44-50. 45. Rosenklint A Jorgensen PB: Evaluation of angiographic methods in the diagnosis of brain death. Correlation with local and systemic blood pressure and intracranial pressure. Neuroradiology 1974; 7:215-219. 46. Vatne K, Nakstad P, Lundar T: Digital subtraction angiography (DSA) in the diagnosis of brain death. A comparison of conventional cerebral angiography with intravenous and intraarterial DSA. Neuroradiology 27:155-157, 1985. 47. Reid RH, Gulenchyn KY, Ballinger JR: Clinical use of technetium-99m HM-PAO for determination of brain death. J Nucl Med 1989; 30:1621-1626. 48. Chatrian GE: Electrophysiological evaluation of brain death: a critical appraisal. In Aminoff MJ, ed: Electrodiagnosis in Clinical Neurology. Edinburgh: Churchill Livingstone, 1980, chapter 7. 49. Durocq X, Hassler W, Moritake K, et al: Consensus opinion on the diagnosis of cerebral circulatory arrest using Dopplersonography: Task Force Group on Cerebral Death of the Neurosonology Research Group of the World Federation of Neurology. J Neurol Sci 1998; 159:145-150. 50. Conference of Medical Royal Colleges and their Faculties in the UK: Report of the Working Party on Organ Transplantation in

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Neonates. London: Department of Health and Social Security, 1988. 51. Task Force for the Determination of Brain Death in Children: Guidelines for the determination of brain death in children. Arch Neurol 1987; 44:587-588. 52. Volpe JJ: Brain death determination in the newborn. Pediatrics 1987; 80:293-297.

53. Medical Task Force on Anencephaly: The infant with anencephaly. N Engl J Med 1990; 322:669-674. 54. La Puma J: Discovery and disquiet: research on the brain dead. Ann Intern Med 1989; 109:606-608. 55. Emanuel LL, Barry MI, Stoeckle JD, et al: Advance directives for medical care: a case for greater use. N Engl J Med 1991; 324:889-895.

CHAPTER

9

THE PERSISTENT VEGETATIVE STATE (PROLONGED POSTCOMA UNRESPONSIVENESS) AND POSTHYPOXIC BRAIN INJURY ●

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Bruce Day Prolonged survival in a vegetative state is one of the most harrowing events encountered in modern medicine. Although the condition provides intellectual challenges to the expertise of medical ethicists, legal practitioners, and legislators, the patient’s family members and others intimately involved in the daily care of the patient are usually caught in a web of despair, unresolved grief, anger, a pervading sense of futility, and fading hope. Adversarial relationships between medical staff and family may arise, especially if iatrogenic issues such as anesthetic catastrophes are present. Family members may clutch at slim hopes offered by media reports of recovery after prolonged coma or vegetative states. Physicians may be torn by the conflict between limited resources and the pressure to persevere with intensive support, potentially restricting access to patients with substantially better chances of recovery. Decisions to continue or withdraw support are often charged with ethical and medicolegal implications, inasmuch as either course of action can be construed to be contrary to the “best interests” of the patient. The various terms vegetative state (persistent and permanent) and postcoma unresponsiveness are used to describe the clinical emergence of the patient from deep coma to a state in which the sleep-wake cycle is reestablished but the patient shows no clinical evidence of cognitive interaction with the world around him or her. When the state is deemed to be unremitting (more than 3 months after anoxic brain damage* or more than 12 months after traumatic brain injury) the term permanent vegetative state is recommended. Expert groups in the United States1 and Europe have suggested using only the terms vegetative state and permanent vegetative state because the term persistent has become shrouded with ambiguity. The terms vegetative state and persistent vegetative state do not

*Some authorities, such as the Royal College of Physicians of London,2 recommend that a 6-month period for nontraumatic etiologies elapse before the declaration of permanence. However, Jennett3 (2002, p 61) states that “the Task Force concluded from analysis of the 754 cases reviewed that the vegetative state could reasonably be declared permanent 3 months after nontraumatic damage and 12 months after head injury in both children and adults.” He further stated (p 64) that “given the interest in late recoveries provoked by the time limits proposed by the Task Force for declaring permanence, it might have been expected that most exceptions to these since then would have been reported, but only two have been.”

imply irreversibility; however, the term permanent vegetative state carries prognostic implications. For the situation in which some minimal level of purposeful response to environmental stimuli is observed, the term minimally conscious state has been advocated.4 The terminological uses vary, and some authors5 have advocated avoiding the term vegetative in view of its potentially pejorative connotations, but the original description6 remains widely accepted.

CRITERIA Vegetative State The salient features of the vegetative state† are as follows: 1. Long periods of wakefulness (spontaneous eye opening) without clinical evidence of purposeful responsiveness. Reflex responses and withdrawal to noxious stimulation may occur. 2. Roving eye movements but no sustained tracking of visual stimuli. 3. No response to verbal command. 4. No articulation or mouthing of words. 5. No bladder or bowel control. Movements such as yawning, grunting, grimacing, startle myoclonus, chewing, swallowing, bruxism, posturing, tearing, and even brief visual fixation may occur, but evidence of a purposeful act clearly linked to a stimulus is lacking. Such patients usually have varying degrees of spastic quadriparesis or decerebrate rigidity, often with preserved brainstem reflexes, including autonomic reflexes that control respiration and, occasionally, swallowing. There is usually a release (disinhibition) of primitive reflexes such as grasp reflexes and pouting reflexes. Joint contractures tend to develop with time. Rudimentary evidence of cognitive function such as response to command, consistent visual fixation or orientation to and tracking of a visual stimulus, smiling at jokes, or vocalizing recognizable words are inconsistent with the diagnosis.

†

For a full description of the various diagnostic criteria used internationally, see Jennett (2002).3

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The Minimally Conscious/Responsive State Patients may improve from the vegetative state to demonstrate clearly discernible evidence of self or environmental awareness. The term minimally conscious state4 or minimally responsive state7 has been proposed to describe the condition of such patients. Minimal criteria such as the ability to follow a simple command, the presence of intelligible verbalization, or sustained visual following have been proposed to identify this state. Such responses may be intermittent and more easily evoked by family than by medical staff. Repeated observations may be necessary to distinguish this state from the vegetative state. Such purposeful responses clearly exclude a diagnosis of vegetative state, but difficulties defining the level of cognitive function sufficient to exceed a diagnosis of the minimally conscious state have limited widespread application of the term. The reestablishment of interactive communication, including orientation to place, the ability to give accurate autobiographical information, and the appropriate use of objects, are generally considered to indicate that the patient is functioning at a level higher than the minimally conscious state. It is important to note that the lack of behavioral manifestations of self or external awareness cannot by themselves prove the absence of a residual or rudimentary subjective awareness. It may not be possible clinically to distinguish a minimally responsive patient with residual cognitive function from one who lacks adequate afferent processing or efferent control to reliably demonstrate understanding or performance of a requested task. Indeed, Owen and colleagues8 reported three patients with clinical diagnoses of persistent vegetative state who demonstrated “covert cognitive processing” in positron emission tomographic scanning with a facial recognition task. It is also conceivable that patients may satisfy the criteria for the minimally conscious state on a “good” day and, perhaps as a consequence of infection, electrolyte disturbance, or fatigue, show no sign of awareness on a “bad” day.9 Because of such patients, the boundary between the vegetative state and the minimally conscious state may not be as discontinuous as the definitions suggest.

Locked-In Syndrome The locked-in syndrome refers to a state in which cognitive processing is clearly evident but severe paralysis prevents articulation or gestural expression of awareness. Communication may be achieved by encoding eyelid or ocular movement. In severe cases, the diagnosis may depend on the demonstration of a normal reactive alpha rhythm on the electroencephalogram (EEG).10 Such patients usually have isolated lesions of the ventral pons with preserved cerebral hemispheres. Locked-in syndrome may also occur as a consequence of severe peripheral nerve or muscle disease.

Akinetic Mutism The term akinetic mutism has been used to describe a range of cases in which varying degrees of consciousness, paralysis, and mutism may be present. Various pathological findings have been described,11 including infarction of the anterior cingulate gyrus.12 Cairns and associates13 described an adolescent with a craniopharyngioma who developed repeated episodes of “silent

immobility” with open and apparently attentive eyes and occasional whispered monosyllables whose state was reversed on several occasions by aspiration of the tumor. A similar case with improvement after shunting has been described more recently.14 Akinetic mutism has been divided into frontal and mesencephalic types, the latter distinguished by the presence of vertical gaze palsy or ophthalmoplegia. Cyclosporine neurotoxicity15 and baclofen toxicity16 may each cause a reversible state of akinetic mutism. Severe frontal abulia (for example, caused by bilateral anterior cerebral artery infarction or a ruptured anterior communicating aneurysm) may be impossible to distinguish on clinical criteria from either akinetic mutism or the minimally conscious state.

EPIDEMIOLOGY The incidence and prevalence of vegetative state in the community vary widely in accordance with the sources of the data. A comprehensive review3 of the epidemiology of vegetative state revealed prevalence rates in the United States ranging from 24 to 168 per million of the population in studies dating from 1990 to 1994. The Multi-Society Task Force on Persistent Vegetative State (1994) accepted an estimate from Ashwal and colleagues17 of 56 to 140 per million. The incidence of vegetative survivors after all acute causes at 1, 3, and 6 months has been estimated for the United Kingdom, the United States, and France.3 The incidence falls with time as patients either die or attain higher levels of function and is also heavily influenced by the level of head injury in the community. At 1 month after injury, the incidence ranges from 14 per million in the United Kingdom to 67 per million in France. By 6 months after the cerebral insult, the incidence of survival in a vegetative state is 5 per million in the United Kingdom, 17 per million in the United States, and 25 per million in France. The relative contribution of traumatic to nontraumatic causes of vegetative state also varies considerably, depending on the source of the data. Studies have shown the contribution of head injury ranging from 24%18 to 72%.1 Some studies include patients who decline into a vegetative state as a consequence of progressive neurodegenerative disorders, as opposed to progressing to a vegetative state from coma caused by an acute cerebral insult. This and other case ascertainment issues continue to complicate the epidemiological data.

PATHOLOGY Hypoxic/ischemic cerebral injury, cerebrovascular disease, and traumatic brain injury are the major causes of the vegetative state. Although patients with advanced neurodegenerative disorders (e.g., Alzheimer’s disease) may enter a state clinically indistinguishable from the vegetative state, this chapter is restricted to discussion of patients in a state of postcoma unresponsiveness. Patients may also recover to a state of postcoma unresponsiveness after severe bacterial meningitis, viral encephalomyelitis, or acute disseminated encephalomyelitis. In the setting of cerebral anoxia or diffuse ischemia, there is usually extensive neocortical laminar necrosis and bilateral hippocampal, amygdalar, and thalamic damage.19,20 The Purkinje cell layer of the cerebellum is similarly vulnerable to

chapter 9 the persistent vegetative state and posthypoxic brain injury diffuse ischemic injury. A second pattern of brain damage occurs after a short episode of profound hypotension, in which the ischemic damage is confined to the arterial boundary zones. This produces wedge-shaped zones of ischemia with additional bilateral thalamic damage and varying involvement of the hippocampus. After severe traumatic brain injury, the brunt of the pathology is subcortical and conforms to the diffuse shearing injuries now known as diffuse axonal injury (DAI), as described by Strich in 195621 and 1961.22 DAI is graded into types I to III; grade I is defined as diffuse subcortical shearing injury without callosal or brainstem involvement, grade II indicates additional focal lesions in the corpus callosum, and grade III indicates additional lesions in both the corpus callosum and the dorsolateral region of the rostral brainstem. Patients with DAI grade I are unlikely to remain in a prolonged vegetative state unless there is coexisting evidence of a hypoxic/ischemic insult. Coexisting evidence of hypoxic/ischemic damage in post-traumatic cases is not an uncommon finding.20 It is thought to reflect respiratory or circulatory failure at the time of head injury, although disturbances of cerebral autoregulation may also play a role. On the other hand, significant brainstem damage is a rare finding in prolonged survival in a vegetative state, which explains the recovery of sleep-wake function and autonomic cardiorespiratory control in this state. It appears that thalamic damage may play a critical role in the genesis of prolonged postcoma unresponsiveness, as cases with relatively little cortical damage are well described. Adams and associates20 published detailed studies of the pathological findings in both nontraumatic and traumatic cases and compared the latter group with 35 traumatic cases in which patients recovered to a state better than vegetative state before death. In summary, patients who remained in a vegetative state generally had more extensive DAI, thalamic damage, or both. Patients with lesser degrees of subcortical damage nearly always had extensive thalamic damage. Higher functioning patients rarely had both bilateral thalamic damage and extensive DAI, and if thalamic damage was present, it was considered to be of a lesser degree. Thus, extensive bilateral damage to the thalamus appears to be critical for the development of the vegetative state, especially if damage elsewhere is minimal.

DIAGNOSIS Misdiagnoses of the vegetative state and the minimally conscious state appear to be common.23 Repeated clinical assessments are necessary to clearly establish whether reliable evidence of cognitive function is present in a severely braindamaged patient. Patients are often in an intensive care environment when the diagnosis is first considered, and varying levels of potentially sedating medications may complicate the assessment. Similarly, metabolic manifestations of other major organ involvement may confound the clinical picture. Neurologists and intensive care physicians may disagree as to whether visual fixation or tracking is present or whether a particular movement is purposeful or reflexive. Nursing staff are often particularly helpful in determining whether an orienting or purposeful response can be consistently linked to a particular stimulus, especially if there is some fluctuation caused by extraneous factors such as seizures or bolus doses of anticonvulsants.

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NEUROPHYSIOLOGICAL ASSESSMENT Clinical neurophysiological evaluation of the comatose patient has long been recognized to play an important role in determining both diagnosis and prognosis. In the modern intensive care environment, patients who remain in a coma after anoxic cerebral injury typically undergo electroencephalographic testing and somatosensory evoked potential (SSEP) testing, in view of the powerful prognostic information that these tests can provide. Usually these tests have been undertaken well before the patient has “emerged” to a vegetative state, and the results, if gravely abnormal, assist in the decision to withdraw cardiopulmonary support. Conversely, unexpectedly favorable electrophysiological findings lead the clinician to reassess the prognosis.

Electroencephalography Certain electroencephalographic patterns are known to be associated with extremely grave outcomes. Care must be taken to ensure that sedative medications, hypothermia, and severe metabolic disturbances are not confounding the interpretation of the record. In the setting of anoxic/ischemic cerebral injury, several electroencephalographic patterns have been associated with either a fatal outcome or, at best, survival with severe neurological sequelae.24 Of these patterns, the isoelectric or “flat” EEG after the first 24 hours is invariably associated with a poor outcome. The burst-suppression pattern (Fig. 9–1), especially if accompanied by generalized (typically facial and axial) myoclonic status25; the continuous bilateral periodic EEG or generalized epileptiform EEG (Fig. 9–2); and alpha (Fig. 9–3) and theta coma (Fig. 9–4) patterns usually but not invariably indicate a poor prognosis. Serial EEGs are sometimes necessary to identify a deteriorating trend. The isoelectric EEG is used in many countries as a confirmatory test for brain death, and the technique has been standardized.26 The recording must be undertaken for a minimum of 30 minutes at a sensitivity of 2 μV/mm using a minimum of eight channels with double-distance (>10 cm) electrodes in the 10-to-20 montage with filters set at less than 1 Hz and at 70 Hz. At these sensitivities, artifact is common, and the technician must take great care to identify all sources of artifact. ECG artifact is usually present in all channels, and this can usually be readily distinguished from activity of cerebral origin. The burst-suppression EEG pattern is usually readily identified; however, this pattern is also seen with the use of anesthetic agents—in particular, propofol and midazolam—and careful documentation of the use of such agents is necessary to avoid incorrect interpretation of the EEG. Even short-acting barbiturates can saturate adipose tissue after prolonged use, resulting in very prolonged excretion times. The continuous bilateral periodic EEG and generalized epileptiform records can be confused with nonconvulsive electrographic status epilepticus. The distinction may well be semantic. In general, patients who develop clinically subtle or nonconvulsive status epilepticus after anoxic cerebral injury do not do well, and aggressive trials of anticonvulsants are typically futile. If doubts remain on clinical grounds (e.g., a known epileptic patient who suffers a near-drowning event), a suitable trial of an anticonvulsant therapy is prudent, and SSEPs can be used as a more reliable guide to prognosis.

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Fp1–F3 F3–C3 C3–P3 P3–O1 Fz–Cz Cz–Pz Fp2–F4 F4–C4 C4–P4 P4–O2 150 ␮V 1sec ■

Figure 9–1. Burst suppression electroencephalographic pattern two days after prolonged cardiac arrest. (Reproduced with permission from the American Journal of EEG Technology. Drury I.: The EEG in hypoxic-ischemic encephalopathy. Am J EEG Technol 1988; 28:129-137.)

Periodic complexes are also characteristic of advanced renal and hepatic failure, but these are readily ruled out by appropriate biochemical investigations. Alpha and theta coma patterns are rare electroencephalographic findings. The salient features of alpha coma pattern are widespread monorhythmic alpha frequency activity, devoid of the typical waxing and waning amplitude of normal alpha waves, and unreactive to eye opening. The alpha frequency activity in alpha coma pattern is often anterior predominant, as opposed to true alpha activity with its occipital predominance. Theta coma pattern tends to be seen more frequently in elderly patients and usually shows some degree of low-amplitude burst suppression. Although alpha and theta coma patterns are considered grave, rare patients have made a satisfactory recovery. The evolution from alpha or theta coma pattern to a burstsuppression pattern in the first week indicates a hopeless prognosis. In contrast, patients who develop continuous mixed frequencies or some degree of reactivity might be expected to show further gains. Alternatively, more benign electroencephalographic findings are sometimes very helpful in the decision to continue intensive support. In general, near normal EEGs or EEGs with mixed frequencies and some degree of reactivity to auditory, visual, or noxious stimulation indicate a more favorable prognosis, although varying proportions of such patients are left with neurological disability. Similarly, the rare comatose patients who manifest sleeplike changes (vertex waves, K complexes, and spindles on EEG) usually have a good prognosis. Apart from the technical difficulties often experienced in obtaining good-quality EEGs in patients with severe traumatic brain injury, prognostication for this group based on electroencephalographic findings is recognized to be less reliable. The presence of reactivity to auditory, visual, or noxious stimulation, which may be either “attenuation” or “paradoxical” (decrease or increase in background amplitude after stimulation), implies a better outcome.27 Such a finding suggests that the patient is very unlikely to remain in merely a permanent

vegetative state after emerging from coma. Electroencephalographic reactivity has been demonstrated in the cat to depend on an intact reticular activating system and preserved thalamocortical pathways.28 Head-injured patients with less favorable electroencephalographic findings may still do well, however, and in this group the additional use of other neurophysiological parameters—in particular, SSEPs—may help refine prognostication.

SOMATOSENSORY EVOKED POTENTIALS The bilateral absence of thalamocortical waveforms (N19/P22 or N1) in comatose patients after either anoxic cerebral injury or severe head injury29 indicates an extremely bleak prognostic outcome. If the study is performed with appropriate care, this is the most robust electrophysiological finding in the intensive care environment. In the setting of coma after anoxia, patients with this finding do not improve beyond the vegetative state. Repeated studies30 have shown this finding to have 100% specificity when the SSEPs are performed after 24 hours of coma. In patients with traumatic brain injury, care should be taken to rule out significant cervical trauma or brainstem pathology that may interrupt large fiber sensory pathways at that level and hence may complicate SSEP interpretation. Access and technical factors such as prominent scalp edema or hematoma can also make results of SSEP studies more difficult to interpret in head injury. In addition, the use of barbiturateinduced coma in severely head-injured patients may attenuate low-amplitude waveforms (B. Day, personal observation, 2003); therefore, SSEP studies for prognostication in these patients should be delayed until the barbiturate-induced coma therapy is withdrawn. Well-formed, normal-latency Erb’s point potentials and cervical potentials are important quality assurance requirements before prognostication can be made without thalamocortical waveforms (Fig. 9–5). Although higher stimulus intensities can be used in comatose patients, the stimulus frequency should be less than 5 Hz. If these technical issues do not

chapter 9 the persistent vegetative state and posthypoxic brain injury Fp1–A1 Fp2–A2 F2–A1 F4–A2 C3–A1 C4–A2 P3–A1 P4–A2 O1–A1 O2–A2 EKG 30 ␮V 1sec ■

Figure 9–2. Continuous periodic anterior predominant sharp waves on electroencephalography after prolonged cardiac arrest. (Reproduced with permission from the American Journal of EEG Technology.)

Fp1–A1 Fp2–A2 F3–A1 F4–A2 C3–A1 C4–A2 P3–A1 P4–A2 O1–A1 O2–A2 F7–A1 F8–A2 T3–A1 T4–A2 T5–A1 T6–A2 70 ␮V 1 sec ■

Figure 9–3. Diffuse unreactive alpha frequency activity on electroencephalography after cardiac arrest. (Reproduced with permission from the American Journal of EEG Technology.)

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FP2–F4 PARIETAL

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complicate interpretation, bilateral absence of cortical SSEP responses is also 100% specific for an outcome no better than vegetative state in patients with traumatic brain injury. The high specificity of the bilateral absence of cortical waveforms is, however, accompanied by a low sensitivity (28% to 73%).30 Many patients with preserved but abnormal cortical waveforms nonetheless have very poor neurological outcomes, and the finding of normal cortical responses is not necessarily predictive of a favorable outcome. Unilateral delayed or lowamplitude cortical responses tend to be associated with a more severe residual neurological deficit in the stimulated limb, whereas a well-formed normal-latency cortical waveform is suggestive of a higher level of function in the corresponding limb, but the positive predictive value of such findings varies sufficiently between studies that their clinical utility is limited. For patients in whom the cortical waveforms (N19/P22 or N1) are present, some attempt to improve the sensitivity of SSEP studies has been undertaken by examining later waveforms, particularly the N70 (also called N3)31,32 (Fig. 9–6). No patient with bilaterally absent N19/P22 or N70 potentials “awakened” (“awakening” being defined as following commands or having comprehensible speech). No patient with absent N19/P22 potentials had preserved N70 waveforms. Patients in whom the N70 waveforms were present but prolonged beyond 176 milliseconds did not “awaken.” When the absence of the N70 or an N70 latency of more than 176 milliseconds was used instead of bilaterally absent N19/

P22 potentials for predicting nonawakening, the sensitivity of SSEP testing increased from 55% to 67%, and the specificity remained at 100%. Identification of the N70 waveform and determination of its peak latency can be technically more difficult, however, and it is more sensitive to the effects of anesthetic medications than is the N19/P22 waveform.

5 ␮V 5 ms

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Figure 9–5. Bilateral (superimposed) absence of cortical waveforms with normal-latency, well-defined Erb’s point and cervical waveforms in a patient after prolonged anoxic cerebral injury. C3, C4′ are each 2 cm posterior to C3, C4.

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BIOCHEMICAL MARKERS Cerebrospinal Fluid Creatine Kinase BB activity Elevated creatine kinase BB (205 U/L) isoenzyme activity measured in the cerebrospinal fluid 48 to 72 hours after cardiopulmonary arrest has been reported to have 100% specificity and 48% sensitivity for never awakening33 (as defined previously). Using a lower cutoff increases the sensitivity but lowers the specificity. Using this parameter in conjunction with SSEP studies further increases sensitivity to 78% without sacrificing the 100% specificity required for making decisions about withdrawal of life support.31

Serum Astroglial S-100 Protein The calcium-binding modulator protein S-100 is an established biochemical marker of central nervous system injury.34 Increased serum levels (0.2 μg/L) in comatose patients 24 to 48 hours after out-of-hospital cardiopulmonary arrest were invariably associated with a fatal outcome within 14 days.35

Serum Neuron-Specific Enolase Serum concentrations of neuron-specific enolase exceeding 33 ng/mL were also predictive of a poor prognostic outcome in comatose patients, with a high degree of specificity (100%), when measured within 72 hours after out-of-hospital cardiopulmonary arrest.36 The role of biochemical markers, especially when used in conjunction with neurophysiological tests, is likely to become increasingly important in establishing the early prediction of outcome from coma caused by anoxic ischemic injury or severe head injury.30

IMAGING STUDIES Although computed tomographic and magnetic resonance imaging (MRI) studies are often routinely performed in patients with prolonged postcoma unresponsiveness after hypoxic brain

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injury, these studies only rarely provide useful prognostic information. Diffusion-weighted MRI in the acute stage when the patient is still comatose may show diffuse cortical enhancement that is consistent with laminar infarction (Fig. 9–7A-D). Late imaging usually shows diffuse cortical atrophy (see Fig. 9–7E and F), but correlation between the degree of atrophy and outcome is imprecise. In one notable case, a 60-year-old academician was able to resume his career after emerging from a vegetative state of 8 weeks’ duration, despite generalized cerebral atrophy evident on the computed tomographic head scan.37 For patients in a post-traumatic vegetative state, more extensive MRI changes of DAI involving the corpus callosum and dorsolateral brainstem are correlated with continuing postcoma unresponsiveness.38 Magnetic resonance spectroscopy and diffusion tensor imaging have yet to be subjected to prospective longitudinal randomized studies in patients with prolonged postcoma unresponsiveness after anoxic cerebral injury or head injury, although early studies39 suggest that such techniques hold promise. Measurements of cerebral metabolism and brain activation with positron emission tomographic scanning and functional MRI studies after sensory stimulation are providing important insights into the pathophysiology of the vegetative state (see Laureys et al, 2004).40 These techniques are methodologically complex and careful interpretation is required, but important differences between the vegetative state and the minimally conscious state are beginning to emerge. Overall, patients who remain in a vegetative state have cerebral metabolic rates of the order of 30% to 40% of normal41 (Fig. 9–8), marginally lower than those in minimally conscious patients. A notable finding in the vegetative state is the extent of the metabolic impairment in the polymodal association cortices. These regions are important for higher order processing of incoming afferent information necessary for orientation, attention, recognition, memory, and language42 (Fig. 9–9). Such studies will potentially provide important new insights into prognostic and ethical issues, such as the presence of “covert cognitive processing”; however, current methodological complexities and problems with analysis and interpretation limit their clinical application.

PROGNOSTIC, MANAGEMENT, AND ETHICAL CONSIDERATIONS The phenomenon of prolonged survival in a vegetative state after coma is a direct consequence of advances in modern medical practice, particularly of the popular promotion of techniques such as cardiopulmonary resuscitation and highly expeditious emergency rescue and retrieval systems, coupled with access to sophisticated intensive care facilities. As a consequence, many busy intensive care units are faced on a daily basis with acutely comatose patients with potentially very poor but ultimately uncertain prognoses for independent recovery. Although ethical concerns dictate that economic considerations be set aside in the management of such patients, many intensive care services in large tertiary hospitals have problems with both significant access and cost containment. Ongoing futile management represents a serious misallocation of limited health care resources, as well as an unnecessary addition to the family’s distress. There is little doubt that prolonged survival in

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Figure 9–7. Magnetic resonance imaging (MRI) findings in a 50-year-old patient who suffered a severe anoxic injury, emerging from coma to a vegetative state after 2 weeks to remain in a permanent vegetative state for 6 months before death. A, Sagittal T1-weighted MRI performed on day 6 after anoxic injury. B, Axial T1-weighted MRI on day 6 after anoxic injury. C and D, Diffusionweighted images performed on day 6 after the anoxic event, showing diffuse cortical enhancement. E and F, Sagittal and axial T1-weighted images from the same patient 3 months after the anoxic event showing diffuse cortical atrophy and ex vacuo dilatation of the ventricles.

chapter 9 the persistent vegetative state and posthypoxic brain injury 100 90 Cerebral metabolism (%)

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Figure 9–8. Cerebral metabolism in various states. (From Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537-546. Copyright 2004. Reprinted with permission from the American Academy of Opthalmology.)

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Figure 9–9. Resting cerebral metabolism in a healthy individual (“Conscious control”) and patients in the vegetative state, with locked-in syndrome, and in the minimally conscious state. Sagittal images showing reduced activity in the medial posterior cortex (precuneus and adjacent cingulate cortex). (From Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537-546. Copyright 2004. Reprinted with permission from the American Academy of Opthalmology.)

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a vegetative state represents a disastrous outcome, particularly if it results from overly zealous application of intensive care support of comatose patients in the presence of extremely grave prognostic indicators. There is therefore an urgent need to refine neurophysiological, biochemical, and cerebral metabolic activity imaging studies further as early prognostic indicators to assist clinicians and families make the painful decisions regarding ongoing support. Once the patient has emerged from coma into a vegetative state with autonomous respiratory function, the ethical issues regarding support become much more vexed. As indicated previously, the vegetative state, especially in its early phase, cannot be considered irreversible. The significant difference in the chances for recovery from the vegetative state that arise as a consequence of anoxic cerebral injury as distinct from that caused by head injury is reflected in the difference in elapsed time before the vegetative state can be considered permanent (Fig. 9–10). Even after these times have elapsed, there are occasional single case reports of late recovery. Review of many of these cases reveals a small error rate for declaring permanence.3 Since the Multi-Society Task Force review of late recovery cases in 1994, only two cases of late recovery have been reported,43,44 which perhaps reflects more widespread acceptance of the

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definitional criteria and time constraints on the determination of permanence. There are few useful data to guide clinicians in predicting recovery from a vegetative state once the diagnosis is established. It is generally considered that the prognosis for emergence is better after trauma than after hypoxia and that younger patients have a better chance of recovery. A short duration of coma before eye opening has been postulated to indicate an improved likelihood of further gains in function beyond a vegetative state.5 Recovery of visual pursuit or of a blink response to visual threat are often the first signs of recovery beyond vegetative state, and the early finding of such signs may suggest a better chance of further gains. Evidence on the quality of recovery from vegetative state is also very limited. A large study from France of 522 patients who were vegetative 1 month after head injury showed that although 61% had regained consciousness after 1 year of follow-up, only 14% had become independent. The statistics were markedly affected by age: only 5% of adults became independent, whereas 24% of those younger than 20 years reached this level.45 In the nontraumatic vegetative state, only 1% of patients who remained vegetative at 3 months and none who remained vegetative at 6 months achieved an independent outcome by 1 year.1

Figure 9–10. Outcome for patients in a persistent vegetative state after traumatic or nontraumatic injury. Note that after nontraumatic causes of persistent vegetative state (PVS) in both children and adults, if consciousness has not been achieved by 3 months, no further recovery can be anticipated. (From Multi-Society Task Force on Persistent Vegetative State: Medical aspects of the persistent vegetative state. Parts 1 and 2. N Engl J Med 1994; 330:1499-1508 and 1572-1579. Copyright 1994 Massachusetts Medical Society. All rights reserved.)

chapter 9 the persistent vegetative state and posthypoxic brain injury Conversely, very prolonged survival in the vegetative state is also unusual, although survival (up to 41 years)46 has been described. In the Multi-Society Task Force review, mean survival in a vegetative state after acute cerebral injury ranged from 2 to 5 years1 with a 70% rate of mortality by 3 years and an 84% rate of mortality by 5 years. However, long-term survival figures are likely to be heavily influenced by decisions to limit treatment. The decision to withdraw or withhold support (usually only artificial hydration and nutritional support, but occasionally antibiotics for intercurrent infections) from a patient in the permanent vegetative state is an emotional, ethical, and medicolegal challenge. The relevant legal protocols vary between jurisdictions. The ethical considerations hinge on the concepts of patient autonomy, the presence of advance directives, the wishes of family or other proxies, and the ability of a surrogate to act on behalf of an incompetent patient. A full discussion of the ethical and legal issues involved is beyond the scope of this chapter but is well covered in several monographs.3,47

K E Y

P O I N T S

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Diagnosis of a vegetative state (postcoma unresponsiveness) depends on careful and repeated clinical assessment for the absence of evidence of a purposeful response to environmental stimuli.

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Diagnosis of a vegetative or persistent vegetative state does not necessarily indicate irreversibility. Diagnosis of permanent vegetative state is reasonably appropriate for patients remaining in a vegetative state for 3 months after anoxic cerebral injury and 12 months after severe head injury. According to these criteria, a diagnosis of permanent vegetative state carries an extremely high likelihood that this state will continue indefinitely.

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Certain neurophysiological and biochemical investigations undertaken early in the course of comatose patients after anoxic cerebral injury and severe head injury can provide highly predictive indicators that a patient will not recover to a state better than vegetative.

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Further studies of neurophysiological and biochemical markers of cerebral injury, both alone and in combination, are likely to refine further the ability to predict such a devastating outcome and thus help prevent ongoing futile interventions.

Suggested Reading Jennett B: The Vegetative State: Medical Facts, Ethical and Legal Dilemmas. Cambridge, UK: Cambridge University Press, 2002. Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537-546. The Multi-Society Task Force on Persistent Vegetative State: Medical aspects of the persistent vegetative state. Parts 1 and 2. N Engl J Med 1994; 330:1499-1508 and 1572-1579.

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References 1. Multi-Society Task Force on Persistent Vegetative State: Medical aspects of the persistent vegetative state. Parts 1 and 2. N Engl J Med 1994; 330:1499-1508 and 1572-1579. 2. Royal College of Physicians of London: The Vegetative State, Guidance on Diagnosis and Management. Clin Med 2003; 3:249-254. 3. Jennett B: The Vegetative State: Medical Facts, Ethical and Legal Dilemmas. Cambridge, UK: Cambridge University Press, 2002. 4. Giacino JT, Ashwal S, Childs N, et al: The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 58:349-353. 5. National Health and Medical Research Council: Post-coma unresponsiveness (vegetative state): a clinical frame work for diagnosis. Canberra, Australia: National Health and Medical Research Council, 2004. 6. Jennett B, Plum F: Persistent vegetative state after brain damage: a syndrome in search of a name. Lancet 1972; 299:734-737. 7. American Congress of Rehabilitation Medicine: Recommendations for use of uniform nomenclature pertinent to patients with severe alterations in consciousness. Arch Phys Med Rehabil 1995; 76205-76209. 8. Owen AM, Menon DK, Johnsrude IS, et al: Detecting residual cognitive function in persistent vegetative state. Neurocase 2002; 8:394-403. 9. Thomasma DC, Brumlik J: Ethical issues in the treatment of patients with a remitting vegetative state. Am J Med 1984; 77:373-377. 10. Bauer G, Gerstenbrand F, Rumpl E: Varieties in locked-in syndrome. J Neurol 1971; 221:77-91. 11. Plum F, Posner JB: The Diagnosis of Stupor and Coma, 2nd ed. Philadelphia: FA Davis, 1972, pp 24-25. 12. Freeman FR: Akinetic mutism and bilateral anterior cerebral artery occlusion. J Neurol Neurosurg Psychiatry 1971; 34:693698. 13. Cairns H, Oldfield RC, Pennybaker JP, et al: Akinetic mutism with an epidermoid cyst of the third ventricle. Brain 1941; 64:237-290. 14. Abekura M: Akinetic mutism and magnetic resonance imaging in obstructive hydrocephalus: case illustration. J Neurosurg 1998; 88:161. 15. Bird GL, Meadows J, Goka J, et al: Cyclosporin associated akinetic mutism and extrapyramidal syndrome after liver transplantation. J Neurol Neurosurg Psychiatry 1990; 53: 1068-1071. 16. Rubin DI, So EL: Reversible akinetic mutism possibly induced by baclofen. Pharmacotherapy 1999; 19:468-470. 17. Ashwal S, Bale JF, Coulter DL, et al: The persistent vegetative state in children: report of the Child Neurology Society Ethics Committee. Ann Neurol 1992; 32:570-576. 18. Sato S, Imamura H, Ueki K, et al: Epidemiological survey of vegetative state patients in the Tokohu District, Japan. Neurol Med Chir (Tokyo) 1979; 8:327-333. 19. Kinney HC, Samuels MA: Neuropathology of the persistent vegetative state—a review. J Neuropathol Exp Neurol 1994; 53:548-558. 20. Adams JH, Graham DI, Jennett B: The neuropathology of the vegetative state after an acute brain insult. Brain 2000; 123:1327-1338. 21. Strich SJ: Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry 1956; 19:163-185. 22. Strich SJ: Shearing of nerve fibres as a cause of brain damage due to head injury. Lancet 1961; 278:443-448.

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23. Andrews K: International Working Party on the Management of the Vegetative State: summary report. Brain Injury 1996; 10:797-806. 24. Young GB: The EEG in coma. J Clin Neurophysiol 2000; 17:473-485. 25. Wijdicks EF, Parisi JE, Sharbrough FW: Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994; 35:239-243. 26. Silverman D, Saunders MG, Schwab RS, et al: Cerebral death and the electroencephalogram: Report of the ad hoc committee of the American Electroencephalographic Society on EEG Criteria for determination of cerebral death. JAMA 1969; 209:1505-1510. 27. Gutling E, Gonser A, Imhof HG, et al: EEG reactivity in the prognosis of severe head injury. Neurology 1995; 45:915918. 28. Moruzzi G, Magoun HW: Brainstem reticular formation and activation of the EEG. 1949. J Neuropsychiatry Clin Neurosci 1995; 7:251-267. 29. Carter BG, Butt W: Review of the use of somatosensory evoked potentials in the prediction of outcome after severe brain injury. Crit Care Med 2001; 29:178-186. 30. Zandbergen EGJ, de Haan RJ, Stoutenbeek CP, et al: Systematic review of early prediction of poor outcome in anoxicischaemic coma. Lancet 1998; 352:1808-1812. 31. Sherman AL, Tirschwell DL, Micklesen PJ, et al: Somatosensory potentials, CSF creatine kinase BB activity and awakening after cardiac arrest. Neurology 2000; 54:889-894. 32. Madl C, Kramer L, Yeganehfar W, et al: Detection of nontraumatic comatose patients with no benefit of intensive care treatment by recording of sensory evoked potentials. Arch Neurol 1996; 53:512-516. 33. Tirshwell DL, Longstreth WT Jr, Rauch-Matthews ME, et al: Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurological prognosis after cardiac arrest. Neurology 1997; 48:352-357.

34. Raabe A, Grolms C, Sorge O, et al: Serum S-100B protein in severe head injury. Neurosurgery 1999; 45:477-483. 35. Rosen H, Rosengren L, Herlitz J, et al: Increased serum levels of the S-100 protein are associated with hypoxic brain damage after cardiac arrest. Stroke 1998; 29:473-477. 36. Fogel W, Krieger D, Veith M, et al: Serum neuron-specific enolase as early predictor of outcome after cardiac arrest. Crit Care Med 1997; 25:1133-1138. 37. Falk RH: Physical and intellectual recovery following prolonged hypoxic coma. Postgrad Med J 1990; 66:384-386. 38. Kampfl A, Schmutzhard E, Franz G, et al: Prediction of recovery from post traumatic vegetative state with cerebral magnetic-resonance imaging. Lancet 1998; 351:1763-1767. 39. Ricci R, Barbarella G, Musi P, et al: Localised proton MR spectroscopy of brain metabolism in vegetative patients. Neuroradiology 1997; 39:313-319. 40. Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537546. 41. Tommasino C, Grana C, Lucignani G, et al: Regional cerebral metabolism of glucose in comatose and vegetative state patients. J Neurosurg Anesthesiol 1995; 7:109-116. 42. Baars B, Ramsøy T, Laureys S: Brain, conscious experience and the observing self. Trends Neurosci 2003; 26:671-675. 43. Childs NL, Mercer WN: Brief report: late improvement in consciousness after post-traumatic vegetative state. N Engl J Med 1996; 334:24-25. 44. Dyer C: Hillsborough survivor emerges from permanent vegetative state. BMJ 1997; 314:996. 45. Danze F, Veys B, Lebrun T, et al: Prognostic factors of posttraumatic vegetative states: 522 cases. Neurochirurgie 1994; 40:348-357. 46. Sibbison JB: USA: right to live, or right to die? Lancet 1991; 337:102-103. 47. Bernat JL: Ethical Issues in Neurology, 2nd ed. Boston: Butterworth Heinemann, 2002.

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Bruce J. Tonge and Nicole J. Rinehart

Autism and attention deficit hyperactivity disorder (ADHD) are the two main classes of neurodevelopmental disorders that begin in early childhood. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)1 specifies that the diagnosis of ADHD cannot be made if the symptoms occur in a child with autism. However, symptoms of attention deficit and hyperactivity are common problems in children with autism, which points toward some neuropathophysiological characteristics shared between these two groups of neurodevelopmental disorders. Autism is a generic term referring to a group of related conditions defined in the DSM-IV-TR1 and the International Classification of Diseases, Tenth Revision (ICD10),2 as pervasive developmental disorders. The term autistic spectrum disorders is frequently used but lacks any international agreement regarding its definition.3 The term is sometimes used to refer to a group of related conditions similar to pervasive developmental disorders. It is also used to describe the range of intellectual abilities, from severe disability to normal ability, found in children with autism. The concept of a spectrum has also been applied to describe developmental changes, such as improvement in language ability, which might occur over time in an individual with autism. In this chapter, autism refers to the pervasive developmental disorders, which share the core features of severe and pervasive impairment in social and communication skills, together with the presence of restricted and repetitive patterns of behavior and interests. The onset of these disorders occurs within the first 3 years of life, but the clinical picture may change with development. In DSM-IV-TR1 the pervasive developmental disorders comprise the categories of Autistic Disorder, Asperger Disorder, Rett’s Disorder, Childhood Disintegrative Disorder, and Pervasive Developmental Disorder–Not Otherwise Specified (PDD-NOS). Autism was first described by Leo Kanner in 1943 for a group of 11 children who had the distinctive core features of social, language, and communication disturbance and an obsessive desire for sameness.4 In the following year, Hans Asperger described a group of 16 children and adolescents who had deficits in communication and social skills together with obsessional interest, intolerance of change, and motor clumsiness.5 Unlike the children described by Kanner, these young people were of normal intellectual ability and did not have any delay or abnormality in their language development. This has become the differentiating feature of Asperger’s disorder from autistic disorder. This review focuses on the assessment, pathophysiologic aspects, and treatment of the

two main pervasive developmental disorders, autistic disorder and Asperger’s disorder. The problem of excessive hyperactive, inattentive, and impulsive behavior in children has been described in the medical literature from the 19th century.6 Current theories regarding the etiology of developmentally excessive inattentiveness and hyperactivity encompass an interaction of genetic predisposition, central nervous system dysfunction resulting from prenatal and early postnatal traumatic or toxic events, and environmental and social influences. The concept of minimal brain damage with associated soft neurological signs led to theories of dysfunction of the thalamus and prefrontal circuits to account for the hyperactivity and inattention, respectively. Current interest is focused on deficiencies of executive function and inhibition of attention resulting from such dysfunction, particularly affecting the right prefrontal cortex and associated basal ganglia structures.7 These primary deficits affect the development of working memory, emotional regulation, motivation, and the development of language and morality.7 Historically, the approach to the diagnosis of ADHD has differed between North America and Europe. Clinicians in Europe have sought for evidence of neurological dysfunction and pervasive symptoms of inattention and hyperactivity in all contexts. Clinicians in North America have taken a more qualitative approach to diagnosis, acknowledging that symptoms may vary in different settings and subdividing the diagnosis into the number of symptoms in each of the dimensions of inattention or hyperactivity/impulsiveness. Thus, a child may receive a diagnosis of ADHD predominantly hyperactive type or predominantly inattentive type. There has been an attempt to bring the diagnostic criteria for ADHD in the DSM-IV-TR into line with the criteria for hyperkinetic disorder in the ICD-10.2 Although the criteria used in both classification systems are now virtually identical, there are still differences regarding the number of criteria required and the pervasiveness of symptoms. As a consequence, application of ICD-10 criteria is more restrictive and conservative, which has implications for studies of epidemiology and etiology. The discovery in 1937 of the therapeutic effect of dextroamphetamine on concentration and hyperactivity in children with disruptive behavior has also influenced approaches to diagnosis and the interest taken by society in these behavioral problems.8 Regardless of an element of social determinism inherent in the diagnosis of ADHD, there is no doubt that young people

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with pervasive difficulties with attention, impulsiveness, and motor hyperactivity are at great risk of suffering educational, social, emotional, and behavioral problems during childhood and subsequent mental health, relationship, occupational, forensic, and substance abuse problems in adult life. This chapter focuses on advances in the understanding of the neuropathophysiology and treatment of ADHD.

EPIDEMIOLOGY Autism There is evidence that the prevalence of autism is increasing. More than 23 prevalence studies of autism have been reported in the literature from 1966 to 1997. In most studies before 1990, investigators reported prevalence rates of 4 to 5 per 10,000. In more recent studies in which rigorous diagnostic criteria and standardized diagnostic assessment were used, investigators have found rates of approximately 10 to 12 per 10,000.9 Since the mid-1990s in a number of countries, specialist children’s services have reported an increasing demand for services for children with autism. For example, in Iceland, the prevalence of autism and the demand for services are reported to have doubled.10 Reviews indicate that the apparent increase in prevalence is probably a result of differences in ascertainment and diagnosis and an increasing awareness of autism by the general public.9 At least 14 different approaches to diagnosis have been used in prevalence studies. For example, when DSMIV-TR or ICD-10 diagnostic criteria are used, the prevalence of autism is two to three times higher than that found with the application of the earlier criteria of Kanner.9 The inclusion of subcategory diagnoses of pervasive developmental disorders such as PDD-NOS or atypical autism leads to further increases of prevalence to approximately 27 to 30 per 10,000.9 In several longitudinal studies, researchers using equivalent methods of diagnosis over time, but with relatively small sample sizes, have not found significant changes in prevalence rates in subsequent birth cohorts.9,11 There is no evidence that prevalence varies between countries or racial groups, and social class and level of parental education are not associated with autism.9 Autistic disorder is more common in boys than in girls (ratio, 4:1), and the gender distribution is even more marked for Asperger’s disorder (ratio, 10:1 to 13:1). This gender distribution might point to the possibility of an X-linked element to the disorder, but research has failed to confirm this explanation.

Attention Deficit/Hyperactivity Disorder Estimates of the prevalence of ADHD vary widely according to the diagnostic criteria, measures used, ascertainment methods, and demographics of the population. For example, in a populationwide study in the United States in which parent- and selfreport screening questionnaires were used, a prevalence of ADHD of up to 20% was identified.12 Population rates of 1% to 2% are found if prevalence is based on the application of the restrictive ICD-10 criteria2 without the presence of comorbid conditions.13 Prevalence rates of 5% to 10% are found in studies in which the more inclusive DSM-IV-TR criteria, which allow

some variability of symptoms and the presence of comorbidity, are used.14 Studies with DSM-IV-TR criteria reveal that the combined inattentive-hyperactive subtype of ADHD is the most common manifestation. For example, a clinic study demonstrated that 60% of young people with a diagnosis of ADHD had the combined subtype, 30% had the inattentive subtype, and 10% had the hyperactive-impulsive subtype.15 Note that the subtypes are designated on the basis of symptom predominance; meeting criteria for one subtype, such as inattentive subtype, does not preclude the presence of some symptoms from another subtype, such as hyperactive symptoms. Community studies reveal that the childhood prevalence of ADHD is approximately three times higher in boys than in girls but is more likely to decrease over time in male patients while remaining stable into adulthood in female patients.16 Symptoms usually reduce with maturation, but at least 30% of children with ADHD continue to suffer from the disorder in adulthood.17 Because of differences in diagnostic criteria and methods of ascertainment, the prevalence of ADHD in adults varies between 0.3% and 5%.17 Approximately a third of these adults are likely to suffer from a comorbid affective disorder as well, and the majority have associated social, marital, employment, and legal problems.18

CLINICAL FEATURES Autism Autism manifests with delays and abnormalities in the development of language and social skills, and the presence of rigid, repetitive, stereotyped play and behavior, often in association with intellectual disability and a variety of neurological conditions such as epilepsy. Therefore, the assessment and diagnosis is multifaceted, involving medical, cognitive, language, developmental, and mental state assessments.19 A reliable diagnosis can be made in patients aged 2 years and older. In view of the value of early intervention, early diagnosis is important and can be facilitated with the use of screening tools completed by parents (e.g., the Developmental Behavior Checklist),20 and clinician-completed checklists (e.g., the Checklist for Autism in Toddlers).21 Diagnosis is enhanced by the use of a structured, reliable, and valid parental interview and child observation schedule,22 such as the Autism Diagnostic Interview/Revised23 and the Autism Diagnostic Observation Schedule.24 All children with autism have impaired social interactions, which may change as they develop. Infants with autism do not anticipate social interactions, such as being picked up, or seek physical comfort or parental attention. Preschool children with autism usually avoid eye contact and do not engage in social imitation such as waving goodbye. They are unresponsive to the feelings and emotions of others. They are aloof and unable to engage effectively with other children or understand reciprocal social interactions. As such children grow older, there may be an increased interest in other people, but social skills are often stilted and learned in an inflexible manner, leading the children to appear odd and socially clumsy. Parents usually first seek help because their children have language delay and a lack of nonverbal communication and easily becomes frustrated. About 50% of children with autism fail to develop functional

chapter 10 autism and attention deficit/hyperactivity disorder speech and learn only slowly to compensate with gesture. Language development is often abnormal in the remainder, with echolalia, self-directed jargon, and the repetition of irrelevant phrases (for example, from a television show). The correct use of pronouns and the related development of a sense of self and others are delayed. Poor comprehension, problems expressing needs by words and gesture, and difficulty in social understanding are frequently the causes of frustration and disturbed behavior. Children who do develop functional language usually have difficulty in using language socially and in initiating or sustaining a reciprocal conversation. For example, the child may talk at others in a socially inappropriate manner. In contrast to children with autistic disorder, young people with Asperger’s disorder have no delay in the development of normal expressive and receptive language, including the use of communicative phrases by the age of 3 years. However, children with Asperger’s disorder have problems in their social use of language, such as being verbose and preoccupied with a favorite topic. Their speech may appear odd because of the use of an unusual accent or because of the presence of abnormalities in pitch and volume; for example, delivery may be flat and monotonous. The play, behavior, and daily life of children with autism are usually rigid and repetitive. Younger autistic children may line up toys or objects or may be preoccupied with special objects such as stones, and they become distressed if these activities are interrupted. Their ritualistic play lacks imagination and social imitation. With development, play may become more complex, such as reenacting scenes from a favorite video story, but is usually still repetitive. Older autistic children may develop preoccupations with themes such as train timetables or dinosaurs, and this is the focus of their play, drawing, and conversation. They may have a number of rituals associated with daily life, such as a fixed order for bathing and dressing or an insistence on wearing the same clothes or taking the same route to a familiar place. Change or unexpected events, such as the arrival of a new student in the classroom, can be distressing. There may be a number of perceptual or sensory abnormalities such as hyperacusis or tactile sensitivity, manifesting, for example, as an aversion to having their hair brushed. Some children with autism have a remarkable lack of sensitivity to pain. Children with autism are usually visually attentive; for example, they may study the detail in a picture book or closely observe spinning wheels, the edges of objects, or reflections in water. There are usually some motor mannerisms, such as hand flapping, tiptoe walking, and gait abnormality. Approximately 80% of children with autism also have intellectual disability, and other emotional and behavioral disturbances are common. Children with autistic disorder who have intellectual abilities within the normal range are referred to as high functioning. The individual cognitive profiles of children with autism usually show a wide scatter of abilities, with deficits in verbal and social comprehension tasks and more ability with visuomotor performance skills. In contrast, children with Asperger’s disorder have overall normal intellectual abilities but usually have relative deficits in visuomotor tasks and motor skills in comparison with their verbal performance. Children with autism often have a range of disruptive behaviors such as stubbornness, self-injury, and aggression, which place a high burden of care on parents and teachers. These disruptive behaviors are the main cause of failure in school and community activities and lead to more restrictive care. High

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levels of anxiety are common and prevent these children from learning, coping with change, and participating in family and community activities. The anxiety associated with autism is likely to persist into adult life.25 Children with autism are also likely to suffer from depression, particularly during adolescence. This may manifest as mood disturbance and irritability, sleep and appetite disturbance, and thoughts of suicide, which may be enacted.26 The increased vulnerability to depression during adolescence may be associated with self-awareness of the disability, but pubertal brain development and a family history of depression may also contribute. At least 13% of children with autism also meet diagnostic criteria for ADHD,27 but the DSM-IV-TR specifically precludes the diagnosis of ADHD “during the course of a Pervasive Developmental Disorder” (p. 93).1 Nevertheless, symptoms of attention deficit and hyperactivity in children with autism impede and disrupt their learning, school adjustment, and family life. These symptoms of ADHD are responsive to educational, behavioral, and pharmacological managements used for children with ADHD, although not always as successfully.26 Children with autism also have an increased risk of suffering tic disorder or Gilles de la Tourette syndrome, with the tics becoming more prevalent during times of stress and anxiety, such as a change in school placement.26 Epilepsy occurs in approximately 20% of young people with autism, emerging most commonly in early childhood or during adolescence. It is seen more frequently in children with more severe levels of intellectual disability.26 Young people with Asperger’s disorder also suffer from a similar range of mental health problems but are even more likely to have higher levels of disruptive and antisocial behavior and to suffer from anxiety and depression.28 They may also have an increased risk of developing psychosis during adolescence or early adult life.

Attention Deficit/Hyperactivity Disorder The diagnosis of ADHD is based on a clinical judgment that there are sufficient symptoms of inattention and hyperactivity/impulsivity, together with the decision that these symptoms cause significant impairment in daily functioning in at least two settings and are not consistent with the developmental level of the child.1 Therefore, the diagnosis requires a careful and comprehensive history of the child’s development and behavior from the parents and other informants such as the teacher, together with observation of the child during both structured and unstructured activities. A structured cognitive assessment, apart from providing information on specific learning difficulties and related problems such as deficits in short-term auditory memory, also reveals problems with concentration and distractibility—that is, with sustained, directed attention. The use of structured behavior rating scales, such as the Conner’s Parent and Teacher Rating Scales,29 may be useful for screening and as a measure of response to treatment. Apart from high levels of distractibility and inattention, children with ADHD are disorganized and are usually unable to follow routine or complete tasks.1 They have difficulty monitoring their behavior and therefore often interrupt others, have difficulty following rules, and display inappropriate and impulsive behavior.1 Those who also suffer from hyperactivity are constantly restless and fidgety, have difficulty remaining seated, and behave as if they are driven by a motor. These behaviors are

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influenced by aspects of the environment, such as the degree of external stimulation and sensory complexity. Therefore, observers may report differences in behavior, depending on the context. For example, a teacher in a busy, noisy classroom setting is more likely to observe inattention than is a teacher’s aide who has the child for individual teaching in a quiet library environment. However, the symptoms and impairments are usually observed, at least to some extent, in all aspects of the child’s daily life. Young people with ADHD have a range of associated problems. Their primary symptoms often lead to hostile interactions with other children, who may reject them. ADHD is frequently complicated by the presence of other psychopathological conditions: in particular, conduct disorder (25%), oppositional defiant disorder (35%), depression (15%), and anxiety disorder (25%).30 The majority of children with ADHD have various learning difficulties and poor school performance in relation to their intellectual abilities.31 Approximately 25% of individuals with ADHD have intellectual disability, including delayed language development.31 Children with ADHD have difficulty falling asleep and wake early, and their sleep is often unsettled and complicated by breathing and snoring difficulties.32 Adolescents with ADHD are at risk for delinquent behavior and abuse of nicotine, alcohol, and other substances, perhaps as a means of self-medication.33 Young people who are treated with stimulant medication for ADHD are less likely to use substances than are adolescents with ADHD who are not receiving treatment.33 There is also an association between the use of alcohol, tobacco, and other substances during pregnancy and the birth of a child with ADHD, but the mechanisms for these associations are likely to reflect the complex interaction of genes and environment.33 The assessment and diagnosis of ADHD for the first time in adults is difficult.34 Such an adult may not be living in a situation in which others can report on behaviors and symptoms to help the clinician reach a judgment on the severity of symptoms and the degree of disability. The presence of other comorbid psychiatric illnesses complicates the presentation. Adults are not able to reliably remember their childhood; therefore, if possible, a history of the manifestation of the disorder throughout childhood should be obtained from other persons or from school reports.34 Adults with ADHD are usually less disruptive and hyperactive than are children with ADHD, but they usually remain impulsive, disorganized, inattentive, and restless.34

ETIOLOGY AND PATHOPHYSIOLOGY Autism Neurocognitive Theories There are three main cognitive theories of autism: the “theoryof-mind,”35 the “executive dysfunction” theory,36 and the theory of “weak central coherence.”37 Deficiencies in theory-of-mind— that is, the ability to understand that other people have unique perspectives and thoughts that are sometimes contextually independent—are thought to be linked to the social-communicative deficits associated with autism.35 Weak central coherence, a deficit in the ability to integrate details into a coherent global perception, is thought to be linked to the tendency of

individuals with autism to be preoccupied with parts of objects and to miss the “bigger picture.”37 Executive functioning refers to the role of the frontostriatal circuits in coordinating cognitive-motor output so that behavior is well timed, planned, adaptable, appropriate, and relevant38 (and see Chapter 7). The repetitive, stereotyped, and restricted behaviors seen in autism are thought to result, in part, from deficient executive functioning.39 Poor performance on tests of executive functioning “. . . is found more consistently in autism than in any other form of childhood psychopathology” (p. 103).40 It is not clear which, if any, of these cognitive deficits is central to the psychiatric and neurological symptoms that characterize autism.41 Volkmar and colleagues42 argued that the main criticism leveled at theory-of-mind is that it cannot account for the clinical phenomenology of autism, because the social deficits characteristic of autism appear at a point in development before normally developing children demonstrate the acquisition of a theory-of-mind. Furthermore, children with autism and normal intelligence are reported to perform at an age-appropriate level on theory-of-mind tasks,43 although some authors disagree with this conclusion.44,45 Other, more primary deficits reflect problems with “weak central coherence.” Studies suggest that problems in moving attentional focus away from the detail of an object may better account for why individuals with autism appear to get “stuck” on detail and have a poor ability to appreciate the object’s gestalt.46,47 The broader executive dysfunction theory of autism (including attentional dysfunction) is perhaps the most appealing theory from a cognitive neuroscience perspective, inasmuch as it enables the linking of more specific cognitive deficits to possible impairments in specific neurological circuitries. Contemporary cognitive research has focused on uncovering distinct executive functioning profiles48 that might distinguish children with autism from those with other neurodevelopmental disorders: for example, ADHD, obsessive compulsive disorder, Gilles de la Tourette disorder, schizophrenia, and depression.49 Standardized neuropsychological tests—for example, the Wisconsin Card Sort Test, the Tower of Hanoi, and the Stroop Color-Word Test—have demonstrated that the profile of autism is characterized primarily by deficient cognitive flexibility and planning,48 with intact sustained and directed attention50 and intact cognitive inhibition.48 However, results of attempts to measure impairment of cognitive inhibition in autism with novel approaches that align more closely to a child’s everyday experiences—for example, generating novel verbal utterances, ideas, and drawings—challenge the view that this area of cognition is intact in autism.51,52 Some studies suggest that measures of “motor” functioning in autism may provide a more useful neurobiological probe than do more complex cognitive-social measures, which do not define discrete neural pathways.53,54 Motor studies of young people with autism (3 to 21 years of age) demonstrate movement anomalies commensurate with basal ganglia dysfunction.55-57 For example, atypical upper-body motor preparation with intact execution,58 reduced motor evoked potentials,59 and postural abnormalities60 have been reported. Studies of gait in autism also suggest a cerebellar contribution to motor dysfunction: for example,61 gait variability60,61 and difficulty with straight-line walking, which are consistent with a cerebellar ataxic gait disturbance.62 An important issue in the cognitive description of autism is the question of so-called “knock-on” effects: that is, how one

chapter 10 autism and attention deficit/hyperactivity disorder potentially primary cognitive deficit may have downstream effects on other emerging skills.41 A neurocognitive comparison of normally intelligent individuals with autism and those with Asperger’s disorder can be used to illustrate the potential “knock on” effects of disordered and delayed language, because this is the clearest point of neurological departure between these disorders in the first 3 years of life. Neurocognitive comparisons of individuals with autism and those with Asperger’s disorder have revealed quantitative and qualitative differences in executive functioning,63,64 which potentially represent downstream neural and environmental consequences of language deficits in autism. For example, executive functioning anomalies show a lateralization pattern consistent with left-hemisphere dysfunction for autism, but not in Asperger’s disorder.65 A better understanding of the primacy of cognitive deficits and how they unfold and link to the psychiatric and neurological symptoms of autism is likely to come from detailed prospective studies of the newborn siblings of autistic children, who are themselves at higher genetic risk of developing autism than are unrelated newborns.

Neuroanatomical and Neuroimaging Studies There is no consistent neuroimaging marker that has been identified for autism. Structural changes in the brains of individuals with autism include slightly increased average brain volume, decreased gray matter volumes in the limbic system (an area important for social cognition), reduced neuron numbers in the vermis of the cerebellum, and gross structural changes in cerebellum66,67 and the parietal lobes68 (areas important for efficient attention). A reduction in neuronal integrity in prefrontal areas and concurrent abnormalities in the frontal cortex and cerebellum67 possibly underlie the repetitive behavioral symptoms that characterize autism.69 Several imaging studies have uncovered left hemisphere impairment in autism.70 One review71 concluded that although many structural abnormalities have been identified in individuals with autism, the findings are inconsistent and not specific. Functional magnetic resonance imaging (fMRI) has the potential to more clearly elucidate the neurobiological substrates that underpin faulty cognitive-motor processes in autism. There have been several attempts to link the socialcommunicative deficits with particular neural regions using neuroimaging techniques,72-74 but there have been relatively few attempts to study frontal regions associated with executive functioning. A study of the application of fMRI during a mental rotation task75 revealed that individuals with autism and Asperger’s disorder showed decreased activation in the highly interconnected cortical and subcortical frontal structures, including lateral and medial premotor cortex, frontal eye fields, caudate, dorsolateral prefrontal cortex, and anterior cingulate cortex, suggestive of disruption to multiple frontostriatal circuits. Although advances in the cognitive neuroscience of executive function and attention enable investigators to more clearly study the component processes and anatomical substrates of autism,76 a more comprehensive understanding of the brainbehavior disruption that characterizes autism is likely to come from a larger systematic examination of cognitive processing, in which the cognitive and anatomical specificity afforded by fMRI and event-related methods are used.

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Genetic Theories In fewer than 10% of cases, autism is associated with defined environmental causes, such as rubella and cytomegalovirus, fetal infections, perinatal brain injury, toxins, and specific genetic abnormalities such as tuberous sclerosis and fragile X syndrome.77 A suggested link between measles, mumps, and rubella vaccination and the use of thimerosal in vaccines as a cause of the increased prevalence of autism has been discounted by several comprehensive studies.78 Thimerosal has not been in vaccines in North America and Japan since the mid-1990s, during the time of reported increases in prevalence. The cause of the majority of cases remains unknown, but they are almost certain to have a multifactorial and complex genetic basis. The 3:1 predominance of autism in boys is probably not X-linked but might be accounted for by a malespecific excess of linkage peaks at the chromosomal locus 17q11.79 If an older sibling has autism, the risk that a subsequent full sibling will have autism is 2% to 8%. The concordance for autism in monozygotic twins is 60% for autistic disorder and 92% for the spectrum of pervasive developmental disorder. For dizygotic twins, the concordance for either diagnosis is up to 10%.7 Studies of individuals with autism suggest that chromosome 15q11-q13 is a candidate region for genetic risk factors.80 There is also an increased frequency of the chromosome 4B null allele and of variant serotonin transporter gene alleles at chromosomal locus 17q11-q12.77 Studies of multiplex families (those with more than one case of autism) also suggest linkage at chromosomal loci 7q31-q33, 2q31-q33, and 3p25-p26 sites.77,81 These family studies point to the possible involvement of multiple genetic risk factors.

Attention Deficit/Hyperactivity Disorder Neurocognitive Theories DSM-IV-TR criteria preclude a comorbid diagnosis of ADHD and autism.1 However, this is at odds with the frontostriatal model of developmental dysfunction proposed by Bradshaw,38 which links these disorders by virtue of shared neural circuitry. The frontostriatal model of developmental dysfunction also predicts that the two disorders are likely to share “common heritability factors” (p. 262).38 In addition, both disorders share a number of neurotransmitter abnormalities, including of dopamine, noradrenaline, acetylcholine, γ-amino butyric acid, and serotonin.38 The likelihood of comorbidity between these two conditions is confirmed by study findings that indicate that at least 13% of children with autism also meet criteria for ADHD.27 In contrast to autism, the executive frontostriatal profile of ADHD is characterized by inhibitory deficits82 and problems with sustained attention.83,84 The classic neuropsychological paradigms used to measure these inhibitory deficits include the Stop Signal Task and the Stroop Color-Word Task. Children with ADHD are generally slower to inhibit their responses on the Stop Signal Task and exhibit more false alarms; these abnormalities have been associated with decreased orbitofrontal and anterior cingulate cortex activation.85 On the Stroop task, children with ADHD are typically slower at calling out the color in which the incongruent words are printed, because of problems with inhibiting the more automatic word-reading response. Deficien-

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cies of sustained attention in children with ADHD have been demonstrated on the Continuous Performance Task, a measure of sustained attention that requires participants to identify a target stimuli interspersed within a series of irrelevant distractor stimuli,83 and on the Test of Everyday Attention, a standardized test that analyzes component attentional deficits.86 Whereas planning and cognitive flexibility deficits are prominent in the cognitive profiles of children with autism, these areas of cognition are relatively intact in children with ADHD.48 Brain lateralization is potentially another point of neurocognitive difference between children with ADHD and those with autism. Whereas children with autism have been shown to display deficiencies in right hemispace performance on executive function tasks, implicating left hemisphere dysfunction,65 there is evidence that the performance of nonmedicated children with ADHD on a line-bisection task is consistent with right hemisphere dysfunction.87

Neuroanatomical and Neuroimaging Studies As is the case with autism, no consistent structural abnormalities have been recorded for individuals affected by ADHD. Whereas autism has been associated with larger whole-brain volumes and left hemisphere anomalies, ADHD has been associated in some but not all studies with smaller whole-brain volumes,88 and right, rather than left, prefrontal anomalies.87 As with autism, structural anomalies have been reported in the basal ganglia, cerebellum, and corpus callosum.88,89 Neural regions that subserve key attentional and inhibitory functions—for example, the dorsolateral prefrontal, lateral temporal, and posterior parietal regions—have been shown to be dysfunctional in fMRI studies of individuals with ADHD.90 Children with ADHD also show decreased left caudate activation when engaged in a response inhibition task, which is potentially linked to the core symptoms of hyperactivity, disinhibition, and inattention.91 A separate fMRI study in which the same mental rotation task was used for a group of normally intelligent adolescents with ADHD (mean age 14.6 years)92 and a group with autism (mean age 14.7 years)75 revealed similar patterns of reduced prefrontal activation for both disorders, which is consistent with the frontostriatal model of neurodevelopmental disorders.38 Therefore, inherited or environmentally determined developmental dysfunction of frontostriatal circuits may manifest predominantly as autism or as ADHD, depending on the particular regions that are defective.

Genetic Theories Evidence from twin studies and molecular genetic studies points to an inherited basis for ADHD in approximately 80% of cases, with perinatal brain injury responsible for the remainder.93 The cause in the inherited cases is likely to be a complex interaction of multiple genes; in some individuals, there is also an interaction with perinatal brain injury or other environmental traumas such as fetal alcohol exposure or postnatal malnutrition. There have been a large number of candidate gene and linkage studies of ADHD, using a variety of case-control and multiplex family methods, as well as dimensional or categorical definitions of ADHD. As a consequence, they have produced conflicting results. The most consistent findings implicate dopamine D4 and D5 receptors and the dopamine transporter and the serotonin

transporter genes as candidate risk factor genes in ADHD.94,95 Genetic screening for ADHD is not yet possible, and recognition of the complex gene-environment interaction associated with each individual with ADHD is central to clinical management.95

TREATMENT Autism There is a wide range of approaches to the treatment and management of autism but relatively little empirical evidence to support claims of effectiveness. In view of the devastating and persistent nature of the disorder, parents understandably try interventions that promise cure, regardless of a lack of scientific evidence.96 The U.S. National Academy of Sciences concluded that there is no single intervention or treatment that is effective for all individuals with autism.97 The best outcomes are produced by a combination of educational, behavioral, communication, and social skills training approaches, together with medication if indicated, designed to target the specific needs of each child and also to provide education, support, and skills training for the parents.

Behavioral Management Difficult behaviors such as self-injury can be eliminated, and competent behaviors such as remaining seated with other children can be taught, after an identification of the antecedents and consequences of the target behaviors. New skills can be taught with the use of positive reinforcement, physical and verbal prompts, and incrementally shaping behavior, by breaking a desired outcome into small steps (chaining). An analysis of the communicative function of a negative behavior may facilitate the development of more positive behaviors that achieve the same communicative outcome. Time out, the withdrawal of attention, and the use of a loss of favorite activities or privileges may help immediately to decrease undesirable behaviors but should be used in conjunction with approaches that then teach appropriate behaviors. Aversive, cruel, and abusive responses to negative behaviors create further adverse consequences and are unethical. There is some evidence that the application of an intensive 40-hour-per-week behavioral program (applied behavior analysis) might be associated with significant and sustained improvement, particularly in cognitive skills.98 Some parents may report satisfaction with applied behavior analysis programs, but the costs of therapy can be prohibitive, and replication of the initial study in a randomized controlled trial with comprehensive outcome measures is required.

Education The provision of a structured and consistent educational program individually designed for the child with autism facilitates development and learning. The level of the child’s intellectual and language impairment must be taken into account, and techniques that entail use of visual means of communication and learning are usually necessary. Integration into mainstream classrooms is desirable but depends on the provision of adequate education aide support and classroom resources. Children with autism who become isolated and unoccupied in class usually become increasingly disruptive or withdraw into ritualistic, nonfunctional behaviors.

chapter 10 autism and attention deficit/hyperactivity disorder Communication Skills Improving the capacity of a child with autism to more effectively communicate reduces inappropriate behavior and distress. The augmentation of spoken communication with visual and nonverbal communication, such as the use of pictures and line drawings, helps improve communication skills. Social skills may also be improved through the use of cartoons or social stories that teach appropriate social behavior, such as catching a bus to school.99

Parent Training Effective management involves collaboration between parents, teachers, and clinicians. The involvement of parents of preschool children with autism in a structured education and skills training program is associated with reduced parental stress and a sustained improvement in parental mental health, and it also facilitates developmental progress and behavioral improvement in the child.100

Pharmacotherapy Evidence for the effectiveness of medication in the treatment of disturbed emotions and behaviors in individuals with autism is derived mostly from studies of adults with intellectual disability. Drugs should be prescribed only after an assessment has defined the specific symptoms or disorder, such as depression, that is the focus of treatment. Before the implementation of medication, it is necessary to record a baseline measure of target symptoms—for example, with a behavior checklist—in order to follow response to treatment and monitor side effects.20 Compliance is improved when the parents and individual with autism are involved in regular review. There is some evidence that neuroleptic medication (e.g., haloperidol, risperidone) reduces aggressive, disruptive, and stereotypical behaviors and anxiety.101 However, it may produce side effects, including sedation, dystonic reactions, and increased weight gain. Tricyclic antidepressants (e.g., imipramine, clomipramine) are effective anxiolytics and may also reduce repetitive behaviors.102 Caution should be exercised, because of the potential cardiotoxic effects of tricyclic antidepressants. Case reports indicate that the selective serotoninreuptake inhibitors such as fluoxetine may reduce anxiety and associated obsessive-compulsive behaviors, although the side effects (excitation, nausea, and headache) can be troublesome. Lithium and other mood stabilizers may reduce episodes of disruptive, aggressive, and self-injurious behavior, particularly if there is a family history of bipolar disorder. Other drugs such as stimulant medication, clonidine, and naltrexone are used to treat disruptive behaviors and symptoms of attention deficit and hyperactivity, but evidence of their efficacy is lacking.

Attention Deficit/Hyperactivity Disorder A multimodal approach to management, including medication, special education, behavior modification, and parent education and skills training, is likely to lead to the greatest treatment response.103 Medication is the most important aspect of treatment, but multimodal treatments that account for the complex learning, behavioral, and social problems of the child improve outcomes.104 An elimination diet is effective for children in

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whom the specific provocative food, such as those containing tartrazine, can be identified, but it is of benefit to fewer children than is medication.105 Stimulants (methylphenidate and dexamphetamine) are the most frequently used medications. They are indirect catecholamine agonists, which facilitate the action of dopamine and noradrenaline agonists by inhibiting reuptake and facilitating release, as well as antagonizing α2-adrenergic receptors.106 There have been many randomized placebo-controlled trials of the efficacy of stimulant medication. These have clearly demonstrated immediate improvement in inattention, impulsivity, and hyperactivity and a reduction in aggression.104,105 The longer term effects on learning and academic achievement are less clear, and there is a lack of good long-term evidence for the effectiveness of stimulant medication.105 Anorexia, insomnia, irritability, and emotional distress are significant side effects that may necessitate cessation of treatment. The use of long-acting preparations may reduce some side effects and improve compliance. There is some evidence that prolonged treatment does not increase the risk of subsequent drug abuse.103,107 Stimulant medication is less effective in preschool children and young people with intellectual disability, including those with autism, and these groups are more likely to suffer adverse side effects.108 The presence of comorbid anxiety disorder also militates against the effectiveness of stimulant medication. Children who have side effects, or who are unresponsive to stimulant medication, may benefit from treatment with tricyclic antidepressants (imipramine) or perhaps clonidine. These agents reduce hyperactivity and improve behavior but are less effective for inattention and learning. In view of the potential cardiotoxic effects of tricyclic antidepressants, review of the cardiovascular system is indicated.105 The combination of stimulant medication and nighttime clonidine is used to overcome insomnia, and neuroleptic medication may be added to control aggressive behavior, but there are no long-term studies regarding the safety or efficacy of combination treatments. Atomoxetine, an inhibitor of the presynaptic norepinephrine transporter, has been shown in several randomized controlled trials to be at least as effective as methylphenidate in the treatment of inattention, impulsiveness, and hyperactivity.109,110 Reported side effects include decreased appetite, somnolence, fatigue, irritability, and some increase in pulse rate and blood pressure. A single morning dose produces a therapeutic effect throughout the day, and insomnia is not a side effect. Parents are understandably apprehensive regarding the use of medication, but compliance is improved with regular review of response and monitoring of side effects.

CONCLUSIONS AND RECOMMENDATIONS Both pervasive developmental disorders and ADHD are serious neurodevelopmental conditions that cause profound distress, impairment, and disability for the individual child, stress and burden for the parents and family, and long-term cumulative costs for the community. Diagnosis depends on the careful and systematic gathering of a developmental history and on observation of behavior in a variety of settings, supplemented by a comprehensive cognitive assessment. The management of autism relies on a multimodal program of structured and targeted behavioral and educational interventions supplemented, when indicated, by pharmacotherapy. Effective medications are

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available for the treatment of ADHD but should be prescribed in the setting of a comprehensive educational and behavioral management program. The active involvement of parents as partners in management, together with the provision of education and skills training, further helps to consolidate treatment response, relieve family stress, and improve parental mental health. Current research into the neuropsychological features of these conditions, together with advances in understanding of central nervous system abnormalities and contributory genetic factors, is likely to lead to the elucidation of more specific neurobiological markers that will aid in the specificity of the diagnosis and the elucidation of subtypes of these disorders, with implications for treatment.

Suggested Reading Barkley RA: Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment, 2nd ed. New York: Guilford Press, 1998. Bock G, Goode J: Autism: Neural Basis and Treatment Possibilities. Novartis Foundation Symposium, No. 251. London: Wiley, 2003. Bradshaw JL: Developmental Disorders of the Frontostriatal System: Neuropsychological, Neuropsychiatric and Evolutionary Perspectives. Hove, UK: Psychological Press, 2001. Brereton AV, Tonge BJ: Preschoolers with Autism: An Education and Skills Training Program for Parents. London: Jessica Kingsley, 2005. Cohen DJ, Volkmar FR, eds: Handbook of Autism and Pervasive Developmental Disorders, 2nd ed. New York: John Wiley, 1997.

References

K E Y

P O I N T S

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The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) specifies that the diagnosis of attention deficit/hyperactivity disorder (ADHD) cannot be made if the symptoms occur in a child with autism. However, symptoms of attention deficit and hyperactivity are a common problem in children with autism, which points toward some neuropathophysiological characteristics shared between these two groups of neurodevelopmental disorders.

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The frontostriatal model of developmental dysfunction links autism and ADHD by virtue of shared neural circuitry and predicts that the two disorders are likely to share common heritability factors. In addition, both disorders share a number of neurotransmitters, including dopamine, noradrenaline, acetylcholine, γ-amino butyric acid, and serotonin.

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Children with autism have an increased risk of suffering tic disorder or Gilles de la Tourette syndrome, with the tics becoming more prevalent during times of stress and anxiety, such as a change in school placement.

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Epilepsy occurs in approximately 20% of young people with autism, emerging most commonly in early childhood or during adolescence and more frequently in children with more severe levels of intellectual disability.

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Standardized neuropsychological tests have demonstrated that the profile of autism is characterized primarily by deficiencies in cognitive flexibility and planning, whereas the neuropsychological profile of ADHD is characterized predominately by inhibitory deficits and problems with sustained attention.

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The management of autism relies on a multimodal program of structured and targeted behavioral and educational interventions supplemented, when indicated, by pharmacotherapy.

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Effective medications are available for the treatment of ADHD but should be prescribed in the setting of a comprehensive educational and behavioral management program.

1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association, 2000. 2. World Health Organization: International Statistical Classification of Diseases and Related Health Problems, 10th Revision. Geneva: World Health Organization, 1992. 3. Tonge BJ: Autism: time for a national approach to early assessment and management [Editorial]. Med J Aust 1996; 165:244-245. 4. Kanner L: Autistic disturbances of affective contact. Nervous Child 1943; 2:217-250. 5. Asperger H: Die “autistichen psychopathen” in kindersalter. Arch Psychiatrie Nervenkrankheiten 1944; 117:76-136. 6. Sandberg S, Barton J: Historical development. In Sandberg S, ed: Hyperactivity Disorders of Childhood. Cambridge, UK: Cambridge University Press, 1996, pp 1-25. 7. Barkley RA: Behavioural inhibition, sustained attention, and executive functions: constructing a unified theory of ADHD. Psychol Bull 1997; 121:65-94. 8. Bradley C: The behavior of children receiving Benzedrine. Am J Psychiatry 1937; 94:577-585. 9. Fombonne P: Epidemiological surveys of autism and other pervasive developmental disorders. J Autism Dev Disord 2003; 33:365-382. 10. Magnusson P, Saemundsen E: Prevalence of autism in Iceland. J Autism Dev Disord 2001; 31:153-163. 11. Fombonne P, Du Mazaubrunc C, Cans C, et al: Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997; 36:15611569. 12. Wolraich ML, Hannah JN, Baumgaertel A, et al: Examination of DSM-IV criteria for attention deficit/hyperactivity disorder in a country wide sample. J Dev Behav Pediatr 1998; 19:162168. 13. Swanson JM, Sargeant JA, Taylor E, et al: Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998; 351:429-433. 14. Bird HR, Gould MS, Staghezza BM: Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Am Acad Child Adolesc Psychiatry 1993; 32:361-368. 15. Faraone SV, Biederman J, Weber W, et al: Psychiatric, neuropsychological and psychosocial features of DSM IV subtypes of attention-deficit/hyperactivity disorder: results from a clinically referred sample. J Am Acad Child Adolesc Psychiatry 1998; 37:185-193. 16. Szatmari P, Offord DR, Boyle MH: Correlates, associated impairments and patterns of service utilization of children

chapter 10 autism and attention deficit/hyperactivity disorder

17. 18. 19. 20.

21. 22. 23. 24.

25. 26. 27. 28. 29. 30. 31. 32. 33.

34. 35. 36. 37. 38.

with attention deficit disorder: findings from the Ontario Child Health Study. J Child Psychol Psychiatry Allied Disciplines 1989; 30:205-217. Mannuzza S, Klein RG, Bessler A, et al: Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry 1998; 155:493-498. McCann S, Roy-Byrne P: Screening and diagnostic utility of self report attention deficit hyperactivity disorder scales in adults. Compr Psychiatry 2004; 45:175-183. Filipek PA, Accardo PJ, Ashwal S, et al: Practice parameter: screening and diagnosis of autism. Neurology 2000; 55:468479. Einfeld SL, Tonge BJ: Manual for the Developmental Behaviour Checklist (Edition 2). Melbourne, Australia: Monash University Centre for Developmental Psychiatry and Psychology and School of Psychiatry, University of New South Wales, 2002. Baron-Cohen S, Allen J, Gillberg C: Can autism be detected at 18 months? The needle, and the CHAT. Br J Psychiatry 1992; 161:839-934. Pipek PA, Accardo PJ, Baranek GT, et al: The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord 1999; 29:437-482. LeCouteur A, Rutter M, Lord C, et al: Autism Diagnostic Interview: a standardized investigator based instrument. J Autism Dev Disord 1989; 19:363-387. Lord C, Rutter M, Goode S, et al: Autism Diagnostic Observation Schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 1989; 19:185-212. Tonge BJ, Einfeld SL: Psychopathology and intellectual disability: the Australian Child to Adult Longitudinal Study. Int Rev Res Ment Retard 2003; 26:61-91. Tonge BJ: Autism: time for a national approach to early assessment and management [Editorial]. Med J Aust 1996; 165:244-245. Keen D, Ward S: Autistic spectrum disorder: a child population profile. Autism 2004; 8:39-48. Tonge BJ, Brereton AV, Gray KM, et al: Behavioural and emotional disturbance in high functioning autism and Asperger disorder. Autism Int J Res Pract 1999; 2:117-130. Conners CK: Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment monitoring. J Clin Psychiatry 1998; 59:24-30. Jensen PS, Martin D, Cantwell DP: Comorbidity in ADHD: implications for research, practice and DSM-V. J Am Acad Child Adolesc Psychiatry 1997; 36:1065-1079. Mannuzza S, Klein RG, Bessler A, et al: Educational and occupational outcome of hyperactive boys grown up. J Am Acad Child Adolesc Psychiatry 1997; 36:1222-1227. Corkum P, Tannock R, Moldofsky H: Sleep disturbances in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1998; 37:637-646. Whalen CK, Jamner LD, Henker B, et al: The ADHD spectrum and everyday life: experience sampling of adolescent moods, activities, smoking and drinking. Child Dev 2002; 73:209227. Toone B: Attention deficit hyperactivity disorder in adulthood. J Neurol Neurosurg Psychiatry 2004; 75:523-525. Baron-Cohen S, Leslie AM, Frith U: Does the autistic child have a “theory of mind”? Cognition 1985; 21:37-46. Russell J: Autism as an Executive Disorder. New York: Oxford University Press, 1997. Frith U, Happe F: Autism: beyond “theory of mind.” Cognition 1994; 50:115-132. Bradshaw JL: Developmental Disorders of the Frontostriatal System: Neuropsychological, Neuropsychiatric and Evolutionary Perspectives. Hove, UK: Psychology Press, 2001.

137

39. Turner M: Annotation: repetitive behavior in autism: a review of psychological research. J Child Psychol Psychiatry 1999; 40:839-849. 40. Russell J, Jarrold C, Hood B: Two intact executive capacities in children with autism: implications for the core executive dysfunctions in the disorder. J Autism Dev Disord 1999; 29: 103-112. 41. Happe F: Cognition in autism: one deficit or many ? In Novartis Foundation Symposium: Autism: Neural Basis and Treatment Possibilities. London: Wiley, 2003, pp 198-212. 42. Volkmar FR, Klin A, Pauls D: Nosological and genetic aspects of Asperger syndrome. J Autism Dev Disord 1998; 28:457461. 43. Dahlgren SO, Trillingsgaard A: Theory of mind in nonretarded children with autism and Asperger’s syndrome: a research note. J Child Psychol Psychiatry Allied Disciplines 1996; 37:759-763. 44. Baron-Cohen S, O’Riordan M, Stone V, et al: Recognition of faux pas by normally developing children and children with Asperger syndrome or high-functioning autism. J Autism Dev Disord 1999; 29:407-415. 45. Baron-Cohen S, Jolliffe T, Mortimore C, et al: Another advanced test of theory of mind: evidence from very high functioning adults with autism or Asperger syndrome. J Child Psychol Psychiatry 1997; 38:813-822. 46. Rinehart NJ, Bradshaw JL, Moss SA, et al: A deficit in shifting attention present in high functioning autism but not Asperger’s disorder. Autism Int J Res Pract 2001; 5:67-80. 47. Rinehart NJ, Bradshaw JL, Moss SA, et al: Atypical interference of local detail on global processing in high functioning autism and Asperger’s disorder. J Child Psychol Psychiatry 2000; 41:796-778. 48. Ozonoff S, Jensen J: Brief report: specific executive function profiles in three neurodevelopmental disorders. J Autism Dev Disord 1999; 29:171-177. 49. Sheppard DM, Bradshaw JL, Purcell R, et al: Tourette’s and comorbid syndromes: Obsessive compulsive and attention deficit hyperactivity disorder. A common etiology? Clin Psychol Rev 1999; 19:531-552. 50. Noterdaeme M, Amorosa H, Mildenberger K, et al: Evaluation of attention problems in children with autism and children with a specific language disorder. Eur Child Adolesc Psychiatry 2001; 10:58-66. 51. Turner MA: Generating novel ideas: fluency performance in high-functioning and learning disabled individuals with autism. J Child Psychol Psychiatry 1999; 40:189-201. 52. Rinehart NJ, Bradshaw JA, Moss SA, et al: Pseudo-random number generation in children with high-functioning autism and Asperger’s disorder: further evidence for a dissociation in executive functioning? Autism J Res Pract. 2006; 10:70-85. 53. Mari M, Castiello U, Marks D, et al: The reach-to-grasp movement in children with autism spectrum disorder. Philos Trans R Soc Lond B Biol Sci 2003; 358:393-403. 54. Minshew NJ, Sung K, Jones BL, et al: Underdevelopment of the postural control system in autism. Neurology 2004; 63:2056-2061. 55. Maurer RG, Damasio AG: Childhood autism from the point of view of behavioral neurology. J Autism Dev Disord 1982; 12:195-205. 56. Damasio AR, Maurer RG: A neurological model for childhood autism. Arch Neurol 1978; 35:777-786. 57. Vilensky JA, Damasio AR, Maurer RG: Gait disturbances in patients with autistic behavior. Arch Neurol 1981; 38:646649. 58. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: An examination of movement kinematics in young people with high-functioning autism and Asperger’s disorder: further evidence for a motor planning deficit. J Autism Dev Disord. In press.

138

Section

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59. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: Movement-relatedpotentials in autism and Asperger’s disorder. Dev Med Child Neurol. 2006; 48:272-277. 60. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: Kinematic gait function in children with high functioning autism and Asperger’s disorder. Eur Child Adolescent Psychiatry (In Press). 61. Hallet M, Lebiedowska MK, Thomas SL, et al: Locomotion of autistic adults. Arch Neurol 1993; 50:1304-1308. 62. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: Kinematic gait function in newly diagnosed children with autism (3-5 years). Dev Med Child Neurol (In Press) 63. Rinehart NJ, Bradshaw JL, Brereton AV, et al: A clinical and neurobehavioural review of high-functioning autism and Asperger’s disorder. Aust N Z J Psychiatry 2002; 36:762-770 64. Rinehart NJ, Bradshaw JL, Tonge BJ, et al: A neurobehavioural examination of individuals with high-functioning autism and Asperger’s disorder using a fronto-striatal model of dysfunction. Behav Cogn Neurosci Rev 2002; 1(2):164-177. 65. Rinehart NJ, Bradshaw JL, Brereton AV, et al: Lateralization in individuals with high-functioning autism and Asperger’s disorder: a frontostriatal model. J Autism Dev Disord 2002; 32:321-332. 66. Abell F, Krams M, Ashburner J, et al: The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. Neuroreport 1999; 10:1647-1651. 67. Carper RA, Moses P, Tigue ZD, et al: Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage 2002; 16:1038-1051. 68. Giedd JN, Castellanos FX: Developmental disorders. In Krishnan KRR, Doraiswamy PM, eds: Brain Imaging in Clinical Psychiatry. New York: Marcel Dekker, 1997, pp 121137. 69. Murphy DG, Critchley HD, Schmitz N, et al: Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Arch Gen Psychiatry 2002; 59:885-891. 70. Muller RA, Pierce K, Ambrose JB, et al: Atypical patterns of cerebral motor activation in autism: a functional magnetic resonance study. Biol Psychiatry 2001; 49:665-676. 71. Sokol DK: Neuroimaging in autistic spectrum disorder (ASD). J Neuroimaging 2004; 14:8-15. 72. Haznedar MM, Buchsbaum MS, Wei TC, et al: Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 2000; 157:1994-2001. 73. Happe F, Ehlers S, Fletcher P, et al: “Theory of mind” in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996; 8:197-201. 74. Haznedar MM, Buchsbaum MS, Metzger M, et al: Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 1997; 154:1047-1050. 75. Silk TJ, Rinehart NJ, Bradshaw JL, et al: Visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorder: a functional MRI study. Am J Psychiatry. (In Press). 76. Fan J, McCandliss BD, Sommer T, et al: Testing the efficiency and independence of attentional networks. J Cogn Neurosci 2002; 14:340-347. 77. Muhle R, Trentacost SV, Rapin I: The genetics of autism. Pediatrics 2004; 113:472-486. 78. Tidmarsh F, Volkmar F: Diagnosis and epidemiology of autism spectrum disorders. Can J Psychiatry, 2003; 48:517523. 79. Stone JL, Merrimon B, Cantor RM, et al: Evidence for sexspecific risk alleles in autism spectrum disorder. Am J Hum Genet 2004; 75:1117-1123. 80. McCauley JL, Olson LM, Delahanty R, et al: A linkage disequilibrium map of the 1-Mb 15g12 GABA(A) receptor subunit

81. 82. 83. 84. 85. 86.

87.

88.

89. 90. 91.

92.

93. 94. 95. 96. 97. 98.

99. 100.

cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet 2004; 131:51-59. Rabionet R, Jaworski JM, Ashley-Kock AE, et al: Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes. Neurosci Lett 2004; 382:209-214. Barkley RA: Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 1997; 121:65-94. Barkley RA: The executive function and self-regulation: an evolutionary neuropsychological perspective. Neuropsychol Rev 2001; 11:1-29. Nichols SL, Waschbusch DA; A Review of the Validity of laboratory cognitive tasks used to assess symptoms of ADHD. Child Psychiatry Hum Dev 2004; 34:297-315. Casey J, Trainor RJ, Orendi JL, et al: A developmental functional MRI study of prefrontal activation during performance of a go–no-go task. J Cogn Neurosci 1997; 9:835-847. Manly T, Anderson V, Nimmo-Smith I, et al: The differential assessment of children’s attention: the Test of Everyday Attention for Children (TEA-Ch), normative sample and ADHD performance. J Child Psychol Psychiatry 2001; 42:1065-1081. Sheppard DM, Bradshaw JL, Mattingley JB, et al: Effects of stimulant medication on the lateralisation of line bisection judgements of ADHD children. J Neurol Neurosurg Psychiatry 1999; 66:57-63. Castellanos FX, Giedd JN, Marsh JL, et al: Quantitative brain magnetic resonance imaging in attention deficit hyperactivity disorder. Arch Gen Psychiatry 1996; 53:607616. Hill DE, Yeo RA, Campbell RA, et al: Magnetic resonance imaging correlates of attention-deficit/hyperactivity disorder in children. Neuropsychology 2003; 17:496-506. Sowell ER, Thompson PM, Welcome SE, et al: Cortical abnormalities in children and adolescents with attention deficit hyperactivity disorder. Lancet 2003; 362:1699-1707. Rubia K, Overmeyer S, Taylor E, et al: Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry 1999; 156:891-896. Silk T, Vance A, Rinehart NJ, et al: Fronto-parietal activation in attention deficit hyperactivity disorder, combined type: functional magnetic resonance imaging study. Br J Psychiatry. 2005; 187:282-283. Voeller KKS: Attention deficit hyperactivity disorder (ADHD). J Child Neurol 2004; 19:798-814. Bobb AJ, Castellanos FX, Addington AM, et al: Molecular genetic studies of ADHD: 1991 to 2004. Am J Med Genet B Neuropsychiatr Genet 2005; 132:109-125. Yeh M, Morley KI, Hall WD: The policy and ethical implications of genetic research on attention deficit hyperactivity disorder. Aust N Z J Psychiatry 2004; 38(1-2):10-19. Volkmar F, Lord C, Bailey A, et al: Autism and pervasive developmental disorders. J Child Psychol Psychiatry 2004; 45:135170. National Research Council: Educating Young Children with Autism. Washington, DC: National Academies Press, 2001. Lovaas I, Calouri K, Jada J: The nature of behavioral treatment and research with young autistic persons. In Gillberg C, ed: Diagnosis and Treatment of Autism. New York: Plenum Press, 1989, pp 285-305. Gray CA, Garand JD: Social stories: improving responses of students with autism with accurate social information. Focus Autistic Behav 1993; 8:1-10. Brereton AV, Tonge BJ: Preschoolers with Autism: An Education and Skills Training Program for Parents. London: Jessica Kingsley, 2005.

chapter 10 autism and attention deficit/hyperactivity disorder 101. Aman MG: A double-blind, placebo-controlled trial of risperidone in children with autistic disorder. N Engl J Med 2002; 347:314-321. 102. Gordon CT, State RC, Nelson JE, et al: A double blind comparison clomipramine, desipramine and placebo in the treatment of autistic disorder. Archs Gen Psychiatry 1993; 50:441-447. 103. Zametkin AJ, Ernst M: Problems in the management of attention-deficit/hyperactivity disorder. N Engl J Med 1999; 340:40-46. 104. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999; 56:1073-1086. 105. Hill P: Attention deficit hyperactivity disorder. Arch Dis Child 1998; 79:381-386. 106. Solanto MV: Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity dis-

107.

108. 109.

110.

139

order: a review and integration. Behav Brain Res 1998; 94:127-152. Hechtman L, Weiss G: Controlled prospective 15 year follow up of hyperactives as adults: non medical drug and alcohol use and antisocial behaviour. Can J Psychiatry 1986; 31:557567. Mayes SD, Crites DL, Bixler EO, et al: Methylphenidate and ADHD: influence of age, IQ and neurodevelopmental status. Dev Med Child Neurol 1994; 36:1099-1107. Kratochvil CJ, Heiligenstein MD, Dittmann R, et al: Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 2002; 41:776-784. Kelsey DK, Sumner CR, Casat CD, et al: Once-daily atomoxetine treatment for children with attention deficit/hyperactivity disorder, including an assessment in the evening and morning behavior: a double-blind placebo-controlled trial. Pediatrics 2004; 114:111-118.

CHAPTER

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DELIRIUM ●

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●

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Kim Jeffs and Pe¯teris Da¯rzinsˇ

The key features of delirium are acute change in cognitive status, fluctuation in consciousness, deficits in attention, and perceptual disturbances.1 Nonarbitrary definitions of these features, especially consciousness and attention, are lacking, and this limits the ability to define delirium precisely.

Delirium may be caused by specific brain injury (e.g., herpes simplex encephalitis), but more often, delirium is a nonspecific response of the brain to challenges from systemic illness or medications. Delirium can occur in otherwise normal brains with extreme physiological challenge (e.g., intensive care admission), but in diseased brains (e.g., Alzheimer’s dementia), even apparently trivial challenges, such as a urinary tract infection or constipation, may trigger delirium. Delirium may be caused by just one factor (e.g., recreational drug use) but commonly appears to result from a combination of harmful factors. In most cases, delirium is easy to recognize once it is considered and an adequate history has been obtained. Although a diagnostic workup—and therapy, if indicated—for specific brain injury is always important, this situation is rare. More commonly, multiple possible etiological factors are identified, and attention needs to be directed to each of these. Masterful delirium management seldom requires a single clever diagnosis; more commonly, management requires insightful clinical practice that can detect multiple potential contributors and ameliorate each of these. A collaborative team approach is the key to success. Truly outstanding clinicians manage this well, through attention to systems issues aimed at the prevention and optimal management of delirium. Delirium is common and is associated with a higher risk of death, persistent cognitive impairment, institutionalization, and prolonged hospitalization. There is some evidence that prevention of delirium is often possible, but prevention strategies remain underused. Because delirium treatments have limited efficacy, and because neuropathological insights are of limited clinical relevance, the emphasis of any discussion of delirium must be on prevention.

Delirium is common (Table 11–1). The prevalence of delirium in hospitalized older patients is 14% to 60%; the rates are higher in surgical patients (particularly those with hip fracture or requiring emergency surgery).2-6 Approximately 1 per 10 elderly patients presenting to hospital are delirious, and a further 10% to 40% develop delirium while hospitalized.7 Delirium occurs in up to 45% of hospitalized patients with preexisting cognitive impairment.8 Delirium is even more common in patients nearing the end of life, occurring in up to four fifths of such patients.9,10 Delirium occurs in 10% of patients presenting to emergency departments and is almost universal in intensive care units.11-16 Of patients admitted to post–acute care facilities, 16% have a diagnosis of delirium, and a further 23% to 53% have symptoms of delirium at the time of admission.17,18 Despite the high incidence and prevalence of delirium, it remains underrecognized by clinicians—up to 90% of cases in in-patients are missed.13,19-26 Furthermore, patients are discharged home from the emergency department without delirium being recognized, and this has been linked to increased mortality.12,13,23

DEFINITION

Clinical Syndromes

Many terms have been used to describe the delirious state, including acute organic brain syndrome, acute confusional state, toxic psychosis, intensive care unit (ICU) syndrome, and postoperative psychosis. This variation reflects the difficulty in describing the syndrome or syndromes that are now most commonly called delirium. The most common definition used in delirium research is that of the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Fig. 11–1).1

Delirium is not a homogenous disorder; rather, it is a complex clinical syndrome with diverse etiologies and presentations. Delirium tremens is the classic picture of delirium with which most clinicians are familiar. Agitation; being out of touch with reality, with visual, tactile, and auditory hallucinations; obvious fear; and suspicion and mistrust of others typify the hyperactive form of delirium. The hypoactive form of delirium is recognized from apathy in patients with marked cognitive impairment. Hypoactive delirium is easily missed, inasmuch as

EPIDEMIOLOGY Prevalence and Incidence

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Figure 11–1. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for delirium. Washington DC: American Psychiatric Association, 1994.

T A B L E 11–1. Delirium in Various Settings Setting

Age

Method of Detecting Delirium

Rate

Study

Mixed* Post–acute care facilities Post–acute care facilities Critical care unit Critical care unit§ Critical care unit§ Critical care unit Emergency department Emergency department Medical inpatients Medical inpatients Medical inpatients Patients with hip fracture Patients with hip fracture¶¶ Patients with hip fracture¶ Patients with hip fracture¶ Major abdominal surgery** Patients undergoing elective orthopedic or urological surgery

>75 >65 >65 All >65 >65 >18 >65 >70 >65 >70 >65 >65 >65 >65 >50 >65 >65

Organic Brain Syndrome Scale Confusion Assessment Method Minimum Data Set—Post Acute Care‡ Confusion Assessment Method Confusion Assessment Method Confusion Assessment Method Intensive Care Delirium Screening Checklist Confusion Assessment Method Confusion Assessment Method Confusion Assessment Method Psychiatric interview Confusion Assessment Method DSM-III criteria Confusion Assessment Method Organic Brain Syndrome Scale Confusion Assessment Method Confusion Assessment Method Screening tool based on DSM-IV criteria

43.9% 15.6%† 23% 7.3% 70% 83% 45% 9.6%¶ 10.1% 12.0% 20.4% 21.3% 44-66% 14.6% 48.5% 28% 34.5% 5.1%

Sandberg et al, 19993 Kiely et al, 200317 Marcantonio et al, 200318 Rincon et al, 200114 McNicoll et al, 200315 Ely et al, 200194 Roberts et al, 200595 Elie et al, 200019 Hustey and Meldon, 200213 Cole et al, 20024 Johnson et al, 199296 Jeffs et al, 200440 Gustafson et al, 199120 Marcantonio et al, 199897 Edlund et al, 200198 Zakriya et al, 200299 Shigeta et al, 2001100 Dai et al, 2000101

*Hospital patients, patients in residential aged care facilities, and patients receiving home medical care. † A further 12.6% had two symptoms of delirium, and 39.5% had one symptom of delirium. ‡ Delirium is defined as the presence of one or more symptoms of delirium on the Minimum Data Set—Post Acute Care. § Cumulative incidence of delirium. ¶ Includes definite and probable delirium. ¶¶ Patients interviewed by telephone and face to face 1 month after repair of hip fracture. **Study of 29 patients in whom melatonin levels were investigated. DSM, Diagnostic and Statistical Manual of Mental Disorders.

chapter 11 delirium there are no behavioral disturbances that bring attention to the patients and the patients seldom volunteer that they are experiencing psychotic thoughts or bizarre sensations. About 25% of cases of delirium are of the hyperactive form, another 25% are of the hypoactive form, and the remainder of patients with delirium have both hyperactive and hypoactive features.3,27,28 The cause of delirium cannot be reliably diagnosed from the subtype observed, although drug withdrawal states more commonly manifest with the hyperactive form and metabolic encephalopathies with the hypoactive form.28,29 Infection may manifest with either form of delirium.30,31 Patients who have some of the key features of delirium but do not fully satisfy the DSM-IV criteria experience adverse events similar to those who do meet the criteria. This “subsyndromal delirium” has been associated with poor outcomes, and there is probably a relationship between the number of features present and the risk of adverse outcomes.32,33

Course Delirium often lasts for a few days or a week, but some patients experience prolonged delirium. One study showed that only approximately one fifth of patients have complete resolution of delirium at 6 months.34 Symptoms of memory impairment, inattention, and disorientation may still be present 12 months after an episode of delirium.35 Prolonged delirium leads to diagnostic difficulty, especially when the precipitating event has apparently resolved, and it may be difficult to distinguish delirium from dementia. Dementia with Lewy bodies, with its characteristic attentional fluctuations causes particular difficulty (see Chapter 71). Nearly one in five patients has a new diagnosis of dementia in the year after an episode of delirium.36 The existence of prolonged delirium also makes it difficult to predict recovery of individual patients and complicates decisions about rehabilitation potential and long-term care.

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burden for health care systems as a result of increased duration of hospitalization and increased postdischarge costs.44-46

RISK FACTORS Baseline Vulnerability Factors that increase vulnerability to delirium include preexisting cognitive impairment, comorbid illness, and sensory deficits (Table 11–2).11,45,47,48 A delirium risk prediction model based on the presence or absence of cognitive impairment, severe illness, visual impairment, and dehydration at the time of admission to hospital shows that when one or two risk factors are present, the rate of incident delirium is 16% to 23%, whereas when three or four risk factors are present, the rate of delirium is 32% to 83%.48 The magnitude of the noxious event or events necessary to produce a delirious episode is inversely proportional to the degree of baseline vulnerability. In vulnerable people, delirium acts as a sensitive, but not specific, indicator of illness.

Precipitating Factors The study of precipitating factors is plagued by confounding variables. The confounding variables (in this case, putative risk factors for delirium, such as prescription of new medications or insertion of a urinary catheter) are related to both the study factor (sickness that necessitates hospitalization and in turn may necessitate the new medications or catheterization) and the outcome factor (delirium that may be caused by the sickness, the interventions, or both). Confounding cannot be adjusted for statistically. Because it would be unethical to subject healthy people to medications, procedures, or hospitalization to test these as independent risk factors for delirium, the evidence

Sequelae Physical Delirium is associated with major morbidity and mortality. Patients suffering from delirium have an initial mortality rate of up to 26%.37 Twelve months after an episode of delirium, patients are twice as likely to have died than are similar patients who have not had delirium.36,38 Mortality rates as high as 75% three years after an episode of delirium have been reported.39 Complications attributable to delirium include malnutrition, dehydration, pneumonia, pressure sores, and falls. Patients with delirium suffer greater functional decline in hospital, and are more likely to require rehabilitation or long-term residential care.34,40-43 Patients with hyperactive delirium are more likely to fall while hospitalized.30 Patients with hypoactive delirium are generally sicker, remain hospitalized longer, and are more likely to develop pressure sores.30

Social and Economic Delirium often imposes a heavy burden on the families of those affected as they come to terms with a serious condition that substantially alters the behavior of their family member and that has an uncertain prognosis. It also creates an economic

T A B L E 11–2. Baseline Vulnerability and Precipitating Factors for Delirium Risk Factor* Cognitive impairment/dementia11,45,47,48 Number of major diagnostic categories45 Depression11,45 Alcoholism11,45 Severe medical illness11,58 Male gender11 Abnormal sodium11,47 Hearing impairment11 Visual impairment11,48 Diminished ADL11 Fever or hypothermia47 Psychoactive drug use47 Azotemia/dehydration47 Use of physical restraints52 Malnutrition52 More than three medications added in 24 hours52 Use of indwelling urinary catheter52 Any iatrogenic event52 *References cited as superscripts. ADL, activities of daily living.

Adjusted Relative Risk 2.1-5.3 1.7 1.9-3.2 3.3-5.7 3.5-5.9 1.9 2.2-6.2 1.9 1.7-3.5 2.5 5.0 3.9 2.0-2.9 4.4 4.0 2.9 2.4 1.9

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regarding precipitating factors comes from descriptive studies. Nonetheless, the weight of evidence shows that many events may precipitate delirium. Delirium is a syndrome with multifactorial etiologies; therefore, in any one patient, it is usual for a number of factors to contribute to delirium.49-51 Five independent risk factors associated with the hospitalization process that appear to increase the risk of developing delirium are (1) the addition of more than three medications in any 24-hour period, (2) the use of physical restraints, (3) the presence of malnutrition, (4) the insertion of an indwelling urinary catheter,

and (5) any iatrogenic adverse event.52 The risk of delirium rises proportionately with the number of risk factors. Of importance is that these precipitating factors are potentially avoidable. Patients with three or more precipitating factors have an 8% per day risk of developing delirium.52 Other environmental factors, such as frequent room changes, absence of a clock, or absence of reading glasses, are associated with increased “severity” of delirium.53 Figure 11–2A depicts a hospital environment likely to produce delirium, whereas Figure 11–2C depicts a hospital environment likely to decrease the risk of delirium.

A 1. Bed at "orthopedic height" 2. Cot sides up—hence bed at "neurosurgical height" 3. Treatment given via indwelling intravenous line 4. Urinary continence managed by indwelling urinary catheter 5. Physical restraint 6. Spectacles not on (out of reach) 7. Hearing aids not in (on the floor) 8. Drink not accessible 9. Call bell out of reach 10. Polypharmacy (pills on the table) 11. Bright light on despite it being night time 12. Music despite it being night time 13. No clock 14. No orienting information

B ■

Figure 11–2. A, Example of suboptimally managed illness in an older patient. B, Fourteen aspects of care that increase the risk of delirium.

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C 1. Patient sitting out of bed 2. Patient dressed in normal day attire rather than pajamas 3. Spectacles are on and clean 4. Hearing aids are in and ears have been cleared of wax 5. A drink is within easy reach 6. Call bell is within easy reach 7. Orienting information is available, including a clock 8. The bed is at an appropriate height 9. The patient is engaged in cognitively stimulating activities 10. No unnecessary indwelling devices 11. No polypharmacy

D ■

Figure 11–2, cont’d. C, Example of a well-managed illness in an older patient. D, Eleven aspects of care that decrease the risk of delirium.

PATHOPHYSIOLOGY It is not surprising, in view of the myriad of etiologies and manifestations of delirium, that there is no one satisfactory unifying pathophysiological explanation. In addition, the neural mechanisms by which delirium is produced are poorly understood. To date, proposed pathophysiological mechanisms remain excessively simplistic or, when detailed, cannot explain adequately the various manifestations of delirium. It is not clear whether delirium is the final common pathway for a broad range of insults or whether the different causes of delirium have different pathophysiological processes that are clinically indis-

tinguishable. Delirium is believed to occur as a result of perturbation to systems that have little reserve, and this fits well with the clinical risk prediction tools. A number of neurotransmitter systems have been implicated in the pathophysiology of delirium. Abnormalities of the cholinergic system are the best studied. The notion that a central cholinergic deficiency leads to delirium is supported clinically by the observation that anticholinergic medications are potent causes of delirium.54,55 Investigators measuring serum anticholinergic activity have reported increased levels associated with the presence of delirium, with levels falling after resolution of delirium.56 Physostigmine, a reversible

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anticholinesterase inhibitor, has been used to treat anticholinergic delirium with some success.57 Cholinesterase inhibitors have been proposed as a means of treating delirium, with some case reports of success, but, conversely, tacrine has been reported to cause delirium.58,59 Excess dopamine has been implicated in the pathogenesis of delirium, and dopamine antagonists are used to treat delirium.60,61 Both serotonin excess and deficiency have been implicated; serotonin excess appears more likely to be associated with medication-related delirium.55 There is no conclusive evidence to relate either dopamine or γ-amino butyric acid to medical or surgical delirium, but perturbation of its activity has been linked with hepatic encephalopathy and benzodiazepine intoxication or withdrawal states.62,63 Hypercortisolism, such as that occurring in Cushing’s syndrome, is known to have effects on cognition, as well as on mood and sleep, but no decisive link with delirium has been established.55 Animal models such as stressed rats show changes in steroid sensitive hypothalamic neurones that can be prevented by adrenalectomy.64

CLINICAL FEATURES Symptoms, Signs, and Corroborative History Many delirious patients do not volunteer any symptoms. Patients’ families or involved health professionals might report changed cognition, fluctuations in alertness, sleep-wake cycle disturbance, or psychotic features. Nursing staff members commonly report nocturnal agitation. Delirium may manifest only as a “failure to thrive.” When patients fail to improve as clinically expected a high level of suspicion for underlying delirium is warranted. A corroborative history that provides information about patients’ baseline cognitive function and the rate of deterioration of cognition may help the clinician identify possible etiologies for delirium, such as changes to medications, constipation, other recent illnesses, and substance abuse.

may yield evidence of a concomitant neurological disorder or a preexisting condition that has increased the vulnerability to delirium. The most common neurological signs in patients with delirium are signs of Alzheimer’s disease (including frontal lobe release signs and apraxia) and vascular-type dementias (including subtle bradykinesia, hypertonicity [gegenhalten], and extensor plantar responses). There may also be evidence of other neurodegenerative disorders such as Parkinson’s disease or a prior focal cerebral lesion such as a stroke or tumor. Patients with small infarcts that result in Wernicke’s aphasia without other focal signs sometimes receive misdiagnoses of delirium. The lack of disturbance of sustained directed attention helps rule out delirium, and the characteristic language disturbance helps make a positive diagnosis of Wernicke’s syndrome (see Chapter 3). There is a wide range of cerebral pathological processes that increase the risk of delirium; the neurological examination may yield evidence of these. Nystagmus and ataxia may be present in medication toxicity, and cranial nerve palsies may be present in Wernicke’s encephalopathy. Asterixis is observed in renal and hepatic failure. Meningism suggests meningitis. The presence of herpes simplex encephalopathy is suggested by fever, meningism, and rapid onset of recent memory loss, together with drowsiness. Differentiation of delirium from depression can be particularly challenging; depressive features such as apathy and complaints of depressed mood are common in delirium. Up to one half of the patients referred for psychiatric consultation for depressive symptoms in hospital actually have delirium.68-70 The differentiation of the disorders is especially important because many antidepressants have anticholinergic properties that have a marked potential to aggravate delirium. Conversely, when depression is misdiagnosed as chronic delirium, the opportunity for antidepressant therapy is lost. Table 11–3 outlines useful features for the differentiation of delirium from other common conditions.

General Physical Examination Cognitive Examination Fluctuating impairment of sustained directed attention is a key feature of delirium and may become apparent when patients have difficulty attending to questions in the medical interview or are easily distracted during conversation. Attention may be formally assessed by such items such as the Digit Span Memory Test or Trail Making Test.65 Restlessness or picking at the bedclothes may indicate underlying psychotic features. Patients should be questioned with regard to worrying thoughts or unusual sensory experiences in order to elicit the presence of hallucinations or delusions. Incorporating a screening test for cognition, such as the Mini Mental State Examination, in the initial assessment of hospitalized older patients could substantially improve the detection of delirium.66,67 Poor test performance would prompt clinicians to seek other evidence of delirium.

Neurological Examination Other than fluctuating attention and disordered thought, there are no specific signs of delirium. The neurological examination

The presence of delirium should prompt a thorough physical examination, with a focus on potential causes for delirium, particularly for evidence of occult infection. Chest and urinary sepsis should be sought. The patient should be examined for the presence of dehydration and constipation. The examination should include a search for signs of renal, respiratory, or hepatic failure. Review of the medication chart is a crucial part of the examination.

Diagnostic Instruments There is no single diagnostic test for the presence of delirium; the reference standard instrument is a formal psychiatric assessment. The Confusion Assessment Method (Fig. 11–3) is relatively short, and nonmedical staff can be trained to administer it.71 However, this test is not valid when administered by nurses involved in the routine care of patients unless they also perform the Mini Mental State Examination.72

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CONFUSION ASSESSMENT METHOD (SHORT FORM) 1. Acute onset and fluctuating course a. Is there evidence of an acute change in mental status from the patient’s baseline? b. Did the (abnormal) behavior fluctuate during the day (i.e., tend to come and go or increase and decrease in severity)?

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Figure 11–3. The Confusion Assessment Method (Short Form). From Inouye SK et al: Annals of Internal Medicine 1990; 113:941-948.

2. Inattention Did the patient have difficulty focusing attention (e.g., was easily distractible or had difficulty keeping track of what was being said)? 3. Disorganized thinking Was the patient’s thinking disorganized or incoherent (e.g., engaged in rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject)? 4. Altered level of consciousness Alert Vigilant (hyperalert) Lethargic (drowsy, easily roused) Stupor (difficult to rouse) Coma (unrousable)

Do any ticks appear in the box?

If either 1a or 1b AND 2 are present AND EITHER 3 or 4 are present, then a diagnosis of delirium is suggested.

T A B L E 11–3. Differential Diagnosis of Delirium Diagnosis Feature

Delirium

Dementia*

Depression

Onset

Acute (hours to days)

Insidious (generally more than 6 months)

Variable

Course

Fluctuating (both within a 24-hour period and from day to day) Clouded Impaired Difficulty maintaining and shifting attention Poor short-term memory

Progressive decline

Diurnal variation in symptoms Clear Not impaired May be impaired

Consciousness Orientation Attention Memory Psychotic symptoms Response to repeated questions

Hallucinations and delusions common Little or no change

Clear until end stage Increasing impairment with duration Generally intact until late stages Poor short-term memory Uncommon

Memory intact (may have some difficulty with registration) Not common (mood congruent)

Patient will try again but is likely to provide incorrect response

“Don’t know,” followed by correct answer

*Exceptions include Dementia with Lewy bodies, which has a fluctuating course and is manifested by attentional disturbance and hallucinations (see Chapter 70).

MANAGEMENT Aims of Management The best available evidence suggests that prevention of delirium is more effective than its treatment.37,73,74 Useful principles for the treatment of established delirium focus on investigation of possible causes, prevention of complications, and the management of behavioral disturbance.

Prevention With rare exceptions, hospital design and budgets are incompatible with truly optimal patient-centered care. Patients are

managed for the comfort and convenience of the system rather than in a way that is optimal for them. For example, patients are left dressed in pajamas rather than being dressed in daytime attire. Mobilization is discouraged by the delivery of meals to patients, instead of their being served in dining rooms. Sometimes patients are expected to remain in or near their beds for the nurses’ convenience (to facilitate medication administration and recording of nursing observations) and for the physicians’ convenience (to ensure that patients can be easily found during ward rounds). Patients are required to fit into hospital time frames (for example, early morning surgical ward rounds) rather than being allowed to follow normal daily routines. Hospitals are often noisy and are brightly lit, day and night. These environmental factors are disorienting and can contribute to delirium, especially in patients with dementia, as do invasive devices and polypharmacy.

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Addressing the known risk factors for delirium can prevent the occurrence of delirium while the patient is hospitalized.75 One multidisciplinary intervention reduced the rate of incident delirium by one third in medical patients at intermediate to high risk.75 This program aimed to ameliorate the delirium risk factors of cognitive impairment, dehydration, immobility, sensory impairment, and sleep disturbance.76 Education programs or clinical guidelines for hospital staff that were aimed at the prevention of delirium have yielded mixed results.77,78 Perioperative interventions that have reduced delirium incidence include the provision of continuous supplementary lowflow oxygen, the use of analgesic protocols, and a geriatric consultation service to elderly patients with hip fracture.33,79,80

ogy but is often unhelpful in elucidating the etiology of delirium. Only rarely is delirium the result of a primary neurological event.6,81 Focal neurological signs or a history of head trauma would prompt urgent cerebral computed tomography or magnetic resonance imaging. The electroencephalogram characteristically shows generalized background slowing and only rarely helps establish the cause of delirium. However, the excessive frontal beta activity of benzodiazepine or barbiturate intoxication can be a helpful diagnostic pointer. The electroencephalogram can rule out nonconvulsive status epilepticus, which can at times be indistinguishable from hypoactive delirium, and it may also assist in the differentiation of delirium from functional psychoses (the end stage of Wernicke’s encephalopathy).82

Investigating the Cause of Delirium Investigation is directed toward the likely cause. In children, the emphasis is on the search for infection. In young adults, investigations focus on drug intoxication/withdrawal and central nervous system infections, including the human immunodeficiency virus, and rare encephalopathies (arteritis, disseminated neoplasm). In older people, the causes of delirium are the causes of acute illness in older people; medication side effects, metabolic derangement, and occult infections are the most common. Investigations are directed at these and at ruling out less common etiological factors (Table 11–4). Medications are responsible for 22% to 39% of cases, and thus a medication review, including over-the-counter drugs, often identifies a potential cause (Table 11–5).6 In addition to obvious candidates (e.g., sedatives or hypnotics, anticonvulsants, and antidepressants), many common medications (e.g., frusemide, digoxin, and prednisolone) have significant anticholinergic activity and may contribute to the development of delirium.56 In up to 62% of cases, more than one etiological factor is involved.49-51 Figure 11–4 provides a suggested algorithm for the investigation of the cause of delirium. No clear cause can be found in some cases.6 The search for potential causes for delirium is complicated by the frequently atypical disease manifestations in elderly patients, in addition to the obvious practical difficulties of documenting histories from confused patients. The investigation of delirium must be considered in view of the patients’ own constellation of illnesses, and any algorithm can act only as a guide. Neuroimaging such as computed tomography of the brain commonly reveals underlying pathol-

T A B L E 11–4. Important Causes of Delirium Drugs Intoxication Withdrawal Interactions with other drugs Interactions with disease Infections Metabolic derangement Surgery Environmental Disorienting environment (no clock, frequent room changes) Physical restraints Bladder catheter Iatrogenic events

Treatment Wernicke’s encephalopathy is more common than usually realized, and 1% to 5% of postmortem specimens show evidence of Korsakoff’s pathology in two Australian coronial series.83 Most patients present with only a delirium, rather than with the classic triad of memory loss, ocular signs, and confabulation. For this reason, all patients presenting with delirium for which another cause is not immediately apparent should receive thiamine. It is disappointing that for as common and as serious a condition as delirium, there are few well-conducted trials. There is no specific therapy for delirium. Management centers on the diagnosis and elimination of any underlying etiological factors, the prevention of further harm or injury to patients, and the provision of support while natural recovery is awaited. There seems no reason to abandon the doctrine of “first do no harm” in the management of delirium and, in the absence of good evidence of benefit for particular therapies, plenty of reason to choose therapy with minimal potential for harm.

Nonpharmacological Measures With the exception of physical restraints, which worsen delirium and cause serious injuries and deaths, the use of nonpharmacological measures in the treatment of established delirium is not associated with harm and hence should be used exhaustively as the mainstay of management.52,53,72,84-89 Nonpharmacological management focuses on providing prompts to assist orientation, an environment conducive to appropriate rest, and activities to maintain cognitive stimulation and physical activity. Providing verbal and visual reminders of the date, time, place, and the daily schedule helps. When appropriate, clean spectacles and functioning hearing aids help this orient-

T A B L E 11–5. Drugs Commonly Implicated in Delirium Anticholinergic agents (many commonly used drugs have anticholinergic properties) Antidepressants Antiparkinsonian Benzodiazepines Histamine (H2) receptor antagonists Opioid analgesics Steroidal and nonsteroidal anti-inflammatory drugs

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GUIDELINES FOR THE MANAGEMENT OF A PERSON WITH DELIRIUM Patient appears “off color” Relatives/caregivers concerned

Cognitive assessment: Confusion Assessment Method or DSM-IV

No features of delirium present

Features of delirium present

Supportive care: • Adequate nutrition and hydration • Avoid restraints, IDC • Mobilize • Quiet room, adequate lighting • Appropriate sensory aids • Orientation and reassurance • Education for family/caregivers

Investigations for the cause of delirium: • History (especially corroborative) • Physical examination • Medication review • Laboratory parameters: FBE, CU, glucose, CRP, calcium, urinalysis, pulse oximetry, EKG, drug levels if appropriate • CXR

Is behavior unsafe or impeding care? Bedside aids: • Bed that can be lowered to floor level • Secure ward with activities available

Potential cause for delirium found (n.b. may be >1)

Treat infection, discontinue drug, rehydrate, etc.

Commence low-dose neuroleptic (e.g., haloperidol 0.25–0.5 mg every 30 minutes until behavior settles, then give total amount split into 2 equal doses over the day)

History of trauma/fall Focal neurology on anticoagulants

Computed tomography of the brain

Cause of delirium remains unclear

Consider: • TFTs • EEG • Lumbar puncture • Cerebral MRI • B12/folate

Monitor for efficacy and side effects OK Wean once behavior settled or cause of delirium treated

Not OK Try another agent (e.g., risperidone or shortacting benzodiazepine)

Delirium improves

Discharge with appropriate supports or to rehabilitation Follow up cognitive assessment to assess for resolution of delirium or for presence of undetected dementia ■

Figure 11–4. Guidelines for the management of a person with delirium. CRP, C-reactive protein; CU, creatinine and urea; CXR, chest radiograph; ECG, electrocardiogram; EEG, electroencephalography; FBE, full blood examination; IDC, indwelling (urinary) catheter; MRI, magnetic resonance imaging; n.b., nota bene; TFT, thyroid function test.

ing process. Nursing provided by a small number of nurses (primary nursing) is less disorienting than team nursing. For agitated patients, a person who sits with the patient can improve safety. Equipment that immobilizes patients, such as indwelling urinary and intravenous catheters, should be

avoided. Patients should ambulate at least three times daily; participation in self-care tasks helps achieve this. Sensitive involvement of patients in normal daily activities helps them maintain mobility and adequate nutrition and minimizes constipation and urine retention. It is preferable to care

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for delirious patients in single rooms, where noise and distractions can be kept to a minimum, and a few objects brought from home can provide a sense of familiarity.38 Some institutions have designed rooms specifically to manage delirious patients, but these have yet to be prospectively evaluated.90 Restless patients who are at great risk of falling and yet do not reliably stay in bed can be managed by a combination of close supervision while they are ambulant, together with nursing in an electronic bed that can be lowered almost to ground level. The bed is raised when nursing care is provided or to assist the patient in rising to walk, and then it is lowered to ground level when it is time to sleep. If patients then fall out of bed, they are unlikely to injure themselves, and they cannot readily get up to walk unsupervised if they attempt to do this alone. Patients must be examined for dehydration, pressure sores, and pneumonia at least daily. An alternating pressure air mattress may help to nurse patients with (hypoactive) delirium. Supportive care is also required for the patients’ families, who need explanation of the disease process, strategies to deal with often disturbing behavior, and frank discussion regarding the guarded prognosis.

Ethical Issues and Decision-Making Capacity Many patients with delirium lose the capacity to make healthrelated or other decisions during the delirium. Some may never regain this capacity, whereas for others, this incapacity is temporary and may fluctuate from hour to hour and day to day. Therefore, this capacity must be assessed whenever decisions are to be made. Adequate assessments are seldom performed, and the use of surrogate decision makers is suboptimal.27 A formal capacity assessment process may help provide valid assessments.93

CONCLUSION Delirium is a challenging disorder, but it is one of the neurological disorders in which clinicians can genuinely improve their patients’ well-being, principally through the provision of good general medical and nursing care. There remains scandalously little evidence to support therapeutic recommendations. The profession must rise to the challenge of designing and implementing trials to guide management of this common and potentially devastating condition.

Pharmacological Measures There is a paucity of research into the pharmacological management of delirium, and there is no evidence to suggest that the use of antipsychotic or other medications alters the natural history of delirium or improves outcome.91 Mainly, there is no evidence of benefit, but there is also evidence of little or no benefit. Antipsychotic drugs are often employed, but they can have unwanted side effects. The aim of treatment must be to relieve suffering or to ensure the safety of patients. Chemical restraint should be avoided, because oversedation leads to falls, pneumonia, and pressure sores. Agitation in delirium may be caused by fear from misperceptions, hallucinations, or delusions. Antipsychotic agents may relieve some of the symptoms. Some patients without obvious agitation experience marked delusional thoughts that might lead them to refuse food, fluids, or medications. The aim of pharmacotherapy for patients with nonspecific delirium is to treat the symptoms. The aim is not to sedate patients, not to make them less mobile, or not to make them less disruptive to nursing staff or family members, but to decrease inner turmoil. Most evidence regarding pharmacotherapy in delirium comes from case reports or small, uncontrolled series.91 Haloperidol at a low dosage (e.g., starting at 0.5 to 1 mg) can be effective in controlling psychotic symptoms and is probably superior to benzodiazepines.60 Care must be taken to avoid oversedation, and patients must be monitored for adverse effects such as postural hypotension, extrapyramidal side effects, and neuroleptic malignant syndrome. If a psychoactive agent fails, it seems prudent to discontinue it rather than continuing it and adding to it. If it is still believed to be required, another agent could be commenced in place of the first. Delirium tremens is a different situation and is best treated with benzodiazepines.92 See Chapter 117 for a withdrawal management protocol. Figure 11–4 provides a guide to the management of patients with delirium.

K E Y

P O I N T S

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Delirium is an extremely important disorder.

●

Delirium may account for as much inpatient morbidity and mortality as all other neurological syndromes combined; however, it is often not recognized.

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Delirium (1) is common in sick people; (2) is frequently undetected; (3) is associated with major adverse outcomes, including death and functional decline, leading to increased health care costs; (4) is potentially preventable in hospitalized patients, through the use of a systems approach; and (5) is most likely the final clinical manifestation of multiple, as yet poorly understood, pathological processes.

●

Clinicians should have a high index of suspicion for delirium when a patient appears to be nonspecifically unwell.

●

There is no specific therapy for delirium.

●

There is scant evidence to guide clinicians in the use of potentially harmful medications for the management of delirium.

●

The greatest advance physicians could make at this stage is to improve systems of care to reduce the incidence of delirium, to increase its recognition, and to optimize its management.

Suggested Reading Darzins P, Molloy D, Strang D: Who can decide? The six step capacity assessment process. Adelaide, Australia: Memory Australia Press, 2000, p 144. Inouye SK: Delirium: A Barometer for Quality of Hospital Care. Hosp Pract (Minneap) 2001; 36(2):15-16, 18. Lindesay J, Rockwood K, Macdonald A: Delirium in Old Age. Oxford, UK: Oxford University Press, 2002, p 238.

chapter 11 delirium Rockwood K, Bhat R: Should We Think Before We Treat Delirium? Intern Med J 2004; 34:76-78. Weber JB, Coverdale JH, Kunik ME: Delirium: Current Trends in Prevention and Treatment. Intern Med J 2004; 34:115-121.

References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 2. Rockwood K: Acute confusion in elderly medical patients. J Am Geriatr Soc 1989; 37:150-154. 3. Sandberg O, Gustafson Y, Brannstrom B, et al: Clinical profile of delirium in older patients. J Am Geriatr Soc 1999; 47:13001306. 4. Cole MG, McCusker J, Dendukuri N, et al: Symptoms of delirium among elderly medical inpatients with or without dementia. J Neuropsychiatry Clin Neurosci 2002; 14:167-175. 5. Fick D, Foreman M: Consequences of not recognizing delirium superimposed on dementia in hospitalized elderly individuals. J Gerontol Nurs 2000; 26:30-40. 6. Inouye SK: The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients. Am J Med 1994; 97:278-288. 7. Roche V: Southwestern Internal Medicine Conference. Etiology and management of delirium. Am J Med Sci 2003; 325:2030. 8. Rockwood K: The occurrence and duration of symptoms in elderly patients with delirium. J Gerontol 1993; 48:M162M166. 9. Caraceni A, Nanni O, Maltoni M, et al: Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care. Cancer 2000; 89:1145-1149. 10. Casarett DJ, Inouye SK: Diagnosis and management of delirium near the end of life. Ann Intern Med 2001; 135:32-40. 11. Elie M, Cole MG, Primeau FJ, et al: Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 1998; 13:204212. 12. Naughton BJ, Moran MB, Kadah H, et al: Delirium and other cognitive impairment in older adults in an emergency department. Ann Emerg Med 1995; 25:751-755. 13. Hustey FM, Meldon SW: The prevalence and documentation of impaired mental status in elderly emergency department patients. Ann Emerg Med 2002; 39:248-253. 14. Rincon HG, Granados M, Unutzer J, et al: Prevalence, detection and treatment of anxiety, depression, and delirium in the adult critical care unit. Psychosomatics 2001; 42:391396. 15. McNicoll L, Pisani MA, Zhang Y, et al: Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003; 51:591-598. 16. Bergeron N, Skrobik Y, Dubois MJ: Delirium in critically ill patients. Crit Care 2002; 6:181-182. 17. Kiely DK, Bergmann MA, Murphy KM, et al: Delirium among newly admitted postacute facility patients: prevalence, symptoms, and severity. J Gerontol A Biol Sci Med Sci 2003; 58:M441-M445. 18. Marcantonio ER, Simon SE, Bergmann MA, et al: Delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery. J Am Geriatr Soc 2003; 51:4-9. 19. Elie M, Rousseau F, Cole M, et al: Prevalence and detection of delirium in elderly emergency department patients. CMAJ 2000; 163:977-981.

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20. Gustafson Y, Brannstrom B, Norberg A, et al: Underdiagnosis and poor documentation of acute confusional states in elderly hip fracture patients. J Am Geriatr Soc 1991; 39:760-765. 21. Inouye SK: The recognition of delirium. Hosp Pract (Off Ed) 1991; 26(4A):61-62. 22. Johnson J: Identifying and recognizing delirium. Dement Geriatr Cogn Disord 1999; 10:353-358. 23. Kakuma R, du Fort GG, Arsenault L, et al: Delirium in older emergency department patients discharged home: effect on survival. J Am Geriatr Soc 2003; 51:443-450. 24. Cameron DJ, Thomas RI, Mulvihill M, et al: Delirium: a test of the Diagnostic and Statistical Manual III criteria on medical inpatients. J Am Geriatr Soc 1987; 35:1007-1010. 25. Milisen K, Foreman MD, Wouters B, et al: Documentation of delirium in elderly patients with hip fracture. J Gerontol Nurs 2002; 28:23-29. 26. Rockwood K, Cosway S, Stolee P, et al: Increasing the recognition of delirium in elderly patients. J Am Geriatr Soc 1994; 42:252-256. 27. Auerswald KB, Charpentier PA, Inouye SK: The informed consent process in older patients who developed delirium: a clinical epidemiologic study. Am J Med 1997; 103:410-418. 28. Meagher DJ, O’Hanlon D, O’Mahony E, et al: Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci 2000; 12:51-56. 29. Camus V, Gonthier R, Dubos G, et al: Etiologic and outcome profiles in hypoactive and hyperactive subtypes of delirium. J Geriatr Psychiatry Neurol 2000; 13:38-42. 30. O’Keeffe ST, Lavan JN: Clinical significance of delirium subtypes in older people. Age Ageing 1999; 28:115-119. 31. Ross CA, Peyser CE, Shapiro I, et al: Delirium: phenomenologic and etiologic subtypes. Int Psychogeriatr 1991; 3:135147. 32. Cole MG: Delirium: effectiveness of systematic interventions. Dement Geriatr Cogn Disord 1999; 10:406-411. 33. Marcantonio E, Ta T, Duthie E, et al: Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair. J Am Geriatr Soc 2002; 50:850-857. 34. Levkoff SE, Evans DA, Liptzin B, et al: Delirium. The occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med 1992; 152:334-340. 35. McCusker J, Cole M, Dendukuri N, et al: The course of delirium in older medical inpatients: a prospective study. J Gen Intern Med 2003; 18:696-704. 36. Rockwood K, Cosway S, Carver D, et al: The risk of dementia and death after delirium. Age Ageing 1999; 28:551-556. 37. Cole MG, Primeau FJ, Elie LM: Delirium: prevention, treatment, and outcome studies. J Geriatr Psychiatry Neurol 1998; 11:126-137. 38. Meagher DJ: Delirium: optimising management. BMJ 2001; 322:144-149. 39. Curyto KJ, Johnson J, TenHave T, et al: Survival of hospitalized elderly patients with delirium: a prospective study. Am J Geriatr Psychiatry 2001; 9:141-147. 40. Jeffs K, Lim W, Berlowitz D, et al: Delirium in a culturally diverse medical inpatient population. Poster 4 presented at the Annual Scientific Meeting—Australian Society for Geriatric Medicine, Fremantle, Western Australia, April 2004. 41. Francis J: Outcomes of delirium: can systems of care make a difference? J Am Geriatr Soc 1997; 45:247-248. 42. Inouye SK, Rushing JT, Foreman MD, et al: Does delirium contribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med 1998; 13:234-242. 43. O’Keeffe S, Lavan J: The prognostic significance of delirium in older hospital patients. J Am Geriatr Soc 1997; 45:174-178. 44. McCusker J, Cole MG, Dendukuri N, et al: Does delirium increase hospital stay? J Am Geriatr Soc 2003; 51:1539-1546.

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45. Pompei P, Foreman M, Rudberg MA, et al: Delirium in hospitalized older persons: outcomes and predictors. J Am Geriatr Soc 1994; 42:809-815. 46. Stevens LE, de Moore GM, Simpson JM: Delirium in hospital: does it increase length of stay? Aust N Z J Psychiatry 1998; 32:805-808. 47. Francis J, Martin D, Kapoor WN: A prospective study of delirium in hospitalized elderly. JAMA 1990; 263:1097-1101. 48. Inouye SK, Viscoli CM, Horwitz RI, et al: A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119:474481. 49. Brauer C, Morrison RS, Silberzweig SB, et al: The cause of delirium in patients with hip fracture. Arch Intern Med 2000; 160:1856-1860. 50. Rudberg MA, Pompei P, Foreman MD, et al: The natural history of delirium in older hospitalized patients: a syndrome of heterogeneity. Age Ageing 1997; 26:169-174. 51. Webster R, Holroyd S: Prevalence of psychotic symptoms in delirium. Psychosomatics 2000; 41:519-522. 52. Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275:852857. 53. McCusker J, Cole M, Abrahamowicz M, et al: Environmental risk factors for delirium in hospitalized older people. J Am Geriatr Soc 2001; 49:1327-1334. 54. Clary G, Ranga Krishnan K: Delirium: diagnosis, neuropathogenesis, and treatment. J Psychiatr Pract 2001; 7:310323. 55. Flacker JM, Lipsitz LA: Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol A Biol Sci Med Sci 1999; 54:B239-B246. 56. Tune L, Carr S, Cooper T, et al: Association of anticholinergic activity of prescribed medications with postoperative delirium. J Neuropsychiatry Clin Neurosci 1993; 5:208-210. 57. Granacher RP, Baldessarini RJ, Messner E: Physostigmine treatment of delirium induced by anticholinergics. Am Fam Physician 1976; 13:99-103. 58. Trzepacz PT, Ho V, Mallavarapu H: Cholinergic delirium and neurotoxicity associated with tacrine for Alzheimer’s dementia. Psychosomatics 1996; 37:299-301. 59. Fischer P: Successful treatment of nonanticholinergic delirium with a cholinesterase inhibitor. J Clin Psychopharmacol 2001; 21:118. 60. Breitbart W, Marotta R, Platt MM, et al: A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153:231-237. 61. Platt MM, Breitbart W, Smith M, et al: Efficacy of neuroleptics for hypoactive delirium. J Neuropsychiatry Clin Neurosci 1994; 6:66-67. 62. Basile AS, Jones EA, Skolnick P: The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991; 43:27-71. 63. Jones EA, Skolnick P, Gammal SH, et al: NIH conference. The gamma-aminobutyric acid A (GABAA) receptor complex and hepatic encephalopathy. Some recent advances. Ann Intern Med 1989; 110:532-546. 64. Olsson T: Activity in the hypothalamic-pituitary-adrenal axis and delirium. Dement Geriatr Cogn Disord 1999; 10:345-349. 65. Hodges J: Cognitive Assessment for Clinicians. Oxford, UK: Oxford University Press, 1999. 66. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198.

67. Rockwood K, Bhat R: Should we think before we treat delirium? Intern Med J 2004; 34:76-78. 68. Armstrong SC, Cozza KL, Watanabe KS: The misdiagnosis of delirium. Psychosomatics 1997; 38:433-439. 69. Farrell KR, Ganzini L: Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med 1995; 155:2459-2464. 70. Nicholas LM, Lindsey BA: Delirium presenting with symptoms of depression. Psychosomatics 1995; 36:471-479. 71. Inouye SK, van Dyck CH, Alessi CA, et al: Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Int Med 1990; 113:941-948. 72. Inouye SK, Foreman MD, Mion LC, et al: Nurses’ recognition of delirium and its symptoms: comparison of nurse and researcher ratings. Arch Intern Med 2001; 161:2467-2473. 73. Britton A, Russell R: Multidisciplinary team interventions for delirium in patients with chronic cognitive impairment. Cochrane Database Syst Rev 2004; (2):CD000395. 74. Cole MG, Primeau F, McCusker J: Effectiveness of interventions to prevent delirium in hospitalized patients: a systematic review. CMAJ 1996; 155:1263-1268. 75. Inouye SK, Bogardus ST Jr, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669-676. 76. Inouye SK, Bogardus ST Jr, Baker DI, et al: The Hospital Elder Life Program: a model of care to prevent cognitive and functional decline in older hospitalized patients. Hospital Elder Life Program. J Am Geriatr Soc 2000; 48:1697-1706. 77. Young LJ, George J: Do guidelines improve the process and outcomes of care in delirium? Age Ageing 2003; 32:525-528. 78. Tabet N, Hudson S, Sweeney V, et al: An educational intervention can prevent delirium on acute medical wards. Age Ageing 2005; 34:152-156. 79. Seibert CP: Recognition, management, and prevention of neuropsychological dysfunction after operation. Int Anesthesiol Clin 1986; 24:39-58. 80. Gustafson Y, Brannstrom B, Berggren D, et al: A geriatricanesthesiologic program to reduce acute confusional states in elderly patients treated for femoral neck fractures. J Am Geriatr Soc 1991; 39:655-662. 81. Flacker JM, Marcantonio ER: Delirium in the elderly. Optimal management. Drugs Aging 1998; 13:119-130. 82. Ebersole J, Pedley T: Current Practice of Clinical Electroencephalography, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2003. 83. Harper C, Sheedy D, Lara A, et al: Prevalence of WernickeKorsakoff syndrome in Australia: has thiamine fortification made a difference? Med J Austr 1998; 168:542-545. 84. Cole MG, McCusker J, Bellavance F, et al: Systematic detection and multidisciplinary care of delirium in older medical inpatients: a randomized trial. CMAJ 2002; 167(7):753-759. 85. Cole MG, Primeau FJ, Bailey RF, et al: Systematic intervention for elderly inpatients with delirium: a randomized trial. CMAJ 1994; 151:965-970. 86. Weber JB, Coverdale JH, Kunik ME: Delirium: current trends in prevention and treatment. Intern Med J 2004; 34:115121. 87. Webster JR, Chew R, Mailliard L, et al: Improving clinical and cost outcomes in delirium: use of practice guidelines and a delirium care team. Ann Long Term Care 1999; 7:128-134. 88. Lundstrom M, Edlund A, Karlsson S, et al: A multifactorial intervention program reduces the duration of delirium, length of hospitalization, and mortality in delirious patients. J Am Geriatr Soc 2005; 53:622-628. 89. Naughton BJ, Saltzman S, Ramadan F, et al: A multifactorial intervention to reduce prevalence of delirium and shorten hospital length of stay. J Am Geriatr Soc 2005; 53:18-23.

chapter 11 delirium 90. Flaherty JH, Tariq SH, Raghavan S, et al: A model for managing delirious older inpatients. J Am Geriatr Soc 2003; 51:1031-1035. 91. American Psychiatric Association: Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156(5, Suppl):1-20. 92. Mayo-Smith MF, Beecher LH, Fischer TL, et al: Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004; 164:1405-1412. 93. Darzins P, Molloy D, Strang D: Who can decide? The six step capacity assessment process. Adelaide, Australia: Memory Australia Press, 2000. 94. Ely EW, Inouye SK, Bernard GR, et al: Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001; 286:2703-2710. 95. Roberts B, Rickard C, Rajbhandari D, et al: Multicentre study of delirium in ICU patients using a simple screening tool. Aust Crit Care 2005; 18:6-14.

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96. Johnson JC, Kerse NM, Gottlieb G, et al: Prospective versus retrospective methods of identifying patients with delirium. J Am Geriatr Soc 1992; 40:316-319. 97. Marcantonio ER, Michaels M, Resnick NM: Diagnosing delirium by telephone. J Gen Intern Med 1998; 13:621-623. 98. Edlund A, Lundstrom M, Brannstrom B, et al: Delirium before and after operation for femoral neck fracture. J Am Geriatr Soc 2001; 49:1335-1340. 99. Zakriya KJ, Christmas C, Wenz JF Sr, et al: Preoperative factors associated with postoperative change in confusion assessment method score in hip fracture patients. Anesth Analg 2002; 94:1628-1632. 100. Shigeta H, Yasui A, Nimura Y, et al: Postoperative delirium and melatonin levels in elderly patients. Am J Surg 2001; 182:449-454. 101. Dai YT, Lou MF, Yip PK, et al: Risk factors and incidence of postoperative delirium in elderly Chinese patients. Gerontology 2000; 46:28-35.

CHAPTER

12

MOTOR SPEECH AND SWALLOWING DISORDERS ●

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Richard A. L. Macdonell and Rhonda Holmes

Motor speech relies on a complex interaction of the resonatory, respiratory, articulatory, and laryngeal neuromuscular systems.1 Coordination of the neuromuscular components of the latter three systems is also essential for the execution of swallowing. Different neurological disorders affecting motor speech production may give it particular features that aid in anatomically localizing the disorders; there is, frequently, also an associated abnormality of the swallow mechanism.2

ANATOMY Corticobulbar Tract Upper motor neuron (UMN) pathways responsible for motor speech and swallowing originate in the motor cortex in each cerebral hemisphere and descend through the genu and posterior limb of the internal capsule, via the cerebral peduncle, to the pons and medulla (and upper cervical cord for the spinal nucleus of cranial nerve XI). At these levels, they synapse with the various lower motor nuclei responsible for supplying the bulbar muscles: cranial nerves V, VII, IX, and X; the cranial portion of cranial nerve XI (which contributes to the motor component of the vagus nerve [cranial nerve X]); and cranial nerve XII. The UMN pathways are known as the corticobulbar tracts, and are generally bilateral (contralateral and ipsilateral). There are, however, important exceptions, such as cranial nerve XII and the lower facial muscles, which receive their upper motor connection predominantly from contralateral corticobulbar fibers (Fig. 12–1). Emotional involuntary movements and voluntary facial movements may at times be clinically dissociated, which suggests that a separate supranuclear pathway for control of involuntary facial movements probably also exists. These fibers do not pass through the internal capsule, and it appears that the right cerebral hemisphere is dominant for expression of facial emotion.3

Lower Cranial Nerves Assessment of the bulbar cranial nerves and their function is extremely important when disorders of motor speech and swallowing are considered. These cranial nerves exit the brainstem at the level of the pons or medulla and leave the cranium

through the skull base, traveling either through the retropharynx or across the angle of the mandible to innervate the muscles of the face, mouth, soft palate, pharynx, and larynx (Fig. 12–2). The trigeminal nerve (V) innervates the muscles of mastication and the tensor veli palatini and communicates sensation from the face, mouth, teeth, mucosal lining, and anterior two thirds of the tongue (via the lingual nerve). The facial nerve (VII) supplies the muscles of facial expression and conveys taste from the anterior two thirds of the tongue (via the chorda tympani and lingual nerve). The glossopharyngeal nerve (IX) conveys taste from the posterior one third of the tongue, as well as sensation from this portion of the tongue, the fauces, the pharynx to about the level of the epiglottis, and the eustachian tube. It also provides the motor supply to the stylopharyngeus and, in part, to the superior and middle pharyngeal constrictor muscles through a contribution to the pharyngeal plexus. The vagus nerve (X) conveys sensation from the tympanic membrane, pharynx, larynx, and esophagus. One of its branches, the recurrent laryngeal nerve, innervates all the intrinsic muscles of the larynx other than the cricothyroideus, whereas the superior laryngeal nerve innervates the cricothyroideus and conveys sensation from the larynx and the base of the tongue. The vagus also contributes to the innervation of the pharyngeal constrictors through the pharyngeal plexus. The hypoglossal nerve (XII) innervates the muscles of the tongue, with the exception of the palatoglossus, which is supplied by the vagus nerve.4

Bulbar and Pseudobulbar Palsies UMN lesions affecting the corticobulbar tracts can be distinguished from disorders of the lower cranial nerves or their nuclei by the distinctive changes to speech that are associated with damage to these tracts, described in the next sections. The features of such corticobulbar tract lesions are collectively known as pseudobulbar palsy, a term used to distinguish them from the true bulbar palsy, which results from pathology affecting the lower cranial nerves or their nuclei. There may, in addition to speech, be other distinguishing features on examination, typical of all UMN disorders, such as increased muscle tone (as evidenced by slow side-to-side movement of the tongue) and exaggerated reflexes (gag or jaw reflex), without signs of muscle wasting, atrophy, or fasciculations. A patient

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C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s Motor cortex Internal capsule

Corticobulbar tract

Cranial nerve (motor) nuclei III

Midbrain

IV

Medial lemniscus Corticospinal tract Midbrain-pons

Corticobulbar tract

V

Pons-medulla

VI VII

Pyramid

Medial lemniscus Medulla

X Solitary (IX) XII Ambiguus (IX) Medulla

Pyramid

XI Medulla ■

pathway have been classified as aphasia, apraxia of speech (AOS), and dysarthria, each of which may then be subclassified further, depending on the nature of the dysfunction and its cause. Dysarthria and AOS are termed disorders of motor speech because they exist at the output level of the motor system and disrupt only sound output, sparing semantics and syntax. The patient has a full knowledge of words they are finding difficult to articulate. This serves to distinguish these disorders from aphasia, which is defined as “a disorder of linguistic processing characterized by a disturbance in the comprehension and formulation of language caused by dysfunction in specific brain regions.”5,6 Aphasia is discussed in detail in Chapter 3 and is not considered further here.

Figure 12–1. Corticobulbar tract. The fiber bundle originates primarily from the motor and premotor cortices and descends in the basilar region of the brainstem to supply cranial nerves V to XI bilaterally and, mainly contralaterally, nerve XII and a portion of nerve VII. (Adapted from Curtis BA, Jacobson S, Marcus EM, eds: An Introduction to Neurosciences. Philadelphia: WB Saunders, 1972.)

with bulbar palsy, in contrast, has the hallmarks of a lower motor neuron (LMN) disorder: namely, muscle weakness, wasting, and fasciculations.

DISORDERS OF MOTOR SPEECH Verbal communication involves a sequence of processes culminating in the motor execution of a cortically determined set of instructions to produce speech. Disorders of this complex

Apraxia of Speech Abnormalities of speech after neurological insult were subdivided into aphasias and dysarthrias before the contribution of Darley, who with colleagues delivered an unpublished paper on the topic in 1969.7 In this lecture, Darley was the first to use the term apraxia of speech and to attribute a specific disorder of speech—interposed between aphasia and dysarthria—to impaired motor programming,8,9 The term apraxia had long been used in other contexts to describe the inability to carry out a motor command despite normal comprehension and the normal ability to carry out the motor act in another context, such as by imitation or with use of a real object.10 This three-level model of sound-level speech production disorders survived without challenge until the late 1990s. In 1997, van der Merwe10 proposed a four-stage model in which there was an explicit division between “speech motor planning” and “speech motor programming.” Previously, these terms had been used interchangeably. In this model, speech motor planning involves two stages (linguistic-symbolic planning and motor planning) and refers to the planning of the temporal and spatial goals of the articulators. This is followed by a third stage, speech motor programming, which refers to the selection and sequencing of motor programs for the movements of the individual muscles of these articulators (including the vocal cords). The final stage is the execution stage, which refers to the actual realization of speech on an articulatory level. This model makes a clear assignment of AOS to the motor level of impairment as a disorder of speech motor programming.6 Aphasias are disorders of the stages of linguistic-symbolic and motor planning in this system, and dysarthrias are disorders of the execution stage. AOS is a syndrome in which a sequence of single sounds (phonemes), especially consonant sounds, are disrupted and inconsistently misarticulated, in contrast to the consistently abnormal articulation of dysarthria. A further identifying feature of AOS is that comprehension and automatic or reactive speech are normal, but volitional or purposive speech contains substitutions, additions, prolongations, and reversal of phonemes.9 The sufferer repeats incorrect initial phonemes, words, or phrases, which results in a labored, perseverative speech pattern. This may superficially resemble stuttering, but the effortful blocking on a correct initial phoneme typical of stuttering is not seen. AOS, according to this definition, is commonly encountered during attempted speech production in the aphasias, and the sites of lesions that produce a nonfluent

chapter 12 motor speech and swallowing disorders ■

Tensor veli palatini muscle

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Figure 12–2. Anatomy of the lower cranial nerves and muscles involved in motor speech and swallowing.

Mandibular nerve Lateral pterygoid plate Middle meningeal artery Pterygomaxillary fissure

Levator veli palatini muscle Superior constrictor muscle

Maxillary artery

Styloglossus muscle Stylopharyngeus muscle Glossopharngeal nerve Hypoglossal nerve

Buccinator muscle Lingual nerve

Digastric tendon Internal laryngeal nerve

Hyoglossus muscle Mylohyoid muscle

Vagus nerve Stylohyoid muscle Thyroid membrane Thyroid lamina Inferior constrictor muscle

External laryngeal nerve Cricothyroid muscle

Esophagus

Recurrent laryngeal nerve Trachea

aphasia and AOS may overlap.6 One literature review suggests that cortical-subcortical lesions in the lower part of the left precentral gyrus in most right-handed persons, and a lesion of the corresponding region in the right hemisphere in some left-handed individuals, are the most likely to produce AOS.11 A lesion in Broca’s area may cause a combined syndrome of AOS, orobuccal dyspraxia, and nonfluent aphasia. This symptom complex is frequently referred to as Broca’s aphasia. Patients with AOS frequently have a co-occurring limb dyspraxia and/or orobuccal dyspraxia, which makes it difficult for them to execute simple motor commands accurately, although strength and sensation are intact. In response to requests to point to their own body parts, affected patients provide a head nod; in response to requests to perform specific facial movements such as blowing out a match, licking a stamp, or blowing a kiss, patients may perform groping movements or an approximation of the requested movements. Such responses may mistakenly be interpreted as a comprehension deficit. Patients frequently find it easier to perform these tasks when asked to imitate the examiner. In contrast, a patient with dysarthria always demonstrates the same level of difficulty when using orobuccal muscles, regardless of whether the task is mime or imitation, and during volitional movement and the semivolitional response to emotion.

Dysarthria Dysarthria is defined as a group of speech disorders resulting from disturbance in the control of speech mechanisms that, in turn, results from damage to the central or peripheral nervous systems, including muscles and neuromuscular junctions.12 There is consistently abnormal articulation of phonemes during both automatic and volitional speech. It is caused by the impaired functioning of one or several of the components of the motor speech subsystems (respiration, phonation, resonation, and articulation). Dysphonia is a subset of dysarthria, and the term refers specifically to a disruption of phonation, resulting in an abnormal voice sound without disturbance of articulation. The definition encompasses all disorders of voice sound, both organic and psychogenic. Speech is produced by co-coordinated contraction of the muscles of the larynx, pharynx, and tongue, linked to the expiration phase of respiration. At a cortical level, articulation requires the coordinated bilateral movements of the muscles concerned, which is effected by fibers passing from the inferior region of the left lateral frontal lobe to the corresponding region of the right hemisphere via the corpus callosum.13 The motor speech system relies on the normal function of the various elements of the nervous system involved in the control of motor speech: namely, UMNs and LMNs; the

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coordinating and regulating influence of extrapyramidal, cerebellar, and sensory pathways; and the final output through neuromuscular junctions and muscles.14 Disorders affecting each part of this extensive control, effector, and feedback network have distinct effects on speech, which can be identified through the clinical examination. The nature of the change in speech therefore has localizing significance, which can be used to classify the motor speech disorder as AOS or a particular type of dysarthria.

Upper Motor Neuron Lesions In view of the bilateral nature of the majority of the UMN input to the cranial nerves responsible for speech, unilateral UMN lesions produce a relatively mild dysarthria that reflects primarily weakness and some loss of skilled movement. Bilateral UMN lesions have a much more severe effect that reflects both bilateral weakness and loss of skilled movement, as well as an increase in muscle tone (spasticity).15 The dysarthria accompanying such pathology is known as spastic dysarthria and is one of the features of pseudobulbar palsy. The speech changes characteristic of this condition include slow rate of speech, imprecise consonants, distorted vowels, hypernasality, monotone pitch, short phrases, and a strained-strangled quality to the voice. A number of neurological conditions can affect these pathways and cause a spastic dysarthria (Table 12–1).

Lower Motor Neuron Lesions LMN lesions affecting the cranial nerves involved in speech production, their neuromuscular junctions, or the muscles that the LMNs innervate cause weakness without change in muscle tone. A unilateral LMN lesion has more severe effects than does a unilateral UMN lesion. The dysarthria resulting from unilateral or bilateral LMN palsies is called a flaccid dysarthria and is one of the components of bulbar palsy. Which exact speech disorder accompanies a LMN lesion depends on the nerve or nerves involved. A brainstem stroke, for example, may affect several cranial nerves, whereas a mediastinal mass may affect only the left recurrent laryngeal nerve. Patients are usually able to compensate if damage is unilateral, whereas a bilateral lesion usually results in a severe impairment. The principal causes of flaccid dysarthria are listed in Table 12–1. The output of the direct pathway (UMN and LMN) is controlled by feedback loops involving auditory and somatosensory pathways and extrapyramidal and cerebellar systems. Disorders of each pathway may have a specific effect on speech. Reduced auditory acuity caused by sensorineural deafness, for example, usually causes an increase in vocal loudness, in order to provide feedback to enable the subject to monitor the output.

Cerebellar Disorders Disorders involving cerebellar pathways cause loss of the normal coordination and timing of speech output. This can lead to random breaks between words and syllables, vowel distortions, prolongations of sounds, and the use of equal stress on each syllable, thereby creating a “rambling” or “scanning” quality to the speech (ataxic dysarthria) (see Table 12–1). The

T A B L E 12–1. Examples of Neurological Conditions Causing Dysarthria or Neurogenic Dysphagia Reduced Awareness* Dementias, including Alzheimer’s disease Delirium Cerebral neoplasms and other mass lesions (e.g., subdural, abscess) Upper Motor Neuron–Pseudobulbar Palsy (Spastic Dysarthria) Stroke Cortical: uncommon cause of dysphagia, usually bilateral lesions Subcortical and midbrain: usually bilateral lesions, more common cause than cortical stroke Multiple sclerosis Motor neuron disease: amyotrophic lateral sclerosis (ALS) Traumatic brain injury (increases in severity and likelihood with increasing grade of injury) Central pontine myelinolysis Hypoxic encephalopathy Cerebral palsy Extrapyramidal Disorders (Hyperkinetic or Hypokinetic Dysarthria) Parkinson’s disease Progressive supranuclear palsy Huntington’s disease Multiple system atrophy (MSA) Wilson’s disease Torticollis Cerebellar Disorders (Ataxic Dysarthria) Inherited: e.g., spinocerebellar ataxias, Friedrich’s ataxia, vitamin E deficiency Acquired: e.g., stroke, neoplasm, paraneoplastic syndromes (anti-Yo, anti-Ma, anti-Hu antibodies), toxicity (alcohol), multiple sclerosis, hypothyroidism, vasculitis (systemic lupus erythematosus), MSA Lower Motor Neuron–Bulbar Palsy (Flaccid Dysarthria) Motor neuron diseases Inherited: bulbospinal muscular atrophy (Kennedy’s syndrome), FALS Acquired: ALS, progressive muscular atrophy/progressive bulbar palsy Stroke: infarct or hemorrhage in pons or medulla Multiple sclerosis Mass lesions Neoplasm: intra-axial: brainstem (glioma); extra-axial (meningioma); nasopharynx (nasopharyngeal carcinoma, metastasis) Brainstem abscess (e.g., caused by Listeria) After radiotherapy to head and neck Paraneoplastic syndromes (anti-Ma antibodies) Infectious disorders: diphtheria, polio Neuropathy Inherited: dHMN-VII, HMSN-IIC (vocal cord paralysis) Acquired: Guillain-Barré syndrome, diabetes Syringobulbia Neuromuscular Junction Myasthenia gravis, botulism, Lambert-Eaton myasthenic syndrome Muscle Inherited: oculopharyngeal dystrophy, myotonic dystrophy Acquired: inflammatory myopathies (polymyositis, dermatomyositis, inclusion body myositis), hypothyroidism, critical care neuromyopathy Traumatic Includes iatrogenic injury: trauma to cranial nerve XII during carotid endarterectomy, oral/pharyngeal dysphagia after tracheostomy or after intubation Psychogenic Psychogenic aphonia, psychogenic spasmodic dysphonia, psychogenic dysphagia *These are uncommon causes of dysarthria; they more commonly cause dysphagia. dHMN-VII, distal hereditary motor neuropathy type VII; FALS, familial amyotrophic lateral sclerosis ; HMSN-IIC, hereditary motor sensory neuropathy type IIC.

chapter 12 motor speech and swallowing disorders dysarthria accompanying focal cerebellar lesions tends to occur particularly with lesions of the vermal and (usually) left dorsal intermediate zone of the cerebellum, whereas it is typically not seen with lateral neocerebellar lesions.13

Extrapyramidal Disorders Extrapyramidal disorders, such as Parkinson’s disease or Huntington’s disease, result in hyperkinetic or hypokinetic dysarthria. The most common dysarthria accompanying Parkinson’s disease is a hypokinetic dysarthria, characterized by rapid speech rate (festination), slurring of words and syllables, and trailing off at the end of sentences. The voice is soft and monotonous, without the usual inflections. The speech disorder accompanying Huntington’s disease is hyperkinetic dysarthria, which results in an uncontrolled loud, harsh voice, poorly coordinated with breathing. Chorea and myoclonus may cause abrupt interruption between or within words by the superimposition of abnormal respiratory, phonatory, or articulatory movements.15

Mixed Dysarthrias In some situations, more than one type of dysarthria may be present, giving rise to a mixed dysarthria. An example is motor neuron disease, in which there may be a pseudobulbar palsy resulting from involvement of UMN pathways and a true bulbar palsy resulting from loss of anterior horn cells from the cranial nerve nuclei of the brainstem. The resultant speech exhibits features of a mixed spastic and flaccid dysarthria. Similarly, a patient with multiple sclerosis may exhibit a mixed spastic and ataxic dysarthria as a result of combined UMN and cerebellar damage by the disease process.

Dysphonia A circumscribed lesion affecting the vagus nerve or one of its branches, which supply the muscles of the larynx, may cause dysphonia in isolation. In the case of unilateral damage, the voice is usually breathy and soft. The voice may become harsh as the patient attempts to compensate for the soft voice and strains to increase vocal loudness. In some instances, a patient may produce two distinct vocal pitches (diplophonia) as a result of the differing masses and vibratory capacities of the two vocal folds. If the vagus lesion is high, there may also be a nasal quality resulting from the associated weakness of the soft palate and inability to prevent air from escaping through the nose during phonation. If the damage is bilateral, the vocal folds may be either abducted or adducted. If the vocal folds are adducted, the patient may present with inspiratory stridor, inasmuch as the vocal cords normally abduct during inspiration. Dysphonia may also be produced by conditions that cause weakness of the respiratory muscles—such as Guillain-Barré syndrome or a high cervical spinal cord lesion—because insufficient airflow is produced for phonation.15 Abnormalities of phonation become more apparent the longer the subject speaks, and asking the patient to read aloud from a magazine is a good means of bringing out these features.

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Spasmodic Dysphonia Spasmodic dysphonia appears to result from a dystonia restricted to the phonatory apparatus, but it can occasionally co-occur with other dystonias, such as writer’s cramp and blepharospasm. More sufferers are women, and speaking gradually becomes more of an effort. Usually, attempts to speak result in co-contraction (adduction) of the vocal folds, causing a strained, strangled-sounding voice. In rare cases, the problem may be a breathy, soft voice; in these patients, the dystonia causes abduction of the vocal cords. In either instance, other activities involving use of the same muscles, such as swallowing and singing, are usually unimpeded.15

Nonorganic Disorders of Voice Voice disorders may have a psychological basis, rather than being the result of pathology affecting neural pathways or muscular control. The most common psychogenic speech disorders affect voice, fluency, or prosody. Prosody is the term used to describe all the variations in time, pitch, and loudness that accomplish emphasis, lend interest to speech, and characterize individual and dialectical modes of expression.16 Psychogenic speech disorders are not unusual and can account for up to 5% of acquired communication disorders.15 The most common is aphonia (hoarseness), but psychogenic spasmodic dysphonia, particularly adductor spasm, is also encountered.

Psychogenic Aphonia Aphonia is a common conversion symptom. Patients with conversion aphonia involuntarily whisper. The sharpness of the whisper, which often appears strained, contrasts with the weak, breathy whisper of a patient with vocal fold paralysis. The cough is usually normal, illustrating the retained ability to produce normal vocal fold adduction, and there is no inspiratory stridor, inasmuch as the involuntary ability to abduct the vocal folds during inspiration is unimpaired.

Psychogenic Spasmodic Dysphonia Establishing the diagnosis of this condition is very difficult in some cases, and distinction from an organic disorder such as a focal dystonia (see previous discussion) can be challenging. Symptom reversibility in some patients may be the only way to confirm the diagnosis. The adductor form is the most common and is characterized by a continuous or intermittent strained, jerky, grunting, squeezed, groaning, and effortful quality to the voice.15 The nature of the voice disorder is very similar to that in neurogenic spasmodic (adductor) dysphonia, although underlying voice tremor or evidence of laryngeal dystonia (e.g., adduction of the vocal cords during inspiration seen during laryngoscopy) (Fig. 12–3) is not ordinarily encountered in psychogenic etiologies unless a combination of causes is present.

CLINICAL ASSESSMENT OF SPEECH Clinical examination of speech requires the assessment of three aspects of speech production:15

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Base of tongue

Epiglottis

Vestibular folds (false vocal cords) Trachea

Vocal folds (true vocal cords)

Arytenoid cartilage Cuneiform cartilage

Corniculate cartilage

A

■

B

Figure 12–3. A, Illustration of vocal cords viewed from above, showing their relationship to the paired cartilages of the larynx and epiglottis. B, Endoscopic view of the vocal cords. (From Seeley RR, Stephens TD, Tate P: Anatomy and Physiology. St. Louis: Mosby–Year Book, 1992.)

1. Samples of contextual speech (e.g., reading a standard paragraph aloud) and of spontaneous speech. The latter is best assessed during the documentation of the history, when the patient’s speech is at its most natural. 2. Vowel prolongation (sustained “aah. . . .”). 3. Alternate motion of the lips, tongue, and jaw, tested by having the patient repeat “puh” (labial), “tuh” (anterior lingual) and “kuh” (posterior lingual) rapidly and evenly: “puh-tuh-kuh-puh-tuh-kuh . . .” A full neurological examination must be completed in any patient with dysarthria or dysphonia, with particular attention to the function of cranial nerves V to XII. During the acute stage of a unilateral UMN lesion, the tongue may deviate toward the weak side (i.e., toward the side opposite the lesion) on protrusion, and the palate moves toward the lesion side on elevation. There may also be facial weakness contralateral to the lesion side, affecting the muscles of the lower face. A pseudobulbar palsy is typically accompanied by an exaggerated jaw jerk, a brisk gag response, and slow, stiff, repetitive tongue movements. In addition to the cranial nerve examination, there may be other confirmatory findings in the limbs indicating unilateral or bilateral UMN pathology, such as increased tone, increased reflexes, and extensor plantar responses. A flaccid dysarthria is usually accompanied by other signs of bulbar weakness, such as a wasted appearance of or fasciculations in the tongue, unilateral or bilateral palatal weakness (tested by asking the patient to say “ah”), and a reduced or absent gag reflex. The acute phase of an UMN lesion such as stroke may also impair or abolish the gag reflex before the onset of spasticity but does not produce other LMN features such as muscle wasting or fasciculation. There may be other features of anterior horn cell loss on examination, such as muscle wasting, weakness, and fasciculations in the limbs, which point to a diagnosis of motor neuron disease. Myasthenia gravis may also manifest with symptoms of a flaccid dysarthria. The dysarthria accompanying this disease

typically becomes more severe the longer the patient talks, and speech recovers after rest. There should be no UMN signs and no signs of muscle wasting or fasciculation. There may be evidence of fatigability in other muscle groups, such as ptosis that increases with prolonged upward gaze, ocular movement weakness, or declining proximal limb girdle strength during sustained exercise. An ataxic dysarthria is usually accompanied by other signs of cerebellar dysfunction (see Chapter 7), particularly a widebased gait and, often, incoordination of the limbs and abnormalities in eye movement. Patients with Parkinson’s disease and a hypokinetic dysarthria ordinarily have other features of the disease, such as masklike, expressionless facies, bradykinesia, rigidity, and tremor, whereas a patient with a hyperkinetic dysarthria may exhibit other features of a movement disorder, such as choreiform movements or myoclonic jerks. The nature of the dysarthria and the findings on examination should indicate which further investigations, such as magnetic resonance imaging, nerve conduction study/ electromyography, repetitive stimulation studies, or blood tests, are likely to lead to the correct diagnosis. An assessment by a speech pathologist is often helpful in clarifying the type and nature of the dysarthria, when this is unclear, and in arranging speech rehabilitation. This assessment may involve formal instrumental speech analysis and fiberoptic stroboscopic laryngoscopy, which are available in some centers.

MANAGEMENT OF MOTOR SPEECH DISORDERS Treatment options for the dysarthric patient depend on the etiology of the speech defect. Recovery of function may be a realistic goal for a patient with a mild dysarthria as a result of a stroke, but is not a possibility for a patient with a progressive neurological disease such as motor neuron disease.15 In this case, compensation of function is more appropriate. Compensation may involve speech strategies such as overarticulation, alternative communication devices, management of the environment, or prosthetic devices.

chapter 12 motor speech and swallowing disorders Management approaches can be separated into three broad areas: medical, prosthetic, and behavioral.15 Because of the heterogeneous nature of the dysarthric population, a single approach is very rarely adequate; often, all three approaches are used in conjunction.

Medical Management Pharmacological The first consideration in the management of any motor speech disorder is to ensure that any underlying neurological problem receives appropriate pharmacological treatment. This can have a dramatic positive effect on speech: For example, acetylcholinesterase antagonists for the treatment of myasthenia gravis can improve or restore speech,17 and botulinum toxin has been shown to reduce vocal fold spasm in cases of spasmodic dysphonia.18 There are inconsistent reports of the effects of dopaminergic agents on speech intelligibility in Parkinson’s disease: Some investigators have reported a trend for improvement of speech,19 whereas others have reported no difference.20,21 Some drugs—for example, benzodiazepines and anticonvulsants—may have a negative effect on speech, and this may result in a worsening of the dysarthria.17

Surgical Surgery may be the treatment of choice for patients who have severe hypernasality as the result of velopharyngeal incompetence.22 Pharyngoplasties and construction of pharyngeal flaps can be performed by otolaryngologists to rectify such speech defects. Patients with unilateral vocal fold paralysis may be referred for medialization procedures such as thyroplasty23,24 or vocal fold augmentation techniques.25,26

Prosthetic Management Numerous available appliances can improve the communication of dysarthric speakers. Palatal lifts may be used for hypernasal patients who have a hyporeflexive gag.27 Voice amplifiers allow patients with reduced modal loudness to increase their speech volume. Other devices, such as pacing boards and delayed auditory feedback, are used during behavioral therapy to slow speech production rate.19 Patients who are severely dysarthric or anarthric may need to use augmentative or alternative communication devices.28 These range from simple devices such as picture or alphabet boards to more advanced devices such as computers with voice synthesizers. Assessment and decision making about the appropriateness of prosthetic devices is the realm of the speech pathologist.

Behavioral Management When providing behavioral treatment, the speech pathologist analyzes the severity of the patient’s dysarthria and identifies the cluster of deviant speech symptoms. In the case of a mildto-moderate dysarthria, patients usually receive direct therapy aimed at recovering as much speech function as possible; the goal is to improve intelligibility while maintaining speech naturalness.15,29 Direct therapy approaches that are supported

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by the literature include use of various biofeedback devices aimed at improving respiratory support30 and improving respiratory/phonatory coordination and control.31,32 Effortful closure techniques to increase adduction of vocal folds in cases of hypoadduction33,34 and tension-reducing strategies to reduce hyperadduction are also supported.35 A large body of research has demonstrated the efficacy of an intensive treatment program, which focuses on increased vocal loudness, in mild to moderate cases of Parkinson’s disease.27 Various studies have shown benefits of rate-control techniques, such as pacing and delayed auditory feedback, to slow speech rate.36-39 In cases of severe dysarthria, indirect therapy may be used; this is aimed at optimizing the communication environment, and training caretakers to repair communication breakdowns.40 Behavioral management is the foundation of treatment for AOS. Unlike treatment for dysarthria, in which the aim is to improve physiological support for speech that is appropriately planned and programmed, the treatment of AOS focuses on reorganizing the disturbed programs for speech movements, which are then able to be implemented by an intact neuromuscular speech system. Most treatment goals for AOS are aimed at improving articulation and prosody through the use of imitation and cuing in a progressive hierarchy of intensive drills.15

NEUROGENIC DYSPHAGIA Neuromuscular Control of Swallowing Normal swallowing is a complex sensorimotor behavior involving the coordinated contraction and inhibition of the muscles around the mouth and the tongue, larynx, pharynx, and esophagus bilaterally (Fig. 12–4).41 The act of swallowing has been subdivided into three phases: oral, pharyngeal, and esophageal, after Magendie’s classic description (Fig. 12–5).42 The initial (oral) phase is voluntary, whereas the latter two phases are semiautonomous reflex responses. The motor events of swallowing, however, are best described as occurring in two stages: the first (“oropharyngeal”) stage, which incorporates the first two phases of swallowing, and the subsequent (“esophageal”) stage or phase.43,44

Oral Phase of Swallowing The act of swallowing commences before food or fluid is actually placed in the mouth. The anticipation, smell, or presence of food stimulates saliva production in the mouth, which is necessary to commence the digestive processes and lubricate the bolus of food for the swallow. Once the bolus enters the mouth, the duration of the oral phase is highly variable, depending on the taste, texture, and consistency of the food and on the hunger, motivation, and consciousness of the subject.43 The motor events accompanying this phase involve lip closure, tension within the buccinator muscles, downward movement of the soft palate (allowing breathing during mastication), and actual chewing of the food. The final step generally takes place with the positioning of the adequately chewed and mixed bolus of manageable size, usually on the mid-dorsum of the tongue. The tongue subsequently sweeps the bolus posteriorly, forming a rolling wave of contact stripping against the hard palate, pushing the bolus toward the posterior tongue surface and into

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Tubal eminence Jugular bulb Sigmoid sinus Inferior alveolar nerve Lingual nerve Tensor palati Digastric muscle Medial pterygoid muscle Palatopharyngeus muscle Stylohyoid muscle Mylohyoid nerve and muscle Internal laryngeal nerve Thyrohyoid muscle Thyroid gland Parathyroid gland

Dorsum sellae Basilar sinus Mastoid air cells Salpingopharyngeal muscle Superior construictor muscle Glossopharyngeal nerve Hypoglossal nerve Greater cornu of hyoid Inferior constrictor muscle Cricopharyngeus muscle

Recurrent laryngeal nerve Longitudinal muscle Esophagus Circular muscle

A

Pharyngeal palate

Orifice of eustachian tube

Oral palate

Salpingopharyngeal fold

Uvula Superior constrictor muscle Genioglossus muscle

Middle constrictor muscle Epiglottis

Geniohyoid muscle Hyoid bone Ventricular fold (false cord) Laryngeal ventricle Vocal fold (true cord)

Laryngeal aditus Thyropharyngeus muscle Interarytenoid muscle Cricoid cartilage

Thyroid cartilage Trachea

Esophagus

Thyroid gland

B ■

Figure 12–4. The nasopharynx opened to view the soft palate from behind (A) and in midline section (B). (A from Last RJ: Anatomy: Regional and Applied, 7th ed. Edinburgh: Churchill Livingstone, 1984. B from Groher ME: Dysphagia: Diagnosis and Management, 2nd ed. Boston: ButterworthHeinemann, 1992.)

chapter 12 motor speech and swallowing disorders ■

Superior constrictor muscle

Epiglottis Middle constrictor muscle Inferior constrictor muscle Pharyngoesophageal constrictor Esophagus

A

B

C

D

E

F

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Figure 12–5. The three phases of swallowing. A, Oral phase: A bolus of food (yellow) is pushed against the hard palate and posteriorly toward the oropharynx by a stripping action of the tongue against the palate. (Black arrows indicate movement of the bolus). B to E, Pharyngeal phase: The soft palate is elevated, closing off the nasopharynx, and the pharynx is elevated by the palatopharyngeal and salpingopharyngeal muscles. Successive contractions of the pharyngeal constrictors (C and D) force the bolus through the pharynx and into the esophagus. As this occurs, the epiglottis is bent down over the opening of the larynx, largely by the force of the bolus pressing against it. (Red arrows indicate muscle movement). E, The tonically active pharyngoesophageal constrictor relaxes (outward direction red arrows), allowing the bolus to enter the esophagus. F, During the esophageal phase, the bolus is moved by successive contractions of the esophagus toward the stomach. (From Seeley RR, Stephens TD, Tate P: Anatomy and Physiology. St. Louis: Mosby–Year Book, 1992.)

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the oropharynx.1 The oral phase may be disrupted by disorders of the motor nerves responsible for muscle function in this area (cranial nerves V, VII, IX, X, and XII) or by disorders of their central control, impairing coordinated mastication and posterior bolus movement (e.g., Huntington’s disease.)

it is actively closed in the resting state. It is opened by a complex series of actions, including laryngeal elevation.39 There is no voluntary control of the lower esophageal sphincter.

Assessment of Patients with Dysphagia Pharyngeal Phase of Swallowing The oral and pharyngeal phases are highly interrelated, and the distinction between them is often unclear. All of the events, from the initiation of the swallowing reflex until the esophageal phase, are probably under the control of a central pattern generator in the brainstem.44,45 As the bolus enters the pharynx, it triggers the swallow reflex. The nature of the triggering is not known.43 It is assumed that the afferent pathway is conveyed through the trigeminal, glossopharyngeal, and vagus nerves from sensory fibers innervating the pharynx. These fibers converge in the brainstem in the tractus solitarius and synapse in the nucleus tractus solitarius. Cortical descending inputs reach similar areas of the nucleus tractus solitarius. There is also sensory input to cortical regions involved in initiating swallowing.46,47 The initiation or triggering of swallowing is probably more complex than a simple brainstem reflex and may depend on structures above the brainstem. The swallow reflex consists of several movements (see Fig. 12–5):48 1. Elevation and retraction of the velum and complete closure of the velopharyngeal port to prevent material from entering the nasal cavity. 2. Elevation and anterior movement of the hyoid and larynx. 3. Closure of the larynx at the level of the true vocal folds, false vocal folds, and aryepiglottic folds, and by the epiglottis, to prevent food from entering the airway. 4. Opening of the cricopharyngeal sphincter to allow material to pass from the pharynx to the esophagus. The normally tonically active cricopharyngeus muscle relaxes and opens as the larynx moves anterosuperiorly. 5. Ramping of the base of the tongue to deliver the bolus to the pharynx, followed by tongue base contraction to contact the anteriorly bulging posterior pharyngeal wall. 6. Progressive top-to-bottom contraction of the pharyngeal constrictors. These oral and pharyngeal movements rely on the coordinated bilateral contraction and relaxation of muscles innervated by the lower cranial nerves.

Clinicians should be alert to the clinical signs of swallowing disorders (dysphagia), which may suggest that oral feeding is not safe. Eating is a demanding cognitive process requiring planning and judgment, intact bulbar musculature, and neural control systems.49 Patients presenting with confusion after any cause of neurological impairment may not be mentally able to eat safely. All patients presenting with dysarthria should also be suspected of having dysphagia, because of shared neuroanatomical pathways. However, dysphagia may also occur independently of dysarthria. Dysphagia is potentially lifethreatening and must be evaluated promptly. During history taking, patients may complain of difficulties during the act of swallowing, such as food sticking in the back of the throat, regurgitation, or dribbling. Others may not report dysphagia at all and present with complications such as recurrent chest infections caused by “silent” aspiration. Other manifestations that may warrant a dysphagia examination include wetsounding voice, coughing on saliva or food, pain on swallowing (odynophagia), slowed eating rate, unexplained weight loss, and difficulty chewing. Neurogenic dysphagia may result from UMN or LMN disorders, including those affecting neuromuscular junctions or muscle (see Table 12–1).

Medical History A standard medical history should include details regarding any history of pneumonia, reflux, or swallowing problems. The patient should be asked about complaints, including duration and frequency of the swallowing difficulty; associated symptoms such as pain, choking, coughing during meals; nasal regurgitation; weight loss; and the length of time taken to eat meals. Although patients often reliably report the presence of a problem affecting deglutition (oral-pharyngeal transfer), their reports of the level at which a bolus is arrested after entering the pharynx are notoriously inaccurate; pharyngeal and upper and lower esophageal difficulties are often perceived as a problem “in the throat.” A list of current medications should be analyzed for use and possible side effects. Drugs that have anticholinergic side effects, such as tricyclic antidepressants, reduce saliva production and thereby reduce the ability to lubricate the bolus in preparation for swallowing.

Esophageal Phase of Swallowing The esophageal phase starts from the time the bolus enters the esophagus at the upper esophageal sphincter until it passes through the lower esophageal sphincter and enters the stomach. This transit time ranges between 8 and 20 seconds. A peristaltic wave begins at the top of the esophagus and pushes the bolus ahead of it as it travels toward the stomach. The upper esophageal sphincter is formed by the cricopharyngeus muscle and the cricoid cartilage and, as such, can be affected by disorders of voluntary skeletal muscle, whereas the lower esophageal sphincter is formed by smooth muscle. Opening of the upper esophageal sphincter is partially under voluntary control, and

Oral Peripheral Examination Impaired dentition and any dryness or inflammation of the oral mucosa should be particularly noted. The cranial nerve examination should include the assessment of taste. Sweet, sour, salty, bitter, and, possibly, umami (the taste of the glutamate moiety in monosodium L-glutamate, a compound that occurs naturally in protein-rich and other foods50) constitute the basic taste qualities; all others are flavors, their appreciation depending on an intact sense of smell. Taste is tested on the anterior two thirds of the tongue (enervated by the facial nerve) with sugar, salt, vinegar, quinine, and, if required, monosodium L-

chapter 12 motor speech and swallowing disorders glutamate, in that order. The patient sticks out the tongue to one side, keeps it out through the test, and does not talk. The four or five possible tastes are written on a card. The tip of the tongue is held gently with a piece of gauze, and the side of the tongue is moistened about one inch from the tip with a little of the test substance. The patient indicates the taste by pointing to the appropriate line on the card. Between tests, the patient rinses out the mouth with water. Alternatively, an electrical device (Rion Electrogustometer, Sensonics, Inc.) can be used, but this is expensive and a little cumbersome for easy bedside use. Testing taste on the posterior one third of the tongue (glossopharyngeal nerve) is so difficult by conventional means that it is hardly worth attempting. An electrogustometer is needed to acquire the information. Olfaction should also be tested by a smell identification test, such as those produced by Sensonics, Inc. (see Chapter 13). Hyposmia or anosmia may impede swallowing by impairing anticipatory salivation.

Oral Trials Patients with oral and pharyngeal dysphagia as a result of bulbar impairment are generally referred for speech pathology assessment. Speech pathologists provide oral trials, usually starting with the consistency that would be easiest for the patient to manage. In a neurologically impaired patient, the safest consistency is generally a thickened fluid rather than a thin fluid.51 This is because weak or uncoordinated swallowing mechanisms render it difficult to initiate reflexes rapidly enough to protect the airway and do not have the precise, welltimed movements necessary to move boluses of thin fluids, which tend to fragment, safely through the hypopharynx. The examiner palpates the patient’s thyroid notch between the

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hyoid bone and larynx and feels for the anterosuperior excursion of the larynx during swallowing trials (Fig. 12–6).51 In cases of severe brainstem stroke, the swallow reflex may be absent. This palpation position also gives an indication of tongue movement during the oral phase and may reveal repetitive tongue pumping, as is frequently observed in patients with Parkinson’s disease. Examiners should make note of any delay between tongue movement and laryngeal excursion, because this may be correlated with delayed initiation of the swallow reflex. Patients should be asked to phonate after oral trials, as an indication of laryngeal protection. If the voice sounds wet after swallow, it may indicate either laryngeal penetration or aspiration. Laryngeal penetration occurs when foreign material enters the laryngeal vestibule to the level of the vocal folds. Aspiration occurs when foreign material enters the larynx below the level of the vocal folds (see Fig. 12–3). When material is aspirated in the absence of the protective cough reflex, as may be indicated by a wet-sounding voice, it is referred to as silent aspiration. This is a common phenomenon, occurring in up to two thirds of patients in the acute poststroke phase.52 Extreme caution is needed when oral trials are initiated in patients with illnesses often associated with neurogenic dysphagia, because there is the potential to cause serious negative health consequences, including aspiration pneumonia, malnutrition, and death.53-55 Ice chips are frequently used when cautious testing is required, because very small amounts are able to be presented, and the cold provides heightened sensory input that may help to stimulate a swallow in some patients.56,57 Some clinicians use cervical auscultation to listen to laryngeal and pharyngeal noises during swallowing, to determine whether pooling or aspiration has occurred,57,58 although the reliability of this technique is not yet established. Pulse oximetry may be

Epiglottis Superior thyroid notch Hyoid bone

Cuneiform cartilage

Thyrohyoid ligament

Corniculate cartilage Arytenoid cartilage

Thyroid cartilage

Cricothyroid ligament Cricoid cartilage Thyroid gland Parathyroid gland Tracheal cartilage

A ■

Trachea

Anterior

Membranous part of trachea

B

Posterior

Figure 12–6. Anatomy of the larynx. A, Anterior view. B, Posterior view. (From Seeley RR, Stephens TD, Tate P: Anatomy and Physiology. St. Louis: Mosby–Year Book, 1992.)

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used to observe drops in oxygen saturation levels. It has been suggested that a decline of more than 4% during swallowing may be indicative of episodes of penetration or aspiration.59,60 Other clinical signs of aspiration include gurgling breath sounds, wet-sounding voice, and dyspnea. Fatigue is a factor that affects patients with neurogenic dysphagia; several boluses should therefore be tried before a decision regarding oral feeding is made. The cough is the most important protective mechanism preventing aspiration, and patients who are unable to produce a volitional cough at the clinical examination may be unable to expectorate material from their upper airway, should the need arise. The bedside clinical examination has been shown to miss up to 40% of cases of silent aspiration,51 and patients without adequate airway protection, as provided by a volitional cough, may benefit from more objective assessments such as videofluoroscopic swallowing studies (VFSS) or fiberoptic endoscopic evaluation of swallowing (FEES). These procedures, described later, enable clinicians to perform conservative swallowing examinations of the dysphagic patient and more objectively determine the risks associated with oral feeding. The presence of a tracheostomy tube, as may be encountered in patients with brainstem strokes or patients with motor neuron disease, necessitates a specific dysphagia assessment approach.61 It has been shown that tracheostomy tubes anchor the larynx and that cuffed tubes splint open the airway, thereby impeding the protective laryngeal closure mechanism. In addition, the upper airway sensory characteristics are altered, and the pressure gradients within the larynx, which help prevent penetration by foreign material, are reduced. It is generally accepted that tracheostomy cuffs should be deflated during oral trials. It has also been suggested that a one-way speaking valve may help normalize the upper airway characteristics and therefore possibly improve swallowing safety and function.61,62

■

Figure 12–7. Videofluoroscopic swallowing study (VFSS) demonstrating aspiration of the barium-laced puree into the trachea (arrow).

Fiberoptic Endoscopic Evaluation of Swallowing FEES, first described in 1988,63 involves insertion of a fiberoptic nasoendoscope into the nasopharynx to obtain a view of the hypopharynx and larynx. The image is displayed on a video monitor, allowing the patient and health professionals to view the patient’s swallow clearly as foods and fluids of different consistencies are provided. Direct images of the mucosa, secretion management, and the biomechanical relationships of the structures crucial in swallowing are obtained. Because of the lack of radioactive exposure in this procedure, in comparison with VFSS, FEES is a useful biofeedback and therapy tool (Fig. 12–8).

Instrumental Assessment After a comprehensive clinical dysphagia examination, further and more objective assessments may be necessary to assist the diagnostic and management processes. These include videofluoroscopic and endoscopic swallowing studies and manometry.

Videofluoroscopic Swallowing Study VFSS is a dynamic radiographic study used to evaluate the oral and pharyngeal phases of the swallow. The patient is provided with foods and fluids of differing consistencies that are mixed with a radiopaque substance such as barium. Moving images provide an indication of the interrelationships between the swallowing structures during transit of the bolus. These images allow observation of any pooled material in the pharynx and help delineate the timing and quantity of aspiration in real time. VFSS may aid in clarifying the physiological basis of the patient’s dysphagia. If possible, it is beneficial to include a full esophageal view in each VFSS to provide further information about possible retrograde aspiration and reflux, as well as esophageal causes of dysphagia. Although the procedure is usually performed in the lateral plane, an anteroposterior view may be useful for highlighting asymmetrical dysphagia (e.g., with unilateral stroke) and assist in implementing appropriate swallowing strategies (Fig. 12–7).

Manometry Manometric studies are used to assess peristalsis of the pharynx and esophagus. Pharyngeal manometry requires pressure sensors that are sensitive enough to detect the rapid changes in pressure that occur during the swallow reflex. These studies usually need to be combined with VFSS in order to make accurate judgments regarding the causes of pressure changes49 and are not commonly used in clinical practice.

Management of Patients with Neurogenic Dysphagia One of the primary considerations in treating patients with neurogenic dysphagia is their potential for safe oral intake. If oral intake is not an option, then enteral nutrition must be considered.

Oral Feeding Patients with neurological swallowing disorders who are able to tolerate oral intake may require modifications to the consistency of their diet. Patients with oral-stage problems affecting tongue and lip function often benefit from pureed food.48

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A Median glossoepiglottic fold

Pharyngeal surface of tongue Epiglottic vallecula Epiglottis Hyoid bone

Lateral glossoepiglottic fold Tubercle of epiglottis

Aryepiglottic fold Vocal fold

Ventricle of larynx

Rima glottidis

Cuneiform tubercle

Piriform recess

Pharyngeal wall (cut)

Corniculate tubercle

Mucous membrane on back of cricoid cartilage

B ■

Figure 12–8. A, Fiberoptic endoscopic evaluation of swallowing (FEES) with residual puree around the epiglottic rim, valleculae, and piriform fossae. B, The larynx as seen from above (inverted compared with A).

However, some of these patients require increased sensory input to stimulate saliva flow, mastication, and triggering of the swallowing reflex and may respond better to semisolid textures or foods of different temperatures and strong flavors.64 Patients with delay of the swallow reflex may need fluids to be thickened so that they pass slowly as a cohesive bolus in a more controlled manner through the pharynx. In patients with weak pharyngeal musculature, in which pharyngeal dysmotility and pooling are a problem, fluids may need to be of a slightly thickened nectarlike consistency, making pharyngeal pooling less likely. Flaky textures and foods consisting of dual consistencies (e.g., cereal

flakes with milk) are notoriously difficult for patients with neurogenic dysphagia to manage, because of the level of swallowing coordination necessary to maintain these textures in a cohesive bolus. In cases in which some recovery of swallowing function is expected, such as stroke, traumatic brain injury, and neurosurgery, a modified diet should be only a temporary measure while swallowing rehabilitation takes place. The ultimate aim is to return the patient to as normal a diet as possible. In progressive neurological diseases, diet modification may be a precursor to enteral nutrition.

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Nonoral Feeding When patients are unable to eat an oral diet sufficient to sustain their nutritional needs, they require enteral feeding. Enteral feeding may accompany oral intake or, in cases of severe dysphagia, may be the only means of nutrition. If recovery of swallowing function to full quantities of oral diet is expected in the short term, a nasogastric tube is appropriate. For long-term nutrition, an endoscopic or radiographic percutaneous gastrostomy may be performed; in patients with gastroesophageal reflux, a jejunostomy may be a more appropriate option.64,65

may enable a patient to visualize and perform vocal fold closure techniques, thereby increasing airway protection during swallowing. Surface electromyography has been used to demonstrate effort behind swallowing.71 Investigators have reported the use of electrical stimulation techniques as a therapeutic tool to improve swallowing.73,74 The use of such devices is not well supported; many questions regarding the type and degree of stimulation, the placement of electrodes, and patients who may gain the most benefit from the technique remain unanswered.

Swallowing Therapy Rehabilitation of neurogenic dysphagia requires treatment programs individually tailored with regard to the underlying etiology and clinical manifestation. Patients within the same diagnostic category can have very different clinical manifestations of dysphagia, requiring different treatment approaches. The following are some general therapy approaches used by speech pathologists when treating patients with neurogenic dysphagia.

Swallowing Strategies/Maneuvers Altered swallowing postures may increase safety during oral intake. Postures include chin tuck, in which the chin is placed on the chest to provide more airway protection66; supraglottic swallow, which closes the airway at the level of the vocal folds, thereby affording more control in protecting the airway during the swallow67; and head turn to the side of pharyngeal weakness, to move the bolus through the stronger side.68 There is some preliminary evidence that the following techniques may also strengthen weakened pharyngeal musculature: effortful swallow to improve pharyngeal clearance69 and the Mendelsohn maneuver, a prolonged laryngeal elevation that helps in opening the upper esophageal sphincter.70

Education of Patients/Caregivers Successful dysphagia management depends on patients and caregivers’ being fully informed and cognizant of the implications of the dysphagia diagnosis. Some clinicians find that patients respond well to education with FEES or VFSS, either to support rationales for their recommendations or as a therapy tool to educate patients in swallowing techniques. Other advice may be appropriate for the patient, including initiating small boluses, taking small meals frequently, using double swallows to clear oral or pharyngeal pooling, minimizing distractions such as conversation during eating, alternating solids with fluids to clear pharyngeal residue, and ensuring that meals are taken in an upright position. A number of illnesses causing neurogenic dysphagia also affect executive function (e.g., progressive supranuclear palsy, pseudobulbar palsy resulting from bilateral strokes), thereby reducing the ability to self-monitor the cognitively demanding process of swallowing and making the adoption of safe swallowing strategies difficult. In such cases, it is wise to educate family and caregivers in providing direct assistance, to ensure that the feeding process is a safe one.

Biofeedback Positive results have been obtained with different types of biofeedback to instruct patients on expected targets.71,72 FEES

K E Y

P O I N T S

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Motor speech disorders and aphasias should be differentiated by careful bedside assessment, with particular note of comprehension and formulation of language, consistency of articulation, and sound.

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The clinical examination should be used to look for signs that help to localize pathology affecting motor speech or swallowing to UMNs or LMNs, neuromuscular junctions, or muscle.

●

The presence of dysarthria should always raise suspicion about the possibility of concomitant neurogenic dysphagia.

●

Bedside clinical examination misses up to 40% of cases of silent aspiration. Patients without evidence of adequate airway protection, as provided by a strong, volitional cough, may benefit from more objective assessments such as VFSS or FEES.

●

Fatigue is a factor that affects patients with neurogenic dysphagia; several boluses should be tried before a decision regarding oral feeding is made.

Suggested Reading Duffy JR: Motor Speech Disorders. Substrates, Differential Diagnosis and Management. St. Louis: Mosby, 1995. Freed DB: Motor Speech Disorders: Diagnosis and Treatment. San Diego, CA: Singular Publishing Group, 2000. Groher ME, ed: Dysphagia: Diagnosis and Management, 3rd ed. Boston: Butterworth-Heinemann, 1997, pp 223-243. Logemann JA: Evaluation and treatment of swallowing disorders, 2nd ed. Austin, TX: Pro-Ed, 1998.

References 1. Rosenfield DB, Barroso AO: Difficulties with speech and swallowing. In Bradley WG, Daroff RB, Fenichel JM, et al, eds: Neurology in Clinical Practice, 3rd ed. New York: ButterworthHeinemann, 2000. 2. Brazis PW, Masdeu JC, Biller J: Localization in Clinical Neurology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2001. 3. Borod JC, Koff E, Lorch MP, et al: Emotional and nonemotional facial behaviour in patients with unilateral brain damage. J Neurol Neurosurg Psychiatry 1988; 51:826-832. 4. Seikel JA, King DW, Drumright DG: Anatomy and physiology for speech and language. San Diego, CA: Singular Publishing Group, 1997.

chapter 12 motor speech and swallowing disorders 5. Damasio AR: Aphasia. N Engl J Med 1992; 326:531-539. 6. Maassen B, Kent RD, Peters HFM, et al, eds: Speech Motor Control in Normal and Disordered Speech. Oxford, UK: Oxford University Press, 2004. 7. Darley FL, Aronson AE, Brown JR: Audio Seminars in Speech Pathology—Motor Speech Disorders. Philadelphia: WB Saunders, 1975. 8. Darley FL, Aronson AE, Brown JR: Motor Speech Disorders. Philadelphia: WB Saunders, 1975, pp 250-269. 9. Kirshner HS: Aphasia. In Bradley WG, Daroff RB, Fenichel JM, et al, eds: Neurology in Clinical Practice, 3rd ed. New York: Butterworth-Heinemann, 2000, pp 141-169. 10. van der Merwe A: A theoretical framework for the characterization of pathological speech sensorimotor control. In McNeil MR, ed: Clinical Management of Sensorimotor Speech Disorders. New York: Thieme, 1997, pp 1-25. 11. Sugishita M, Konno K, Kabe S, et al: Electropalatographic analysis of apraxia of speech in a left hander and in a right hander. Brain 1987; 110:1393-1417. 12. Pryse Phillips W: Companion to Clinical Neurology, 2nd ed. Oxford, UK: Oxford University Press, 2003. 13. Brain R: Speech Disorders—Aphasia, Apraxia and Agnosia. London: Butterworths, 1965. 14. Guenther FH: Neural control of speech movements. In Meyer A, Schiller N, eds: Phonetics and Phonology in Language Comprehension and Production: Differences and Similarities. Berlin, Mouton de Gruyter, 2002. 15. Duffy JR: Motor Speech Disorders. Substrates, Differential Diagnosis and Management. St. Louis: Mosby, 1995. 16. Monrad-Krohn GH: Dysprosody or altered “melody of language.” Brain 1947; 70:405-415. 17. Vogel D, Carter JE: The Effects of Drugs on Communication Disorders. San Diego, CA: Singular Publishing Group, 1995. 18. Duffy JR, Yorkston KM, Buekelman DR, et al: Medical interventions for spasmodic dysphonia and some related conditions [Technical Report 2]. Minneapolis, MN: Academy of Neurological Communication Disorders and Sciences, 2001. 19. Rigrodsky S, Morrison EB: Speech changes in parkinsonism during L-dopa therapy: preliminary findings. J Am Geriatr Soc 1970; 18:142-151. 20. Larson KK, Ramig LO, Scherer RC: Acoustic and glottographic voice analysis during drug-related fluctuations in Parkinson’s disease. J Med Speech Pathol 1994; 2:227-239. 21. Poluha PC, Teulings HL, Brookshire RH: Handwriting and speech changes across the levodopa cycle in Parkinson’s disease. Acta Psychol (Amsterdam) 1998; 100:71-84. 22. Johns DF: Surgical and prosthetic management of neurogenic velopharyngeal incompetency in dysarthria. In Johns DF, ed: Clinical Management of Neurogenic Communicative Disorders, 2nd ed. Boston: Little, Brown, 1995, pp 168-173. 23. Isshiki N, Okamura H, Ishikawa T: Thyroplasty type 1 (lateral compression) for dysphonia due to vocal cord paralysis or atrophy. Acta Otolaryngol 1975; 80:465. 24. Sasaki CT, Leder SB, Petcu L: Longitudinal voice quality changes following Isshiki thyroplasty type I: the Yale experience. Laryngoscope 1990; 100:849-852. 25. Ford CN, Bless DM: Clinical experience with injectable collagen for vocal fold augmentation. Laryngoscope 1986; 96:863869. 26. Mikaelian DO, Lowry LD, Sataloff RT: Lipoinjection for unilateral vocal cord paralysis. Laryngoscope 1991; 101:465-468. 27. Bedwinek AP, O’Brian RL: A patient selection profile for the use of speech prosthesis in adult disorders. J Commun Disord 1985;18:169-182. 28. Beukelman DR, Mirenda P: Augmentative and Alternative Communication, 2nd ed. Baltimore: Paul H. Brooks, 1998. 29. Brookshire RH: An Introduction to Neurogenic Communication Disorders, 4th ed. St. Louis: Mosby–Year Book, 1992.

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30. Yorkston KM, Spencer MS, Duffy J: Behavioral management of respiratory/phonatory dysfunction from dysarthria: a systematic review of the evidence. J Med Speech Lang Pathol 2003; 11(2):13-38. 31. Murdoch BE, Pitt G, Theodoros DG, et al: Real-time continuous visual biofeedback in the treatment of speech breathing disorders following childhood traumatic brain injury: report of one case. Pediatr Rehabil 1999; 3(1):5-20. 32. Thompson-Ward EC, Murdoch BE, Stokes PD: Biofeedback rehabilitation of speech breathing for an individual with dysarthria. J Med Speech Lang Pathol 1997; 5:277-290. 33. Dworkin J, Meleca R: Vocal pathologies: diagnosis, treatment and case studies. San Diego, CA: Singular Publishing Group, 1997. 34. Yamaguchi H, Yotsukura T, Sata H, et al: Pushing exercise program to correct glottal incompetence. J Voice 1993; 7:250256. 35. Murry T, Woodson G: Combined-modality treatment of adductor spasmodic dysphonia with Botulinum toxin and voice therapy. J Voice 1995; 9:460-465. 36. Ramig LO, Pawlas AA, Countryman S: The Lee Silverman Voice Treatment. Iowa City, IA: National Center for Voice and Speech, 1995. 37. Yorkston KM, Hammen VL, Beukelman DR, et al: The effect of rate control on the intelligibility and naturalness of dysarthric speech. J Speech Hear Disord 1990; 55:550-560. 38. Thomas-Stonell N, Leeper HA, Young P: Evaluation of a computer-based program for training speech rate with children and adolescents with dysarthria. J Med Speech Lang Pathol 2001; 9:17-29. 39. Downie AW, Low JM, Lindsay DD: Speech disorder in parkinsonism: usefulness of delayed auditory feedback in selected cases. Br J Disord Commun 1981; 16:135-139. 40. Berry WR, Sanders SB: Environmental education: the universal management approach for adults with dysarthria. In Berry WR, ed: Clinical Dysarthria. Boston: College-Hill, 1983. 41. Ropper A, Victor M: Disorders of speech and language. In Victor M, Ropper A, eds: Adam’s and Victor’s Principles of Neurology. New York: McGraw-Hill, 2001. 42. Magendie F: Précis Elémentaire de Physiologie, vol 2. Paris: Mequignon-Marvis, 1836, p 628. 43. Ertekin C, Aydogdu I: Neurophysiology of swallowing. Clin Neurophysiol. 2003; 114:2226-2244. 44. Miller AJ: Deglutition. Physiol Rev 1982; 62:129-184. 45. Jean A, Amri M, Calas A: Connections between the medullary swallowing area and the trigeminal motor nucleus of the sheep studied by tracing methods. J Auton Nerv Syst 1983; 7:8796. 46. Miller AJ: The Neuroscientific Principles of Swallowing and Dysphagia. San Diego, CA: Singular Publication Group, 1999. 47. Jean A: Brainstem control of swallowing: neuronal network and cellular mechanisms. Physiol Rev 2001; 81:929-969. 48. Logemann JA: Evaluation and Treatment of Swallowing Disorders, 2nd ed. Austin, TX: Pro-Ed, 1998. 49. Miller RM: Clinical examination for dysphagia. In Groher ME, ed: Dysphagia: Diagnosis and Management, 3rd ed. Boston: Butterworth-Heinemann, 1997, pp 223-243. 50. Chaudhari N, Landin MA, Roper SD: A metabotropic glutamate receptor variant functions as a taste receptor. Nature Neurosci 2000; 3:113-119. 51. Linden P, Siebens AA: Dysphagia: predicting laryngeal penetration. Arch Phys Med Rehabil 1983; 64:28. 52. Ramsey DJ, Smithard DG, Kalra L: Early assessments of dysphagia and aspiration risk in acute stroke patients. Stroke 2003; 34:1252-1257. 53. Langmore SE, Terpenning MS, Schork A, et al: Predictors of aspiration pneumonia; how important is dysphagia? Dysphagia, 1998; 13:69-81.

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54. Odderson R, Keaton JC, McKenna BS: Swallow management in patients on an acute stroke pathway: quality is cost effective. Arch Phys Med Rehabil 1995; 76:1130-1133. 55. Smithard DG, O’Neill PA, Park C, et al: Complications and outcome after acute stroke: Does dysphagia matter? Stroke 1996; 27:1200-1204. 56. Lazzara G, Lazarus C, Logemann JA: Impact of thermal stimulation on the triggering of the swallowing reflex. Dysphagia 1986; 1:73-77. 57. Hamlet SL, Penney DG, Formolo J: Stethoscope acoustics cervical auscultation of swallowing. Dysphagia, 1994; 9:63-68. 58. Takahashi K, Groher ME, Mihi K: Methodology for detecting swallowing sounds. Dysphagia 1994; 9:54-62. 59. Sellars C, Dunnet C, Carter R: A preliminary comparison of videofluoroscopy of swallow and pulse oximetry in the identification of aspiration in dysphagic patients. Dysphagia 1998; 13:82-86. 60. Sherman B, Nisenboum JM, Jesberger BL, et al: Assessment of dysphagia with the use of pulse oximetry. Dysphagia 1999; 14:152-156. 61. Dikeman KJ, Kazandjian MS: Communication and Swallowing Management of Tracheostomized and Ventilator-Dependent Adults, 2nd ed. San Diego, CA: Singular Publishing Group, 2003. 62. Elpern EH, Scott MG, Petro L, et al: Pulmonary aspiration in mechanically ventilated patients with tracheostomies. Chest 1994; 105:563-566. 63. Langmore SE, Schatz K, Olsen N: Fiberoptic endoscopic examination of swallowing safety: a new procedure. Dysphagia 1988; 2:216-219. 64. Miller RM, Groher ME: General treatment of neurologic swallowing disorders. In Groher ME, ed: Dysphagia: Diagnosis and

65. 66. 67. 68. 69. 70. 71. 72. 73. 74.

Management, 3rd ed. Boston: Butterworth-Heinemann, 1997, pp 223-243. Workman JR, Pillsbury HC III, Hulka G: Surgical intervention in dysphagia. In Groher ME, ed: Dysphagia: Diagnosis and Management, 3rd ed. Boston: Butterworth-Heinemann, 1997. Welch MV, Logemann JA, Rademaker AW, et al: Changes in pharyngeal dimensions effected by chin tuck. Arch Phys Med Rehabil 1993; 74:178-181. Martin BJW, Logemann JA, Shaker R, et al: Normal laryngeal valving patterns during three breath-hold maneuvers: a pilot investigation. Dysphagia 1993; 8:11-20. Logemann J, Kahrilas P, Kobara M, et al: The benefit of head rotation on pharyngesophageal dysphagia. Arch Phys Med Rehabil 1989; 70:767-771. Crary MA: A direct intervention program for chronic neurogenic dysphagia secondary to brainstem stroke. Dysphagia 1995; 10:6-18. Jacob P, Kahrilas PJ, Logemann JA, et al: Upper esophageal sphincter opening and modulation during swallowing. Gastroenterology 1989; 97:1469-1478. Huckabee ML, Cannito M: Outcomes of swallowing rehabilitation in chronic brainstem dysphagia: a retrospective evaluation. Dysphagia 1999; 14:93-109. Pouderoux P, Kahrilas PJ: Eglutitive tongue force modulation by volition, volume, and viscosity in humans. Gastroenterology 1995; 108:1418-1426. Freed ML, Freed L, Chatburn RL, et al: Electrical stimulation for swallowing disorders caused by stroke. Respir Care 2001; 46:466-474. Leelamanit V, Limsakul C, Geater A: Synchronized electrical stimulation in treating pharyngeal dysphagia. Laryngoscope 2002; 112:2204-2210.

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OF ●

13

SMELL ●

●

AND TASTE

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Graeme M. Gonzales and Mark J. Cook

The “chemical” senses of smell and taste are the human organism’s means of qualitatively analyzing the chemical composition of its immediate environment. Although impairment of smell or taste is not generally perceived to be as disabling as impairment of sight or hearing, hyposmia (impaired olfaction) or hypogeusia (impaired taste) may nevertheless cause substantial loss in quality of the esthetic and hedonistic aspects of the individual’s life, may contribute to comorbid conditions such as poor nutritional intake in the elderly, and, uncommonly, may be an early sign of a serious underlying disorder.1 Unpleasant smells or tastes may trigger recognition of toxins in food or the environment not otherwise detectable by the other senses. Smell via pheromones is an important component of courtship and mating in the life cycles of other species but to a far lesser extent in Homo sapiens, which is not known to possess a vomeronasal organ or a discrete pheromonal system.2 Loss of olfaction or gustation may go relatively unnoticed by the patient; in other cases, a perceived hypersensitivity of the chemical senses or inappropriate activation of sensory pathways may be the cause of symptoms.

within glomeruli, with second-order afferent neurons. Considerable convergence and information processing occur within the olfactory bulb and tract.5 Significant inhibitory and interglomerular innervation occurs within the bulb3 and is believed to modulate afferent excitatory transmission even at this level. Significant bilateral communication occurs at multiple levels within the olfactory pathways, beginning from the anterior olfactory nuclei (which are collections of neuronal bodies lying posteriorly within the olfactory tracts) and extending to the thalami and cortical olfactory areas. In humans, neurons of the olfactory tracts terminate, without synapse in the thalami, in regions collectively termed the primary olfactory cortex (lateral olfactory gyrus, piriform cortex, and periamygdaloid areas). These sites subsequently project to the hypothalamus, limbic structures, entorhinal cortex, and other areas. A minority of relays project through the dorsomedial nucleus of the thalamus. Olfactory and other areas of cortex in turn project centrifugally back to the olfactory bulbs and may modulate feedback inhibition or facilitation of afferent stimuli. Finally, the trigeminal nerve is also important in the perception of smell, mediating tactile, noxious, and pain stimuli in the nasopharynx and associated structures.6

DISORDERS OF SMELL Clinical Approach to Olfactory Disorders Aspects of the Anatomy and Physiology of Olfaction The primary sensory neurons of the olfactory pathway continuously die and are continuously replaced, being generated from the basal cells of the olfactory epithelium.3 The ciliated olfactory neurons have a lifespan of between 30 and 60 days3 and can be regenerated after damage or loss.4 The olfactory epithelium secretes mucus, which bathes the sensory dendritic surface of the olfactory neurons and provides a medium to dissolve odorants. Odorant signal transduction occurs through binding to G protein–coupled olfactory receptors, of which about 350 forms occur in humans. As might be expected, congenital genetically based specific anosmias (for certain odorants) have been reported, analogous to various forms of color blindness (see Hawkes, 2002). The bipolar olfactory neurons constituting the first cranial nerve pass through the cribriform plate of the ethmoid bone and synapse in the olfactory bulb,

Neurological disorders of olfaction can be conveniently approached according to symptom presentation (anosmia or hyposmia; hyperosmia or dysosmia), anatomical site of dysfunction (Table 13–1), or etiology (Table 13–2).7 A careful history and examination usually allow the clinician to make a provisional diagnosis and target subsequent investigations. Upper respiratory tract infection is the most common cause of neural olfactory dysfunction, accounting for up to 33% of cases. However, in up to 40% of patients with olfactory dysfunction, no cause for their symptoms is found.8

History The nature of the olfactory abnormality, its temporal course, and its variation with differing stimuli should be clarified as precisely as the patient’s recall, cognitive state, and descriptive abilities allow. Dysosmia refers to a general distortion of smell

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T A B L E 13–1. Potential Anatomical Sites of Olfactory Disturbance Anatomical Site of Damage

Typical Cranial Nerve I Finding

Other Neurological and Medical Findings

Common Etiologies

Sensory receptors and primary neuron

Hyposmia or anosmia Dysosmia Can be unilateral

With trauma, rare nasal leaks of CSF

Head trauma Upper respiratory infections Nasal or sinus disease Toxic exposure

Secondary neurons Olfactory bulb cells Anterior olfactory nucleus Medial and lateral striae

Hyposmia or anosmia Dysosmia Can be unilateral

Foster Kennedy syndrome Disinhibition, change in personality Gait dyspraxia, disinhibition, change in personality

Meningioma Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease) Frontal lobe tumors Pituitary tumors Aneurysms

Medial dorsal nucleus the of thalamus

Decreased odor identification Normal or increased odor thresholds*

Signs of Wernicke-Korsakoff syndrome: ataxia, extraocular paresis, nystagmus, memory problems including confabulations

Wernicke-Korsakoff syndrome Infarctions

Primary and secondary olfactory cortices

Decreased odor identification Normal or increased odor thresholds*

Lip smacking, automatisms during seizures Dementia, memory loss Tremor, bradykinesia Chorea, dementia Contralateral weakness, aphasia, homonymous quadrant visual field defects

Epilepsy Neurodegenerative disorders Alzheimer’s disease Parkinson’s disease Huntington’s disease Tumors or infarcts

From Doty RL: Cranial nerve I: olfactory nerve. In Goetz CG, ed: Textbook of Clinical Neurology, 2nd ed. Philadelphia: WB Saunders, 2003, p 101, Table 7-1. *Because of bilateral cortical and subcortical representation of olfactory function, unilateral lesions at this level generally do not cause clinically meaningful olfactory dysfunction. CSF, cerebrospinal fluid.

T A B L E 13–2. Causes of Olfactory Disturbance Mechanical Cause Craniofacial trauma Surgery Frontal or intracranial mass lesion (e.g., malignancy, aneurysm) Environmental Cause Radiation treatment Tobacco smoking Environmental toxin (e.g., benzene, chlorine, formaldehyde, acetone, lead) Inhaled cocaine Neurologic or Psychiatric Disorder Epilepsy or seizure disorder Psychotic disorder (e.g., schizophrenia) Depression or other affective disorder Neurodegenerative disorders (especially Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease) Migraine Stroke Korsakoff’s syndrome Infections Viral respiratory tract infection Systemic viral infections (influenza, HIV/AIDS) Acute bacterial sinusitis AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.

Chronic or recurrent sinusitis Meningitis, encephalitis Metabolic Organ Dysfunction Hepatic failure Renal failure Vitamin deficiency states (A, B6, B12) Zinc, copper deficiency states Drugs (see Table 13–3) Disseminated malignancy/cachexia Vasculitic disorders Endocrine Thyroid dysfunction Diabetes mellitus Pituitary adenoma Cushing’s syndrome Menopause Pseudohypoparathyroidism Miscellaneous Allergic rhinitis/sinusitis Pregnancy Aging Kallman’s syndrome and other cilia dysfunction syndromes Turner’s syndrome

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T A B L E 13–3. Drugs That May Impair Olfaction or Gustation* Antianxiety Agents Alprazolam (Xanax) Buspirone (BuSpar)

Gold (Myochrysine) Hydrocortisone Penicillamine (Cuprimine)

Antibiotics Ampicillin Azithromycin (Zithromax) Ciprofloxacin (Cipro) Clarithromycin (Biaxin) Enalapril (Vaseretic) Griseofulvin (Grisactin) Metronidazole (Flagyl) Ofloxacin (Floxin) Terbinafine (Lamisil) Ticarcillin (Timentin) Tetracycline

Antimanic Drugs Lithium

Anticonvulsants Carbamazepine (Tegretol) Phenytoin (Dilantin) Antidepressants Amitriptyline (Elavil) Clomipramine (Anafranil) Desipramine (Norpramin) Doxepin (Sinequan) Imipramine (Tofranil) Nortriptyline (Pamelor) Antihistamines and Decongestants Acetazolamide (Diamox) Amiloride (Midamor) Amiodarone (Cordarone, Pacerone) Betaxolol (Betoptic) Captopril (Capoten) Diltiazem (Cardizem) Enalapril (Lexxel, Vasotec, Vaseretic) Hydrochlorothiazide (Esidrix) Nifedipine (Procardia) Nitroglycerin Propafenone (Rythmol) Propranolol (Inderal) Spironolactone (Aldactone) Tocainide (Tonocard) Anti-inflammatory Agents Auranofin (Ridaura) Beclomethasone (Beclovent, Beconase) Budesonide (Rhinocort) Colchicine Dexamethasone (Decadron) Flunisolide (Nasalide, Aerobid) Fluticasone (Flonase)

Antimigraine Agents Dihydroergotamine (Migranal) Naratriptan (Amerge) Rizatriptan (Maxalt) Sumatriptan (Imitrex) Antineoplastics Cisplatin (Platinol) Doxorubicin (Adriamycin) Levamisole (Ergamisol) Methotrexate (Rheumatrex) Vincristine (Oncovin) Antiparkinsonian Agents Levodopa (Larodopa; with carbidopa: Sinemet) Antipsychotics Clozapine (Clozaril) Trifluoperazine (Stelazine) Antithyroid Agents Methimazole (Tapazole) Propylthiouracil Antiviral Agents Ganciclovir (Cytovene) Interferon (Roferon-A) Zalcitabine (HIVID) Bronchodilators Bitolterol (Tornalate) Pirbuterol (Maxair) Lipid-Lowering Agents Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Pravastatin (Pravachol) Muscle Relaxants Baclofen (Lioresal) Dantrolene (Dantrium) Pancreatic Enzyme Preparations Pancrelipase (Cotazym) Smoking Cessation Aids Nicotine (Nicotrol)

From Doty RL, Bromley SM: Effect of drugs on olfaction and taste. Otolaryngol Clin North Am 2004; 37:1231, Box 1. *Most of these agents are noted in the Physician’s Desk Reference as having adverse effects on the olfactory system.

sense, whereas troposmia refers to distortion in quality of a particular normal smell stimulus. Whether the smell concerned is pleasant, unpleasant, or excessively unpleasant (cacosmia) may be important. Complaints of nasal discharge or unilateral epistaxis are suggestive of an upper airway abnormality. Traumatic head injury is an important cause of smell and taste disorders and may account for up to 23% of cases of documented hyposmia.9 Intracranial surgery likewise may cause hyposmia. Any variation of intensity with a particular stimulus or scent, particular hyperosmia, should be noted. The possibility of preg-

nancy should be considered in the female patient of childbearing potential with hyperosmia or dysosmia.10 The medical history and drug history may reveal use of agents known to impair olfaction (Table 13–3). A history of smoking, alcohol consumption, and recreational drug use should be documented.11 The medical history may be notable for sinusitis or other rhinal disease,12 thyroid or other endocrine disease, hepatic or renal impairment, Parkinson’s disease13 or other neurodegenerative conditions,14 stroke, or features such as deafness or diabetes that are suggestive of a mitochondrial dis-

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T A B L E 13–4. Office Tests Commonly Used in Olfactory Assessment University of Pennsylvania Smell Identification Test (UPSIT) Pocket Smell Test Brief Smell Identification Test (B-SIT) Connecticut Clinical Research Center Test (CCCRC) Smell Threshold Test Sniffin’ Sticks

order. Association of a smell, particularly a strongly unpleasant or noxious one, with a period of amnesia, loss of awareness, or other suggestive symptoms, can indicate a focal seizure disorder.15 The patient may perceive an odor when no stimulus is present (phantosmia). A history from an observer can prove invaluable in this circumstance. Olfactory hallucinations are an uncommon manifestation of schizophrenia, being noted in approximately 6% of patients.16 A family history may also yield clues in regard to any of these conditions. Other important points include occupational or other exposure to toxins or fumes, past treatment with radiation, the psychiatric history, and past intracranial or systemic infection, including human immunodeficiency virus infection.17 Congenital hyposmia is known to be associated with immotility or absence of olfactory epithelial cilia, most commonly in association with hypogonadotropic hypogonadism (Kallman’s syndrome).18 Headache or other symptoms suggestive of an enlarging intracranial mass or of frontal region dysfunction may herald a progressive frontal, temporal, or anterior fossa tumor. It should be remembered that a significant decline in olfactory acuity is seen with aging, particularly in the sixth and seventh decades.19 Quality-of-life questionnaires have been developed to try to reproduce reliably the largely subjective perception of olfactory dysfunction.1

Examination Office assessment of olfactory dysfunction by the general neurologist includes targeted neurological examination and a general medical examination, including ears and oropharynx; both examinations are guided by the history. Unilateral olfactory acuity can be assessed by sequential nasal occlusion, and a number of formal office tests of olfactory dysfunction are available (Table 13–4). The four-alternative forced-choice structure of the 40-item University of Pennsylvania Smell Identification Test (UPSIT) odor identification test may enable malingering to be detected on the basis of a performance significantly worse than that expected by chance alone, which may be useful in medicolegal cases involving trauma or toxic exposure. Formal gustatory examination should also be performed, because many causes of olfactory and taste impairment may also affect taste and smell, respectively. Endoscopic examination of the upper respiratory tract, performed by a suitably skilled and experienced clinician with appropriate equipment, should be considered, especially if a tumor or other rhinological cause is suspected.8 A Mini Mental State Examination, neuropsychological, or formal psychiatric evaluation may be indicated.

Investigation of Olfactory Disorders Computed tomography of the head, orbits, and nasopharynx is the initial imaging modality of choice.7 Lesions causing bony destruction or infiltration are readily visualized, as are most collections or intracranial masses large enough to cause neural distortion or compression. Magnetic resonance imaging and angiography with paramagnetic contrast material remain the “gold standards” for detecting subtle neuraxial lesions, small anterior fossa masses, and other nonbony structural abnormalities, such as caudate atrophy in early Huntington’s disease or focal frontal or temporal cortical epileptogenic foci. Blood and other body fluid analyses are useful for screening for specific etiologies such as infection or vitamin B12 deficiency. Electroencephalography is useful in diagnosing seizure disorders. Cerebrospinal fluid analysis and measurement of the intrathecal pressure should be performed if basal meningitis is suspected. Biopsy and histological or other examinations may be performed on suspect mass lesions. More extensive psychophysical investigation of olfactory disturbances may include threshold determination, odor discrimination, and odor memory tests, as well as odor identification tests such as the UPSIT. Odor event–related potentials and electro-olfactography are techniques generally confined to specialized clinical or research centers (see Hawkes, 2002).

Principles of Management of Olfactory Disorders Therapy for olfactory disorders is most usefully directed at the underlying cause of dysosmia.11 Rhinological causes of olfactory dysfunction are most easily accessible. Specific treatment may include topical or systemic antihistamines or antiallergy agents, antimicrobial therapy, or invasive interventions for recurrent sinusitis, obstruction, or malignancy. Neurological causes of olfactory dysfunction often resolve if the primary site of dysfunction is at the olfactory nerve, because of regeneration of bipolar neurons from the basal layer. However, avoidance of environmental agents or cessation of medications known to induce dysosmia may not fully reverse the deficit.20 Likewise, olfactory disturbance caused by chemotherapy or radiotherapy for malignancy may or may not improve after conclusion of treatment. Smoking cessation is medically advisable for many reasons, and normosmia usually is successfully restored if the hyposmia was attributable to this cause. Treatment of intracranial causes of sensorineural dysosmia has varying success. A focal epileptogenic lesion may respond to anticonvulsants or be amenable to surgical excision, as may a frontal meningioma or other surgically accessible mass. However, deficits may be irreversible if tissue damage is permanent. Most neurodegenerative illnesses associated with olfactory disturbance are incurable. As mentioned previously, olfaction is vital to the appreciation of drink, food, and other pleasurable aspects of normal life and is important in the detection of dangerous or unpleasant odorants such as household cooking gas or spoiled food. Elderly persons especially may develop unrecognized hyposmia. They are therefore at increased risk of not recognizing such threats. Loss of smell may also be misinterpreted as anhedonia or depression. Loss of taste, too, is important in the elderly (see later discussion). Age-related hyposmia is not reversible. Counseling, heightened awareness, and physical safety measures

chapter 13 disorders of smell and taste such as gas and smoke detectors are useful interventions. An acute sense of smell is important in many professions and trades (plumber, parfumier, chef or baker, winemaker, physician), and occupational compensation may be warranted. This should always be considered in managing the patient whose sense of smell affects his or her livelihood, according to the individual laws in the state or country concerned.7 Because many cases of olfactory disturbance are not amenable to treatment or, at best, are only partially treatable, a supportive and sympathetic attitude toward the patient is always important. Appropriate education of the patient about the disorder can help greatly toward the patient’s understanding and coping with the disability.

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routes of these pathways are less well delineated. Many fibers decussate at this level, and unilateral lesions of the medulla oblongata are not well described as causing taste disturbances. The pathways then ascend, largely via the central tegmental tract (not the medial lemniscus as previously thought) to the ventral posterior median nucleus of the thalamus and from there to the anteroinferior sensory and motor cortex, superior temporal gyrus, frontal operculum, and anterior insula. These pathways are, again, separate from somatosensory cortical representations of the tongue and palatal structures. Other pathways may synapse with the hypothalamus and limbic structures to mediate autonomic and emotional aspects of taste.6

Clinical Approach DISORDERS OF TASTE Aspects of the Anatomy and Physiology of Gustation The five currently recognized tastes are salty, sour, bitter, sweet, and umami (conveniently described as the taste of glutamate).21 Smell, texture, other somatosensory perceptions (such as those elicited by menthol or chili), as well as taste, collectively contribute to the perception of flavor of ingested substances. Taste receptors are found within taste buds on the tongue, soft palate, pharynx, larynx, and upper esophagus. Individual taste receptors are responsive to all tastants with varying sensitivity, and each taste bud appears to exhibit one preferential sensitivity. The popular notion that a particular taste is “localized” onto any one area of the tongue is therefore largely inaccurate.3 Taste receptors, like olfactory bipolar cells, continuously regenerate from basal cells, being replaced approximately every 10 to 20 days. Like odorants, tastants need to be dissolved to interact with receptors, in this case in saliva. Salty (Na+) and sour (H+) tastants appear to evoke taste receptor depolarization through direct interaction with apical ion channels. Bitter and sweet tastants evoke depolarization via G protein–mediated secondmessenger mechanisms, largely involving cyclic adenosine monophosphate and inositol 1,4,5-triphosphate, respectively. Taste receptors synapse with high convergence onto primary afferent neurons, which are unipolar neurons with cell bodies in the genicular ganglion of the facial nerve and the petrosal and nodose (inferior) ganglia of the glossopharyngeal and vagal nerves, respectively. Afferent fibers from the anterior two thirds of the tongue travel proximally via the chorda tympani. Afferent fibers from the posterior third of the tongue and other posterior structures travel proximally in the greater petrosal nerve branch of the facial nerve (inferior soft palate) and the lingual branch of the glossopharyngeal nerve, together with the internal laryngeal branch of the vagus nerve (epiglottis and extreme pharyngeal part of tongue). Somatosensory afferent fibers are also believed to travel proximally along similar routes, except that somatosensory fibers from the anterior two thirds of the tongue remain with the lingual branch of the mandibular nerve (V3), rather than departing with the chorda tympani. The afferent cranial nerves synapse, in descending order, caudally, ipsilaterally in the medulla of brainstem, and in the rostral third of the nucleus of the tractus solitarius with secondary gustatory neurons. At this level, taste afferent fibers are organized separately from somatosensory information. The subsequent

The complaint of “loss of taste” (ageusia or hypogeusia) in food discrimination is related more often to an olfactory deficit (described previously) than to true impairment of gustation.22 Again, a careful history usually allows the clinician to interpret the patient’s symptom correctly. The evaluation of taste dysfunction is directed toward establishing which modalities (sweet, salty, bitter, sour umami) are preferentially impaired; whether the impairment can be localized anatomically within the sensorineural gustatory pathways as described previously; and whether a cause, treatable or otherwise, can be identified. Isolated disorders of taste caused by central nervous system lesions are rare.21 Abnormal taste (dysgeusia) is usually unpleasant; it may be strongly revolting (cacogeusia), and it may be hallucinatory (phantogeusia), as in a seizure or psychotic disorder, or real, as with a purulent nasopharyngeal infection. Hypergeusia is difficult to quantify and, more rarely, is a symptom prompting medical attention.

History Common causes of taste dysfunction are listed in Table 13–5. They can be conveniently grouped into peripheral, central, and systemic causes. However, the anatomical site sometimes cannot be well localized. The clinician should attempt to gain as clear a description as possible of the exact nature of the patient’s taste disturbance, of any associated symptoms that may localize a lesion or suggest an underlying cause, and of recent respiratory infection. The clinician should also obtain medical and surgical histories23,24; a family history; and a careful history of prescription drug, tobacco, alcohol, and recreational drug use. Inquiry should be made into possible olfactory dysfunction. Important symptoms include xerostomia (dry mouth) or dry eyes; oral, head, facial, or neck pain; facial rash; balance difficulty, oscillopsia, or tinnitus; mouth ulcers or oral thrush; headache; and evidence of oculomotor weakness, facial weakness, or speech disturbance. Mechanical trauma causes isolated dysgeusia less frequently than it does olfactory dysfunction.9 Drugs known to be associated with taste dysfunction are listed in Table 13–3. Prior neck manipulation or trauma should prompt consideration of cervical cerebral arterial dissection.21 Symptoms suggestive of a seizure disorder in association with a powerful, intrusive, clearly abnormal taste in the absence of a tastant (phantogeusia) should prompt consideration of a focal seizure disorder. Unilaterality of taste dysfunction strongly suggests a cause below the level of the thalamus. Anhedonia should prompt consideration of a thalamic lesion or depression. Atten-

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T A B L E 13–5. Common Causes of Sensorineural Taste Disturbance Peripheral (Facial Nerve) Bell’s palsy Trauma Surgical procedures (e.g., uvulopalatopharyngoplasty) Herpetic or other facial neuritis Meningitis, mastoiditis Basal skull mass lesions (e.g., meningioma, cholesteatoma) Vestibular schwannoma Parotid malignancy Sarcoidosis Central Intra-axial tumor or other mass lesion Ischemic or hemorrhagic stroke Neurodegenerative disease Multiple sclerosis Epilepsy or seizure disorder Systemic Disease Vasculitis Poorly Localizable Migraine Psychiatric disease Dysautonomic disorders Guillain-Barré syndrome Drug or environmental toxin related Idiopathic Age-related hypogeusia

tion should be paid to the patient’s nutritional state, body mass index, and history of recent weight loss. Again, it should be remembered that an age-related decline in taste acuity may be seen in the normal individual.19

be established by serial dilutions of the tastants down to the lowest recognizable concentration. Standardized “test strips” and other kits are commercially available with specific stimulus concentrations. It should be noted whether the deficit is unilateral or bilateral and whether the abnormality occurs on the anterior two thirds or posterior one third of the tongue. Taste examination of palatopharyngeal structures seldom adds additional useful information. Differentiation between phantom and real tastes can be made by applying topical anesthesia to the tongue. Phantogeusia can intensify after this. Formal magnitude-matching tests can be performed through comparison with another, normal, sensory modality in the patient, such as with a controlled frequency-specific aural stimulus. However, these are usually performed in specialized referral centers for taste disorders.

Investigation of Gustatory Disorders The broad principles of investigation for taste disorders are similar to those for olfactory disorders. If a peripheral cause or localized central lesion is suspected, computed tomography and magnetic resonance imaging of the head, brain and brainstem, anterior cranial structures, internal acoustic meatus, and skull are required. Analyses of blood and body fluids, including cerebrospinal fluid analysis, are useful for a few specific causes such as infection, diabetes, or metabolic organ dysfunction. Suspect or abnormal masses should be subjected to biopsy where accessible. Directed investigation of suspected underlying causes of gustatory dysfunction is dictated by the clinical findings. Electrogustometry can be used to quantify dysgeusia objectively and assist with anatomical localization in difficult cases.26 Electrogustometry can also be used to assess glossopharyngeal nerve dysfunction. However, its use is more common in specialized otolaryngological and chemosensory disturbance clinics.

Principles of Management of Gustatory Disorders Examination Office assessment of gustatory dysfunction includes examination of modality and lingual site of taste dysfunction, targeted neurological examination, and a general medical examination including nose, ears, and oropharynx. Formal otorhinolaryngological endoscopy may be necessary. Height and weight should be recorded, body mass index calculated, and attention paid to signs of protein or micronutrient malnutrition. The aims of neurological examination should be primarily to localize the anatomical site of taste disturbance if possible, and to seek evidence of a generalized process—such as sarcoidosis— that could be selectively affecting taste pathways. On oral examination, particular note should be taken of xerostomia, leukoplakia, ulcers, salivary gland enlargement, and oral hygiene. Dentures or other oral prostheses may interfere with palatal taste sensations. Psychiatric assessment may be warranted if depression or psychosis is suspected. Various methods of taste examination are described. A simple office spatial taste test is performed to assess tastant recognition of the four basic tastes (excluding umami); cotton-tipped swabs are used to apply strong sour, sweet, salty, or bitter solutions to separate areas of the patient’s tongue.25 A crude sensitivity threshold can

Specific therapy for taste disturbance should be directed at the underlying cause when possible. In certain circumstances, taste disturbance may be self-limited and recover with time. Drug cessation in cases of drug-induced dysgeusia does not always reverse the disturbance, and many patients who do recover take months to years to do so.20 Prediction of dysgeusia when drug treatment begins is difficult in the individual patient. Although zinc and other micronutrient or vitamin supplementation are advocated by some authorities, it has not been shown to be of great benefit in the treatment of taste disorders outside of true deficiency states.21 The specific therapy for taste dysfunction is otherwise unsatisfactory, and many patients are left with permanent dysgeusia. Many patients with taste abnormalities, particularly elderly patients, have diabetes, congestive cardiac failure, or hypertension. Hypogeusia may prompt patients to add inordinate amounts of sugar or salt to their food, thereby potentially exacerbating these medical disorders.25 Patient education and counseling are therefore particularly important in supportive treatment of taste abnormalities in these patients. Consultation with a nutritionist may be of value. Finally, the intractable nature of these disabilities means that a supportive and sympathetic attitude toward the patient must always constitute an integral part of his or her care.

chapter 13 disorders of smell and taste

K E Y

P O I N T S

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Smell and taste disorders are seldom the initial manifestation of serious illness, but they may cause significant morbidity and may be overlooked unless specifically sought by the clinician.

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Smell and taste disorders are usually related either to agerelated sensory loss or to an identifiable underlying cause. A broad diagnostic approach usually identifies potential causes of olfactory or gustatory dysfunction, including local and central (e.g., neurodegenerative) disorders.

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Otorhinolaryngological disorders are frequently the cause of olfactory or gustatory dysfunction, and assessment of the patient with a smell or taste disorder may need to be performed in coordination with an otorhinolaryngology specialist.

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Causes of smell and taste dysfunction are often related, and impairments of both sensory modalities may therefore be present.

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Primary treatment of smell and taste dysfunction often yields unsatisfactory results. Therapy for smell and taste disorders is best directed at the underlying cause, when that is treatable. Patient education and supportive measures are also important in minimizing the morbidity associated with these disorders.

Suggested Reading Buck LB: Smell and taste: the chemical senses. In Kandel ER, Schwartz JH, Jessell TM, eds: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. Hawkes CH: Smell and Taste Complaints. Boston: ButterworthHeinemann, 2002. Heckmann JG, Heckmann SM, Lang CJG, et al: Neurological aspects of taste disorders. Arch Neurol 2003; 60:667-671. Hummel T, Nordin S: Olfactory disorders and their consequences for quality of life. Acta Otolaryngologica 2005; 125:116-121. Mann N: Management of smell and taste problems. Cleve Clin J Med 2002; 69:329-336. Wrobel BB, Leopold DA: Clinical assessment of patients with smell and taste disorders. Otolaryngol Clin North Am 2004; 37:11271142.

References 1. Hummel T, Nordin S: Olfactory disorders and their consequences for quality of life. Acta Otolaryngologica 2005; 125:116-121. 2. Keverne EB: Brain evolution, chemosensory processing, and behavior. Nutr Rev 2004; 62(11): S218-S223.

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3. Buck LB: Smell and taste: the chemical senses. In Kandel ER, Schwartz JH, Jessell TM, eds: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. 4. Upadhyay UD, Holbrook EH: Olfactory loss as a result of toxic exposure. Otolaryngol Clin North Am 2004; 37:1185-1207. 5. Buck LB: Olfactory receptors and odor coding in mammals. Nutr Rev 2004; 62(11):S184-S188. 6. Williams PL, Warwick R, Dyson M, et al, eds: Gray’s Anatomy, 37th ed. New York: Churchill Livingstone, 1989. 7. Doty RL: Cranial nerve I: olfactory nerve. In Goetz CG, ed: Textbook of Clinical Neurology, 2nd ed. Philadelphia: WB Saunders, 2003, pp 99-110. 8. Wrobel BB, Leopold DA: Clinical assessment of patients with smell and taste disorders. Otolaryngol Clin North Am 2004; 37:1127-1142. 9. Reiter ER, DiNardo LJ, Costanzo RM: Effects of head injury on olfaction and taste. Otolaryngol Clin North Am 2004; 37:11671184. 10. Nordin S, Broman DA, Olofsson JK, et al: A longitudinal descriptive study of self reported abnormal smell and taste perception in pregnant women. Chem Senses 2004; 29:391-402. 11. Mann N: Management of smell and taste problems. Cleve Clin J Med 2002; 69:329-336. 12. Raviv JR, Kern RC: Chronic sinusitis and olfactory dysfunction. Otolaryngol Clin North Am 2004; 37:1143-1157. 13. Katzenschlager R, Lees AJ: Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr Opin Neurol 2004; 17:417-423. 14. Hawkes C: Olfaction in neurodegenerative disorder. Mov Disord 2003; 18:364-372. 15. Acharya V, Acharya J, Luders H: Olfactory epileptic auras. Neurology 1998; 51:56-61. 16. Sadock BJ, Sadock VA. Schizophrenia. In Sadock, BJ, Kaplan HI, Sadock VA, eds: Kaplan & Sadock’s Synopsis of Psychiatry. Lippincott Williams & Wilkins, 2003, pp 471-504. 17. Heald AE, Pieper CF, Schiffman SS: Taste and smell complaints in HIV infected patients. AIDS 1998; 12:1667-1674. 18. Afzelius BA: Cilia related diseases. J Pathol 2004; 204:470-477. 19. Seiberling KA, Conley DB: Aging and olfactory and taste function. Otolaryngol Clin North Am 2004; 37:1209-1228. 20. Doty RL, Bromley SM: Effects of drugs on olfaction and taste. Otolaryngol Clin North Am 2004; 37:1229-1254. 21. Heckmann JG, Heckmann SM, Lang CJG, et al: Neurological Aspects of Taste Disorders. Arch Neurol 2003; 60:667-671. 22. Pribitkin E, Rosenthal MD, Cowart BJ: Prevalence and causes of severe taste loss in a chemosensory clinic population. Ann Otol Rhinol Laryngol 2003; 112:971-978. 23. Kamel UF: Hypogeusia as a complication of uvulopalatopharyngoplasty and use of taste strips as a practical tool for quantifying hypogeusia. Acta Otolaryngol 2004; 124:12351236. 24. Collet S, Eloy P, Rombaux P, et al: Taste disorders after tonsillectomy: case report and literature review. Ann Otol Rhinol Laryngol 2005; 114:233-236. 25. Brackmann DE, Fetterman BL: Cranial nerve VII: facial nerve. In Goetz CG, ed: Textbook of Clinical Neurology, 2nd ed. Philadelphia: WB Saunders, 2003, pp 181-194. 26. Tomita H, Ikeda M: Clinical use of electrogustometry: strengths and limitations. Acta Otolaryngol Suppl 2002; (546):27-38.

SECTION II Anthony H. V. Schapira

SLEEP AND SLEEP DISORDERS ✺

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Timothy A. Roehrs and Thomas Roth

Sleep is an essential and appetitive behavior characterized by minimal movement; reduced responsiveness to stimuli; reversibility; and species-specific diurnal timing, duration, and preferred posture.1 The appetitive and essential nature of sleep is clearly evident in the human’s inability to maintain continuous wakefulness for more than 2 to 3 days. As a state of sleep need progressively increases with attempts at prolonged wakefulness, sleep begins to intrude into wakefulness as brief microsleeps occurring during ongoing behavior and as longer episodes of unintended sleep during periods of inactivity.2 The inability to completely deprive oneself of sleep after 2 to 3 days, in contrast to one’s ability to avoid food or fluids and thereby deprive oneself to death, demonstrates the compulsory nature of sleep. In fact, the compulsory nature of sleep accounts for much of the morbidity associated with sleep loss (e.g., car accidents). Sleep in humans is recognized behaviorally by its recumbence and eye closure, but some mammals sleep with open eyes (e.g., cattle) or while standing (e.g., horse, elephant).1 The immobility of the sleep state is relative in that sleep walking and talking occur in some human sleep disorders and, among animals, some fish swim in place and mammals move about periodically. The two characteristics of arousability and rapid reversibility differentiate sleep from death, coma, and hibernation. Nonvisual sensory monitoring of both exogenous and endogenous stimuli continues during the sleep state. For example, a vital stimulus, hypoxemia, readily arouses even a severely sleep-deprived individual; similarly, a parent is easily aroused by the cry of his or her baby. In fact, sensory discrimination continues during sleep, inasmuch as a parent does not arouse to the cry of another baby, corrected for stimulus intensity differences. Average daily sleep time varies from 2 to 20 hours among mammals, typically being 8 hours for humans.3 The single best correlate of variation in sleep length among mammals appears to be metabolic rate.3 Whereas the major sleep period in humans typically occurs as a single bout during the dark hours, for some mammals sleep is linked to the daylight period and occurs in multiple bouts.

NATURE OF SLEEP Because sleep would be disrupted if it were assessed behaviorally (e.g., testing arousal threshold), sleep scientists measure

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sleep electrophysiologically, which is less obtrusive and more precise.4 The simultaneous recording of the electroencephalogram (EEG), the electro-oculogram, and the electromyogram are the accepted standard measures of sleep and waking, a standardized procedure termed polysomnography. The polysomnogram correlates well with behavioral observations. But it also reveals further subtleties not apparent behaviorally or subjectively. Sleep is an active, complex, and highly organized process composed of two distinct brain states of sleep: rapid eye movement (REM) and non-rapid eye movement (NREM).

Electrophysiology of NREM and REM sleep In contrast to the electroencephalographic low voltage (10 to 30 μV) and fast frequency (16 to 35 Hz) of activated wakefulness, the cortical EEG (C3/4 to A1/2) of relaxed, eyes-closed wakefulness is characterized by increased voltage (20 to 40 μV) and an 8- to 12-Hz frequency. During the transition to sleep, sometimes called drowsy sleep or transitional sleep, the electroencephalographic frequency becomes mixed, whereas the voltage remains at the level of relaxed wakefulness. In NREM sleep, electroencephalographic voltage is further increased and frequency is further slowed. When arousal threshold is highest, the EEG of NREM sleep has a 0.5- to 2-Hz frequency with voltages of 75 μV and higher, which is termed slow-wave sleep. The electromyographic activity, highest in wakefulness, is gradually reduced during NREM sleep, although limb and body movements occur aperiodically during NREM and there is voluntary control of musculature. The electro-oculograms of wakefulness reveal rapid eye movements, which, during the transition to NREM sleep, become slow and rolling. Of importance is that the rolling eye movements mark the onset of the functional blindness all humans experience during sleep. The electrooculogram becomes quiescent during slow-wave sleep. After 90 to 120 minutes of NREM sleep, the healthy normal person enters REM sleep. The electro-oculogram of REM sleep is characterized by rapid conjugate eye movements (hence the name of this sleep state). The cortical EEG of REM sleep reverts to the low-voltage, mixed-frequency pattern of drowsy sleep. The second defining characteristic of REM sleep is its skeletal muscle atonia, which is reflected in the electromyogram achieving its lowest level of the night. The muscle atonia of REM sleep occurs through a

chapter 14 the physiology of sleep process of postsynaptic inhibition of motor neurons at the dorsal horn of the spinal cord. Another important feature of REM sleep is its tonic and phasic components. The tonic components of REM sleep are the persistent muscle atonia and the desynchronized EEG. The phasic components are intermittent and include bursts of eye movements occurring against a background of electro-oculographic quiescence. Coupled with the eye movement bursts are muscle twitches, typically involving peripheral muscles. These twitches are superimposed on the tonic muscle atonia of REM and probably reflect sympathetic drive breaking through the postsynaptic inhibition (see the following discussion of the autonomic nervous system during sleep).

Physiological Function during Sleep Autonomic Nervous System The activity of the autonomic nervous system varies between the two sleep states (NREM and REM) and the wakefulness state.5 Parasympathetic activity increases during NREM sleep in relation to wakefulness. It remains relatively increased during both tonic and phasic REM sleep. Sympathetic activity remains constant during wakefulness and NREM sleep and is slightly reduced during tonic REM sleep. Consequently, parasympathetic activity predominates during sleep with the exception of phasic REM sleep. Sympathetic drive is dramatically increased during phasic REM sleep, and it predominates despite the increased parasympathetic activity of phasic REM sleep.

Respiratory System Breathing patterns and the control of respiration are different in sleep and wakefulness.6 Minute ventilation is decreased from waking levels by 13% to 15% during NREM sleep. Two factors are responsible: First, the nonmetabolic drive to breathe in wakefulness is removed with the onset of NREM sleep; second, airflow resistance is enhanced, as a result of a reduction of upper airway dilator muscle tone that occurs in conjunction with the general reduction of skeletal muscle tone of sleep. During the tonic skeletal muscle atonia of REM sleep, airway resistance is further increased in comparison with that of NREM sleep, resulting in a twofold increase in relation to that of wakefulness. This heightened airway resistance, coupled with the autonomic nervous system sympathetic activation, particularly in phasic REM sleep, leads to irregular breathing patterns and even respiratory pauses during REM sleep. Metabolic control of breathing is also altered by the NREM and REM sleep states. Hypoxic ventilatory drive is reduced in NREM sleep and declines further in REM sleep. Hypercapnic drive, although also reduced in NREM sleep in relation to wakefulness, is virtually absent in REM sleep. Breathing during NREM sleep is controlled primarily by arterial levels of CO2; thus, when levels of CO2 are below the elevated threshold of NREM sleep, the effort to breathe ceases. Consequently, at transitions from wakefulness to sleep, breathing often becomes periodic as a result of this shifting of the hypercapnic set point. Individuals with fragmented sleep characterized by frequent wake-sleep transitions often have frequent central apnea events. For example, many elderly persons have central apnea,

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which results from fragmented sleep and itself further fragments sleep. On the other hand, in view of the absence of hypercapnic drive in REM sleep, obstructive apneas that occur during REM sleep are prolonged relative to NREM apneas.

Thermal Regulation Altered thermoregulation is also displayed in the NREM and REM sleep states.7 The thermal set point is reduced in NREM sleep in relation to the wakefulness state. Consequently, sweating and shivering occur at lower temperatures during NREM sleep than during wakefulness. Again, REM sleep is unique in that there is no temperature regulation during REM sleep and sweating and shivering cease during REM sleep. If a person remained in REM sleep long enough, body temperature would equilibrate to the ambient temperature. However, REM episodes are never much longer than 30 minutes, and thus noticeable body temperature fluctuations do not occur during REM sleep.

REGULATION OF SLEEP AND WAKEFULNESS Wakefulness, sleep, and its constituent REM and NREM states are regulated by three hypothesized processes: a homeostatic process that is driven by the prior amount of sleep and wakefulness, a circadian process that organizes sleep and wakefulness episodes across the 24-hour day, and an ultradian process that controls the expressions of REM and NREM within the sleep period. The NREM and REM states are interdependent, whereas both the homeostatic and circadian systems are independent but interacting. Knowledge about the neurobiology of the circadian system, although far from complete, is more advanced than that of the homeostatic system. Little is known yet about the ultradian system, and how these three processes interact to produce REM or NREM sleep at a given time of day.

Homeostatic Regulation Homeostatic regulation of sleep has been inferred from measurement of the amount of electroencephalographic slow-wave activity during the sleep period, the auditory arousal threshold during sleep, the total amount and continuity of sleep, and the speed of falling asleep at night and during the day.8 Reductions of sleep time yield increases in these various measures, whereas increases in sleep time yield reductions in these measures, with two exceptions: sleep continuity and arousal threshold, which behave conversely. For example, computer-assisted quantification of slow-wave activity during sleep shows an increased amount of slow-wave activity during recovery sleep after total or partial sleep deprivation. During normal sleep, in the absence of prior deprivation, the amount of slow-wave activity diminishes in each successive NREM sleep cycle across the night. Measuring the speed of falling asleep throughout the day on a standard measure, the Multiple Sleep Latency Test, also suggests the existence of an underlying homeostatic process for sleep.4 A single night in which sleep time is reduced by 2 to 8 hours produces a linear increase in the speed of falling asleep on the Multiple Sleep Latency Test the following day, and nightly sleep durations reduced by as little as 1 to 2 hours across successive nights accumulate to increase speed of falling asleep the following day. Conversely, extension of sleep

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duration beyond 8 hours, or a compensatory nap, produces a reduction in the speed of falling asleep on the Multiple Sleep Latency Test.9

Circadian Regulation In addition to, and independent of, the homeostatic process is a circadian process that organizes sleep and wakefulness according to the 24-hour day and in phase with the light-dark cycle. The suprachiasmatic nucleus is the biological clock.10 It receives input from the retinohypothalamic tract that serves to synchronize the suprachiasmatic nucleus to the light-dark cycle. The suprachiasmatic nucleus efferent fibers then convey circadian timing signals that regulate a variety of physiological rhythms. Circadian phase typically is documented in humans by recording body temperature and in animals by recording wheel running. The daily human body temperature nadir occurs between 3:00 and 5:00 AM; a secondary decline in body temperature appears at about midday and peaks between 5:00 and 8:00 PM. The speed of falling asleep and the duration of sleep episodes parallel the body temperature rhythm; rapid sleep onsets and long durations occur over the temperature nadirs, whereas long onsets and short durations occur over temperature peaks. Hormonal and metabolic rhythms also are driven by the suprachiasmatic nucleus. For example, thyroid-stimulating hormone, cortisol, prolactin, growth hormone, and melatonin all show a circadian rhythm. Some of these hormones are linked to sleep (i.e., prolactin and growth hormone); that is, their release is delayed when sleep is delayed, at least acutely. Other hormones (e.g., cortisol) are directly linked to the lightdark cycle with their basal circadian rhythm remaining regardless of the timing of sleep. Melatonin is considered to be the internal hormonal signal that communicates the light-dark cycle throughout the body.11 Its production and release are controlled by the suprachiasmatic nucleus, and it is expressed during darkness and suppressed during light. The release of melatonin attenuates the alerting pulse of the suprachiasmatic nucleus, thereby facilitating sleep onset in the dark. A brief pulse of light interrupting darkness produces a rapid decline in melatonin levels, which continues for the duration of the light pulse. Its hypnotic capacity, beyond its chronobiotic characteristic, is unclear.

Homeostatic and Circadian Interaction Models that conceptualize the interaction of the homeostatic and circadian processes have been developed; the most widely cited model is the two-process of Borbely and colleagues.12 In this model, the sleep process (process S) builds during wakefulness and decreases during sleep. The circadian process (process C) promotes wakefulness and gates the expression of sleep at the appropriate circadian phase, if process S has reached its threshold. Another model, the opponent-process model, assigns the role of actively promoting wakefulness to the suprachiasmatic nucleus, the circadian pacemaker, which opposes an accumulating sleep drive.13 The alerting signal of the suprachiasmatic nucleus has a circadian rhythm, which, when absent or low, allows the expression of the sleep drive. When present at its peak, the alerting signal opposes the expression of sleep even when the sleep drive approaches its

peak level. Although these models clearly have heuristic value, several critical questions remain. The biochemical or molecular substrates of process S, or the “sleep drive,” are not known, and the neurobiological pathways by which process C interacts with sleep mechanisms have not been identified. On the other hand, an understanding of the neurobiological controls of wakefulness and sleep is emerging, which is discussed as follows.

NEUROBIOLOGICAL CONTROLS OF WAKE AND SLEEP Wake Giuseppe Moruzzi and Horace Winchell Magoun in 1949 identified an ascending arousal system, which they termed the reticular activating system, that regulates the level of forebrain wakefulness, but its origins were not characterized until 2001.15 The system consists of two main pathways: one innervating the thalamus and the other extending into the hypothalamus.15 The thalamic path originates from cholinergic pedunculopontine and laterodorsal tegmental (PPT-LDT) nuclei, and the hypothalamic path consists of noradrenergic locus ceruleus and serotoninergic dorsal and median raphe nuclei projections, which are joined at the hypothalamus by histaminergic tuberomammillary nucleus projections. These all project diffusely to the cortex. Electrophysiological recordings have verified the role of these nuclei in wakefulness.14 The locus ceruleus, dorsal and median raphe, and tuberomammillary nuclei fire at their fastest rate during wakefulness, are slowed in slow-wave sleep, and silent in REM sleep. In contrast, the PPT-LDT nuclei fire at their fastest rate during REM sleep, also fire during wakefulness, and are silent during slow-wave sleep.

Sleep The critical element in initiating sleep is inhibitory pulses generated by neurons in the ventrolateral preoptic (VLPO) nucleus, which project to the tuberomammillary, locus ceruleus, and dorsal and median raphe nuclei and to the PPT-LDT nuclei.14 The majority of these projections are γ-amino butyric acid mediated (GABAergic) and galaninergic and appear to inhibit the monoaminergic and cholinergic arousal systems. Electrophysiological recordings of neurons in the VLPO nucleus have shown that they fire at highest rates during sleep and are silent during wakefulness. The relation of the VLPO nucleus to monoaminergic and cholinergic arousal systems is reciprocal. The VLPO nucleus receives input from these systems that, during wakefulness, inhibit the VLPO nucleus’s sleep-promoting effect. The VLPO nucleus also receives input from the retina and the suprachiasmatic nucleus, which may provide the circadian signal for sleep initiation. But this step has not been verified.

Bistable Flip-Flop The reciprocal relation of the VLPO nucleus to monoaminergic and cholinergic arousal systems was characterized as a bistable flip-flop by Saper and colleagues.15 Rapid firing of the VLPO

chapter 14 the physiology of sleep nucleus inhibits the arousal system, which in turn disinhibits its own firing. Similarly, rapid firing of the arousal systems inhibits the VLPO nucleus, which thereby disinhibits the firing of these systems. Such a model, derived from electrical engineering, provides for stability of sleep and wakefulness states, no intermediate states, and rapid transitions between states. Once the sleep or wakefulness threshold is reached, a rapid reversal of firing patterns occurs. Because circadian signals and homeostatic sleep drive change slowly and continuously, a bistable system ensures rapid transitions and no entry into intermediate states. Saper and colleagues incorporated the recently discovered orexin/hypocretin peptides into the model in the role of stabilizing behavioral state.14 Orexin/hypocretin peptides were discovered in 1998 by two different investigating groups as neurotransmitters synthesized in the lateral hypothalamus. Orexin/hypocretin neurons were found to innervate all the ascending arousal systems and, furthermore, to project to the VLPO nucleus. On the basis of gene knockout studies in mice and genetic studies of humans with narcolepsy, both which show that the absence of orexin/hypocretin signaling via the type 2 receptor leads to intrusions of sleep into wakefulness, it appears that these neurons have an important role in maintaining wakefulness and further stabilizing sleep-wake state.14

SUMMARY Sleep is a vital, active, and highly organized behavior that has a dramatic effect on many aspects of physiology. It is controlled by two independent but interacting systems: a homeostatic and a circadian system. An additional system, an ultradian process, organizes the expression of two distinct states of sleep, REM and NREM, into 90- to 120-minute cycles. The neurobiological control of sleep and wakefulness involves cholinergic and monoaminergic substrates that promote arousal and GABAergic and galaninergic neurons that promote sleep. These two systems interact in a reciprocal inhibitory manner to maintain stable sleep and wakefulness. Control of sleep and wakefulness through these systems has been modeled as a bistable flip-flop switch. Behavioral state is further stabilized by the recently identified orexin/hypocretin peptides that affect both sides of the flip-flop circuit.

K E Y

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Sleep is a behavioral state that is characterized by minimal movement, reduced responsiveness to stimuli, reversibility, and species-specific diurnal timing, duration, and posture.

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Electrophysiological assessment of sleep has revealed that it is an active, complex, and highly organized process composed of two distinct brain states of sleep: REM and NREM.

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The REM and NREM states of sleep are associated with differing physiological characteristics and regulation.

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Wakefulness and the constituent states of sleep are regulated by three hypothesized processes—homeostatic, circadian, and ultradian—that are independent but interactive.

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Neurobiological control of sleep and wakefulness involves cholinergic and monoaminergic substrates that promote arousal and GABAergic and galaninergic neurons that promote sleep.

Suggested Reading Borbely AA, Achermann PA: Sleep homeostasis and models of sleep regulation. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 405-417. Carskadon MA, Dement WC: Normal human sleep: an overview. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 13-23. Czeisler CA, Turek FW: Melatonin, sleep and circadian rhythms: current progress and controversies [Special Issue]. J Biol Rhythms 1997; 12:485-708. Roth T, Roehrs T: An overview of normal sleep and sleep disorders. Eur J Neurol 2000; 7(Suppl 4):3-8. Saper CB, Chou TC, Scammell TE: The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24:726731.

References 1. Tobler I: Is sleep fundamentally different between mammalian species? Behav Brain Res 1995; 69:35-54. 2. Roehrs T, Carskadon MA, Dement WC, et al: Daytime sleepiness and alertness. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 39-50. 3. Zepelin H, Siegel JM, Tobler I: Mammalian sleep. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 91-100. 4. Rechtschaffen A, Kales A: A Manual of Standardized Techniques and Scoring System for Sleep Stages of Human Sleep. Los Angeles: Brain Information Service/Brain Research Institute, University of California at Los Angeles, 1968. 5. Roth T, Roehrs T: An overview of normal sleep and sleep disorders. Eur J Neurol 2000; 7(Suppl 4):3-8. 6. Issa FG, Suratt PM, Remmers JE, eds: Sleep and Respiration. New York: John Wiley, 1990. 7. Heller HC: Temperature, thermoregulation, and sleep. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 292-304. 8. Borbely AA, Achermann PA: Sleep homeostasis and models of sleep regulation. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 405-417. 9. Roehrs T, Shore E, Papineau K, et al: A two-week sleep extension in sleepy normals. Sleep 1996; 19:576-582. 10. Turek FW, Dugovic C, Laposky AD: Master circadian clock, master circadian rhythm. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 318320. 11. Czeisler CA, Turek FW: Melatonin, sleep and circadian rhythms: current progress and controversies [Special Issue]. J Biol Rhythms 1997; 12:485-708.

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12. Achermannn P, Dijk DJ, Brunner DP, et al: A model of human sleep homeostasis based on EEG slow-wave activity: quantitative comparison of data and simulations. Brain Res Bull 1993; 31:97-113. 13. Egar DM, Dement WC, Fuller CA: Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 1993; 13:1065-1079.

14. Moruzzi G, Magoun H: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949; 1:455-473. 15. Saper CB, Chou TC, Scammell TE: The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24:726-731.

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John W. Winkelman and Milena Pavlova

Difficulty with the regulation of sleep and wake states is present in up to 25% of the general population on a chronic basis and in up to one half of all individuals on occasion. For some, the primary concern is difficulty falling asleep, whereas for others it may be maintaining sleep or awakening feeling unrefreshed, even after a full night’s rest. Other individuals report excess daytime sleepiness, having difficulty maintaining alertness at inopportune or embarrassing times, or interference of sleepiness at times with productivity or even safety. The evaluation and treatment of such patients are the domains of sleep disorders medicine, a field that combines elements of neurology, psychiatry, pulmonary medicine, and otolaryngology. One of the most important motivations to the development of the field of sleep disorders has been the recognition of the effect of these conditions on multiple aspects of health. For instance, insomnia, the most common sleep disorder, has been hypothesized to account for $10 billion to $15 billion in direct and indirect costs to society, is associated with substantial decrements in quality of life, has been hypothesized to predispose sufferers to a variety of medical disorders, and has been clearly documented to be associated with substantial incident risks of major depression and other psychiatric disorders. Similarly, obstructive sleep apnea is clearly associated with excessive daytime sleepiness and an increase in motor vehicle accidents and is believed to contribute to hypertension and, potentially, premature mortality. A nosology of sleep disorders, the International Classification of Sleep Disorders, now in its second edition (ICSD-2),1 developed by the American Academy of Sleep Medicine (Table 15–1), has existed for more than 20 years. Its codes are consistent with the existing codes of the International Classification of Disease, 10th edition. The ICSD-2 organizes sleep disorders in eight categories on the basis of their predominant manifesting symptom and/or etiological basis: the insomnias; the sleep-related breathing disorders; hypersomnia not caused by a sleep-related breathing disorder; the circadian rhythm disorders; the parasomnias; the sleep-related movement disorders; and two miscellaneous categories comprising normal variants, isolated symptoms, and other sleep disorders. Readers are referred to Chapters 16 and 37 for detailed descriptions of obstructive sleep apnea and restless legs syndrome (RLS).

INSOMNIA Insomnia is defined as a difficulty in falling asleep, a difficulty in staying asleep, or nonrestorative sleep (awakening feeling unrefreshed). It is usually classified as transient, short-term, or chronic, according to the duration of symptoms, although many affected individuals describe recurrent episodes of short-term insomnia, which complicates classification. It may also be classified, on the basis of the predominant insomnia complaint, as initial insomnia, sleep maintenance insomnia, or insomnia with premature terminal awakening. This division, however, is also overly simplistic, inasmuch as many patients with chronic or recurrent short-term insomnia have an evolution of symptoms over time: Initial insomnia may develop into frequent or prolonged nocturnal awakenings or a mixture of the two. Thus, etiological inferences based on the type of manifesting symptom are bound to be confounded by these symptomatic fluctuations.

Epidemiology, Consequences, and Diagnosis of Insomnia Insomnia has also traditionally been characterized as primary or secondary on the basis of its presumed etiology. Insomnia is referred to as secondary when it is believed to be a symptom of an underlying medical, psychiatric, or sleep disorder, or when it follows medication use. This diagnosis is based on a plausible mechanism by which the underlying disorder causes insomnia (e.g., pain, shortness of breath), the occurrence of insomnia after that of the underlying condition, and a course that follows the severity of the underlying condition. According to this schema, treatment of the underlying cause should resolve the insomnia symptom. In contrast, primary insomnia is considered to be caused by physiological and cognitive hyperarousal, both within the sleep environment and during the day. The distinctions between primary and secondary insomnia have more recently been questioned, however, because of the difficulties in making this distinction, the recognition that secondary insomnia may evolve into primary insomnia, and the fact that some insomnia vulnerability factors may predispose persons with medical disorders to develop insomnia. The point prevalence of insomnia that lasts more than a few weeks is approximately 10% to 15% of the general population.2

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T A B L E 15–1. International Classification of Sleep Disorders, 2nd Edition Insomnia ADJUSTMENT Insomnia (Acute Insomnia) Psychophysiological Insomnia Paradoxical Insomnia Idiopathic Insomnia Insomnia Due to Mental Disorder Inadequate Sleep Hygiene Behavioral Insomnia of Childhood Insomnia Due to Drug or Substance Insomnia Due to Medical Condition Insomnia Not Due to Substance or Known Physiological Condition, Unspecified (Nonorganic Insomnia [NOS]) Physiological (Organic) Insomnia, Unspecified Sleep-Related Breathing Disorders Central Sleep Apnea Syndromes Primary Central Sleep Apnea Central Sleep Apnea Due to Cheyne-Stokes Breathing Pattern Central Sleep Apnea Due to High-Altitude Periodic Breathing Central Sleep Apnea Due to Medical Condition Not Cheyne-Stokes Central Sleep Apnea Due to Drug or Substance Primary Sleep Apnea of Infancy (formerly “Primary Sleep Apnea of Newborn”) Obstructive Sleep Apnea Syndromes Obstructive Sleep Apnea, Adult Obstructive Sleep Apnea, Pediatric Sleep-Related Hypoventilation/Hypoxemic Syndromes Sleep Related Nonobstructive Alveolar Hypoventilation, Idiopathic Congenital Central Alveolar Hypoventilation Syndrome Sleep-Related Hypoventilation/Hypoxemia Due to Medical Condition Sleep-Related Hypoventilation/Hypoxemia Due to Pulmonary Parenchymal or Vascular Pathology Sleep-Related Hypoventilation/Hypoxemia Due to Lower Airway Obstruction Sleep-Related Hypoventilation/Hypoxemia Due to Neuromuscular and Chest Wall Disorders Other Sleep-Related Breathing Disorder Sleep Apnea/Sleep Related Breathing Disorder, Unspecified Hypersomnias of Central Origin Not Due to a Circadian Rhythm Sleep Disorder, Sleep-Related Breathing Disorder, or Other Cause of Disturbed Nocturnal Sleep Narcolepsy with Cataplexy Narcolepsy without Cataplexy Narcolepsy Due to Medical Condition Narcolepsy, Unspecified Recurrent Hypersomnia Kleine-Levin Syndrome Menstrual-Related Hypersomnia Idiopathic Hypersomnia with Long Sleep Time Idiopathic Hypersomnia without Long Sleep Time Behaviorally Induced Insufficient Sleep Syndrome Hypersomnia Due to Medical Condition Hypersomnia Due to Drug or Substance Hypersomnia Not Due to Substance or Known Physiological Condition (Nonorganic Hypersomnia [NOS]) Physiological (Organic) Hypersomnia, Unspecified (Organic Hypersomnia, NOS) Circadian Rhythm Sleep Disorders Circadian Rhythm Sleep Disorder, Delayed Sleep Phase Type (Delayed Sleep Phase Disorder) Circadian Rhythm Sleep Disorder, Advanced Sleep Phase Type (Advanced Sleep Phase Disorder) Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type (Irregular Sleep-Wake Rhythm) Circadian Rhythm Sleep Disorder, Free-Running Type (Nonentrained Type) Circadian Rhythm Sleep Disorder, Jet Lag Type (Jet Lag Disorder) Circadian Rhythm Sleep Disorder, Shift Work Type (Shift Work Disorder) Circadian Rhythm Sleep Disorder Due to Medical Condition Other Circadian Rhythm Sleep Disorder (Circadian Rhythm Disorder, NOS) Other Circadian Rhythm Sleep Disorder Due to Drug or Substance Parasomnias Disorders of Arousal (from NREM Sleep) Confusional Arousals Sleepwalking Night Terrors Parasomnias Usually Associated with REM Sleep REM Sleep Behavior Disorder (Including Parasomnia Overlap Disorder and Status Dissociatus) Recurrent Isolated Sleep Paralysis Nightmare Disorder Reprinted from American Academy of Sleep Medicine: International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd ed. Rochester, MN: American Academy of Sleep Medicine, 2005.

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T A B L E 15–1. International Classification of Sleep Disorders, 2nd Edition—cont’d Other Parasomnias Sleep-Related Dissociative Disorders Sleep Enuresis Sleep-Related Groaning (Catathrenia) Exploding Head Syndrome Sleep-Related Hallucinations Sleep-Related Eating Disorder Parasomnia, Unspecified Parasomnia Due to Drug or Substance Parasomnia Due to Medical Condition Sleep Related Movement Disorders Restless Legs Syndrome Periodic Limb Movement Disorder Sleep-Related Leg Cramps Sleep-Related Bruxism Sleep-Related Rhythmic Movement Disorder Sleep-Related Movement Disorder, Unspecified Sleep-Related Movement Disorder Due to Drug or Substance Sleep-Related Movement Disorder Due to Medical Condition Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues Long Sleeper Short Sleeper Snoring Sleep Talking Sleep Starts (Hypnic Jerks) Benign Sleep Myoclonus of Infancy Hypnagogic Foot Tremor and Alternating Leg Muscle Activation During Sleep Propriospinal Myoclonus at Sleep Onset Excessive Fragmentary Myoclonus Other Sleep Disorders Other Physiological (Organic) Sleep Disorder Other Sleep Disorder Not Due to Substance or Known Physiological Condition Environmental Sleep Disorder NREM, non–rapid eye movement; REM, rapid eye movement.

However, because of its association with medical and psychiatric illnesses, up to 50% of individuals seen in medical practices report at least mild insomnia.3 Results of studies in individuals older than 65 suggest a 5% incidence and a 5% to 15% yearly rate of remission of insomnia.4,5 Female gender, increasing age, psychiatric and medical illnesses, substance use, low income, unemployment, and being single are all risk factors for having insomnia, although some of these may be consequences of insomnia rather than vulnerability factors.6-8 There is increasing recognition of the adverse consequences of insomnia. Multiple studies have demonstrated that persistent insomnia is associated with a substantial increased risk of incident depression.9 Insomnia is also associated with globally worsened quality of life, even when psychiatric illness10 or medical comorbidity3 is accounted for. The decrements in physical functioning, general health perception, and vitality are as substantial as, or more so than, those observed with congestive heart failure.3 Furthermore, there are suggestions that insomnia is associated with an increased risk of work-related and motor vehicle accidents, as well as falls by elderly persons.11 Finally, health costs in individuals with insomnia are elevated, even when comorbid medical and psychiatric illnesses are accounted for.12 The concept of hyperarousal is being used to unify the understanding of the pathophysiology of primary insomnia.13-15 From a physiological perspective, individuals with insomnia

have elevated evening cortisol levels,16 increased 24-hour whole body metabolic rate,17 increases in both waking and sleeprelated global cerebral glucose metabolism (Fig. 15–1),18 and high-frequency electroencephalographic (EEG) activity during sleep.19 It is unclear which neural circuits are responsible for

Ascending reticular activating system ■

Figure 15–1. Areas in which metabolism did not decrease from sleep to wakefulness in insomniac patients. (From Nofzinger EA, Buysse DJ, Germain A, et al: Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2168.)

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these disparate findings. Similarly, cognitive arousal is considered to be central to the generation and maintenance of insomnia. It is hypothesized that cognitive and physiological hyperarousal become paired with the sleep environment, which gradually worsens sleep and increases these arousal processes in that setting, creating a vicious cycle of insomnia.15,20 Maladaptive compensatory strategies, such as spending excess time in bed, daytime napping, and alcohol and caffeine intake can then exacerbate this process. The evaluation of patients with insomnia involves identifying the scope and duration of the complaint, including its effects on daytime functioning, and searching for potential etiologies. Behaviors and cognitions relevant to sleep during both daytime and evening should be solicited from the patient. In particular, explicit focus on the period in bed both before sleep and at nocturnal awakenings may assist with determining physical or mental events that interfere with sleep. Sleep diaries may help in elucidating predictable changes in sleep quality that are based on day of the week and/or work schedules. Factors that worsen or improve sleep quality longitudinally should also be identified. Life events that have a temporal relationship to the onset of sleep problems can frequently assist in identifying potential causes of insomnia, particularly in individuals with insomnias of shorter duration. In individuals with chronic insomnia, such events may have occurred many years in the past and may not be clear, or the insomnia may have a more insidious waxing course of severity. Identification of potential medical, sleep-related, and psychiatric causes of insomnia is essential for optimal treatment, because treatment of such causes may at times eliminate the insomnia complaint. Insomnia in elderly persons, in whom frequent nocturnal awakenings are the most common complaint, is particularly related to medical illness,21 and careful attention to patients’ medical problems may provide guides to the etiology of insomnia in this group. The most common medical disorders associated with insomnia are listed in Table 15–2. In addition, all psychiatric disorders can and frequently do cause insomnia, and assessments for depression and anxiety disorders are an essential feature of the insomnia evaluation. However, it should be made clear that approximately 40% of individuals with insomnia do not have a psychiatric disorder,22 and thus the assumption that insomnia is necessarily caused by psychiatric illness is ill founded. Polysomnography can also assist with the assessment of insomnia in some cases. This diagnostic procedure is not recommended for most individuals with insomnia23; however, when the clinician suspects sleep apnea or periodic limb movements of sleep (PLMSs), or when the patient reports frequent brief awakenings, polysomnography is indicated for further evaluation.

Treatment of Insomnia The treatment of insomnia is best achieved by addressing all possible underlying contributing factors, whether they are related to medical or psychiatric causes, poor sleep habits, or counterproductive sleep-related cognitions. A combination of approaches is generally recommended. For individuals with insomnia of recent onset, an identifiable precipitant (a physical or emotional stressor) is usually present, and the duration of

T A B L E 15–2. Medical Disorders or Conditions Commonly Associated with Insomnia Cardiovascular Congestive heart failure with paroxysmal nocturnal dyspnea and/or Cheyne-Stokes respiration Nocturnal angina Pulmonary Chronic obstructive pulmonary disease Asthma Nocturnal cough Gastrointestinal Gastroesophageal reflux disease Irritable bowel syndrome Musculoskeletal Arthritis Fibromyalgia Traumatic injury Endocrine Perimenopause or menopause Diabetes Thyroid disease Renal Insufficiency or Failure

the complaint is often short. If, in such individuals, the insomnia is associated with substantial concern or daytime dysfunction, short-term use of a hypnotic agent is recommended so as to minimize the immediate effect of the insomnia and to prevent the development of a more chronic conditioned insomnia. In individuals with chronic primary insomnia, and in some individuals with secondary insomnia, first-line treatments are modification of sleep-related behaviors and attitudes, called cognitive-behavioral therapy. Cognitive-behavioral therapy has a number of components: (1) limitation of time in bed (sleep restriction and stimulus control), which produces mild sleep deprivation, thus allowing shorter sleep onset and reduction in the number and duration of awakenings, and reduces the duration of time awake in bed, limiting negative associations to the sleep environment; (2) relaxation techniques, which reduce physiological and cognitive arousal in the sleep setting by use of yoga, meditation, and/or biofeedback; (3) cognitive restructuring, which addresses catastrophic beliefs and attitudes regarding sleeplessness, replacing them with more rational expectations of sleep and effects of insomnia; and (4) sleep hygiene, which refers to a variety of habits that promote good sleep such as regular bedtimes and waking times, daily exercise, avoidance of napping, careful use of alcohol and caffeine, and reduction in behaviors that promote nocturnal emotional and physical arousal (e.g., work, emotional stimulation, nighttime exercise). Cognitive-behavioral therapy has been shown to produce consistent reduction in sleep onset latency and wake time during the night, as well as smaller increases in total sleep time.24,25 These gains have generally been maintained over periods of up to 24 months. Pharmacological therapies for insomnia have evolved since the 1950s from barbiturates to long-acting benzodiazepines, then to shorter acting benzodiazepines, and, since the

chapter 15 primary disorders of sleep α1

T A B L E 15–3. Benzodiazepine Receptor Agonists Commonly Used for the Treatment of Insomnia Agent (Brand Name) *

α2

α3

α4

■

Figure 15–2. γ-Amino butyric acid A (GABAA) receptor subtypes, localization and function in mouse brain. (From Mohler H, Fritschy J, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2-8.)

mid-1990s, to non-benzodiazepine receptor agonists (BzRAs). In addition, there has been a trend away from these approved medications for insomnia and toward the use of sedating medications with original indications for other disorders (e.g., antidepressants, anticonvulsants, antipsychotics), to the point at which antidepressants constitute more than 50% of all prescription medications for insomnia.26 Recommendations as to the appropriate use of hypnotics in the treatment of insomnia are evolving, and this and other treatment issues in insomnia were reviewed in a state-of-the-science National Institute of Mental Health consensus statement.27 Benzodiazepines and BzRAs bind at an allosteric site on the γ-amino butyric acid A (GABAA) receptor complex, influencing GABA binding and chloride flux. The BzRAs demonstrate relatively selective binding for GABAA receptors that contain α1 subunits. The α1 subunits mediate the sedative, amnestic, and anticonvulsant properties of these agents but few of the muscle relaxant and anxiolytic aspects (Fig. 15–2).28 However, it is unclear whether the relative receptor selectivity of the BzRAs have clinical significance in terms of efficacy or short- or longterm tolerability. More important than the receptor-binding characteristics of these agents are the major differences between the half-lives of these agents, which, when combined with dosage, determine the duration of the medication’s effects. Half-lives of hypnotics in this class vary from 1 to more than 100 hours (Table 15–3). Because of the variability of sleep complaints, medication choices in this class are usually based on matching the patient’s sleep complaint with an appropriate half-life agent, so as to maximize the opportunity for sleep but minimize waking hangover effects. Meta-analyses have demonstrated the efficacy of benzodiazepines and BzRAs in reducing sleep onset latency, decreasing

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Flurazepam (Dalmane) Estazolam (Prosom)* Temazepam (Restoril)* Triazolam (Halcion)* Eszopiclone (Lunesta) Zolpidem (Ambien) Zaleplon (Sonata)

Dosage Range

Half-Life

15-30 mg 1.0-2.0 mg 7.5-30 mg 0.125-0.25 mg 1-3 mg 5-10 mg 5-10 mg

50-100 hours 10-20 hours 4-18 hours 2-3 hours 5.5-8 hours 2-3 hours 1-2 hours

Benzodiazepines.

the amount of wakefulness after sleep onset, and in increasing total sleep time in patients with primary insomnia.29 However, when a meta-analysis of benzodiazepines alone was performed, the absolute size of this effect for sleep onset latency was not dramatic: a reduction of 4.2 minutes when assessed by polysomnography and of 14.3 minutes by self-report. On the other hand, total sleep time was increased by a mean of 61.8 minutes.30 The majority of these efficacy data come from shortduration studies. For instance, the median duration of the studies in the benzodiazepine and BzRA meta-analysis was 7 days; the common duration of insomnia complaints, in contrast, is often months to years. Studies addressing the longer term efficacy of these medications in continuous and intermittent use have been performed. Eszopiclone, the S-isomer of the commonly prescribed hypnotic zopiclone, has been shown to produce persistent benefits for sleep onset latency, wakefulness after sleep onset, total sleep time, and daytime functioning for 6 months of nightly use in comparison with placebo in patients with primary insomnia.31

PERIODIC LIMB MOVEMENT DISORDER PLMSs are commonly recorded movements during sleep consisting of repetitive dorsiflexion of the foot and/or lower leg. Movements are generally subtle and may not be recognized by a bed partner, although in more severe forms, they are more obvious. PLMS may or may not be associated with arousals from sleep, and indices of the number of movements with and without arousal per hour of sleep are derived. The term periodic limb movement of sleep is derived from the strict periodicity of movements, which occur at 15- to 30-second intervals during sleep. Movements are roughly 2 seconds in duration (Fig. 15–3). When a sleep complaint occurs in the presence of PLMS, in the absence of other known causes of sleep disruption, a diagnosis of periodic limb movement disorder is given. PLMSs are commonly recorded on overnight polysomnography, and population estimates of the prevalence of PLMSs exceeding five per hour range from 11% to 58%.32 PLMSs are more commonly recorded in elderly persons, in patients taking antidepressants, and in a number of medical conditions (end-stage renal disease, congestive heart failure, diabetes) and neurological or sleep disorders (obstructive sleep apnea, narcolepsy, Parkinson’s disease, multiple sclerosis). Although approximately 80% of individuals with RLS demonstrate PLMS, only a small proportion of those with PLMS describe symptoms

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EEG

Chin EMG Heart rate R.A.T. EMG L.A.T. EMG

30 sec. ■

Figure 15–3. Periodic limb movements of sleep (PLMS) as recorded on polysomnography. EEG, electroencephalogram; EMG, electromyogram; L.A.T., left anterior tibialis; R.A.T., right anterior tibialis.

of RLS. Controversy exists regarding the clinical importance of PLMS for sleep quality or daytime alertness; some studies show a lack of correlation between PLMS index and subjective or objective sleep quality or daytime sleepiness, and others show some mild associations.33 There is substantial evidence that PLMSs are associated with dopaminergic dysregulation at either spinal or higher central nervous system levels. Dopaminergic antagonists can produce PLMS,34 whereas dopaminergic agonists are extremely effective in reducing PLMS.35 Disorders characterized by dopaminergic deficiency (e.g., narcolepsy, rapid eye movement [REM] sleep behavior disorder [RBD]) are accompanied by high rates of PLMS. Functional imaging of the brain has demonstrated small but consistent reductions in dopaminergic function in PLMS. Finally, dopaminergic metabolites have been observed to be correlated with the number of PLMSs.36 The presence of PLMS in quadriplegic patients suggests that the motor programs for these movements exist in the spinal cord and are somehow disinhibited in patients with excessive movements during sleep. Clinically, periodic limb movement disorder should be suspected when an individual (or his or her bed partner) reports kicking or jerking of his or her legs during sleep and has a complaint of sleep disruption or excess daytime sleepiness that cannot be accounted for by another cause. Polysomnography is necessary to make the diagnosis of periodic limb movement disorder, both to document the PLMS but also to exclude other causes of repetitive leg movements—most prominently, obstructive sleep apnea. The differential diagnosis of nocturnal leg movements in the sleep period includes RLS (in which leg restlessness is reported before sleep onset), anxiety (in which leg movements are observed during wakefulness, not sleep), nocturnal seizures (which produce abnormal EEG changes), obstructive sleep apnea (in which characteristic respiratory abnormalities are observed), or RBD (in which movements are dream enactments, occur during REM sleep, and are not periodic). Treatment of periodic limb movement disorder begins with an accurate diagnosis and proceeds to consideration of eliminating potential precipitating or exacerbating agents (e.g., antidepressants). PLMS can be dramatically reduced with the addition of dopaminergic agents, at least within the context of RLS. However, there is some suggestion that EEG arousals may persist even with elimination of the manifest motor activity. For

this reason, coadministration of substitution of a benzodiazepine has also been advocated. Although studies of triazolam in patients with PLMS did not reveal a reduction in the periodic limb movement index, improvements in leg movements associated with arousal, sleep architecture, and daytime alertness were all demonstrated,37 even after 12 weeks of nightly use.38 Use of clonazepam in small numbers of patients was effective in reducing the number of PLMs, as well as improving scores on sleep continuity measures.39

EXCESS DAYTIME SLEEPINESS Excess daytime sleepiness has numerous causes. Clinical diagnostic algorithms proceed from a determination of sleep quantity to an evaluation of sleep quality and then to assessment of potential contributors to an intrinsic excess sleep drive. Insufficient sleep is the most common cause of excess daytime sleepiness among both adults and children. Because of its pervasiveness, careful attention to sleep times is required in individuals with a description of excess daytime sleepiness. Sleep quantity is determined by history, sleep logs, and if necessary, polysomnography. Any cause of poor sleep quality can produce excess daytime sleepiness, although the most common are sleep apnea, neurological, pulmonary and cardiac diseases, and environmental sleep disruption. The underlying cause of sleep disruption is commonly discernible from the history and/or physical examination, although polysomnography may be required for some disorders (e.g., sleep apnea). Finally, if excessive daytime sleepiness is present, and if sleep quantity and quality appear to be sufficient, a primary disorder of sleepiness or a medication effect should be suspected. These are discussed as follows.

Excess Daytime Sleepiness as a Result of Medical and Neurological Diseases Multiple neurological diseases can cause sleepiness: either by disrupting the mechanisms involved in sleep homeostasis or by simply disrupting nighttime sleep. For example, cerebral traumatic injury or thalamic lesions (such as bilateral medial thalamic infarcts) can impair the central mechanisms of sleep-wake regulation, while pain from diabetic neuropathy of multiple

chapter 15 primary disorders of sleep sclerosis can cause sleep fragmentation and thus result in excessive sleepiness. Some specific examples are described as follows.

Stroke Common Comorbid Conditions One common cause of excessive sleepiness in the general population is sleep apnea. This condition is also quite common in patients with stroke.40 Symptoms of sleepiness and snoring may in fact be associated with higher risk of first-ever stroke.41,42 Prevalence after stroke may be even higher: Harbison and associates42 reported that up to 94% of patients had a respiratory disturbance index of 10 or above on polysomnography, performed in the 2 weeks after a stroke. Patients more likely to have more severe sleep apnea were older and more likely to have lacunar infarcts and greater prestroke disability. Sleepdisordered breathing improved over time, but about 72% of the patients had clinically important sleep apnea 6 weeks later. As good-quality sleep may improve recovery from illness, treatment of sleep apnea can also hasten recovery from stroke. Patients with sleep apnea may have more residual symptoms of stroke after rehabilitation,43 whereas treatment of sleep apnea, when present in a patient with stroke, may hasten the rehabilitation process.44

Role of Specific Vascular Lesions Sleepiness after stroke is common.45-47 Hemispheric stroke can result in insomnia, hypersomnia, or sleep disruption, but most EEG changes are transient.46,48,49 There can be alterations of sleep architecture, including REM sleep, especially within the first 3 days after the event.49 Increased slow-wave activity may be seen in the contralateral hemisphere.46 Consolidated sleep and high sleep efficiency are likely to herald a good clinical outcome.48,49 Rare alterations of sleep architecture include REM sleep abnormalities. For example, there are reports of dream loss with bilateral posterior cerebral artery infarcts50 and lesions of the pontine tegmentum can lead to absence of REM sleep,51 as well as to hypersomnia.52 Additional sleep disruption in patients who have had a stroke may be secondary to bulbar involvement, as well as to discomfort from pain and spasticity. Therefore, treatment is generally targeted at the cause and can include continuous positive airway pressure, bilevel positive airway pressure, or conservative measures for treatment of sleep apnea, if present. Treatment of spasticity can include higher doses of muscle relaxants (typically baclofen), especially in the evening, inasmuch as most have sedating properties.

Multiple Sclerosis Patients with multiple sclerosis frequently complain of sleepiness, fatigue, and cognitive problems, as well as sleep disruption. Common causes for impairment of sleep and resulting sleepiness are described as follows.

Impaired Sleep as a Result of Pain, Spasticity, or Nocturia Spasticity may be associated with nocturnal pain and consequently sleep fragmentation. Muscle relaxants can effectively

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improve sleep. Because urinary symptoms are common in multiple sclerosis, nocturia can also fragment sleep. Treatment with desmopressin may be effective in reducing the nocturnal voids by 31% to 54% and, in one study, increased the initial sleep period or mean maximum period of uninterrupted sleep by approximately 2 hours.53

Associated Psychiatric Disorders Many patients with multiple sclerosis have associated depressive or other psychiatric symptoms.54-56 These symptoms may vary in intensity, depending on the short-term risk of disability or wheelchair dependence.56 Because both depression and anxiety are associated with sleep disturbance, they can contribute to sleep impairments in patients with multiple sclerosis.

Immunological Factors Immunological factors, which are involved in the pathogenesis of multiple sclerosis, may also have somnogenic effects. These include interleukin-1,57 which is known to be associated with sleepiness. Fatigue may be more prominent in patients who have markers of immune activation, including inductors of lymphocyte B cells, increase in helper T cells, interleukin-2 receptor cells, or other markers.54

Impaired Sleep-Wake Regulation as a Result of Plaques Because demyelination can involve various pathways involved in the regulation of sleep and wakefulness, it would be logical to expect an independent effect of the focal dysfunction, depending on the location of the multiple sclerosis plaques. Indeed, case reports have suggested some such effects. For example, Oka and colleagues58 reported signs of narcolepsy associated with multiple sclerosis. Plazzi and Montagna59 reported RBD as a first symptom of multiple sclerosis. However, plaque location and burden are variable, and most sleep problems are multifactorial.

Medication Effect Most muscle relaxants have sedating properties. Although their use at night improves sleep continuity, daytime use may be associated with undesirable sleepiness. This effect is more pronounced at the beginning of treatment, and some tolerance may develop over time. Pain management, when necessary, may lead to further sedation. Steroid treatment may be associated with decreased slow-wave sleep, increased sleep onset latency, and increased wakefulness after sleep onset.60 Certain sleep architecture abnormalities, resembling the ones seen in depression (shorter REM latency and increase in REM density), have also been reported.61 Interferon treatment may also be associated with increased somnolence.62,63

Treatment In most cases, treatment should be targeted to the cause of sleep disruption. For example, treatment of the urinary frequency will probably improve sleep continuity as a result of fewer episodes of nocturia. Relief of spasticity and pain with gabapentin or baclofen may improve sleep as well.64 Most muscle relaxants can help additionally with sleep onset and continuity through their sedating properties.

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When sleepiness continues despite optimal treatment of the underlying symptoms, the addition of modafinil can safely and effectively improve vigilance.65,66

Parkinson’s Disease Patients with Parkinson’s disease frequently report sleepiness. This is reported on standardized instruments67,68 and also confirmed in standardized laboratory tests of sleepiness (i.e., a multiple sleep latency test), as well as a maintenance of wakefulness test. These impairments are correlated with poor sleep.69 Sleepiness should be distinguished from fatigue, which is also prevalent among patients with Parkinson’s disease.70,71 Longer disease duration, as well as anticholinergic medications, are associated with especially impaired sleep.72

Sleep Disruption from Parkinson’s Disease Itself One cause of sleep fragmentation in Parkinson’s disease is the degeneration of dopaminergic neurons in the central nervous system. Because dopamine is involved in the regulation of the sleep-wake cycle, dopamine depletion, as well as dopaminergic stimulation in a dopamine-depleted state, may lead to sleepiness. In addition, alterations of levels of the hypothalamic peptide hypocretin, which have been reported to be extremely low or absent in narcolepsy, have been implicated in the pathogenesis of sleepiness in Parkinson’s disease, because hypocretin may have a role in the dopamine release mechanism.73,74 In addition, reports have implicated genetic polymorphism in D2 receptors in sleep attacks.75 Sleep in patients with Parkinson’s disease can be additionally disrupted by pathological motor phenomena. Patients may have nocturnal akinesia, tremor and rigidity, freezing, and motor restlessness, as well as motor behavior during REM sleep or PLMS. Other causes include nocturia, which is common in these patients.

Vivid Dreams Vivid dreams are another potential cause of sleep disruption. This phenomenon may be more prevalent with the use of dopamine agonists and may be more likely to occur in patients who also have hallucinations. In a 6-year prospective study, patients with hallucinations had similar sleep patterns as did those without hallucinations, but vivid dreams were associated with significantly poorer sleep.76

Effects of Medications Sleepiness, as well as arousal, can be increased by levodopa, as well as by dopamine agonists. For example, irresistible sleep attacks (“sudden onset of sleep”) have been reported with all of the dopamine agonists, although some patients experience insomnia. Medications that have stimulant metabolites (selegiline, amantadine) may lead to sleep fragmentation.

RBD Sleep Behavior Disorder RBD is common in patients with Parkinson’s disease. For example, Schenck and associates77 reported that 38% of the patients with Parkinson’s disease develop RBD. Possible causes in both disorders include loss of striatal dopamine transporters78 and resulting abnormal muscle tone, including loss of REM atonia.

Treatment The first step of treatment is control of sleep-disrupting factors. In patients with refractory sleepiness, modafinil can be helpful to control residual sleepiness with minimal side effects.79 Counseling about driving may be appropriate as well, because episodes of irresistible sleepiness may occur, not preceded by obvious warning.

Other Neurological Diseases Multisystem Atrophy Multisystem atrophy may be associated with a high prevalence of apnea, mainly central.80,81 In addition, patients may have laryngeal stridor, which may lead to vocal cord paralysis and risk for sudden death.82-84 Depending on the clinical circumstances, the patients may require assisted ventilation or surgical procedures.

Dystonia Sleep alterations with cervical dystonia are correlated with the severity of the disease, especially frequency of spasms.85,86 Spasms can persist in sleep even in the absence of EEG arousals but become progressively less severe with sleep depth.

Cerebellar Atrophy Among patients with spinocerebellar ataxia, sleep complaints seem most common in spinocerebellar ataxia type 3.87 Contributing factors include higher frequencies of neuropathy and RLS with this form. Thus, treatment includes pain relief in the case of neuropathy and dopamine agonists or gabapentin if RLS is present.

Poliomyelitis and Postpolio Syndrome Among patients with postpolio syndrome, the incidence of both obstructive and central apneas during sleep is higher than that in the general population. These disturbances are more prominent in patients who have had respiratory involvement during the initial illness.88 Thus, treatment is targeted at treatment of the sleep breathing disorder.

Cervical Myelopathy Patients with cervical myelopathy have a higher prevalence of respiratory disturbances during sleep. In a study of 50 randomly selected tetraplegic patients, 55% of the men and 20% of the women had a respiratory disturbance index of 5 or higher.89 Mid- and low cervical lesions may also lead to delayed apneas, and these can sometimes be very severe.90 In an isolated case, anterior spinal artery syndrome led to continuous central apneas during sleep.91 Additional problems may include bradycardia, with or without hypotension.91 Thus, treatment should involve careful evaluation and treatment of sleep breathing disturbance (e.g., with continuous positive airway pressure). Other causes of sleep impairment in these patients involve neurological deficits, pain, spasticity, and injury to the pathways involved in melatonin secretion. A study of patients with tetraplegia caused by cervical and upper thoracic injuries demonstrated near absence of melatonin in the patients with cervical lesions.92 To date, however, there are no reports of successful treatment with exogenous melatonin in these patients.

chapter 15 primary disorders of sleep Dementia Dementia can be the result of various conditions, including neurodegenerative, vascular, infectious, and other causes. The most common form is Alzheimer’s disease. Patients may have reduced sleep efficiency and increased number of arousals, and the severity of these findings tends to parallel that of the dementia itself. Abnormalities of sleep architecture, such as increased REM latency and decreased slow-wave sleep, have also been reported, but these findings are less consistent. Circadian rhythm abnormalities are also seen, discussed in more detail in the section “Circadian Rhythm Disorders.” Treatment of sleep disturbances is challenging in patients with dementia. Because poor sleep can negatively affect cognition, evaluation early in the course for common sleep disorders, such as sleep apnea and RLS, is warranted. As dementia patients may have more severe cognitive impairments, as well as paradoxical agitation with benzodiazepines, nonbenzodiazepine hypnotics are generally preferred.

Epilepsy Effects of Seizures on Sleep Sleepiness is common among patients with epilepsy. As in other neurological conditions, sleepiness is multifactorial, secondary to the effects of sleep fragmentation from the disorder itself, as well as from effects of antiepileptic medications, most of which have sedative properties (Table 15–4). Nocturnal seizures can be associated with sleep fragmentation, and arousal or awakening may occur before or after the event. Frequently, temporal lobe seizures occur after awakening, and frontal lobe seizures occur during sleep. However, the causal relationship is still debated. Sleep is also disrupted in patients with localized epilepsy, independently from any seizures. Patients with temporal lobe epilepsy (TLE) report multiple awakenings, even on the nights when they have not had a seizure.

Diurnal and nocturnal variations in seizure rate have led to examinations of the relationship of seizures to sleep. In two prospective studies, researchers examined the distribution of seizures in relation to sleep stage and depth. Both Herman and colleagues in 200193 and Minecan and coworkers in 200294 reported that of all sleep stages, non-REM sleep, especially stage 2 sleep, is associated with the highest proportion of seizures. T A B L E 15–4. Medications Associated with Sleepiness and Insomnia

Anticonvulsants Dopamine agonists or precursors Interferons SSRIs

Occurrence of seizures during sleep (versus wakefulness) may depend on epileptogenic region. A study of intracranial recordings in patients with TLE revealed a tendency toward arousal before a seizure in almost all of the patients.95 However, patients with frontal lobe epilepsy tended to have seizures during sleep, and these were usually not associated with abrupt arousal from sleep.93,96

Effects of Sleep on Interictal Discharges Interictal discharges distinguish patients with epilepsy from healthy individuals. Interictal discharges are not evenly distributed through all sleep stages. Multiple studies have reported a higher rate of interictal discharges during stages 3 and 4 sleep than in stages 1 and 2 sleep in patients with TLE97,98 and those with generalized epilepsy.99,100 The effect of sleep stage on interictal discharges in patients with TLE was robust: most patients had a higher interictal discharge rate in deep non-REM sleep, and this rate was up to nine times higher than the interictal discharge rate during wakefulness. A caveat to this interpretation is that sleep preferentially occurs at specific circadian times; therefore, it is possible that these sleep-related effects are at least partially caused by an underlying circadian rhythm in interictal discharge propensity.

Seizures and Circadian Rhythm Pavlova and associates101 analyzed data from 26 consecutive patients with confirmed TLE or other localization-related epilepsy. To test for any systematic day/night pattern in seizure frequency, they divided the 24-hour period into six 4-hour “bins” and compared the proportion of seizures across bins. In the TLE group, there was a clear peak in the time of occurrence of seizures: 50% occurred between the hours of 15:00 and 19:00 (see Fig. 15–1). In the patients with other localization-related epilepsies, there was a peak in seizure frequency between the hours of 19:00 and 23:00.

NARCOLEPSY

Effects of Sleep on Seizures

Medications Associated with Sleepiness

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Medications Associated with Insomnia β Blockers Steroids SSRIs Antimigraine medications (especially ones containing caffeine)

Tricyclic antidepressants Opiates SSRI, selective serotonin reuptake inhibitor.

Although narcolepsy is relatively rare, its features are so distinctive that it remains the most commonly discussed and researched of the primary disorders of sleepiness. Dramatic advances in the biology of this disorder have furthered the understanding of the disease process, as well as of sleep-wake regulation. Narcolepsy is characterized by excess daytime sleepiness and dysregulation of REM processes. The first of these is assessed clinically and verified by the multiple sleep latency test, in which the patient is allowed five nap opportunities, each 2 hours apart, beginning 2 hours after awakening. An average latency to sleep onset of less than 5 minutes across the five naps is indicative of pathological daytime sleepiness. The REM dysregulation is verified by the appearance of more than one REM period during the multiple sleep latency test nap, with or without an early appearance of REM during the overnight polysomnography. Ironically, most narcoleptic patients also demonstrate poor nocturnal sleep quality, describing frequent nighttime awakenings. Clinically, REM dysregulation in narcolepsy is characterized by the inappropriate appearance of the REM phenomena muscle paralysis and dreams during wakefulness or at the sleep-wake transition. Cataplexy is a sudden onset of muscle atonia in the antigravity and facial muscles, resulting in falls,

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difficulty holding objects, or twitching of agonist and antagonist muscles in these areas. Cataplexy is usually stimulated by laughter, telling a joke, anger, surprise, or other emotional processes. Sleep paralysis is the appearance of REM atonia in wakefulness, leading to brief (seconds to minutes), usually frightening inability to move voluntary musculature in the presence of full alertness, either on awakening or at the transition from wakefulness to sleep. Concomitant paralysis of the accessory muscles of inspiration may result in the sensations of dyspnea. Hypnogogic (at sleep onset) or hypnopompic (at awakening) hallucinations is the appearance of the hallucinatory phenomena of dreams during wakefulness. Usually these are fragmentary and brief (hearing the telephone or one’s name being called) or seeing a shadow of a person, although in rare cases they may be more elaborate. Although these REM phenomena are occasionally reported in isolation by individuals without narcolepsy, they are common, and frequently observed as a group, in this disorder. Narcolepsy is currently classified as existing with or without cataplexy. The exact percentage of individuals with the excess daytime sleepiness of narcolepsy who also have cataplexy is unclear but is thought to be 50% to 80% of cases. Narcolepsy is present in 0.05% of adults. Its onset occurs most commonly in the second decade of life, but initial appearance of symptoms in the 30s is not uncommon. The mean time between symptom onset and diagnosis is frequently prolonged, because of the misdiagnosis of narcolepsy as a psychiatric disorder or a manifestation of laziness. Narcolepsy is a chronic but nonprogressive disorder. However, some individuals experience the onset of cataplexy a number of years after the onset of daytime sleepiness. Equal numbers of men and women are affected, and no clear ethnic variations have been reported. Major progress in the understanding of the pathophysiology of narcolepsy has been made since the mid-1990s, stimulated by findings derived from molecular biology. A mutation in the gene that codes for the receptor for the hypothalamic peptide hypocretin was determined to be responsible for the Doberman pinscher model of narcolepsy.102 At the same time, Chemelli and associates103 found that when the gene for the same peptide (which they called orexin) was knocked out in mice, the mice exhibited behavioral states consistent with narcolepsy. In humans, the dramatic reduction in hypothalamic neurons responsible for the production of hypocretin (orexin)104 and the absence of this ligand in the cerebrospinal fluid105 of narcoleptic patients have confirmed the importance of hypocretin (orexin) in human narcolepsy with cataplexy. The excess expression of the specific human leukocyte antigen genotype DQB1*0602 in individuals with narcolepsy (85% of narcoleptics versus 25% of the general population) is suggestive of an immunological etiology of narcolepsy. However, neither immunological abnormalities nor antigenic targets have been identified in human narcolepsy. Treatment of narcolepsy is directed independently for the daytime sleepiness and REM dysregulation (Table 15–5). It is essential to stress the importance of adequate nocturnal sleep and the value of daytime napping, if feasible, as means of minimizing excess daytime sleepiness in narcolepsy. Stimulant medications, which have been available since the 1950s, have been the traditional mainstay of narcolepsy pharmacological treatment. These medications both release the catecholamines norepinephrine and dopamine and block their reuptake into their releasing neurons, enhancing their effects. They are effec-

T A B L E 15–5. Medications Used for the Treatment of Narcolepsy Medication Modafinil (Provigil) Dextroamphetamine (Dexedrine and others) Methylphenidate (Ritalin and others)

T1/2 (Hours)

Tmax

FDA Schedule

15 5-10

2-4 3

IV II

3

1.9

II

FDA, U.S. Food and Drug Administration; T1/2, half-life; Tmax, time to maximal serum concentration.

tive in promoting wakefulness in narcolepsy, allowing a more normal level of professional and social functioning. In addition, controlled-release preparations of methylphenidate and amphetamines have been developed, allowing once- to twiceper-day dosing. However, there are persistent concerns regarding their potential for abuse and the not uncommon side effects of headache, anorexia, mood alterations, and blood pressure and pulse elevations. First-line treatment of excess daytime sleepiness has become modafinil, a long-acting agent that only partially acts on the dopaminergic system, and thus has substantially less risk of abuse, and that has fewer sympathomimetic side effects. Treatment of the REM dysregulation–related symptoms (principally cataplexy) is achieved with REM suppressants. Tricyclic antidepressants, which once had a primary role in treatment, have been replaced by the better tolerated and safer selective serotonin reuptake inhibitors (Tables 15–6 and 15–7). Both of these classes of medications suppress cataplexy, sleep paralysis, and hynogogic hallucinations. Cataplexy, which does not respond to these agents, may be successfully treated with γ-hydroxybutyrate, a short-acting sedating medication that is given twice during the night and has demonstrated benefit in reducing daytime cataplectic attacks, as well as daytime sleepiness.

T A B L E 15–6. Overview of Parasomnias Non-REM Parasomnias

REM-Related Parasomnias

Stage of arousal Time of night EEG with event

II, III, IV First third N.A.

EMG with event Relative unresponsiveness during event Autonomic activity

Low Yes

REM Any time Characteristic of REM High, variable Yes

Amnesia Confusion after episode Family history of parasomnias

Low (confusional arousal) High (sleep terror) Yes Yes Yes

High No No No

EEG, electroencephalography; EMG, electromyography; N.A., not applicable; REM, rapid eye movement.

chapter 15 primary disorders of sleep T A B L E 15–7. Pharmacological Treatment of Parasomnias Drug

Dosage

Non-REM Parasomnias Triazolam Zolpidem Lorazepam Clonazepam

0.125-0.5 mg 5-10 mg 1-2 mg 0.5-2.0 mg

REM-Related Parasomnias Clonazepam Lorazepam Melatonin Pramipexole

0.5-2.0 mg 1.0-2.0 mg 3-15 mg 0.5-1.0 mg

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toxic, or structural abnormalities. Electroencephalograms can be characterized by fast (14- to 16-Hz), nonreactive background activity.111 Plasma and cerebrospinal fluid may show a marked increase in a benzodiazepine-like endogenous substance, endozepine-4.111,112 Flumazenil, a benzodiazepine receptor antagonist, may promptly resolve the syndrome.

CIRCADIAN RHYTHM DISORDERS

REM, rapid eye movement.

IDIOPATHIC HYPERSOMNIA A number of less common causes of excess daytime sleepiness are recognized. Principal among these is idiopathic hypersomnolence; patients experience the excess daytime sleepiness of narcolepsy but do not have any of the REM-related symptoms. Individuals report normal nocturnal sleep (in contrast to narcolepsy) but severe difficulty arousing from sleep in the morning or from daytime naps. These naps are longer than the ones in patients with narcolepsy and may take 2 to 3 hours. Even after these long naps, patients are only partially refreshed. Diagnosis is made by polysomnography and results of the multiple sleep latency test. Overnight polysomnography demonstrates high sleep efficiency, and the multiple sleep latency test reveals pathologically shortened sleep latency (similar to narcolepsy), but without the appearance of REM periods during daytime naps. Because medical and neurological disorders (described previously) can lead to excess daytime sleepiness, this is generally a diagnosis of exclusion. As suggested by its name, the cause of idiopathic hypersomnolence is unknown. Treatment is targeted to symptomatic relief of the daytime somnolence. Modafinil (at dosages of 200 to 400 mg/day) can be used, as can conventional stimulants (e.g., amphetamines, methylphenidate).

KLEINE-LEVIN SYNDROME The Kleine-Levin syndrome is characterized by periodic, sudden-onset episodes of hypersomnia, compulsive hyperphagia, and hypersexuality, lasting from a few days to a few weeks, with complete remission in between. Various other behavioral disturbances may occur during the episodes. The cause and pathogenesis of Kleine-Levin syndrome remain unknown. It is more common in men, but female patients have been described as well, and the ratio is probably 4:1.106-108 When seen in young women, it can have a catamenial pattern.108 Diagnosis is made on the presence of the classic triad after other causes of excessive sleepiness are ruled out. Treatment can include stimulants or modafinil for hypersomnolence and possibly lithium salts.109,110

IDIOPATHIC RECURRENT STUPOR Idiopathic recurring stupor is a syndrome of spontaneous stupor or coma that is not associated with known metabolic,

Circadian Rhythm Effects on Normal and Abnormal Neurophysiological Functions Normal neurophysiological functions are affected by the circadian system independently of sleep or wakefulness state and time awake. Subjective alertness, cognitive performance, and short-term memory are lowest close to the time of the temperature minimum, or the “biological night” (e.g., see Johnson et al,74 and Dijk et al113). Mood in healthy subjects is also modulated by a nonadditive interaction between the sleep-wake cycle and the circadian phase, and this modulation may be implicated in mood disorders.114 Multiple neurological conditions have a circadian pattern. Patients with various forms of dementia may have transient changes in mental status, including agitation, hallucinations, and delusions. These are especially prominent in the evening hours, and this situation thus has been termed sundowning. Patients with epilepsy may also have specific exacerbations related to circadian rhythms (see “Epilepsy” section).

Disorders of the Circadian Rhythm Delayed Sleep Phase Syndrome Delayed sleep phase syndrome (DSPS) is a disorder of the phase relationships between the desired sleep times and the circadian system manifesting as a tendency to fall asleep much later than desired and awakening later than the desired time. As a result, these patients frequently come to medical attention with complaints of insomnia. DSPS is an especially frequent cause of insomnia in the young adult.115

Diagnosis The International Classification of Sleep Disorders1 has established the following “minimal criteria” for diagnosis: (1) The patient is unable to initiate sleep at the desired time and difficulty awakening; (2) timing of the habitual sleep episode is delayed (late); (3) symptoms are present for 1 month or more; (4) when constraints permit (e.g., when not working or attending classes), the patient opts for delayed timing of the major sleep episode, which is believed to be of good quality and quantity, and can awaken from this sleep episode without difficulty and remains on this delayed sleep-wake schedule without difficulty; and (5) subjective sleep data (e.g., sleep-wake diary) for 2 weeks or more verify the presence of the delayed, habitual sleep-wake schedule. In most cases, the diagnosis can be made from the history, in addition to a sleep-wake diary. In some instances, documenting sleep-wake times through wrist actigraphy can be helpful as well.

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Treatment

Non–24-Hour Rhythm Disturbance

The most powerful factors that entrain the circadian rhythm are (1) light, which provides information about the time of the “day,” and (2) melatonin, which provides information about the time of “night.” On the basis of these, several major approaches have been proposed:

Light is the primary stimulus that synchronizes the endogenous circadian rhythm with the environmental conditions. It is perceived by the retinal cells, and the signal is transmitted to the circadian pacemaker, the suprachiasmatic nucleus, via the retinohypothalamic tract. Because the circadian period tends to be close to but slightly longer than 24 hours, daily exposure to light ensures that sleep occurs during the night time for most people. Impairment or absence of light perception can lead to disruption or lack of synchronization between the circadian sleep promoting mechanisms and the scheduled time to sleep. This can occur in blind people. Klein and colleagues129 described such a cause of insomnia in a blind person, confirming that sleep was most likely to occur close to the subject’s temperature minimum.

1. Chronotherapy was proposed by Czeisler and colleagues,116 on the basis of the assumption that the patient’s schedule cannot be advanced. Thus, the patient is advised to delay his or her wake sleep times by 3 hours every 24 hours until the desired sleep time is reached. 2. Phototherapy (light treatment) is considered useful because bright light can shift the “biological night” of individuals (as measured by major physiological parameters, such as core body temperature) in experimental conditions.117-120 The rapidity and degree of change depend on the intensity of the stimulus and its timing in relation to the subject’s core body temperature minimum at the start of the treatment. Empirical use of bright light can be used for treatment of DSPS, administered in the hours between 6:00 and 9:00 AM at 2000 to 2500 lux with reasonable success. The optimal duration of therapy is not established, although a treatment for 2 weeks for 2 hours every morning has been reported as successful.121,122 3. Melatonin can be used to shift the circadian rhythm and can be a reasonable alternative treatment. Administration of 5 mg at 10:00 P.M. has been reported successful in two studies123,124 and well tolerated. Unlike the use of some hypnotics, treatment is not associated with a “hangover effect,” but some patients have reported morning fatigue.124 Because the effects on the reproductive system development are not fully known, caution has been advised for younger patients. Other reported treatment options include vitamin B12 supplementation. In a two-patient report of an adolescent who did not have a vitamin B12 deficiency, administration of high-doses vitamin B12 was successful. However, no randomized studies have been performed. None of these approaches has been compared head to head, and thus none is established as superior to the others. In additional, patients vary widely with regard to compliance, and thus any one of these methods or a combination can be used, depending on the clinical circumstances.

Advanced Sleep Phase Syndrome In advanced sleep phase syndrome, as in DSPS, the “biological night” of the patient is believed to be “locked” in an adverse time in relation to the desired bedtime but occurs hours earlier rather than later. This disturbance is more frequent among older individuals. Occasional familial forms exist as well.125-127 Like that of DSPS, diagnosis is based on clinical history and can be confirmed by sleep diary or objective measures, such as wrist actigraphy. Treatment options are similar to those for DSPS. Phototherapy, as evening bright light, at 2000 to 2500 lux in the hours between 8:00 and 11:00 P.M. for 2 to 3 hours, can be used.123 However, the effectiveness of bright light has been questioned in one study.128

Jet Lag A similar desynchronization between the environmental night and the “biological night” occurs during travel across time zones in a short period of time; this desynchronization is commonly known as jet lag. Like non–24-hour rhythm disturbance, it can manifest as insomnia, difficulty with concentration, or sleepiness and could be logically expected to modify disorders that have a circadian pattern. Typically, adjustment to eastbound travel is found to be more difficult. Treatment can include phase advance before travel,130,131 use of bright light, or use of melatonin.132,133

PARASOMNIAS The term parasomnia is derived from the Latin para, meaning “next to,” and somnus, referring to sleep. In the International Classification of Sleep Disorders, 2nd edition, parasomnias are defined as “undesirable physical or experiential events that accompany sleep.”1 Parasomnias are traditionally divided into those arising from non-REM sleep (also known as confusional arousals) and those occurring during REM sleep. These two types of parasomnias can often be distinguished by their distinctive time of night occurrence, type of mentation during the event, mental status on awakening, duration, degree of amnesia for the event, and associated autonomic activation. Thus, with a few simple questions, parasomnias can often be correctly classified by the clinician.

Non-REM Parasomnias The understanding of non-REM parasomnias is based on the concept that arousal from sleep is not an all-or-none phenomenon but rather a continuum of alertness, judgment, and control over behavior. Behaviors or affective expression can occur during full or partial sleep states, which are at least partially divorced from full awareness, both during the event and on awakening. Most commonly, such behaviors are dissociated motor activities (walking, eating, sexual behavior) or emotional responses (fear, anger, sexual excitement).134 They are distinct from waking behavior in that complex mentation is usually not present, feedback from the environment is usually given less

chapter 15 primary disorders of sleep salience, and sound judgment is usually not present. It is unclear to what extent these behaviors or emotional states are related to waking motivation, psychological state, or psychopathology. It is clear that these behaviors run in families.135 Phenotypically, they share many features: They are commonly brief, are more frequently expressed in children, are associated with amnesia, and occur in the first 1 to 2 hours of sleep, usually arising during slow-wave sleep. Non-REM parasomnias are best conceptualized along a continuum of emotional/motoric/ autonomic arousal, in which confusional arousals have the least arousal and sleep terrors the most. Confusional arousals are usually brief, simple, motor behaviors, which usually occur without substantial affective expression. Mental confusion with automatic behavior, indistinct speech, and relative unresponsiveness to the environment are hallmarks of a confusional arousal.136 Sitting up in bed with simple vocalization or picking at bedclothes are common examples. If interrupted by family members, responses may be absent, incomplete, or inappropriate. Sleepwalking involves more elaborate behavior than simple confusional arousals, but it forms a continuum with the latter. Simple motivations without substantial emotional involvement, such as attempts to use the bathroom, go to the kitchen, or, in some cases, leave the home, are usually pursued. Although the walker’s eyes are open, behavior may be clumsy.137,138 Dreaming is usually not present, and individuals (if awakened) report only simple mentation. As in confusional arousals, sleepwalkers usually return to sleep, but if aroused by family members or as a result of their inappropriate behavior, sleep inertia may be present. In rare cases, individuals may become agitated if sleepwalking episodes are interrupted. Sleep terrors have many of the properties of other non-REM parasomnias but are characterized by more intense autonomic, motor, and affective expression (and experience). In children, sleep terrors are classically heralded by a piercing scream, with extreme fear, crying, and inconsolability.139 In adults, agitation is common, frequently with the belief that there is an imminent threat, with the requirement of escape or defense.140 For this reason, sleep terror sufferers may cause injury to themselves, to others, or to property in their highly agitated state. As in sleepwalking, dreaming is usually not reported, but simple thoughts are present (“The room is on fire” or “I am being attacked”), which can be difficult to dispel, even after the sufferer has awakened. They may incorporate an individual into the threatening scenario if they are interfered with, potentially harming that individual. For this reason, it is recommended that individuals experiencing a sleep terror be gently redirected in an attempt to raise their level of consciousness. Non-REM parasomnia variants have also been identified in adults: excessive sleep inertia (or “sleep drunkenness”),141 abnormal sleep-related sexual behavior (“sexsomnia”),142 and sleep-related violence.143 Amnesia for non-REM parasomnias is often so dense that without a bed partner’s or parent’s report, or evidence from the episode, these episodes might go unnoticed. Epidemiological information is therefore unreliable. In view of this caveat, approximately 10% to 20% of children and 2% to 5% of adults report a history of confusional arousals.136 Sleepwalking occurs in 10% to 20% of children and 1% to 4% of adults.136,144 Sleep terrors are less common than sleepwalking; approximately 5% of children and 1% to 2% of adults report a history of such

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events.136 In approximately 80% of adults with sleepwalking, this parasomnia is a continuation of a childhood behavior, although many such persons do not come to medical attention until their 20s or 30s. There is a wide range of sleepwalking frequency; most sleepwalkers present with only occasional episodes, although those who frequently sleepwalk are the ones who usually come to medical attention. The expression of all non-REM parasomnias appears to depend on a genetic predisposition combined with a precipitating event, which may be endogenous (e.g., respiratory obstructive event, pain, leg movement of sleep) or exogenous (e.g., forced awakening or environmental disruption).144,145 In predisposed individuals, sleep deprivation, medications, sleep disorders, stress, and circadian misalignment may all aggravate or expose this underlying parasomnia. It is unclear why such partial arousals are more common in children. Nevertheless, genetic factors in non-REM parasomnias are evidenced by both epidemiological studies and studies of twins.145,146 Risk of sleepwalking is approximately doubled if one parent has a sleepwalking history and tripled when both parents have such a history. There do not appear to be gender or racial differences in the prevalence rates of these parasomnias. Even in individuals with frequent episodes, parasomnia episodes are often not observed in the sleep laboratory.147 Sleep studies, however, are often performed in such patients (particularly in an adult with new-onset sleepwalking) to determine whether there are potential precipitating events occurring during sleep, such as a sleep-related breathing disorder, PLMSs, nocturnal seizures, or RBD. When they are observed, the electroencephalogram may show delta waves (characteristic of slow-wave sleep), theta or alpha activity, or alternation between sleep and waking activity.148 There is an unclear relationship between psychiatric disorders and non-REM parasomnias.134 Although childhood sleepwalking does not appear to be associated with psychiatric disorders, a variety of psychiatric disorders may increase the risk of persistent sleepwalking into adulthood.136,149 However, it is not believed that sleepwalking represents latent psychopathology.150 Nonetheless, psychiatric medications may raise the risk of sleepwalking, because of their sleep-disruptive or sleep-enhancing properties.151 Similarly, stress, sleep deprivation,152 and chaotic sleep schedules may increase the risk of sleepwalking, and each of these precipitants may be more common in the psychiatric patient. When seeing a patient with abnormal nocturnal behavior, the clinician needs to consider a number of disorders. These include nocturnal panic attacks, nocturnal dissociative episodes, frontal or temporal lobe seizures, delirium associated with medical or neurological disorders, and RBD. A daytime history of behaviors similar to the nocturnal behaviors (e.g., panic or dissociative episode) would certainly direct the diagnosis away from a non-REM parasomnia. Similarly, overnight polysomnography might assist in the diagnosis of RBD or a seizure disorder.

Treatment of Non-REM Parasomnias The decision to treat non-REM parasomnias is based on the frequency of the event, the risk of associated injury to self or others, and the distress the behavior is causing the patient or family members.136 Fortunately, for the majority of adult

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sufferers, parasomnias occur infrequently, but unfortunately, their appearance is unpredictable. Therefore, the decision to treat must be carefully considered, particularly when the sleepwalker engages in high-risk behaviors. For most children, parasomnias do not necessitate treatment, unless there is risk of harm, and although the parents’ sleep may be disrupted, the child is usually unaware of the events. Regularization of the sleep-wake cycle and avoidance of sleep deprivation reduce the frequency of events. For those children and young adults who do sleepwalk, enhancing the safety of the sleeping environment, such as locking doors and windows and keeping hallways and stairs well lit, is essential. When treatment of sleepwalking or sleep terrors in an adult is warranted, a three-step approach is used: modification of predisposing and precipitating factors, enhancing safety of the sleeping environment, and, when these are not successful, pharmacotherapy. Sleep disorders (e.g., sleep apnea, PLMSs), symptoms of medical disorders (pain, nocturia, dyspnea), or medications that are thought to be contributing to sleep instability should be modified to the extent possible. As described previously, the safety of the environment should be maximized. The majority of data on the treatment of non-REM parasomnias exist for clonazepam (0.5 to 1.0 mg one hour before bed), which has been used successfully for sleepwalking and sleep terrors for extended periods without the development of tolerance in most patients.153 However, if the parasomnia occurs within the first half of the sleep period, short-acting benzodiazepine receptor agonists such as triazolam (0.125 to 0.25 mg) or zolpidem (5 to 10 mg) are recommended, to minimize daytime carryover effects. It is unclear whether these medications work by suppressing arousals during sleep or decreasing slow-wave sleep, and no controlled trials testing their efficacy have been performed. However, because of favorable clinical experience, they are first-line agents in the treatment of these disorders.

An animal model of RBD, in which lesions around the locus ceruleus produced “REM sleep without atonia” was developed well before the discovery of RBD and implicates these brainstem areas in the control of motor activity in REM sleep.157 In patients with RBD, dopamine transporter abnormalities in the nigrostriatal system have been demonstrated.158 Similarly, a reduction in neurons around the locus ceruleus has been seen.159 However, more widespread central nervous system dysfunction is suggested by data showing slowing of the EEG pattern during wakefulness as well as subtle neuropsychological dysfunction in patients with idiopathic RBD.160 The diagnosis of RBD is made by polysomnography, which demonstrates elevated muscle tone or excessive phasic muscle activity in the submental and anterior tibialis electromyogram during REM sleep.1 At times, body movements are manifest during REM on sleep study. Excess PLMSs may also be observed during both REM and non-REM sleep. Otherwise, polysomnography findings are generally normal. First-line treatment of RBD consists of benzodiazepine receptor agonists. The most commonly used agent is clonazepam (0.5 to 1.0 mg), which has been shown to substantially decrease the number and extent of pathological dream-enacting behaviors.153 In general, the medication is well tolerated for this indication; however, because of the age of most of the patients with RBD and the long half-life of clonazepam, excess daytime sleepiness and/or cognitive impairments may occur. In this case, shorter acting benzodiazepines (e.g., lorazepam, 1 to 2 mg) may be used. Other medications, particularly melatonin (3 to 15 mg one hour before bed)161 and pramipexole (0.5 to 1.0 mg one hour before bed), have also been used with some success.162 These alternatives are appropriate for patients for whom a benzodiazepine is associated with cognitive or motor side effects or is contraindicated because of substance abuse. Certainly, removal of potentially offending medications, such as antidepressants, should be attempted if clinically possible. In addition, as with the non-REM parasomnias, safety of the sleeping environment for both the patient and the bed partner is essential.

REM Sleep Behavior Disorder RBD is characterized by pathological appearance of the normal features of REM sleep. In RBD, the usual atonia of REM sleep is absent; this allows the sleeper to enact dreams, which, when agitated or violent, can result in injury to the sleeper or bed partner.154 During such episodes, the sleeper’s eyes are closed, and the sleeper is unresponsive to the environment until awakened, at which point he or she achieves rapid and full alertness and reports a dream that usually corresponds to the exhibited behavior. It is this agitation and/or injury that bring the patient to medical attention, usually at the behest of the bed partner. Episodes of full-blown RBD are intermittent, but sleeptalking, shouting, vivid dreams, or fragmentary motor activity may commonly occur between such events. RBD is a chronic disorder, usually observed in men older than 50 and in individuals with certain neurological disorders. In particular, RBD is often present in individuals with αsynucleinopathies (Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy).155 RBD may also be a heralding symptom of neurological illness: In one study, twothirds of patients with RBD monitored for 10 years developed Parkinson’s disease.156 RBD may also be precipitated by treatment with serotonergic antidepressants.

K E Y

P O I N T S

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Sleep disorders can be classified into the insomnias, the hypersomnias, circadian rhythm disorders, and the parasomnias.

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Chronic insomnia, which is present in approximately 10% of adults, has substantial consequences for daytime functioning and has been associated with an increased incidence of major depression.

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Both cognitive behavioral therapy and pharmacotherapy have roles in the treatment of insomnia.

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Excess daytime sleepiness can be the result of multiple neurological disorders, and treatments can either be empirical or directed to the underlying disorders.

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Parasomnias, when frequent or associated with risk of injury, are usually treated with benzodiazepine-receptor agonists.

chapter 15 primary disorders of sleep Suggested Reading Krystal AD, Walsh JK, Laska E, et al: Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26:793-799. Peyron C, Faraco J, Rogers W, et al: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6:991-997. Riemann D, Voderholzer U: Primary insomnia: a risk factor to develop depression? J Affect Disord 2003; 76:255-259. Ripley B, Overeem S, Fujiki N, et al: CSF. hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57:2253-2258. Schenck CH, Bundlie SR, Mahowold MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996; 46:388-393.

References 1. American Academy of Sleep Medicine: International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd ed. Rochester, MN: American Academy of Sleep Medicine, 2005. 2. Ohayon MM: Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002; 6:97-111. 3. Katz DA, McHorney CA: The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract 2002; 51:229-235. 4. Foley DJ, Monjan A, Simonsick EM, et al: Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6800 persons over three years. Sleep 1999; 22:S366-S372. 5. Dodge R, Cline MG, Quan SF: The natural history of insomnia and its relationship to respiratory symptoms. Arch Intern Med 1995; 155:1797-1800. 6. Klink ME, Quan SF, Kaltenborn WT, et al: Risk factors associated with complaints of insomnia in a general adult population. Influence of previous complaints of insomnia. Arch Intern Med 1992; 152:1634-1637. 7. Foley DJ, Monjan AA, Brown SL, et al: Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995; 18:425-432. 8. Ohayon MM, Roth T: What are the contributing factors for insomnia in the general population? J Psychosom Res 2001; 51:745-755. 9. Riemann D, Voderholzer U: Primary insomnia: a risk factor to develop depression? J Affect Disord 2003; 76:255-259. 10. Léger D, Scheuermaier K, Philip P, et al: SF-36: evaluation of quality of life in severe and mild insomniacs compared with good sleepers. Psychosom Med 2001; 63:49-55. 11. Avidan AY, Fries BE, James ML, et al: Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005; 53:955-962. 12. Simon GE, VonKorff M: Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry 1997; 154:14171423. 13. Bonnet MH, Arand DL: Hyperarousal and insomnia. Sleep Med Rev 1997; 1:97-108. 14. Drake C, Richardson G, Roehrs T, et al: Vulnerability to stressrelated sleep disturbance and hyperarousal. Sleep 2004; 27:285-291. 15. Tang NK, Harvey AG: Effects of cognitive arousal and physiological arousal on sleep perception. Sleep 2004; 27: 69-78.

199

16. Vgontzas AN, Bixler EO, Lin HM, et al: Chronic insomnia is associated with nyctohemeral activation of the hypothalamicpituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 2001; 86:3787-3794. 17. Bonnet MH, Arand DL: Situational insomnia: consistency, predictors, and outcomes. Sleep 2003; 26:1029-1036. 18. Nofzinger EA, Buysse DJ, Germain A, et al: Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2128. 19. Krystal AD, Edinger JD, Wohlgemuth WK, et al: NREM sleep EEG frequency spectral correlates of sleep complaints in primary insomnia subtypes. Sleep 2002; 25:630640. 20. Perlis ML, Giles DE, Mendelson WB, et al: Psychophysiological insomnia: the behavioural model and a neurocognitive perspective. J Sleep Res 1997; 6:179-188. 21. Vitiello MV, Moe KE, Prinz PN: Sleep complaints cosegregate with illness in older adults: clinical research informed by and informing epidemiological studies of sleep. J Psychosom Res 2002; 53:555-559. 22. Ford DE, Kamerow DB: Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989; 262:1479-1484. 23. Sateia MJ, Doghramji K, Hauri PJ, et al: Evaluation of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 2000; 23:243-308. 24. Morin CM, Culbert JP, Schwartz SM: Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry 1994; 151:1172-1180. 25. Edinger JD, Glenn DM, Bastian LA, et al: Sleep in the laboratory and sleep at home II: comparisons of middle-aged insomnia sufferers and normal sleepers. Sleep 2001; 24:761770. 26. Walsh JK: Pharmacologic management of insomnia [Review]. J Clin Psychiatry 2004; 65(Suppl 16):41-45. 27. National Institutes of Health: State-of-the-science conference statement: manifestations and management on chronic insomnia in adults. Available at: http://consensus.nih.gov/ta/ 026/InsomniaDraftStatement061505.pdf (accessed March 9, 2006). 28. Mohler H, Fritschy J, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2-8. 29. Nowell PD, Mazumdar S, Buysse DJ, et al: Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997; 278:2170-2177. 30. Holbrook AM, Crowther R, Lotter A, et al: Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000; 162:225-233. 31. Krystal AD, Walsh JK, Laska E, et al: Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26:793-799. 32. Morrish E, King MA, Pilsworth SN, et al: Periodic limb movement in a community population detected by a new actigraphy technique. Sleep Med 2002; 3:489-495. 33. Carrier J, Frenette S, Montplaisir J, et al: Effects of periodic leg movements during sleep in middle-aged subjects without sleep complaints. Mov Disord 2005; 20:1127-1132. 34. Cohrs S, Rodenbeck A, Guan Z, et al: Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl) 2004; 174:421-429. 35. Montplaisir J, Nicolas A, Denesle R, et al: Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999; 52:938-943. 36. Cohrs S, Guan Z, Pohlmann K, et al: Nocturnal urinary dopamine excretion is reduced in otherwise healthy subjects with periodic leg movements in sleep. Neurosci Lett 2004; 360:161-164.

200

Section

II

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37. Doghramji K, Browman CP, Gaddy JR, et al: Triazolam diminishes daytime sleepiness and sleep fragmentation in patients with periodic leg movements in sleep. J Clin Psychopharmacol 1991; 11:284-290. 38. Bonnet MH, Arand DL: Chronic use of triazolam in patients with periodic leg movements, fragmented sleep and daytime sleepiness. Aging (Milano) 1991; 3:313-324. 39. Peled R, Lavie P: Double-blind evaluation of clonazepam on periodic leg movements in sleep. J Neurol Neurosurg Psychiatry 1987; 50:1679-1681. 40. Parish JM, Somers VK: Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc 2004; 79:1036-1046. 41. Davies DP, Rodgers H, Walshaw D, et al: Snoring, daytime sleepiness and stroke: a case-control study of first-ever stroke. J Sleep Res 2003; 12:313-318. 42. Harbison J, Ford GA, James OF, et al: Sleep-disordered breathing following acute stroke. Q J Med 2002; 95:741-747. 43. Cherkassky T, Oksenberg A, Froom P, et al: Sleep-related breathing disorders and rehabilitation outcome of stroke patients: a prospective study. Am J Phys Med Rehabil 2003; 82:452-455. 44. Kaneko Y, Hajek VE, Zivanovic V, et al: Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep 2003; 26:293-297. 45. De Groot MH, Phillips SJ, Eskes GA: Fatigue associated with stroke and other neurologic conditions: implications for stroke rehabilitation. Arch Phys Med Rehabil 2003; 84:17141720. 46. Muller C, Achermann P, Bischof M, et al: Visual and spectral analysis of sleep EEG in acute hemispheric stroke. Eur Neurol 2002; 48:164-171. 47. Bliwise DL, Rye DB, Dihenia B, et al: Greater daytime sleepiness in subcortical stroke relative to Parkinson’s disease and Alzheimer’s disease. J Geriatr Psychiatry Neurol 2002; 15:6167. 48. Vock J, Achermann P, Bischof M, et al: Evolution of sleep and sleep EEG after hemispheric stroke. J Sleep Res 2002; 11:331338. 49. Bassetti CL, Aldrich MS: Sleep electroencephalogram changes in acute hemispheric stroke. Sleep Med 2001; 2:185194. 50. Bischof M, Bassetti CL: Total dream loss: a distinct neuropsychological dysfunction after bilateral PCA stroke. Ann Neurol 2004; 56:583-586. 51. Gironell A, de la Calzada MD, Sagales T, et al: Absence of REM sleep and altered non-REM sleep caused by a haematoma in the pontine tegmentum. J Neurol Neurosurg Psychiatry 1995; 59:195-196. 52. Arpa J, Rodriguez-Albarino A, Izal E, et al: Hypersomnia after tegmental pontine hematoma: case report. Neurologia 1995; 10:140-144. 53. Cvetkovic RS, Plosker GL: Desmopressin: in adults with nocturia. Drugs 2005; 65:99-107. 54. Irarte J, Subira M, Castro PL Modalities of fatigue in multiple sclerosis: correlation with clinical and biologic factors. Mult Scler 2000; 6:124-130. 55. Janssens AC, van Doorn PA, de Boer JB, et al: Impact of recently diagnosed multiple sclerosis on quality of life, anxiety, depression and distress of patients and partners. Acta Neurol Scand 2003; 108:389-395. 56. Janssens AC, van Doorn PA, de Boer JB, et al: Perception of prognostic risk in patients with multiple sclerosis: the relationship with anxiety, depression, and disease-related distress. J Clin Epidemiol 2004; 57:180-186. 57. Rothwell NJ, Luheshi GN: Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 2000; 23:618-625.

58. Oka Y, Kanbayashi T, Mezaki T, et al: Low CSF hypocretin1/orexin-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis. J Neurol 2004; 251:885-886. 59. Plazzi G, Montagna P: Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis. Sleep Med 2002; 3:437-439. 60. Vgontzas AN, Chrousos GP: Sleep, the hypothalamicpituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am 2002; 31:15-36. 61. Antonijevic IA, Steiger A: Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis. Psychoneuroendocrinology 2003; 28:780-795. 62. Kimura M, Majde JA, Toth LA, et al: Somnogenic effects of rabbit and recombinant human interferons in rabbits. Am J Physiol 1994; 267:R53-R61. 63. Munschauer FE 3rd, Kinkel RP: Managing side effects of interferon-beta in patients with relapsing-remitting multiple sclerosis. Clin Ther 1997; 19:883-893. 64. Mueller ME, Gruenthal M, Olson WL, et al: Gabapentin for relief of upper motor neuron symptoms in multiple sclerosis. Arch Phys Med Rehabil 1997; 78:521-524. 65. Zifko UA, Rupp M, Schwarz S, et al: Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002; 249:983-987. 66. Rammohan KW, Rosenberg JH, Lynn DJ, et al: Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72:150. 67. Johns M: Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth sleepiness scale. Chest 1993; 103:30-36. 68. Tan EK, Lum SY, Fook-Chong SMC, et al: Evaluation of somnolence in Parkinson’s disease: comparison with age- and sex-matched controls. Neurology 2002; 58:465-468. 69. Stevens S, Cormella CL, Stepanski EJ: Daytime sleepiness and alertness in patients with Parkinson disease. Sleep 2004; 27:967-972. 70. Alves G, Wentzel-Larsen T, Larsen JP: Is fatigue an independent and persistent symptom in patients with Parkinson disease? Neurology 2004; 63:1908-1911. 71. Serrano C, Garcia-Borreguero D: Fluctuations in cognition and alertness in Parkinson’s disease and dementia. Neurology 2004; 63:S31-S34. 72. Nausieda PA, Weiner WJ, Kaplan LR, et al: Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis. Clin Neuropharmacol 1982; 5:183194. 73. Ripley B, Overeem S, Fujiki N, et al: CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57:2253-2258. 74. Johnson MP, Duffy JF, Dijk DJ, et al: Short-term memory, alertness and performance: a reappraisal of their relationship to body temperature. J Sleep Res 1992; 1:24-29. 75. Rissling I, Geller F, Brandmann O, et al: Dopamine receptor gene polymorphisms in Parkinson’s disease patients reporting “sleep attacks.” Mov Disord 2004; 19:1279-1284. 76. Goetz CG, Wuu J, Curgian LM, et al: Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005; 64:81-86. 77. Schenck CH, Bundlie SR, Mahowold MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996; 46:388-393. 78. Eisensehr I, Linke R, Tatsch K, et al: Increased muscle activity during rapid eye movement sleep correlates with decrease

chapter 15 primary disorders of sleep

79.

80. 81.

82. 83.

84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.

97. 98.

of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003; 26:507-512. Hogl B, Saletu M, Brandauer E, et al: Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a doubleblind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002; 25:905-909. Guilleminault C, Lehrman K, Forno L, et al: Sleep apnoea syndrome: states of sleep and autonomic dysfunction. J Neurol Neurosurg Psychiatry 1977; 40:718-725. Castaigne P, Laplane D, Autret A, et al: [Shy-Drager syndrome with disturbances of the respiratory rhythm and consciousness. A propos of an anatomo-clinical case]. Rev Neurol 1977; 113:455-466. Munschauer FE, Loh L, Bannister R, et al: Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 1990; 40:677-679. Isozaki E, Hayashi M, Hayashida T, et al: [Vocal cord abductor in multiple system atrophy—paradoxical movement of vocal cords during sleep]. Rinsho Shinkeigaku 1996; 36:52933. Sadaoka T, Kakitsuba N, Fujiwara Y, et al: Sleep-related breathing disorders in patients with multiple system atrophy and vocal fold palsy. Sleep 1996; 19:479-484. Sforza E, Montagna P, Defazio G, Lugaresi E. Sleep and cranial dystonia. Electroencephalogr Clin Neurophysiol 1991; 79:166-169. Silvestri R, De Domenico P, Di Rosa AE, et al: The effect of nocturnal physiological sleep on various movement disorders. Mov Disord 1990; 5:8-14. Schols L, Haan J, Riess O, et al: Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology 1998; 51:1603-1607. Steljes DG, Kryger MH, Kirk BW, et al: Sleep in postpolio syndrome. Chest 1990; 98:133-140. Stockhammer E, Tobon A, Michel F, et al: Characteristics of sleep apnea syndrome in tetraplegic patients. Spinal Cord 2002; 40:286-294. Lu K, Lee TC, Liang CL, et al: Delayed apnea in patients with mid- to lower cervical spinal cord injury. Spine 2000; 25:1332-1338. Manconi M, Mondini S, Fabiani A, et al: Anterior spinal artery syndrome complicated by the Ondine curse. Arch Neurol 2003; 60:1787-1790. Kneisley LW, Moskowitz MA, Lynch HG: Cervical spinal cord lesions disrupt the rhythm in human melatonin excretion. J Neural Transm Suppl 1978; 13:311-323. Herman ST, Walczak TS, Bazil CW: Distribution of partial seizures during the sleep-wake cycle: differences by seizure onset site. Neurology 2001; 56:1453-1459. Minecan D, Natarajan A, Marzec M, et al: Relationship of epileptic seizures to sleep stage and sleep depth. Sleep 2002; 25:899-904. Malow BA, Kushwala R, Lin X, et al: Relationship of interictal epileptiform discharges to sleep depth in partial epilepsy. Electroencephalogr Clin Neurophysiol 1997; 102:20-26. Crespel A, Baldy-Moulinier M, Coubes P: The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia 1998; 39:150-157. Malow BA, Lin X, Kushwaha R, et al: Interictal spiking increases with sleep depth in temporal lobe epilepsy. Epilepsia 1998; 39:1309-1316. Sammaritano M, Gigli GL, Gotman J: Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 1991; 41:290-297.

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99. Ross JJ, Johnson LC, Walter RD: Spike and wave discharges during stages of sleep. Arch Neurol 1966; 14:399-407. 100. Sato S, Dreifus FE, Penry JK: The effect of sleep on spikewave discharges in absence seizures. Neurology 1973; 23:1335-1345. 101. Pavlova MK, Shea SA, Bromfield EB: Day/night patterns of focal seizures. Epilepsy Behav 2004; 5:44-49. 102. Lin L, Faraco J, Li R, et al: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98:365-376. 103. Chemelli RM, Willie JT, Sinton CM, et al: Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98:437-451. 104. Peyron C, Faraco J, Rogers W, et al: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6:991-997. 105. Nishino S, Ripley B, Overeem S, et al: Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001; 50:381-388. 106. Mayer G, Leonhard E, Krieg J, et al: Endocrinological and polysomnographic findings in Kleine-Levin syndrome: no evidence for hypothalamic and circadian dysfunction. Sleep 1998; 21:278-284. 107. Billiard M, Guilleminault C, Dement WC: A menstruationlinked periodic hypersomnia. Kleine-Levin syndrome or new clinical entity? Neurology 1975; 25:436-443. 108. Kesler A, Gadoth N, Vainstein G, et al: Kleine-Levin syndrome (KLS) in young females. Sleep 2000; 23:1-5. 109. Muratori F, Bertini N, Masi G: Efficacy of lithium treatment in Kleine-Levin syndrome. Eur Psychiatry 2002; 17:232-233. 110. Visscher F, Smit LM, Smith F, et al: The Kleine-Levin syndrome. Tijdschr Kindergeneeskd 1989; 57:218-221. 111. Tinuper P, Montagna P, Plazzi G, et al: Idiopathic recurring stupor. Neurology 1994; 44:621-625. 112. Rothstein JD, Guidotti A, Tinuper P, et al: Endogenous benzodiazepine receptor ligands in idiopathic recurring stupor. Lancet 1992; 340:1002-1004. 113. Dijk DJ, Duffy JF, Czeisler CA: Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance. J Sleep Res 1992; 1:112-117. 114. Boivin D: Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. J Psychiatry Neurosci 2000; 25:446-458. 115. Okawa M, Uchiyama M, Ozaki S, et al: Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology. Psychiatry Clin Neurosci 1998; 52:483-490. 116. Czeisler CA, Richardson GS, Coleman RM, et al: Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep 1981; 4:1-21. 117. Dijk DJ, Beersma DG, Daan S, et al: Bright morning light advances the human circadian systems without affecting the NREM sleep homeostasis. Am J Physiol 1989; 256:R100-R111. 118. Czeisler CA, Kronauer RE, Allan JS, et al: Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 1989; 244:1328-1333. 119. Minors DS, Waterhouse JM, Wirz-Justice A: A human phaseresponse curve to light. Neurosci Lett 1991; 133:36-40. 120. Morris M, Lack L, Dawson D: Sleep-onset insomniacs have delayed temperature rhythms. Sleep 1990; 13:1-14. 121. Rosenthal NE, Joseph-Vanderpool JR, Levendosky AA, et al: Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome. Sleep 1990; 13:354-361. 122. Chesson AL Jr, Littner M, Davila D, et al: Practice parameters for the use of light therapy in the treatment of sleep disorders. Sleep 1999; 22:641-660.

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123. Dahlitz M, Alvarez B, Vignau J, et al: Delayed sleep phase syndrome response to melatonin. Lancet 1991; 337:1121-1124. 124. Dagan Y, Yovel I, Hallis D, et al: Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Chronobiol Int 1998; 15:181-190. 125. Reid KJ, Chang AM, Dubocovich ML, et al: Familial advanced sleep phase syndrome. Arch Neurol 2001; 58:1089-1094. 126. Zucconi M: Familial advanced sleep phase syndrome. Sleep Med 2002; 3:177-178. 127. Satoh K, Mishima K, Inoue Y, et al: Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 2003; 26:416417. 128. Palmer CR, Kripke DF, Savage HC Jr, et al: Efficacy of enhanced evening light for advanced sleep phase syndrome. Behav Sleep Med 2003; 1:213-226. 129. Klein T, Martens H, Dijk DJ, et al: Circadian sleep regulation in the absence of light perception: chronic non–24-hour circadian rhythm sleep disorder in a blind man with a regular 24-hour sleep-wake schedule. Sleep 1993; 16:333-343. 130. Eastman CI, Gazda CJ, Burgess HJ, et al: Advancing circadian rhythms before eastward flight: a strategy to prevent or reduce jet lag. Sleep 2005; 28:33-44. 131. Burgess HJ, Crowley SJ, Gazda CJ, et al: Preflight adjustment to eastward travel: 3 days of advancing sleep with and without morning bright light. J Biol Rhythms 2003; 18:318-328. 132. Oxenkrug GF, Requintina PJ: Melatonin and jet lag syndrome: experimental model and clinical implications. CNS Spectr 2003; 8:139-148. 133. Herxheimer A, Waterhouse J: The prevention and treatment of jet lag. BMJ 2003; 326:296-297. 134. Schenck CH, Mahowald MW: Parasomnias. Managing bizarre sleep-related behavior disorders. Postgrad Med 2000; 107: 145-156. 135. Mahowald MW: Parasomnias. Med Clin North Am 2004; 88:669-678. 136. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry 1999; 60:268-276. 137. Kavey NB, Whyte J, Resor SR Jr, et al: Somnambulism in adults. Neurology 1990; 40:749-752. 138. Crisp AH: The sleepwalking/night terrors syndrome in adults. Postgrad Med J 1996; 72:599-604. 139. Mehlenbeck R, Spirito A, Owens J, et al: The clinical presentation of childhood partial arousal parasomnias. Sleep Med 2000; 1:307-312. 140. Schenck CH, Boyd JL, Mahowald MW: A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997; 20:972-981. 141. Roth B, Nevsimalova S, Rechtschaffen A: Hypersomnia with “sleep drunkenness.” Arch Gen Psychiatry 1972; 26:456-462. 142. Shapiro CM, Trajanovic NN, Fedoroff JP: Sexsomnia—a new parasomnia? Can J Psychiatry 2003; 48:311-317. 143. Cartwright R: Sleepwalking violence: a sleep disorder, a legal dilemma, and a psychological challenge [Review]. Am J Psychiatry 2004; 161:1149-1158. 144. Laberge L, Tremblay RE, Vitaro F, et al: Development of parasomnias from childhood to early adolescence. Pediatrics 2000; 106:67-74.

145. Hublin C, Kaprio J, Partinen M, et al: Parasomnias: cooccurrence and genetics. Psychiatr Genet 2001; 11:65-70. 146. Hublin C, Kaprio J, Partinen M, et al: Prevalence and genetics of sleepwalking: a population-based twin study. Neurology 1997; 48:177-181. 147. Broughton RJ: Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in “dreaming sleep.” Science 1968; 159:1070-1078. 148. Gaudreau H, Joncas S, Zadra A, et al: Dynamics of slow-wave activity during the NREM sleep of sleepwalkers and control subjects. Sleep 2000; 23:755-760. 149. Gau SF, Soong WT: Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a case-control study. Aust N Z J Psychiatry 1999; 33:734-739. 150. Hartman D, Crisp AH, Sedgwick P, et al: Is there a dissociative process in sleepwalking and night terrors? Postgrad Med J 2001; 77:244-249. 151. Landry P, Warnes H, Nielsen T, et al: Somnambulistic-like behaviour in patients attending a lithium clinic. Int Clin Psychopharmacol 1999; 14:173-175. 152. Joncas S, Zadra A, Paquet J, et al: The value of sleep deprivation as a diagnostic tool in adult sleepwalkers. Neurology 2002; 58:936-940. 153. Schenck CH, Mahowald MW: REM sleep parasomnias. Neurol Clin 1996; 14:697-720. 154. Schenck CH, Mahowald MW: REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002; 25:120-138. 155. Boeve BF, Silber MH, Parisi JE, et al: Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003; 61:40-45. 156. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 1996; 46:388-393. 157. Hendricks JC, Morrison AR, Farnbach GL, et al: A disorder of rapid eye movement sleep in a cat. J Am Vet Med Assoc 1981; 178:55-57. 158. Eisensehr I, Linke R, Noachtar S, et al: Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain 2000.123:1155-1160. 159. Turner RS, D’Amato CJ, Chervin RD, et al: The pathology of REM sleep behavior disorder with comorbid Lewy body dementia. Neurology 2000; 55:1730-1732. 160. Gagnon JF, Fantini ML, Bedard MA, et al: Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia. Neurology 2004; 62:401-406. 161. Boeve BF, Silber MH, Ferman TJ: Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4:281-284. 162. Fantini ML, Gagnon JF, Filipini D, et al: The effects of pramipexole in REM sleep behavior disorder. Neurology 2003; 61:1418-1420.

CHAPTER

16

SLEEP APNEA ●

●

●

●

Adrian J. Williams

The sleeping patient is still a patient. His disease may progress differently in sleep, or disease may originate in sleep. (Eugene Robin, 1958) Sleep-disordered breathing is the broad term used to describe the endpoint of a number of conditions of diverse etiology that can disrupt breathing during sleep. Apnea is defined as the cessation of breathing for more than 10 seconds. Hypopnea refers to a reduction in tidal volume without total cessation of respiration. Degrees of hypopnea are recognized: either substantial (>50% reduction in airflow) or moderate (<50% reduction in airflow with desaturations of >3%, or electroencephalographic evidence of arousal). Episodes of apnea and hypopnea often, if not always, coexist; apnea represents the more severe end of the spectrum of reduction in tidal volume (Fig. 16–1). Apneas and hypopneas may develop as a result of lack of drive to breathe, which is a central phenomenon, or as a result of narrowing of the upper airway, which is an obstructive phenomenon. These are considered separately. Brief episodes of apnea or hypopnea are a feature of normal sleep, occurring most commonly during the transition from wakefulness to sleep when the level of arterial carbon dioxide tension in the body is reset to a level that is higher by approximately 5 mm Hg (0.7 kPa). Such transitional apneas occur in most individuals but can be very pronounced in patients with frequent arousals during sleep. In an attempt to differentiate between normal and abnormal frequencies of apneic or hypopneic levels, the apnea-hypopnea index, referring to the number of episodes of apnea and hypopnea per hour of sleep, is used. The upper limit of normal has traditionally been considered to be five events per hour, but some authors have suggested a higher cutoff level, 10 events per hour. Sleep-disordered breathing is common, and its prevalence increases with age. It is often accompanied by hypoxemia, changes in heart rate and blood pressure, and arousals that may fragment sleep and lead to daytime fatigue and somnolence, as well as cognitive and cardiovascular changes, known as the sleep apnea syndrome. Despite this, most cases remain undiagnosed and untreated.

OBSTRUCTIVE SLEEP APNEA-HYPOPNEA Epidemiology Obstructive sleep apnea-hypopnea (OSAH) is an increasingly important disease with numerous clinically relevant consequences, including neurocognitive and cardiovascular sequelae.1-3 The prevalence of this disease varies, depending on the definitions (of hypopnea) used. Young and colleagues4,5 showed that 4% of men and 2% of women in a middle-aged North American population had symptoms of OSAH and an apneahypopnea index exceeding 5. However, 24% of men aged 30 to 60 and 9% of women had an abnormal apnea-hypopnea index but without excessive sleepiness, which had been used to define the former statistics. Cardiovascular risk assessments, however, have shown a dose-response relationship between the apneahypopnea index and various sequelae; thus, the definition and epidemiology are still evolving (Young, Peppard, Gottlieb 2002).

Pathophysiology Considerable progress has been made in understanding the genesis of obstructive events. The upper airway is anatomically small, and augmented pharyngeal dilator muscle activation maintains airway patency while the patient is awake but not while asleep, when an increase in upper airway resistance is found. Snoring, an important marker of increased upper airway resistance, is in part genetically determined,6 which perhaps reflects anatomical contributions such as a degree of retrognathia or overbite. Racial differences may be explained by this (apnea is more frequent among African Americans).7 Airway muscle tone insufficient for the airway size may allow intraluminal negative pressure to collapse the pharyngeal “tube.” Additional anatomical factors include enlarged tonsils or adenoids, vascular perfusion, the posture of the individual (supine versus lateral) and, of importance, fat accumulated in the pads in the lateral pharyngeal wall (Fig. 16–1).8 During wakefulness, augmented pharyngeal dilator muscle activity maintains airway potency. At sleep onset and/or during

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APNEIC

Clinical Manifestations/Sequelae OSAH should be suspected in patients who snore intrusively and who are obese (body mass index > 30) and/or in whom apneas have been witnessed. However, more subtle manifestations can occur (e.g., in the 30% who are not obese); therefore, questioning with regard to daytime sleepiness and sleep quality is mandatory. Poor sleep quality and daytime sleepiness are largely the results of sleep fragmentation by repetitive arousals. The neurocognitive sequelae of recurrent arousals also include reduced performance in neuropsychological tests, lengthened reaction times, altered quality of life, and an increased risk of vehicular accidents and work-related accidents.1,8 A causal relationship to all is supported by the response to treatment with continuous positive airway pressure (CPAP), which improves these sequelae.11-13 Because of its practical importance, more should be said about sleep apnea and driving. Human error is a major determinant in automobile accidents; inattention, improper lookout, and other perceptual and cognitive errors account for up to 40% of cases. Progressive daytime sleepiness can enhance inattention and thereby increase the risk of accidents in such patients. OSAH is an important cause of daytime sleepiness, along with cognitive impairment, and consequently contributes to the problem of drowsy driving. Sleep-related vehicular accidents are not only more common than is generally realized (Maycock found that 29% of 4600 respondents in a U.K. survey admitted to having felt close to falling asleep at the wheel in the previous year, and 18% had accidents in the previous 3 years) but are also more liable to result in death or serious injury as a result of the relatively high speed of the vehicles on impact. The financial and human costs can be considerable. The determination that sleeping at the wheel is the cause of an accident is based on the following: ■ The absence of skid marks. ■ The fact that for 7 seconds, the driver could have clearly seen

at the point of runoff or the object hit (which implies prolonged inattention rather than momentary distraction). ■ Other causes such as mechanical failure are eliminated. ■

Figure 16–1. Restriction of the airway during an apneic event.

rapid-eye-movement sleep (with active inhibition of muscles), this reflex activity is diminished, and if airway anatomy is abnormal, the airway is compromised, which leads to hypopneas and/or apneas. As a result, hypoxia and hypercapnia occur; ventilation is stimulated, often with arousal from sleep; and airway patency is reestablished. With the return to sleep, the cycle is repeated. It is possible, then, to conceive of a continuum of disordered breathing from snoring alone to an inability to breathe and sleep at the same time. Additional risk factors for OSAH are obesity, male gender, and increasing age. Of patients with OSAH, 70% are obese (pharyngeal size is diminished); sleep laboratories report a fivefold or sixfold increased risk of OSAH in men in comparison with women; and the prevalence increases with age.9 An evolving literature10 also suggests an important concept of snoring-induced traumas causing sensory and/or motor neuronal damage, as well as actual damage to the muscle (Boyd, Petrof, and Hamid, 2004).

It is appreciated that drivers who are able to respond after these accidents seldom acknowledge having fallen asleep. A strong association between sleep apnea and the risk of traffic accidents is now well documented. A Spanish study revealed that 102 drivers received emergency treatment after vehicular accidents and were more likely by a factor of 6 to have OSAH. Results of a French study suggested that approximately one half of drivers involved in sleep-related vehicular accidents have sleep disorders and that 31% have clear indications of OSAH. In addition, patients with OSAH in many other studies have been shown to have an increased rate of accidents. It is important to stress, however, that although patients with OSAH as a group are at increased risk, not all patients are at the same risk; results of the largest study to date suggested that increased automobile accidents may be restricted to patients with more severe apnea [age > 40], although sleep-related vehicular accidents are recognized to be multifactorial in origin. Driver performance can be measured by simulators of varying degrees of sophistication, and some patients with OSAH perform as poorly as subjects intoxicated with alcohol. Beneficial effects of treatment, including CPAP and surgery, have also been shown with these simulators. The U.K. Driver and Vehicle

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Figure 16–2. A composite of: abdominal and thoracic respiband (respiratory inductance plethysmography) set-up; overnight oximetry demonstrating repetitive desaturations typical of obstructive apnoeas; a 30 sec epoch of the polysomnogram with electroocculogram and electroencephalogram showing sleep onset and a mixed apnoea with initial absence of effort (sleep onset induced) followed by paradoxical movement of the abdomen and thoracic bands indicating effort.

Licensing Agency (DVLA) has a guide for medical practitioners in which it is pointed out that it is the duty of the license holder to notify the DVLA of any medical condition that may affect safe driving. There are some circumstances in which the license holder cannot, or will not, do this. Under these circumstances, the General Medical Council has issued clear guidelines: Make sure that the patients understand that the condition may impair their ability to drive and explain to the patients they have a legal duty to inform the DVLA. If the patient continues to drive but is not fit to do so, the physician should make every reasonable effort to persuade them to stop. This may include telling their next of kin. If the individuals cannot be persuaded to stop driving, the practitioner should disclose relevant medical information immediately in confidence to the medical adviser of the DVLA, informing the patient of the decision to do so. Sleep disorders are specifically mentioned under the Respiratory Disorders Section where the Group 1 entitlement states, “driving must cease if continuing to cause excessive awake time sleepiness, but driving will be permitted when satisfactory control of symptoms is achieved,” whilst for Group 2 entitlement, “cease driving on diagnosis. When it is confirmed by specialist assessment that the condition is

adequately controlled, driving may be resumed subject to review.” Readers should consult their national driving agencies for local recommendations or regulations as these may vary between countries. The cardiovascular sequelae are best considered as immediate and delayed. The immediate response to the obstructed breathing is an increase in negative intrapleural pressure with increased venous return (and increased output of atrial natriuretic peptide and resulting nocturia) and reduced cardiac output (due to the increased afterload). At the same time, the associated hypoxemia promotes sympathetic activation and circulatory vasoconstriction. With the return of airflow, the augmented preload leads to increases in stroke volume and in systemic blood pressure. This occurs repeatedly, and the normal nocturnal fall in blood pressure may be lost. A delayed effect on diurnal blood pressure may then follow. Indeed, it is appreciated that as much as one third of “essential” hypertension is associated with OSAH.14,15 A causal relationship is, again, supported by the response to treatment (with CPAP)16 (Pepperell, 2002). The combination of immediate and delayed hemodynamic effects in OSAH have been associated with increased risk of myocardial infarction and

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congestive heart failure, and there is evidence of a link between these and stroke.17 Additional links have been demonstrated with insulin resistance.18 The combination of obesity, insulin resistance (with or without diabetes), hypertension, and cardiovascular disease is typical of the metabolic syndrome, or syndrome X. Because these may all be associated with OSAH also, OSAH should obviously be considered as well; some authorities refer to it as syndrome Z.19 Finally, consideration might be given to the role of chronic hypercapnia in the setting of OSAH. Obesity is complicated in 10% of patients with OSAH by CO2 retention (in part caused by the increased load on the respiratory system), but OSAH alone may produce this through repeated bouts of CO2 retention at night, compensatory bicarbonate retention, and a daytime metabolic alkalosis that necessitates compensation. Evidence for this comes, again, from response to treatment with CPAP. One clinical variant of this is the pickwickian syndrome, so named after the “fat boy,” Joe, in Charles Dickens’ “Posthumous Papers of the Pickwick Club” who was, like the patient reported, obese, a snorer, sleepy, and in heart failure (dropsy). All these patients also have CO2 retention and sleep apnea, usually obstructive. In the example shown in Figure 16–2, a sleep-onset central apnea is followed by a hypopnea associated with efforts to breathe, registered by abdominal and thoracic impedance plethysmography. The hypopnea in this instance, however, resulted from ineffectual diaphragm contraction, evidenced by the paradoxical inward movement of the abdomen, presumably caused by the excessive abdominal load.

Diagnosis The initial evaluation of the patient with suspected OSAH is based on identification of disease markers by history and, to a lesser extent, physical examination. The physician may then choose to proceed with a relatively simple and inexpensive investigation such as overnight oximetry to confirm the presence of sleep-disordered breathing before other investigations such as nocturnal polysomnography.

History Although not every patient with OSAH is a middle-aged obese snorer with hypersomnolence, disease markers—which may be associations, risk factors, or disease effects—greatly contribute to the diagnosis of OSAH. As previously noted, it is well established that male gender and high body mass index are important risk factors for the development of OSAH. The prevalence of the disease also increases with age. Snoring is common (70% to 95%) and in some cases, it may even be the only symptom. Excessive daytime somnolence is highly correlated with the presence of OSAH. It is, however, important to rule out other causes of hypersomnolence, especially sleep deprivation. Cognitive effects of sleep apnea such as memory loss have previously been described. A history of alcohol ingestion, as well as a complete drug history, should be obtained. The interview should be extended to include questioning of the bed partner. This can yield invaluable information regarding important features of the disease of which the patient may be unaware, such as snoring, gasping, apnea, cyanosis, pathological somnolence, and changes in cognition.

Finally, it is important to note whether the patient has a history suggestive of other respiratory or cardiovascular disease that could be exacerbated by the presence of OSAH.

Physical Examination A thorough physical examination should be performed. The relationship between weight and height, as well as neck size, should be noted. The astute clinician looks for evidence of uncommon conditions associated with obstructive apnea, such as Marfan syndrome and acromegaly. General examination should include examination of thyroid status. The clinician should also look for the presence of oropharyngeal crowding, micrognathia, or macroglossia. An examination of the cardiovascular and respiratory systems should follow. It is particularly important to note the patient’s blood pressure, signs of right or left ventricular impairment, and evidence of associated obstructive or restrictive lung disease.

Investigations Overnight oximetry is a useful screening test for patients suspected of having OSAH. It is highly specific and relatively inexpensive. It is simple to perform and noninvasive, and it can be performed reliably in the community. Its sensitivity has been reported to be as high as 70%, but its specificity is closer to 90%.20 A number of automated devices have been used in an attempt to improve the specificity of oximetry without resorting to polysomnography. These devices may include sound recorders for assessment of snoring, thermistors for detection of airflow, transducers for measurement of chest and abdominal wall movement with breathing, and accelerometers or other sensors for detecting limb movement. Several reports have confirmed that both sensitivity and specificity can be quite high, but these monitors tend to be expensive and generally inferior to full polysomnography equipment. Polysomnography remains the “gold standard” for the diagnosis of OSAH, even though it requires expensive equipment in a dedicated sleep laboratory and highly trained personnel. During polysomnography, continuous and simultaneous recordings are made: electrocardiography; electroencephalography, with at least three channels; chin and leg electromyography; electro-oculography; oxygen saturation measurement, with finger or ear oximetry; airflow measurement, with nasal pressure; measurement of chest and abdominal wall movement, with inductance bands; and snoring evaluation, with a microphone and sound recorder. The patient is, ideally, supervised throughout the study, and although unsupervised studies can be performed, the technician’s observations often prove very useful. The recording is digitized and recorded on a computer before analysis. With polysomnography, apneas and hypopneas can be recognized with relative ease and classified into obstructive, central, and mixed events. Changes in sleep stage and arousals are noted on the basis of electroencephalographic, electro-oculographic, and electromyographic features and are related to respiratory events. The severity of sleep apnea is indicated by the apnea-hypopnea index and indices of oxygen desaturation.

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Treatment

Oral Appliances

When the primary problem is an abnormally small upper airway, treatment is aimed at rectifying this. Cures may be potentially effected with surgical removal of obstructing tonsils and adenoids, substantial weight loss, and, in rare cases, prevention of supine sleep. There currently exist no drugs that increase further upper airway dilator activity. Medical treatment then relies on devices to produce dilatation of the pharyngeal airway: nasal CPAP, which acts as a pneumatic splint, and oral appliances, which advance the mandible and hence the tongue.

Oral appliances are generally less effective but often preferred by patients and have an evidence base to support their use.

Nasal Continuous Positive Airway Pressure This remains the treatment of choice with substantial grade A evidence summarized by a Cochrane Review. Important immediate benefits are seen in sleepiness, cognition, quality of life, accidents, and blood pressure reduction, and reduced cardiovascular events are anticipated. However, compliance with CPAP is imperfect; approximately 20% of patients do not adhere to the CPAP regimen. Remedial, if imperfect, strategies include heated humidification, use of nasal decongestants, and intensive follow-up (cognitive behavioral therapy). Bilevel positive airway pressure is no better tolerated (Fig. 16–3).

Pragmatic Approach The author believes that thinner, younger patients with the primary complaint (needing remedying) of snoring are likely to use and benefit from an oral appliance, whereas older, heavier patients with the primary complaint of sleepiness require CPAP. Oral appliances can be considered also for those who refuse CPAP or in whom it fails. For completeness, surgical treatment must be mentioned. The most common surgical procedure is uvulopalatopharyngoplasty, in which the uvula and redundant soft tissue of the soft palate are resected. The reduction in apnea-hypopnea index is, however, small; only 41% of patients who undergo this procedure have an apnea-hypopnea index of less than 20.21 Results of newer techniques such as radiofrequency ablation have also been disappointing. However, for the patient with the primary complaint of snoring with little or no apnea, these procedures may be considered.

CENTRAL SLEEP APNEA Unlike obstructive apnea, in which there is marked respiratory effort against a closed upper airway, central sleep apnea (CSA) involves repetitive cessation of airflow in the absence of respiratory effort (Fig. 16–4).

Etiology and Pathogenesis

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Figure 16–3. Continuous positive airway pressure (CPAP) mask.

CSA is a heterogeneous disease entity. In general, patients can be classified into two broad groups based on wakefulness levels of arterial carbon dioxide tension (PaCO2) and their ventilatory response to carbon dioxide. The first group consists of patients who tend to hypoventilate, have high levels of PaCO2 in the absence of intrinsic lung disease, and have a blunted ventilatory response to carbon dioxide. They tend to have recurrent episodes of respiratory failure. Patients within this group often have a clinical picture that merges into the spectrum of primary alveolar hypoventilation. Many of them are obese and have features of the obesity-hypoventilation syndrome. At the other end of the spectrum of CSA is the second group of patients, who either ventilate normally or hyperventilate and have normal or low wakefulness PaCO2 levels and a normal or exaggerated ventilatory response to carbon dioxide. These patients often present with clinical features typical of sleep apnea. Many of them have Cheyne-Stokes respiration (CSR). Even though the clinical and physiological differences between the two groups are marked, the two groups may have similar nocturnal apneic events and sleep architecture. CSR is characterized by alternating periods of hyperventilation and hypoventilation or apnea. It was first described by Hippocrates, but the classic descriptions were made by John Cheyne and William Stokes in the 19th century. The etiology and pathogenesis of CSR have been argued since the description by John Cheyne of a patient with both enlarged cerebral

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Figure 16–4. Central apnea. bpm, beats per minute; SpO2, pulse oximetry.

ventricles and heart disease who had periodic breathing. Autopsy studies have shown that most subjects with CSR have structural abnormalities of the brain. The disease is, however, seen frequently in patients with cardiovascular disease, particularly heart failure. Therefore, theories suggesting both neurological and cardiovascular mechanisms in the pathogenesis of the disease have been postulated. Proposed neurological abnormalities include cyclical medullary depression or medullary hyperexcitability alternating with periods of depression. Described cardiovascular abnormalities involve a circulatory delay related to heart failure. It is now known that both neurological and cardiovascular factors contribute to the pathogenesis of the disease and that if the relationship between these cardiac and neurological components is altered, the stability of the respiratory control system is lost. Such disturbance in the control system may arise by prolongation of the circulation time or by the system’s becoming more dependent on the arterial partial pressure of oxygen rather than carbon dioxide. Patients with heart failure and CSR often hyperventilate. They have lower PaCO2 both when awake and during sleep than do control subjects with heart failure but no CSR or CSA. Circulatory delay is a well-known feature of heart failure, and animal models suggest that circulatory delay can indeed lead to periodic breathing. Whether the changes observed in animal models of CSR are also valid in humans with heart failure remains controversial, because the magnitude of circulatory delay necessary to produce CSR in animals is rarely if ever seen in humans. Nonetheless, a strong correlation has been noted between circulation time and CSR-CSA cycle length in humans. Arousal and apnea termination are associated with the hyperventilation stage of CSR. Termination of apnea in patients with periodic breathing appears to be related largely to

chemoreceptor input, which is in contrast to the proposed mechanism for apnea termination in OSAH, in which mechanoreceptor input from the lungs is believed to be of primary importance. Arousals disrupt sleep and are associated with lack of slow-wave sleep but surprisingly little daytime hypersomnolence (Cormican, Williams 2005).

Prevalence The exact prevalence of CSA remains unclear. It does, however, appear to be particularly high in patients with neurological disease, including structural brainstem and cerebrovascular disease, as well as in patients with cardiac dysfunction. Several studies have shown that significant left ventricular impairment is associated with sleep-disordered breathing, CSA, and CSR. Sleep-disordered breathing has been reported to occur in up to 50% of patients with stable congestive heart failure, and left ventricular systolic dysfunction may be an independent risk factor for sleep apnea in these patients.22 One small study showed that approximately 40% of patients on a heart transplantation waiting list had periodic breathing and CSA. In another study, patients with left ventricular impairment caused by ischemic heart disease were found to have cyclical oxygen desaturations with a frequency 10 times higher than those observed in healthy controls.23 Similar results suggesting a very high prevalence of CSR and central apnea have been reported in patients with dilated cardiomyopathy.

Morbidity and Mortality In one relatively small study designed to determine the effect of CSA with or without CSR on morbidity and mortality, CSR was found in 60% of patients with CSA. Patients with severe

chapter 16 sleep apnea CSR had more central apneas, more but shorter desaturations, and more awakenings and spent more time awake during the night. Heart failure was associated with CSR. Even though patients with severe CSR were at almost twice the risk of dying than were those with no apnea, CSR was not found to be an independent risk factor for increased mortality risk. On the basis of the limited information available, it appears that even though CSA is associated with significant morbidity, the prognosis in patients with CSA is largely dependent on the underlying disease and not on the presence of sleep apnea per se.

Diagnosis A history of cardiac dysfunction, cerebrovascular disease, or structural brainstem disease should alert the clinician to the possibility of CSA. Obese patients may have central apnea as part of the obesity-hypoventilation syndrome. Daytime hypercapnia in the absence of structural lung disease may be an indicator of worsening hypoventilation during sleep. Most patients with CSA, however, have normal or exaggerated ventilation during wakefulness. Most patients with cardiac failure belong to this group. The bed partner may note apneic episodes in the absence of respiratory effort. Screening tests such as overnight oximetry and some more sophisticated techniques are often useful, but their sensitivity and specificity in patients with CSA have not been established. The diagnosis relies ultimately on demonstration of repetitive apnea or hypopnea in the absence of respiratory effort during polysomnography.

Treatment In patients with CSA, treatment of the underlying cause, whenever possible, is of paramount importance. In patients with heart failure, angiotensin-converting enzyme inhibition with captopril increases the proportion of sleep spent in slow-wave and rapid-eye-movement sleep. Apneic episodes, arousals, and episodes of desaturation are also reduced. In patients with advanced heart failure, CSR has been cured by heart transplantation.

1. Drugs Respiratory stimulants such as methylxanthines appear to be a logical treatment for CSA, but large controlled studies have not been performed. In two small studies that included patients with heart failure, administration of theophylline resulted in a reduction in CSR and an improvement in oxygen desaturation events and sleep disruption.24,25 Aminophylline has also been reported to ameliorate CSA caused by structural brainstem disease. The tricyclic antidepressant imipramine may also reduce the number of apneic episodes and improve both nocturnal and diurnal symptoms in patients with CSA. Oxygen administration appears to be beneficial for the patients with heart failure and CSA. Oxygen may not only relieve hypoxemia but may also reduce apneic episodes and arousals and may improve sleep duration and quality. Oxygen may also be beneficial in patients with primary alveolar hypoventilation and CSA, again not only by relieving hypoxia and its cardiovascular complications but also by reducing the number and duration of apneic events.

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2. Noninvasive Continuous Positive Airway Pressure Use of nasal CPAP is a relatively well-described form of treatment for CSA. Its mechanism of action remains unclear, but CPAP administration may raise the level of PaCO2 above the apneic threshold in patients with CSA who have CSR. The acute hemodynamic effects of nasal CPAP administration in patients with heart failure remain highly controversial; authors of a number of small studies have reported conflicting results. Some investigators have reported adverse hemodynamic effects, including a fall in cardiac index and a rise in systemic vascular resistance, and acute left ventricular failure occurring shortly after initiation of treatment has been described.26 Conversely, other studies have reported that CPAP either does not change or may improve the cardiac index in patients with left ventricular dysfunction and elevated pulmonary arterial wedge pressure.27 Regardless of these findings, long-term administration of nasal CPAP to patients with advanced cardiac failure and CSR appears to reduce the number of apneic events and to improve symptoms of sleep apnea and oxygen saturation. Left ventricular function and inspiratory muscle strength may also improve, and daytime breathlessness and fatigue may be ameliorated. Moreover, nasal CPAP is known to improve the imbalance between sympathetic and parasympathetic tone in heart failure, as evidenced by reductions in both nocturnal and daytime catecholamine levels and an increase in heart rate variability. Nasal CPAP also appears to be effective in reducing hypoventilation and hypoxemia in patients with primary and central alveolar hypoventilation.

3. Noninvasive and Invasive PositivePressure Ventilation Although positive-pressure ventilation, including nasal bilevel positive airway pressure, seems to be a logical treatment for CSA, and although it has been used fairly extensively, little evidence regarding its use is available from controlled studies. It has, nonetheless, been shown to be effective in patients with CSA, including primary alveolar hypoventilation, in whom apneic events are reduced and hypercapnia and hypoxemia are corrected. It may be particularly useful in patients unresponsive to treatment with nasal CPAP or in those who hypoventilate.

CONCLUSIONS Sleep apnea is a common disturbance with many effects on sleep and daytime functioning. Obstructive sleep apnea is linked to many important adverse daytime consequences such as poor performance, accidents, hypertension, heart disease, stroke, and insulin resistance. The close association with obesity and the current epidemic of obesity mean that in the future, these disorders will become more prevalent, and thus clinicians need to remain alert to them and to be proactive in their evaluation of sleep. To this end, sleep-related questions should be routine and include those about snoring, daytime sleepiness (with the Epworth Sleepiness Scale [Table 16–1]), witnessed apneic events, nocturia, sleep duration, and sleep quality. Other parts of this book point out additional questions

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T A B L E 16–1. The Epworth Sleepiness Scale How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Use the following scale to choose the most appropriate number for each situation: 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing Situation Sitting and reading Watching TV Sitting inactive in a public place (e.g., a theater or a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in traffic

Chance of Dozing –––––––––– –––––––––– –––––––––– –––––––––– –––––––––– –––––––––– –––––––––– ––––––––––

Scoring Total the points from all situations. If your score is 1-6, you are getting enough sleep. A score of 7-8 is average. If your score is 9 and up, seek the advice of a sleep specialist in your area without delay.

of importance, such as those aimed at identifying cataplexy and restless legs syndrome and injury in sleep. Simple approaches to diagnosis through nocturnal oximetry are encouraged, and referral for more complex studies should be contemplated if results are equivocal.

K E Y

P O I N T S

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Obstructive sleep apnea is a disease of increasing importance because of its neurocognitive and cardiovascular consequences, not least stroke and hypertension.

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A characteristic history is found with snoring and sleepiness, and obesity is common among affected patients.

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Diagnosis is often possible through the use of overnight pulse oximetry, which is recommended as the first diagnostic approach.

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Nasal CPAP is unequivocally effective, particularly in substantially lowering blood pressure and relieving sleepiness.

Suggested Reading Boyd J, Petrof B, Hamid Q, et al: Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170:541-546. Cormican L, Williams AJ: Sleep disordered breathing in congestive heart failure. Br J Cardiol 2005; 12:171-172. Pepperell J, Ramdassingh-Dow S, Crosthwaite N, et al: Ambulatory blood pressure after therapeutic and subtherapeutic nasal con-

tinuous positive airway pressure for obstructive sleep apnea: a randomised parallel trial. Lancet 2002; 359:204-210. Young T, Peppard P, Gottlieb D: The epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165:1217-1239.

References 1. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J: The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999; 340:847-851. 2. Shahar E, Whitney CW, Redline S, et al: Sleep disordered breathing and cardiovascular disease: cross sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163:19-25. 3. Peppard P, Young T, Palta M, et al: Prospective study of the association between sleep disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384. 4. Young T, Palta M, Dempsey J, et al: The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993; 32:1230-1235. 5. Young T, Peppard P, Gottlieb D: The epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165:1217-1239. 6. Desai A, Cherkas L, Spector T, et al: Genetic influences in self reported symptoms of OSA—a Twin Study. Twin Res 2004; 7:589-595. 7. Redline S, Tishler PV, Hans MG, et al: Racial differences in sleep-disordered breathing in African-Americans. Am J Respir Crit Care Med 1997; 155:186-192. 8. Schwab RJ, Gupta KB, Gefter WB, et al: Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing: significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995; 152:1673-1689. 9. Bixler EO, Vgontzas AN, Ten Have T, et al: Effects of age on sleep apnea in men: prevalence and severity. Am J Respir Crit Care Med 1998; 157:144-148. 10. Boyd J, Petrof B, Hamid Q, et al: Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170:541-546. 11. Jenkinson C, Davies RJ, Mullins R, et al: Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999; 353:2100-2105. 12. Engleman HM, Martin SE, Kingshott RN, et al: Randomised placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 1998; 53:341-345. 13. Jenkinson C, Stradling J, Petersen S: Comparison of three measures of quality of life outcome in the evaluation of continuous positive airways pressure therapy for sleep apnea. J Sleep Res 1997; 6:199-204. 14. Berry RB, Gleeson K: Respiratory arousal from sleep: mechanisms and significance. Sleep 1997; 20:654-675. 15. Williams AJ, Houston D, Finberg S: Sleep apnea and essential hypertension. Am J Cardiol 1985; 55:1019-1022. 16. Pepperell J, Ramdassingh-Dow S, Crosthwaite N, et al: Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnea: a randomised parallel trial. Lancet 2002; 359: 204-210. 17. Yaggi HK, Concato J, Kernan WN, et al: Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353:2034-2041. 18. Ip M, Lam B, Ng M, et al: Obstructive sleep apnea is independently associated with insulin resistance. Am J Res Crit Care 2002; 165:670-676.

chapter 16 sleep apnea 19. Wilcox I, McNamara SG, Collins F, et al: Syndrome Z: the interaction of sleep apnea, vascular risk factors and heart disease. Thorax 1998; 53:S5-S28. 20. Williams AJ, Yu G, Santiago S, et al: Screening for sleep apnea using pulse oximetry. Chest 1991; 100:631-635. 21. Hudgel DW: Availability of a meta-analysis of the surgical treatment of obstructive sleep apnea. Chest 1997; 111:265-266. 22. Markides V, Williams AJ: Detection of sleep apnea in the cardiac care unit. In Mohsenifar Z, Shah PK, eds: Practical Critical Care Cardiology. New York: Marcel Dekker, 1998, pp 90-124. 23. Rasche K, Hoffarth HP, Marek W, et al: Nocturnal oxygen saturation in patients with coronary heart disease dependent on degree of left ventricular functional impairment. Pneumonologie 1991; 45:261-264.

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24. Dowdell WT, Javaheri S, McGinnis W: Cheyne Stokes respiration presenting as sleep apnea syndrome. Am Rev Respir Dis 1990; 141:871-879. 25. Tomcsanyi J, Karlocai K: Effect of theophylline on periodic breathing in congestive heart failure measured by transcutaneous oxygen monitoring. Eur J Clin Pharmacol 1994; 46:173174. 26. Liston R, Deegan PC, McCreery C, et al: Haemodynamic effects of nasal continuous positive pressure in severe congestive heart failure. Eur Respir J 1995; 8:430-435. 27. Naughton MT, Rahman MA, Hara K, et al: Effect of continuous airway pressure on left ventricular transmural pressure in patients with congestive cardiac failure. Circulation 1995; 91:1725-1731.

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17

TOURETTE’S SYNDROME, TICS AND OBSESSIVE-COMPULSIVE DISORDERS ●

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Anette Schrag and Mary M. Robertson

TICS AND GILLES DE LA TOURETTE SYNDROME Once considered a rarity, Gilles de la Tourette syndrome is now recognized to be a relatively common disorder, which may be associated with considerable psychiatric comorbidity and impaired psychosocial functioning. Gilles de la Tourette syndrome is defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) as a combination of multiple motor tics and at least one vocal tic that cannot be explained by another cause and has persisted for at least 1 year.1,2 The current criteria no longer require that these tics produce significant distress or impairment, and a large proportion of people who fulfill these criteria are not aware of their tics or are not disturbed by them. However, in the tertiary referral setting and in patients with more severe or frequent tics or with associated comorbidity, there are both considerable psychosocial impairment and reduced quality of life.3 Gilles de la Tourette syndrome is frequently undiagnosed; tics may be misinterpreted as a “nervous habits” or, particularly in children, as inattention or inability to sit still. On occasion, tics are mistaken for another movement disorder or a psychiatric disease. In addition to Gilles de la Tourette syndrome, tics can occur in chronic tic disorders that are purely motor or verbal and in transient tic disorders that do not last more than 1 year. The latter are common phenomena in childhood. Tics may also occur as a side effect of drugs or toxins and may be a manifestation of an underlying neurological disorder, usually associated with other phenomena but occasionally as the first or only manifesting symptom (see later discussion).

Characteristics of Tics Tics are abrupt, recurrent, and stereotyped but nonrhythmic movements. They can affect any body part, can be simple or complex, and manifest with motor or vocal actions. Examples of simple motor tics are eye blinking, nose twitching, eye rolling, and head nodding, and simple verbal tics include sniffing, throat clearing, or coughing. Examples of complex motor tics are jumping, touching, or twirling, and complex verbal tics include barking or uttering a string of words. Many patients experience a premonitory sensation before a tic, which can be localized or generalized. Characteristically, tics increase with stress and anxiety, but also with relaxation, and can be sup-

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pressed for a period of time by concentration. However, this typically leads to a buildup of tension, and there is often a rebound after the suppression of tics. In Gilles de la Tourette syndrome, tics wax and wane over time, moving from one body part to another or changing characteristics. In addition to tics, other phenomena in this syndrome include echolalia (copying what other people say), echopraxia (copying what other people do), palilalia (repeating the last word or part of a sentence) and palipraxia (repeating the last action). Coprolalia (inappropriate, involuntary swearing) and copropraxia (inappropriate, involuntary obscene gestures) occur only in about 10% to 15% of patients with Gilles de la Tourette syndrome and are frequently disguised (e.g., by coughing or transformation of the word). The onset of motor tics in this syndrome is in childhood and occurs between ages 2 and 21 years; on average, onset occurs at ages 5 to 7 years. Verbal tics typically manifest a few years later, and coprolalia has a mean onset at age 15 years.

Differential Diagnosis of Tics Other brief movement disorders may be difficult to distinguish from tics. Tics may particularly resemble dystonia, tremor, myoclonus, chorea, and akathisia (for a review of hyperkinetic movement disorders, see Chapters 33 to 37). They also need to be distinguished from mannerisms (bizarre execution of purposeful acts), stereotypies (purposeless, repetitive movements often over long periods of time, as in a learning disability), and other medical conditions, such as coughing or sniffing in upper respiratory tract infections or eye blinking in allergy or blepharospasm. Particularly difficult may be the distinction between tics and other features of Gilles de la Tourette syndrome, such as obsessive-compulsive behaviors (OCBs), attention deficit/hyperactivity disorder (ADHD), antisocial behaviors and movement disorders associated with treatment.4 These differentiations are particularly important for appropriate pharmacological management.

Epidemiology Tics occur in 3% to 22% of children at some stage during their development5 but are transient in the majority. The more severe Gilles de la Tourette syndrome affects approximately 1% of chil-

chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders dren, and prevalence rates range from 0.4 to 1.8%.6-13 However, although the disorder typically starts in childhood, on average between the ages of 5 and 7 years,14,15 and typically increases until the age of 13 years, it often improves in adolescence so that by the age of 18 years, 50% of those affected are virtually free of tics.16 The prevalence rate is higher in special educational populations, such as those with learning difficulties17 or autism.18 About three to four times as many boys as girls are affected.14 Prevalence rates and clinical characteristics are broadly similar across countries.14 In rare cases, tic disorders with both motor tics and verbalizations begin in adulthood. Some of these patients have been described to have had compulsive tendencies in childhood or a family history of tics or OCB. In comparison with patients with Gilles de la Tourette syndrome that started in childhood, patients with adult-onset tic disorder more often had a potential trigger event, have more severe symptoms and greater social morbidity, and increased sensitivity and poorer response to neuroleptics.19

Diagnosis Tics and Gilles de la Tourette syndrome are clinical diagnoses. In cases of classic Gilles de la Tourette syndrome, no diagnostic tests are required. However, atypical cases, such as those without waxing and waning over time, those with adult onset, and particularly those with abnormalities on neurological examination, should be further investigated, including measurements of copper and ceruloplasmin for Wilson’s disease, full blood count for acanthocytes, and magnetic resonance imaging of the brain. Neuroimaging has also provided insight in the pathophysiology of Gilles de la Tourette syndrome: reduced volumes and abnormal asymmetry as well as altered dopamine metabolism of the basal ganglia, particularly the caudate20,21, and frontal lobe abnormalities,22 all of which implicate the frontal-striatal-thalamic-frontal circuitry.

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A genes have been implicated,34,36 and linkage to chromosome 17 has been demonstrated.37 However, despite many years of research by a number of groups worldwide, no single genetic cause has been found for Gilles de la Tourette syndrome. This suggests that other factors also play a role in the etiology of this disorder. An increasingly popular hypothesis suggests that Gilles de la Tourette syndrome is the product of an interaction between a genetic vulnerability and environmental factors. Stressors at various times of the life cycle have been implicated, particularly perinatal injury, but also stressors during pregnancy, such as severe nausea, vomiting, and antiemetic medication, which may alter dopaminergic receptors.16,38-41 Particularly intriguing has been the association of group A β-hemolytic streptococcal infections with a syndrome of sudden-onset neuropsychiatric disturbances, including OCD, tics, and other psychopathology in children. This syndrome has been termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).42 More recently, laboratory evidence of streptococcal infection in patients with Gilles de la Tourette syndrome has been reported, including elevated antistreptolysin O titers and anti–basal ganglia antibodies in up to 25% of patients with Gilles de la Tourette syndrome.43,44 An autoimmune mechanism has therefore been suggested as a contributor to the development of tics in this syndrome.44,45 Although the majority of studies have supported this notion,43-46 others have disputed this association,47,48 and whether anti–basal ganglia antibodies play a role in the development of Gilles de la Tourette syndrome currently remains a controversy.17 Although it seems clear that there is a strong genetic component in the etiology of Gilles de la Tourette syndrome and it seems that streptococcal infection causes the syndrome, it may be that individuals inherit a susceptibility to this syndrome and that environmental factors such as perinatal injury or an autoimmune response to streptococcal infections trigger the development of this syndrome in some individuals.

Etiology Tics can be symptomatic; for example, in neurodegenerative conditions, such as Huntington’s disease, they can be the first manifesting symptom. They can also represent a sequela of trauma or encephalitis, or they can represent extrapyramidal side effects of neuroleptic medication or cocaine abuse. However, the most common cause for chronic tic disorders is Gilles de la Tourette syndrome; this applies to adults, with childhood tics that have recurred or in whom previous tics may have been unnoticed or forgotten until an increase in tic severity brought them to medical attention. Suggestions for the etiology of Gilles de la Tourette syndrome have included genetic influences, infections, and perinatal difficulties. There is a wealth of evidence pointing toward genetic causes, including family studies, which suggested an autosomal dominant inheritance pattern with variable expression and penetrance.23-25 There is also growing evidence for bilineal transmission, with the father typically affected by childhood tics and the mother by symptoms of obsessive-compulsive disorder (OCD).26-28 Genetic studies have led to the identification of several regions of interest on chromosomes 2, 4, 8, and 1129-32 and, more recently regions of interest on the chromosomes 5, 10, 13,33 7,34 and 18.35 In addition, the DRD4 and MOA-

Psychopathology Gilles de la Tourette syndrome is associated with increased rates of a number of comorbid psychiatric conditions (see Robertson, 200049 and 200350). Although some of these are likely to represent a manifestation of or be integral to Gilles de la Tourette syndrome, others may be the consequence of the social and emotional consequences of this disorder. An investigation of 3500 patients with Gilles de la Tourette syndrome worldwide demonstrated that across all ages, 88% of individuals had associated psychiatric comorbidity, and male patients were more likely to have comorbid disorders.14 Only those with comorbid disorders had more severe behavioral problems such as anger control problems and self-injurious behavior, as well as sleep difficulties and coprolalia. The presence of such behavioral problems should therefore alert the clinician to the possible presence of comorbidity, the management of which is often at least as important as tic reduction. The spectrum of comorbid disorders includes OCD, other anxiety disorders, mood disorders, ADHD, and other behavior disorders, including self-injurious behavior.51 Although the exact relationship of these to Gilles de la Tourette syndrome is unclear, a strong association exists between Gilles de la Tourette

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syndrome and OCD and OCB, and a number of studies have suggested that these reflect the variable expression of a single disorder.24,26,27,50 OCD in patients with Gilles de la Tourette syndrome has, however, been found to differ in clinical manifestation from primary OCD, with predominant checking, counting, and symmetry obsessions and less frequent obsessions with contamination and violence.52-57 The rate of ADHD is also increased in patients with Gilles de la Tourette syndrome, and although the relationship between Gilles de la Tourette syndrome and ADHD is less clear, it has been suggested that some types are related genetically to Gilles de la Tourette syndrome. Depending on whether or not the International Classification of Diseases and Health-Related Problems, 10th Revision, or DSM-IV-TR criteria are used, the prevalence of ADHD in youngsters is between 1% and 9%.58 In patients with Gilles de la Tourette syndrome, the prevalence of ADHD is much greater and may be as high as 60%.14 This is not confined to chronic populations: Even in an epidemiological study conducted on members of the Israeli Defense Force, the prevalence of ADHD in Gilles de la Tourette syndrome was 8%, in comparison with 4% in the population without Gilles de la Tourette syndrome, a difference that was statistically significant.59 Personality disorders in adulthood in patients with Gilles de la Tourette syndrome are likely to be related to comorbid ADHD in childhood rather than to the syndrome itself. Whether other psychiatric comorbid conditions such as conduct disorder, oppositionaldefiant disorder, personality disorder, rage, and impulsivity are clearly more prevalent in patients with Gilles de la Tourette syndrome or their apparent prevalence is a result of referral bias in Gilles de la Tourette syndrome clinics is currently unknown. The multiple medications used for Gilles de la Tourette syndrome (see later discussion) may lead to increase. Anxiety and cognitive disorders, and anxiety may occur as a result of having Gilles de la Tourette syndrome and its social and personal consequences. The rate of depression, on the other hand, is clearly increased among patients with Gilles de la Tourette syndrome and is likely to be multifactorial in origin.60-63

Prognosis Clearly, for symptomatic tics in the context of another neurological disorder or as a drug effect, the prognosis is associated with the underlying disorder. The prognosis of individuals with Gilles de la Tourette syndrome varies widely; whereas those with mild tics without coprolalia or associated comorbidity mostly do not suffer impairment of social or personal function, those at the other end of the spectrum can be severely disabled. Children may be disadvantaged in school, particularly if comorbidity is present,64,65 but, as mentioned previously, tics often improve in adolescence.15,57 When the affected individuals and their environments receive appropriate explanation of this disorder and understand it, most do not need regular follow-up. Adult-onset cases appear to have worse morbidity and worse response to treatment, but this is rare. Overall, health-related quality of life has been shown to be worse in patients with Gilles de la Tourette syndrome than in controls, although it is better than in patients with intractable epilepsy.3 Factors associated with poorer health-related quality of life in this study in a tertiary referral center were employment status, tic severity, obsessive-compulsive symptoms, anxiety, and depression.

Management Many individuals with mild Gilles de la Tourette syndrome are not aware of their tics or do not find them bothersome and may never come to medical attention. For those who have come to medical attention, a diagnosis of their condition, explanation, and reassurance are often all that is required. When medication is considered in more severe cases, patient and physician should take into account the severity, frequency, and interference of tics; the presence and severity of comorbid conditions; the patient’s life style, requirements, expectations, and attitudes; and the long-term nature of pharmacological treatments, which may have reversible or irreversible side effects. Ideally, treatment should be multidisciplinary.

Nonpharmacological Treatment Supportive psychotherapy and psychological education are very important for all patients and their families, particularly if the patients are young. More specific behavioral treatment has been shown to produce better results than psychotherapy in adult patients with Gilles de la Tourette syndrome and include habit reversal training, graded exposure, social skills training, imaginal exposure, massed negative practice, contingency management, relaxation training, and biofeedback.66,67

Pharmacological Treatment Pharmacological treatment is based primarily on neuroleptic medication, and the individual’s response is idiosyncratic. Thus, an individual may respond to one particular neuroleptic agent but not another. Haloperidol, pimozide, sulpiride, and tiapride have all been shown to be more effective than placebo, and the doses required for tics in Gilles de la Tourette syndrome are much lower than those used for schizophrenia or mania. Although side effects at these doses are less common, all these agents carry the risk of extrapyramidal side effects, including acute dystonic reactions, parkinsonism, and tardive dyskinesia. In addition, sedation, cognitive side effects, depression, and social phobias can be dose limiting. Pimozide also must be used with caution because it has a higher rate of cardiac side effects than do other neuroleptic medications. In addition, an increase in prolactin levels with these drugs may necessitate discontinuation. The newer “atypical” antipsychotic agents have been demonstrated to be useful in treating patients with Gilles de la Tourette syndrome. Their chief advantage is the lower risk of extrapyramidal side effects. The main side effect is weight gain and, in some individuals, the precipitation of diabetes mellitus. It is therefore recommended that fasting glucose levels be checked in patients, particularly if they have put on weight. The atypical antipsychotic agents successfully used for treatment of Gilles de la Tourette syndrome have included risperidone,68 olanzapine,69 quetiapine,70 aripiprazole,71 and ziprasidone.72 It has also been suggested that quetiapine does not lead to hyperprolactinemia73 and may therefore merit further studies in patients with Gilles de la Tourette syndrome. In patients with severe vocal tics, which may not respond well to oral pharmacological treatment, botulinum toxin injections may be useful.74 Other suggested alternatives for the treatment of Gilles de la Tourette syndrome have included the neuroleptics amisulpride, aripiprazole, ziprasidone, fluphenazine, metoclopramide,

chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders piquindone, and tetrabenazine and agents from other substance groups, such as clonazepam, calcium channel antagonists, celecoxib, dopamine agonists, and selegiline. In severe, medically intractable cases, various surgical approaches have been tried with little success.75 However, in a literature review, Rauch and associates76 suggested that there is no compelling evidence that any neurosurgical procedure is superior to all others, and such surgery is not recommended outside specialist centers. Deep brain stimulation of the thalamus, which is largely reversible, is currently being explored as a treatment option for severe tics and OCD.77 The treatment of comorbid conditions requires additional drug choices. OCD and OCB often respond to selective serotonin reuptake inhibitors or the tricyclic antidepressant clomipramine, which inhibits both serotonin and noradrenaline uptake. In some countries, the use of some of these agents (e.g., paroxetine) is contraindicated in children. When ADHD exists comorbidly, the α2-adrenergic agonist clonidine and, in the United States, guanfacine can be useful for tics, impulse control, and ADHD, but electrocardiography and blood pressure control are recommended for patients taking these drugs. These agents must not be discontinued suddenly, because of rebound hypertension. Children with ADHD may require the addition of a psychostimulant such as methylphenidate. Previous concerns about exacerbation of tics with this medication have not been substantiated, and the management of ADHD may be more important than that of tics. An alternative may be the nonstimulant selective norepinephrine reuptake inhibitor atomoxetine.78,79 Depression in Gilles de la Tourette syndrome should be treated like primary depression or, for depression associated with other chronic disorders, by using cognitivebehavioral approaches, education, psychotherapeutic treatments, and pharmacotherapy.

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OBSESSIVE-COMPULSIVE DISORDER Obsessions are intrusive and recurrent thoughts, which include intrusive doubts, images, impulses, or ruminations (continuous pondering). They are recognized by affected individuals as their own thoughts, but they are characteristically egodystonic—that is, unwelcome and uncomfortable—to the individual, who usually tries to avoid or suppress them.52 Common obsessions are concerned with contamination, violence, sex, blasphemy, and numbers. Rarer obsessions are arithmomania (obsession with counting), onomatomania (the desire to utter a forbidden word), and folie de pourquoi (irresistible habit of repetitively asking the same banal question). Compulsions are carried out in response to these obsessions in a stereotyped manner, with reluctance, in order to neutralize or prevent a dreaded event. However, they are often not realistically related to the obsession, are considered unreasonable by the individual, and are excessive and time consuming. If the compulsion is suppressed, anxiety results until the compulsive behavior is performed. Common compulsive behaviors include washing, checking, arranging, counting, or mental rituals. Patients try to avoid situations that may provoke obsessions. Although obsessions and compulsions are common in the general population, a diagnosis of OCD according to DSMIV-TR requires that obsessions and compulsions cause marked distress or significantly interfere with a person’s functioning and do not occur in the context of a medical illness. There is considerable phenotypic variability of obsessions and compulsions, and the existence of specific subtypes has therefore been postulated: for example, familial and related to tic disorders, familial and unrelated to tics, and sporadic OCD.80 However, the existence of these different subtypes has been controversial.81

Conclusions and Recommendations

Epidemiology

Tics and Gilles de la Tourette syndrome occur more frequently than previously believed but are frequently unrecognized. The diagnoses of tics and Gilles de la Tourette syndrome are clinical, but diagnostic differentiation of tics from other movement disorders, associated phenomena in Gilles de la Tourette syndrome, and side effects of medication can be difficult. Tics may also occur in the context of other neurological conditions and as a consequence of neuroleptic treatment or drug abuse. In adults and those presenting with atypical features, these differential diagnoses should be explored. However, only in patients with atypical features are investigations required. In Gilles de la Tourette syndrome, there is no doubt that genetic factors play an important role in its etiology, but no single gene has been identified, and environmental factors such as infection or perinatal injury may also play a role. Tics in Gilles de la Tourette syndrome are often associated with significant psychiatric comorbidity and impaired psychosocial functioning and quality of life. Although tics in Gilles de la Tourette syndrome often improve in adolescence, patients with a more severe tic disorder that interferes with their lives and those with associated psychiatric comorbid conditions often require long-term treatment with pharmacological or nonpharmacological approaches. These should be tailored to the individual’s needs, with consideration of comorbid conditions and the context of the individual’s life.

OCD has a lifetime prevalence of 1.8% to 3.5% in the population with an onset in childhood or adolescence and a slight preponderance among girls.82-84 OCBs are much more common and may be part of the spectrum of normal behavior. OCD occurs worldwide with similar core features, but the content of the obsessions appears to be related to cultural context.85

Diagnosis Obsessions and compulsions are diagnosed clinically. Obsessions and compulsions should be distinguished from psychosis, in which voices or thoughts are experienced as coming from outside; from impulsive thoughts, which are egosyntonic (i.e., not uncomfortable or alien); and from rituals, which are purposeful actions, often with a cultural significance. Tics and compulsions can be difficult to distinguish, and they overlap. However, compulsions are typically preceded by obsessions and cognitions, and suppression of compulsions is typically followed by anxiety, whereas tics are typically preceded premonitory sensations and an urge to perform the tic, with no anxiety after suppression but physical discomfort and frequent rebound of tics afterward. Obsessions and compulsions are also common in other psychiatric disorders, including depression, schizophrenia, and

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obsessional (anankastic) personality disorder, and they overlap with Gilles de la Tourette syndrome, as discussed previously. Segregation analysis in families with Gilles de la Tourette syndrome and OCD suggested that OCD and Gilles de la Tourette syndrome are variant expressions of the same syndrome. A concurrent obsessional (anankastic) personality is present in about 70% of cases.52 They may also occur in generalized anxiety disorder, puerperal illness (as a fear of harming the baby), anorexia nervosa, Huntington’s disease, encephalitis lethargica, PANDAS, manganese poisoning and after head injury. In these psychiatric and neurological disorders, other features are present, but even in pure OCD, soft neurological signs such as astereognosia or agraphesthesia may be present.52

Etiology Obsessions were originally believed to be rooted in repressed impulses or in an aggressive or sexual nature,86 and other explanations have included obsessions as a result of aberrant learning.87 An increase in severity of OCD is also often seen when depression or stressful life events occur. However, obsessions and compulsions are seen in the context of a number of neurological disorders, such as Huntington’s disease or encephalitis lethargica, implicating underlying brain abnormalities, particularly in the frontal cortex and basal ganglia. Functional imaging studies and neuropsychological testing also provide increasing evidence that OCD is associated with abnormal functioning of the orbitofrontal cortex, the cingulate, and the caudate, and biochemical abnormalities, especially involving serotonin, are believed to be important in the pathophysiology of OCD.88 Increased rates of obsessions and compulsions in families of patients with OCD suggest that genetic factors play a role in the etiology of OCD, and twin studies with higher concordance rates in monozygous twins than in dizygous twins have supported the importance of genetic factors. In addition, abrupt onset or exacerbations of OCD or tics or both have been described after streptococcal infections (see previous discussion), suggestive of environmental causes. Neuroimaging studies reveal increased basal ganglia volumes, and the proposed cause involves the cross-reaction of streptococcal antibodies with basal ganglia tissue. A genetic susceptibility to PANDAS has been postulated.89

Prognosis Mild cases of obsessions and compulsions are often self-limited within 1 year. OCD is a chronic disorder but typically runs a fluctuating course with periods of long remissions and the greatest prevalence in mid-adult life. A meta-analysis of studies with up to 16 years’ follow-up revealed persistence rates of 41% for full OCD and 60% for full or subthreshold OCD.90 Comorbid psychiatric illness and poor initial treatment response were poor prognostic factors. Depression and abuse of alcohol and anxiolytics is common. Quality of life has been found to be significantly related to severity of obsessions, whereas the severity of compulsive rituals did not affect quality-of-life ratings. However, the single greatest predictor of poor quality of life was comorbid depression severity,91 and suicide rates are increased, particularly in

patients with comorbid depression. This is contrary to previous notions that suicide is uncommon in patients with OCD.

Management In many cases, obsessions and compulsions do not necessitate treatment, and the fluctuating course needs to be considered before treatment starts. In cases in which treatment is required, cognitive-behavioral therapy has been successful, including exposure and response prevention for compulsions, and habituation training and thought-stopping for obsessions.92 Psychoeducation can also be a valuable source. Pharmacological treatment is often effective, although up to 50% of patients may require more than one treatment trial. Effect medication includes the serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), and the tricyclic antidepressant clomipramine (which has a less favorable side effect profile). Of importance is that the doses of these medications required for treatment of OCD are often higher than those for depression. In addition, in severe cases, augmentation with neuroleptic medication, including risperidone and olanzapine, has been suggested. In cases in which all other classic treatments have failed after a minimum of 5 years, psychosurgery is occasionally considered. Capsulotomy, cingulotomy, subcaudate tractotomy, and limbic leukotomy, performed by radiofrequency thermolesions or radiosurgery,93-96 and the largely reversible deep brain stimulation97 have all been used. These surgical approaches are aimed at altering the neural circuits between the frontal lobes and different structures of the limbic system, but they are used very rarely.

Conclusions and Recommendations OCD is a common disorder with a wide phenotype, and it overlaps with Gilles de la Tourette syndrome. There may be different subtypes of OCD, and although streptococcal infection has been associated with OCD and with symptoms of Gilles de la Tourette syndrome, genetic factors are clearly implicated in OCD. OCD can also occur in the context of other psychiatric or neurological syndromes and is then associated with greater morbidity and worse quality of life. Management comprises cognitive-behavioral treatment and a number of pharmacological treatment options; in extremely rare cases of intractable and disabling OCD, patients may undergo surgery. Future research will address the etiological questions relating to genetic and environmental causes of OCD, its overlap with other psychiatric conditions, and improved management options.

K E Y

P O I N T S

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Gilles de la Tourette syndrome affects approximately 0.5% to 1% of all school-aged children, but severity of tics often improves in adolescence.

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Tics also occur in other neurological disorders and as a result of neuroleptic medication or drug abuse, particularly in adults.

chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders ●

There is a strong genetic component in the etiology of Gilles de la Tourette syndrome, but no single gene has been identified; it is likely to be multifactorial, including possible infectious or perinatal factors.

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Gilles de la Tourette syndrome is frequently associated with obsessive-compulsive symptoms and other psychopathology, including depression and ADHD; these affective and behavioral disorders are major contributors to impaired psychosocial functioning.

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Management of Gilles de la Tourette syndrome focuses on the aspects of the syndrome that are individually most important, including tics and the behavioral and affective disorders.

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OCD affect approximately 1.9% to 3.5% of the population, but milder obsessive-compulsive symptoms are more common.

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Obsessions are repetitive, intrusive thoughts that are unpleasant to the individual but are recognized as the individual’s own; compulsive behaviors are carried out to neutralize or prevent obsessions.

●

Treatment of obsessive-compulsive symptoms includes cognitive-behavioral therapy, supportive therapy, and pharmacotherapy, including selective serotonin reuptake inhibitors and clomipramine.

Suggested Reading Husted DS, Shapira NA: A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation. CNS Spectr 2004; 9:833-847. Leckman JF: Phenomenology of tics and natural history of tic disorders. Brain Dev 2003; 25(Suppl 1):S24-S28. Pauls DL: An update on the genetics of Gilles de la Tourette syndrome. Psychosom Res 2003; 55:7-12. Robertson MM: Tourette syndrome, associated conditions and the complexities of treatment. Brain 2000; 123(Pt 3):425-462. Singer HS: Tourette’s syndrome: from behaviour to biology. Lancet Neurol 2005; 4:149-159.

References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association, 2000. 2. World Health Organization: Internation Classification of Diseases and Health-Related Problems, 10th revision. Geneva: World Health Organization, 1992. 3. Elstner K, Selai CE, Trimble MR, et al: Quality of life (QOL) of patients with Gilles de la Tourette’s syndrome. Acta Psychiatr Scand 2001; 103:52-59. 4. Kompoliti K, Goetz CG: Hyperkinetic movement disorders misdiagnosed as tics in Gilles de la Tourette syndrome. Mov Disord 1998; 13:477-480. 5. Gadow KD, Nolan EE, Sprafkin J, et al: Tics and psychiatric comorbidity in children and adolescents. Dev Med Child Neurol 2002; 44:330-338. 6. Kurlan R, McDermott MP, Deeley C, et al: Prevalence of tics in school children and association with placement in special education. Neurology 2001; 57:1383-1388.

219

7. Hornsey H, Banerjee S, Zeitlin H, et al: The prevalence of Tourette syndrome in 13–14-year-olds in mainstream schools. J Child Psychol Psychiatry 2001; 42:1035-1039. 8. Kadesjo B, Gillberg C: Tourette’s disorder: epidemiology and comorbidity in primary school children. J Am Acad Child Adolesc Psychiatry 2000; 39:548-555. 9. Khalifa N, von Knorring AL: Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Dev Med Child Neurol 2003; 45:315-319. 10. Lanzi G, Zambrino CA, Termine C, et al: Prevalence of tic disorders among primary school students in the city of Pavia, Italy. Arch Dis Child 2004; 89:45-47. 11. Wang HS, Kuo MF: Tourette’s syndrome in Taiwan: an epidemiological study of tic disorders in an elementary school at Taipei County. Brain Dev 2003; 25(Suppl 1):S29-S31. 12. Jin R, Zheng RY, Huang WW, et al: [Study on the prevalence of Tourette syndrome in children and juveniles aged 7-16 years in Wenzhou area]. Zhonghua Liu Xing Bing Xue Za Zhi 2004; 25:131-133. 13. Mason A, Banerjee S, Eapen V, et al: The prevalence of Tourette syndrome in a mainstream school population. Dev Med Child Neurol 1998; 40:292-296. 14. Freeman RD, Fast DK, Burd L, et al: An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol 2000; 42:436-447. 15. Leckman JF, Zhang H, Vitale A, et al: Course of tic severity in Tourette syndrome: the first two decades. Pediatrics 1998; 102:14-19. 16. Leckman JF, Dolnansky ES, Hardin MT, et al: Perinatal factors in the expression of Tourette’s syndrome: an exploratory study. J Am Acad Child Adolesc Psychiatry 1990; 29:220-226. 17. Eapen V, Robertson MM, Zeitlin H, et al: Gilles de la Tourette’s syndrome in special education schools: a United Kingdom study. J Neurol 1997; 244:378-382. 18. Baron-Cohen S, Scahill VL, Izaguirre J, et al: The prevalence of Gilles de la Tourette syndrome in children and adolescents with autism: a large scale study. Psychol Med 1999; 29:11511159. 19. Eapen V, Lees AJ, Lakke JP, et al: Adult-onset tic disorders. Mov Disord 2002; 17:735-740. 20. Peterson BS, Thomas P, Kane MJ, et al: Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry 2003; 60:415-424. 21. Singer HS, Szymanski S, Giuliano J, et al: Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by PET. Am J Psychiatry 2002; 159:1329-1336. 22. Kates WR, Frederikse M, Mostofsky SH, et al: MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome. Psychiatry Res 2002; 116:6381. 23. Curtis D, Robertson MM, Gurling HM: Autosomal dominant gene transmission in a large kindred with Gilles de la Tourette syndrome. Br J Psychiatry 1992; 160:845-849. 24. Eapen V, Pauls DL, Robertson MM: Evidence for autosomal dominant transmission in Tourette’s syndrome. United Kingdom cohort study. Br J Psychiatry 1993; 162:593-596. 25. Pauls DL, Leckman JF: The inheritance of Gilles de la Tourette’s syndrome and associated behaviors. Evidence for autosomal dominant transmission. N Engl J Med 1986; 315: 993-997. 26. Kurlan R, Eapen V, Stern J, et al: Bilineal transmission in Tourette’s syndrome families. Neurology 1994; 44:23362342. 27. McMahon WM, van de Wetering BJ, Filloux F, et al: Bilineal transmission and phenotypic variation of Tourette’s disorder in a large pedigree. J Am Acad Child Adolesc Psychiatry 1996; 35:672-680.

220

Section

III

Neuropsychiatry

28. Hanna PA, Janjua FN, Contant CF, et al: Bilineal transmission in Tourette syndrome. Neurology 1999; 53:813-818. 29. Simonic I, Nyholt DR, Gericke GS, et al: Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p11, 8q22 and 11q23-24 in South African Afrikaners. Am J Med Genet 2001; 105:163-167. 30. Simonic I, Gericke GS, Ott J, et al: Identification of genetic markers associated with Gilles de la Tourette syndrome in an Afrikaner population. Am J Hum Genet 1998; 63:839-846. 31. A complete genome screen in sib pairs affected by Gilles de la Tourette syndrome. The Tourette Syndrome Association International Consortium for Genetics. Am J Hum Genet 1999; 65:1428-1436. 32. Merette C, Brassard A, Potvin A, et al: Significant linkage for Tourette syndrome in a large French Canadian family. Am J Hum Genet 2000; 67:1008-1013. 33. Curtis D, Brett P, Dearlove AM, et al: Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5, 10 and 13. Psychiatr Genet 2004; 14:83-87. 34. Diaz-Anzaldua A, Joober R, Riviere JB, et al: Association between 7q31 markers and Tourette syndrome. Am J Med Genet A 2004; 127:17-20. 35. Cuker A, State MW, King RA, et al: Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/ chronic tic disorder at 18q22. Am J Med Genet A 2004; 130: 37-39. 36. Diaz-Anzaldua A, Joober R, Riviere JB, et al: Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population. Mol Psychiatry 2004; 9:272-277. 37. Paschou P, Feng Y, Pakstis AJ, et al: Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region. Am J Hum Genet 2004; 75:545-560. 38. Santangelo SL, Pauls DL, Goldstein JM, et al: Tourette’s syndrome: what are the influences of gender and comorbid obsessive-compulsive disorder? J Am Acad Child Adolesc Psychiatry 1994; 33:795-804. 39. Lees AJ, Robertson M, Trimble MR, et al: A clinical study of Gilles de la Tourette syndrome in the United Kingdom. J Neurol Neurosurg Psychiatry 1984; 47:1-8. 40. Burd L, Severud R, Klug MG, et al: Prenatal and perinatal risk factors for Tourette disorder. J Perinat Med 1999; 27:295-302. 41. Burnstein MH: Tourette’s syndrome and neonatal anoxia: further evidence of an organic etiology. J Psychiatry Neurosci 1992; 17:89-93. 42. Swedo SE, Leonard HL, Garvey M, et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998; 155:264-271. 43. Cardona F, Orefici G: Group A streptococcal infections and tic disorders in an Italian pediatric population. J Pediatr 2001; 138:71-75. 44. Church AJ, Dale RC, Lees AJ, et al: Tourette’s syndrome: a cross sectional study to examine the PANDAS hypothesis. J Neurol Neurosurg Psychiatry 2003; 74:602-607. 45. Muller N, Riedel M, Straube A, et al: Increased antistreptococcal antibodies in patients with Tourette’s syndrome. Psychiatry Res 2000; 94:43-49. 46. Pavone P, Bianchini R, Parano E, et al: Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 2004; 30:107-110. 47. Singer HS, Loiselle CR, Lee O, et al: Anti-basal ganglia antibodies in PANDAS. Mov Disord 2004; 19:406-415. 48. Singer HS: PANDAS and immunomodulatory therapy. Lancet 1999; 354:1137-1138.

49. Robertson MM: Tourette syndrome, associated conditions and the complexities of treatment. Brain 2000; 123(Pt 3):425462. 50. Robertson MM: The heterogeneous psychopathology of Tourette syndrome. In Bedard MA, Agid Y, Chouinard S, et al, eds: Mental and Behavioral Dysfunction in Movement Disorders. Totowa, NJ: Humana Press, 2003, pp 433-466. 51. Kurlan R, Como PG, Miller B, et al: The behavioral spectrum of tic disorders: a community-based study. Neurology 2002; 59:414-420. 52. Katona C, Robertson MM: Gilles de la Tourette Syndrome. Psychiatry at a Glance, 3rd ed. Oxford, UK: Blackwell Science, 2005. 53. Eapen V, Robertson MM, Alsobrook JP, et al: Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder: differences by diagnosis and family history. Am J Med Genet 1997; 74:432-438. 54. Frankel M, Cummings JL, Robertson MM, et al: Obsessions and compulsions in Gilles de la Tourette’s syndrome. Neurology 1986; 36:378-382. 55. Leckman JF, Pauls DL, Zhang H, et al: Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome. Am J Med Genet B Neuropsychiatr Genet 2003; 116:60-68. 56. Miguel EC, Leckman JF, Rauch S, et al: Obsessive-compulsive disorder phenotypes: implications for genetic studies. Mol Psychiatry 2004; 10:258-275. 57. Coffey BJ, Miguel EC, Biederman J, et al: Tourette’s disorder with and without obsessive-compulsive disorder in adults: are they different? J Nerv Ment Dis 1998; 186:201-206. 58. Swanson JM, Sergeant JA, Taylor E, et al: Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998; 351:429-433. 59. Apter A, Pauls DL, Bleich A, et al: An epidemiologic study of Gilles de la Tourette’s syndrome in Israel. Arch Gen Psychiatry 1993; 50:734-738. 60. Robertson MM, Trimble MR, Lees AJ: The psychopathology of the Gilles de la Tourette syndrome. A phenomenological analysis. Br J Psychiatry 1988; 152:383-390. 61. Robertson MM, Channon S, Baker J, et al: The psychopathology of Gilles de la Tourette’s syndrome. A controlled study. Br J Psychiatry 1993; 162:114-117. 62. Robertson MM, Banerjee S, Hiley PJ, et al: Personality disorder and psychopathology in Tourette’s syndrome: a controlled study. Br J Psychiatry 1997; 171:283-286. 63. Rickards H, Robertson M: A controlled study of psychopathology and associated symptoms in Tourette syndrome. World J Biol Psychiatry 2003; 4:64-68. 64. Carter AS, O’Donnell DA, Schultz RT, et al: Social and emotional adjustment in children affected with Gilles de la Tourette’s syndrome: associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder. J Child Psychol Psychiatry 2000; 41:215-223. 65. Brand N, Geenen R, Oudenhoven M, et al: Brief report: cognitive functioning in children with Tourette’s syndrome with and without comorbid ADHD. J Pediatr Psychol 2002; 27:203208. 66. Wilhelm S, Deckersbach T, Coffey BJ, et al: Habit reversal versus supportive psychotherapy for Tourette’s disorder: a randomized controlled trial. Am J Psychiatry 2003; 160:11751177. 67. Piacentini J, Chang S: Behavioral treatments for Tourette syndrome and tic disorders: state of the art. Adv Neurol 2001; 85:319-331. 68. Scahill L, Leckman JF, Schultz RT, et al: A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 2003; 60:1130-1135.

chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders 69. Budman CL, Gayer A, Lesser M, et al: An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001; 62:290-294. 70. Parraga HC, Parraga MI, Woodward RL, et al: Quetiapine treatment of children with Tourette’s syndrome: report of two cases. J Child Adolesc Psychopharmacol 2001; 11:187-191. 71. Kastrup A, Schlotter W, Plewnia C, et al: Treatment of tics in Tourette syndrome with aripiprazole. J Clin Psychopharmacol 2005; 25:94-96. 72. Sallee FR, Kurlan R, Goetz CG, et al: Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 2000; 39:292-299. 73. Kunwar AR, Megna JL: Resolution of risperidone-induced hyperprolactinemia with substitution of quetiapine. Ann Pharmacother 2003; 37:206-208. 74. Porta M, Maggioni G, Ottaviani F, et al: Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci 2004; 24:420-423. 75. Robertson M, Doran M, Trimble M, et al: The treatment of Gilles de la Tourette syndrome by limbic leucotomy. J Neurol Neurosurg Psychiatry 1990; 53:691-694. 76. Rauch SL, Baer L, Cosgrove GR, et al: Neurosurgical treatment of Tourette’s syndrome: a critical review. Compr Psychiatry 1995; 36:141-156. 77. Temel Y, Visser-Vandewalle V: Surgery in Tourette syndrome. Mov Disord 2004; 19:3-14. 78. Newcorn JH, Spencer TJ, Biederman J, et al: Atomoxetine treatment in children and adolescents with attention-deficit/ hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry 2005; 44:240-248. 79. Castellanos FX, Acosta MT: [Tourette syndrome: an analysis of its comorbidity and specific treatment]. Rev Neurol 2004; 38(Suppl 1):S124-S130. 80. Pauls DL, Alsobrook JP, Goodman W, et al: A family study of obsessive-compulsive disorder. Am J Psychiatry 1995; 152:7684. 81. McKay D, Abramowitz JS, Calamari JE, et al: A critical evaluation of obsessive-compulsive disorder subtypes: symptoms versus mechanisms. Clin Psychol Rev 2004; 24:283-313. 82. Angst J, Gamma A, Endrass J, et al: Obsessive-compulsive severity spectrum in the community: prevalence, comorbidity, and course. Eur Arch Psychiatry Clin Neurosci 2004; 254:156164. 83. Mohammadi MR, Ghanizadeh A, Rahgozar M, et al: Prevalence of obsessive-compulsive disorder in Iran. BMC Psychiatry 2004; 4:2.

221

84. Cillicilli AS, Telcioglu M, Askin R, et al: Twelve-month prevalence of obsessive-compulsive disorder in Konya, Turkey. Compr Psychiatry 2004; 45:367-374. 85. Fontenelle LF, Mendlowicz MV, Marques C, et al: Trans-cultural aspects of obsessive-compulsive disorder: a description of a Brazilian sample and a systematic review of international clinical studies. J Psychiatr Res 2004; 38:403-411. 86. Freud S: Obsessions and phobias, their psychical mechanisms and their aetiology. In Strachey J, ed: The Standard Edition of the Complete Psychological Works. London: Hogarth Press, 1895. 87. Rachman S, Hodgson RJ: Obsessions and Compulsions. Englewood Cliffs, NJ: Prentice-Hall, 1980. 88. Evans DW, Lewis MD, Iobst E: The role of the orbitofrontal cortex in normally developing compulsive-like behaviors and obsessive-compulsive disorder. Brain Cogn 2004; 55:220234. 89. Arnold PD, Richter MA: Is obsessive-compulsive disorder an autoimmune disease? CMAJ 2001; 165:1353-1358. 90. Stewart SE, Geller DA, Jenike M, et al: Long-term outcome of pediatric obsessive-compulsive disorder: a meta-analysis and qualitative review of the literature. Acta Psychiatr Scand 2004; 110:4-13. 91. Masellis M, Rector NA, Richter MA: Quality of life in OCD: differential impact of obsessions, compulsions, and depression comorbidity. Can J Psychiatry 2003; 48:72-77. 92. Geffken GR, Storch EA, Gelfand KM, et al: Cognitive-behavioral therapy for obsessive-compulsive disorder: review of treatment techniques. J Psychosoc Nurs Ment Health Serv 2004; 42:44-51. 93. Kim MC, Lee TK, Choi CR: Review of long-term results of stereotactic psychosurgery. Neurol Med Chir (Tokyo) 2002; 42:365-371. 94. Lippitz BE, Mindus P, Meyerson BA, et al: Lesion topography and outcome after thermocapsulotomy or Gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere. Neurosurgery 1999; 44:452-458. 95. Mindus, Jenike MA: Neurosurgical treatment of malignant obsessive compulsive disorder. Psychiatr Clin North Am 1992; 15:921-938. 96. Mindus P, Rasmussen SA, Lindquist C: Neurosurgical treatment for refractory obsessive-compulsive disorder: implications for understanding frontal lobe function. J Neuropsychiatry Clin Neurosci 1994; 6:467-477. 97. Kopell BH, Greenberg B, Rezai AR: Deep brain stimulation for psychiatric disorders. J Clin Neurophysiol 2004; 21:51-67.

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SCHIZOPHRENIA AND SCHIZOPHRENIA-LIKE PSYCHOSIS ●

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Gary Price and Maria A. Ron

The first part of this chapter deals with schizophrenia as a primary illness, and the second describes schizophrenia-like features that appear in the context of other neurological illness.

SCHIZOPHRENIA Schizophrenia is a brain disease as common as multiple sclerosis that impairs the ability to work, independent living, and interpersonal relationships. The effect of schizophrenia on health care budgets is substantial and accounts for 1.5% to 3% of total national health care expenditure.1 Kraeplin2 introduced the term dementia praecox to refer to a cluster of symptoms that included catatonia and paranoia and carried a poor prognosis. The term schizophrenia was first used by Bleuler,3 who believed that certain “fundamental symptoms” were present in all affected patients. Current diagnostic classifications, such as the International Classification of Mental and Behavioural Disorders, 10th revision (ICD-10)4 and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV),5 still require the presence of a cluster of symptoms, in the absence of drug abuse or other organic brain disease, to establish the diagnosis (Table 18–1).

Epidemiology The incidence of schizophrenia is rather similar across different countries, with rates between 0.16 to 0.42 per 1000 and with a prevalence around 1% when narrow diagnostic criteria are used.6 There are some remote populations with an increased incidence and prevalence, such as the Afro-Caribbean population in the United Kingdom (incidence ratios above 7),7 and others with reduced rates, such as the Hutterites of South Dakota (ratio of observed to predicted mean rates, 0.48),8 and genetic and environmental factors probably contribute to this variability. Schizophrenia is common in men and women equally, and its onset may occur at any age, although it often starts between the ages of 15 and 45, with an earlier onset in men.9

Clinical Features and Natural History Schizophrenia is characterized by a multitude of symptoms that vary between patients and encompass a variety of mental

functions such as perception, emotion, and language (see Table 18–1). The symptoms of schizophrenia are often categorized as positive and negative. Positive symptoms include delusions, passivity phenomena, and hallucinations. Negative symptoms include apathy and social withdrawal. Functional imaging studies (positron emission tomography) have suggested that auditory hallucinations are accompanied by increased blood flow10 in subcortical nuclei, limbic structures, and paralimbic regions, and functional magnetic resonance imaging (MRI) demonstrates increased activation in the inferior frontal and temporal cortex.11 The neural correlates of other symptoms are less well understood. Psychotic symptoms usually start in late adolescence or early adulthood,12 tend to persist throughout the illness,13 and are often associated with poor psychosocial functioning.14 For many patients, schizophrenia starts with a prodromal period lasting from months to years. The symptoms of the prodromal stage may include depression, anxiety, dysphoria, social withdrawal, and cognitive underfunctioning, as well as attenuated psychotic symptoms.15 The outcome of schizophrenia is variable. Harrison and Eastwood16 found that one third of patients had recovered at follow-up 15 or 25 years later and that for many patients, schizophrenia is a relapsing-remitting disorder. The study also showed that lack of improvement early in the illness is predictive of persistence of symptoms and long-term disability. Other studies have revealed that an early onset of psychosis is associated with a more severe illness, irrespective of duration of illness.17

Cognitive Deficits Cognitive impairment is an integral feature of schizophrenia. Attention, executive function, and memory are most commonly impaired.18 Cognitive deficits are already present at the onset of psychosis19,20 and are present irrespective of medication.21 Some patients appear to undergo a decline in general intellectual function in the prodromal stages of the illness or during the onset of psychosis.22,23 After the onset of psychosis, cognitive impairments do not generally deteriorate further, which suggests that they are independent of clinical symptoms and the effects of medication.24 Large-scale studies have found that schizophrenic patients perform worse than healthy controls

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T A B L E 18–1. Key Symptoms of Schizophrenia with Exclusion Criteria

across a range of cognitive tasks,25,26 that cognitive impairment in a given function is predictive of impairment in all others,27 and that this impairment is global, variation between patients being a matter of degree. Other studies have found evidence for a subgroup of patients with isolated executive dysfunction.22,28 Deficits in executive function may be related to an increased genetic susceptibility to schizophrenia29 and may be part of the schizophrenia endophenotype.30 Similarly episodic memory deficits may be associated with an earlier age at onset,29 and this may suggest that early brain insults (e.g., hypoxia) that constitute a risk factor for young age at onset may, through their action on the amygdala and hippocampus, may also be responsible for the memory deficits. Functional imaging studies have shown reduced blood flow (positron emission tomography31,32) and reduced activation (functional MRI33) in the dorsolateral and other prefrontal areas of the cortex in schizophrenic patients in comparison with normal controls in response to executive function tasks. The neural correlates of other cognitive deficits are less well understood. The effect of typical neuroleptics on cognition is still controversial, although the blockade of dopamine D2 receptors achieved by these drugs may have a negative effect on cognition.34 In contrast, atypical neuroleptics, with antipsychotic effects not mediated by D2 blockade, may preserve or enhance cognition.35

Genetics Twin studies in schizophrenia have shown concordance rates of 41% to 65% in monozygotic pairs and 0% to 28% in dizygotic pairs and a heritability rate of 80% of 85%,36 which are suggestive of an important genetic contribution. The genetic risk for an individual increases with the degree of relation to the

affected relative: 40.8% if there is an affected monozygotic twin, 5.3% in siblings of affected patients,37 and a lifetime risk ranging from 3.1% to 16.9% in first-degree relatives of schizophrenic probands.38 A younger age at onset is associated with a higher familial risk for schizophrenia.39 A polygenic model—that is, the combined effects of multiple susceptibility genes—is the more likely pattern of inheritance. The way these susceptibility genes operate remains to be determined, but the clusters of genes operating in different individuals are likely to be heterogeneous, and they may be influenced by environmental factors. Of the susceptibility genes possibly associated with schizophrenia, catechol-O-methyl-transferase (COMT) is the most likely. COMT is predominantly expressed in prefrontal and hippocampal neurons and implicated in interneuronal monoaminergic signaling, especially dopamine. Hemideletion of chromosome 22q11, where COMT maps, results in the velocardiofacial syndrome40 with a greatly increased risk (24% in a study sample of patients with velocardiofacial syndrome) of schizophrenia-like psychosis.41 Other possible susceptibility genes, suggested by association studies, are DISC1 (“disrupted in schizophrenia”), a complex gene with effects on cytoskeletal proteins, cell migration, and membrane trafficking of receptors likely to influence hippocampal structure and function42; neuregulin 1 (NRG1) with effects in signaling and hence in neuronal development and plasticity; dysbindin (DTNBP1), widely expressed in neurons, including those in the dorsolateral prefrontal cortex, hippocampus, and substantia nigra, with effects on trafficking and tethering of receptors N-methyl-D-aspartate [NMDA], nicotinic acid, and γ-amino butyric acid A [GABAA]), and likely to contribute to glutamatergic hippocampal pathology; the regulator of G protein signaling 4, expressed in the dorsolateral prefrontal cortex involved in signaling; and the metabotropic glutamate receptor gene (GRM3), expressed presynaptically in neurons, astrocytes, and oligodendrocytes and likely to affect glutamatergic neurotransmission in the hippocampus and prefrontal cortex. Other genes associated with glutamatergic transmission and implicated in schizophrenia include G72 and D-amino acid oxidase (DAAO), which appear to directly affect NMDA receptors, and proline dehydrogenase (PRODH), which affects glutamatergic synapses by several mechanisms (Fig. 18–1).43,44 Most of the susceptibility genes so far identified have an effect on the molecular biology of the synapse, particularly glutamatergic synapses, but also influence the dopaminergic and GABAergic systems, thus causing malfunction of cortical microcircuits, which probably explains the pattern of symptoms and cognitive deficits that characterize schizophrenia.44

Neuropathology Imaging studies have demonstrated loss of brain volume in schizophrenic patients in comparison with controls45,46 and have highlighted pathological changes in the hippocampus and prefrontal cortext47 and in the superior temporal cortex and thalamus.46 More recent studies with magnetization transfer imaging, a technique sensitive to subtle neuropathological changes (e.g., changes in cell membranes and myelin) have demonstrated diffuse cortical abnormalities in patients with chronic schizophrenia.48 In patients with first episodes,49 these

chapter 18 schizophrenia and schizophrenia-like psychosis ■

PRODH Presynaptic neuron

DTNBP1 Glutamate

P5C

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Glial cell NRG1 Synapse

Glutamate

KAR DAAO

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mGluR

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Figure 18–1. Schizophrenia susceptibility genes and synaptic plasticity. Hypothetical scenario in which genes (in italics) may have shared effect on synapses, through influences on their formation, plasticity, or signaling properties. Only glutamatergic synapse is shown, but γ-amino butyric acid–mediated (GABAergic), cholinergic, and monoaminergic synapses (especially relevant to catechol-Omethyl-transferase [COMT]) are also probably involved. Also omitted is the issue of localization of pathology. Solid arrows indicate direct interactions; dotted arrows indicate indirect interactions. ErbB4, NRG7 receptor; Gq, subtype of guanosine triphosphate–binding proteins, KAR, kainate receptor; mGluR, metabotropic glutamate receptor; NMDAR, Nmethyl-D-aspartate receptor; P5C, pyrroline-5carboxylate; PSD, postsynaptic density proteins. (From Harrison PJ, Owen MJ: Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361:417-419.)

RGS4

abnormalities are limited to the medial prefrontal cortex, insula, and fasciculus uncinatus in the absence of atrophy. Imaging abnormalities are already evident before or at the time of the first episode of illness (Fig. 18–2)50 and may be present in unaffected relatives,51 which suggests that these abnormalities may be related to the genetic predisposition or early environmental factors, rather than to the illness itself. These changes, modest and often nonspecific, are not diagnostic of schizophrenia and may be present in other psychoses. The most consistent histological findings are decreases in neuronal size in the hippocampus and neocortex with reduced dendritic arborization and synaptic abnormalities.52 Levels of N-acetyl aspartate, a marker of neuronal integrity, measured in vivo with magnetic resonance spectroscopy, are reduced in the hippocampus53 and prefrontal cortex,54 which is in keeping with these findings. Neuronal loss in the dorsomedial nucleus of the thalamus and pulvinar have been less consistently reported.55 Reduction in the number of oligodendrocytes, important in myelination and synaptic integrity, whether primary or secondary to these neuronal changes, have also been reported.56 These quantitative alterations of the normal neural circuitry may result in subtle loss of cortical volume and thickness.16 Longitudinal imaging studies have not provided clear evidence of progression of brain abnormalities (see Shenton et al [2001]46 for a review), although loss of cortical volume may occur in the early stages of the illness in subgroups of patients with early onset and severe symptoms.57 Other investigators, using diffusion tensor imaging, have described axonal and myelin abnormalities in the corpus callosum of patients with chronic schizophrenia,58 which are absent at the onset of schizophrenia.59 Neuropathologically, astrogliosis and neurodegenerative changes, including those of Alzheimer’s disease, are not overrepresented in schizophrenia, which suggests that apparent clinical deterioration may be difficult to explain as a result of a neurodegenerative process.60-62 In contrast, abnormalities of neuronal migration, evidenced by aberrantly located

neurons in the lamina II of the entorhinal cortex and neocortical white matter, are strongly suggestive of disruption of normal brain development (for a review, see Harrison [1999]63). Further evidence for schizophrenia as a disorder of normal brain development is found in epidemiological studies that suggest early environmental factors that increase the risk for schizophrenia in later life. Evidence points toward a small winter-spring excess of births among patients with schizophrenia,64 as well as exposure to the influenza virus prenatally.65,66 Obstetrical complications are also linked to this risk, although the mechanisms are uncertain.67

Neurochemistry The dopamine hypothesis has been the chief neurochemical hypothesis in schizophrenia since the early 1960s68 and is supported by observations that dopamine D2 receptor blocking is common to all antipsychotic drugs.69 The mechanism and exact location of dopaminergic abnormalities in schizophrenia still remain unclear, and the dopamine hypothesis has undergone some revision since its initial inception. According to the hypothesis as it stands now, there exists a dopaminergic imbalance between the hyperactive subcortical, mesolimbic dopamine pathways (resulting in positive symptoms), and the hypoactive mesocortical dopaminergic connections to the prefrontal cortex (resulting in negative symptoms and cognitive impairment).70 The alternative glutamate hypothesis is based on the observation that the NMDA glutamate receptor antagonist phencyclidine causes psychosis that resembles both the positive and negative symptoms of schizophrenia.71 The glutamate hypothesis in its most simplified form is that a reduction in glutamate neurotransmission at the NMDA receptor results in symptoms of schizophrenia.72 However, the dopamine and glutamate hypotheses are not mutually exclusive, inasmuch as reciprocal synaptic relations between forebrain dopaminergic projections and glutamatergic systems have been described.73

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A

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Figure 18–2. Magnetization transfer ratio reductions in patients with first-episode schizophrenia in comparison with controls, demonstrating bilateral reductions in (A) Prefrontal cortex, sagittal section, (B) Subcortical white matter and prefrontal cortex axial section, (C) Insula, sagittal section, (D) Subcortical white matter, coronal section. (From Bagary MS, Symms MR, Barker GJ, et al: Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch Gen Psychiatry 2003; 60:779-788. Copyright © 2003 American Medical Association. All rights reserved.)

There is also evidence of dysfunction of the GABAergic system in schizophrenia (see Benes and Berretta74): namely, the reduction of specific GABAergic interneurons (paralbuminimmunoreactive cells) in the prefrontal cortex and hippocampus.75 Various subtypes of GABA neurons provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits believed to be involved in schizophrenia. The evidence for the role of the serotonergic system in schizophrenia is unclear, although there are serotonergic hallucinogens that block 5-hydroxytryptamine 2 receptors,76 and 5-hydroxytryptamine 2A receptor antagonism may contribute to the efficacy of atypical neuroleptics.77

The Pathophysiology of Schizophrenia One of the greatest challenges facing psychiatry today is to propose an explanatory theory that encompasses the often disparate facts known about schizophrenia and is able to accommodate emerging knowledge. There is evidence for a genetic predisposition, and a number of possible candidate genes with effects on the molecular biology of the synapse, as well as on the dopaminergic and GABAergic systems, have been identified.44 Histological findings such as aberrant neuronal clusters in the entorhinal cortex and an absence of gliosis also imply a neurodevelopmental etiology. Early environmental insults are

chapter 18 schizophrenia and schizophrenia-like psychosis additionally implicated, and these include complications of pregnancy and delivery.67 Abnormalities in cortical circuitry, induced by developmental and environmental factors, may limit neuronal information-processing capacity, and demands made on this malfunctioning system later in life may result in the emergence of psychotic symptoms and cognitive deterioration. The neurodevelopmental theory presupposes that pathological changes are not progressive and that changes in brain volume detected during the illness may be the consequence of disease-related changes in neuroplasticity (e.g., unstimulating environments, medication).78

Treatment of Schizophrenia Drug Treatment Neuroleptics have been used in the treatment of acute and chronic psychosis since the 1950s. The antipsychotic effect of the first-generation typical neuroleptics such as haloperidol and chlorpromazine depends on their action on the dopamine D2 receptors, and hallucinations are blocked when about 70% of the D2 receptors are occupied by neuroleptic drugs.79 Dopamine D3 and D4 receptor antagonism does not appear to be as important for antipsychotic effects.79 Antipsychotic agents may also affect brain structure directly: There are reports, albeit with a small sample size, of reversal of the superior temporal gyrus volume loss with neuroleptic treatment in a 1-year follow-up.80 Although typical antipsychotics have beneficial effects on positive symptoms, they are less effective in treating negative symptoms and cognitive impairment.81 They also have serious unwanted effects, such as extrapyramidal side effects (EPSEs), tardive dyskinesia, and neuroleptic malignant syndrome (NMS). Clinical EPSEs include acute dystonia, subjective feelings of restlessness (akathisia), and parkinsonism. Positron emission tomographic studies suggest that EPSEs are related to dopamine D2 occupancy in the range of 75% to 80%,82 but D1 antagonism has also been implicated.83 Although traditional neuroleptics do not necessarily lead to EPSEs, the therapeutic window between therapeutic effect and EPSE is small, and thus many patients receiving these medications have EPSEs. Tardive dyskinesia is a potentially irreversible side effect of long-term treatment with neuroleptic drugs and is characterized by abnormal involuntary hyperkinetic movements such as grimacing, lip smacking, tongue protrusion, and rapid eye blinking. Involuntary rapid movements of the fingers, arms, legs, and trunk may also occur. Various hypotheses, including overactivity in the striatal dopamine system,84 abnormal GABA-related striatal neurons,85 and free radical production73 have been proposed as pathophysiological mechanisms. Epidemiological data indicate that increasing age86 and female gender are risk factors for tardive dyskinesia.87 The outcome of tardive dyskinesia is more favorable in younger patients.87 Discontinuation of neuroleptic drugs or the use of a drug with fewer EPSEs (e.g., clozapine) is the first action of treatment. NMS is a life-threatening syndrome characterized by fever, muscular rigidity, and raised serum creatine kinase concentration. The incidence has been estimated to be between 0.07 and

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0.9,88,89 and onset can occur within hours but is usually 4 to 14 days after starting neuroleptic therapy. The mechanism of NMS is uncertain, but the most widely accepted mechanism is of blockage of dopamine receptors in the nigrostriatal tracts.90 An alternative hypothesis suggests an imbalance between serotonin and dopamine.91 Risk factors for developing NMS include dehydration, male gender, the presence of organic brain disease or mental retardation, and rapid escalation of ingestion of neuroleptic drugs.92,93 The mortality rate has been reported at 8%,94 but most patients recover within 14 days.93 In NMS, antipsychotics should be discontinued, and, in general, intensive care treatment is required. Drugs that have been used in the treatment of NMS include dopamine agonists such as bromocriptine and apomorphine. If restarting a neuroleptic is deemed necessary, it is worth switching to a neuroleptic in a different chemical class and with a lower D2 affinity than the drug that produced the NMS.95 Other side effects of neuroleptics include weight gain, diabetes, sedation, sexual dysfunction, postural hypotension, and cardiac conduction problems, including sudden cardiac death. Gastric complications can be varied and paralytic ileus has been reported. Maintenance treatment with antipsychotic medication decreases relapse rates96; however, a substantial proportion of patients suffer relapse despite taking medication, and poor compliance is also a problem. A second generation of so-called atypical neuroleptics (e.g., clozapine, risperidone, quetiapine, olanzapine) has been developed with a spectrum of receptor effects different from those of typical neuroleptics and less severe side effects, resulting in better compliance and improved therapeutic outcome.97 Clozapine is the prototype of this class of neuroleptic. Kane and colleagues98 established the antipsychotic efficacy of clozapine in previously treatment-resistant patients without side effects, and this has been confirmed in other studies.99,100 Clozapine also has an effect on negative symptoms and cognitive functioning.100 One of the properties of clozapine is its high dissociation constant at the D2 receptor, which results in fewer EPSEs.101 Clozapine also has affinities for other nondopamine receptors such as 5-hydroxytryptamine 2, and its α2-adrenoceptor antagonism is believed to contribute to the freedom from EPSEs (see Reynolds102 for review). Clozapine may cause potentially fatal agranulocytosis, and regular blood monitoring is required. Other unwanted effects include hypersalivation, weight gain, and a lowering of the seizure threshold. The increased risk of stroke in older adults with dementia has also been linked to atypical antipsychotics.103 Recent developments in understanding the mechanism of action of antipsychotic medications has led to the development of the partial D2 and 5-hydroxytryptamine 1A receptor agonist aripiprazole,104 which is antipsychotic and possibly without EPSEs.105 Future drug treatments may continue to focus on partial agonism to improve antipsychotic symptoms or focus on NMDA-glutamatergic modulators.106 In the United Kingdom, the guidelines of the National Institute of Clinical Excellence recommend the use of atypical neuroleptics as first-line treatment, because of fewer side effects and efficacy comparable with those of typical neuroleptics, and the use of clozapine in treatment-resistant patients. Early treatment is recommended because of the possible association between a longer duration of untreated psychosis and poor outcome.107

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Psychological Treatments The use of psychological treatments has been shown to improve the outcome of schizophrenia when they are integrated with pharmacological treatments. Promising results have been reported with cognitive-behavioral therapy. A meta-analysis by Gould and associates108 showed it to be effective for positive symptoms. By challenging the patient’s interpretation of psychotic phenomena, this therapy reduces the frequency of relapse and the degree of distress. There is also evidence to suggest that cognitivebehavioral therapy may ameliorate negative symptoms.109 Cognitive-behavioral therapy has also been used in the prodromal phase of the illness in an attempt to delay or avoid the development of florid symptoms, with promising results.110 Family therapy has also been helpful as an adjuvant to pharmacological treatment in patients exposed to home environments with high levels of criticism, hostility, or emotional over-involvement.111,112 Supported employment programs are also promising.113

SCHIZOPHRENIA-LIKE PSYCHOSIS IN NEUROLOGICAL ILLNESS The association of epilepsy with schizophrenia-like symptoms was described in the 1960s,114 and similar symptoms have been described in association with other neurological diseases. These psychoses are included in the DSM-IV under the category of “Psychotic Disorder due to a General Medical Condition.” Initially, diseases involving the temporal lobes were believed to be more likely to cause psychotic symptoms,115 but more recent studies have described this association with extratemporal or diffuse pathology,116 and it has been suggested that damage to the dopaminergic limbic projections may be the common mechanism.117 The symptoms are similar to those of schizophrenia, although visual hallucinations, flat affect, passivity feelings, and catatonia may be commoner in patients with neurological disease,118,119 as are complex and specific delusional symptoms (e.g., morbid jealousy, erotomania, delusional parasitosis). Treatment follows the same protocol as that of schizophrenia, but the choice of medication may be dictated by the underlying neurological disease (e.g., danger of aggravating symptoms in patients with Parkinson’s disease). Features and treatment of schizophrenia-like psychosis associated with some neurological diseases are discussed in the following sections. Conditions in which psychotic symptoms are common (e.g., epilepsy, Parkinson’s disease, diffuse Lewy body disease) or where the mechanisms leading to psychosis shed some light onto schizophrenia research are included here.

Epilepsy The classification of psychotic symptoms in epilepsy is based on their temporal relationship to seizures: ictal, postictal, and interictal (see Sachdev120 for review). The combined prevalence of these syndromes is around 2% to 7%.121 In ictal psychosis, the psychotic episode may be an expression of nonconvulsive status epilepticus (i.e., absence status epilepticus, simple partial status epilepticus, and partial complex status epilepticus). Patients may experience delusions and hallucinations while in

a state of altered consciousness.122 Ictal psychoses usually last hours or days, and electroencephalographic (EEG) abnormalities help establish the diagnosis.120 Postictal psychoses account for 25% of psychotic episodes of epilepsy.123 They are usually brief and follow clusters of seizures or an increase in seizure frequency, usually after a lucid period of up to 1 week.124 EEG abnormalities may persist during the psychosis, and consciousness may be normal or impaired.121 The psychotic symptoms include paranoid delusions and hallucinations, and mood abnormalities are common.125 When psychotic symptoms develop gradually and in parallel to increases in seizure activity, the term peri-ictal psychosis may be used, in distinction to postictal psychosis.121 In peri-ictal psychosis, consciousness is usually impaired, and the EEG recording reflects increased epileptic activity.121 Interictal psychoses are not related to ictal activity and can develop when seizures are infrequent or fully controlled.120 They are the commonest psychoses and occur in 4% to 18% of epileptic patients, mostly in those with temporal lobe epilepsy.121 They can last from days to weeks but, once established, may follow a chronic course. Paranoid delusions, auditory hallucinations, and affective symptoms are common,120 and cognitive deficits are similar to those of schizophrenia.126 In some patients, the emergence of psychotic symptoms is accompanied by a normalization of the EEG recording127 or coincides with the use of some anticonvulsants such as vigabatrin and zonisamide, and recurrence of seizure activity ameliorates the psychosis.128 Schizophrenia-like psychosis can also appear after temporal lobe surgery for epilepsy, and it remains to be determined whether surgery is incidental and psychosis would have eventually emerged or whether surgery is a risk factor. If the latter is correct, a mechanism similar to forced normalization127 may also operate in these patients. Of postsurgical psychoses, 85% follow right temporal lobectomies and are usually short-lived, although they may follow a chronic course.129 The pathophysiology of the interictal psychosis is uncertain, but the lack of correlation with seizure frequency and the increased incidence in patients with mesial temporal sclerosis suggest that the epilepsy and the psychotic symptoms may be manifestations of a common pathology, rather than that the epileptic activity causes psychosis, although it is possible that stimulation of temporolimbic circuits may predispose to psychosis.120 Interictal psychoses have been considered a contraindication to temporal lobe surgery for the control of epilepsy, but this opinion has been revised,130 and some patients appear to benefit from surgery.131 Antipsychotic medication is usually needed to treat interictal psychosis, and atypical neuroleptics at low doses to avoid increased seizure activity are the best choice.

Parkinson’s Disease and Diffuse Lewy Body Disease Psychotic symptoms occur in 50% of patients at some time during the illness and increase with age and severity of the disease. Paranoid ideas and visual hallucinations are the most common psychiatric symptoms, occurring in 10% to 40% of patients.132 Visual hallucinations are usually complex and may be accompanied by auditory and tactile hallucinations.133 Vivid

chapter 18 schizophrenia and schizophrenia-like psychosis nightmares and reduction of rapid eye movement sleep have been observed in 80% of those who experienced psychotic symptoms.132 The pathophysiology of psychosis in Parkinson’s disease is complex. Dopaminergic medication plays a role in treatment, although psychotic symptoms are not related to the dose of medication,134 and they have even been reported in Parkinson’s disease before the introduction of levodopa therapy.134 In young patients, receptor hypersensitivity in the mesolimbic system may be relevant to psychiatric symptoms whereas in elderly patients, serotonergic hyperactivity caused by dopaminergic agonists (i.e., bromocriptine, lisuride, pergolide, cabergoline, ropinirole, and pramipexole) may be more relevant.135 In elderly patients, diffuse Lewy body disease or coexisting pathological processes such as cerebrovascular and Alzheimer’s disease may also play a role. In diffuse Lewy body disease, complex and vivid visual hallucinations occur in up to 80% of patients. Children and animals figure prominently in these hallucinations, and abnormalities of visual perception are common. Auditory hallucinations and paranoid delusions are less frequent (20% to 30%). Depression, apathy, irritability, and nocturnal confusion are also common, together with cognitive impairment involving executive functions, memory, and visuospatial functions. Fluctuations in psychiatric symptoms and cognition are the hallmarks of the disease. Deficits in presynaptic cholinergic transmission in the diencephalon and brainstem, in addition to deficits of dopaminergic transmission, may predispose to psychosis. In Parkinson’s disease, treatment strategies involve fostering good sleep habits and avoiding sensory overload.135 Progressive reduction of anticholinergic medication and dopamine agonists should be attempted, followed by reduction of the levodopa dosage, but in many patients, mobility reduction may become intolerable before psychotic symptoms are controlled, and antipsychotic medication is often required. Atypical antipsychotics should be tried; clozapine, with its low incidence of EPSEs may be the drug of choice.136 Other atypical neuroleptics (quetiapine, olanzapine, risperidone, and aripiprazole) can also be used in these patients, and the treatment may need to be long term. In diffuse Lewy body disease, reduction of dopaminergic medication should also be attempted. Frequent adverse reactions to neuroleptics has made their use problematic. Anticholinesterase inhibitors may be the drugs of choice, and their use can also be extended to patients with Parkinson’s disease.135

Psychosis in Traumatic Brain Injury The prevalence of schizophrenia-like symptoms is increased with traumatic brain injury.115,137 In head injuries of moderate severity, damage to the left temporal lobe appears to be a risk factor for psychosis.138 In subjects with a genetic vulnerability, minor trauma may be the trigger, rather than the cause of psychosis.139 Psychotic symptoms tend to appear 4 or 5 years after the injury, but their appearance could be delayed by many years. Psychotic symptoms that appear immediately after the injury are usually part of a confusional state and tend to be mild and transient. As in other schizophrenia-like psychosis, symptoms may follow a prodrome characterized by social isolation and nonspecific symptoms. Mood changes and agitation are

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common, and negative symptoms infrequent. Diffuse cognitive deterioration often accompanies psychotic symptoms in these patients.138 Chronicity is the rule, and treatment with neuroleptics is often required, although comprehensive studies of outcome are not available.

Demyelinating Diseases Schizophrenia-like psychosis is uncommon in multiple sclerosis. Psychotic symptoms tend to appear when muscular sclerosis is well established, usually in patients with lesions in temporal lobe white matter, and usually respond to antipsychotic medication.140 In contrast, psychotic symptoms are far more frequent in metachromatic leukodystrophy, an autosomal recessive disease resulting from a mutation on chromosome 22q that leads to a deficit of the enzyme arylsulfatase A and accumulation of metachromatic material (sulfatides) in the brain and peripheral nervous system, which causes demyelination.141 Patients with the juvenile- and adult-onset forms of metachromatic leukodystrophy have higher arylsulfatase A activity and have a more protracted course than do those with the late infantile forms, and they often present with a schizophrenia-like illness.141 Usually it is only when neurological symptoms, progressive cognitive decline leading to dementia, or white matter MRI abnormalities become apparent that metachromatic leukodystrophy is diagnosed.142 Myelin abnormalities in the prefrontal white matter and frontotemporal connections, detectable by MRI, are likely to play a role in the emergence of psychosis. The high prevalence of psychosis in this age group is in contrast to the low prevalence in multiple sclerosis,143 which suggests that age may determine the psychiatric manifestations of demyelination.31 Treatment of symptoms is based on isolated case reports that indicate that psychosis in patients with metachromatic leukodystrophy improves with neuroleptic treatment.31

K E Y

P O I N T S

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Schizophrenia has a prevalence of approximately 1% and may result in significant functional disability.

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The symptoms of schizophrenia are often categorized as positive and negative. Positive symptoms include delusions, passivity phenomena, and hallucinations. Negative symptoms include apathy and social withdrawal.

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Cognitive impairment is an integral feature of the illness.

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Drug treatment should be in the form of newer (atypical) antipsychotics.

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Symptoms similar to schizophrenia have been described in association with other neurological diseases.

Suggested Reading Harrison PJ: The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122:593624. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10:40-68.

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Joyce E, Huddy V: Defining the cognitive impairment in schizophrenia. Psychol Med 2004; 34:1151-1155. Shenton ME, Dickey CC, Frumin M, et al: A review of MRI findings in schizophrenia. Schizophr Res 2001; 49:1-52. Rapoport JL, Giedd JN, Blumenthal J, et al: Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999; 56:649-654.

References 1. Knapp M, Mangalore R, Simon J: The global costs of schizophrenia. Schizophr Bull 2004; 30:279-293. 2. Kraeplin E: Psychiatrie. Ein Lehrbuch für Studirende und Aerzte. Fünfte, vollständig umgearbeitete Auflage. Leipzig: Barth Verlag, 1896. 3. Bleuler E: Dementia praecox oder die Gruppe der Schizofrenien. In Aschaffenburg G, ed: Handbuch der Psychiatrie. Leipzig: G. Aschaffenburg, 1911-1928. 4. World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization, 1992. 5. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 6. Jablensky A, Sartorius N, Ernberg G, et al: Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 1992; 20:1-97. 7. Harrison G, Glazebrook C, Brewin J, et al: Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom. Psychol Med 1997; 27:799-806. 8. Nimgaonkar VL, Fujiwara TM, Dutta M, et al: Low prevalence of psychoses among the Hutterites, an isolated religious community. Am J Psychiatry 2000; 157:1065-1070. 9. Hafner H, Hambrecht M, Loffler W, et al: Is schizophrenia a disorder of all ages? A comparison of first episodes and early course across the life-cycle. Psychol Med 1998; 28:351365. 10. Silbersweig DA, Stern E, Frith C, et al: A functional neuroanatomy of hallucinations in schizophrenia. Nature 1995; 378:176-179. 11. Shergill SS, Brammer MJ, Williams SC, et al: Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 2000; 57:1033-1038. 12. Hafner H, Maurer K, Loffler W, et al: The influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry 1993; 162:80-86. 13. Arndt S, Andreasen NC, Flaum M, et al: A longitudinal study of symptom dimensions in schizophrenia. Prediction and patterns of change. Arch Gen Psychiatry 1995; 52:352-360. 14. Fenton WS, McGlashan TH: Testing systems for assessment of negative symptoms in schizophrenia. Arch Gen Psychiatry 1992; 49:179-184. 15. Davidson L, McGlashan TH: The varied outcomes of schizophrenia. Can J Psychiatry 1997; 42:34-43. 16. Harrison PJ, Eastwood SL: Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 2001; 11:508-519. 17. Suvisaari JM, Haukka J, Tanskanen A, et al: Age at onset and outcome in schizophrenia are related to the degree of familial loading. Br J Psychiatry 1998; 173:494-500. 18. Gold S, Arndt S, Nopoulos P, et al: Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia. Am J Psychiatry 1999; 156:1342-1348.

19. Bilder RM, Lipschutz-Broch L, Reiter G, et al: Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophr Bull 1992; 18:437-448. 20. Hoff AL, Riordan H, O’Donnell DW, et al: Neuropsychological functioning of first-episode schizophreniform patients. Am J Psychiatry 1992; 149:898-903. 21. Joyce E, Hutton S, Mutsatsa S, et al: Executive dysfunction in first-episode schizophrenia and relationship to duration of untreated psychosis: the West London Study. Br J Psychiatry Suppl 2002; 43:s38-s44. 22. Weickert TW, Goldberg TE, Gold JM, et al: Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000; 57:907-913. 23. Fuller R, Nopoulos P, Arndt S, et al: Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry 2002; 159:1183-1189. 24. Joyce E, Huddy V: Defining the cognitive impairment in schizophrenia. Psychol Med 2004; 34:1151-1155. 25. Townsend LA, Malla AK, Norman RM: Cognitive functioning in stabilized first-episode psychosis patients. Psychiatry Res 2001; 104:119-131. 26. Addington J, Brooks BL, Addington D: Cognitive functioning in first episode psychosis: initial presentation. Schizophr Res 2003; 62:59-64. 27. Dickinson D, Iannone VN, Wilk CM, et al: General and specific cognitive deficits in schizophrenia. Biol Psychiatry 2004; 55:826-833. 28. Goldstein G, Shemansky WJ: Influences on cognitive heterogeneity in schizophrenia. Schizophr Res 1995; 18:59-69. 29. Tuulio-Henriksson A, Partonen T, Suvisaari J, et al: Age at onset and cognitive functioning in schizophrenia. Br J Psychiatry 2004; 185:215-219. 30. Glahn DC, Therman S, Manninen M, et al: Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry 2003; 53:624-626. 31. Weinberger DR, Lipska BK: Cortical maldevelopment, antipsychotic drugs, and schizophrenia: a search for common ground. Schizophr Res 1995; 16:87-110. 32. Meyer-Lindenberg A, Miletich RS, Kohn PD, et al: Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5:267271. 33. Volz HP, Gaser C, Hager F, et al: Brain activation during cognitive stimulation with the Wisconsin Card Sorting Test—a functional MRI study on healthy volunteers and schizophrenics. Psychiatry Res 1997; 75:145-157. 34. Gallhofer B, Lis S, Meyer-Lindenberg A, et al: Cognitive dysfunction in schizophrenia: a new set of tools for the assessment of cognition and drug effects. Acta Psychiatr Scand Suppl 1999; 395:118-128. 35. Keefe RS, Silva SG, Perkins DO, et al: The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 1999; 25:201-222. 36. Cardno AG, Gottesman II: Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics. Am J Med Genet 2000; 97:12-17. 37. Cardno AG, Marshall EJ, Coid B, et al: Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56:162-168. 38. Gershon ES, DeLisi LE, Hamovit J, et al: A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 1988; 45:328-336. 39. Kendler KS, MacLean CJ: Estimating familial effects on age at onset and liability to schizophrenia. I. Results of a large sample family study. Genet Epidemiol 1990; 7:409-417.

chapter 18 schizophrenia and schizophrenia-like psychosis 40. Driscoll DA, Spinner NB, Budarf ML, et al: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 1992; 44:261-268. 41. Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56:940-945. 42. Hodgkinson CA, Goldman D, Jaeger J, et al: Disrupted in schizophrenia 1: association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. 43. Harrison PJ, Owen MJ: Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361:417-419. 44. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10:40-68. 45. Lawrie SM, Whalley H, Kestelman JN, et al: Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 1999; 353:30-33. 46. Shenton ME, Dickey CC, Frumin M, et al: A review of MRI findings in schizophrenia. Schizophr Res 2001; 49:152. 47. Wright IC, Rabe-Hesketh S, Woodruff PW, et al: Metaanalysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157:16-25. 48. Foong J, Symms MR, Barker GJ, et al: Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging. Brain 2001; 124:882-892. 49. Bagary MS, Symms MR, Barker GJ, et al: Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch Gen Psychiatry 2003; 60:779-788. 50. Gur RE, Turetsky BI, Cowell PE, et al: Temporolimbic volume reductions in schizophrenia. Arch Gen Psychiatry 2000; 57:769-775. 51. McIntosh AM, Job DE, Moorhead TW, et al: Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives. Biol Psychiatry 2004; 56:544552. 52. Blennow K, Davidsson P, Gottfries C-G, et al: Synaptic degeneration in thalamus in schizophrenia [Letter]. Lancet 1996; 348:692-693. 53. Maier M, Ron MA, Barker GJ, et al: Proton magnetic resonance spectroscopy: an in vivo method of estimating hippocampal neuronal depletion in schizophrenia. Psychol Med 1995; 25:1201-1209. 54. Bertolino A, Roffman JL, Lipska BK, et al: Reduced Nacetylaspartate in prefrontal cortex of adult rats with neonatal hippocampal damage. Cereb Cortex 2002; 12:983-990. 55. Byne W, Buchsbaum MS, Kemether E, et al: Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. Arch Gen Psychiatry 2001; 58:133-140. 56. Uranova NA, Vostrikov VM, Orlovskaya DD, et al: Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 2004; 67:269-275. 57. Rapoport JL, Giedd JN, Blumenthal J, et al: Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999; 56:649-654. 58. Foong J, Maier M, Clark CA, et al: Neuropathological abnormalities of the corpus callosum in schizophrenia: a diffusion tensor imaging study. J Neurol Neurosurg Psychiatry 2000; 68:242-244. 59. Price G, Bagary MS, Cercignani M, et al: The corpus callosum in first episode schizophrenia: a diffusion tensor imaging study. J Neurol Neurosurg Psychiatry 2005; 76:585-587.

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60. Arnold SE, Trojanowski JQ, Gur RE, et al: Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55:225-232. 61. Purohit DP, Perl DP, Haroutunian V, et al: Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 1998; 55:205-211. 62. Falke E, Han LY, Arnold SE: Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia. Psychiatry Res 2000; 93:103-110. 63. Harrison PJ: The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122:593-624. 64. Torrey EF, Miller J, Rawlings R, et al: Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 1997; 28:1-38. 65. Wright P, Takei N, Rifkin L, et al: Maternal influenza, obstetric complications, and schizophrenia. Am J Psychiatry 1995; 152:1714-1720. 66. Brown AS, Begg MD, Gravenstein S, et al: Serologic evidence of prenatal influenza in the etiology of schizophrenia. Obstet Gynecol Surv 2005; 60:77-78. 67. Cannon M, Jones PB, Murray RM: Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002; 159:1080-1092. 68. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963; 20:140-144. 69. Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192:481-483. 70. Davis KL, Kahn RS, Ko G, et al: Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148:1474-1486. 71. Luby ED, Cohen BD, Rosenbaum G, et al: Study of a new schizophrenomimetic drug: sernyl. AMA Arch Neurol Psychiatry 1959; 81:363-369. 72. Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia [Review]. Am J Psychiatry 1991; 148:1301-1308. 73. Carlsson M, Carlsson A: Interactions between glutamatergic and monoaminergic systems within the basal ganglia— implications for schizophrenia and Parkinson’s disease. Trends Neurosci 1990; 13: 272-274. 74. Benes FM, Berretta S: GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25:1-27. 75. Reynolds GP, Beasley CL, Zhang ZJ: Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons. J Neural Transm 2002; 109:881-889. 76. Gouzoulis-Mayfrank E, Hermle L, Thelen B, et al: History, rationale and potential of human experimental hallucinogenic drug research in psychiatry. Pharmacopsychiatry 1998; 31(Suppl 2):63-68. 77. Meltzer HY, Matsubara S, Lee JC: Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D2 and serotonin 2 pKi values. J Pharmacol Exp Ther 1989; 251:238-246. 78. Weinberger DR, McClure RK: Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 2002; 59:553-558. 79. Seeman P: Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 1992; 7:261-284.

232

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80. Keshavan MS, Haas GL, Kahn CE, et al: Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? J Psychiatr Res 1998; 32:161-167. 81. Hawkins KA, Mohamed S, Woods SW: Will the novel antipsychotics significantly ameliorate neuropsychological deficits and improve adaptive functioning in schizophrenia? Psychol Med 1999; 29:1-8. 82. Farde L, Nordstrom AL, Wiesel FA, et al: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992; 49:538-544. 83. Casey DE: Dopamine D1 (and D2 [haloperidol]) antagonists in drug-naïve monkeys. Psychopharmacology (Berl) 1992; 107:18-22. 84. Klawans HL Jr, Rubovits R: An experimental model of tardive dyskinesia. J Neural Transm 1972; 33:235-246. 85. Gunne LM, Haggstrom JE: Pathophysiology of tardive dyskinesia. Psychopharmacology Suppl 1985; 2:191-193. 86. Jeste DV, Caligiuri MP, Paulsen JS, et al: Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 1995; 52:756-765. 87. Kane JM, Jeste DV, Barnes TRE, et al: Tardive Dyskinesia: A Task Force Report of the American Psychiatric Association. Washington, DC: American Psychiatric Association, 1992. 88. Gelenberg AJ, Bellinghausen B, Wojcik JD, et al: A prospective survey of neuroleptic malignant syndrome in a shortterm psychiatric hospital. Am J Psychiatry 1988; 145:517-518. 89. Keck PE, Sebastianelli J, Pope HG, et al: Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989; 50:352-355. 90. Adnet P, Lesteval P, Krivosic-Horber R: Neuroleptic malignant syndrome. Br J Anaesth 2000; 85:129-135. 91. Ames D, Wirshing W: Ecstasy, the serotonin syndrome and neuroleptic malignant syndrome: a possible link? JAMA 1993; 269:869. 92. Sachdev P, Mason C, Hadzi-Pavlovic D: Case-control study of neuroleptic malignant syndrome. Am J Psychiatry 1997; 154:1156-1158. 93. Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987; 22:1004-1020. 94. Levinson DF, Simpson GM: Neuroleptic-induced extrapyramidal symptoms with fever: heterogeneity of the “neuroleptic malignant syndrome.” Arch Gen Psychiatry 1986; 43: 839-848. 95. Pelonero AL, Levenson JL, Pandurangi AK: Neuroleptic malignant syndrome: a review. Psychiatr Serv 1998; 49:11631172. 96. Gilbert P, Harris MJ, McAdams LA: Neuroleptic withdrawal in schizophrenic patients: a review of the literature. Arch Gen Psychiatry 1995; 52:173-188. 97. Leucht S, Barnes TR, Kissling W, et al: Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003; 160:1209-1222. 98. Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789-796. 99. Simpson GM, Josiassen RC, Stanilla JK, et al: Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry 1999; 156:1744-1750. 100. Wahlbeck K, Cheine M, A Essali, et al: Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and metaanalysis of randomized trials. Am J Psychiatry 1999; 156:990999. 101. Seeman P, Tallerico T: Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to

102. 103. 104.

105. 106. 107. 108. 109.

110.

111.

112. 113. 114. 115.

116. 117. 118. 119. 120. 121. 122. 123.

brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998; 3:123-134. Reynolds GP: Receptor mechanisms in the treatment of schizophrenia. J Psychopharmacol 2004; 18:340-345. Wooltorton E: Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002; 167:12691270. Lawler CP, Prioleau C, Lewis MM, et al: Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20:612-627. Taylor DM: Aripiprazole: a review of its pharmacology and clinical use. Int J Clin Pract 2003; 57:49-54. Heresco-Levy U: N-Methyl-D-aspartate (NMDA) receptor– based treatment approaches in schizophrenia: the first decade. Int J Neuropsychopharmacol 2000; 3:243-258. Wyatt RJ, Henter ID: The effects of early and sustained intervention on the long-term morbidity of schizophrenia. J Psychiatr Res 1998; 3:169-177. Gould RA, Mueser KT, Bolton E, et al: Cognitive therapy for psychosis in schizophrenia: an effect size analysis. Schizophr Res 2001; 48:335-342. Sensky T, Turkington D, Kingdon D, et al: A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication. Arch Gen Psychiatry 2000; 57:165-172. McGorry P, Yung AR, Phillips LJ, et al: Randomized controlled trial of interventions designed to reduce the risk of progression to first episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry 2002; 59:921-928. Vaughn CE, Leff JP: The influence of family and social factors on the course of psychiatric illness. A comparison of schizophrenic and depressed neurotic patients. Br J Psychiatry 1976; 129:125-137. Pitschel-Walz G, Leucht S, Bauml J, et al: The effect of family interventions on relapse and rehospitalization in schizophrenia—a meta-analysis. Schizophr Bull 2001; 27:73-92. Bond GR, Becker DR, Drake RE, et al: Implementing supported employment as an evidence-based practice. Psychiatr Serv 2001; 52:313-322. Slater E, Beard AW, Glithero E: The schizophrenia-like psychosis of epilepsy. Br J Psychiatry 1963; 109:95-105. Davidson K, Bagley CR: Schizophrenia-like psychosis associated with organic disorders of the central nervous system: a review of the literature. In Herrington RN, ed: Current Problems in Neuropsychiatry. British Journal of Psychiatry Special Publication No. 4. Ashford, Kent, UK: Hedley Brothers, 1969. Feinstein A, Ron MA: Psychosis associated with demonstrable brain disease. Psychol Med 1990; 20:793-803. Cummings JL: Organic psychosis [Review]. Psychosomatics 1988; 29:16-26. Johnstone EC, Cooling NJ, Frith CD, et al: Phenomenology of organic and functional psychoses and the overlap between them. Br J Psychiatry 1988; 153:770-776. Toone BK, Garralda EM, Ron MA: The psychosis of epilepsy and the functional psychosis. A clinical and phenomenological evaluation. Br J Psychiatry 1982; 141:256-261. Sachdev P: Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry 1998; 155:325336. Gaitatzis A, Trimble MR, Sander JW: The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004; 110:207-220. Wolf P, Trimble MR: Biological antagonism and epileptic psychosis. Br J Psychiatry 1985; 146:272-276. Dongier S: Statistical study of clinical and electroencephalographic manifestations of 536 psychotic episodes occurring in 516 epileptics between clinical seizures. Epilepsia 1959; 1:117-142.

chapter 18 schizophrenia and schizophrenia-like psychosis 124. Torta R, Keller R: Behavioral, psychotic, and anxiety disorders in epilepsy: etiology, clinical features, and therapeutic implications. Epilepsia 1999; 40(Suppl 10):S2-S20. 125. Logsdail SJ, Toone BK: Post-ictal psychoses. A clinical and phenomenological description. Br J Psychiatry 1988; 152: 246-252. 126. Nathaniel-James DA, Brown RG, Maier M, et al: Cognitive abnormalities in schizophrenia and schizophrenia-like psychosis of epilepsy. J Neuropsychiatry Clin Neurosci 2004; 16:472-479. 127. Landolt H: Some clinical EEG correlations in epileptic psychoses (twilight states). EEG Clin Neurophysiol 1953; 5:121. 128. Kanner AM: Psychosis of epilepsy: a neurologist’s perspective. Epilepsy Behav 2000; 1:219-227. 129. Trimble MR: The Psychoses of Epilepsy. New York: Raven Press, 1991. 130. Toone BK: The psychoses of epilepsy. J Neurol Neurosurg Psychiatry 2000; 69:1-4. 131. Reutens DC, Savard G, Andermann F, et al: Results of surgical treatment in temporal lobe epilepsy with chronic psychosis. Brain 1997; 120:1929-1936. 132. Sánchez-Ramos JR, Ortoll R, Paulson GW: Visual hallucinations associated with Parkinson’s disease. Arch Neurol 1996; 53:1265-1268. 133. Fenelon G, Mahieux F, Huon R, et al: Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000; 123:733-745.

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134. Burn DJ, Troster AI: Neuropsychiatric complications of medical and surgical therapies for Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17:172-180. 135. Wint DP, Okun MS, Fernandez HH: Psychosis in Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17:127-136. 136. Friedman JH, Factor SA: Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 2000; 15:201-211. 137. Wilcox JA, Nasrallah HA: Childhood head trauma and psychosis. Psychiatry Res 1987; 21:303-306. 138. Sachdev P, Smith JS, Cathcart S: Schizophrenia-like psychosis following traumatic brain injury: a chart-based descriptive and case-control study. Psychol Med 2001; 31:231-239. 139. Fujii DE, Ahmed I: Risk factors in psychosis secondary to traumatic brain injury. J Neuropsychiatry Clin Neurosci 2001; 13:61-69. 140. Feinstein A, du Boulay G, Ron MA: Psychotic illness in multiple sclerosis. A clinical and magnetic resonance imaging study. Br J Psychiatry 1992; 161:680-685. 141. Black DN, Taber KH, Hurley RA: Metachromatic leukodystrophy: a model for the study of psychosis. J Neuropsychiatry Clin Neurosci 2003; 15:289-293. 142. Hyde TM, Ziegler JC, Weinberger DR: Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992; 49:401-406. 143. Ron MA, Feinstein A: Multiple sclerosis and the mind. J Neurol Neurosurg Psychiatry 1992; 55:1-3.

CHAPTER

19

AFFECTIVE DISORDERS ●

●

●

●

Gad A. Marshall and Jeffrey L. Cummings

Affect refers to the external expression of emotions, whereas mood refers to the internal expression or feeling of emotions. Typically, affect and mood are congruent.1 However, in some conditions, they may be dissociated: Individuals with pseudobulbar palsy may have bursts of laughter or crying, which do not reflect how they feel at the time, whereas individuals with parkinsonism who do not have a depressed mood may appear depressed because of limited facial expressions. Mood has many manifestations, ranging from depression to euphoria. Neuropsychiatric manifestations, such as changes in mood and affect, are very common in neurological conditions such as neurodegenerative diseases (Alzheimer’s disease: apathy, agitation, depression, irritability, anxiety, psychosis; Parkinson’s disease: depression, anxiety, psychosis; frontotemporal dementia: disinhibition, apathy), cerebrovascular disease (depression, apathy, psychosis), epilepsy (depression, psychosis), and multiple sclerosis (depression, eutonia, irritability, anxiety).2 These manifestations have a significant effect on individuals’ quality of life and caregiver burden. This chapter focuses on dysphoria (sadness) as the main feature of depression and elevated mood (exaggerated feeling of happiness) and expansive mood (expression of feelings without restraint and exaggerated sense of self-importance) as aspects of mania.1 We also discuss the personality change seen with apathy (lack of motivation). We provide information about prevalence, characteristics, course, and precipitating factors of mood changes in neurological conditions. The neuroanatomical localization of mood changes—commonly involving the basal ganglia and the frontal and anterior temporal regions— is reviewed. Finally, issues concerning treatment of mood changes in neurological conditions are discussed, and practical treatment algorithms are offered. A discussion of primary mood disorders and miscellaneous neurological conditions with mood changes, such as pseudobulbar palsy, Klüver-Bucy syndrome, ictal affect, hypothalamic lesions, and catastrophic reactions, is beyond the scope of this chapter.

DEPRESSION Depression is a common feature of many neurological conditions, but it is often underdiagnosed and undertreated. It can manifest as a symptom or as a syndrome complex such as a

major depressive episode. Mood changes in depression consist of sadness and inability to experience pleasure (anhedonia), putatively mediated by the limbic system. They are often accompanied by feelings of worthlessness and hopelessness (mediated by the dorsolateral prefrontal cortex), guilt, helplessness, and, in extreme situations, suicidal ideation. Affective changes in depression include changes in facial expressions (reduced or immobile expression [hypomimia], sad expression, or furrowed brow), crying, and avoidance of eye contact. Reduced interest in or reduced initiation of new activities is often present (mediated by the anterior cingulate cortex and related structures). Cognitive changes include reduced associations and executive and visuospatial dysfunction. Changes in verbal expression include increased speech latency, slow rate and reduced volume of speech, decreased spontaneous speech, and lack of emotional inflection (dysprosody). Neurovegetative changes mediated by the hypothalamus include appetite alterations, sleep disturbances, libido loss, and diurnal mood variations. Motor changes include slumped shoulders and head, decreased gestures, slowing of movements and gait, and catatonia (mediated by the basal ganglia).3,4 Depression in neurological conditions occurs most commonly with the involvement of the frontal region (orbitofrontal and dorsolateral prefrontal cortices), temporal region (anterior temporal and paralimbic cortices), and basal ganglia (usually the caudate), mediated by the frontal-subcortical circuits. Lesions of the left hemisphere more commonly cause depression than do lesions of the right hemisphere (Fig. 19–1).2,5,6 Neurological conditions often can mask depression. Aphasic patients may not be able to voice their depressive feelings, whereas patients with dysprosody caused by basal ganglia or right hemisphere involvement may not be able to inflect their voice to convey their mood. In contrast, there are conditions that can imitate depression. Apathy, which is a common symptom in many neurological conditions, is commonly mistaken for depression. Patients with pseudobulbar palsy, parkinsonism, multiple sclerosis, and lesions causing emotional facial paresis may appear depressed without being so.3,7 The diagnosis of depression in neurological conditions is usually based on the criteria proposed for primary depression in the Diagnostic and Statistical Manual of Mental Disorders1 and is often classified as major depression or minor depression (according to the criteria for dysthymic disorder). Alternatively, the presence of depression is assessed with specific rating scales

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A

C

B ■

Figure 19–1. Brain regions associated with depression in neurological conditions. A, Coronal section through the corpus striatum. B, Left lateral view. C, Bottom view. The caudate (A, in red), orbitofrontal region (B and C, in purple), and anterior temporal regions (B and C, in pink), with a left-sided predominance, are highlighted in these illustrative maps. The localization of lesions associated with depression is often not as definitive as suggested here (see text).

such as the Neuropsychiatric Inventory8 or the Geriatric Depression Scale.9 Depression can herald the onset or occur during the course of neurological conditions as a neurobiological component of those conditions or simply as a psychiatric comorbid condition. Cognitive changes seen in primary depression may sometimes imitate dementia, whereas depressive symptoms seen in dementia may sometimes imitate primary depression.3 The different presentations of depression in neurological conditions are described in the following sections and are summarized in Table 19–1. Table 19–2 lists neurological agents and psychotropic medications associated with depression.

Alzheimer’s Disease Alzheimer’s disease is the most common form of dementia and produces cognitive impairment, functional deterioration, and behavioral changes. Among patients with Alzheimer’s disease, the prevalence of major depression has been reported as 1.1% to 23%10-15; that of minor depression, 13.9% to 34%10,13-15; and that of general depressive symptoms, 20.1% to 54.9%.16-20 As demonstrated, the reported rates of depression in Alzheimer’s disease have a wide range because of the different measures and criteria used. The criteria in the National Institute of Mental Health Provisional Diagnostic Criteria for Depression in

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T A B L E 19–1. Neurological Conditions Manifesting with Depression Condition

Prevalence of Depression

Specific Features and Localization

Alzheimer’s disease

MaD: 1%-23% MiD: 14%-34% DS: 20%-55% MaD: 8%-38% MiD: 10%-32% DS: 34%-47% MaD: 8%-34%

Milder depression and irritability greater functional deficits; depression heralds diagnosis of Alzheimer’s disease; frontal and parietal involvement

Parkinson’s disease Stroke Vascular dementia Epilepsy Multiple sclerosis Traumatic brain injury115,116 Huntington’s disease94,117 Frontotemporal lobar degeneration107 Wilson’s disease94

MaD: 29%-45% DS: 30%-34% MaD: 6%-30% MaD: 16% (lifetime, 50%) DS: 79%-85% MaD: 17%-33% MaD: 22% DS: 30% MaD: 20%

Anxiety, greater motor fluctuations, greater cognitive impairment, akinetic-rigid variant; frontal (left) involvement More common in women than in men; depression associated with larger lesions; frontal, temporal, caudate involvement Increases with time, lower education level, and greater functional deficits Increased suicide rate among patients with ictal and interictal forms; temporal (left), frontal involvement Irritability, frustration, increased suicide rate; arcuate fasciculus (left) involvement Anxiety, aggressive behavior, lower education level, alcohol abuse, executive dysfunction; frontal (left) involvement Increased suicide rate; medial caudate, orbitofrontal involvement Depression in semantic dementia is worse than in frontal variant of frontotemporal dementia Lenticular nuclei

DS, general depressive symptoms; MaD, major depression; MiD, minor depression.

Alzheimer’s Disease reflect the generally more mild depression in Alzheimer’s disease, requiring the presence of only 3 (of 11) depressive symptoms (rather than 5 as in primary major depression), including irritability and social withdrawal as symptoms, and not requiring the presence of symptoms to be nearly daily over 2 weeks.21,22 Depression in Alzheimer’s disease is associated with greater functional deficits, wandering behavior, agitation, anxiety,

T A B L E 19–2. Neurological Agents and Psychotropic Medications Associated with Depression3,78,82 Antiparkinsonian drugs Anticonvulsants

Sedative-hypnotics

Neuroleptics Psychostimulants

Miscellaneous

Amantadine Bromocriptine Levodopa Phenobarbital Primidone Tiagabine Vigabatrin Felbamate Topiramate Benzodiazepines Chloral hydrate Clomethiazole Clorazepate Butyrophenones Phenothiazines Amphetamines Diethylpropion Fenfluramine Phenmetrazine Acetazolamide Azathioprine Baclofen Cholinesterase inhibitors Corticosteroids Interferon-β1b/interferon-βa (possibly)

apathy, disinhibition, and irritability.14,18,23-25 Depressed Alzheimer’s disease patients often complain more about difficulties in thinking and concentration than about depressed mood and neurovegetative changes.26,27 Depressive symptoms tend to be episodic and recur frequently in Alzheimer’s disease.28,29 Frequency of mild depressive symptoms is correlated with severity of cognitive impairment15,30,31 but is not related to self-awareness of cognitive deficits.32 Depressive symptoms tend to occur early in the course of Alzheimer’s disease and may precede the diagnosis.15,33-35 Risk factors for developing depression in Alzheimer’s disease include female gender, lower education level, early-onset disease, family history of depression, and possibly premorbid history of depression.15,25,31,33,36,37 Depression in Alzheimer’s disease has been correlated mostly with frontal and parietal dysfunction. Functional imaging studies showed localization of associated lesions to the bilateral superior frontal and left anterior cingulate cortices38 or the parietal lobe,39 and quantified electroencephalographic recording pointed toward abnormalities of the parietal lobes.40 Pathological and neurochemical studies of patients with Alzheimer’s disease and depression demonstrated greater involvement of the locus ceruleus (noradrenergic system) and, to a lesser degree, the substantia nigra (dopaminergic system) and dorsal raphe nucleus (serotonergic system), with relative preservation of the nucleus basalis of Meynert (cholinergic system).41-44 Mild cognitive impairment is often a transitional stage between normal aging and dementia. The prevalence of depressive symptoms among patients with mild cognitive impairment has been reported as 9.3% to 47%.16,17,45-47 One study reported that 85% of depressed patients with mild cognitive impairment went on to develop dementia, which again emphasizes the importance of depression in heralding the diagnosis of Alzheimer’s disease.46

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Parkinson’s Disease and Parkinsonian Syndromes Parkinson’s disease is the second most common neurodegenerative disease (after Alzheimer’s disease) and has a range of motor manifestations, cognitive impairment, and behavioral disturbances. Among patients with Parkinson’s disease, the prevalence of major depression has been reported as 7.7% to 38%48-50; that of minor depression, 10% to 32%48,50; and that of general depressive symptoms, 34% to 47%.49,51-55 Depression in Parkinson’s disease is associated with less self-punitive ideation, more anxiety, dysautonomia, and greater motor fluctuations (“on-off” phenomenon). It is correlated with advanced stage of disease and greater cognitive impairment.49-51,54,56-59 Depression is more common in the akinetic-rigid Parkinson’s disease variant than the classic tremor-predominant type.48,51 Risk factors for depression in Parkinson’s disease include premorbid history of depression, greater functional deficits, lower cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, early-onset Parkinson’s disease, more left hemisphere involvement, and, possibly, female gender.50,51,57 Depression in Parkinson’s disease is associated with frontal lobe dysfunction, often of the left hemisphere, and is correlated with involvement of the dopaminergic, noradrenergic, and serotonergic systems.50,51,60 Neuropsychological studies show a relationship with disruption of frontal-lobe related tasks.61 Functional imaging studies show a localization of depressionrelated dysfunction in the bilateral medial prefrontal and anterior cingulate cortices62 or caudate and inferior orbitofrontal cortex.63 Depression has been reported in other parkinsonian syndromes. Among patients with dementia with Lewy bodies, the prevalence of major depression has been reported as 19% to 33.3%12,64 and that of general depressive symptoms, 47.5%.12 Among patients with progressive supranuclear palsy, the prevalence of general depressive symptoms has been reported as 18% to 25%,53,65 whereas that among patients with corticobasal degeneration has been reported as 73%.65

Cerebrovascular Disease Depression in cerebrovascular disease has been described in the context of vascular depression, discrete strokes, and vascular dementia. Patients with vascular depression have clinical or imaging evidence of cerebrovascular disease, as well as vascular risk factors.66 In comparison with patients with primary depression, patients with vascular depression are older at onset of mood changes and have greater functional disability and cognitive impairment (mostly in verbal fluency and naming), greater psychomotor retardation, greater anhedonia, less agitation, lesser feelings of guilt, less insight, and less family history of depression.66,67 Vascular depression is associated with single or multiple lesions that disrupt the striatopallidothalamocortical (prefrontal) pathways.66,68 The prevalence of major depression among patients who have suffered strokes has been reported as 8.3% to 33.6%.69-71 Poststroke major depression is more common in women (23.6%), in whom it is associated with more left hemisphere lesions and a history of psychiatric disorder and cognitive impairment, whereas in men (12.3%), it is associated with greater functional deficits.72 Depression has been shown to be more common with larger lesion volumes.71 Lesions in the frontal and temporal lobes, basal ganglia (especially the head of

the caudate), and ventral brainstem circuitry are associated with depression.70,73 However, there is a tendency for depression after the acute poststroke period to be related to lesions of the left frontal region, whereas depression in the chronic poststroke period is associated with lesions of the right posterior region.4,74 Vascular dementia is the second most common dementia and is associated with executive dysfunction, motor symptoms, and significant behavioral changes. Among patients with vascular dementia, the prevalence of major depression has been reported as 29% to 45%,64,75 and that of general depressive symptoms, 29.7% to 34.2%.19,75,76 Depressive symptoms in vascular dementia tend to increase with time and are related to lower education level and greater functional deficits.25,76

Epilepsy Epilepsy is common and is associated with significant behavioral disturbances. The prevalence of major depression among patients with epilepsy has been reported as 6% to 30%.77,78 Depression in epilepsy is associated with decreased quality of life and increased suicide rate (5 to 10 times higher than in the general population).77-79 Ictal and interictal forms of depression have been reported in epilepsy: The “interictal dysphoric disorder” resembles dysthymia and consists of depressed mood, low energy, pain, insomnia, irritability, euphoria, fear, and anxiety, whereas ictal depression usually occurs as an “aura” for a seizure and consists of guilt, anhedonia, and suicidal ideation.77 Depression is more common in patients with temporal (often left) and frontal seizure foci, and the hippocampus and amygdala appear to play a role as well.77,80,81

Multiple Sclerosis Multiple sclerosis is an autoimmune disease with widespread physical, cognitive, and behavioral changes. Among patients with multiple sclerosis, the prevalence of major depression has been reported as 15.7% (lifetime prevalence, 50%)82,83 and that of general depressive symptoms, 79% to 85%.84,85 Depression in multiple sclerosis is associated with discouragement, irritability, frustration, higher rate of suicide (seven times higher than in the general population), and greater volume of lesions and cerebral atrophy.82 Depression in multiple sclerosis has been associated with lesions of the arcuate fasciculus, more so on the left.86

Treatment of Depression Few controlled clinical trials have addressed depression in neurological conditions, and no medications have been approved by the U.S. Food and Drug Administration (FDA) specifically for this indication. For most conditions, clinicians have used medications studied in primary depression, which are often not as well tolerated and not as effective in neurological conditions. Therefore, a good adage is “Start low and go slow.” Direct treatment of the neurological condition may be helpful in treating the secondary depression. In dementias with cholinergic deficits, the use of cholinesterase inhibitors has proved helpful in the treatment of neuropsychiatric manifestations,87 as

chapter 19 affective disorders well as in depression specifically.88 There is also some evidence that memantine, an N-methyl-D-aspartate antagonist approved by the FDA for the treatment of Alzheimer’s disease, may have similar effects.89 In Parkinson’s disease, selegiline, a monoamine oxidase type B inhibitor, and D3 receptor agonists, such as pramipexole and ropinirole, have shown antidepressant effects.90,91 The first-line antidepressants in most neurological conditions are the selective serotonin reuptake inhibitors, because of their tolerability, safety, and apparent efficacy (especially sertraline and citalopram in Alzheimer’s disease and epilepsy). Serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and mirtazapine, appear to be good alternative firstline agents because of their tolerability, but they are newer agents and have not been studied adequately. Tricyclic antidepressants and monoamine oxidase inhibitors have been shown to be effective but often are not tolerated as well, especially by elderly patients, and therefore are considered second-line agents. If the patient’s depression resolves, the antidepressant should be continued for 3 to 6 months and then gradually tapered, while the patient is monitored closely for recurrence of depression.4,78,92 In patients with severe depression that is refractory to medical treatment, electroconvulsive therapy and repetitive transcranial magnetic stimulation may be effective (especially in Parkinson’s disease).90 Electroconvulsive therapy should not be performed in patients with elevated intracranial pressure, headache, or focal neurological deficits. Figure 19–2 provides an algorithm for the treatment of depression in neurological conditions.

Depression

Treat neurological condition

Mania has been reported in multiple neurological conditions and as a consequence of medication use. It consists of elevated or expansive mood, irritability (often associated with aggressiveness), accelerated and/or disorganized thought or speech, distractibility, poor judgment, psychomotor agitation, expansive gestures and facial expressions, and neurovegetative changes (decreased need for sleep, hypersexuality, and increased energy). Mania may be accompanied by moodcongruent hallucinations or delusions. Hypomania is similar to mania but milder and is not accompanied by psychosis. Many patients with secondary mania caused by a focal lesion have a family history of psychiatric morbidity. Certain neurological conditions, such as pseudobulbar palsy, may imitate mania.1,3 Mania in neurological conditions has been correlated with lesions of the frontal region (especially the orbitofrontal area), basal ganglia (especially the inferior caudate), thalamus, and inferior temporal region, usually lateralized to the right, which possibly reflects overactivity of the paleocortical limbic division (Fig. 19–3).2,5 The different manifestations of mania in neurological conditions are described and summarized in Table 19–3. Table 19–4 lists neurological agents and psychotropic medications associated with mania.

Cerebrovascular Disease Mania has been described in patients with focal strokes. It is often associated with hyperkinetic movement disorders (hemi-

If symptoms relapse, restart effective agent; if response is inadequate, reenter algorithm

SSRI

Another SSRI or SNRI

TCA or MAO-I

ECT or rTMS

Symptom resolution

Continue treatment for 3–6 months; slowly withdraw and follow closely ■

MANIA

239

Figure 19–2. Algorithm for the treatment of depression in neurological conditions. Nonsolid arrows indreate next step if response to treatment is adequate. Solid arrows indicate next step if response to previous treatment is inadequate. ECT, electroconvulsive therapy; MAOI, monoamine oxidase inhibitor; rTMS, repetitive transcranial magnetic stimulation; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. (Adapted from Cummings JL: The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, 2003.)

ballismus, chorea, postural tremor, hemidystonia).93 Lesions are usually right-sided and involve subcortical and midline structures (especially the thalamus), damaging the frontalbasal ganglia-thalamocortical circuits.93

Extrapyramidal Disorders Although not as common as depression, mania is seen in patients with Huntington’s disease. Among such patients, the prevalence of mania and hypomania has been reported as 4.8% and 10%, respectively. Mania in Huntington’s disease consists of euphoria or irritability, grandiosity, overactivity, impulsiveness, and decreased need for sleep.94 Patients with Parkinson’s disease treated with dopaminergic agents or surgically (deep brain stimulation, pallidotomy, or thalamotomy) may develop mania. Among patients with medically treated Parkinson’s disease, the prevalence of mania has been reported as 1% (euphoria, 10%).3,95

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A ■

B Figure 19–3. Brain regions associated with mania and elevated mood in neurological conditions. A, Bottom view. B, Coronal section through the mammillary bodies. The orbitofrontal (A, in purple) and inferior temporal regions (A, in pink), caudate (B, in red), and thalamus (B, in green), with a right-sided predominance, are highlighted in these illustrative maps.

T A B L E 19–3. Neurological Conditions Manifesting with Mania and Elevated Mood

T A B L E 19–4. Neurological Agents and Psychotropic Medications Associated with Mania and Elevated Mood

Condition

Prevalence of Mania

Specific Features and Localization

Antiparkinsonian drugs

Stroke

Rare

Huntington’s disease

5% (hypomania, 10%) 9%

Hyperkinetic movement disorders; right thalamus (frontal, basal ganglia) involvement Euphoria or irritability, grandiosity, overactivity, impulsiveness, insomnia Irritability, aggressiveness; brief duration; family history; post-traumatic seizures; right thalamus, caudate, orbitofrontal, and inferior temporal involvement Late-onset presentation usually without family history and with dementia Eutonia; possible genetic predisposition in women

Traumatic brain injury

Human immunodeficiency virus118 Multiple sclerosis82

Alzheimer’s disease119 Miscellaneous98

8% Twice more common than in general population 2.2%

May precede cognitive decline Frontotemporal dementia, neurosyphilis, CreutzfeldtJakob disease, tumors (hypothalamic involvement)

Anticonvulsants

Sedative-hypnotics

Antidepressants

Antipsychotics Miscellaneous

Amantadine Bromocriptine Levodopa Lisuride Piribedil Procyclidine Selegiline Carbamazepine Phenytoin Barbiturates Ethosuximide Clonazepam Phenacemide Alprazolam Triazolam Buspirone Meprobamate Bupropion SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) TCAs (phenelzine) MAOIs (clomipramine imipramine, desipramine, amitriptyline) Mirtazapine Nefazodone Trazodone Olanzapine Risperidone Baclofen Psychostimulants Corticosteroids

MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.3,120,121

chapter 19 affective disorders Traumatic Brain Injury Mania has been observed after traumatic brain injury. The prevalence of such mania has been reported as 9%. In traumatic brain injury, mania is associated with irritability and aggressiveness and is usually short-lasting (about 2 months). Risk factors for developing mania in TBI include family history of mood disorders, post-traumatic seizures, and premorbid diencephalic and frontal subcortical atrophy. Mania in traumatic brain injury is related to lesions localized in the right hemisphere, particularly the thalamus, caudate, and orbitofrontal and inferior temporal regions.96,97

241

ued for 3 to 6 months and then gradually tapered, while the patient is monitored closely for recurrence of mania. In the acute stages of mania or in mania with mood-congruent delusions and hallucinations, an atypical antipsychotic may be added. Atypical antipsychotics may be the best choice for management of mania in some patients. If sedation is desired, a benzodiazepine may be added. If patients are resistant to mood stabilizers, electroconvulsive therapy may be considered.3,82,94,99 Figure 19–4 provides an algorithm for the treatment of mania in neurological conditions.

APATHY Treatment of Mania Essentially no clinical trials have addressed mania in neurological conditions, and no medications have been approved by the FDA for this indication. For most conditions, clinicians have used medications studied in primary bipolar illness. However, before mood stabilizer treatment is initiated, the underlying condition should be treated or, in the case of medication-induced mania, the offending agent discontinued.98 The commonly used mood stabilizers include lithium, valproate, carbamazepine, and atypical antipsychotics. Patients with mania in some neurological conditions, such as Huntington’s disease or human immunodeficiency virus infection, do not respond as well to lithium and are more vulnerable to its toxic effects. Lamotrigine and gabapentin are newer anticonvulsants that may have a role as mood stabilizers as well. If the patient’s mania resolves, the mood stabilizer should be contin-

Apathy is a common neuropsychiatric symptom in neurological conditions, especially in neurodegenerative diseases. It consists of loss of interest, emotions, or motivation, and in extreme situations, patients become akinetic and mute. Apathy may resemble depression and may coexist with a mood disorder, but it has been shown to be a separate entity. The decreased motivation seen in apathy (mediated by the anterior cingulate cortex) is associated with lack of concern (mediated by the parietal lobe), impaired cognition (mediated by the neocortex), placidity and impaired emotional memory (mediated by the medial temporal lobe), inattention (mediated by the dorsolateral prefrontal cortex), decreased experience of emotion (mediated by the limbic system), and decreased perception and expression of emotion (mediated by the right hemisphere).3-5,100,101 As just mentioned, apathy in neurological conditions has been related to lesions localized to the anterior cingulate gyrus, nucleus accumbens, globus pallidus, substantia nigra, and

■

Mania

and elevated mood in neurological conditions. Nonsolid arrows indicate next step if response to treatment is adequate. Solid arrows indicate next step if response to previous treatment is inadequate. ECT, electroconvulsive therapy.

Treat underlying condition Add atypical antipsychotic for acute mania or mania with psychosis

Add benzodiazepines for sedation

Lithium, valproate, carbamazepine, atypical antipsychotics

If symptoms relapse, restart effective agent; if response is inadequate, reenter algorithm

Lamotrigine, gabapentin

ECT

Figure 19–4. Algorithm for the treatment of mania

Symptom resolution

Continue treatment for 3–6 months; slowly withdraw and follow closely

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A

C

B ■

Figure 19–5. Brain regions associated with apathy in neurological conditions. A, Left midsagittal view. B, Coronal section through the anterior commissure. C, Coronal section through the midbrain and pons. The anterior cingulate gyrus (A, in yellow), nucleus accumbens (B, in pink), globus pallidus (B, in turquoise), substantia nigra (C, in blue), and thalamus (C, in green) are highlighted in these illustrative maps.

thalamus, which make up the anterior cingulate-subcortical circuit, responsible for mediating motivation (Fig. 19–5).2,4-6 The different manifestations of apathy in neurological conditions are listed in Table 19–5.

Alzheimer’s Disease Apathy is the most common neuropsychiatric symptom in Alzheimer’s disease. Among patients with Alzheimer’s disease, the prevalence of apathy has been reported as 28.5% to 70%.4,16,17,19,102 It has been shown to be associated with executive dysfunction and severity of cognitive impairment but

remaining distinct from depression.30,102 Apathy often heralds the diagnosis of Alzheimer’s disease or becomes apparent early in its course.33,103 Apathy has been reported among patients with mild cognitive impairment with a prevalence of 11.1% to 39%.16,17,47 Apathy in Alzheimer’s disease is associated in most cases with lesions of the anterior cingulate gyrus. Functional imaging studies showed localization to the anterior cingulate bilaterally104 or the prefrontal and anterior temporal regions.105 One pathological study showed increased pathological burden in the anterior cingulate gyrus of patients with Alzheimer’s disease and apathy.106

chapter 19 affective disorders Frontotemporal Dementia Frontotemporal dementia is a degenerative dementia in which prominent behavioral changes manifest early in its course. The prevalence of apathy among patients with frontotemporal dementia has been reported as 68% to 90%.4,107,108 Apathy occurs early in the course of frontotemporal dementia, is associated with loss of emotions and loss of interest, and is more common in the frontal variant of frontotemporal dementia.107,108

Parkinson’s Disease and Parkinsonian Syndromes Apathy has been reported in the various parkinsonian syndromes. The prevalence of apathy among patients with Parkinson’s disease has been reported as 16.5% to 20%.4,53,54 Apathy in Parkinson’s disease is correlated with advanced stage of disease, greater cognitive impairment, and executive dysfunction.54,109 The prevalence of apathy among patients with progressive supranuclear palsy has been reported as 84% to 90%,4,53 and apathy has been associated with lesions of the orbitofrontal and medial frontal circuits.53 Among patients who have dementia with Lewy bodies and corticobasal degeneration, the prevalence of apathy has been reported as 90% and 40%, respectively.4

Cerebrovascular Disease Apathy in cerebrovascular disease has been described in the context of stroke and vascular dementia. The prevalence of apathy among stroke patients has been reported as 56.7% and

has been associated with predominantly right hemisphere lesions and decreased heart rate reactivity to mental stress.110 The prevalence of apathy among patients with vascular dementia has been reported as 22.6% to 47%.19,108

Treatment of Apathy No clinical trials have addressed apathy in neurological conditions, and no medications have been approved by the FDA for this indication. Direct treatment of the neurological condition may be helpful in treating the associated apathy. The use of cholinesterase inhibitors in dementias with cholinergic deficits (Alzheimer’s disease, vascular dementia, dementia with Lewy bodies) has been shown to improve neuropsychiatric symptoms and apathy (and visual hallucinations) in particular.87,88,111,112 Psychostimulants and related agents have been commonly used to treat severe apathy in neurological conditions. These drugs, which include methylphenidate, dextroamphetamine, atomoxetine, and modafinil, have been used successfully in patients with dementia and stroke.113,114 Some antidepressants with activating properties (fluoxetine and desipramine) and dopaminergeric agents (amantadine and bromocriptine) have been used successfully in patients with Huntington’s disease and akinetic mutism.2,94 If treatment is successful, the medication should be continued for 3 to 6 months and then gradually tapered, while the patient is monitored closely for recurrence of apathy (this does not apply to cholinesterase inhibitors). Figure 19–6 provides an algorithm for the treatment of apathy in neurological conditions.

Apathy

T A B L E 19–5. Neurological Conditions Manifesting with Apathy Condition

Prevalence of Apathy

Specific Features and Localization

Alzheimer’s disease

29%-70%

Associated with executive dysfunction and severity of cognitive impairment; distinct from depression; apathy heralds diagnosis of Alzhermer’s disease; anterior cingulate involvement Occurs early in the course of disease, more common in frontal variant Occurs in advanced stage of disease; greater cognitive impairment and executive dysfunction Orbitofrontal and medial frontal circuit involvement Decreased heart rate reactivity to mental stress; right hemisphere lesions Right hemisphere lesions

Frontotemporal dementia

68%-90%

Parkinson’s disease

17%-20%

Progressive supranuclear palsy Stroke

84%-90%

Traumatic brain injury110 Huntington’s disease94 Multiple sclerosis85

46%

57%

48% 20%

Disregard for appearance and personal hygiene Variable correlations with imaging changes

243

Treat neurological condition If symptoms relapse, restart effective agent; if response is inadequate, reenter algorithm

Psychostimulant

Antidepressant or dopaminergic agent

Symptom resolution

Continue treatment for 3–6 months; slowly withdraw and follow closely ■

Figure 19–6. Treatment of apathy in neurological conditions. Nonsolid arrows indicates next step if responce to treatment is adequate. Solid arrow indicates next step if response to previous treatment is inadequate.

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P O I N T S

●

Mood symptoms and syndromes are common in neurological conditions.

●

Mood symptoms are most prevalent among patients with neurodegenerative diseases, cerebrovascular disease, traumatic brain injury, and multiple sclerosis.

●

Depression and apathy are common, whereas mania is rare, in neurological conditions.

●

Mood symptoms in neurological conditions are associated with lesions of the basal ganglia and the frontal and temporal regions.

●

In treatment, the neurological condition should be targeted first (e.g., cholinesterase inhibitors for dementia).

●

Conventional treatments used in primary psychiatric disorders are used in patients with neurological conditions with mood symptoms despite little evidence of their efficacy in these conditions.

●

The adage “Start low and go slow” applies to patients with neurological conditions, who are more sensitive to conventional medications.

Acknowledgment Figures 19-1, 19-3, and 19-5 were created with the assistance of Dr. Liana G. Apostolova.

Suggested Reading Aarsland D, Litvan I, Larsen JP: Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:42-49. Cummings JL: Principles of neuropsychiatry: towards a neuropsychiatric epistemology. Neurocase 1999; 5:181-188. Cummings JL: Cognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis. Neurobiol Aging 2000; 21:845-861. Cummings JL: The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, 2003. Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New York: Oxford University Press, 2003.

References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association, 2000. 2. Cummings JL: Principles of neuropsychiatry: towards a neuropsychiatric epistemology. Neurocase 1999; 5:181-188. 3. Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New York: Oxford University Press, 2003. 4. Cummings JL: The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, 2003. 5. Mega MS, Cummings JL, Salloway S, et al: The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci 1997; 9:315-330.

6. Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol 1993; 50:873-880. 7. Hopf HC, Muller-Forell W, Hopf NJ: Localization of emotional and volitional facial paresis. Neurology 1992; 42:19181923. 8. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314. 9. Yesavage JA, Brink TL, Rose TL, et al: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982; 17:37-49. 10. Gilley DW, Wilson RS, Bienias JL, et al: Predictors of depressive symptoms in persons with Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci 2004; 59:P75-P83. 11. Weiner MF, Doody RS, Sairam R, et al: Prevalence and incidence of major depressive disorder in Alzheimer’s disease: findings from two databases. Dement Geriatr Cogn Disord 2002; 13:8-12. 12. Ballard C, Holmes C, McKeith I, et al: Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 1999; 156:1039-1045. 13. Starkstein SE, Chemerinski E, Sabe L, et al: Prospective longitudinal study of depression and anosognosia in Alzheimer’s disease. Br J Psychiatry 1997; 171:47-52. 14. Lyketsos CG, Steele C, Baker L, et al: Major and minor depression in Alzheimer’s disease: prevalence and impact. J Neuropsychiatry Clin Neurosci 1997; 9:556-561. 15. Migliorelli R, Teson A, Sabe L, et al: Prevalence and correlates of dysthymia and major depression among patients with Alzheimer’s disease. Am J Psychiatry 1995; 152:37-44. 16. Geda YE, Smith GE, Knopman DS, et al: De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI). Int Psychogeriatr 2004; 16:51-60. 17. Hwang TJ, Masterman DL, Ortiz F, et al: Mild cognitive impairment is associated with characteristic neuropsychiatric symptoms. Alzheimer Dis Assoc Disord 2004; 18:17-21. 18. Cummings JL: The impact of depressive symptoms on patients with Alzheimer disease [Comment]. Alzheimer Dis Assoc Disord 2003; 17:61-62. 19. Lyketsos CG, Steinberg M, Tschanz JT, et al: Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 2000; 157:708-714. 20. Frisoni GB, Rozzini L, Gozzetti A, et al: Behavioral syndromes in Alzheimer’s disease: description and correlates. Dement Geriatr Cogn Disord 1999; 10:130-138. 21. Olin JT, Schneider LS, Katz IR, et al: Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry 2002; 10:125-128. 22. Olin JT, Katz IR, Meyers BS, et al: Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry 2002; 10:129-141 [Erratum in Am J Geriatr Psychiatry 2002; 10:264]. 23. Espiritu DA, Rashid H, Mast BT, et al: Depression, cognitive impairment and function in Alzheimer’s disease. Int J Geriatr Psychiatry 2001; 16:1098-1103. 24. Fitz AG, Teri L: Depression, cognition, and functional ability in patients with Alzheimer’s disease. J Am Geriatr Soc 1994; 42:186-191. 25. Hargrave R, Reed B, Mungas D: Depressive syndromes and functional disability in dementia. J Geriatr Psychiatry Neurol 2000; 13:72-77. 26. Heun R, Kockler M, Ptok U: Lifetime symptoms of depression in Alzheimer’s disease. Eur Psychiatry 2003; 18:63-69. 27. Devanand DP, Jacobs DM, Tang MX, et al: The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry 1997; 54:257-263.

chapter 19 affective disorders 28. Marin DB, Green CR, Schmeidler J, et al: Noncognitive disturbances in Alzheimer’s disease: frequency, longitudinal course, and relationship to cognitive symptoms. J Am Geriatr Soc 1997; 45:1331-1338. 29. Levy ML, Cummings JL, Fairbanks LA, et al: Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer’s disease. Am J Psychiatry 1996; 153:1438-1443. 30. Mega MS, Cummings JL, Fiorello T, et al: The spectrum of behavioral changes in Alzheimer’s disease. Neurology 1996; 46:130-135. 31. Devanand DP, Sano M, Tang MX, et al: Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Arch Gen Psychiatry 1996; 53:175-182. 32. Cummings JL, Ross W, Absher J, et al: Depressive symptoms in Alzheimer disease: assessment and determinants. Alzheimer Dis Assoc Disord 1995; 9:87-93. 33. Jost BC, Grossberg GT: The evolution of psychiatric symptoms in Alzheimer’s disease: a natural history study. J Am Geriatr Soc 1996; 44:1078-1081. 34. Berger AK, Fratiglioni L, Forsell Y, et al: The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology 1999; 53:1998-2002. 35. Chen P, Ganguli M, Mulsant BH, et al: The temporal relationship between depressive symptoms and dementia: a community-based prospective study. Arch Gen Psychiatry 1999; 56:261-266. 36. Harwood DG, Barker WW, Ownby RL, et al: Association between premorbid history of depression and current depression in Alzheimer’s disease. J Geriatr Psychiatry Neurol 1999; 12:72-75. 37. Strauss ME, Ogrocki PK: Confirmation of an association between family history of affective disorder and the depressive syndrome in Alzheimer’s disease. Am J Psychiatry 1996; 153:1340-1342. 38. Hirono N, Mori E, Ishii K, et al: Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology 1998; 50:380-383. 39. Sultzer DL, Mahler ME, Mandelkern MA, et al: The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:476-484. 40. Pozzi D, Golimstock A, Petracchi M, et al: Quantified electroencephalographic changes in depressed patients with and without dementia. Biol Psychiatry 1995; 38:677683. 41. Zubenko GS: Clinicopathologic and neurochemical correlates of major depression and psychosis in primary dementia. Int Psychogeriatr 1996; 8(Suppl 3):219-223; discussion, Int Psychogeriatr 1996; 8(Suppl 3):269-272. 42. Forstl H, Burns A, Luthert P, et al: Clinical and neuropathological correlates of depression in Alzheimer’s disease. Psychol Med 1992; 22:877-884. 43. Zubenko GS, Moossy J, Kopp U: Neurochemical correlates of major depression in primary dementia. Arch Neurol 1990; 47:209-214. 44. Zubenko GS, Moossy J: Major depression in primary dementia. Clinical and neuropathologic correlates. Arch Neurol 1988; 45:1182-1186. 45. Feldman H, Scheltens P, Scarpini E, et al: Behavioral symptoms in mild cognitive impairment. Neurology 2004; 62:1199-1201. 46. Modrego PJ, Ferrandez J: Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol 2004; 61:1290-1293. 47. Lyketsos CG, Lopez O, Jones B, et al: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impair-

48. 49. 50. 51. 52. 53.

54. 55. 56. 57. 58. 59. 60. 61. 62. 63.

64. 65. 66. 67. 68. 69.

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ment: results from the cardiovascular health study. JAMA 2002; 288:1475-1483. Starkstein SE, Petracca G, Chemerinski E, et al: Depression in classic versus akinetic-rigid Parkinson’s disease. Mov Disord 1998; 13:29-33. Tandberg E, Larsen JP, Aarsland D, et al: The occurrence of depression in Parkinson’s disease. A community-based study. Arch Neurol 1996; 53:175-179. Cole SA, Woodard JL, Juncos JL, et al: Depression and disability in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1996; 8:20-25. Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 1992; 149:443-454. Shulman LM, Taback RL, Rabinstein AA, et al: Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002; 8:193-197. Aarsland D, Litvan I, Larsen JP: Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:4249. Aarsland D, Larsen JP, Lim NG, et al: Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67:492-496. Dooneief G, Mirabello E, Bell K, et al: An estimate of the incidence of depression in idiopathic Parkinson’s disease. Arch Neurol 1992; 49:305-307. Norman S, Troster AI, Fields JA, et al: Effects of depression and Parkinson’s disease on cognitive functioning. J Neuropsychiatry Clin Neurosci 2002; 14:31-36. Tandberg E, Larsen JP, Aarsland D, et al: Risk factors for depression in Parkinson disease. Arch Neurol 1997; 54:625630. Berrios GE, Campbell C, Politynska BE: Autonomic failure, depression and anxiety in Parkinson’s disease. Br J Psychiatry 1995; 166:789-792. Richard IH, Justus AW, Kurlan R: Relationship between mood and motor fluctuations in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:35-41. Mayeux R, Stern Y, Cote L, et al: Altered serotonin metabolism in depressed patients with Parkinson’s disease. Neurology 1984; 34:642-646. Kuzis G, Sabe L, Tiberti C, et al: Cognitive functions in major depression and Parkinson disease. Arch Neurol 1997; 54:982986. Ring HA, Bench CJ, Trimble MR, et al: Depression in Parkinson’s disease. A positron emission study. Br J Psychiatry 1994; 165:333-339. Mayberg HS, Starkstein SE, Sadzot B, et al: Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson’s disease. Ann Neurol 1990; 28:5764. Ballard C, Bannister C, Solis M, et al: The prevalence, associations and symptoms of depression amongst dementia sufferers. J Affect Disord 1996; 36:135-144. Litvan I, Cummings JL, Mega M: Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiatry 1998; 65:717-721. Alexopoulos GS, Meyers BS, Young RC, et al: Clinically defined vascular depression. Am J Psychiatry 1997; 154:562565. Krishnan KR, Hays JC, Blazer DG: MRI-defined vascular depression. Am J Psychiatry 1997; 154:497-501. Alexopoulos GS, Meyers BS, Young RC, et al: “Vascular depression” hypothesis. Arch Gen Psychiatry 1997; 54:915922. Toso V, Gandolfo C, Paolucci S, et al: Post-stroke depression: research methodology of a large multicentre observational study (DESTRO). Neurol Sci 2004; 25:138-144.

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70. Kim JS, Choi-Kwon S: Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000; 54:1805-1810. 71. Sharpe M, Hawton K, House A, et al: Mood disorders in longterm survivors of stroke: associations with brain lesion location and volume. Psychol Med 1990; 20:815-828. 72. Paradiso S, Robinson RG: Gender differences in poststroke depression. J Neuropsychiatry Clin Neurosci 1998; 10:41-47. 73. Starkstein SE, Robinson RG, Berthier ML, et al: Differential mood changes following basal ganglia vs thalamic lesions. Arch Neurol 1988; 45:725-730. 74. Shimoda K, Robinson RG: The relationship between poststroke depression and lesion location in long-term follow-up. Biol Psychiatry 1999; 45:187-192. 75. Reichman WE, Coyne AC: Depressive symptoms in Alzheimer’s disease and multi-infarct dementia. J Geriatr Psychiatry Neurol 1995; 8:96-99. 76. Li YS, Meyer JS, Thornby J: Longitudinal follow-up of depressive symptoms among normal versus cognitively impaired elderly. Int J Geriatr Psychiatry 2001; 16:718-727. 77. Kanner AM: Depression in epilepsy: a frequently neglected multifaceted disorder. Epilepsy Behav 2003; 4(Suppl 4):1119. 78. Kanner AM: Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry 2003; 54:388-398. 79. Johnson EK, Jones JE, Seidenberg M, et al: The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia 2004; 45:544-550. 80. Hecimovic H, Goldstein JD, Sheline YI, et al: Mechanisms of depression in epilepsy from a clinical perspective. Epilepsy Behav 2003; 4(Suppl 3):S25-S30. 81. Victoroff JI, Benson F, Grafton ST, et al: Depression in complex partial seizures. Electroencephalography and cerebral metabolic correlates. Arch Neurol 1994; 51:155-163. 82. Feinstein A: The neuropsychiatry of multiple sclerosis. Can J Psychiatry 2004; 49:157-163. 83. Patten SB, Beck CA, Williams JV, et al: Major depression in multiple sclerosis: a population-based perspective. Neurology 2003; 61:1524-1527. 84. Zephir H, De Seze J, Stojkovic T, et al: Multiple sclerosis and depression: influence of interferon beta therapy. Mult Scler 2003; 9:284-288. 85. Diaz-Olavarrieta C, Cummings JL, Velazquez J, et al: Neuropsychiatric manifestations of multiple sclerosis. J Neuropsychiatry Clin Neurosci 1999; 11:51-57. 86. Pujol J, Bello J, Deus J, et al: Lesions in the left arcuate fasciculus region and depressive symptoms in multiple sclerosis. Neurology 1997; 49:1105-1110. 87. Wynn ZJ, Cummings JL: Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer’s disease. Dement Geriatr Cogn Disord 2004; 17:100-108. 88. Feldman H, Gauthier S, Hecker J, et al, Donepezil MSAD Study Investigators Group: A 24-week, randomized, doubleblind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001; 57:613-620 [Erratum in Neurology 2001; 57:2153]. 89. Tariot PN, Farlow MR, Grossberg GT, et al, Memantine Study Group: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291:317-324. 90. Tom T, Cummings JL: Depression in Parkinson’s disease. Pharmacological characteristics and treatment. Drugs Aging 1998; 12:55-74. 91. Cummings JL: D-3 receptor agonists: combined action neurologic and neuropsychiatric agents [Comment]. J Neurol Sci 1999; 163:2-3.

92. Lyketsos CG, Olin J: Depression in Alzheimer’s disease: overview and treatment. Biol Psychiatry 2002; 52:243-252. 93. Berthier ML, Kulisevsky J, Gironell A, et al: Poststroke bipolar affective disorder: clinical subtypes, concurrent movement disorders, and anatomical correlates. J Neuropsychiatry Clin Neurosci 1996; 8:160-167. 94. Rosenblatt A, Leroi I: Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics 2000; 41:24-30. 95. Cummings JL: Behavioral complications of drug treatment of Parkinson’s disease. J Am Geriatr Soc 1991; 39:708-716. 96. Wright MT, Cummings JL, Mendez MF, et al: Bipolar syndromes following brain trauma. Neurocase 1997; 3:111-118. 97. Jorge RE, Robinson RG, Starkstein SE, et al: Secondary mania following traumatic brain injury. Am J Psychiatry 1993; 150:916-921. 98. Mendez MF: Mania in neurologic disorders. Curr Psychiatry Rep 2000; 2:440-445. 99. Dunn RT, Frye MS, Kimbrell TA, et al: The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol 1998; 21:215-235. 100. Marin RS: Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991; 3:243-254. 101. Levy ML, Cummings JL, Fairbanks LA, et al: Apathy is not depression. J Neuropsychiatry Clin Neurosci 1998; 10:314319. 102. McPherson S, Fairbanks L, Tiken S, et al: Apathy and executive function in Alzheimer’s disease. J Int Neuropsychol Soc 2002; 8:373-381. 103. Cummings JL: Cognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis. Neurobiol Aging 2000; 21:845-861. 104. Migneco O, Benoit M, Koulibaly PM, et al: Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer’s disease and nondemented patients. Neuroimage 2001; 13:896-902. 105. Craig AH, Cummings JL, Fairbanks L, et al: Cerebral blood flow correlates of apathy in Alzheimer disease. Arch Neurol 1996; 53:1116-1120. 106. Tekin S, Mega MS, Masterman DM, et al: Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 2001; 49:355-361. 107. Bozeat S, Gregory CA, Ralph MA, et al: Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 2000; 69:178-186. 108. Bathgate D, Snowden JS, Varma A, et al: Behaviour in frontotemporal dementia, Alzheimer’s disease and vascular dementia. Acta Neurol Scand 2001; 103:367-378. 109. Pluck GC, Brown RG: Apathy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002; 73:636-642. 110. Andersson S, Krogstad JM, Finset A: Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 1999; 29:447-456. 111. Erkinjuntti T, Kurz A, Gauthier S, et al: Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet 2002; 359:1283-1290. 112. McKeith I, Del Ser T, Spano P, et al: Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031-2036. 113. Galynker I, Ieronimo C, Miner C, et al: Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci 1997; 9:231-239.

chapter 19 affective disorders 114. Watanabe MD, Martin EM, DeLeon OA, et al: Successful methylphenidate treatment of apathy after subcortical infarcts. J Neuropsychiatry Clin Neurosci 1995; 7:502-504. 115. Dikmen SS, Bombardier CH, Machamer JE, et al: Natural history of depression in traumatic brain injury. Arch Phys Med Rehabil 2004; 85:1457-1464. 116. Jorge RE, Robinson RG, Moser D, et al: Major depression following traumatic brain injury. Arch Gen Psychiatry 2004; 61:42-50. 117. Mayberg HS, Starkstein SE, Peyser CE, et al: Paralimbic frontal lobe hypometabolism in depression associated with Huntington’s disease. Neurology 1992; 42:1791-1797.

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118. Lyketsos CG, Hanson AL, Fishman M, et al: Manic syndrome early and late in the course of HIV. Am J Psychiatry 1993; 150:326-327. 119. Lyketsos CG, Corazzini K, Steele C: Mania in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:350-352. 120. Aubry JM, Simon AE, Bertschy G: Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. J Clin Psychiatry 2000; 61:649-655. 121. Sultzer Dl, Cummings JL: Drug-induced mania—causative agents, clinical characteristics and management: a restrospective analysis of the literature. Med Toxicol Adverse Drug Exp 1989; 4:127-143.

CHAPTER

20

CONVERSION AND DISSOCIATION SYNDROMES ●

●

●

●

Christopher Bass

Social historians have confidently asserted that conversion hysteria has disappeared from clinical practice, to be replaced by syndromes characterized by fatigue and other medically unexplained disorders.1,2 Although the florid manifestations of hysteria seen in the days of Pierre Janet are less common in the 21st century, the evidence from clinical practice is that patients with conversion disorders are not infrequently encountered by neurologists in both outpatient and inpatient settings.3 Indeed, it has been shown that symptoms considered “functional,” “psychogenic,” “medically unexplained,” or “hysterical” account for up to one third of new referrals to neurology outpatient departments.3,4 In a German survey, Rief and colleagues5 found a 2% base rate of unexplained paralysis or localized weakness in the population and a 5% base rate for “impaired coordination or balance” and “unpleasant numbness or tingling sensations.” In this chapter, the diverse manifestations of conversion and dissociation disorders are described, and the advances in approaches to treatment are outlined.

PROBLEMS WITH DEFINITION There are a number of problems with the definition of the conversion disorder. First, physical disorder must be excluded, but the rate of neurological comorbidity is known to be high in patients with conversion disorder,6 and distinguishing which symptoms are accounted for by organic disease and which are not can be difficult. Second, it is stated that6a a temporal association between a psychological stressor and the onset on the disorder should be identified, but in practice, this is often impossible to establish, and doing so depends to a large extent on the skill of the interviewing physician. Finally, by definition, the process should be unconsciously mediated, but in practice it is difficult (some authorities would say impossible) to distinguish between symptoms that are not consciously produced and those that are intentionally manufactured. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition,6a provides no criteria for distinguishing conscious from unconscious intent, and many authors have argued that the criteria of whether the patients are consciously aware of producing these symptoms should be excluded from the diagnosis of conversion disorder.7 A question often asked by neurologists, when confronted with a patient with unexplained loss of function of the limb, is

“How do I distinguish between conversion disorder, factitious disorder, and malingering?” For the reasons just described, it is difficult to answer this question, because a patient’s “awareness” or “motivations” are not knowable. Various attempts have been made to provide adequate definitions, but all have their limitations (Table 20–1). Attempts to “demedicalize” this complex diagnostic field have introduced the concepts of “free will” and patient choice,8 and motor symptoms of hysteria have been discussed as “disorders of willed action.”9 Neurologists require considerable skills to diagnose and manage these conditions, which can be among the most taxing in the speciality.10 The term conversion is conventionally applied to somatic symptoms, whereas if the symptom is psychological (e.g., a loss of memory or an external hallucination) rather than physical (e.g., a loss of power), it is regarded as dissociative. Dissociation has attracted considerable interest, and in a major review of the topic, Holmes and colleagues (2005)11 drew a distinction between two qualitatively distinct, clinically relevant forms of dissociation, labeled compartmentalization (type 1) and detachment (type 2)12 (Table 20–2). Compartmentalization phenomena are characterized by impairment in the inability to control processes or actions that would usually be amenable to such control and that are otherwise functioning normally. This category encompasses unexplained neurological symptoms (including dissociative amnesia) and benign phenomena such as those produced by hypnotic suggestion. In contrast, detachment phenomena are characterized by an altered state of consciousness associated with a sense of separation from the self, the body, or the world. Depersonalization, derealization, and out-of-body experiences constitute archetypal examples of detachment in this account. Evidence suggests that these phenomena are generated by a common pathophysiological mechanism involving the top-down inhibition of limbic emotional processing by frontal brain systems. Although these two types of dissociation are typically conflated, evidence suggests that different pathological mechanisms may be operating in each case. Support for the compartmentalization model comes from psychophysiological research, which suggests that psychogenic illness is associated with a deficit in attentional, conscious processing and the preservation of preattentive, preconscious processes. According to Brown,13 there is very little difference between “negative” symptoms, such as sensory loss and paralysis, and “positive” symptoms, such as tremor and dystonia, in

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T A B L E 20–1. Relationships between Conversion Hysteria, Factitious Disorder, and Malingering Subject Insight Aware Hysterical conversion Factitious disorder Malingering

Target of Deception

Unaware

Conscious Self

+

+

+ +

Other + +

Perceived Outcome

Motivation/Reason

Sick and disabled role Sick and disabled role Sick and disabled role

Care/dependency Care/dependency Personal benefit (e.g., financial, avoiding prison)

From Halligan P, Bass C, Oakley D: Willful deception as illness behaviour. In Halligan P, Bass C, Oakley D, eds: Malingering and Illness Deception. Oxford, UK: Oxford University Press, 2003, pp 3-28.

EPIDEMIOLOGY

T A B L E 20–2. Classification of Two Types of Pathological Dissociation Type 1 Dissociation (Compartmentalization)

Type 2 Dissociation (Detachment)

Conversion disorders Dissociative amnesia Dissociative fugue Dissociative identity disorder

Depersonalization/derealization Peritraumatic dissociation Out-of-body experiences Autoscopy (?)

From Brown RJ: The cognitive psychology of dissociative states. Cogn Neuropsychiatry 2002; 7:221-235.

terms of basic underlying mechanisms. According to this view, all symptoms result from a loss of normal high-level attentional control over low-level processing systems; in this sense, all symptoms can be viewed as involving a form of compartmentalization. In each case, the “dissociation” between high- and low-level control results from the repetitive reallocation of high-level attention onto “rogue representations” in memory, causing low-level attention to misinterpret this stored information as an account of current rather than past processing activity. The model is shown diagrammatically in Figure 20–1.

In 1976, an editorial in the British Medical Journal suggested that hysteria was “virtually a historical curiosity in Britain.”14 Despite this assertion, the published evidence suggests that it is as common as other disabling conditions such as multiple sclerosis and schizophrenia.15 In a comprehensive review of the literature, Akagi and House15 concluded that the lowest prevalence data suggested a rate of about 50 per 100,000 for cases of conversion disorder known to health services at any one time, with perhaps twice that number affected over a 1-year period. These prevalence studies suggest that the burden of disability associated with chronic hysteria is far higher than a typical practicing psychiatrist might expect or than is reflected in standard textbooks of psychiatry or clinical neurology.

CLINICAL FEATURES Conversion Disorder Motor Symptoms The most typical motor symptoms are paralyses, functional weakness, gait disturbances, seizures resembling epilepsy, and abnormal movements. ■

Operation perceived as effortful and deliberate: associated with self-awareness.

Secondary attentional system

Operation perceived as intuitive, effortless, and self-evident.

Primary attentional system

Spread of activation in perceptual and memorial systems

Activation of perceptual hypotheses

Creation of primary representations

Experience

Figure 20–1. The generation of experience and control of action by the cognitive system. This model suggests that the management of behavior is governed by systems that operate without direct volitional control. This is important in that it allows for functional dissociations between the experience of volition and the control of thought and action. (From Brown RJ: Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model. Psychol Bull 2004; 130:793-812.)

Activation of thought and action schemata

Behavior

chapter 20 conversion and dissociation syndromes The Clinical Approach The physician must not only rule out neurological disorder with the usual methods of history taking, examination, and investigation, but at the same time seek the “positive signs” of hysteria and establish that there is an appropriate psychosocial background for the emergence of medically unexplained symptoms. Since the mid-1990s, diagnostic procedures have improved, and the availability of noninvasive, accurate imaging has drastically reduced the rates of organic pathology that remains undetected in patients with diagnoses of hysteria. Indeed, several studies have reported rates of misdiagnosis of between 0% and 4% in regional and tertiary neurological centers,16 which suggests that a diagnosis of conversion disorder can be made relatively confidently and accurately. In the following section, the process of diagnosis is briefly outlined through the history, examination, and investigation.

The History The onset, temporal sequence, and character of the presenting complaint may not be typical of a neurological disorder, and a number of other features may emerge, especially after an interview with a family member or a review of the hospital and general practitioner notes. Previous Unexplained Symptoms. There is accumulating evidence that the more unexplained symptoms the patient has, the more likely the primary symptom is to be unexplained.17 In one study of patients with medically unexplained motor symptoms, additional unexplained symptoms, including paresthesia (65%), pseudo-epileptic seizures (23%), and memory impairment (20%), were reported.18 It is, therefore, often useful when conversion disorder is being considered as a diagnosis to obtain a printout of the patient’s history from the primary care physician. This may reveal repeated presentations to different specialists, as well as a history of repeated surgical procedures, particularly without clear evidence of pathology. Psychiatric Comorbidity. Rates of depression (38% to 50%) and anxiety (10% to 16%) have been identified in a number of studies. In one small prospective controlled study, there was a fourfold increase in depression among patients with conversion disorder in comparison with matched controls with similar organic disability.19 Recent Life Events or Difficulties. An increased number of life events in the year preceding symptom onset have been recorded in small controlled studies of unexplained motor symptoms20 and pseudoseizures.21 More recent evidence suggests that when patients are interviewed carefully, some report symptoms of panic just before the onset of, for example, functional weakness (J. Stone, personal communication, 10.2.2006). Judicious questions about sensations of sweating, dizziness, and breathing difficulty may reveal these somatic symptoms of anxiety, which may also be reported before the onset of sensory symptoms (see later section on sensory symptoms). Secondary Gain/Litigation. This is a complex issue, but impending litigation has been described in a number of studies of patients with unexplained motor symptoms and tremor.18,21 Neurological Comorbidity. In one study in the United Kingdom, 42% of patients with unexplained motor symptoms had a comorbid neurological disease and, interestingly, one half of these had a peripheral origin.18 Epilepsy is believed to coexist in a significant percentage of patients with nonepileptic seizures.22

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History from Relative/Informant. There is a considerable amount of evidence to suggest that the observations and attitudes of caretakers may be important in the perpetuation of medically unexplained symptoms, especially motor conversion symptoms. For example, Davison and associates23 found caretakers to be ill informed and dissatisfied with the advice they had received from doctors about their relatives’ diagnosis and disabilities.

The Examination and Diagnostic Discrepancies There is often a discrepancy between the patient’s concept of the symptoms and the physician’s knowledge of the anatomy and physiology. The way in which a patient moves or undresses may indicate a global affectation that is incompatible with a specific nerve lesion or with a hemiplegia. Give-way weakness is often used as a diagnostic test of hysterical paralyses, but it is unreliable. Unilateral functional weakness of a leg, if severe, tends to produce a characteristic gait in which the leg is dragged behind the body as a single unit, like a sack of potatoes. The hip is either held in external or internal rotation so that the foot points inward or outward. The most impressive quantitative discrimination to date between hysterical and neurological weakness is reported in a study of Hoover’s sign—the involuntary extension of hysterically paralyzed leg when the “good leg” is flexing against resistance. Ziv and colleagues24 demonstrated a clear difference in the pattern of response between neurological and psychogenic patient groups. It should be borne in mind, however, that the patient may have both a functional disorder and an organic disorder.25

Individual Symptoms Paralyses Paralyses may affect one or more limbs or one side of the face. They may be flaccid or occur with contractures. In a hysterical spasm, both arm and leg are contracted on the same side of the body, the hand is closed tightly, the knee is flexed, and perhaps the leg and the foot are drawn up. Paralysis with contractures is one of the most extreme examples of disability caused by hysterical illness. Hysterical paraplegia has been described,26 and both spinal and orthopedic surgeons, as well as rehabilitation specialists and neurologists, should be alert to the development of this disorder in their patients.27 These patients have the potential to use considerable health care resources.28

Abnormal Movements Psychogenic movement disorders are believed to account for 1 per 30 patients attending a movement disorder clinic21 and have been the subject of a book.29 Since the mid-1980s, a number of case series of patients with psychogenic dystonia have been reported. Fahn and Williams30 described 21 cases in 1988, and Lang31 subsequently described 18 more. Clinical features that suggest a psychogenic movement disorder are shown in Table 20–3. In a systematic study of 103 patients with fixed dystonia, Schrag and associates (2004)32 found that 37% fulfilled criteria for psychogenic dystonia and 29% fulfilled criteria for somatization disorder, which is characterized by chronic, multiple,

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T A B L E 20–3. Features Suggestive of a Psychogenic Movement Disorder Abrupt onset Inconsistent movements (changing characteristics over time) Incongruous movements (movements do not fit with recognized patterns or with normal physiological patterns) Presence of additional types of abnormal movements that are not consistent with the basic abnormal movement pattern or are not congruous with a known movement disorder, particularly: Rhythmical shaking Bizarre gait Deliberate slowness in carrying out the requested voluntary movement Bursts of verbal gibberish Excessive startle (bizarre movements in response to sudden, unexpected noise or threatening movement) Entrainment of the psychogenic tremor to the rate of the requested rapid successive movement the patient is asked to perform Demonstrating exhaustion and fatigue Spontaneous remissions Movements disappear with distraction Response to placebo, suggestion, or psychotherapy Presence as a paroxysmal disorder Dystonia beginning as a fixed posture Adapted from Fahn S: Psychogenic movement disorders. In Marsden CD, Fahn S, eds: Movement Disorders: 3. Oxford, UK: Butterworth-Heinemann, 1995, pp 359-372.

persistent, medically unexplained symptoms. Although many patients fulfilled strict criteria for a somatoform disorder/ psychogenic dystonia, the diagnosis remained uncertain in a proportion of patients, and whether the disorder was primarily neurological or psychiatric remains an open question. Such patients require the services of a multidisciplinary team.

Seizures (Psychogenic Nonepileptic Seizures) It is estimated that more than 25% of patients receiving a diagnosis of refractory epilepsy in a chronic epilepsy clinic do not have epilepsy.33 Although the population incidence of psychogenic nonepileptic seizures (PNESs) may be only 4% that of epilepsy, PNES constitutes a large share of the workload of neurologists and of emergency and general physicians. A number of details in the patient’s history may suggest a diagnosis of PNES rather than epileptic seizures (Table 20–4). PNESs can be distinguished from epileptic seizures: PNESs generally occur in the presence of an audience or when another person is close by. They may be precipitated by stress but more often seem to occur in response to the social setting. The fall to the ground is not usually abrupt, and movements may follow the fall with clutching, but the characteristic regular tonicclonic sequence of epilepsy is not found. Tongue biting and incontinence of urine are rare in hysterical seizures, the corneal reflexes are preserved, and the plantar muscles are flexed, unless previously abnormal. Firm handling and pressure on the supraorbital nerves to the point of pain may arouse the patient. PNESs occur most often among epileptic patients or among others who have seen epileptic seizures. A few epileptic patients learn how to induce ictal discharges and can produce extra seizures. Although rarely available during a seizure, the

T A B L E 20–4. Details in Patients’ History That May Suggest a Diagnosis of Psychogenic Nonepileptic Seizures Rather Than Epileptic Seizures Feature in History Manifestation at age <10 years Change in symptoms Aggravation by AEDs Seizures in presence of physicians Recurrent “status epilepticus” Multiple unexplained physical symptoms Multiple operations/ invasive tests Psychiatric treatment Sexual and physical abuse

Psychogenic Nonepileptic Seizures

Epileptic Seizures

Unusual

Common

Occasional Occasional Common

Rare Rare Unusual

Common

Rare

Common

Rare

Common

Rare

Common Common

Rare Rare

Adapted from Reuber M, Elger C: Psychogenic non epileptic seizures: review and update. Epilepsy Behav 2003; 4:205-216. AED, antiepileptic drug.

electroencephalogram is generally abnormal in epilepsy and normal during hysterical seizures.22 It usually takes several years to arrive at the diagnosis of PNES, and 75% of patients (with no additional epilepsy) are treated with anticonvulsants initially. If PNES is not diagnosed and managed early, significant iatrogenic harm may occur. The outcome is not always favorable in these patients: in one study carried out at a mean of 11.9 years after manifestation and 4.1 years after diagnosis of PNES, 71% of patients continued to have seizures and 56% were dependent on Social Security. Outcome was better in patients with greater educational attainments, younger age at onset and diagnosis, attacks with less dramatic features, and fewer additional medically unexplained complaints.34 It has been reported that patients with PNES have a consistently different psychosocial profile from patients with motor conversion symptoms. In a prospective study of consecutive neurological inpatients with either motor conversion or pseudoseizures of recent onset, patients with PNES were younger, more likely to have both an emotionally unstable personality disorder and a worse perception of parental care, more likely to report incest, and more likely to have reported more life events in the 12 months before symptom onset than were patients with motor conversion symptoms.20

Sensory Symptoms Sensory Disturbance The clinical detection and localization of sensory dysfunction is probably one of the least reliable areas of the neurological examination. Sensory loss may involve one half of the entire body from head to toe or from right to left. It may affect the whole of a limb and characteristically has a glove or stocking distribution on the arms or legs or both. The sensory loss generally fails to fit in with known anatomical boundaries but conforms more with the patient’s concept of physiology and anatomy. Thus, hysterical sensory loss is likely to stop sharply at the midline, whereas nonhysterical sensory change only

chapter 20 conversion and dissociation syndromes approaches the midline, inasmuch as at this point segmental nerves overlap by one or two centimeters on each side. Unfortunately, these classic signs are often unreliable. Gould and coworkers35 found “psychogenic” features on sensory examination in more than one half of their neurological patient group, and diminished vibration sense over the affected part of the forehead was noted in 69 of 80 patients with neurological disorders.36 This study also revealed that “midline splitting” of sensory function was not helpful in determining whether there was an underlying neurological disorder. These clinical findings should clearly be interpreted with circumspection. Hemisensory disturbances can often manifest as emergencies; sometimes the patient ascribes the symptoms to “a stroke,” in association with anxiety and panic and other physical symptoms of anxiety.37 These symptoms may be provoked by hyperventilation38 or hypnotic suggestion.39 The pathophysiological mechanisms underlying these changes are not as yet understood. Toth40 described 34 patients with the “hemisensory syndrome,” in which patients present with hemisensory disturbance and intermittent blurring of vision in the ipsilateral eye (asthenopia) and sometimes ipisilateral hearing problems as well. Hemisensory symptoms are increasingly recognized in patients with chronic pain and in patients with reflex sympathetic dystrophy.

Visual Disturbances Ophthalmologists have estimated that psychogenic visual disorders account for up to 5% of their practice.41 Simple observation of visually guided behavior sometimes reveals telling inconsistencies, particularly in the case of severe apparent visual loss. A number of reliable optometric techniques are available to support bedside tests and the diagnosis of psychogenic visual loss, field disturbance, or gaze abnormality (for more details, see Stone and Zeman16). Disabling hysterical blindness presents more difficulties. Evoked potential studies help demonstrate intact visual pathways.

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There is little chance of improvement once the symptoms have become chronic and enduring.42 The etiological implications accruing from follow-up studies43,44 are that a short history and young age are predictors of good outcome, whereas the presence of a personality disorder, chronicity of symptoms, receipt of disability benefits, and involvement with litigation predict poor recovery. Ron42 wrote an excellent recent review of this topic. Patients with chronic motor symptoms (e.g., unilateral functional weakness), as well as those with sensory symptoms, appear to do particularly poorly. In particular, patients with unexplained motor symptoms who are referred to tertiary care centers continue to do very poorly after discharge. Despite the stability of the diagnosis, a pattern of multiple hospital referrals continues for many of these patients once they have been discharged from the tertiary care center. Interviews of patients conducted an average of 6 years after their original admission to a tertiary care center revealed that many continued to be referred to neurologists and other specialists but that subsequent psychiatric referral was rare.43 Many changed their primary care physician after discharge from the hospital, and a disproportionate number of repeated referrals was made by primary care physicians who had known their patients for less than 6 months. Psychological attribution of symptoms was rare, and many patients felt dissatisfied with the treatment they had received. Many were exposed to unnecessary iatrogenic harm. These consistent findings of very poor outcome after discharge from neurological outpatient and inpatient services in patients with both unexplained motor disorders and PNES suggest that every neurological service should have access to referral to specialist liaison psychiatry services. Such patients are often very difficult to treat and, because of their poor prognosis, should have a reasonable chance of obtaining early and appropriate management for their primary disorder.44,45 Without appropriate treatment, the prognosis is poor (Table 20–5).

MANAGEMENT

PROGNOSIS Outcome in published studies depends to some degree on the setting: tertiary referral centers tend to attract patients with chronic or intractable symptoms. Better outcomes appear to be associated with short or acute onset and early improvement.

Resources Before any discussion of treatment, it is important to consider the resources available to the neurologist to manage these

T A B L E 20–5. Follow-up Studies (1998 to 2003) of Patients with Unexplained Motor Symptoms Sample Size

Mean Follow-up (Years)

Axis I

Axis II

Outcome/Disability at Follow-up

Crimlisk et al, 199818

64

6.0

75%*

53%*

Binzer and Kullgren, 199860 Feinstein et al, 200161

30

1.0

33%*

50%*

50% either had retired on grounds of ill health or were on sick leave 43% not working at 1 year

42‡

3.2

95%†

45%†

§

12.5

—

—

Study/Year

Stone et al, 2003

44

47

Persistence of abnormal movements in >90%; 57% disabled 83% reported weakness or sensory symptoms; 30% had taken medical retirement

Axis I: mental illness; axis II: personality disorder. All patients presented to secondary or tertiary care centers, which contributes to the poor prognosis. *Diagnoses at baseline. † Diagnoses at follow-up. ‡ All patients had hyperkinetic movement disorder (i.e., tremor, dystonia, myoclonus). § 55% manifested weakness; 45% manifested only sensory symptoms.

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patients. In contrast to disorders such as multiple sclerosis and schizophrenia, which have similar prevalences, there are no designated resources for patients with psychogenic disorders. Some neurologists may have no access whatsoever to mental health resources, whereas others may have close collaborative links with either clinical psychology or psychiatry services. There is no doubt that the successful management of these patients requires the cooperation of a number of clinical specialties, including psychologists, nurses, physiotherapists, and occupational therapists. Some patients may be so disturbed or disabled (or both) that they may require inpatient admission to a specialized unit with access to both mental health and medical nurses, as well as to physiotherapists and occupational therapists. In the opinion of this writer, every neurology service should have access to a specialist liaison psychiatry service.46

Management Strategies for the Neurologist First, the diagnosis has to be established by a neurologist after relevant organic disease has been ruled out. Second, the neurologist not only must explain to the patient that there is no serious underlying organic disease but also must provide an explanation for the symptoms that is comprehensible to the patient. During the initial assessment, it is important for the neurologist to inquire about a number of psychosocial problems as part of the general interview. Key questions include the following: 1. “Have you experienced any distressing setbacks or reversals in the last 6-9 months?” (life events) 2. “How have you been feeling in your mood? Have you been feeling low; or tense or wound up; or panicky?” (anxiety and depression) 3. “What do you think is causing the symptoms? What is your worst fear?” (illness beliefs) 4. “What impact are the symptoms having on your life?” (functional impairment) Armed with this information, the neurologist may be able to make some kind of initial formulation, such as the following: We have completed our tests, and I am pleased to say that all results are normal, and we have not found any evidence of disease. However, I know that your symptoms are distressing, and they are certainly real. I recall your telling me that the weakness in your left leg began 9 months ago with altered sensation in your left toes. You also said that you became tense and upset at work around this time, with problems with your sleep and memory and feeling panicky in crowds. I am struck by the fact that these symptoms came on soon after your disagreement with your manager and failure to get a promotion, and life has been difficult for you since then. Have you thought about it like that? After this, the neurologist may wish to help the patient establish mind-body links by saying something like the following: You have what we call functional weakness: All the parts of the nervous system are there but are just not working properly, so that when you try to move your leg, it doesn’t do it as well as it should. Sometimes stress can cause these symptoms, which are often accompanied by feelings of frustration, worry, and sadness but these are not the cause of the

problem. Stress is a common problem and can lead to hypertension and duodenal ulcers, as well as what we call functional weakness. This explanation can be supplemented by giving the patient a fact sheet containing information about functional weakness, which contains information about how to become involved with rehabilitation (J. Stone, personal communication, 2006). It is worth noting at this stage that patients prefer the term functional rather than hysterical, when their unexplained weakness, seizures, and other symptoms are being referred to.46 The neurologist can supplement this interview by using rating scales, which provide useful baseline pretreatment information. They include the Hopkins Symptom Checklist somatization scale to measure somatic symptoms47; the Hospital Anxiety and Depression Scale to measure anxiety and depression48 (the Beck Depression and Anxiety scales are also useful); and the Illness Perception Questionnaire, which provides a rating of illness attitudes and concerns.49 There are several measures of functional impairment, including the Dartmouth Primary Care Cooperative Information Project50 and the Barthel index.51

Referral to Psychiatrist/Psychologist Discussing referral to a mental health specialist with the patient is a skilled process requiring the neurologist to provide a rationale for the referral without alienating the patient. Neurologists in training are not routinely taught these skills. One suggested method might be to use the following explanations: ■ “You have a number of physical and psychological (stress)

symptoms at present.” ■ “The physical symptoms are real but do not reflect any

underlying damage.” ■ “In our experience, it is as important to deal with the psy-

chological as well as the physical symptoms in problems like this (such as functional weakness).” ■ “Would you like me to organize a referral to a psychiatrist/ psychologist who has a specific interest in your problems?” ■ [If relevant] “This person works in the general hospital and has had a lot of experience dealing with patients with similar problems.”

Further Management Traditional behavioral approaches to treatment are based on the premise that the symptoms reported by the patient are interpreted as physical but are amenable to recovery. The aim of treatment is to bring about a gradual increase in function through a combination of physical and occupational therapies. The patient receives rewards and praise for improvement of function, and reinforcement is withdrawn for continuing signs of disability. Avoiding direct confrontation of psychological problems and providing “face-saving” techniques are also regarded as key components.52 More recently, the approach to patients has changed from a predominantly medical one to one in which psychological and sociocultural aspects are equally important, and the need for organized specialist rehabilitation services involving a multi-disciplinary team is recognized as essential.

chapter 20 conversion and dissociation syndromes What Is the Evidence? With one or two exceptions,53 there are no large, randomized, controlled studies of treatment in patients with conversion disorders. Nor is there any good evidence to support the use of one specific intervention, such as biofeedback, hypnosis, or psychotherapy. Although repeated case series have documented the effectiveness of multidisciplinary inpatient behavioral treatment, there is little controlled research. In an innovative approach, a “strategic behavioral intervention” was shown to be superior to standard behavioral treatment for chronic nonorganic motor disorders.7 In this method, patients and their families were told that full recovery constituted proof of an organic etiology, whereas failure to recover was definite proof of psychiatric etiology. This approach clearly requires special facilities and trained personnel.

A Framework for Rehabilitation

Cognitive-behavioral therapy is concerned mainly with helping the patients overcome identified problems and ascertain specified goals. It discourages “maintaining factors” such as repeated body self-checking and excessive bed rest, and challenges patients’ negative or false beliefs about symptoms. Chalder described specific cognitive-behavioral therapy–based treatment for patients with conversion disorders.58 A cognitivebehavioral approach may also help with the formulation. An example is given in Figure 20–2.

Pharmacological Treatments There is evidence from randomized controlled trials and systematic reviews that antidepressants (both tricyclic antidepressants and selective serotonin reuptake inhibitors) can be useful in the treatment of patients with medically unexplained symptoms (such as poor sleep and pain), whether depression is present or not.59

In the absence of good experimental evidence, a possible framework for future research has been developed; it is based on published evidence and described in the World Health Organization’s International Clarification of Functioning, Disability and Health,54 which is particularly useful for patients in whom there is a disability that is out of proportion to known disease and signs. The model provides opportunities for intervention and is well suited to the kind of multidisciplinary approach that is likely to be successful in these patients. The model emphasizes that whatever the primary cause of an illness, many factors have an influence on its manifestations. It has been pointed out that patients experience a sense of control and influence over their behavior by choosing (whenever possible) between different courses of action.55,56 The notions of free will and personal responsibility remain a core belief for most democratic and legal conceptions of human nature, and they may help explain illness not produced by disease, injury, psychopathology, or psychosocial factors. For example, a 44-year-old woman with a long history of irritable bowel syndrome and facial pain developed a sudden loss of sensation and weakness of both legs soon after a traumatic separation from her husband. All neurological investigations yielded normal results, and despite attempts made by the medical staff to link her symptoms to distressing life events, she retired to a wheelchair and endorsed a “medical” view of her illness, joining the local multiple sclerosis society. This state was reinforced by the family and medical services, which provided sick notes and disability aids.

A

Previous experience (My father died of a brain tumor.)

B Formation of dysfunctional assumptions (I should always be able to explain my symptoms; symptoms always mean there is something wrong.)

C

Critical incident (My best friend died of cancer last month; I’m having a lot of headaches.)

D Activation of assumptions

Psychological Treatments Because patients with conversion disorders share features in common with patients with other medically unexplained syndromes, treatments that have been used in these latter disorders may have potential. Most of the evidence-based treatments in this field involve cognitive-behavioral therapy (see Kroenke and Swindle57) or interpersonal therapy. These usually have to be undertaken by trained clinical psychologists or other clinicians. However, increasing numbers of specialist nurses are being trained to deliver these treatments; therefore, they should become more widely available.

255

E

Negative automatic thoughts/images (I could have a brain tumor; this will get worse.)

• Behavior • Mood ■

• Thoughts • Physiology

Figure 20–2. Example of a cognitive behavioral formulation in a patient with headaches.

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P O I N T S

●

Clinical assessment supported by appropriate imaging and other paraclinical tests should allow the neurologist to establish a confident diagnosis of conversion disorder.

●

It is often difficult for the clinician to differentiate between symptoms attributable to conversion disorder, fabricated illness, and malingering. In cases in which the diagnosis is unclear, a psychiatric opinion should be sought.

●

Before the clinical examination of the patient in whom conversion disorder is suspected, the neurology team should attempt to obtain (and document in the medical file) as much medical history from the primary care physician and other medical records as possible. These records may reveal extensive histories of medically unexplained symptoms and/or unnecessary surgery.

●

It is important for the neurologist to establish an early diagnosis of conversion disorder. This is easier if, at an early stage in the interview with the patient, psychosocial factors are discussed. Early diagnosis and referral prevent iatrogenic harm, which is particularly likely to occur in patients with PNES and functional weakness.

●

Neurology services should have access to a designated liaison psychiatry service. This is essential because conversion disorders and PNES have poor prognoses if they are not treated. Neurology services without access to liaison psychiatry should lobby their managers to provide one.

Suggested Reading Hallett M, Fahn S, Jancovic J, et al, eds: Psychogenic Movement Disorders: Psychobiology and Treatment of a Functional Disorder. New York: Lippincott Williams & Wilkins, 2005. Halligan P, Bass C, Marshall J, eds: Contemporary Approaches to the Study of Hysteria. Clinical and Theoretical Perspectives. Oxford, UK: Oxford University Press, 2001. Holmes EA, Brown R, Mansell W, et al: Are there two qualitatively distinct forms of dissociation? A review and some clinical implications. Clin Psychol Rev 2005; 25:1-23. Reuber M, Elger CE: Psychogenic non-epileptic seizures: review and update. Epilepsy Behav 2003; 4:205-216. Schrag A, Trimble M, Quinn N, et al: The syndrome of fixed dystonia: an evaluation of 103 patients. Brain 2004; 127:2360-2372.

References 1. Micale M: Approaching hysteria. Princeton, NJ: Princeton University Press, 1994. 2. Showalter E: Hystories. Hysterical Epidemics and Modern Culture. New York: Columbia University Press, 1997. 3. Carson A, Ringbauer B, Stone J, et al: Do medically unexplained symptoms matter? A prospective cohort study of 300 new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry 2000; 68:207-211. 4. Fink P, Hansen MS, Sondergaard L, et al: Mental illness in new neurological patients. J Neurol Neurosurg Psychiatry 2003; 74:817-819.

5. Rief W, Hessel A, Braehler E: Somatisation symptoms and hypochondriacal features in the general population. Psychosomat Med 2001; 63:595-602. 6. Eames P: Hysteria following brain injury. J Neurol Neurosurg Psychiatry 1992; 55:1046-1051. 6a. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 7. Shapiro A, Teasell RW: Behavioural interventions in the rehabilitation of acute v chronic non-organic (conversion/factitious) motor disorders. Br J Psychiatry 2004; 185:140-146. 8. Halligan P, Bass C, Oakley D: Willful deception as illness behaviour. In Halligan P, Bass C, Oakley D, eds: Malingering and Illness Deception. Oxford, UK: Oxford University Press, 2003, pp 3-28. 9. Spence S: Hysterical paralyses as disorders of action. Cogn Neuropsychiatry 1999; 4:203-226. 10. Fahn S: Psychogenic movement disorders. In Marsden CD, Fahn S, eds: Movement Disorders: 3. Oxford, UK: Butterworth Heinemann, 1995, pp 359-372. 11. Holmes E, Brown R, Mansell W, et al: Are there two qualitatively distinct forms of dissociation? A review and some clinical implications. Clin Psychol Rev 2005; 25:1-25. 12. Brown RJ: The cognitive psychology of dissociative states. Cogn Neuropsychiatry 2002; 7:221-235. 13. Brown RJ: Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model. Psychol Bull 2004; 130:793-812. 14. The search for a psychiatric Esperanto [Editorial]. BMJ 1976; 2:600-601. 15. Akagi H, House A: The clinical epidemiology of hysteria: vanishingly rare, or just vanishing? Psychol Med 2002;32:191-194. 16. Stone J, Zeman A: Hysterical conversion—a view from clinical neurology. In Halligan P, Bass C, Marshall J (eds): Contemporany Approaches to the study of Hysteria. Oxford, UK: Oxford University Press, 2001, pp 102-125. 17. Wessely S, Nimnuan C, Sharpe M: Functional somatic syndromes: one or many? Lancet 1999; 354:936-939. 18. Crimlisk H, Bhatia K, Cope H, et al: Slater revisited: 6 year follow up study of patients with medically unexplained motor symptoms. BMJ 1998; 316:582-586. 19. Binzer M, Andersen P, Kullgren G: Clinical characteristics of patients with motor disability due to conversion disorder: a prospective control group study. J Neurol Neurosurg Psychiat 1997; 63:83-88. 20. Stone J, Sharpe M, Binzer M: Motor conversion symptoms and pseudoseizures: a comparison of clinical characteristics. Psychosomatics 2004; 45:492-499. 21. Factor S, Podskalny R, Molho E: Psychogenic movement disorders: frequency, clinical profile and characteristics. J Neurol Neurosurg Psychiatry 1995; 59:406-412. 22. Reuber M, Elger C: Psychogenic non epileptic seizures: review and update. Epilepsy Behav 2003; 4:205-216. 23. Davison P, Sharpe M, Wade D, et al: “Wheelchair” patients with non-organic disease: a psychological enquiry. J Psychosom Res 1999; 47:93-103. 24. Ziv I, Djaldetti R, Zoldan Y, et al: Diagnosis of “non-organic” limb paresis by a novel objective motor assessment: the quantitative Hoover’s test. J Neurol 1998; 245:797-802. 25. Stone J, Zeman A, Sharpe M: Functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2002; 73:241-245. 26. Baker J, Silver J: Hysterical paraplegia. J Neurol Neurosurg Psychiatry 1987; 50:375-382. 27. Heruti R, Reznik J, Adunski A, et al: Conversion motor paralysis disorder: analysis of 34 consecutive referrals. Spinal Cord 2002; 430:335-340. 28. Allanson J, Wade D, Bass C: Characteristics of patients with persistent severe disability and medically unexplained neuro-

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29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

43. 44. 45. 46.

logical symptoms: a pilot study. J Neurol Neurosurg Psychiatry 2002; 73:307-309. Hallett M, Fahn S, Jankovic J, et al, eds: Psychogenic Movement Disorders: Psychobiology and Treatment of a Functional Disorder. New York: Lippincott Williams & Wilkins, 2005. Fahn S, Williams D: Psychogenic dystonia. Adv Neurol 1988; 50:431-455. Lang AE: Psychogenic dystonia: a review of 18 cases. Can J Neurol Sci 1995;22:136-143. Schrag A, Trimble M, Quinn N, et al: The syndrome of fixed dystonia: an evaluation of 103 patients. Brain 2004; 127:23602372. Smith D, Defalla B, Chadwick D: The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. Q J Med 1999; 92:15-23. Reuber M, Pukrop R, Bauer J, et al: Outcome in psychogenic nonepileptic seizures: 1 to 10 year follow up in 164 patients. Ann Neurol 2003; 53:305-311. Gould R, Miller B, Goldberg M, et al: The validity of hysterical signs and symptoms. J Nerv Ment Dis 1986; 174:593-597. Rolak L: Psychogenic sensory loss. J Nerv Ment Dis 1988; 176:686-687. Blau N, Wiles M, Solomon F: Unilateral somatic symptoms due to hyperventilation. BMJ 1983; 286:1108. O’Sullivan G, Harvey I, Bass C, et al: Psychophysiological investigations of patients with unilateral symptoms in the hyperventilation syndrome. Br J Psychiatry 1992; 160:664-667. Fleminger J, McClure G, Dalton R: Lateral response to suggestion in relation to handedness and the side of psychogenic symptoms. Br J Psychiatry 1098; 136:562-566. Toth C: Hemisensory syndrome is associated with a low diagnostic yield and a nearly uniform benign prognosis. J Neurol Neurosurg Psychiatry 2003; 74:1113-1116. Kathol R, Cox T, Corbett J, et al: Functional visual loss: I. A true psychiatric disorder? Psychol Med 1983; 13:307-314. Ron M: The prognosis of hysteria/somatisation disorder. In Halligan P, Bass C, Marshall J, eds: Contemporary Approaches to the Study of Hysteria. Oxford, UK: Oxford University Press, 2001, pp 271-283. Crimlisk H, Bhatia K, Cope H, et al: Patterns of referral in patients with medically unexplained motor symptoms. J Psychosom Res 2000;49: 217-219. Stone J, Sharpe M, Rothwell P, et al: The 12-year prognosis of unilateral functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2003; 74:591-596. Gotz M, House A: Prognosis of symptoms that are medically unexplained. BMJ 1998; 317:536. Stone J, Wojcik W, Durrance D, et al: What should we say to patients with symptoms unexplained by disease? The “number needed to offend.” BMJ 2002; 325:1449-1450.

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47. Derogatis L, Melisaratos N: The Brief Symptom Inventory: an introductory report. Psychol Med 1983; 13:595-605. 48. Zigmond A, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983; 67:361-370. 49. Weinman J, Petrie K, Moss-Morris R, et al: The Illness Perception Questionnaire: a new method for assessing the cognitive representation of illness. Psychol Health 1996; 11:431445. 50. Jenkinson C, Mayou R, Day A, et al: Evaluation of the Dartmouth COOP charts in a large-scale community survey in the United Kingdom. J Public Health Med 2002; 24:106-111. 51. Wade D, Collin C: The Barthel ADL Index: a standard measure of physical disability? Int Disabil Stud 1988; 10:64-67. 52. Teasell R, Shapiro A: Rehabilitation of chronic motor conversion disorder. Crit Rev Phys Rehabil Med 1993; 5:1-13. 53. Moene F, Spinhoven P, Hoogduin K, et al: A randomised controlled clinical trial on the additional effect of hypnosis in a comprehensive treatment programme for inpatients with conversion disorder of the motor type. Psychother Psychosom 2002; 71:66-76. 54. World Health Organization: International Clarification of Functioning, Disability and Health. Geneva: World Health Organization, 2001. Available at: http://www3.who.int/ icficftemplate.cfm. 55. Wade D, Halligan P: New wine in old bottles: the WHO ICF as an explanatory model of human behaviour. Clin Rehabil 2003; 17:349-354. 56. Wade D: Medically unexplained disability—a misnomer, and an opportunity for rehabilitation. Clin Rehabil 2001; 15:343-347. 57. Kroenke K, Swindle R: Cognitive behavioural therapy for somatisation and symptom syndromes: a critical review of controlled clinical trials. Psychother Psychosom 2000; 69:205-215. 58. Chalder T: Cognitive behavioural therapy as a a treatment for conversion disorders. In Halligan P, Bass C, Marshall J, eds: Contemporary Approaches to the Study of Hysteria: Clinical and Theoretical Perspectives. Oxford, UK: Oxford University Press, 2001, pp 298-311. 59. O’Malley P, Jackson J, Santoro J, et al: Antidepressant therapy for unexplained symptoms and symptom syndromes. Fam Pract 1999; 48:980-990. 60. Binzer M, Kullgren G: Motor conversion disorder. A prospective 2- to 5-year follow-up study. Psychosomatics 1998; 39:519527. 61. Feinstein A, Stergiopoulos V, Fine J, et al: Psychiatric outcome in patients with a psychogenic movement disorder: a prospective study. Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:169-176.

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OF THE VISUAL ●

●

●

SYSTEM

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Desmond Kidd

VISUAL ACUITY A sizeable minority of patients who are referred to a neuroophthalmology clinic have a refractive error as the only cause for the visual symptoms. It is thus essential to assess visual acuity only after having ensured that any refractive error has been corrected. The patient should be assessed with spectacles on, and if the acuity is abnormal, the clinician should add a pinhole to the lens and repeat the assessment. A standard distance acuity should be assessed using a Snellen 6 m Chart placed 6 m from the patient in a brightly illuminated position. Low luminance reduces visual acuity because foveal ganglion cells have high light thresholds. LogMAR charts are similar but allow comparison of repeated measurements in a statistical way. Near acuity can be assessed using Jaeger charts held by the patient at whatever distance is comfortable. Patients with refractive, corneal, or lens problems may have better near than distance acuity, and patients with accommodative and convergence disorders may have better distance acuity than those with near acuity. A more sensitive assessment of visual acuity involves the use of contrast sensitivity threshold measurements using wall charts or computer programs. These measure the sensitivity of minimum spatial resolution of gratings. In patients with amblyopia, a neutral density filter placed in front of the affected eye will not cause a substantial further loss of visual acuity (a 2.0 log filter reduces acuity in normal people by a factor of 2.0), whereas patients with reduced acuity due to a problem causing delayed optic nerve conduction demonstrate a much greater fall in visual acuity such as 6/9 to 6/60). Color vision is assessed using pseudo-isochromatic plates such as Ishihara, Hardy-Rand-Ritter, and Dvorine plates. These are all easy and quick to use, although they cannot be used to assess the severity of the loss of color vision and they do not provide an adequate assessment of blue-green disorders. More complicated measurements such as the Farnsworth Munsell 100 hue test and others are better but much more time consuming. These tests are useful in the assessment of visual loss due to optic nerve and macular problems. Congenital color blindness occurs in 8% of males and is symmetrical; an asymmetrical loss of color vision is always acquired. The prevalence of color blindness is as follows: Red-green males Red-green females Blue-yellow Achromacy

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8% 0.4% 0.005% 0.003%

Köllner’s rule states that loss of red-green discrimination occurs in optic nerve disorders and loss of blue/yellow discrimination arises in macular problems. There are exceptions to this rule, however, because optic neuropathies that involve disruption of the papillomacular bundle (e.g., optic neuritis) will cause red-green color deficits, whereas those that disrupt fibers arising from the perifoveal fields (e.g., glaucoma and papilloedema) will cause blue-yellow deficits (as well as a proportionately smaller reduction in visual acuity).

VISUAL FIELD EXAMINATION The assessment of the visual field is of crucial importance to the examination of the visual system because it is the most helpful aspect of the examination in determining the anatomical substrate of the visual symptom. Confrontation methods are adequate only if carried out very carefully indeed. Wiggling fingers only detect field defects that are absolute; that is, there is no vision within that field, and some may have no vision within a hemianopic field but are nonetheless able to perceive movement. Finger counting is better; the patient must focus on the examiner’s eye and say or copy the number of fingers presented to the four quadrants and the central field. Use of a small target such as a hat pin is more accurate; a white hat pin plots out the peripheral field and the red is used for central defects, particularly optic nerve disorders in which, as noted earlier, red-green color deficits arise. The principle behind dynamic perimetric methods of field analysis such as the Goldman is that the examiner is identifying successive boundaries of vision known as differential light sensitivities (DLSs). These are the thresholds within which it is possible for that part of the retina to identify when a light projected is more bright than the background. The fovea is most sensitive, and this reduces with distance from the fovea. The temporal field changes slowly with distance from the fovea, whereas the DLS on the nasal side reduces abruptly. A normal Goldman field is shown in Figure 21−1. The advantage of this method of field assessment is that the skilled examiner can plot very carefully visual field abnormalities and can return over and over again to check the boundaries of the field. Automated static perimetry is available in all ophthalmic departments, can be carried out in around 10 minutes, is easy to administer, and does not require so much skill to perform. It is less sensitive a measure than the Goldman when the exam-

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Figure 21–1. Normal Goldman field.

iner is highly skilled in use of the latter. Automated static field tests identify the threshold of accurate vision within the four visual quadrants within a 10-, 24-, 30-, or 70-degree field. Fields can be recorded for comparison with subsequent examinations; reliability can be assessed by noting fixation losses and falsepositive and -negative errors. The gray scale indices note the mean or pattern deviation of the patient’s responses to those of age-matched normal controls (Fig. 21−2).

Factors that influence the precision of these field examinations include cognitive function and tiredness, refractive errors, and ophthalmic disorders such as cataract. The field is plotted at a certain level of background illumination because the threshold varies with background luminance up to a certain point and then increases in a linear way with suprathreshold background luminance. Examples of common field defects that are seen are shown in Figures 21−3 to 21−8.

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Figure 21–2. Normal Humphrey field, left, upper field; right, lower field.

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Figure 21–3. Upper quadrantinopia due to a left temporal infarction, left, upper field; right, lower field.

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Figure 21–4. Congruous but incomplete hemianopia due to an infarction of the left occipital lobe, left, upper field; right, lower field.

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Figure 21–5. Bitemporal hemianopia due to a craniopharyngioma, left, upper field; right, lower field.

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Figure 21–6. Centrocecal scotoma due to toxic amblyopia.

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Figure 21–7. Arcuate scotoma due to glaucoma.

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Figure 21–8. Enlarged blind spots due to bilateral papilloedema.

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The examination involves inspection of pupil size and shape at rest. Each should be round and of the same size. Pupil size can be measured using a ruler or more easily using a pupil gauge such as that seen on a hand-held pinhole occluder. The pupils should then be inspected in light and dark—particularly if there is inequality in room lighting. Physiological anisocoria is detectable in 20% of young people and increases in prevalence with age to 33% of people over the age of 60 years. The inequality increases in dark in the case of physiological anisocoria and to a greater degree in the case of Horner’s syndrome. It may also be affected by anxiety, which increases sympathetic drive, and by fatigue.

Pupillary Reaction to Light The pupil should be assessed by a bright (but not too bright) light source such as a fully charged ophthalmoscope light source with low background illumination (just enough to see the pupil in darkness). The patient will be looking into the distance in order to prevent meiosis in accommodation. The light source is applied to the pupil for 2 or 3 seconds, and the response amplitude and reaction speed are noted. This should be repeated several times. The latency of redilatation should also be observed; early pupillary escape, in which redilation occurs earlier on one side and sometimes even before the light source is removed, implies a mild afferent pupillary defect.

Consensual Response When light is applied to one eye, the pupillary response in the other should be equal in amplitude and synchronous because the decussation of pupillary fibers in the midbrain is 50%.

Near Response ■

Figure 21–9. Amsler grid with central field defect due to agerelated macular dystrophy.

The Amsler grid is useful for plotting central field distortions, such as macular disorders, but also very small central field abnormalities due to, for example, optic neuropathy. The patient plots out the abnormality on the grid himself (Fig. 21−9). Tangent screen testing is also easy and rapid; a 1-m screen can be attached to the wall of a clinic room, and a light source with varying target size and luminance can be used very accurately to plot out a visual field. The contour of light sensitivity to the target of the same size and luminance is termed an isopter. Different target sizes and luminances give rise to different isopters, and so the field is plotted.

The patient is instructed to look into the distance and then at a target held at the nearest point of distinct vision (25 cm in emmetropic people). A brisk and symmetrical meiosis should follow as convergence occurs. The speed and amplitude of the near response are noted and compared with the direct light response; light-near dissociation may arise in upper midbrain lesions due to compressive, infiltrative, or inflammatory causes (including, of course, neurosyphilis), severe bilateral optic neuropathies, and isolated parasympathetic nerve disorders.

Pupillary Dilatation The pupil returns to its size appropriate for low levels of background illumination 12 to 15 seconds after a bright light source is removed from the eye. In patients with Horner’s syndrome, there is a dilatation lag, in which the affected side dilates more slowly than the normal side, and an increase in anisocoria is seen.

PUPILS

Relative Afferent Pupillary Defect

Patients with recent-onset pupillary mydriasis may complain of blurring of vision and photophobia, but most patients have no symptoms.

Everyone knows about this test and medical students believe that they should also perform it, but it is very complicated and requires skill and experience in order to perform it well. The

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eyes may be covered and uncovered in turn or the swinging light test may be applied. In the latter, the light source is applied in turn to each eye for 3 to 5 seconds repeatedly. The trick is to vary the time taken to move from one eye to the other; often, the relative afferent pupillary defect (RAPD) can be brought out thus. Great care should be taken to not apply the light source to one eye for longer than the other, to apply the light source to the same amount of retina in each eye (this is particularly important if there is ocular misalignment), and to ensure that there is no accommodative meiosis. Provided the test is performed properly, the examiner is able to see that there is pupillary dilatation on the side of a unilateral optic neuropathy when the light source returns to that side. Neutral density filters can be used, first, to measure the severity of the RAPD and, second, to bring it out if by regular testing the result is equivocal. The grading of RAPD is as follows:

A

B

Grade 1: weak initial contraction followed by a greater redilatation 0.4 log unit Grade 2: a slight stall in movement followed by dilatation 0.7 log unit Grade 3: immediate pupillary dilatation 1.1 log units Grade 4: pupillary dilatation during prolonged illumination of the good eye for 6 seconds 2.0 log units Grade 5: no signs of constriction no light transmission Pupillography, in which infrared cameras are used to measure pupil size and shape in darkness and light, can be used to measure pupillary reaction times, amplitude, and latency.

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Figure 21–10. Pupillary responses in Horner’s syndrome (A) in light, (B) in dark, (C) following instillation of 10% cocaine, and (D) following instillation of 1% hydroxamphetamine; the lesion is postganglionic.

Pharmacological Testing Horner’s syndrome consists of meiosis and ipsilateral partial ptosis, apparent enophthalmos, and absence of sweating of the face ipsilaterally. The anisocoria is more evident in dark than in the light. The direct responses are normal. There is a failure of the affected pupil to dilate with 10% cocaine solution. Hydroxyamphetamine 1% dilates the affected pupil if the lesion is central or preganglionic, and no response occurs if the lesion is postganglionic (Fig. 21-10). Holmes-Adie syndrome consists of subacute severe mydriasis, which partially resolves over many months. It is associated with absent reflexes and rarely autonomic failure (Ross syndrome). The anisocoria is more marked in light than in dark. Pupils are tonic; denervation is rarely complete so vermiform movements (movements of the parts of the iris that have not been denervated) can be seen on slit lamp examination. Pilocarpine 0.1% constricts the affected pupil more than the normal owing to denervation supersensitivity (Fig. 21−11). Tonic pupils also occur following damage due to trauma and more commonly to inflammation due to viral infections and uveitis. A partial third nerve palsy manifested only as mydriasis does not show denervation hypersensitivity and so does not constrict with 0.1% pilocarpine but does with 1.0%. Finally, a pharmacologically mediated mydriasis will fail to constrict with 1% pilocarpine. In essential anisocoria, the pupils are usually the same size in light and dark; this may be more apparent in dark but not to the same degree as with Horner’s syndrome. There are normal responses to cocaine (Fig. 21−12).

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Figure 21–11. Pupillary responses in tonic pupil (A) in light, (B) in dark, and (C) following instillation of 0.1% pilocarpine solution.

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mesencephalic dysfunction. When entirely lone, they may be associated with Cogan’s twitch.

A

Oculomotor Fascicle or Nerve Lesions Fascicle lesions occur with other central signs such as contralateral hemiparesis or cerebellar signs. Pupils are often but not always affected. Nerve lesions usually but not always are associated with other signs, although these may be minimal even when aneurysm or pituitary adenoma is the cause.

B

Lesions of the Oculosympathetic Pathway These lesions cause ipsilateral Horner’s syndrome.

Neuromuscular Ptosis C ■

Figure 21–12. Pupillary responses in essential anisocoria (A) in

Examples include myasthenia gravis and, much less frequently, Eaton-Lambert syndrome.

light, (B) in dark, and (C) following instillation of 10% cocaine.

Myopathic Ptosis EYELIDS The eyelids are held open predominantly by levator palpebrae superioris, innervated by fibers of the superior division of the oculomotor nerve, which arise in the dorsocaudal nucleus in the midbrain. Hence, lid function may be spared or, alternately, the only presenting manifestation of differently situated midbrain lesions; a lesion of the dorsocaudal nucleus itself causes bilateral complete ptosis. Müller’s muscle is a thin sheet of smooth muscle fibers that attaches the levator to the upper tarsus and is innervated by the sympathetic nerve. The two eyelids are yoked, resulting in synkinetic and symmetrical movement alongside change in gaze, although compensatory lid retraction on the nondiseased side is not common. When the patient is looking forward, the palpebral fissures should be the same and 12 to 15 mm in vertical length. Levator function is assessed by asking the patient to look into extreme downgaze and then extreme upgaze, and the excursion of the eyelid is measured; normal levator function is 12 to 17 mm of movement. Diminished levator function is not due to levator disinsertion or an acquired aponeurotic defect of eyelid control but only to neurogenic or myopathic processes. In aponeurotic ptosis, the levator function is normal and the height of the lid crease is often noticeably greater on the ptotic side. The severity of the ptosis tends to increase in downgaze. It is common in the elderly and in patients following ophthalmic surgery such as cataract extraction, glaucoma procedures, and orbital or eyelid surgery.

Neurogenic Ptosis Central Lesions Cortical lesions are usually unilateral and contralateral, usually temporal and frontal lesions, and occasionally bilateral. Midbrain lesions of the dorsocaudal nucleus are usually bilateral and complete and are associated with other signs of

Congenital myopathic ptosis is only rarely neurogenic and is more often associated with a developmental abnormality of the levator muscle. There is a family history in 15% of cases and 20% of cases are bilateral. Often, there are other ocular problems, particularly superior rectus underaction. Acquired myopathic ptosis includes chronic progressive external ophthalmoplegia (CPEO), myotonic dystrophy, and oculopharyngeal dystrophy. Exophalmos, arising, for example, due to dysthyroid eye disease or to an orbital mass, can be assessed by comparing the supraorbital ridges of the patient from above and more precisely using an exophthalmometer.

OCULOMOTOR SYSTEM Fixation The patient is asked to fixate on a target such as the top letter of the Snellen chart and the efficiency of fixation with both eyes open; then each eye is observed with the other covered. Latent nystagmus and a change of fixation due to phoria can also be seen thus. Further examination of the eyes with fixation eliminated using Frenzel goggles is helpful because vestibular nystagmus is always accentuated under these circumstances. Standard clinical tests of vestibular function such as Hallpike’s maneuver and caloric testing are also important.

Smooth Pursuit The patient is asked to fix on a target such as a pen top or hat pin while it is moved slowly and at steady speed from side to side. Those with abnormalities of smooth pursuit show corrective “catch up” saccades and the pursuit becomes fragmented. An optokinetic drum also shows up abnormalities on one side (there will be fewer corrective saccades on that side). In patients with nystagmus, pursuit can be tested by testing for suppres-

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sion of the vestibulo-ocular reflex; the patient is asked to fixate on the thumb with the arm outstretched while he rotates the head. With abnormalities, there are corrective saccades because the eyes will be taken off track by the slow phase of the vestibulo-ocular reflex.

Vestibulo-ocular Reflex Vigorous head shaking from side to side and then up and down with Frenzel goggles shows abnormalities were there to be a unilateral peripheral vestibular disorder; there may be a brief run of jerk nystagmus with the slow phase in the direction of the abnormality. This may not arise in acute lesions in which complete canal paresis occurs or in bilateral disorders or in central disorders. In central disorders, horizontal head shaking may induce vertical nystagmus. The vestibulo-ocular reflex may be tested at the bedside when the patient fixes on a target and the examiner moves the head rapidly in one or another sideway direction. When the vestibulo-ocular reflex is normal, gaze is held steadily; with a lesion on one side, a corrective saccade arises at the end of the head movement. Visual symptoms due to vestibular problems can also be tested by asking the patient to fix on a Snellen chart while the head is moved from side to side and then up and down at a steady state at about 2 cycles per second: with abnormalities of vestibular gain, a deterioration in acuity of several lines ensues.

Examination of Saccades The patient is asked to fix alternately on two objects (a finger and a nose, a finger and a thumb) placed in horizontal and then vertical planes. The examiner initiates the movement with a command. Attention is made to the character of the movement and its conjugacy, velocity, and accuracy. Slowing can readily be appreciated in this setting or when using a hand-held optokinetic drum. Saccadic latency (the time taken after instruction to initiating the saccade) may be abnormal in reduced levels of consciousness or disorders of attention. It also occurs in Huntington’s disease, Parkinson’s disease, ocular motor apraxia, conditions such as Balint’s syndrome, or the congenital type. Saccadic dysmetria occurs when there is inaccuracy in fixation; hypermetria occurs when there is an overshoot; and hypometria occurs when there is an undershoot. Dysmetric saccades are usually followed by a corrective saccade. Saccadic dysmetria arises in brainstem and cerebellar pathologies, in drowsiness and drug-induced states, and in field defects due to visual pathway lesions.

Saccadic Intrusions Square-wave jerks are involuntary saccades in which the eye moves from its position of fixation and then returns to the correct position after a normal intersaccadic interval (of 130 to 200 milliseconds). When these are small, they are not abnormal, but larger squarewave jerks (of 1 to 5 degrees) are more frequent and are readily seen during a clinical examination of fixation. These arise in cerebellar disorders, progressive supranuclear palsy, and Huntington’s disease. Much larger intrusions, so-called macrosquare wave jerks (of 10 to 40

degrees), have an intersaccadic latency of 100 milliseconds. These arise most commonly in the cerebellar form of multiple system atrophy (MSA-C) and multiple sclerosis. When large saccadic intrusions occur back-to-back in multiples (three to five), without an intersaccadic interval, a condition known as ocular flutter arises; if the condition is manifest as a series of saccadic intrusions in all directions, it is known as opsoclonus. These conditions occur in a variety of brainstem lesions and are due to abnormalities of the pause cells within the pons.

EXAMINATION OF DIPLOPIA The patient is asked to follow a target through its range of movements in the nine directions of gaze. One eye is tested at a time (ductions) and then both are tested together (versions). The patient is asked to comment on the presence and severity of diplopia during version testing, and the eyes are examined for evidence for paresis. The patient notes that the diplopic image is displaced in the direction of the paresis when the direction of gaze is that of the paresis. Covering one eye with a red filter often helps to determine which image is which. Orthoptists use other tests such as the Maddox rod or the Hess chart.

Alternate Cover Test This is most helpful in subtle abnormalities of vergence because when one eye and then the other eye are covered, the patient fixing on a target, the uncovered eye will be required to perform a corrective saccade in order to regain fixation, and so small movements in both horizontal and vertical directions may be seen. Esotropia and exotropia refer to outward and inward movements of the uncovered eye, respectively, when there is a horizontal deviation and hypotropia and hypertropia when there is a vertical one. When the eyes appear not to be misaligned but nonetheless a refixation movement occurs at the alternate cover test, the movement is termed a phoria. The extent of the tropia can be measured in diopters using a prism to correct the diplopia.

Bielschowsky’s Head-Tilt Test This test is undertaken in four stages: 1. Identification of the site of the hyperphoria 2. Identification of whether the deviation is greater in the right or left gaze 3. Identification of whether the deviation is greater in the up or down gaze 4. Measurement of the size of the deviation with the head tilted to the right or to the left In the first stage, the patient is examined with the alternate cover test in the primary position of gaze and this reveals a right-over-left hyperphoria; either the depressors of the right (superior oblique and inferior rectus) or the elevators of the left (inferior oblique and superior rectus) are weak (Fig. 21-13). The second stage, in which the patient is examined again with the alternate cover test but in the left and then right gaze, the right-over-left deviation increases on the left gaze. Hence, the oblique muscles, which exert a greater influence on vertical eye movements in adduction, and the recti, which exert a

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Figure 21–13. Diagram of the Bielschowsky maneuver. This patient has a right IV neuropathy.

greater influence in abduction, can be differentiated. In this case, the right hyperphoria increases in left gaze, so either the right superior oblique or the left superior rectus must be weak. In the third stage, the patient is asked to look up then down in left gaze. If the hyperphoria increases in downgaze, then the oblique is weak; if the hyperphoria increases in upgaze, the rectus must be weak. In this case, the diagnosis is a right superior oblique palsy. The fourth stage measures its severity, the degree of head tilt to the left required to correct the vertical diplopia. This works well for acute palsies, but in longstanding cases, changes in the tone of the reciprocally innervated muscles may give differing abnormalities.

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The neuro-ophthalmological examination is intricate and requires care and practice to perform it well.

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All of the examination can readily be performed at the bedside or in the office with only a few pieces of equipment.

The neurological examination of the visual system begins only after the ophthalmic examination of the visual system has been completed. Corneal abnormalities, lens opacities, and retinal problems can all cause blurring or distortion of vision, which are entirely unrelated to the structure and function of those parts of the nervous system that are responsible for the appreciation of vision.

Suggested Reading Digre KB: Principles and techniques of examination of the pupils, accommodation and the lacrimal system. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-ophthalmology, 5th ed. Baltimore: Williams and Wilkins, 1998, pp 933-961. Johnson CA, Keltner JL: Principles and techniques of examination of the visual sensory system. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-ophthalmology, 5th ed. Baltimore: Williams and Wilkins, 1998, pp 153-237. Leigh RJ, Zee DS: The Neurology of Eye Movements, 2nd ed. Philadelphia: FA Davis, 1991.

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John B. Kerrison and Nancy J. Newman

The study of genetic diseases offers an opportunity to understand the pathophysiology at the molecular level. Identification of genetic defects that lead to clinical syndromes and how a syndrome can be caused by a variety of genetic defects offer powerful insight. In addition, such insights offer a rationale for therapeutic target development. The visual sensory system has been an area of genetic investigation by well-known pioneers including Horner, Leber, Nettleship, Sorsby, Tay, Usher, and Waardenberg. Many basic genetic mechanisms were initially demonstrated in ocular diseases, including X-linked recessive inheritance for color blindness, cytoplasmic inheritance of optic atrophy, inactivation of a single X chromosome in the mosaic pigmentary pattern in females heterozygous for ocular albinism, the two-hit hypothesis of hereditary retinoblastoma, and triallelic inheritance in Usher’s syndrome. A variety of genetic diseases may lead to blindness by affecting the entire globe, primarily the anterior segment (cornea and lens), or primarily the posterior segment (retina and optic nerve) of the eye. Disorders of the globe are often caused by abnormal closure of the fetal fissure resulting in colobomatous malformations and microphthalmia. Nanophthalmos refers to a small but normally formed eye. Anophthalmia, or absence of the eye, results from failure of outgrowth of the primary optic vesicle. Congenital genetic blinding disorders of the anterior segment include congenital cataracts; the Axenfeld-Riger spectrum, which encompasses a variety of anterior segment malformations involving the cornea, anterior chamber angle, and the iris; and Peter’s anomaly, consisting of a central corneal leukoma with varying amounts of iris and lens attachments. Progressive genetic disorders affecting the anterior segment include a variety of corneal dystrophies with gradual deposition of amyloid, mucopolysaccharide, or other components into the cornea. Neural genetic blindness arises from disorders affecting the retina and optic nerve. To a lesser extent, retrogeniculate genetic disorders may affect the vision but often have other neurological manifestations as well. Retina and optic nerve disorders are the focus of this chapter. A highly recommended and thorough discussion of ophthalmic genetics is available in Traboulsi (1998).

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HOW DO PATIENTS WITH NEURAL GENETIC BLINDNESS PRESENT? Genetic blinding diseases may manifest with isolated visual loss or with vision loss as the most prominent manifestation. For example, a patient with bilateral progressive vision loss and a clinical picture of retinitis pigmentosa may, on further questioning, complain of weakness and ataxia leading to a diagnosis of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa). Such patients with primarily visual symptoms generally present to the ophthalmologist, although other features commonly require neurological consultation. In some patients with slowly progressive vision loss with an onset in childhood or early adulthood, ophthalmological findings may be subclinical. Such patients may discover reduced visual acuity on a vision screening test, whether at school or when obtaining a driver’s license. Such patients are then referred for ophthalmological investigation. In other cases, patients with primarily neurological complaints of weakness, numbness, or ataxia may present to the neurologist with a peripheral neuropathy and not be aware of any significant visual loss. An ophthalmological examination might demonstrate a mild bilateral optic neuropathy and suggests Charçot-Marie-Tooth syndrome. Whether patients with a genetically blinding disease present to the ophthalmologist or the neurologist, it is important that patients in whom a genetically blinding disease is suspected undergo a complete evaluation.

CLASSIFICATION OF GENETIC DISEASE Genetically blinding disorders may be classified by localization of vision loss, age of onset, pattern of inheritance, or presence of other symptoms. No single classification is entirely satisfactory. From a clinical point of view, all of these parameters are essential to establishing the diagnosis. We have organized this discussion based on whether the disease primarily affects the retina or optic nerve and the age of onset. Those disorders with prominent neurological or systemic involvement are considered separately.

chapter 22 genetic causes of blindness LOCALIZATION IN THE VISUAL SENSORY SYSTEM Vision loss may occur anywhere in the neural visual sensory system including the retina, optic nerve, chiasm, optic tract, lateral geniculate nucleus, visual radiations, or visual cortex. Most genetic causes of blindness affect the retina or optic nerve. Localization to the retina or optic nerve can usually be confirmed by a comprehensive ophthalmological evaluation but may require ancillary testing. These disorders are typically bilateral and associated with multiple parameters of decreased visual function: visual acuity, color vision, and visual field. The primary distinction between retinal and optic nerve disease is made on ophthalmoscopy with direct observation of the pathology. In several instances, there may no visible abnormalities on ophthalmoscopy, and electrophysiological evaluation with electroretinography (ERG) and visual evoked potential (VEP) is critically important for correct localization.

AGE AT ONSET AND COURSE From a diagnostic point of view, it is useful to consider the age at onset of vision loss. The presence of nystagmus is critical in determining the onset of a potentially blinding genetic disease. Bilateral congenital loss of vision is associated with nystagmus. Nystagmus develops whether the vision loss is caused by genetic or nongenetic mechanisms. Furthermore, nystagmus develops whether the vision loss is due to corneal, lens, retinal, or optic nerve abnormalities. Thus, the nystagmus is thought to arise from abnormal ocular motor adaptation to impaired sensory input. The reason for the development of nystagmus is not understood. Congenital nystagmus most often is caused by Leber’s congenital amaurosis, optic nerve hypoplasia, and ocular albinism. Approximately 10% of patients with congenital nystagmus have no apparent abnormality of the visual sensory system and are referred to as congenital idiopathic or congenital motor nystagmus. The vision in such patients is generally much better than those patients in whom nystagmus is caused by congenital diseases of the retina or optic nerve, probably because the visual loss in the former group of patients is secondary to the nystagmus itself, rather than its cause. Although many well-recognized genetic disorders have their onset and clinical presentation in infancy, others may not be recognized until childhood or early adulthood. Such patients may have subclinical disease or only notice difficulty seeing at night. These disorders are typically slowly progressive and can lead to diagnostic confusion in the early stages when findings are mild. A variety of ancillary testing including electrophysiology and fluorescein angiography can be useful in making a diagnosis. Most genetic diseases are characterized by slowly progressive vision loss. A notable exception to this is Leber’s hereditary optic neuropathy (LHON), which has an acute presentation and may be confused with optic neuritis.

EVALUATION Patients should undergo a complete ophthalmic examination. Refractive errors should be noted as patients with congenital stationary night blindness (CSNB) are myopic whereas patients with Leber’s congenital amaurosis (LCA) are hyperopic. The

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pupil reaction is of interest. Although loss of vision is commonly associated with a reduction in the pupil light reflex and sluggish pupils, the pupils in some congenitally blinding disorders actually constrict in darkness rather than dilate. This finding, referred to as paradoxical pupils, occurs in LCA and CSNB. Color vision testing is abnormal in patients with achromatopsia and cone dystrophy. Additionally, the pattern of visual field loss is often characteristic of the underlying abnormalities. Retinitis pigmentosa tends to produce progressive peripheral constriction of visual fields, whereas cone dystrophy and optic nerve disorders tend to produce central scotomas. Slit lamp biomicroscopy is used to examine for iris transillumination defects by shining a beam of light through the pupil and observing to see if it is reflected through defects in the iris due to lack of pigmentation, as seen in ocular albinism. Ophthalmoscopic examination may reveal a pigmentary retinopathy in patients with retinitis pigmentosa or bilateral optic atrophy in a patient with dominant optic atrophy. In other cases, ophthalmoscopic findings are mild. Many patients with LCA who present in infancy have a normal fundus. Adults with CNSB often have a normal-appearing fundus. ERG is critical in distinguishing these disorders. In macular disease, a multifocal ERG, which can detect focal retinal defects, is more sensitive than a full-field ERG.

RETINAL DISEASES—CONGENITAL Many of the congenital blinding disorders of the retina involve proteins that are members of the phototransduction cascade, primarily affecting photoreceptors. Other disorders affect the structural relationship between the neural retina and the vitreous. LCA is an autosomal recessive syndrome characterized by significantly reduced vision before age one, nystagmus, paradoxical pupillary reactivity, and retinal degeneration. This syndrome has a prevalence of 3:100,000 children and is a common cause of congenital nystagmus. Six LCA-causing genes have been identified, which account for approximately one half of the cases.1 These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The clinical appearance is varying with fundus findings ranging from a retinitis pigmentosa picture with bony spicules to a salt and pepper appearance (Fig. 22−1). Electroretinography (ERG) demonstrates a markedly reduced or nonrecordable scotopic and photopic response, confirming the diagnosis. Although no therapy is presently available, promising gene-based interventions have demonstrated long-term rescue of vision as assessed by psychophysical, behavioral, and molecular biology studies. In a naturally occurring LCA animal model, the RPE65−/− dog, recombinant adenoassociated virus carrying wild-type RPE65 successfully restored visual function.2 Achromatopsia is a rare retinal disorder characterized by a complete absence of cone photoreceptor function. In accordance with the trichromatic theory of vision, individuals with normal color vision can match any color with a combination of three primary colors: red, green, and blue. Dichromats who are missing either the red (protanopes) or green (deuteranopes),

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Figure 22–1. Ophthalmoscopic appearance of the retina in a patient with Leber’s congenital amaurosis caused by mutations in CRB1. (Courtesy of I. H. Maumenee.)

but retain the blue cone function, can only match colors with two primary colors. The red (OPN1LW, opsin 1, long wave sensitive) and green (OPN1MW, opsin 1 medium wave sensitive) photopigments are encoded on the long arm of the X chromosome and, as such, these disorders are transmitted in a pattern of X-linked inheritance. The blue (OPN1SW, opsin 1, short wave sensitive) photopigment is encoded on chromosome 7. Achromats present in infancy with reduced vision, photophobia, total color blindness, nystagmus, and a normal-appearing retina. Achromatopsia refers to a spectrum of disease encompassing complete achromatopsia (rod monochromacy), in which there are no cones; atypical rod monochromacy, in which there are some functioning cones; and blue cone monochromacy, where the red and green photopigments are absent but the blue photopigment is functional. Psychophysical testing in such patients must be performed after age 10 in order to get reproducible results. Genes associated with achromatopsia include CNGA33 and CNGB3,4 encoding the α and β subunits of the cone cyclic nucleotide−gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A third gene identified in achromatopsia is GNAT2,5 encoding the cone specific α unit of transducin, a G protein of the phototransduction cascade. Aniridia is a syndrome in which the most prominent manifestation is absence or hypoplasia of the iris. Importantly, visual acuity is reduced due to hypoplasia of the fovea, macula, or

optic nerve. Patients present with reduced visual acuity, elevated intraocular pressure, and nystagmus and may develop cataract, glaucoma, keratopathy, strabismus, and amblyopia. Aniridia is caused by mutations in PAX6, a homeobox gene on chromosome 11.6 The homeobox encodes the homeodomain, a protein domain that binds DNA and regulates the transcription of other genes. Aniridia is inherited as an autosomal dominant disorder. WAGR syndrome consists of Wilm’s tumor, aniridia, genitourinary abnormalities, and retardation, resulting from a deletion on chromosome 11p. Albinism is traditionally divided into oculocutaneous albinism and ocular albinism. Oculocutaneous albinism is autosomal recessive and has been divided into tyrosinasepositive and -negative forms. Tyrosinase catalyzes three steps in a series of reactions in the melanosome that lead to the formation of melanin from its precursor tyrosine. Major oculocutaneous albinism syndromes include HermanskyPudlak syndrome and Chediak-Higashi syndrome, which are inherited in autosomal recessive manner. Nettleship-Falls ocular albinism is an X-linked recessive disorder characterized by reduced visual acuity, congenital nystagmus, transillumination defects of the iris (Fig. 22−2), hypopigmentation of the uveal tract and retinal pigment epithelium, hypoplasia of the fovea, and abnormal decussation of optic nerve fibers through the chiasm. Strabismus and refractive abnormalities are common. Ocular albinism is caused by mutations in OA1, a member of the G protein−coupled receptor superfamily.7 Hereditary vitreoretinopathies are characterized by degenerative changes involving the vitreous and retina. These include familial exudative vitreoretinopathy, Goldmann-Favre syndrome, Stickler’s syndrome, Knobloch’s syndrome, and Norrie disease. Familial exudative vitreoretinopathy (FEVR) has features similar to retinopathy of prematurity but without premature birth or supplemental oxygen. This autosomal dominant disorder is caused by mutations in the frizzled-4 gene (FZD4)8 and is characterized by peripheral retinal vascular nonperfusion, exudative retinal detachment, and proliferative, cicatricial vitreoretinopathy. With severe loss of vision, patients develop nystagmus and strabismus. Goldmann-Favre syndrome is an autosomal recessive disorder caused by mutations in the nuclear receptor gene NR2E3 with characteristic features of retinitis pigmentosa along with central and peripheral retinoschisis, a splitting of the retina. Stickler’s syndrome, a progressive hereditary arthro-ophthalmopathy, is characterized by high myopia, vitreous degeneration, and retinal detachment (Fig. 22−3) in association with orofacial abnormalities such as Pierre-Robin sequence and musculoskeletal abnormalities such

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Figure 22–2. In a patient with albinism, transillumination of the globe demonstrates the absence of pigment in the iris (left). On ophthalmoscopic examination of the retina, the lack of pigmentation in the retinal pigment epithelium allows easy visualization of the choroidal vessels (right). (Courtesy of I. H. Maumenee.)

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Figure 22–3. Fundus appearance of a total retinal detachment in a patient with Stickler’s syndrome. (Courtesy of I. H. Maumenee.)

as arthritis, scoliosis, and arachnodactyly. It is inherited as an autosomal dominant disorder and caused by mutations in type II collagen (COL2A1). Knobloch’s syndrome is characterized by high myopia, vitroretinal degeneration with retinal detachment, and occipital encephalocele and is caused by a mutation in collagen XVIII (COL18A1). Norrie’s disease is characterized by mental retardation and bilateral retinal detachment presenting early in life. It is inherited as an X-linked disorder caused by mutations in the Norrie gene, which is thought to interact with the FZD4 gene.

RETINAL DISEASES—ONSET IN CHILDHOOD AND ADULTHOOD Retinitis pigmentosa (RP) encompasses a variety of disorders that primarily affect rod photoreceptors. Although a pigmentary retinopathy may occur as a feature of a variety of multisystem diseases discussed at the end of the chapter, it may also occur as an isolated disorder of the retina. Initial vision loss in RP occurs in the midperipheral visual field and initial retinal pathology in the postequatorial fundus. In contrast, cone dystrophies refer to those photoreceptor disorders primarily affecting cones and initially involving the macula. There is considerable overlap between these entities. Inability to see as clearly in dim light as in bright light (nyctalopia) is the initial symptom of the rod dystrophies, followed by loss of peripheral vision. The fundus initially has a gray discoloration at the level of the retinal pigment epithelium (RPE) in areas corresponding to vision loss. With time, pigmented cells migrate into the retina aggregating around blood vessels leading to the characteristic bone spicule appearance and a “waxy” pallor of the optic nerve. The most common hereditary form of RP is autosomal recessive (60%), followed by autosomal dominant (10% to 25%) and X-linked (5% to 18%). The X-linked and recessive forms are more severe than autosomal dominant RP. The first gene

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determined to be mutated in RP was rhodopsin.9 Other genes include peripherin, tissue inhibitor of metalloproteinase, and geronyl-geronyl transferase. More than 20 genes causing RP have been identified. In contrast to retinitis pigmentosa, patients with cone dystrophies present with symptoms of blurred vision and inability to see as clearly in bright light as in dim light (hemeralopia). On examination, patients have central loss of vision which manifests as a reduction in visual acuity or a central scotoma on visual field testing and loss of color vision due to degenerative disease of the cone photoreceptors. In early stages, it may be difficult to diagnose because of a normal appearing ophthalmoscopic examination. Patients eventually develop a pigmentary degeneration of the macula, often described as a bull’s eye maculopathy. In many instances, optic pallor develops, leading one to suspect optic nerve disease rather than retinal disease. The ability to diagnose cone dystrophies in the early stages prior to ophthalmoscopically evident retinal pathology has been advanced by the use of multifocal ERG. Well-known toxicities associated with degenerative cone disease include chloroquine and digoxin. Cone degenerations may be inherited in an autosomal or Xlinked pattern. Genes identified as causing cone degenerations include guanylate cyclase activator-1A (GUCA1A), retinitis pigmentosa GTPase regulator (RPGR), and the CRX gene, a homeobox gene expressed in photoreceptors. Juvenile retinoschisis is an X-linked recessive disorder that manifests in childhood with reduction in visual acuity. The characteristic macular abnormality is a cystlike appearance with spoke like extensions from the fovea. It is highly penetrant in males, whereas carrier females rarely show macular pathology. It is caused by mutations that lead to the pathological development of a schisis or splitting of the retina in the nerve fiber layer. The RS gene is implicated in cell-cell adhesion and phospholipid binding.10 Stargardt’s disease is a storage disease of the retinal pigment epithelium that leads to bilateral progressive loss of central visual acuity. Stargardt’s disease is an autosomal recessive disorder caused by mutations in the ABCR4 gene, encoding an ATP-binding cassette (ABC) transporter.11 Patients often present in the second decade of life with unexplained reduction in visual acuity. Features include subretinal yellow pisiform flecks, referred to as fundus flavimaculatus, and macular changes including increased granularity and a “beaten metal” appearance. ERG shows a moderately reduced photopic response and a nearly normal scotopic response. Fluorescein angiography is important in establishing the diagnosis, demonstrating a “silent choroid sign,” which refers to the darkened appearance of the choroid due to blockage by diffuse storage of material at the RPE (Fig. 22−4). Best’s vitelliform macular dystrophy is an autosomal dominant disease characterized by the development of an eggyellow, slightly raised lesion in the macula that is usually 1 to 3 disc diameters in size. Patients may experience blurred central vision and metamorphopsia. Although the fundus appearance is often dramatic, the visual acuity is often better than 20/40. An abnormal electro-oculogram, which measures the electrical potential across the retinal pigment epithelium, is particularly helpful in the diagnosis of patients. The macular abnormality evolves with time from an “egg yolk” appearance to a “scrambled egg” appearance to a late cicatricial stage. Mutations in VMD2, a gene encoding the bestrophin protein,

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Figure 22–4. Fluorescein angiogram is performed by injecting fluorescein dye into the vein of a patient and taking a series of photographs as the dye passes through the retinal and choroidal vasculature. In a normal ocular fundus, a “background” of fluorescence emanating form the choroid is observed (left). In a patient with Stargardt’s disease (right), fluorescence is “blocked” by deposits in the RPE and referred to as a “dark choroid.” The arrowhead in the right photograph indicates an area of early and late central hyperfluorescence in a bull’s-eye pattern. (Right, reprinted with permission from Margalit E, Sunness JS, Green WR, et al. Stargardt disease in a patient with retinoblastoma. Arch Ophthalmol 2003; 121:1643-1646. Copyright 2003 American Medical Association. All rights reserved.)

have been associated with Best’s disease. Bestrophin localizes to the basolateral plasma membrane of RPE cells12 and is likely involved in chloride ion conductance. Congenital stationary night blindness (CSNB) describes a group of retinal diseases characterized by nyctalopia without progressive retinal degeneration. CSNB may be inherited in an autosomal dominant or X-linked pattern. Two types of ERG abnormalities that may be observed in different subtypes of CSNB are (1) a reduced scotopic ERG waveform in the dark adapted ERG or (2) absence of the b-wave on a dark-adapted bright-flash ERG referred to as a “negative” waveform. Autosomal dominant CSNB has been associated with mutations in either the α or β subunit of rod cGMP phosphodiesterase as well as the rhodopsin gene. X-linked CSNB patients have a myopic tigroid-appearing fundus and congenital nystagmus. The visual acuity is typically better than 20/40. It is caused by mutations in NYX, encoding nyctalopin, and a retina-specific calcium channel α1 subunit gene (CACNA1F).13 Although the typical CSNB fundus doe not have any significant pathologicalfeatures, two types of CSNB stand out. Fundus albipunctatus is a type of CSNB inherited in an autosomal recessive pattern that shows distinct, impressive white, round flecks scattered throughout the fundus. Oguchi’s disease is inherited as an autosomal recessive disorder in which the macular retina has an abnormally dark appearance compared with the rest of the fundus, an appearance that disappears with dark adaptation. It is caused by mutations in the arrestin gene. Choroideremia is an X-linked progressive chorioretinal degeneration characterized by progressive nyctalopia and peripheral vision loss. The fundus undergoes progressive atrophy of the choriocapillaris, the retinal pigment epithelium, and photoreceptors that gradually encroaches on the macula. The appearance is very similar to gyrate atrophy of the retina and choroid. Choroideremia is caused by a mutation in the Rab escort protein-1 gene (REP-1) of geranylgeranyl transferase. This enzyme catalyzes the addition of 20 carbon groups to two cysteines at the carboxyl terminus of Rab proteins.

OPTIC NERVE DISEASES—CONGENITAL Optic nerve hypoplasia may be observed with normal visual acuity in association with a subtle visual field defect or manifest with profound visual loss (Fig. 22−5). In childhood, optic nerve hypoplasia may manifest as a unilateral decrease in vision diagnosed initially as amblyopia or bilateral decreased vision in infancy diagnosed initially as congenital nystagmus. In these instances, it is important to recognize its association with midline forebrain abnormalities, which can result in pituitary hormone deficiencies and even sudden death. Both teratogenic and genetic etiologies have been described. Recognized teratogens associated with optic nerve hypoplasia include alcohol, quinine, and anticonvulsants. Maternal insulin-dependent diabetes mellitus is associated with superior segmental optic nerve hypoplasia as well. Optic nerve hypoplasia has also been observed in association with many ocular and systemic syndromes including chromosomal duplications and deletions. Septo-optic dysplasia (de Morsier’s syndrome) refers to the association of hypoplasia of the anterior visual pathways, absence of the septum pellucidum, and thinning or agenesis of the corpus callosum. Although familial cases have been reported, most cases are sporadic. Mutations in the homeobox containing transcription factor, HESX1, have been implicated with homozygous inheritance, causing the more severe phenotype, and heterozygous inheritance, causing a mild phenotype.14,15 Mutations in PAX6 have been observed with a variety of optic nerve abnormalities including coloboma, morning glory disc anomaly, optic-nerve hypoplasia/aplasia, and persistent hyperplastic primary vitreous.16 Papillorenal syndrome (renal-coloboma syndrome) is a primary dysgenesis that causes vascular abnormalities predominantly affecting the eye, kidney, and urinary tract. The characteristic optic nerve finding in papillorenal syndrome is an absence or attenuation of the central retinal vessels within the optic nerves, with multiple compensatory cilioretinal vessels. Although the abnormality in these patients has been

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Figure 22–5. The optic nerve on the left is hypoplastic. For comparison, a normal optic nerve is shown on the right. Both optic nerves are from the right eye.

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Figure 22–6. A 10-year-old boy presents with a visual acuity of 20/40, bilateral central scotomas, and bilateral temporal optic atrophy (right and left eyes). His father has similar findings. Genetic testing revealed a mutation in OPA1.

referred to as a coloboma, it is not a true coloboma arising from failure of closure of the optic nerve fissure with superonasal displacement of the central retinal vessels.17,18 Papillorenal syndrome is inherited in an autosomal dominant pattern. Mutations in PAX2 have been identified in papillorenal syndrome,19 but it is a heterogeneous disease. Patients should undergo renal function testing including serum creatinine and urea nitrogen measurements, urinalysis to test for microalbuminuria, and renal ultrasound.

OPTIC NERVE—ONSET IN CHILDHOOD AND ADULTHOOD Autosomal dominant optic atrophy is characterized by bilateral insidious vision loss often manifesting in the first or second decade of life. It is inherited in an autosomal dominant pattern

with high penetrance. OPA1, located on the long arm of chromosome 3, accounts for the majority of cases, although there is evidence of genetic heterogeneity. The protein is a dynamin-related GTPase targeted to mitochondria, further demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.20,21 At presentation, the visual acuity is typically 20/40 to 20/60, bilateral, and symmetrical. There is an insidious progression of vision loss, although final visual acuity may vary from 20/20 to no light perception. Most individuals retain a visual acuity of 20/40 to 20/200. Color vision testing has demonstrated a characteristic tritanopic-type deficiency, although a generalized dyschromatopsia is most common. Visual field defects include central and cecocentral scotomas. Optic atrophy is present, often localized to the temporal portion of the optic nerve (Fig. 22−6). Other than sensineural hearing loss, neurological or systemic findings are uncommon.

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The differential diagnosis includes nutritional deficiency, toxic optic neuropathy, and macular dystrophy. Diagnosis is based on family history and clinical examination. Genetic testing has not become widely available for this disorder. Unfortunately, no treatments are available at the present time to prevent vision loss, arrest the progression of vision loss, or restore vision. Wolfram’s disease is an autosomal recessive disease caused by mutations in WFS1 which encodes an integral membrane glycoprotein that localizes primarily in the endoplasmic reticulum.22 The most consistent criteria for diagnosis of this syndrome are juvenile-onset diabetes mellitus and optic atrophy. However, other findings include diabetes insipidus and sensory neural hearing loss. The constellation of findings has led to the acronym DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness. Less commonly recognized features include central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure, startle myoclonus, axial rigidity, and Parinaud’s syndrome.23 Behr’s disease is an autosomal recessive syndrome of optic atrophy, beginning in the first decade of life, associated with pyramidal tract signs, ataxia, mental retardation, nystagmus, urinary incontinence, and pes cavus. Behr’s disease may represent a phenotype that is common to several genetic disorders that are likely metabolic in origin. Methylglutaconic aciduria, diagnosed by increased amounts of 3-methylglutaconic and 3methylglutaric acid in urine, may manifest with this constellation of findings.24 X-linked optic atrophy patients present with vision loss in early childhood, which may be progressive. This rare disease is often associated with other neurological findings, including ataxia, tremor, sensineural deafness, and polyneuropathy.25 Leber’s hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy with bilateral vision loss, typically occurring in young men. LHON is caused by point mutations in the mitochondrial genome at nucleotide positions 3460,26 11778,27,28 and 1448429 in genes encoding subunits of complex I of the respiratory chain, with the 11778 mutation accounting for the majority of cases. As mitochondria are only transmitted by the mother to all offspring, the typical rules of mendelian inheritance do not apply. All children of maternal carriers are at risk of vision loss, although male children are at greater risk of vision loss than their female siblings. The offspring of male carriers are not at risk for vision loss. Vision loss typically begins painlessly in one eye, progressively worsening over a few weeks. Although some individuals subjectively describe visual loss as sudden and complete, others describe progression over the course of a few weeks. Almost all patients develop vision loss in the fellow eye, usually within 6 months of the vision loss in the first eye. Typically, no other symptoms occur at the time of vision loss. Visual acuity is commonly worse than 20/200 in each eye with bilateral central scotomas. On ophthalmoscopy, the optic nerve may appear normal or have a characteristic abnormality that has been described as a triad of circumpapillary telangiectasia (Fig. 22−7), swelling of the nerve fiber layer around the disc, and absence of leakage on fluorescein angiography. The optic nerve progresses to optic atrophy with nonglaucomatous cupping, pallor, and arteriole attenuation. In rare individuals, associated neurological abnormalities may be present such as pathological reflexes, mild cerebellar

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Figure 22–7. The right optic nerve from a patient with Leber’s hereditary optic neuropathy demonstrates circumpapillary telangiectasia and a prominent peripapillary nerve fiber layer.

ataxia, tremor, movement disorders, muscle wasting, and distal sensory neuropathy. In a few pedigrees, more severe neurological deficits may be present such as dystonia, spasticity, and encephalopathic episodes. In addition to neurological abnormalities, some patients may have cardiac conduction defects, and patients should undergo electrocardiography. Patients generally present with unilateral acute or subacute vision loss. The differential diagnosis includes optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, and neoplasm. Definitive diagnosis is made by genetic testing. The prognosis for restoration of vision is typically poor for these individuals. Nevertheless, some individuals may recover vision spontaneously, even years later. Unfortunately, no treatments are available at the present time to prevent vision loss, arrest the progression of vision loss, or restore vision.

RETINOPATHY AND OPTIC NEUROPATHY ASSOCIATED WITH SYSTEMIC AND NEURODEGENERATIVE DISEASE A variety of genetic disorders lead to vision loss in addition to other systemic and neurological symptoms. These include metabolic defects of amino acid, protein, and lipoprotein metabolism; lysosomal storage diseases; lipid metabolic disorders; peroxisomal diseases; mitochondrial genetic disease; neuronal ceroid lipofuscinosis; other neurodegenerative disorders; and a variety of disorders with prominent systemic manifestations. Disorders of amino acid, protein, and lipoprotein metabolism may lead to blindness from retinal degeneration. Gyrate

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Figure 22–8. Corneal clouding is a prominent feature of many lysosomal storage diseases, particularly mucopolysaccharidoses. The picture is from a patient with Maroteaux-Lamy syndrome. (Courtesy of I. H. Maumenee).

atrophy of the retina and choroid is an autosomal recessive disease due to a defect in ornithine aminotransferase leading to serum hyperornithemia. It leads to geographic and roundshaped areas of chorioretinal atrophy that begin peripherally and progress centrally. Cystinosis is an autosomal recessive disease characterized by progressive renal failure, pigmentary retinopathy, and growth retardation due to a deposition of cysteine crystals throughout the body. It is caused by a lysosomal defect preventing transport of cysteine crystals from the lysosome to the cytosol. Cysteine crystals are also deposited in the cornea leading to significant photophobia. Methylmalonic aciduria and homocystinuria result in a pigmentary retinopathy and optic nerve pallor due to an abnormality in cobalamin metabolism. Abetalipoproteinemia is an autosomal recessive disorder associated with a pigmentary retinopathy in which patients have fat malabsorption, progressive ataxia, and abnormal plasma lipids due to deficient beta lipoproteins and chylomicons. Lysosomal storage diseases are caused by enzymatic defects that lead to an accumulation of partially degraded intermediates in cells, tissues, and organs leading to dysfunction. They are generally inherited in an autosomal recessive manner. Mucopolysaccharidoses are caused by defects in specific lysosomal enzymes involved in the degradation of glycosaminoglycans or mucopolysaccharides. General features include facial dysmorphic changes, mental retardation, corneal clouding (Fig. 22−8), and retinal degeneration. Optic disc swelling and optic atrophy are also features of mucopolysaccharidoses. Mucopolysaccharidoses associated with ophthalmological features include Hurler’s syndrome, Scheie’s syndrome, Hunter’s syndrome, Sanfilippo’s syndrome, and Maroteaux-Lamy syndrome. Sialadoses are characterized by the progressive lysosomal storage of sialidated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. There is a progressive accumulation and excretion of sialic acid. Patients develop corneal clouding and a cherry-red spot in the macula. Mucolipidoses have similar features to mucopolysaccharidoses but without mucopolysacchariduria. Patients have a Hurler-like facies, hepatosplenomegaly, and a thickened skull. Major subtypes of mucolipidoses include mucolipidosis II (I cell disease),

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mucolipidosis III, and mucolipidosis IV. Mucolipidosis IV has the most prominent ocular features including corneal clouding and retinal degeneration in addition to hypotonia and psychomotor retardation. Sphingolipidoses are due to an accumulation of glycosphingolipids, an abundant component of neurons. These disorders include the gangliosidoses (GM2 gangliosidoses [type 1: Tay-Sachs disease; type 2: Sandhoff’s disease] and GM1 gangliosidoses [Gaucher’s disease, Farber’s disease, Fabry’s disease, and Neimann-Pick disease]). Tay-Sachs and Sandhoff diseases are notable for the development of a cherry-red spot in the macula in which there is a deep red spot in the fovea surrounded by a ring of opacified retina. In addition, patients have hepatosplenomegaly and skeletal dysostosis. Metachromatic leukodystrophy (MLD) is a lipid metabolic disorder caused by mutations in the arylsulfatase A gene. There are five allelic forms, including late infantile, adult partial cerebroside sulfate deficiency, and pseudo-arylsulfatase deficiency.30 On histopathological staining, there is a metachromatic staining of abnormally stored galactosphingosulfatides in central nervous system white matter. The late infantile form is the most common form of MLD, manifesting in the second year of life with gait disturbance and muscle rigidity. This is followed by progressive mental deterioration and convulsions. A cherry-red spot may be present in the macula and optic atrophy may develop. Peroxisomal disorders are rare disorders affecting multiple tissues, including the eye. These diseases have overlapping clinical manifestations and are classified into two categories. In peroxisome biogenesis disorders, peroxisomal assembly is defective due to abnormal localization of proteins normally targeted to the peroxisomes. This results in severe diseases that commonly affect the retina: Zellweger’s syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum’s disease (IRD). Although these three diseases were described as separate entities before the underlying peroxisomal defect was defined, identification of the underlying molecular defects and better understanding of the resulting biochemical defects, suggest that all three are parts of one spectrum in which ZS represents the more severe form, NALD an intermediate severity, and IRD the least severe. In the most severe form of ZS, children present with seizures, hypotonia, and developmental delay. Ophthalmological abnormalities include cataracts, glaucoma, corneal clouding, pigmentary retinal degeneration, and optic atrophy. In IRD, patients have reduced cognition, hearing loss, and a pigmentary retinopathy. As in classic Refsum’s disease, they have elevated phytanic acid and cholesterol but differ because of the elevation of very-long-chain fatty acids. A second group of peroxisomal disorders are due to gene defects that result in abnormal peroxisome function without affecting its assembly. This group includes entities such as Xlinked adrenoleukodystrophy, primary hyperoxaluria type 1, and classic Refsum’s disease. XLA is characterized by an accumulation of very-long-chain fatty acids of 22 to 30 carbons. Xlinked adrenoleukodystrophy may manifest in childhood with gait disturbance and intellectual deterioration between the ages of 5 and 8. There is impressive inflammation of white matter and demyelination. In latter stages of the disease, patients develop vision loss with optic atrophy. The adult-onset variety of X-linked adrenoleukodystrophy is referred to as adrenomyeloneuropathy. X-linked adrenoleukodystrophy is caused by mutations in ABCD1, a member of the ATP-binding cassette (ABC) transporter superfamily that contains membrane

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Figure 22–9. The nasal fundus of the left eye from a patient with NARP syndrome demonstrates diffuse peripheral bone spicule formation. (Reprinted with permission from Kerrison JB, Biousse V, Newman NJ: Retinopathy of NARP syndrome. Arch Ophthalmol 2000; 118:298. Copyright © 2000 American Medical Association. All rights reserved.)

proteins that translocate a wide variety of substrates across extracellular and intracellular membranes. Primary hyperoxaluria type 1 is an autosomal recessive disorder caused by a defect in the enzyme alanine glyoxylate aminotransferase and characterized by renal failure and elevated intracranial pressure. Patients develop a hyperplasia of the retinal pigment epithelium due to deposition of calcium oxalate crystals. Classic Refsum’s disease is characterized by a pigmentary retinopathy, polyneuropathy, hearing loss, icthyosis, and ataxia due to a defect in phytanoyl-CoA hydroxylase (PAHX) or peroxin-7 (PEX7), which impair the degradation of phytanic acid. Mitochondrial disorders in addition to LHON include NARP, MELAS, and Kearns-Sayre syndrome. NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) is caused by a T-to-G point mutation in nucleotide 8993 of mtDNA, which results in a substitution of a highly conserved leucine by an arginine residue in the mitochondrial ATPase 6 gene.31 As the acronym implies, clinical features include migraine, sensory neuropathy, proximal muscle weakness, ataxia, seizures, dementia, and pigmentary retinopathy (Fig. 22−9). The retinal degeneration in NARP may manifest as a cone-rod dystrophy, a progressive cone dystrophy, a bull’s eye maculopathy, or rodcone type of retinal dystrophy. The severity of NARP appears to correlate with the burden of mutated mitochondria within the population of mitochondria in the cell. The 8993 mutation also causes maternally inherited Leigh disease.32 MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) is caused by a mutation at nucleotide position 3243 affecting the mitochondrial encoded gene for leucine tRNA. Although vision loss in mitochondrial genetic disorders more commonly occurs from retinal degeneration or optic nerve disease, in MELAS, vision loss can occur from damage to the retrochiasmal visual pathways. Other features included diabetes mellitus and deafness. Of note, the A3243G mutation may also be associated with a pigmentary retinopathy or optic neuropathy as well as chronic progressive external ophthalmoplegia (CPEO). Kearns-Sayre syndrome (KSS) is characterized by the triad of external ophthalmoplegia (CPEO), pigmentary retinopathy,

and heart block. Onset is in the first or second decades of life. CPEO is characterized by a bilateral symmetrical ptosis associated with ophthalmoplegia and orbicularis oculi weakness. The pigmentary retinopathy of KSS differs from RP in that the macula is often the first part of the retina to be affected, followed by the retinal periphery. Visual acuity, visual fields, and ERG are usually only mildly affected. Neurological manifestations in KSS may include cerebellar ataxia, hearing loss, dementia, and weakness of facial, pharyngeal, trunk, and extremity muscles. Heart block is a characteristic finding. Skeletal muscle biopsy demonstrates ragged-red fibers. KSS is caused by mitochondrial DNA deletions, usually 1.3 to 7.6 kb in size, affecting 45% to 75% of total mtDNA.33 KSS may be maternally inherited or sporadic. Leigh disease is a subacute necrotizing encephalomyopathy frequently ascribed to mitochondrial respiratory chain deficiency. Patients usually develop an acute or progressive decline in neurological function with characteristic magnetic resonance imaging consisting of symmetrical lesions scattered from the basal ganglia to the brainstem. A pigmentary retinopathy may be present. Although progression of symptoms is expected, some patients may improve. Mutations have been found in many nuclear and mitochondrial encoded genes involved in energy metabolism, specifically oxidative phosphorylation and the generation of ATP. Neuron ceroid lipofuscinoses (NCLs) are a group of typically autosomal recessive disorders characterized by abnormal accumulation of ceroid and lipofuscin in neuronal cells. Six major clinical forms of NCL have been described differing in their age of onset, clinical course, and neuropathological findings. Patients develop progressive psychomotor findings with vision loss being a prominent manifestation. Vision loss in neuronal ceroid lipofuscinosis occurs from both cortical and photoreceptor disease with development of a pigmentary retinopathy, attenuation of blood vessels, and optic atrophy. Diagnosis is made by observation of characteristic inclusions in skin, conjunctival, or rectal biopsy Cerebroretinal neurodegenerative diseases in addition to those discussed can affect the retina and optic nerve to varying degrees. Neurodegenerative disorders that may have pigmentary retinopathy or optic atrophy as a feature include spinocerebellar ataxia, Friedreich’s ataxia, familial dysautonomia, various familial forms of motor and sensory neuropathies, Pelizaeus-Merzbacher disease, Krabbe’s disease, and Hallervorden-Spatz disease.

RETINOPATHY AND OPTIC NEUROPATHY ASSOCIATED WITH DERMATOLOGICAL DISEASE, SKELETAL ANOMALIES, HEARING LOSS, OR RENAL DISEASE Incontinentia pigmenti is an X-linked disorder caused by mutations in a gene encoding necrosis factor-κB essential modulator (NEMO). It manifests in infancy with a bullous dermoid eruption that evolved into characteristic pigmented streaks. Vision loss occurs from retinal vascular occlusions and retinal detachment. Other findings include ischemic or hemorrhagic cerebrovascular events leading to seizures and mental retardation. Cockayne’s syndrome (CS) is an autosomal recessive disorder whose features include dwarfism, precociously senile

chapter 22 genetic causes of blindness appearance, pigmentary retinal degeneration, optic atrophy, deafness, marble epiphyses in some digits, photosensitivity, and mental retardation. Magnetic resonance imaging demonstrates hypomyelination, cerebellar atrophy, and basal ganglia calcification. CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. The CSA and CSB genes are involved with DNA repair. Bardet-Biedel syndrome (BBS) consists of obesity, postaxial polydactyly, hypogonadism, mental retardation, and renal abnormalities. Vision loss occurs due to a pigmentary retinopathy. It is a genetically heterogeneous disorder with linkage to eight loci. Although considered to be autosomal recessive, the discovery of three mutant alleles in single pedigrees led to the conclusion that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. The Laurence-Moon syndrome is differentiated from BBS by the presence of spastic paraplegia and the absence of polydactyly and obesity. Usher’s syndrome comprises a group of autosomal recessive disorders that are characterized by autosomal recessive inheritance, congenital sensorineural hearing loss, and retinitis pigmentosa. In some varieties, vestibular function is not significantly affected. Usher’s syndrome is caused by at least 12 loci with several identified genes: USH2A (encoding usherin), MYO7A (encoding myosin VIIa), CDH23 (encoding cadherin 23), PCDH15 (encoding protocadherin 15), USH1C (encoding harmonin), USH3A (encoding clarin 1), and USH1G (encoding SANS).34 Joubert’s syndrome is an autosomal recessive disorder characterized by psychomotor retardation, absence of the cerebellar vermis, nystagmus, and episodic hypernea. In addition, patients with renal cysts may develop retinal dystrophy.

K E Y

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Congenital loss of vision is associated with nystagmus, thought to develop as an abnormal ocular motor adaptation to impaired sensory input.

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In several instances, there may be no visible abnormalities of the retina or optic nerve on ophthalmoscopy, and electrophysiological evaluation with electroretinography and visual evoked potentials (VEP) is critically important to correct localization.

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Many blinding disorders of the retina involve proteins that are members of the phototransduction cascade.

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Patients with slowly progressive vision loss may not be aware of their deficit. Ophthalmological examination should be considered in a patient with a progressive neurological syndrome that might be associated with retinal or optic nerve disease.

Suggested Reading Newman NJ: Hereditary optic neuropathies. In Miller NR, Newman NJ, Biousse V, Kerrison, JB (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed, Vol 1. Baltimore: Lippincott, Willians, and Wilkins, 2004, pp 465-502

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Repka MX: Degenerative and metabolic diseases in infants and children: In Miller NR, Newman NJ, Biousse V, Kerriscn JB (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed, Vol 2. Baltmore: Lippincott, Willians, and Wilkins, 2004, pp 2469-2512. Traboulsi EI (eds): Genetic Diseases of the Eye. New York: Oxford University Press, 1998. Online Mendelian Inheritance in Man, available at http://www.ncbi.nlm.nih.gov

References 1. Cremers FP, van den Hurk JA, den Hollander AI: Molecular genetics of Leber congenital amaurosis. Hum Mol Genet 2002; 11:1169-1176. 2. Acland GM, Aguirre GD, Ray J, et al: Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28:92-95. 3. Kohl S, Marx T, Giddings I, et al: Total colour blindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 1998; 19:257-259. 4. Sundin OH, Yang JM, Li Y, et al: Genetic basis of total colour blindness among the Pingelapese islanders. Nat Genet 2000; 25:289-293. 5. Kohl S, Baumann B, Rosenberg T, et al: Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet 2002; 71:422-425. 6. Davis A, Cowell JK: Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet 1993; 2:2093-2097. 7. Bassi MT, Schiaffino MV, Renieri A, et al: Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome. Nat Genet 1995; 10:13-19. 8. Robitaille J, MacDonald ML, Kaykas A, et al: Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 2002; 32:326-330. 9. Dryja TP, McGee TL, Hahn LB, et al: Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med 1990; 323:1302-1307. 10. Sauer CG, Gehrig A, Warneke-Wittstock R, et al: Positional cloning of the gene associated with X-linked juvenile retinoschisis. 1997; 17:164-170. 11. Allikmets R, Singh N, Sun H, et al: A photoreceptor cellspecific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997; 15:236-246. 12. Marmorstein AD, Marmorstein LY, Rayborn M, et al: Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci U S A 2000; 97:12758-12763. 13. Strom TM, Nyakatura G, Apfelstedt-Sylla E, et al: An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 1998; 19:260263. 14. Thomas PQ, Dattani MT, Brickman JM, et al: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10:39-45. 15. Tajima T, Hattorri T, Nakajima T, et al: Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 2003; 88:45-50. 16. Azuma N, Yamaguchi Y, Handa H, et al: Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet 2003; 72:1565-1570. 17. Parsa CF, Goldberg MF, Hunter DG: Papillorenal syndrome in a Brazilian family. Arch Ophthalmol 2002; 120:1772-1773; author reply 1773.

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18. Parsa CF, Goldberg MF, Hunter DG: Papillorenal (“renal coloboma”) syndrome. Am J Ophthalmol 2002; 134:300-301; author reply 301. 19. Chung GW, Edwards AO, Schimmenti LA, et al: Renalcoloboma syndrome: report of a novel PAX2 gene mutation. Am J Ophthalmol 2001; 132:910-914. 20. Alexander C, Votruba M, Pesch UE, et al: OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000; 26:211-215. 21. Delettre C, Lenaers G, Griffoin JM, et al: Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000; 26:207-210. 22. Inoue H, Tanizawa Y, Wasson J, et al: A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 1998; 20:143-148. 23. Scolding NJ, Kellar-Wood HF, Shaw C, et al: Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. Ann Neurol 1996; 39:352-360. 24. Sheffer RN, Zlotogora J, Elpeleg ON, et al: Behr’s syndrome and 3-methylglutaconic aciduria. Am J Ophthalmol 1992; 114:494-497. 25. Assink JJ, Tijmes NT, ten Brink JB, et al: A gene for Xlinked optic atrophy is closely linked to the Xp11.4-Xp11.2 region of the X chromosome. Am J Hum Genet 1997; 61:934939.

26. Johns DR, Smith KH, Miller NR: Leber’s hereditary optic neuropathy: clinical manifestations of the 3460 mutation. Arch Ophthalmol 1992; 110:1577-1581. 27. Wallace DC, Singh G, Lott MT, et al: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242:1427-1430. 28. Newman NJ, Lott MT, Wallace DC: The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991; 111:750-762. 29. Johns DR, Heher KL, Miller NR, et al: Leber’s hereditary optic neuropathy: clinical manifestations of the 14484 mutation. Arch Ophthalmol 1993; 111:495-498. 30. Polten A, Fluharty AL, Fluharty CB, et al: Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med 1991; 324:18-22. 31. Holt IJ, Harding AE, Petty RK, et al: A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990; 46:428-433. 32. Tatuch Y, Christodoulou J, Feigenbaum A, et al: Heteroplasmic mtDNA mutation (T-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992; 50:852-858. 33. Zeviani M, Moraes CT, DiMauro S, et al: Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346. 34. Ahmed Z, Riazuddin S, Wilcox E: The molecular genetics of Usher syndrome. Clin Genet 2003; 63:431-444.

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Virtually every pathological process that can damage an organ in the body can damage the optic nerve. Thus, optic neuropathies can be produced by ischemia, inflammation, infection, compression, infiltration, toxic exposure, metabolic dysfunction, and trauma. Unfortunately, regardless of the cause of an acute optic neuropathy, the optic disc—the only portion of the optic nerve that can be observed with an ophthalmoscope—has only two possible appearances: swollen or normal. Even more confusing is that with chronic damage to the optic nerve, the optic disc simply becomes pale. Thus, the determination of the cause of an optic neuropathy usually cannot be made from the appearance of the optic disc alone. It can, however, be made from a complete assessment, including a complete history, a complete examination, and, in many cases, appropriate ancillary studies. Damage to the optic nerve occurs in three main clinical settings: (1) optic disc swelling without visual loss; (2) acute visual loss with and without optic disc swelling; and (3) subacute or insidious visual loss with and without progression and with and without optic disc swelling. In this chapter, the common optic neuropathies within these settings are considered.

OPTIC DISC SWELLING WITHOUT VISUAL LOSS The most common cause of optic disc swelling without visual loss is papilledema. Papilledema is defined as optic disc swelling caused by increased intracranial pressure.1 It may be produced by an intracranial mass, by blockage of the arachnoid villi by blood or protein (e.g., after a subarachnoid hemorrhage or from a spinal cord tumor), by obstruction of flow of cerebrospinal fluid through the ventricles, and by decreased flow of venous blood through dural sinuses. The symptoms of patients with papilledema are mostly those of increased intracranial pressure (e.g., headache, nausea, vomiting). Visual symptoms are minor and include transient obscurations of vision and double vision. The transient obscurations that occur in patients with papilledema are binocular and simultaneous, and they are extremely brief, lasting only a few seconds. They may occur once a day or dozens of times a day; they may be unassociated with activity or they may occur primarily during a change in

posture, as in changing from lying down to sitting up or standing. This is in contrast to the transient visual obscurations that can occur in patients with emboli from the heart or internal carotid arteries. Those tend to be monocular, rarely have any relationship to activity, and tend to last at least 15 seconds and often many minutes. The presence of transient visual obscurations in patients with papilledema has no prognostic significance. Double vision in patients with papilledema is almost always caused by a unilateral or bilateral sixth nerve paresis. The paresis is almost always incomplete. In most cases, it is caused by the effects of the increased intracranial pressure on the abducens nerve and not by direct compression of the nerve by an intracranial mass lesion. Patients with acute papilledema usually do not complain of decreased or blurred vision unless there are hemorrhages or exudates in the macula or subretinal fluid beneath it or there is an intracranial mass that involves the optic nerve, optic chiasm, or both. The visual field in an eye with papilledema is usually initially normal; however, as disc swelling worsens, the physiological blind spot enlarges and may become noticed by the patient. When increased intracranial pressure causes death of axons, field defects similar to those that occur in patients with open-angle glaucoma (i.e., nasal steps and arcuate defects) occur. With continued damage, generalized field constriction occurs. Visual acuity is preserved until damage is very severe. The appearance of papilledema varies with its severity. Early papilledema is characterized by mild swelling and hyperemia of the optic discs (Fig. 23–1). There are often no hemorrhages, and the retinal veins are not dilated. Visual function is usually normal at this time. As papilledema worsens, the disc becomes increasingly swollen and hyperemic, the vessels on the surface of the disc become obscured by the swollen tissue, and peripapillary flame-shaped hemorrhages may appear (Fig. 23–2). Patients with this fully developed papilledema continue to have normal visual acuity and color vision; however, their blind spots are enlarged, and they may have some mild, nonspecific field defects. If intracranial pressure is not lowered, chronic papilledema develops, characterized by a rounding up of the discs, which begin to become pale (Fig. 23–3). During this time, the hemorrhages resolve. The visual acuity may be slightly

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Figure 23–1.

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Early papilledema. Note mild swelling of optic disc.

Figure 23–2.

Fully-developed papilledema. Note moderate swelling of optic disc with peripapillary hemorrhages and exudates.

decreased, but the main visual finding is significant constriction of the visual field. The final stage of papilledema—atrophic papilledema—occurs when the swelling resolves as nerve fibers die, and the optic discs become pallid (Fig. 23–4). At this point, the visual acuity is reduced, and the visual field is markedly constricted, often to only 5 degrees or less. Papilledema is an emergency. Patients in whom this condition is suspected require an immediate assessment, including neuroimaging and, if no mass is present, a lumbar puncture. Treatment is directed at the underlying process, the increased intracranial pressure, or both.

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Figure 23–3.

Chronic papilledema. Note marked disc elevation and obscuration of disc vessels.

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Figure 23–4.

Atrophic papilledema. Note pallor of optic disc.

SUDDEN VISUAL LOSS WITH AND WITHOUT OPTIC DISC SWELLING The most common causes of optic nerve–related acute visual loss are optic neuritis, ischemic optic neuropathy (ION), and Leber’s hereditary optic neuropathy (LHON).

Acute Optic Neuritis Most patients with optic neuritis are women between 25 and 45 years of age, although this condition can also develop in chil-

chapter 23 optic neuropathies

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Figure 23–5.

Acute optic neuritis. Note swelling of optic disc associated with perivascular sheathing.

dren and older patients. Optic neuritis is characterized in more than 95% of cases by the sudden onset of pain, often quite severe, behind or around the eye, followed shortly thereafter by decreased central vision and, in many cases, by central field loss.2 The loss of central vision is variable. It may be extremely mild or quite severe; indeed, in some cases, all vision is lost.

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Figure 23–6.

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Affected patients have decreased color vision that may be worse than the acuity would suggest. A relative afferent pupillary defect is always present unless the patient has experienced a previous attack of optic neuritis or has some other optic neuropathy in the opposite eye or the acute process is bilateral. The affected optic disc appears normal in about two thirds of cases; in the other one third, it is swollen (Fig. 23–5). Most cases of optic neuritis are idiopathic or demyelinating in origin; however, rare cases are caused by such inflammatory or infectious conditions as sarcoid, syphilis, Lyme disease, and cat-scratch disease.2 The natural history of demyelinating or idiopathic optic neuritis is to improve vision to 20/20 or better without treatment. Although a 3-day course of high-dose (1 g/day) methylprednisolone followed by a 2-week course of low-dose (1 mg/kg/day) prednisone may speed recovery by several weeks to a month, this treatment does not affect the ultimate visual outcome. The use of low-dose steroids without first use of highdose steroids in a patient with acute optic neuritis increases the risk of recurrent optic neuritis in the affected eye and the risk of an attack of acute optic neuritis in the other eye. Patients who experience an attack of acute optic neuritis have an increased risk of developing multiple sclerosis, depending in large part on whether white-matter lesions are visible on magnetic resonance images at the time of the acute attack (Fig. 23–6). The presence of even one lesion doubles a patient’s risk of developing multiple sclerosis over the subsequent 10 years.3 Fortunately, there is evidence that the use of interferon β-1a reduces the risk of developing multiple sclerosis in these patients.4 Patients who experience an attack of optic neuritis in one eye have a 10% to 20% risk of developing a similar event in the opposite eye.2 Risk factors for second-eye involvement include

Magnetic resonance images are two different levels showing multiple white-matter lesions in a patient with isolated acute optic neuritis.

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Ischemic Optic Neuropathy

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Figure 23–7.

Acute neuroretinitis. Note swelling of optic disc associated with macular star appearance composed of lipid.

white-matter lesions on magnetic resonance images, a family history of multiple sclerosis, and neurological symptoms. A variant of optic neuritis that has a very different prognosis from the demyelinating or idiopathic form is neuroretinitis.5 This condition begins as an apparently straightforward anterior optic neuritis in which vitreous cells may or may not be present; however, within 1 to 3 weeks, a macular star develops that often persists after the optic disc swelling resolves (Fig. 23–7). Neuroretinitis may be caused by cat-scratch disease, sarcoid, syphilis, tuberculosis, or Lyme disease; however, it is never caused by multiple sclerosis.

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Figure 23–8.

The second major cause of acute visual loss with and without optic disc swelling is ION.6 This condition occurs in three main settings: (1) as a complication of systemic noninflammatory vascular diseases, such as diabetes mellitus, hypertension, and hypercholesterolemia; (2) in the perioperative period, most often after cardiac surgery or back surgery in the prone position; and (3) as a complication of vasculitis, most often temporal (giant cell) arteritis. Nonarteritic ION usually occurs in patients older than 55; equal numbers of men and women are affected. At least one underlying systemic vasculopathy is usually present, but it may or may not have been identified at the time vision is lost. Nonarteritic ION is usually painless. When eye pain is present, it is usually mild, and pain on eye movement is very rare. As in the case of optic neuritis, the degree of visual loss in patients with nonarteritic ION is variable, ranging from 20/20 to hand motion vision or worse. Color vision usually mirrors acuity; the worse the central vision is, the worse the color vision is. The visual field usually shows an altitudinal or arcuate field defect. A relative afferent pupillary defect is always present if the condition is unilateral and there is no optic neuropathy in the opposite eye. Nonarteritic ION may be of the anterior or the retrobulbar variety.7 In anterior ION, which constitutes about 90% of all cases, the optic disc is usually hyperemic, and peripapillary flame-shaped hemorrhages are often present (Fig. 23–8); however, soft exudates (cotton-wool spots) are usually absent. The opposite optic disc is almost always small with little or no cup (see Fig. 23–8), and this morphological anomaly is believed to predispose the nerve to ischemia by causing crowding of the optic nerve axons. Patients with retrobulbar ION have a normal-appearing optic disc. Because this condition is rare in

Acute nonarteritic anterior ischemic optic neuropathy. Note hyperemic optic disc and flame-shaped hemorrhages (left). Opposite optic disc (right) is small and has no cup (disc at risk).

chapter 23 optic neuropathies comparison with anterior ION, retrobulbar ION should be considered a diagnosis of exclusion: that is, other causes of retrobulbar optic neuropathy, particularly an intracranial mass, should be considered. In about 40% of patients with nonarteritic ION, the condition improves spontaneously, although visual acuity is more likely to improve than is visual field.6 No treatment exists for patients whose vision does not recover. In addition, patients who experience an attack of nonarteritic ION are at risk for subsequent cerebrovascular and cardiovascular events, and such patients have an increased rate of mortality in comparison with age- and gender-matched control subjects. Patients who experience an attack of nonarteritic ION have a 10% to 20% risk of experiencing a similar attack in the opposite eye.8 Risk factors for opposite eye involvement include advanced age, severe vascular disease, and persistent poor visual acuity in the affected eye. Perioperative ION occurs most often after back surgery in the prone position and after cardiac surgery in which cardiopulmonary bypass is used. The rates vary from 0.06% to 0.1% after cardiac surgery and from 0.1% to 0.01% after back surgery in the prone position.9,10 The major factors leading to this complication appear to be operative and perioperative anemia and hypotension, although there are cases in which neither of these factors appears to be in evidence. Perioperative ION is often, although not invariably, bilateral; visual acuity in the affected eye is usually very poor, and the optic discs may be swollen or normal in appearance. Spontaneous improvement is rare. There is no proved treatment, but the author believes that anemia and hypotension should be corrected immediately, because there is indirect evidence from cases of nonsurgical anemia or hypotension that vision could improve with this treatment. Nevertheless, the author is unaware of any cases of perioperative ION in which vision has substantially improved after this treatment. Arteritic ION is the least common type of ION. It is usually associated with temporal (giant cell) arteritis,6 but other vasculitides can be responsible, such as periarteritis nodosa. Patients with this condition do not experience eye pain, but they may have headache, scalp tenderness, jaw pain, ear pain, or a combination of these manifestations. Thus, the physician evaluating a patient with possible arteritic ION must ask specifically about these symptoms. The visual manifestations of arteritic ION are typical. Many affected patients have experienced episodes of transient visual loss preceding permanent loss of vision. The episodes are identical with those experienced by patients with carotid artery disease, usually lasting between 15 seconds and one minute or two. The episodes are unilateral, but both eyes may be affected. Once an attack of arteritic ION occurs, the visual acuity loss is usually profound. Many patients become completely blind in the affected eye, and in almost all, vision is worse than 20/400. The condition is usually unilateral, but bilateral simultaneous ION is not uncommon, and bilateral sequential ION is the rule if the condition is not diagnosed correctly and treated within a short time. As with other unilateral optic neuropathies, patients with arteritic ION always have an ipsilateral relative afferent pupillary defect. The absence of this finding in a patient with presumed arteritic ION should raise concern regarding subclinical involvement of the contralateral eye.

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Figure 23–9.

Arteritic anterior ischemic optic neuropathy. Note pallid swelling, indicating an infarction of the disc substance. Also note peripapillary soft exudate (cotton-wool spot).

As with nonarteritic and perioperative ION, arteritic ION may be of the anterior or retrobulbar variety. When the condition is of the anterior type, the optic disc usually shows pallid rather than hyperemic swelling, which indicates a true infarction of the nerve, and one or more soft exudates (cotton-wool spots) are often present (Fig. 23–9). Indeed, in the appropriate clinical setting, the presence of such exudates in a patient with an acute anterior optic neuropathy is almost pathognomonic of arteritic ION. In most patients, regardless of treatment, arteritic ION does not improve. Nevertheless, a small percentage do experience improvement; these are usually patients treated with high-dose systemic corticosteroids (methylprednisolone [Solu-Medrol], 1 g/day). Of more importance, perhaps, is that this treatment substantially reduces, although it does not eliminate, the risk of second-eye involvement and also may protect the patient against other complications of the vasculitis, including stroke, heart attack, and renal failure. Thus, it is crucial to diagnose and treat unilateral arteritic ION as soon as possible.

Leber’s Hereditary Optic Neuropathy LHON can occur at any age but typically manifests in young adults; about eight times more men than women are affected.11 Visual loss is bilateral and simultaneous in about one half the cases; in the remainder, one eye is affected initially, and the other eye becomes affected, in most cases, within 1 month. Whether unilateral or bilateral, the visual loss is always painless, and this distinguishes the condition from acute optic neuritis, which is almost always associated with pain behind or around the eye, often worsening with eye movement (see previous discussion). The rate of visual loss in LHON is slower than that caused by optic neuritis but faster than that caused by most compressive lesions. The nadir, typically about 20/400, is usually reached within 3 to 6 months. The visual loss is

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Figure 23–10.

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Leber’s hereditary optic neuropathy. Note dilated vessels on disc surface and in the peripapillary region in both

fundi.

associated with marked color vision loss; a central or cecocentral scotoma with preservation of the peripheral field in most but not all cases; and either a normal-appearing optic disc or the triad of hyperemic “pseudoedema” of disc, telangiectatic vessels on the disc and in the peripapillary region, and no evidence of leakage on fluorescein angiogram (Fig. 23–10). LHON is a mitochondriopathy. It is, therefore, maternally inherited; more than 90% of cases are caused by mutations at sites 11778 (the most common site), 14484, and 3460. There are a number of other sites at which mutations are responsible for small numbers of cases. Approximately 20% of patients with the pathogenic mutations that cause LHON become symptomatic, but it is not known which factors cause some patients but not others to lose vision. Alcohol abuse, tobacco abuse, and metabolic stress have all been postulated to play a role, but none has been proved to do so.12 The natural history of LHON varies with the site of the mutation.11 Patients with the 11778 mutation have the worst visual prognosis, with a 4% improvement rate, whereas 25% to 40% of patients with mutations at sites 14484 and 3460 experience improvement, often to 20/20 or better. Improvement is associated with breaking up of the central field defects. Unfortunately, there is no definitive treatment for LHON. Although it has been suggested that idebenone, a form of coenzyme Q, may be helpful, there are few data to support this contention, and other “cocktails” of various vitamins and enzymes have not been found to successfully treat or prevent the condition. The diagnosis of LHON should be considered in any patient, young or old, who experiences painless, relatively rapid (too slow for optic neuritis and too fast for most compressive lesions) visual loss in one or both eyes in association with normal-appearing optic discs what appears to be minimal disc swelling (i.e., hyperemic disc) without hemorrhages or exudates.

INSIDIOUS VISUAL LOSS WITH OR WITHOUT OPTIC DISC SWELLING The causes of optic nerve–related insidious visual loss depend in large part on whether the visual loss is unilateral or bilateral. If visual loss is unilateral, a compressive lesion is most likely to be the cause; if the loss is bilateral, a compressive process is still likely, but both toxic and metabolic causes must be considered, as must infiltrative processes.

Compressive Optic Neuropathy A compressive optic neuropathy may be unilateral or bilateral.13 When it is unilateral, the optic disc may be swollen or normal in appearance. When it is swollen, the mass is almost always located within the anterior or middle portion of the orbit (Fig. 23–11). When the disc appears normal, the lesion is located in the posterior orbit, in the optic canal, or intracranially. When the visual loss is bilateral, the lesion is almost always intracranial or in the paranasal sinuses, and the optic discs appear normal, at least initially. Regardless of their location, lesions that compress the optic nerve can produce any level of visual loss and any type of field defect. In most cases, color vision is diminished in the affected eye, and the severity of color deficit may be more than expected in comparison with the severity of visual loss. A relative afferent pupillary defect is present in every patient with a unilateral process. Patients suspected of having a compressive optic neuropathy require neuroimaging. When an orbital or paranasal sinus process is suspected, computed tomographic scanning is the optimum imaging modality, whereas intracranial lesions are best detected with magnetic resonance imaging. The treatment of a compressive lesion of the optic nerve depends on the nature

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Figure 23–11.

Compressive anterior optic neuropathy. Left, Optic disc is moderately swollen. Note absence of hemorrhages. Right, Computed tomographic scan shows intraconal mass. Note compression and medial deviation of the optic nerve by the mass.

of the lesion, as well as its location. Whether a patient improves after successful elimination of the compression process depends in part on how long symptoms have been present and the severity of visual dysfunction before treatment.

toxicity, which can cause complete blindness. The visual loss in patients with toxic or deficiency optic neuropathies is virtually always accompanied by bilateral severe loss of color vision, bilateral central or cecocentral scotomas, and optic discs that appear normal or perhaps slightly swollen (Fig. 23–13).

Infiltrative Optic Neuropathy Like compressive optic neuropathies, infiltrative optic neuropathies may be unilateral or bilateral.13 Any level of visual loss can occur, and any type of visual field defect can be present. As with other optic neuropathies, a relative afferent pupillary defect is always present in unilateral cases. Patients with an infiltrative optic neuropathy may have an optic disc that is truly swollen, a disc that appears swollen but that is actually infiltrated with the underlying lesion, or a normal disc. Disorders most likely to produce an infiltrative optic neuropathy include reticuloendothelial disorders, such as leukemia and lymphoma; inflammatory conditions, such as sarcoidosis; and metastatic tumors, particularly carcinomas (Fig. 23–12). The diagnosis of an infiltrative optic neuropathy may be difficult; however, in many cases, magnetic resonance imaging reveals diffuse or focal enlargement and enhancement of the affected nerve. Both treatment and prognosis depend on the nature and severity of the process.

Toxic and Deficiency Optic Neuropathies These conditions are almost always bilateral, although one eye may be affected days to weeks before the other.14 The loss of vision occurs slowly, usually over one month or more. The eventual nadir is usually about 20/400, except with methanol

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Figure 23–12.

Infiltrative optic neuropathy. Optic disc has a fluffy appearance, which is consistent with infiltration, rather than true swelling.

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Figure 23–13.

Toxic optic neuropathy in a patient taking ethambutol and isoniazid for pulmonary tuberculosis. Both right (left) and left (right) optic discs appear slightly swollen.

Hemorrhages and exudates are almost never seen. Because of the bilaterality of the process, a relative afferent pupillary defect is almost never present. The substances that can cause a toxic optic neuropathy include both common and uncommon medications (Table 23–1). Nutritional optic neuropathies occur in a number of settings. The most common is chronic alcohol abuse; others include starvation, malabsorption syndromes, fad diets, incorrect vegetarianism, and depression (resulting in a poor diet).15 The diagnosis generally becomes apparent with a careful history of medications being taken, exposures to potential toxins, and eating habits. The treatment of toxic or nutritional optic neuropathies is to eliminate the toxin or replace the nutrient. Most, but not all, patients experience improvement; the degree of improvement is related to the duration of symptoms and the severity of visual loss before institution of treatment. The main differential diagnosis of toxic and nutritional optic neuropathies is LHON; however, LHON usually progresses more rapidly than most nutritional or toxic optic neuropathies and does not improve at all when toxic exposure is eliminated or the nutritional deficiency is corrected.

OTHER OPTIC NEUROPATHIES Traumatic Optic Neuropathy The diagnosis of traumatic optic neuropathy is usually quite easy to establish.16 It usually occurs in the setting of blunt head trauma, in which there is often a period of loss of consciousness. The majority of cases appear to result from damage to the optic nerve within the optic canal, where traumatic hemorrhage and swelling produce severe damage to the optic nerve

T A B L E 23–1. Some Reported Causes of Toxic Optic Neuropathy Alcohol Amiodarone Amoproxan Caramiphen Catha edulis (plant) Chlorambucil Chloramphenicol Chlorpropamide Cisplatin Clioquinol Clomiphene Cyclosporine Deferoxamine Dideoxyinosine Disulfiram Ethambutol Ethchlorvynol Ethylene glycol Toxic optic neuropathies

5-Fluorouracil Glue Hexachlorophene Hydroxyquinolones Isoniazid Methanol Methimazole Methylbromide Minoxidil Organophosphates Penicillamine Phenobarbital Streptomycin Tamoxifen Tobacco Tolbutamide Toluene Vincristine

and its blood supply. The severity of visual loss is variable, from mild loss of visual acuity to no light perception. Although some physicians advocate treatment with systemic corticosteroids and others advocate decompression of the optic nerve within the optic canal, there is no evidence that any intervention is better than the natural history of the process.

Radiation-Induced Optic Neuropathy This condition occurs in 10% to 15% of cases in which the optic nerves have received at least 5000 cGy.17 The only exceptions

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Optic neuropathies can be categorized as those that are unassociated with visual loss, those that are associated with sudden visual loss, and those that are associated with subacute or chronic visual loss.

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In patients with acute optic neuropathies, the optic discs are swollen or appear normal, regardless of the cause.

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In patients with chronic optic neuropathies, the optic discs are pale, regardless of the cause.

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Acute papilledema is never associated with visual loss unless the causative lesion damages the intracranial visual sensory pathway or there are associated hemorrhages, exudates, or edema in the macula.

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The most common optic neuropathies that cause sudden visual loss are optic neuritis, ION, and LHON.

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The most common optic neuropathies that cause subacute or chronic visual loss are compressive, toxic, and hereditary optic neuropathies.

Figure 23–14.

Neuroimaging of radiation-induced optic neuropathy. Magnetic resonance image shows enlargement and enhancement of the left optic nerve.

Suggested Reading

appear to be patients with diabetes mellitus and patients receiving chemotherapy for cancer at the time of the irradiation, in which case the condition can occur with smaller doses. A transient type of optic neuropathy can occur during the irradiation itself and is believed to be related to acute swelling of the nerve. This form of optic neuropathy is usually self-limited, and treatment consists of systemic corticosteroids. Most cases of radiation-induced optic neuropathy, however, occur 1 to 8 years after irradiation and consist of a relatively rapid progression of visual loss in one or both eyes, usually associated with an initially normal-appearing optic disc that gradually becomes pale. Neuroimaging in such cases may reveal enhancement and enlargement of one or both optic nerves, but this is not a universal finding (Fig. 23–14). There is no proved treatment for radiation-induced optic neuropathy. Corticosteroids, anticoagulants, and hyperbaric oxygen all have their supporters, but none of these treatments has proved successful in the majority of cases.

CONCLUSION The most important issues in dealing with a patient with an optic neuropathy are the onset of the visual loss; whether there has been any progression and, if so, the speed of the loss of vision; whether the process is unilateral or bilateral; and whether there is swelling of the optic disc. A complete history, a thorough examination, and appropriate ancillary studies help identify the cause of an optic neuropathy in almost 100% of cases.

Burde RM, Savino PJ, Trobe JD, eds: Optic neuropathies. In: Clinical Decisions in Neuro-ophthalmology, 3rd ed. St. Louis: CV Mosby, 2002, pp 27-58. Kline LB: Optic Nerve Disorders. San Francisco: American Academy of Ophthalmology, 1996. Miller NR, Newman NJ: The Essentials: Walsh & Hoyt’s Clinical Neuro-ophthalmology. Baltimore: Williams & Wilkins, 1999, pp 134-322. Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005.

References 1. Friedman DI: Papilledema. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 237-292. 2. Smith CH: Optic neuritis. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 293-348. 3. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophthalmol 2003; 121:944-949. 4. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343:898-904. 5. Williams N, Miller NR: Neuroretinitis. In Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunology. St. Louis: CV Mosby, 1996, pp 601-608. 6. Arnold A: Ischemic optic neuropathy. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuroophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 349-384.

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7. Sadda SR, Nee M, Miller NR, et al: Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol 2001; 132:743-750. 8. Newman NJ, Scherer R, Langenberg P, et al: The fellow eye in NAION: report from the ischemic optic neuropathy decompression trial follow-up study. Am J Ophthalmol 2002; 134:317-328. 9. Kalyani SD, Miller NR, Dong LM, et al: Incidence of and risk factors for perioperative optic neuropathy following cardiac surgery. Ann Thorac Surg 2004; 78:34-37. 10. Chang S-H, Miller NR: The incidence of visual loss due to perioperative ischemic optic neuropathy associated with spine surgery: The Johns Hopkins Hospital experience. Spine 2005; 30:1299-1302. 11. Newman NJ: Hereditary optic neuropathies. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 465-502. 12. Kerrison JB, Miller NR, Hsu F-C, et al: A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000; 130:803-812.

13. Volpe NJ: Compressive and infiltrative optic neuropathies. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 385-430. 14. Phillips PH: Toxic and deficiency optic neuropathies. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 447-464. 15. Hsu C, Miller NR, Wray M: Optic neuropathy from folic acid deficiency without alcohol abuse. Ophthalmologica 2002; 216:65-67. 16. Steinsapir K, Goldberg RA: Traumatic optic neuropathy. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 431-446. 17. Lessell S: Friendly fire: neurogenic visual loss from radiation therapy. J Neuroophthalmol 2004; 24:243-250.

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Eoin O’Sullivan and Elizabeth Graham

The retina reflects many of the pathophysiological processes that occur in the central nervous system (CNS). Indeed the retinal appearances may be diagnostic but, conversely, can be nonspecific; for example, pigmentary retinal changes are part of the diagnostic criteria for Kearns-Sayre syndrome but are also present in many other diseases. Furthermore, in other diseases, the retina may appear clinically normal, but psychophysical and electrophysiological testing reveal abnormalities. In this chapter, both neurological diseases with retinal involvement that patients would tend to present with to a neurologist, as well as diseases that patients would tend to present with to an ophthalmologist but that have neurological involvement, are discussed. Disorders of the choroid that might be apparent on funduscopy are also discussed. The following is a brief description of the embryology, anatomy, and physiology of the retina, highlighting its similarities to the CNS. There is also an explanation of some of the ophthalmological terms that are used in this chapter. The eyeball consists of three layers, which, starting from the outside, are a fibrous layer, a vascular pigmented layer, and a nervous layer. The fibrous layer consists of the sclera, which makes up the posterior five sixths of the eyeball and is opaque, and the cornea, which forms the anterior one sixth and is transparent. The vascular pigmented layer is also known as the uveal tract and consists of the choroid, which is a very vascular layer; the ciliary body; and the iris. The retina constitutes the nervous layer. The cavity behind the cornea and in front of the iris is the anterior chamber, and it is filled with aqueous humor. The vitreous humor fills the eyeball behind the lens. Embryologically, the ectoderm that is derived from the neural tube gives rise to the retina, the fibers of the optic nerve, and the smooth muscle of the iris. The choroid is derived from mesenchyme and is homologous in its embryonic origin with the pia mater and arachnoid tissue. The photoreceptors, consisting of rod and cone cells, are located near the outer surface of the retina. In the process of phototransduction, light energy is absorbed by specialized visual pigments within the outer segments of the photoreceptors, which results in hyperpolarization and the generation of an electrical signal. After photoreception, the signal is conducted to the bipolar cells in the inner nuclear layer, which in turn transmit their signals to the ganglion cells. The axons of

the ganglion cells are collected on the inner surface of the retina and form the optic nerve. There are many interneuronal connections and a variety of neurotransmitters and neuromodulators such as acetylcholine, γ-amino butyric acid (GABA), glutamate, and dopamine, which are involved in the signal processing. At the extreme outer layer of the retina is the retinal pigment epithelium, which is in contact with the outer segments of the photoreceptors. This layer is in contact with Bruch’s membrane, which is the inner layer of the choroid. The choroid provides the blood supply for the outer layers of the retina, including the photoreceptors, whereas the inner layers are supplied by branches of the central retinal artery. The macula lutea is a yellowish, oval area located at the center of the posterior part of the retina. It has a central depression, the fovea centralis. Uveitis, inflammation of the uveal tract, can occur in association with neurological disease. In this chapter, the classification recommended by the Standardization of Uveitis Nomenclature Working Group is used.1 In this classification, the primary site of inflammation in anterior uveitis is the anterior chamber. For intermediate uveitis, it is the vitreous humor. The primary site of inflammation in posterior uveitis can be the retina or choroid. Panuveitis is used when there is no predominant site of inflammation, but inflammation occurs in the anterior chamber, vitreous humor, and retina and/or choroid.

UVEOMENINGEAL SYNDROMES The uveomeningeal syndromes are a heterogeneous group of disorders that share involvement of the uveal tract (which comprises the iris, the ciliary body, and the choroid), retina, and meninges. Causes of this syndrome include infectious, inflammatory, and neoplastic disorders. The infectious and neoplastic causes are discussed elsewhere; in this section, syndromes caused by inflammatory disease are discussed.

Sarcoidosis Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can affect the eye and the CNS, as well as the lungs, skin, and other organs. Of all patients with sarcoidosis, 25% to 60% have ocular involvement, which may be

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the manifesting sign. Sarcoidosis can affect most ocular tissues, but the most common ocular manifestations are uveitis and conjunctival nodules. Uveitis can occur in about 30% of patients before nonocular signs.2 A 10-year follow-up study of patients with uveitis caused by sarcoidosis or presumed sarcoidosis revealed that over this period, the disease spread most often to the CNS.3 Posterior segment involvement is frequently associated with neurological disease.4,5 It may be more common in white patients, especially elderly women,2 although this has not been confirmed by all studies.6 The optic nerve may become swollen because of intraocular inflammation, when visual acuity is usually preserved, or it may be involved either directly by granulomas or as a result of meningeal changes, when loss of visual acuity and field result from compressive optic neuropathy. The classic sign of retinal involvement by sarcoidosis is retinal periphlebitis (Fig. 24–1),7-9 which may be described as similar to candle wax dripping. Other vascular changes include retinal hemorrhages, vein occlusions, neovascularization, and possibly retinal arteriolitis with aneurysm or ectasia formation.10 Focal subretinal lesions have been described, but these do not appear to affect vision.9 Confluent choroidal infiltrates have been described.11 Appearances similar to that of a multifocal choroiditis (Fig. 24–2),12,13 and a serpiginous choroidopathy have been described.14 Multiple sclerosis may include a similar ocular inflammatory manifestation, but the choroid is not involved.

Behçet’s Disease Behçet’s disease is characterized by recurrent episodes of orogenital aphthae and by systemic and retinal venous thrombosis. It remains a clinical diagnosis, and diagnostic criteria have been published.15 The CNS manifestations of Behçet’s disease can be categorized into parenchymal and nonparenchymal involvement (neurovascular Behçet’s disease). Parenchymal CNS manifestations include brainstem and hemisphere

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Figure 24–1. Retinal periphlebitis.

involvement, spinal cord lesions, and meningoencephalitis. Nonparenchymal involvement includes dural sinus thrombosis, arterial occlusion, and arterial aneurysms. These categories have different clinical and prognostic properties.16 The ocular manifestations in the parenchymal category include optic neuritis and ischemic optic neuropathy.17-19 Papilledema caused by intracranial hypertension secondary to dural sinus thrombosis occurs in neurovascular Behçet’s disease20,21 and can result in significant visual loss. Intracranial hypertension can, however, occur in the absence of venous sinus thrombosis or meningitis.18 Inflammatory eye disease occurs in approximately 70% of all patients who may have additional neurological or neuroophthalmological disease. The inflammation usually occurs after the onset of oral aphthosis, but the delay between the two may be as long as 14 years.22 In approximately 10% of patients, intraocular inflammation is the manifesting feature,23 and in rare cases, neither oral nor genital ulcers may occur at all.24 Usually the involvement is bilateral. The main ocular finding is panuveitis, although there may be differing degrees of anterior and posterior segment involvement. The anterior uveitis may be so severe that the inflammatory cells precipitate in the inferior portion of the anterior chamber, forming a hypopyon. Retinal vein occlusion is the most characteristic fundal sign, but others include retinal perivasculitis and retinal infiltrates. The perivasculitis involves mainly the veins and less frequently the arteries. The retinal infiltrates are collections of lymphocytes in the superficial retina and are pathognomonic of Behçet’s disease (Fig. 24–3). They resolve spontaneously and carry no visual morbidity. However, recurrent retinal vein occlusions can result in total attenuation of all vessels and consequent optic atrophy. Macular edema may also cause visual loss. Unfortunately, the visual prognosis is poor in spite of the development of new immunosuppressive therapies. Up to 15% of patients are unresponsive to these therapies,25 and the disease may remain active for many years.

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Figure 24–2. Choroidal lesions in sarcoidosis.

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Figure 24–3. A peripapillary retinal infiltrate and a vein

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Vogt-Koyanagi-Harada (VKH) disease is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin of unknown etiology. VKH disease usually affects darkly pigmented Asian, American Indian, Hispanic, or African-American adults. Like Behçet’s disease, it is diagnosed on clinical findings. Diagnosis can be difficult because there are no specific tests and the clinical features are dependent on the stage of the disease at which the patient is examined. Diagnostic criteria have been published.26 One of the following neurological features has to be present for the diagnosis of VKH: meningismus, tinnitus or cerebrospinal pleocytosis. The ocular features have been divided into early and late manifestations of the disease. In the early manifestation, the retinal and choroidal features are mainly in the form of serous retinal detachments. In the late manifestations, choroidal depigmentation that results in a mottled “sunset glow” appearance, nummular chorioretinal depigmented scars, and retinal pigment epithelium clumping and/or migration26 may be present (Fig. 24–4). Recurrent or chronic uveitis also occurs in the late stage of VKH. The criteria include the presence of bilateral ocular involvement. The integumentary findings are alopecia, poliosis, or vitiligo. A further neurological association with VKH is Guillain-Barré syndrome. Three patients who developed VKH within 3 months of having Guillain-Barré syndrome have been reported.27

Figure 24–4. Pigmentary changes in Vogt-Koyanagi-Harada disease.

occlusion superior to the optic disc.

Vogt-Koyanagi-Harada Disease

In rare cases, venulitis develops. Choroidal involvement can also occur. A postmortem study of patients with systemic lupus erythematosus affecting the brain and eye demonstrated vasculitis in the brain and the choroidal vessels.30 A number of retinal arterioles were occluded with thrombus, but there was no evidence of inflammation of the retinal vessels. Emboli from a diseased heart valve or deposition of immune complexes may have caused the occlusion. A number of the vasculitides affect the retina. This, however, is not always caused primarily by the vasculitis, but it can result from other complications of the disease, such as hypertension. The diseases are discussed according to the size of vessel they affect.

RHEUMATOLOGICAL DISEASES AND THE SYSTEMIC VASCULITIDES Rheumatoid arthritis is associated with corneal and sclera changes but not usually retinal ones. Retinal involvement is, however, a common ocular feature of systemic lupus erythematosus. Indeed, the presence of ocular features may mirror disease activity elsewhere.28,29 Retinal arteriolar occlusion may occur, and multiple cotton-wool spots may be seen (Fig. 24–5).

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Figure 24–5. Multiple cotton-wool spots in systemic lupus erythematosus.

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Large Artery Giant cell arteritis is a necrotizing vasculitis targeting large and medium-sized arteries and affects mainly white patients older than 50 years. Anterior ischemic neuropathy is the most common cause of visual loss in giant cell arteritis, but patients can suffer from either central retinal artery occlusions or, less commonly, branch retinal artery occlusions. Compromised blood flow to the retina may result in signs of ischemia such as cotton-wool spots and hemorrhages. Posture can also affect the ischemia in that vision may be reduced in the upright position, in relation to lying down.31 Poor perfusion of the choroid may result in reduced vision, which can be reversible, but permanent infarction can occur (Fig. 24–6). Treatment is aimed primarily at preventing both visual loss in the second eye and the development of stroke. Takayasu’s disease is another disease of the large vessels. Retinal disease is present in fewer than 50% of patients with Takayasu’s disease.32 The retinal changes include vessel dilation, tortuosity of vessels, arteriovenous anastomoses, and hemorrhages. In many patients, hypertension is probably the major cause of retinal changes; in some patients, however, the changes may result from reduced flow to the retinal circulation (i.e., a hypotensive retinopathy).32

Medium-Sized Artery Ocular involvement occurs in 10% to 20% of patients with polyarteritis nodosa. Retinal artery occlusion, ischemic retinopathy, exudative retinal detachment,33 and choroidal infarcts have been described.34 Kawasaki’s disease tends not to affect the retina, although one postmortem study did yield evidence of retinal ischemia.35

Medium-Sized and Small Vessels Wegener’s granulomatosis is characterized by a systemic vasculitis and necrotizing granulomatous lesions that may be

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Figure 24–6. Choroidal insufficiency in giant cell arteritis.

found in the respiratory tract, kidney, orbit, and brain. Between 30% and 50% of patients with Wegener’s granulomatosis have neurological involvement.36,37 The patterns of neurological involvement have been described as granulomatosis invasion of the orbit, granulomas of the brain and meninges, and vasculitis of the nervous system.36 The orbital involvement usually is from the extension of disease in the paranasal sinuses. Orbital involvement may be the initial sign of the disease, manifesting with orbital pain, rapidly progressing proptosis, and limited eye movements with associated granulomatosis infiltration of adjacent structures. Cranial nerves may also be involved; the optic nerve, the abducens nerve, and the facial nerve are the most commonly affected.37 Retinal and choroidal involvement is rare but may manifest as retinitis, vein occlusion, or an intermediate uveitis.38 Some of these changes, however, may have been secondary to hypertension or cytomegalovirus–associated retinitis. A number of patients taking cyclophosphamide for Wegener’s granulomatosis have developed cytomegalovirusassociated retinitis (Fig. 24–7).39-41 In patients with the limited form of Wegener’s granulomatosis, the neuro-opthalmological features may, again, be the earliest feature of the disease.42 A similar pattern of neuro-ophthalmological involvement is seen, the orbit being affected more frequently than the retina.43 Ocular involvement in the Churg-Strauss syndrome can be in the form of either chronic orbital pseudotumor or ischemic vasculitis. The retinal manifestations of the latter group include retinal artery occlusions.44 Cotton-wool spots in the retina have been described in a patient with microscopic polyangiitis. The patient also had a very severe uveitis that resulted in a hypopyon.45

MULTIPLE SCLEROSIS Manifestations of multiple sclerosis in the eye other than optic neuritis include uveitis and retinal changes, such as periphlebitis or sheathing or cuffing of the retinal veins by lymphocytes and plasma cells.46-49 This may occur in isolation or as part of an intermediate uveitis. Periphlebitis may occur in up

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Figure 24–7. Cytomegalovirus-associated retinitis.

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Figure 24–8. Vascular changes in multiple sclerosis seen on fluorescein angiography.

to 36% of patients with multiple sclerosis50,51 and is usually asymptomatic. These changes are often in the peripheral retina and so cannot be viewed through a direct ophthalmoscope trained on an undilated pupil. Indeed, the changes may be visible only on fluorescein angiography (Fig. 24–8).52 Focal perivenous hemorrhage can also occur. The presence of vascular changes and/or ocular inflammation in patients with optic neuritis is associated with a greater risk of developing multiple sclerosis.52,53 It has been suggested that periphlebitis is a marker for disease activity,50,54 but this has not been confirmed.55 Vascular sheathing can occur in other diseases such as sarcoidosis, systemic lupus erythematosus, Wegener’s granulomatosis, and Behçet’s disease.56 Multiple sclerosis can be differentiated from sarcoidosis inasmuch as it is not associated with choroidal lesions.

Uveitis Studies of records of patients at multiple sclerosis clinics have revealed that 1% to 2% have uveitis, which is a higher frequency than in the general population.57,58 Asymptomatic uveitis has been found in a range from none59 to 18%60 of patients with multiple sclerosis. This range probably reflects the difference in disease activity of the patients in the studies. All types of uveitis are observed; one form of intermediate uveitis, pars planitis, is probably the most common,57,61,62 but this has not been found in all studies.59 There does not seem to be any correlation between the type of multiple sclerosis and uveitis or between the degree of neurological disability and the type of uveitis,57,59 although the presence of optic atrophy may be protective against uveitis.60

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Figure 24–9. Neuroretinitis.

culitis with associated neovascularization63,65 can also result in visual loss. The features that suggest a diagnosis of uveitis rather than optic neuritis include photophobia, floaters, redness of the eye, and the absence of a relative afferent pupillary deficit. Nevertheless, many patients with multiple sclerosis–associated uveitis retain useful vision if it is treated appropriately.62

Neuroretinitis Neuroretinitis is a descriptive term for optic disc swelling and macular exudates (Fig. 24–9) that classically results from infective causes (discussed in the next section). One study has suggested that the presence of neuroretinitis indicated that the patient did not have demyelinating disease.66 Thus, neuroretinitis should be differentiated from cases of optic neuritis that manifest with papillitis. However, in a retrospective review of 35 patients with neuroretinitis, 3 patients were found to have multiple sclerosis, although they also had received interferon β therapy.67

INFECTIONS A number of various infectious agents can cause both retinal and neurological disease. Some, however, usually do so only in the presence of immunosuppression, most often caused by human immunodeficiency virus (HIV) infection. This section therefore deals with infections both in immunocompetent individuals and in those with HIV infection.

Visual Loss In patients with multiple sclerosis and uveitis, visual loss cannot be assumed to result from optic neuritis, because the complications of uveitis such as macular edema63,64 and retinal vas-

Infectious Causes of Neuroretinitis As discussed, the presence of a swollen disc and macular exudates in a starlike pattern is known as neuroretinitis and is

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classically caused by infection. However, other causes such as hypertension can result in the same clinical picture. A number of infections are classically associated with neuroretinitis and can have neurological associations. These include cat-scratch disease, Lyme disease, and syphilis. In very rare cases, toxoplasmosis manifests this appearance.68 The ocular features of these other conditions are discussed as follows, except for toxoplasmosis, which is discussed elsewhere. Cat scratch fever is caused by Bartonella henselae. There may be an associated uveitis, and the other fundal appearances include discrete retinal or choroidal lesions, which are more common than in classic neuroretinitis.69 Lyme disease is a spirochetal infection that results from tickborne transmission of Borrelia burgdorferi. Conjunctivitis is the most common ocular manifestation of early Lyme disease and occurs in approximately 10% of cases. Uveitis is a relatively rare manifestation of Lyme disease, but it may occur in the later stages. Vitritis, choroiditis optic neuritis, and motility problems have also been described.70-74 Exudative detachment associated with the choroiditis74 has been reported, as has a case of retinal vasculitis.75 Syphilis is caused by Treponema pallidum. Between 1995 and 2003, the increase in the incidence of syphilis in the United Kingdom has been more than 10-fold.76 Ocular disease typically occurs in secondary syphilis but is also observed in tertiary syphilis. Uveitis is the most common ocular manifestation in both these stages of the disease.77,78 The retinal changes are essentially similar in both secondary and tertiary syphilis. In keeping with its moniker, the “great imitator,” the disease can affect all structures of the eye. The combination of good visual acuity, reasonable visual fields, mild panuveitis, swollen disc, and afferent papillary defect is highly suggestive of syphilitic infection. In addition to neuroretinitis, the retinal findings include chorioretinitis, retinal vasculitis, serous retinal detachment, and necrotizing retinitis (Fig. 24–10). The necrotizing retinitis may be such that it is difficult to clinically distinguish from acute retinal necrosis (ARN) (discussed later in this chapter). The diagnosis is established by the presence of other systemic

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Figure 24–10. Peripheral retinal changes in syphilis.

features.79 The association with HIV is discussed elsewhere in this chapter.

Tuberculosis Choroidal involvement is probably the most common form of ocular involvement in tuberculosis. Usually it is in the form of choroidal tubercles that are white, gray, or yellow lesions (Fig. 24–11). The patient neither has to be seriously unwell nor has to have miliary tuberculosis for ocular disease to be present.80,81 The ocular disease may manifest many years after the tuberculosis has been found and treated elsewhere in the body.82 Other manifestations include multifocal choroiditis or serpiginouslike choroiditis. Retinal involvement can result from either choroidal extension or bloodborne spread. Retinal involvement can be either as tubercles or as a diffuse retinitis. Neovascularization and retinal vasculitis can also occur.83,84

Whipple’s Disease Whipple’s disease is characterized by arthralgia, abdominal pain, and weight loss. The causative organism is Tropheryma whippelii. Oculomasticatory myorrhythmia is believed to be pathognomonic, but fundal changes also occur. These include vitreous opacities, diffuse chorioretinal inflammation with capillary involvement, and retinitis.85-89

Herpetic Infections Herpesviruses cause ARN. The clinical characteristics for the diagnosis are focal, well-demarcated areas of retinal necrosis, which progresses in a rapid and circumferential manner; occlusive vasculopathy; and a prominent inflammatory reaction (Fig. 24–12).90 ARN may occur in isolation or in association with other forms of herpes infection, such as herpes zoster ophthalmicus. ARN may also be present in association with either

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Figure 24–11. Choroidal changes in tuberculosis.

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An autopsy study of eyes from 235 patients with HIV infection revealed intraocular tuberculosis in only two eyes.98

Retinal Manifestations of HIV Infection

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Figure 24–12. Areas of retinal necrosis in acute retinal

Microvasculopathy is the most common ocular manifestation of HIV infection, being present in 40% to 60% of patients,99 and appears to be inversely related to the CD4 count.100 In the retina, it is most frequently represented by cotton-wool spots, which are usually asymptomatic and resolve after about 6 weeks. Hemorrhages may occur, particularly in patients with low platelet counts or diabetes. They are a response to the HIV infection. Less commonly, patients may develop macular ischemia,101 which is also probably caused by the primary infection. Large retinal vessel disease has been described,102 but this is rare. Progressive visual loss has been described in a patient with HIV infection who had a clinically normal retina but abnormal photoreceptor function on electrophysiological testing.103 This process continued even when the viral load was undetectable.

necrosis.

Cytomegalovirus-Associated Retinitis meningitis or encephalitis. It appears that encephalitis, either concurrent or past, is more likely to be associated with herpes simplex virus type 1 infection, whereas herpes simplex virus type 2 is more likely to be involved in the presence of meningitis, whether past or concurrent.91 Genotypical analysis in two patients who had ARN after encephalitis revealed identical strains of herpes simplex virus type 1 in the brain and eye, suggestive of brain-to-eye transmission of the infection in these patients.92 ARN may occur concurrently with encephalitis or up to 20 years later.93 A case of cerebral vasculitis in which ARN was the only manifestation of any herpetic infection has been reported.94

Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis can occur months to years after measles infection. It usually affects children or young adults, but a case in a 49-year-old man has been described.95 Ocular involvement occurs in about 50% of cases and most often develops at the same time as neurological symptoms. Chorioretinitis with subsequent scarring is the most common retinal appearance. In rare cases, the ocular signs precede the neurological ones.96

Human Immunodeficiency Virus The retinal manifestations of HIV can be subdivided into those resulting primarily from the HIV infection, from associated infections, and from malignancies. The incidence of many of these conditions appears to have decreased since the introduction of highly active antiretroviral therapy.97 Diagnosis can be difficult because the ocular signs may differ from those in an immunocompetent individual, and there may be two concurrent infections. Also interesting is that although HIV has contributed to the increase in incidence of tuberculosis, this may not have been mirrored by an increase of ocular tuberculosis.

Cytomegalovirus-associated retinitis is the commonest ocular infection in patients with acquired immunodeficiency syndrome (Fig. 24–7). However, its incidence has dropped since the introduction of highly active antiretroviral therapy.104 It rarely occurs in patients with a CD4 count lower than 50.100 Cytomegalovirus-associated retinitis occurs mainly in patients with HIV infection but can occur in patients who are immunocompromised for other reasons.41,105 There are two main forms of clinical presentation: a fulminant form and an indolent form. The fulminant form is characterized by confluent retinal necrosis with hemorrhage that in most cases develops in the posterior retina, whereas the indolent form has a more granular form. Up to 15% of patients with cytomegalovirus-associated retinitis are asymptomatic; therefore, screening is required for patients with HIV infection who have low CD4 counts and positive cytomegalovirus serological profiles.

Herpetic Infections Associated with HIV Infection Necrotizing herpetic retinopathy represents a continuum of posterior segment inflammation caused by herpesviruses. The best recognized are ARN and progressive outer retinal necrosis. Usually ARN occurs in immunocompetent patients or in patients with HIV infection but minimal immune dysfunction; progressive outer retinal necrosis occurs in patients with HIV and significant immune compromise. Progressive outer retinal necrosis consists of a retinitis, often in the posterior pole, that is not usually associated with an inflammatory reaction. However, the two diseases can occur simultaneously, one eye having ARN and the other progressive outer retinal necrosis.106 Both necessitate intraocular and systemic antiviral treatment.

Syphilis in HIV Infection Ocular syphilis has been discussed elsewhere, but it has a number of significant features in relation to HIV infection. It can develop when CD4 counts are higher than 200 and can be the manifesting sign of HIV infection. The ocular findings are similar to those in patients without HIV infection, but a rare

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appearance, believed to be more common in patients infected with both HIV and T. pallidum, has been described. This is a placoid chorioretinopathy, consisting of large, yellowish placoid lesions with faded centers in the region of the macula and optic disc.107 There are two important features about syphilis infections in HIV-seropositive individuals. First, it can mimic the appearance of other ocular conditions such as cytomegalovirusassociated retinitis, making diagnosis and treatment difficult. Second, ocular syphilis is associated with CNS involvement in 85% to 100% of patients with HIV infection, as opposed to 35% to 40% of HIV-seronegative patients.108,109

Toxoplasmosis in HIV Infection Toxoplasmosis retinitis can be similar to cytomegalovirus-associated retinitis, but there is usually more inflammation, and it is less likely to be associated with hemorrhage. The classic appearance in an immunocompetent patient is that of a fluffy white chorioretinal lesion in association with an area of scarring in one eye. However, in immunosuppressed patients, it can be bilateral, multifocal, and not associated with an old scar (Fig. 24–13). All of these features are suggestive of a primary infection rather than a reactivation of the condition. More than 50% of patients with ocular toxoplasmosis may have simultaneous toxoplasmosis cerebritis.99 Other fundal appearances include choroiditis, numerous scattered white lesions (a “miliary” pattern),110 a diffuse necrotizing retinitis,111,112 and punctate lesions in the outer retina.113

Malignancies Associated with HIV Infection In patients with HIV infection, ocular non-Hodgkin lymphoma is usually associated with CNS and systemic involvement. The fundal features include necrotizing retinitis, choroidal infiltrates, and vitritis, but these appearances can also be as a result of infection by syphilis, toxoplasmosis, or viruses.114-118 Therefore, the diagnosis must be considered if the retinitis is

unresponsive to antiviral, antisyphylis, and antitoxoplasmosis treatment.

Fungal Infections A number of fungi can affect the brain and the retina. These are most often present in patients who are immunocompromised. The incidence of ocular fungal infections, such as Pneumocystis and Cryptococcus organisms, in HIV-seropositive patients appears to have decreased since the introduction of highly active antiretroviral therapy.97

Mucormycosis Mucormycosis is an acute fungal infection that is rapidly invasive and carries a high mortality rate. Diabetes is a common predisposing factor. There are a number of clinical forms of mucormycosis, the most common being rhino-orbito-cerebral. This form affects the eye, and a necrotic eschar of the nose or hard palate is a characteristic sign. Although orbital cellulitis is the most common form of ocular involvement, serous retinal detachment and retinitis119 and choroidal ischemia have been described.120,121

Candida Albicans A fluffy white chorioretinal lesion with overlying vitreous haze is the typical lesion of C. albicans–related endophthalmitis. The infection may extend into the vitreous humor, causing cotton ball–like opacities characteristic of candidal infection. Progressive retinochoroiditis with satellite lesions may also occur.

Cryptococcus Cryptococcal infection occurs mainly in patients who are HIV-seropositive. Up to 25% of patients with cryptococcal meningitis have neuro-ophthalmological lesions, which makes it the most common cause of acquired immunodeficiency syndrome–related neuro-ophthalmological lesions.99 Cryptococcal choroiditis is, however, rare. It may be may be multifocal, solitary, or confluent (Fig. 24–14).122 The lesions may initially be asymptomatic. Progressive visual loss may occur as a result of papilledema and also fungal optic nerve sheath invasion.123

Pneumocystis Carinii One of the ocular features of P. carinii is choroiditis.124 It is classically bilateral and multifocal. The lesions are distinctive, being yellowish and well demarcated. They are slowly progressive, and usually vision is unaffected. There is not usually any associated ocular inflammation.124,125 In HIV-seropositive patients with presumed P. carinii choroidopathy, the majority had used inhaled pentamidine as prophylaxis against recurrent Pneumocystis-related pneumonia.125

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Figure 24–13. Toxoplasmosis in a patient with human immunodeficiency virus infection.

Pigmentary changes in the retina may occur in patients with mitochondrial disease. These can take a variety of forms and

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Figure 24–14. Cryptococcal choroiditis with a swollen optic disc.

include appearances that have been described as pigment clumping, atrophy, salt-and-pepper retinopathy, and appearances of classic retinitis pigmentosa (Fig. 24–15). Involvement of the macula can occur, as can vascular attenuation. The most common appearance is that of a salt-and-pepper retinopathy. There does not, however, appear to be any link between the presence or type of retinal pigmentary change, the type of genetic defect, biochemical abnormality, and any clinical features. A pigmentary retinopathy is a major diagnostic criterion for the diagnosis of Kearns-Sayre syndrome (the other features being a chronic progressive external ophthalmoplegia; onset before the age of 20; and cardiac conduction abnormalities, elevated cerebrospinal fluid protein levels, or cerebellar dysfunction). Retinal pigmentary degeneration can also be present in patients with chronic progressive external ophthalmoplegia and no other neurological or systemic abnormalities, as well as in otherwise unaffected relatives.126

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Pigmentary retinopathy is also a major diagnostic feature of the syndrome of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP). However, patients who have no retinopathy, no subtle pigmentary retinopathy, and no severe bone spicule pattern have been identified with the same mutation.126 Furthermore, a patient in whom the retinal changes progressed from an initial salt-and-pepper retinopathy to typical retinitis pigmentosa over an 8-year period has been described.127 Other mitochondrial diseases in which retinal changes have been reported include the syndrome of myoclonic epilepsy and ragged red fibers and the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS). The retinal changes in MELAS are in the form of pigmentary changes in the macula.128,129 MELAS is associated with the 3243 mutation, which can also manifest as maternally inherited diabetes and deafness. Macular changes similar to those in MELAS have also been reported in these patients,130,131 which demonstrates the marked overlap between clinical syndromes. Funduscopic abnormalities may be present in patients with Leber’s hereditary optic neuropathy and in their asymptomatic maternal relatives. Especially during the acute phase of visual loss, there may be hyperemia of the optic nerve head, dilation and tortuosity of vessels, hemorrhages, circumpapillary telangiectatic microangiopathy, or circumpapillary nerve fiber layer swelling (pseudoedema). There may be cupping of the optic disc and arterial attenuation.126 In 2 of 20 patients with Leber’s hereditary optic neuropathy, pigmentary changes were noted at the retina.128

NEOPLASIA Metastatic Disease Metastases are probably the most common form of intraocular malignancy and can be associated with concurrent neurological involvement. They tend to involve the choroid but can affect the retina or vitreous humor (Fig. 24–16).132,133 Lung and breast carcinoma are the most common sources of ocular metastases and may be the manifesting sign of the disease.

Lymphoma

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Figure 24–15. Retinitis pigmentosa.

Primary intraocular lymphoma may occur in isolation, without involvement of the CNS. However, because the ocular and the CNS components show identical cytological features and phenotypical expression, the two entities are often considered as one entity: primary CNS lymphoma. Involvement of the eyes in this condition has been reported to occur in 12% to 25% of cases,134-137 and 56% to 80% of patients with intraocular lymphoma eventually develop intracranial involvement.138-142 As yet, it is unknown whether lymphoma cells from the eye can invade the CNS or whether the disease arises multifocally, in the eye and CNS. Experimental data from an animal model suggest that invasion of the CNS from the eye does not occur.143 The clinical features are dependent on the site of lymphoma involvement. The only sign of the disease may be vitreous cellular infiltration with resulting floaters and reduction of acuity.

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Neuro-ophthalmology adequately treated with only local therapy or requires treatment of the entire CNS presumptively.

Paraneoplastic Syndromes Paraneoplastic visual syndromes represent visual dysfunction in the setting of known or suspected malignancies, without direct involvement of the eye or nervous system by tumor, antineoplastic agent toxicity, or opportunistic infection. They are rare, and the fundus may appear normal on presentation. Furthermore, because some patients may present before the diagnosis of a neoplasm, diagnosis can be difficult. These syndromes are characterized by elevated serum levels of autoantibodies directed against tumor antigen that cross-react with retinal proteins, resulting in retinal dysfunction.

Carcinoma-Associated Retinopathy ■

Figure 24–16. Metastatic deposits with associated retinal detachment.

Because this is typically the appearance of a posterior uveitis, ocular lymphomas are described as being one of the masquerade syndromes. Diagnosis at this stage can therefore be difficult. The classic lesions are creamy yellow subretinal infiltrates (Fig. 24–17), with overlying retinal pigment epithelial detachments,142 but they may take on many forms, such as discrete white lesions, suggestive of ARN or toxoplasmosis144; branch retinal artery obstruction with coexistent multifocal chorioretinal scars145; and retinal vasculitis. If patients have combined CNS and eye involvement, therapy for the eyes is typically accomplished as part of the overall treatment plan, including the use of intravitreal methotrexate in some cases. An important question that has not been answered is whether apparently clinically isolated ocular disease is

Carcinoma-associated retinopathy (CAR) was first described in 1976.146 It is associated most commonly with small cell lung cancer and next most commonly with gynecological and breast cancers. Cases associated with other cancers such as non–small cell lung, colon, pancreatic, prostate, larynx, and bladder cancers and lymphoma have also been reported. Overall, the incidences among men and women are equal. Visual loss is usually subacute and bilateral, preceding tumor diagnosis in about 50% of cases. Patients may complain of positive visual phenomena, visual field loss, and night blindness. Initially there may be no retinal signs, but arteriolar narrowing and pigmentary retinal changes develop. Sheathing of the retinal vessels may develop. Electrophysiological testing demonstrates that both rods and cones are affected. The first antigen shown to represent the source of autoimmunity in patients with CAR was the 23-kD protein recoverin.147,148 This is a calcium-binding protein that regulates phosphorylation of the visual pigment rhodopsin during visual transduction. A number of other antigens have since been reported to be associated with CAR. The next most commonly found antigen is the 46-kD protein enolase,149 although a number have now been identified (see review by Chan150). However, the presence of neither anti-recoverin nor antienolase antibodies is diagnostic for CAR. A few patients with anti-recoverin antibodies but with no evidence of malignancy have been described.151,152 Up to two thirds of patients with antienolase antibody–associated retinopathy have no evidence of malignancy.153,154 Furthermore, in patients with anti-enolase antibodies, the retinopathy often develops after the detection of cancer, and the disease course is usually less severe than in patients with anti-recoverin antibodies.154

Melanoma-Associated Retinopathy

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Figure 24–17. Ocular lymphoma. The hazy view is caused by vitreal inflammation.

Because of the relatively greater decrease in incidence of lung cancers in comparison with melanomas, it has been suggested that melanoma-associated retinopathy (MAR) is becoming more common than CAR.150 There are a number of differences between MAR and CAR. In MAR, the diagnosis of melanoma has often been made before the development of visual problems, and the incidence of MAR is higher in men. Patients tend to complain of shimmering vision and night blindness. The degree of visual loss is less severe than in CAR. As in CAR, the initial

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retinal appearances may be normal, but retinal pigment epithelial irregularity, retinal arteriolar attenuation, and optic disc pallor are present in cases in which the symptoms have been present for some time. Vitritis and retinal periphlebitis have been reported.155 Autoantibodies from MAR sera were shown to stain rod bipolar cells in the human retina.156 The specific antigen responsible has not been identified. Retinal cells other than bipolar cells have implicated, and antibodies against a variety of antigens have been identified (see Chan150).

Paraneoplastic Optic Neuritis with Retinitis Paraneoplastic ophthalmological syndromes are usually retinopathies, but in rare cases, the optic nerve is affected. In some patients, both paraneoplastic optic neuritis and a retinopathy coexist. This has been described in patients with small cell lung carcinoma. None had anti-recoverin antibodies, but all had a distinct immunoglobulin G marker antibody to collapsing response-mediator protein-5.157

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Figure 24–18. Macular changes in spinocerebellar ataxia type 7.

Bilateral Diffuse Uveal Melanocytic Proliferation This rare condition often precedes the diagnosis of cancer. Patients present with visual loss and are found to have many round or oval red patches at the level of retinal pigment epithelium and pigmented and nonpigmented melanocytic lesions of the uveal tract. An ultrasonogram reveals extremely thickened choroid. Retinal detachment and cataracts may develop.158 Approximately 25% of patients develop pigmentation of their skin or mucous membranes.159 The most commonly associated neoplasms are ovarian cancers in women and lung and pancreas cancers in men, although it has also been reported in kidney, colon, breast, and esophageal cancers.159,160

MOVEMENT DISORDERS AND ATAXIA Most often the neuro-ophthalmological findings in patients with movement disorders are those of the oculomotor system. Patients with Parkinson’s disease often complain of blurred vision. Retinal appearances are normal, however, but functional abnormalities are present on psychophysical and electrophysiological testing. Some of these are reversible with levodopa (see Jackson and Owsley161 for a review). Patients with Huntington’s disease also demonstrate abnormalities of retinal function on psychophysical testing.162 However, about 50% of patients with Guam amyotrophic lateral sclerosis–parkinsonism–dementia complex (Lytico-Bodig disease) do have retinal pigmentary changes.163 A number of rare movement disorders are associated with retinal changes. Pantothenate kinase–associated neurodegeneration (formerly known as Hallervorden-Spatz syndrome),164 which is caused by a mutation in the PANK2 gene, is characterized by dystonia, parkinsonism, iron accumulation in the brain, and occasionally retinopathy. Electrophysiological abnormalities have been observed in affected patients who have clinically normal eyes.165 The syndrome of hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, which is also caused by a PANK2 mutation,166 also has a pigmentary retinopathy. Aceruloplasminemia is a rare condition that was first described in 1987.167 It also results in iron overload in the brain,

retina, and pancreas. The first patient described was Asian, and the retinal changes were noted in the midperipheral region.167 Subsequently a case was described in a white patient, but the changes were at the macula.168 In Wilson’s disease, there is also a deficiency of ceruloplasmin, but the biochemical problem relates to copper metabolism. Retinal changes have been reported in addition to the familiar Kayser-Fleischer rings in the cornea. However, it is unclear whether these were caused by long-term therapy with pencillamine.169 A number of the ataxias are also associated with retinal pigmentary changes. These include Bassen-Kornzweig disease,170 Refsum’s disease,171 and adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency.172 A deficiency of vitamin E may cause the initial retinopathy; the treatment of these conditions includes vitamin E supplementation.173 Although there are many forms of spinocerebellar ataxia with oculomotor abnormalities, spinocerebellar ataxia type 7 can be differentiated from the other forms by the associated retinal changes. These take the form of progressive macular changes with visual loss (Fig. 24–18).174 Electrophysiological studies have demonstrated that the functional defects are greater than expected from the clinical appearance.175

MUSCLE DISEASES Patients with facioscapulohumeral muscular dystrophy often have retinal telangiectasia. In rare cases, this can have significant visual consequences, such as exudative retinal detachment.176 Myotonic dystrophy is most frequently associated with cataract, but retinal pigmentary changes are also present. They can be peripheral or affect the macula and may slowly progress.177 The classic neuro-ophthalmological feature of dermatomyositis is the heliotrope rash of the eyelids, but a vasculitic retinopathy with retinal hemorrhages and cotton-wool spots may occur. With immunosuppression, visual recovery is usually but not always complete.178

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PHACOMATOSES The phacomatoses are a group of disorders that feature multiple hamartomas of the nervous system, eye, skin, and viscera.

Neurofibromatosis Neurofibromatosis Type 1 The diagnostic criteria for neurofibromatosis type 1 include optic gliomas and Lisch nodules, which are hamartomas of the pigment epithelium. Nevertheless, retinal involvement is rare and generally nonspecific. The retinal lesions include a pigmentary retinopathy,179 retinal hamartomas,180,181 and capillary hemangiomas and combined hamartomas of the retina and pigment epithelium.181 Mild pigmentary changes that resemble cutaneous café au lait spots have been described.180 Myelinated fibers may be present more frequently than in the normal population,182 and vascular occlusions have also been reported,183 but it is unclear whether these are merely coincidental. Neurofibromas of the uveal tract can occur in up to 50% of patients.182,184-189 These are usually pale yellow nodules, but the entire uvea may be thickened by a diffuse neurofibroma. Choroidal nevi may occur more frequently in patients with neurofibromatosis type 1 than in the normal population.190

Neurofibromatosis Type 2 Cataracts and retinal changes are common in patients with neurofibromatosis type 2, whereas Lisch nodules are not as common as in neurofibromatosis type 1.191-196 Indeed, the ocular findings may be the first manifestation of the disease.194 The retinal changes can take the forms of epiretinal membranes,196-198 hamartomas of the retina,194,195 and combined pigment epithelial and retinal hamartomas.191,193,198 Retinal hamartomas are not exclusively associated with severe neurofibromatosis type 2, and neither the type nor the location of the germline neurofibromatosis type 2 mutation is the sole determinant of retinal abnormalities, which can be variably expressed in families with neurofibromatosis type 2.199

Tuberous Sclerosis Hamartomas of the retina are the most prominent ocular manifestation of tuberous sclerosis, present in about 50% of patients and bilateral in 25% of cases. They arise from the ganglion cell layers and infiltrate all layers of the retina. They do not tend to grow or interfere with vision. The appearances are varying, ranging form semitransparent structures to opaque multinodular lesions (Fig. 24–19). Although most lesions remain stable, becoming calcified over time, they can develop in areas of previously normal-appearing retina.200 A case of a patient with a giant cell astrocytoma of the retina with atypical histopathological features and local aggressive behavior has been reported.201 Depigmented pigment epithelial lesions may be present. These can have a shape similar to that of cutaneous mountain ash leaf spots.202-204

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Figure 24–19. Astrocytic hamartoma.

Von Hippel-Lindau Disease The retinal capillary hemangioma is the most frequent and the earliest manifestation of von Hippel-Lindau disease (Fig. 24–20).205-209 The other systemic features include hemangiomas of the CNS; renal cell carcinoma; pheochromocytoma; and renal, pancreatic, and epididymal cysts. The retinal capillary hemangioma is usually an orange-red, circumscribed round lesion. It can enlarge and develop a feeder vessel, and fluid may extravasate, leading to a retinal detachment. Thus, patients should have an annual ophthalmological assessment with dilated funduscopy, because the lesions may be small and situated in the retinal periphery. Retinal capillary hemangiomas can also develop around the optic disc. A rare retinal feature of von Hippel-Lindau disease are retinal “twin vessels,”210 defined as a paired retinal arteriole and venule that are separated by less than the diameter of one venule. Twin vessels are of normal caliber and look like normal retinal vessels except for their course. Retinal capillary hemangiomas not associated with von Hippel-Lindau disease do occur but at a later age (48 years) than in patients with von Hippel-Lindau disease (25 years).211 Nevertheless, the systemic features of von Hippel-Lindau disease must be ruled out in patients presenting with a solitary capillary hemangioma. The presence of multiple retinal capillary hemangiomas (two or more) indicates the presence of underlying von Hippel-Lindau disease.212

Sturge-Weber Syndrome The chief components of the Sturge-Weber syndrome are a cutaneous hemifacial angioma and an ipsilateral angioma of the leptomeninges and brain. Glaucoma is the most common ocular association. Choroidal angiomas are also present; these can affect one or both eyes. Most commonly the angiomas are diffuse, obscuring the normal choroidal markings.213 More rarely, they are localized and may be associated with a serous retinal detachment.214 The retinal vasculature may be abnormal.215

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Figure 24–20. Retinal capillary angioma.

Wyburn-Mason Syndrome The classic Wyburn-Mason syndrome consists of an intracranial arteriovenous malformation and a separate retinal one. The retinal arteriovenous malformation has also been described as an arteriovenous aneurysm or racemose angioma. It is usually unilateral and involves the posterior pole, thus affecting the vision. Often it is stable, but it may enlarge (Fig. 24–21).216,217

Other Phacomatoses The classic ophthalmological lesion of ataxia telangiectasia is telangiectasia of the conjunctiva, and the retina is spared. In Klippel-Trénaunay-Weber syndrome, varicosities of the retinal vasculature and choroidal angiomas have been described.218

CEREBROVASCULAR DISEASE Retinopathy The retinal and cerebral arterioles share common anatomy and physiology. Because the retina is readily visualized, it provides an opportunity to assess the retinal and, by inference, the cerebral circulation. Studies in people with hypertension have

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Figure 24–21. Racemose angioma.

shown that signs of retinopathy are associated with both subclinical and clinical stroke.219-222 Retinal digital photography has been used in large population-based studies to investigate the relationship between retinal findings and systemic disease, including stroke. The images are analyzed in a standardized manner and are used to look for features of retinopathy such as microaneurysms, retinal hemorrhages, cotton-wool spots, arteriovenous nicking, and arteriolar narrowing. The studies include the Atherosclerosis Risk in Communities study, the Beaver Dam Eye Study, and the Blue Mountains Eye Study. The Atherosclerosis Risk in Communities study has demonstrated that after controlling of stroke risk factors such as diabetes and hypertension, the presence of retinopathy was predictive of an incident stroke.223 Retinopathy was also associated with cognitive decline224 and with magnetic resonance imaging findings such as white matter lesions225 and cerebral atrophy.226 The risk of stroke was higher in patients who had both retinopathy and changes noted on cerebral magnetic resonance imaging.225

Retinal Emboli and Arteriolar Occlusion Retinal emboli are usually present at the bifurcation of retinal arterioles and may be reflective or nonreflective. A variety of emboli have been described, but clinically a reliable distinction cannot always be made (Fig. 24–22).227 Emboli are also present in up to about 40% of central retinal artery occlusions (Fig. 24–23) and 70% of branch retinal artery occlusions.228,229 The emboli usually originate from the carotid arteries or a cardiac source. The carotid vessels are the commonest source of emboli in patients with amaurosis fugax or retinal artery occlusion and of asymptomatic emboli,230 but often no embolic source is found.230,231 In elderly patients, the absence of an embolus in a retinal artery occlusion necessitates the exclusion of giant cell arteritis as a diagnosis. Furthermore, the presence of an embolus that is asymptomatic232 or in association with a retinal artery occlusion233 is not a good predictor of carotid artery stenosis. This may be because the emboli result from plaques and are not associated with stenosis per se.232

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Ocular Ischemic Syndrome and Other Ocular Associations with Carotid Artery Disease

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Figure 24–22. Retinal embolus.

Emboli may be asymptomatic. It has been shown that for men with asymptomatic cholesterol emboli, there is an increased risk of stroke, but not myocardial infarction,234 and that patients with an embolus, symptomatic or not, have a reduced survival rate.228 Again, the analysis of digital photographs in large populations has added further information about emboli. The Beaver Dam Eye study found that for asymptomatic retinal emboli, the 10-year cumulative incidence was 1.5%.235 The incidence rose with age, from 1.0% in subjects aged 43 to 54 years to 2.2% in those aged 65 years or older at baseline. They are more common in men than in women. They appear to be transitory, and in approximately 30% of affected eyes, they are multiple. Bilateral ocular involvement is rare. The presence of asymptomatic retinal emboli is associated with carotid artery disease236 and an increased risk of death from stroke, independent of any other risk factors.235

Severe carotid stenosis is associated with venous stasis retinopathy. In this condition, there is an insidious onset of blurred vision in the affected eye. Patients may complain of episodes of transient monocular visual loss precipitated by exercise, eating, or bright lights. Examination reveals dilated and tortuous retinal veins, peripheral hemorrhages, and an easily induced pulsation of the central retinal artery with digital pressure.237,238 Venous stasis retinopathy may progress to ocular ischemic syndrome. This is a severe form of chronic ischemia caused by hypoperfusion of the eye, which affects both its anterior and posterior segments. Neovascularization of the iris, disc, and retina may occur. In patients with minimal or no neovascular changes, carotid endarterectomy appears to improve blood flow through the ophthalmic and central retinal arteries.239 It also appears to prevent progression of ocular ischemic syndrome, if not improve vision in all patients.239 Percutaneous angioplasty and stenting have also been used effectively in a number of patients who had lesions that were not amenable to endarterectomy.240 Patients with carotid occlusive disease may develop neurological symptoms at the same time as a central retinal artery occlusion.240 Carotid artery dissection is classically associated with a painful Horner’s syndrome, but both central and branch retinal artery occlusions can be present in this condition.241-243 Carotid artery disease is also associated with retinal vein occlusions.236

Retinal Vasculitis and Stroke One form of retinal vasculitis is localized to the eye, and fluorescin angiography demonstrates ischemic retinal changes. This condition, known as idiopathic ischemic retinal vasculitis, has a worse visual prognosis than does retinal vasculitis with no associated ischemia.244 Furthermore, after a minimum follow up of 5 years, almost one third of patients in one study had suffered a stroke and/or myocardial infarction.245

Secondary Causes of Stroke Coagulopathies that are associated with stroke, such as hyperhomocysteinemia and antiphospholipid syndrome, also have retinal manifestations such as retinal artery and vein occlusions.246,247

Cerebral Small-Vessel Disease The most common form of cerebral small-vessel disease is acquired degenerative small-vessel disease, and this usually is not clinically manifest before the sixth decade of life. There are, however, a number of other cerebral microangiopathies, several of which affect the eye. These include Susac’s syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and a number of hereditary diseases.

Susac’s Syndrome ■

Figure 24–23. Central retinal artery occlusion with the appearance of a cherry-red spot.

Susac’s syndrome consists of the triad of encephalopathy, branch retinal artery occlusions, and hearing loss, which

chapter 24 retinal disease

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309

Figure 24–24. An area of focal leakage from a retinal arteriole on fluorescein angiography.

occurs most commonly in affected young women.248,249 The branch retinal artery occlusions are often bilateral and may be the manifesting features of the illness, or they may occur later in the clinical course. Fluorescein angiography may reveal focal leakage from retinal arterioles even in the absence of frank occlusion (Fig. 24–24). Such leakage can be used to measure disease activity. The encephalopathy manifests with headache, confusion, memory loss, behavioral changes, dysarthria, and occasional mutism. The hearing loss is usually bilateral and frequently associated with tinnitus and vertigo. Although the presence of encephalopathy, branch retinal artery occlusions, and hearing loss is pathognomonic for Susac’s syndrome, not all elements may be present initially. The condition usually stabilizes after a period of 2 to 4 years. On magnetic resonance images, lesions of the corpus callosum are often present.250

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy CADASIL is caused by mutations of the Notch3 gene, which is located on chromosome 19. In patients with CADASIL vision is usually preserved, although retinal findings such as peripapillary arteriolar sheathing, arteriolar narrowing, ateriovenous nicking,251 and cotton wool spots252 may be present. Visual loss may take the form of a hemianopic defect caused by stroke252 or anterior ischemic optic neuropathy.253 In asymptomatic patients, there may be electrophysiological evidence of retinal dysfunction.254 A histopathological study of four eyes from two patients with CADASIL demonstrated loss of vascular smooth muscle cells in the central retinal artery and its branches, as well as the optic disc. The choroidal circulation was spared, which demonstrated a differential involvement of small blood vessels.255

Other Hereditary Diseases of the Small Vessels There are other rare hereditary conditions that affect the retinal and cerebral circulation. Patients with autosomal dominant

■

Figure 24–25. Retinal hemorrhages in a patient with a subarachnoid hemorrhage.

vascular retinopathy, migraine, and Raynaud’s phenomenon may have a retinopathy that appears very similar to that of diabetic retinopathy. Indeed, a few patients may develop retinal neovascularization, which results in poor vision.256,257 Three other diseases with retinopathy have been linked to the same locus on chromosome 3p21. These are cerebroretinal vasculopathy; the syndrome of hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); and hereditary vascular retinopathy.258 The retinal vascular abnormality constitutes part of the disease title in the syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.259 Fabry’s disease is also accompanied by retinal vascular changes.260 The practical implication of these findings is that all patients with small-vessel disease probably require ophthalmoscopy.261 Finally, of interest is that a high prevalence of migraine has been in reported in CADASIL; HERNS; hereditary vascular retinopathy; and the syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.

Terson’s Syndrome Vitreous hemorrhage occurring in association with subarachnoid hemorrhage is known as Terson’s syndrome.262 However, intraocular hemorrhages of any type (retinal, subhyaloid, or vitreous) have been documented in 10% to 40% of individuals with subarachnoid hemorrhage,263 and reports have not always made a distinction between such types of hemorrhage (Fig. 24–25).264 Furthermore, preretinal hemorrhage may precede vitreous hemorrhage.263,265 Terson’s syndrome is present in between 3% and 13% of patients with a subarachnoid hemorrhage266 and carries an increased mortality rate in relation to patients who have had a subarachnoid hemorrhage but not vitreous hemorrhage.266 It has also been suggested that mild retinal hemorrhages are associated with a better prognosis than

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are large preretinal hemorrhages or vitreous hemorrhages.267 An urgent vitrectomy may be required for visual rehabilitation in patients with bilateral vitreous hemorrhage.

METABOLIC DISEASES IN CHILDREN A variety of ophthalmological features may occur in these diseases, all of which may contribute to visual problems. Thus, it can be difficult to determine the precise cause of visual loss. For example, patients with Hunter’s syndrome may have corneal clouding, pigmentary retinal degeneration, and optic atrophy. Furthermore, there may also be mucopolysaccharide deposition in the occipital cortex. The most common retinal findings are the presence of a macular cherry-red spot (an appearance similar to that of a central retinal artery occlusion; see Fig. 24–23) and pigmentary retinopathy. The cherry-red spot is classically associated with Tay-Sachs disease. However, a form of this finding is present in many of the metabolic diseases, although not necessarily in all patients affected by them. Also, in other conditions it may have prognostic significance; for example, in Farber’s disease, its presence may be correlated with disease severity.268 Pigmentary retinopathy is also present in a number of conditions, although, again, not in all affected individuals. The clinical pattern of the retinopathy is variable. There are a few striking changes associated with the metabolic diseases, such as the absence of retinal pigmentation observed in phenylketonuria and the presence of bilateral parafoveal ringlets observed in hyperoxaluria type 1.269 The cherry-red spot tends to be present in the lysosomal storage diseases such as Tay-Sachs disease, Sandhoff’s disease, type 1 GM1 gangliosidosis, Farber’s disease, Niemann-Pick disease type A, and the sialidoses (namely types 1 and 2), as well as in metachromic leukodystrophy. Retinal pigmentary changes can be present in a number of the following conditions: 1. The mucopolysaccharidoses: namely, Hurler’s syndrome, Hunter’s syndrome, Scheie’s syndrome, and Sanfilippo’s syndrome. It is rarely present in Morquio’s syndrome and is not present in Maroteaux-Lamy or Sly’s syndrome. 2. The disorders of peroxisomes, such as Zellweger’s cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy, infantile Refsum’s disease, and X-linked adrenoleukodystrophy. 3. The juvenile and infantile neuronal ceroid lipofuscinoses. 4. A few other conditions such as mucolipidosis type IV, GM1 gangliosidosis type 2 (in which a cherry-red spot is not present).

K E Y

P O I N T S

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The brain and retina share much in terms of anatomy and physiology.

●

Retinal disease may be the primary manifestation of systemic disease, including inflammation, infection, and metabolic and degenerative disorders.

●

Retinal changes can be diagnostic of a wide range of neurological diseases, from demyelinating to neuromuscu-

Suggested Reading Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology. Philadelphia: WB Saunders, 2000. Gold DH, Weingeist TA, eds: Color Atlas of the Eye in Systemic Disease. Philadelphia: Lippincott Williams & Wilkins, 2001. Miller NR, Newman NJ, eds: Walsh and Hoyt’s Clinical NeuroOphthalmology. Baltimore: William & Wilkins 1998 Riordan-Eva P, Whitcher JP, eds: Vaughan & Asbury’s General Ophthalmology. New York: McGraw-Hill, 2004. Spalton DJ, Hitchings RA, Hunter P, eds: Atlas of Clinical Ophthalmology, 3rd ed. London: Elsevier, 2004.

References 1. Jabs DA, Nussenblatt RB, Rosenbaum JT: Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140:509-516. 2. Rothova A, Alberts C, Glasius E, et al: Risk factors for ocular sarcoidosis. Doc Ophthalmol 1989; 72:287-296. 3. Edelsten C, Pearson A, Joynes E, et al: The ocular and systemic prognosis of patients presenting with sarcoid uveitis. Eye 1999; 13(Pt 6):748-753. 4. Gould H, Kaufman HE: Sarcoid of the fundus. Arch Ophthalmol 1961; 65:453-456. 5. James DG, Neville E, Langley DA: Ocular sarcoidosis. Trans Ophthalmol Soc U K 1976; 96:133-139. 6. Stavrou P, Linton S, Young DW, et al: Clinical diagnosis of ocular sarcoidosis. Eye 1997; 11(Pt 3):365-370. 7. Walsh F: Ocular importance of sarcoid. Arch Ophthalmol 1939; 21:421-438. 8. Sanders MD, Shilling JS: Retinal, choroidal, and optic disc involvement in sarcoidosis. Trans Ophthalmol Soc U K 1976; 96:140-144. 9. Spalton DJ, Sanders MD: Fundus changes in histologically confirmed sarcoidosis. Br J Ophthalmol 1981; 65:348-358. 10. Rothova A, Lardenoye C: Arterial macroaneurysms in peripheral multifocal chorioretinitis associated with sarcoidosis. Ophthalmology 1998; 105:1393-1397. 11. Cook BE Jr., Robertson DM: Confluent choroidal infiltrates with sarcoidosis. Retina 2000; 20:1-7. 12. Lardenoye CW, Van der Lelij A, de Loos WS, et al: Peripheral multifocal chorioretinitis: a distinct clinical entity? Ophthalmology 1997; 104:1820-1826. 13. Thorne JE, Brucker AJ: Choroidal white lesions as an early manifestation of sarcoidosis. Retina 2000; 20:8-15. 14. Edelsten C, Stanford MR, Graham EM: Serpiginous choroiditis: an unusual presentation of ocular sarcoidosis. Br J Ophthalmol 1994; 78:70-71. 15. Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet 1990; 335:1078-1080. 16. Akman-Demir G, Serdaroglu P, Tasci B: Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain 1999; 122(Pt 11):2171-2182. 17. Kansu T, Kirkali P, Kansu E, et al: Optic neuropathy in Behçet’s disease. J Clin Neuroophthalmol 1989; 9:277-280. 18. Kidd D, Steuer A, Denman AM, et al: Neurological complications in Behçet’s syndrome. Brain 1999; 122(Pt 11):21832194. 19. Mitra S, Koul RL: Paediatric neuro-Behçet’s disease presenting with optic nerve head swelling. Br J Ophthalmol 1999; 83:1096. 20. Swerdlow RH, Hanna GR: Behçet’s disease: presentation with sagittal sinus thrombosis diagnosed noninvasively. Headache 1996; 36:115-118.

chapter 24 retinal disease 21. Wechsler B, Vidailhet M, Piette JC, et al: Cerebral venous thrombosis in Behçet’s disease: clinical study and long-term follow-up of 25 cases. Neurology 1992; 42:614-618. 22. Lee E-S, Hur W, Bang D, et al: Prognosis of recurrent oral ulceration in Behçet’s disease. In Godeau P, Wechsler B, eds: Behçet’s Disease. Paris: Elsevier, 1993, pp 291-294. 23. Dilsen N, Konice M, Aral O, et al: Risk factors for vital organ involvement in Behçet’s disease. In Godeau P, Wechsler B, eds: Behçet’s Disease. Paris: Elsevier, 1993, pp 165-169. 24. Lueck, CJ, Pires M, McCartney AC, et al: Ocular and neurological Behçet’s disease without orogenital ulceration? J Neurol Neurosurg Psychiatry 1993; 56:505-508. 25. Muhaya M, Lightman S, Ikeda E, et al: Behçet’s disease in Japan and in Great Britain: a comparative study. Ocul Immunol Inflamm 2000; 8:141-148. 26. Read RW, Holland GN, Rao NA, et al: Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 131:647-652. 27. Najman-Vainer J, Levinson RD, Graves MC, et al: An association between Vogt-Koyanagi-Harada disease and GuillainBarré syndrome. Am J Ophthalmol 2001; 131:615-619. 28. Klinkhoff AV, Beattie CW, Chalmers A: Retinopathy in systemic lupus erythematosus: relationship to disease activity. Arthritis Rheum 1986; 29:1152-1156. 29. Gold DH, Morris DA, Henkind P: Ocular findings in systemic lupus erythematosus. Br J Ophthalmol 1972; 56:800-804. 30. Graham EM, Spalton DJ, Barnard RO, et al: Cerebral and retinal vascular changes in systemic lupus erythematosus. Ophthalmology 1985; 92:444-448. 31. Hollenhorst RW: Effect of posture on retinal ischemia from temporal arteritis. Arch Ophthalmol 1967; 78:569-577. 32. Chun YS, Park SJ, Park IK, et al: The clinical and ocular manifestations of Takayasu arteritis. Retina 2001; 21:132140. 33. Galetta SL: Vasculitis. In Miller NR, Newman NJ, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology. Baltimore: Williams & Wilkins, 1998, pp 3725-3886. 34. Hsu CT, Kerrison JB, Miller NR, et al: Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa. Retina 2001; 21:348351. 35. Font RL, Mehta RS, Streusand SB, et al: Bilateral retinal ischemia in Kawasaki disease: postmortem findings and electron microscopic observations. Ophthalmology 1983; 90:569577. 36. Drachman DA: Neurological complications of Wegener’s granulomatosis. Arch Neurol 1963; 8:145-155. 37. Nishino H, Rubino FA, DeRemee RA, et al: Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 1993; 33:4-9. 38. Bullen CL, Liesegang TJ, McDonald TJ, et al: Ocular complications of Wegener’s granulomatosis. Ophthalmology 1983; 90:279-290. 39. Riordan-Eva P, Williams CE, Wing AJ, et al: Retinal neovascularization secondary to cytomegalovirus retinitis in Wegener’s granulomatosis. J R Soc Med 1993; 86:301-302. 40. Tugal-Tutkun I, Kir N, Gul A, et al: Cytomegalovirus retinitis in a patient with Wegener’s granulomatosis. Ophthalmologica 2000; 214:149-152. 41. Agrawal A, Dick AD, Olson JA: Visual symptoms in patients on cyclophosphamide may herald sight threatening disease. Br J Ophthalmol 2003; 87:122-123. 42. Newman NJ, Slamovits TL, Friedland S, et al: Neuroophthalmic manifestations of meningocerebral inflammation from the limited form of Wegener’s granulomatosis. Am J Ophthalmol 1995; 120:613-621.

311

43. Spalton DJ, Graham EM, Page NG, et al: Ocular changes in limited forms of Wegener’s granulomatosis. Br J Ophthalmol 1981; 65:553-563. 44. Takanashi T, Uchida S, Arita M, et al: Orbital inflammatory pseudotumor and ischemic vasculitis in Churg-Strauss syndrome: report of two cases and review of the literature. Ophthalmology 2001; 108:1129-1133. 45. Mihara M, Hayasaka S, Watanabe K, et al: Ocular manifestations in patients with microscopic polyangiitis. Eur J Ophthalmol 2005; 15:138-142. 46. Arnold AC, Pepose JS, Hepler RS, et al: Retinal periphlebitis and retinitis in multiple sclerosis. I. Pathologic characteristics. Ophthalmology 1984; 91:255-262. 47. Hornstein G: The relation of retinal periphlebitis to multiple sclerosis and other neurological disorders. Acta Neurol Scand 1971; 47:413-425. 48. Rucker CW: Sheathing of the retinal veins in multiple sclerosis. Mayo Clin Proc 1944; 19:176-178. 49. Shaw PJ, Smith NM, Ince PG, et al: Chronic periphlebitis retinae in multiple sclerosis: a histopathological study. J Neurol Sci 1987; 77:147-152. 50. Tola MR, Granieri E, Casetta I, et al: Retinal periphlebitis in multiple sclerosis: a marker of disease activity? Eur Neurol 1993; 33:93-96. 51. Adams CW, Poston RN, Buk SJ, et al: Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 1985; 69:269-283. 52. Lightman S, McDonald WI, Bird AC, et al: Retinal venous sheathing in optic neuritis: its significance for the pathogenesis of multiple sclerosis. Brain 1987; 110(Pt 2):405-414. 53. Engell T, Sellebjerg F, Jensen C: Changes in the retinal veins in acute optic neuritis. Acta Neurol Scand 1999; 100:81-83. 54. Engell T: Neurological disease activity in multiple sclerosis patients with periphlebitis retinae. Acta Neurol Scand 1986; 73:168-172. 55. Birch MK, Barbosa S, Blumhardt LD, et al: Retinal venous sheathing and the blood-retinal barrier in multiple sclerosis. Arch Ophthalmol 1996; 114:34-39. 56. Graham EM, Stanford MR, Sanders MD, et al: A point prevalence study of 150 patients with idiopathic retinal vasculitis: 1. Diagnostic value of ophthalmological features. Br J Ophthalmol 1989; 73:714-721. 57. Biousse V, Trichet C, Bloch-Michel E, et al: Multiple sclerosis associated with uveitis in two large clinic-based series. Neurology 1999; 52:179-181. 58. Edwards LJ, Constantinescu CS: A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler 2004; 10:575-581. 59. Schmidt S, Wessels L, Augustin A, et al: Patients with multiple sclerosis and concomitant uveitis/periphlebitis retinae are not distinct from those without intraocular inflammation. J Neurol Sci 2001; 187:49-53. 60. Graham EM, Francis DA, Sanders MD, et al: Ocular inflammatory changes in established multiple sclerosis. J Neurol Neurosurg Psychiatry 1989; 52:1360-1363. 61. Smith JR, Rosenbaum JT: Neurological concomitants of uveitis. Br J Ophthalmol 2004; 88:1498-1499. 62. Zein G, Berta A, Foster CS: Multiple sclerosis–associated uveitis. Ocul Immunol Inflamm 2004; 12:137-142. 63. Towler HM, Lightman S: Symptomatic intraocular inflammation in multiple sclerosis. Clin Exp Ophthalmol 2000; 28:97-102. 64. Wakefield D, Jennings A, McCluskey PJ: Intravenous pulse methylprednisolone in the treatment of uveitis associated with multiple sclerosis. Clin Exp Ophthalmol 2000; 28:103-106. 65. Vine AK: Severe periphlebitis, peripheral retinal ischemia, and preretinal neovascularization in patients with multiple sclerosis. Am J Ophthalmol 1992; 113:28-32.

312

Section

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66. Parmley VC, Schiffman JS, Maitland CG, et al: Does neuroretinitis rule out multiple sclerosis? Arch Neurol 1987; 44:1045-1048. 67. Williams KE, Johnson LN: Neuroretinitis in patients with multiple sclerosis. Ophthalmology 2004; 111:335-340; discussion, Ophthalmology 2004; 111:340-341. 68. Moreno RJ, Weisman J, Waller S: Neuroretinitis: an unusual presentation of ocular toxoplasmosis. Ann Ophthalmol 1992; 24:68-70. 69. Solley WA, Martin DF, Newman NJ, et al: Cat scratch disease: posterior segment manifestations. Ophthalmology 1999; 106:1546-1553. 70. Aaberg TM: The expanding ophthalmologic spectrum of Lyme disease. Am J Ophthalmol 1989; 107:77-80. 71. Balcer LJ, Winterkorn JM, Galetta SL: Neuro-ophthalmic manifestations of Lyme disease. J Neuroophthalmol 1997; 17:108-121. 72. Breeveld J, Kuiper H, Spanjaard L, et al: Uveitis and Lyme borreliosis. Br J Ophthalmol 1993; 77:480-481. 73. Kuiper H, Koelman JH, Hager MJ: Vitreous clouding associated with Lyme borreliosis. Am J Ophthalmol 1989; 108:453454. 74. Bialasiewicz AA, Ruprecht KW, Naumann GO, et al: Bilateral diffuse choroiditis and exudative retinal detachments with evidence of Lyme disease. Am J Ophthalmol 1988; 105:419420. 75. Smith JL, Winward KE, Nicholson DF, et al: Retinal vasculitis in Lyme borreliosis. J Clin Neuroophthalmol 1991; 11:7-15. 76. Trends in infectious syphilis; update on national data to 2003 and current epidemiological data from the London outbreak. Commun Dis Rep CDR Wkly 2004; 14(31):7-10. 77. Barile GR, Flynn TE: Syphilis exposure in patients with uveitis. Ophthalmology 1997; 104:1605-1609. 78. Deschenes J, Seamone CD, Baines MG: Acquired ocular syphilis: diagnosis and treatment. Ann Ophthalmol 1992; 24:134-138. 79. Cubillan LD, Cubillan EA, Berger TG, et al: Syphilitic uveitis and dermatitis. Arch Ophthalmol 1998; 116:696-697. 80. Jabbour NM, Faris B, Trempe CL: A case of pulmonary tuberculosis presenting with a choroidal tuberculoma. Ophthalmology 1985; 92:834-837. 81. Mansour AM, Haymond R: Choroidal tuberculomas without evidence of extraocular tuberculosis. Graefes Arch Clin Exp Ophthalmol 1990; 228:382-383. 82. Gur S, Silverstone BZ, Zylberman R, et al: Chorioretinitis and extrapulmonary tuberculosis. Ann Ophthalmol 1987; 19:112115. 83. Fountain JA, Werner RB: Tuberculous retinal vasculitis. Retina 1984; 4:48-50. 84. Shah SM, Howard RS, Sarkies NJ, et al: Tuberculosis presenting as retinal vasculitis. J R Soc Med 1988; 81:232-233. 85. Finelli PF, McEntee WJ, Lessell S, et al: Whipple’s disease with predominantly neuroophthalmic manifestations. Ann Neurol 1977; 1:247-252. 86. Avila MP, Jalkh AE, Feldman E, et al: Manifestations of Whipple’s disease in the posterior segment of the eye. Arch Ophthalmol 1984; 102:384-390. 87. Font RL, Rao NA, Issarescu S, et al: Ocular involvement in Whipple’s disease: light and electron microscopic observations. Arch Ophthalmol 1978; 96:1431-1436. 88. Leland TM, Chambers JK: Ocular findings in Whipple’s disease. South Med J 1978; 71:335-338. 89. Rickman LS, Freeman WR, Green WR, et al: Brief report: uveitis caused by Tropheryma whippelii (Whipple’s bacillus). N Engl J Med 1995; 332:363-366. 90. Holland GN: Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol 1994; 117:663-667.

91. Ganatra JB, Chandler D, Santos C, et al: Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol 2000; 129:166-172. 92. Maertzdorf J, Van der Lelij A, Baarsma GS, et al: Herpes simplex virus type 1 (HSV-1)–induced retinitis following herpes simplex encephalitis: indications for brain-to-eye transmission of HSV-1. Ann Neurol 2000; 48:936-939. 93. Kamel OR, Galloway GD, Trew DR: Delayed onset acute retinal necrosis 20 years following herpetic encephalitis. Eye 2000; 14(Pt 5):788-789. 94. Chung GW, Thulborn KR, Pulido JS, et al: Magnetic resonance imaging of diffuse cerebral vasculitis associated with acute retinal necrosis. Arch Ophthalmol 2004; 122:17191720. 95. Gagnon A, Bouchard RW: Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man. Arch Neurol 2003; 60:1160-1161. 96. Berker N, Batman C, Guven A, et al: Optic atrophy and macular degeneration as initial presentations of subacute sclerosing panencephalitis. Am J Ophthalmol 2004; 138:879881. 97. Goldberg DE, Smithen LM, Angelilli A, et al: HIV-associated retinopathy in the HAART era. Retina 2005; 25:633-649; quiz, Retina 2005; 25:682-683. 98. Morinelli EN, Dugel PU, Riffenburgh R, et al: Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology 1993; 100:1014-1021. 99. Jabs DA: Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 1995; 93:623-683. 100. Kuppermann BD, Petty JG, Richman DD, et al: Correlation between CD4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus–related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am J Ophthalmol 1993; 115:575-582. 101. Akduman L, Feiner MA, Olk RJ, et al: Macular ischemia as a cause of decreased vision in a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 1997; 124:699702. 102. Conway MD, Tong P, Olk RJ: Branch retinal artery occlusion (BRAO) combined with branch retinal vein occlusion (BRVO) and optic disc neovascularization associated with HIV and CMV retinitis. Int Ophthalmol 1995; 19:249-252. 103. Donahue SP: Human immunodeficiency virus–associated vision loss: electroretinogram attenuation. Am J Ophthalmol 1998; 126:729-731. 104. Holbrook JT, Jabs DA, Weinberg DV, et al: Visual loss in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active antiretroviral therapy. Arch Ophthalmol 2003; 121:99107. 105. Kuo IC, Kempen JH, Dunn JP, et al: Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004; 138:338-346. 106. Gariano RF, Berreen JP, Cooney EL: Progressive outer retinal necrosis and acute retinal necrosis in fellow eyes of a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 2001; 132:421-423. 107. Gass JD, Braunstein RA, Chenoweth RG: Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990; 97:12881297. 108. Becerra LI, Ksiazek SM, Savino PJ, et al: Syphilitic uveitis in human immunodeficiency virus–infected and noninfected patients. Ophthalmology 1989; 96:1727-1730. 109. Levy JH, Liss RA, Maguire AM: Neurosyphilis and ocular syphilis in patients with concurrent human immunodeficiency virus infection. Retina 1989; 9:175-180.

chapter 24 retinal disease 110. Berger BB, Egwuagu CE, Freeman WR, et al: Miliary toxoplasmic retinitis in acquired immunodeficiency syndrome. Arch Ophthalmol 1993; 111:373-376. 111. Lee YF, Chen SJ, Chung YM, et al: Diffuse toxoplasmic retinochoroiditis as the initial manifestation of acquired immunodeficiency syndrome. J Formos Med Assoc 2000; 99:219-223. 112. Parke DW 2nd, Font RL: Diffuse toxoplasmic retinochoroiditis in a patient with AIDS. Arch Ophthalmol 1986; 104:571575. 113. Moraes HV Jr: Punctate outer retinal toxoplasmosis in an HIV-positive child. Ocul Immunol Inflamm 1999; 7:93-95. 114. Matzkin DC, Slamovits TL, Rosenbaum PS: Simultaneous intraocular and orbital non-Hodgkin lymphoma in the acquired immune deficiency syndrome. Ophthalmology 1994; 101:850-855. 115. Ormerod LD, Puklin JE: AIDS-associated intraocular lymphoma causing primary retinal vasculitis. Ocul Immunol Inflamm 1997; 5:271-278. 116. Rivero ME, Kuppermann BD, Wiley CA, et al: Acquired immunodeficiency syndrome–related intraocular B-cell lymphoma. Arch Ophthalmol 1999; 117:616-622. 117. Schanzer MC, Font RL, O’Malley RE: Primary ocular malignant lymphoma associated with the acquired immune deficiency syndrome. Ophthalmology 1991; 98:88-91. 118. Stanton CA, Sloan B 3rd, Slusher MM, et al: Acquired immunodeficiency syndrome–related primary intraocular lymphoma. Arch Ophthalmol 1992; 110:1614-1617. 119. Kim IT, Shim JY, Yung BY: Serous retinal detachment in a patient with rhino-orbital mucormycosis. Jpn J Ophthalmol 2001; 45:301-304. 120. Newman RM, Kline LB: Evolution of fundus changes in mucormycosis. J Neuroophthalmol 1997; 17:51-52. 121. Kadayifcilar S, Gedik S, Onerci M, et al: Chorioretinal alterations in mucormycosis. Eye 2001; 15:99-102. 122. Verma S, Graham EM: Cryptococcus presenting as cloudy choroiditis in an AIDS patient. Br J Ophthalmol 1995; 79:618619. 123. Garrity JA, Herman DC, Imes R, et al: Optic nerve sheath decompression for visual loss in patients with acquired immunodeficiency syndrome and cryptococcal meningitis with papilledema. Am J Ophthalmol 1993; 116:472-478. 124. Freeman WR, Gross JG, Labelle J, et al: Pneumocystis carinii choroidopathy: a new clinical entity. Arch Ophthalmol 1989; 107:863-867. 125. Shami MJ, Freeman W, Friedberg D, et al: A multicenter study of Pneumocystis choroidopathy. Am J Ophthalmol 1991; 112:15-22. 126. Biousse V, Newman NJ: Neuro-ophthalmology of mitochondrial diseases. Semin Neurol 2001; 21:275-291. 127. Kerrison JB, Biousse V, Newman NJ: Retinopathy of NARP syndrome. Arch Ophthalmol 2000; 118:298-299. 128. Isashiki Y, Nakagawa M, Ohba N, et al: Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand 1998; 76:6-13. 129. Latkany P, Ciulla TA, Cacchillo PF, et al: Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation. Am J Ophthalmol 1999; 128:112-114. 130. Smith PR, Bain SC, Good PA, et al: Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNA(Leu) A to G mutation. Ophthalmology 1999; 106:11011118. 131. Massin P, Virally-Monod M, Vialettes B, et al: Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group. Ophthalmology 1999; 106: 1821-1827.

313

132. Leys AM, Van Eyck LM, Nuttin BJ, et al: Metastatic carcinoma to the retina: clinicopathologic findings in two cases. Arch Ophthalmol 1990; 108:1448-1452. 133. Spraul CW, Martin DF, Hagler WS, et al: Cytology of metastatic cutaneous melanoma to the vitreous and retina. Retina 1996; 16:328-332. 134. DeAngelis LM, Yahalom J, Heinemann MH, et al: Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology 1990; 40:80-86. 135. Hochberg FH, Miller DC: Primary central nervous system lymphoma. J Neurosurg 1988; 68:835-853. 136. Peterson K, Gordon KB, Heinemann MH, et al: The clinical spectrum of ocular lymphoma. Cancer 1993; 72:843-849. 137. Verbraeken HE, Hanssens M, Priem H, et al: Ocular nonHodgkin’s lymphoma: a clinical study of nine cases. Br J Ophthalmol 1997; 81:31-36. 138. Merchant A, Foster CS: Primary intraocular lymphoma. Int Ophthalmol Clin 1997; 37:101-115. 139. Freeman LN, Schachat AP, Knox DL, et al: Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 1987; 94:1631-1639. 140. Chang TS, Byrne SF, Gass JD, et al: Echographic findings in benign reactive lymphoid hyperplasia of the choroid. Arch Ophthalmol 1996; 114:669-675. 141. Rockwood EJ, Zakov ZN, Bay JW: Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). Report of three cases. J Neurosurg 1984; 61:369-374. 142. Corriveau C, Easterbrook M, Payne D: Lymphoma simulating uveitis (masquerade syndrome). Can J Ophthalmol 1986; 21:144-149. 143. Assaf N, Hasson T, Hoch-Marchaim H, et al: An experimental model for infiltration of malignant lymphoma to the eye and brain. Virchows Arch 1997; 431:459-467. 144. Ridley ME, McDonald HR, Sternberg P Jr, et al: Retinal manifestations of ocular lymphoma (reticulum cell sarcoma). Ophthalmology 1992; 99:1153-1160; discussion, Ophthalmology 1992; 99:1160-1161. 145. Gass JD, Trattler HL: Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 1991; 109:11341139. 146. Sawyer RA, Selhorst JB, Zimmerman LE, et al: Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 1976; 81:606-613. 147. Thirkill CE, Tait RC, Tyler NK, et al: The cancer-associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 1992; 33:2768-2772. 148. Polans AS, Burton MD, Haley TL, et al: Recoverin, but not visinin, is an autoantigen in the human retina identified with a cancer-associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:81-90. 149. Adamus G, Aptsiauri N, Guy J, et al: The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopathol 1996; 78:120-129. 150. Chan JW: Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 2003; 48:12-38. 151. Heckenlively JR, Fawzi AA, Oversier J, et al: Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol 2000; 118:1525-1533. 152. Whitcup SM, Vistica BP, Milam AH, et al: Recoverinassociated retinopathy: a clinically and immunologically distinctive disease. Am J Ophthalmol 1998; 126:230-237. 153. Adamus G, Ren G, Weleber RG: Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 2004; 4:5. 154. Weleber RG, Watzke RC, Shults WT, et al: Clinical and electrophysiologic characterization of paraneoplastic and

314

155.

156. 157. 158. 159.

160.

161. 162. 163. 164. 165.

166. 167. 168.

169. 170. 171.

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autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol 2005; 139:780-794. Keltner JL, Thirkill CE, Yip PT: Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 2001; 21:173-187. Milam AH, Saari JC, Jacobson SG, et al: Autoantibodies against retinal bipolar cells in cutaneous melanoma–associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:91-100. Cross SA, Salomao DR, Parisi JE, et al: Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5IgG. Ann Neurol 2003; 54:38-50. Gass JD, Gieser RG, Wilkinson CP, et al: Bilateral diffuse uveal melanocytic proliferation in patients with occult carcinoma. Arch Ophthalmol 1990; 108:527-533. O’Neal KD, Butnor KJ, Perkinson KR, et al: Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome. Surv Ophthalmol 2003; 48:613-625. Chahud F, Young RH, Remulla JF, et al: Bilateral diffuse uveal melanocytic proliferation associated with extraocular cancers: review of a process particularly associated with gynecologic cancers. Am J Surg Pathol 2001; 25:212-218. Jackson GR, Owsley C: Visual dysfunction, neurodegenerative diseases, and aging. Neurol Clin 2003; 21:709-728. Paulus W, Schwarz G, Werner A, et al: Impairment of retinal increment thresholds in Huntington’s disease. Ann Neurol 1993; 34:574-578. Cox TA, McDarby JV, Lavine L, et al: A retinopathy on Guam with high prevalence in Lytico-Bodig. Ophthalmology 1989; 96:1731-1735. Jankovic J, Kirkpatrick JB, Blomquist KA, et al: Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology 1985; 35:227-234. Egan RA, Weleber RG, Hogarth P, et al: Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol 2005; 140:267-274. Houlden H, Lincoln S, Farrer M, et al: Compound heterozygous PANK2 mutations confirm HARP and HallervordenSpatz syndromes are allelic. Neurology 2003; 61:1423-1426. Miyajima H, Nishimura Y, Mizoguchi K, et al: Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 1987; 37:761-767. Dunaief JL, Richa C, Franks EP, et al: Macular degeneration in a patient with aceruloplasminemia, a disease associated with retinal iron overload. Ophthalmology 2005; 112:10621065. Dingle J, Havener WH: Ophthalmoscopic changes in a patient with Wilson’s disease during long-term penicillamine therapy. Ann Ophthalmol 1978; 10:1227-1230. Bassen FA, Kornzweig AL: Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood 1950; 5:381387. Refsum S: Heredopathia atactica polyneuritiformis: a familial syndrome not hitherto described. A contribution to the clinical study of the hereditary disorders of the nervous system. Acta Psychiatr Scand 1946; 38:1-303. Yokota T, Wada Y, Furukawa T, et al: Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 1987; 22:84-87. Berger AS, Tychsen L, Rosenblum JL: Retinopathy in human vitamin E deficiency. Am J Ophthalmol 1991; 111: 774-775. Enevoldson TP, Sanders MD, Harding AE: Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy: a clinical and genetic study of eight families. Brain 1994; 117(Pt 3):445-460.

175. Ahn JK, Seo JM, Chung H, et al: Anatomical and functional characteristics in atrophic maculopathy associated with spinocerebellar ataxia type 7. Am J Ophthalmol 2005; 139:923-925. 176. Fitzsimons RB, Gurwin EB, Bird AC: Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications. Brain 1987; 110(Pt 3):631-648. 177. Kimizuka Y, Kiyosawa M, Tamai M, et al: Retinal changes in myotonic dystrophy: clinical and follow-up evaluation. Retina 1993; 13:129-135. 178. Backhouse O, Griffiths B, Henderson T, et al: Ophthalmic manifestations of dermatomyositis. Ann Rheum Dis 1998; 57:447-9. 179. La Piana FG: Sectoral retinal pigmentation in neurofibromatosis. Ann Ophthalmol 1977; 9:413-422. 180. Cotlier E: Café-au-lait spots of the fundus in neurofibromatosis. Arch Ophthalmol 1977; 95:1990-1992. 181. Destro M, D’Amico DJ, Gragoudas ES, et al: Retinal manifestations of neurofibromatosis: diagnosis and management. Arch Ophthalmol 1991; 109:662-666. 182. Font RL, Ferry AP: The phakomatoses. Int Ophthalmol Clin 1972; 12:1-50. 183. Moadel K, Yannuzzi LA, Ho AC, et al: Retinal vascular occlusive disease in a child with neurofibromatosis. Arch Ophthalmol 1994; 112:1021-1023. 184. Callender GR, Thigpen CA: Two neurofibromas in one eye. Am J Ophthalmol 1930; 13:121-124. 185. Freeman D: Neurofibroma of the choroid. Arch Ophthalmol 1934; 11:641-645. 186. Savino PJ, Glaser JS, Luxenberg MN: Pulsating enophthalmos and choroidal hamartomas: two rare stigmata of neurofibromatosis. Br J Ophthalmol 1977; 61:483-488. 187. Kobrin JL, Blodi FC, Weingeist TA: Ocular and orbital manifestations of neurofibromatosis. Surv Ophthalmol 1979; 24:45-51. 188. Lewis RA, Riccardi VM: Von Recklinghausen neurofibromatosis: incidence of iris hamartomata. Ophthalmology 1981; 88:348-354. 189. Huson S, Jones D, Beck L: Ophthalmic manifestations of neurofibromatosis. Br J Ophthalmol 1987; 71:235-238. 190. Green WR: The uveal tract. In Spencer WH, ed: Ophthalmic Pathology: An Atlas and Textbook. Philadelphia: WB Saunders, 1996, pp 1864-2099. 191. Landau K, Dossetor FM, Hoyt WF, et al: Retinal hamartoma in neurofibromatosis 2. Arch Ophthalmol 1990; 108:328-329. 192. Mautner VF, Lindenau M, Baser ME, et al: The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 1996; 38:880-885; discussion, Neurosurgery 1996; 38:885886. 193. Rettele GA, Brodsky MC, Merin LM, et al: Blindness, deafness, quadriparesis, and a retinal malformation: the ravages of neurofibromatosis 2. Surv Ophthalmol 1996; 41:135-141. 194. Ragge NK, Baser ME, Riccardi VM, et al: The ocular presentation of neurofibromatosis 2. Eye 1997; 11(Pt 1):12-18. 195. Ragge NK, Baser ME, Klein J, et al: Ocular abnormalities in neurofibromatosis 2. Am J Ophthalmol 1995; 120:634-641. 196. Ragge NK: Clinical and genetic patterns of neurofibromatosis 1 and 2. Br J Ophthalmol 1993; 77:662-672. 197. Kaye LD, Rothner AD, Beauchamp GR, et al: Ocular findings associated with neurofibromatosis type II. Ophthalmology 1992; 99:1424-1429. 198. Meyers SM, Gutman FA, Kaye LD, et al: Retinal changes associated with neurofibromatosis 2. Trans Am Ophthalmol Soc 1995; 93:245-252; discussion, Trans Am Ophthalmol Soc 1995; 93:252-257. 199. Baser ME, Kluwe L, Mautner VF: Germ-line NF2 mutations and disease severity in neurofibromatosis type 2 patients with retinal abnormalities. Am J Hum Genet 1999; 64:1230-1233.

chapter 24 retinal disease 200. Zimmer-Galler IE, Robertson DM: Long-term observation of retinal lesions in tuberous sclerosis. Am J Ophthalmol 1995; 119:318-324. 201. Gunduz K, Eagle RC Jr, Shields CL, et al: Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis. Ophthalmology 1999; 106:639-642. 202. Nyboer JH, Robertson DM, Gomez MR: Retinal lesions in tuberous sclerosis. Arch Ophthalmol 1976; 94:1277-1280. 203. Lucchese NJ, Goldberg MF: Iris and fundus pigmentary changes in tuberous sclerosis. J Pediatr Ophthalmol Strabismus 1981; 18:45-46. 204. Awan KJ: Leaf-shaped lesions of ocular fundus and white eyelashes in tuberous sclerosis. South Med J 1982; 75:227-228. 205. Green JS, Bowmer MI, Johnson GJ: Von Hippel-Lindau disease in a Newfoundland kindred. CMAJ 1986; 134:133-138, 146. 206. Hardwig P, Robertson DM: von Hippel-Lindau disease: a familial, often lethal, multi-system phakomatosis. Ophthalmology 1984; 91:263-270. 207. Lamiell JM, Salazar FG, Hsia YE: von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 1989; 68:1-29. 208. Maher ER, Yates JR, Harries R, et al: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77:1151-1163. 209. Moore AT, Maher ER, Rosen P, et al: Ophthalmological screening for von Hippel-Lindau disease. Eye 1991; 5(Pt 6):723-728. 210. de Jong PT, Verkaart RJ, van de Vooren MJ, et al: Twin vessels in von Hippel-Lindau disease. Am J Ophthalmol 1988; 105:165-169. 211. Chang JH, Spraul CW, Lynn ML, et al: The two-stage mutation model in retinal hemangioblastoma. Ophthalmic Genet 1998; 19:123-130. 212. Neumann HP: Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 1987; 16:220-226. 213. Susac JO, Smith JL, Scelfo RJ: The “tomato-catsup” fundus in Sturge-Weber syndrome. Arch Ophthalmol 1974; 92:69-70. 214. Bacin F, Bonnet M, Caujolle JP, et al: [Choroidal angioma and Sturge-Weber syndrome.] J Fr Ophtalmol 1997; 20:405-407. 215. Shin GS, Demer JL: Retinal arteriovenous communications associated with features of the Sturge-Weber syndrome. Am J Ophthalmol 1994; 117:115-117. 216. Hopen G, Smith JL, Hoff JT, et al: The Wyburn-Mason syndrome: concomitant chiasmal and fundus vascular malformations. J Clin Neuroophthalmol 1983; 3:53-62. 217. Effron L, Zakov ZN, Tomsak RL: Neovascular glaucoma as a complication of the Wyburn-Mason syndrome. J Clin Neuroophthalmol 1985; 5:95-98. 218. Brod RD, Shields JA, Shields CL, et al: Unusual retinal and renal vascular lesions in the Klippel-Trénaunay-Weber syndrome. Retina 1992; 12:355-358. 219. Okada H, Horibe H, Yoshiyuki O, et al: A prospective study of cerebrovascular disease in Japanese rural communities, Akabane and Asahi. Part 1: evaluation of risk factors in the occurrence of cerebral hemorrhage and thrombosis. Stroke 1976; 7:599-607. 220. Svardsudd K, Wedel H, Aurell E, et al: Hypertensive eye ground changes: prevalence, relation to blood pressure and prognostic importance. The study of men born in 1913. Acta Med Scand 1978; 204:159-167. 221. Tanaka H, Hayashi M, Date C, et al: Epidemiologic studies of stroke in Shibata, a Japanese provincial city: preliminary report on risk factors for cerebral infarction. Stroke 1985; 16:773-780. 222. Nakayama T, Date C, Yokoyama T, et al: A 15.5-year follow-up study of stroke in a Japanese provincial city. The Shibata Study. Stroke 1997; 28:45-52.

315

223. Wong TY, Klein R, Couper DJ, et al: Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001; 358:1134-1140. 224. Wong TY, Klein R, Sharrett AR, et al: Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002; 33:1487-1492. 225. Wong TY, Klein R, Sharrett AR, et al: Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002; 288:67-74. 226. Wong TY, Mosley TH Jr, Klein R, et al: Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middleaged people. Neurology 2003; 61:806-811. 227. Sharma S, Pater JL, Lam M, et al: Can different types of retinal emboli be reliably differentiated from one another? An inter- and intraobserver agreement study. Can J Ophthalmol 1998; 33:144-148. 228. Savino PJ, Glaser JS, Cassady J: Retinal stroke: is the patient at risk? Arch Ophthalmol 1977; 95:1185-1189. 229. Wilson LA, Warlow CP, Russell RW: Cardiovascular disease in patients with retinal arterial occlusion. Lancet 1979; 1:292294. 230. Babikian V, Wijman CA, Koleini B, et al: Retinal ischemia and embolism: etiologies and outcomes based on a prospective study. Cerebrovasc Dis 2001; 12:108-113. 231. Smit RL, Baarsma GS, Koudstaal PJ: The source of embolism in amaurosis fugax and retinal artery occlusion. Int Ophthalmol 1994; 18:83-86. 232. McCullough HK, Reinert CG, Hynan LS, et al: Ocular findings as predictors of carotid artery occlusive disease: is carotid imaging justified? J Vasc Surg 2004; 40:279-286. 233. Sharma S, Brown GC, Pater JL, et al: Does a visible retinal embolus increase the likelihood of hemodynamically significant carotid artery stenosis in patients with acute retinal arterial occlusion? Arch Ophthalmol 1998; 116:16021606. 234. Bruno A, Jones WL, Austin JK, et al: Vascular outcome in men with asymptomatic retinal cholesterol emboli: a cohort study. Ann Intern Med 1995; 122:249-253. 235. Klein R, Klein BE, Moss SE, et al: Retinal emboli and cardiovascular disease: the Beaver Dam Eye Study. Arch Ophthalmol 2003; 121:1446-1451. 236. Wong TY, Larsen EK, Klein R, et al: Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities & Cardiovascular Health studies. Ophthalmology 2005; 112:540-547. 237. Hedges TR Jr: Ophthalmoscopic findings in internal carotid artery occlusion. Bull Johns Hopkins Hosp 1962; 111:8997. 238. Kearns TP, Hollenhorst RW: Venous-stasis retinopathy of occlusive disease of the carotid artery. Mayo Clin Proc 1963; 38:304-312. 239. Costa VP, Kuzniec S, Molnar LJ, et al: The effects of carotid endarterectomy on the retrobulbar circulation of patients with severe occlusive carotid artery disease: an investigation by color Doppler imaging. Ophthalmology 1999; 106:306310. 240. Wilson WB, Leavengood JM, Ringel SP, et al: Transient ocular motor paresis associated with acute internal carotid artery occlusion. Ann Neurol 1989; 25:286-290. 241. McDonough RL, Forteza AM, Flynn HWJ: Internal carotid artery dissection causing a branch retinal artery in a young adult. Am J Ophthalmol 1998; 125:706-708. 242. Newman NJ, Kline LB, Leifer D, et al: Ocular stroke and carotid artery dissection. Neurology 1989; 39:1462-1464. 243. Godfrey DG, Biousse V, Newman NJ: Delayed branch retinal artery occlusion following presumed blunt common carotid dissection. Arch Ophthalmol 1998; 116:1120-1121.

316

Section

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244. Palmer HE, Stanford MR, Sanders MD, et al: Visual outcome of patients with idiopathic ischaemic and non-ischaemic retinal vasculitis. Eye 1996; 10(Pt 3):343-348. 245. Palmer HE, Zaman AG, Edelsten CE, et al: Systemic morbidity in patients with isolated idiopathic retinal vasculitis. Lancet 1995; 346:505-506. 246. Cobo-Soriano R, Sanchez-Ramon S, Aparicio MJ, et al: Antiphospholipid antibodies and retinal thrombosis in patients without risk factors: a prospective case-control study. Am J Ophthalmol 1999; 128:725-732. 247. Cahill MT, Stinnett SS, Fekrat S: Meta-analysis of plasma homocysteine, serum folate, serum vitamin B(12), and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease. Am J Ophthalmol 2003; 136:1136-1150. 248. Susac JO, Hardman JM, Selhorst JB: Microangiopathy of the brain and retina. Neurology 1979; 29:313-316. 249. O’Halloran HS, Pearson PA, Lee WB, et al: Microangiopathy of the brain, retina, and cochlea (Susac’s syndrome): a report of five cases and a review of the literature. Ophthalmology 1998; 105:1038-1044. 250. Susac JO, Murtagh FR, Egan RA, et al: MRI findings in Susac’s syndrome. Neurology 2003; 61:1783-1787. 251. Haritoglou C, Rudolph G, Hoops JP, et al: Retinal vascular abnormalities in CADASIL. Neurology 2004; 62:1202-1205. 252. Cumurciuc R, Massin P, Paques M, et al: Retinal abnormalities in CADASIL: a retrospective study of 18 patients. J Neurol Neurosurg Psychiatry 2004; 75:1058-1060. 253. Rufa A, De Stefano N, Dotti MT, et al: Acute unilateral visual loss as the first symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Arch Neurol 2004; 61:577-580. 254. Parisi V, Pierelli F, Fattapposta F, et al: Early visual function impairment in CADASIL. Neurology 2003; 60:2008-2010. 255. Haritoglou C, Hoops JP, Stefani FH, et al: Histopathological abnormalities in ocular blood vessels of CADASIL patients. Am J Ophthalmol 2004; 138:302-305. 256. Storimans CW, Van Schooneveld MJ, Oosterhuis JA, et al: A new autosomal dominant vascular retinopathy syndrome. Eur J Ophthalmol 1991; 1:73-78.

257. Terwindt GM, Haan J, Ophoff RA, et al: Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud’s phenomenon. Brain 1998; 121(Pt 2):303-316. 258. Ophoff RA, DeYoung J, Service SK, et al: Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3. Am J Hum Genet 2001; 69:447-453. 259. Vahedi K, Massin P, Guichard JP, et al: Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy. Neurology 2003; 60:57-63. 260. Sher NA, Letson RD, Desnick RJ: The ocular manifestations in Fabry’s disease. Arch Ophthalmol 1979; 97:671-676. 261. Dichgans M: A new cause of hereditary small vessel disease: angiopathy of retina and brain. Neurology 2003; 60:8-9. 262. Terson A: De l’hémorrhagie dans le corps vitre au cours de l’hémorrhagie cerebrale. Clin Ophthalmol 1900; 6:309312. 263. Fahmy JA: Fundal haemorrhages in ruptured intracranial aneurysms. I. Material, frequency and morphology. Acta Ophthalmol (Copenh) 1973; 51:289-298. 264. Manschot WA: Subarachnoid hemorrhage: intraocular symptoms and their pathogenesis. Am J Ophthalmol 1954; 38:501505. 265. Shaw HE Jr, Landers MB, Sydnor CF: The significance of intraocular hemorrhages due to subarachnoid hemorrhage. Ann Ophthalmol 1977; 9:1403-1405. 266. McCarron MO, Alberts MJ, McCarron P: A systematic review of Terson’s syndrome: frequency and prognosis after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2004; 75:491-493. 267. Fahmy JA: Fundal haemorrhages in ruptured intracranial aneurysms. II. Correlation with the clinical course. Acta Ophthalmol (Copenh) 1973; 51:299-304. 268. Cogan DG: Ocular correlates of inborn metabolic defects. Can Med Assoc J 1966; 95:1055-1065. 269. Small KW, Letson R, Scheinman J: Ocular findings in primary hyperoxaluria. Arch Ophthalmol 1990; 108:89-93.

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EXAMINATION OF HEARING AND BALANCE ●

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Brian C. Kung and Thomas O. Willcox, Jr.

Hearing loss and balance disorders are two of the most common reasons that patients visit their physicians. Varying degrees of hearing loss can affect patients at any age. One of every 1000 newborns is affected by some degree of hearing loss, and the prevalence of hearing loss rises with advancing age.1 By age 60, one of every three individuals is affected by hearing loss, and by age 85, one of every two is affected.1 Balance disorder, or “dizziness,” is the ninth most common complaint for which patients visit primary care physicians and the third most common complaint for 65- to 75-year-old patients.2-4 Hearing and balance disorders have a myriad of manifestations and etiologies, some of which are difficult to piece together. Treatment is often multidisciplinary, involving the neurologist, otolaryngologist, audiologist, neurosurgeon, and physical therapist, among others. It is important to recognize the signs and symptoms associated with specific types of hearing loss and balance disorders for the patient to receive proper referrals and proper treatment. The purpose of this chapter is to provide a better understanding of the otolaryngologist’s approach to the hearing and balance examination.

HEARING EXAMINATION There are three main forms of hearing loss: conductive, sensorineural, and mixed. Each can be caused by a wide variety of conditions, ranging from benign conditions, such as cerumen impaction, to potentially life-threatening diseases, such as squamous cell carcinoma of the temporal bone. Usually, conductive hearing loss is caused by a disorder in the external or middle ear, whereas a sensorineural hearing loss is caused by a disorder of the inner ear or neural structures leading from the inner ear to the central nervous system. Hearing loss can lead to speech and developmental delays in children and significant communication problems and decreased quality of life in both children and adults. Many of these conditions are treatable and early recognition is important. A structured hearing evaluation consists of a history, physical examination, and audiological testing; often radiological testing is necessary to lead to the proper diagnosis.

what to look for during the subsequent physical examination and audiological and/or radiographic tests in order to arrive at the correct diagnosis. The severity of the patient’s hearing loss can be assessed just by conversing with the patient in a normal or soft voice and observing whether the patient responds appropriately. If the patient speaks in a very loud voice, it may indicate a sensorineural cause of hearing loss, and if the patient speaks very softly, it may point to a conductive cause, as the patient’s voice may sound louder to the patient (just as a normal hearing person’s would if his or her ears were plugged). Sometimes, discrepancies between the patient’s behavior in conversation and during diagnostic tests can point to malingering as a possible diagnosis. When taking a history of present illness, specific points should be emphasized. These include the patient’s perception of the degree of hearing loss, whether the hearing loss is unilateral or bilateral, and the onset of the hearing loss (sudden within 3 days, rapidly progressive within 1 week, slowly progressive over weeks to years, fluctuating, or stable). The patient may have associated symptoms, such as aural fullness, tinnitus, vertigo, disequilibrium, otalgia, otorrhea, headache, visual problems, and other neurological complaints (facial numbness or weakness, ataxia, oscillopsia, etc.), that may help point to specific causes of hearing loss. The past medical history is also very helpful: cardiovascular, renal, rheumatological, hematological, endocrine, and neurological conditions can predispose a patient to certain types of hearing loss.5 Past surgical history should also be obtained, with special emphasis on head trauma and previous otological or neurological surgery. A history of noise exposure is also important, as excessive noise exposure, either suddenly or over a period of time, can lead to hearing loss. A full account of the patient’s recent medications, including potentially ototoxic medications, should be taken. It is very important to know whether there is a family history of hearing loss, as there is a genetic predisposition for many types of hearing loss, and many genes associated with deafness and predisposition to hearing loss have been identified.1,5

Physical Examination History A thorough history is one of the most important aspects of a hearing evaluation. Often, this gives the physician clues as to

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A complete head and neck examination can give many clues to the cause of a patient’s hearing loss. The auricle and the postauricular area should be examined for deformities, surgical incisions, the presence of a hearing aid, and patency of the external

chapter 25 examination of hearing and balance auditory canal. Something as simple as cerumen impaction can be the cause of hearing loss in some patients, but other conditions, such as foreign bodies, exostoses, canal stenosis/atresia, and carcinoma of the external canal, can be more troublesome. Pneumatic otoscopy can then be used to examine the tympanic membrane and middle ear. Here, the presence of a tympanostomy tube, tympanosclerosis (scarring of the tympanic membrane), tympanic membrane perforation, retraction pocket, fluid in the middle ear, middle ear masses, or otorrhea can be assessed. It is important to obtain a good seal with the speculum in order to assess the mobility of the tympanic membrane. External and middle ear abnormalities usually point to a conductive component of hearing loss. Tuning fork testing is an essential part of the physical examination and can help determine if the cause of hearing loss is conductive, sensorineural, or mixed. The three types of tuning forks that can be used are 256 Hz (middle C), 512 Hz (octave above middle C), and 1024 Hz (two octaves above middle C). The Rinne test is useful in determining if there is a conductive hearing loss and is performed by striking the tuning fork and placing it on the mastoid bone (testing bone conduction). Once the patient stops hearing the sound, the tines of the tuning fork are then placed in front of the external canal (testing air conduction) with the tines oriented in the head-frontal plane, and the patient indicates whether he or she can hear the sound. If the patient can hear the sound, air conduction is greater than bone conduction, and the result is normal, or “positive.” If the patient cannot hear the sound, bone conduction is greater than air conduction, and the result is abnormal, or “negative.” The degree of conductive hearing loss can be estimated based on the results of the Rinne test. A test that is negative at 256 Hz and positive at 512 and 1024 Hz indicates a mild 20- to 30decibel (dB) conductive loss. A test that is negative at 256 and 512 Hz and positive at 1024 Hz indicates a moderate 30- to 45-dB conductive loss. A negative test at all three frequencies indicates a severe 45- to 60-dB conductive loss.6,7 The Weber test is a test used to lateralize the hearing loss. The tuning fork is struck and placed on the patient’s vertex, nasal bones, or maxillary teeth in the midline. The single most clinically useful fork used here is the 512-Hz variety, as the 256-Hz fork can be overly sensitive, leading to many false-positive results, and the 1024-Hz fork may not be sensitive enough.7-9 Lateralization of sound to one ear during the Weber test indicates either a conductive hearing loss in that ear or a greater sensorineural loss in the opposite ear.7 Simple tuning fork tests using only a few frequencies are far from comprehensive. If both ears are symmetrically affected by a sensorineural hearing loss, both the Rinne and Weber tests will be normal, provided the patient is able to hear the tuning fork at all. The physical examination should also include an assessment of any craniofacial deformities or stigmata that may be associated with hereditary causes of hearing loss or associated systemic diseases. Also, a full cranial nerve examination should be performed, as asymmetries in any of the cranial nerves may indicate that hearing loss is just one component of more severe or extensive disease, such as a skull base neoplasm. A decreased corneal blink reflex and hypesthesia of the external auditory canal (Hitselberger’s sign) can be suspicious for an acoustic neuroma. Finally, attention to the nose, nasopharynx, oral cavity, oropharynx, larynx, and hypopharynx can reveal other causes of hearing loss (e.g., the presence of nasopharyngeal carcinoma as the cause of serous otitis media).

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Audiological Testing Audiological testing has been available for decades, but developments over the years have advanced the field of audiology to include tests and procedures that can determine the site of lesion with far greater accuracy than before. Otolaryngologists and audiologists often need to rely on one another to diagnose accurately the cause of a patient’s hearing loss using a combination of the history, physical examination, and results of various audiological tests. The audiological test battery includes audiometry (pure tone and speech), acoustic immittance testing (tympanometry and acoustic reflex testing), electrophysiological testing (auditory brainstem response and electrocochleography), and otoacoustic emission testing.

Pure-Tone Audiometry Pure-tone audiometry is the most commonly used test to measure auditory sensitivity. Pure-tone signals are delivered to the ear via air conduction and bone conduction at a variety of frequencies, and the patient responds to the sound by signaling the examiner with a button or by raising a hand. The response can be modified for pediatric patients or patients who lack the capacity to respond in the conventional manner. Although the entire range of human hearing is from 20 to 20,000 Hz, the typical range of frequencies tested runs from 250 to 8000 Hz, which is the range necessary to understand speech.10 The intensity of a sound presented is represented by a ratio of its sound pressure to a reference sound pressure, defined as the amount of pressure that can just be sensed by a normal human ear at its most sensitive frequency (0.0002 dyne/cm2).11 As the pressure level of a presented sound is often many times the reference sound pressure, the simplest way to present this ratio is to use the decibel, a logarithmic unit: dB = 20 log10(P2/P1)

where P2 is the presented sound pressure and P1 is the reference sound pressure. A sound referenced to the reference sound pressure is known as the absolute sound level, presented as decibels sound pressure level (dB SPL). The normal human ear is variably sensitive to different frequencies throughout its range, so clinically, the easiest reference level to use is the sound pressure level for each tested frequency that can be heard by a normal ear. The sound level is presented as decibels hearing loss, or dB HL.11 For example, if a normal hearing patient responds to a sound P2 that is equal to P1 (what another normal person would hear), then that patient has 20 log10 1 = 20(0) = 0 dB HL. If a patient with hearing loss responds to a sound P2 that is 100 times what a normal person would hear, then that patient has 20 log10 (100/1) = 20(2) = 40 dB HL. If a patient with hyperacusis (supersensitive hearing) responds to a sound P2 that is 1/10 what a normal person would hear, then that patient has 20 log10 (1/10) = 20(−1) = −20 dB HL. These examples help to illustrate that dB is indeed a comparison between sound levels and that 0 dB or negative dB does not mean that there is no sound⎯it just means that the sound is the same as or lower than the reference sound level, respectively. Auditory threshold is defined as the lowest signal intensity at which the signal can be identified 50% of the time.12 Air

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conduction thresholds are determined by presenting sound to the ears via headphones or insert earphones, and bone conduction thresholds are determined by vibrating the mastoid directly. Air conduction thresholds measure the sensitivity of the entire auditory system from the external ear to the auditory cortex. When analyzed alone, they do not provide much information regarding the etiology of hearing loss. However, when they are analyzed together with bone conduction thresholds, which measure the degree of sensorineural hearing loss, they can provide valuable information regarding both the type and severity of the hearing loss.12 When air conduction thresholds are elevated relative to bone conduction thresholds, an “air-bone gap” exists, indicating a conductive hearing loss. Air conduction and bone conduction thresholds showing the same amount of hearing loss indicate a sensorineural hearing loss. A mixed hearing loss is present when both air and bone conduction thresholds are elevated, but air conduction thresholds are more elevated than bone conduction thresholds. The normal region on the audiogram is from 0 to 20 dB HL for adults and from 0 to 15 dB HL for children. Mild hearing loss is 20 to 40 dB HL, moderate loss is 40 to 55 dB HL, moderately severe loss is 55 to 70 dB HL, severe loss is 70 to 90 dB HL, and profound loss is above 90 dB HL. Hearing sensitivity within the speech frequencies is known as the pure-tone average (PTA) and can be calculated by adding the thresholds obtained at 500, 1000, and 2000 Hz and dividing the result by 3.11 For audiometric results to be valid, the patient must respond to stimulation of the ear being tested. When noninsert earphones are used, sounds greater than 40 dB HL presented to one ear can cross over to the opposite ear, most likely with the vibration of the earphone against the skull acting as a bone conductor. The amount of sound needed for crossover to occur is known as the interaural attenuation, which for air conduction is about 50 dB HL for lower frequencies and 60 dB HL for higher frequencies. The interaural attenuation is considerably higher when insert earphones are used. For bone conduction, interaural attenuation is less than 10 dB HL.11 To correct for the presence of interaural attenuation when a true hearing loss is present, masking techniques are used. A narrow band “white” noise is presented to the nontest ear when the true stimulus is being given to the test ear, and with adequate masking, any sound crossing over to the nontest ear is masked by the noise. To work, the masking noise presented to the nontest must be greater than the threshold of hearing for the nontest ear.11 This can be a problem when bilateral hearing loss (especially conductive) exists, as masking presented to the nontest ear can cross back over to the test ear. This is known as a “masking dilemma.”10 In air conduction testing, masking should be used when there is a difference between the air conduction presentation level to the test ear and the bone conduction threshold of the nontest ear of greater than 40 dB for lower frequencies and greater than 60 dB for higher frequencies. In bone conduction testing, masking should be used whenever there is any difference in the air and bone conduction thresholds.10

softest level at which the patient can barely detect the presence of a speech signal 50% of the time.12 The SRT is the softest level at which the patient can repeat 50% of balanced disyllabic words, or spondees (e.g. “hot dog,” “baseball”), correctly.10,12 The SDT should correspond to the PTA, whereas the SRT is usually about 8 to 9 dB higher than the PTA.12 Both SDT and SRT can be measured with bone conduction testing and can be masked if necessary. Discrepancies between the PTA and the SDT or SRT can indicate malingering. The speech discrimination score is a test of the patient’s ability to identify monosyllabic words, or phonemes, at a suprathreshold level, usually about 40 dB above the SRT.10 The speech discrimination score is important in that it helps assess the patient’s ability to understand speech, to communicate effectively, and to benefit from amplification. It also provides some information regarding the patient’s central auditory function.12 In general, patients with conductive hearing loss tend to have excellent speech discrimination scores when presented with sounds loud enough for them to hear. Patients with cochlear sensorineural loss tend to have lower speech discrimination scores, and patients with retrocochlear sensorineural loss (from lesions of the eighth cranial nerve to the auditory cortex) have even lower speech discrimination scores. They may even have lower speech discrimination in the presence of normal pure-tone thresholds.12

Tympanometry Acoustic immittance refers to either acoustic admittance (the ease with which energy flows through a system) or acoustic impedance (the blockage of energy flow through a system).12 In tympanometry, acoustic immittance measures are used to determine the status of the tympanic membrane and middle ear. A probe is placed in the ear canal and an airtight seal is obtained. A tone is introduced into the ear canal and the pressure in the canal is varied. When the pressure in the ear canal is equal to the middle ear pressure, the tympanic membrane will be at its most compliant (highest admittance) and will absorb the sound. This results in a tympanometric peak.10 If eustachian tube function is normal, the middle ear pressure is equal to the atmospheric pressure and the peak occurs at 0 mm H2O⎯this corresponds to a type A tympanogram. If there is negative middle ear pressure, the peak occurs at a negative pressure, corresponding to a type C tympanogram. If there is no peak (flat or type B tympanogram), there is no compliance of the tympanic membrane (no admittance), indicating a middle ear effusion, tympanic membrane perforation, or patent tympanostomy tube. These can be distinguished using ear canal volume measurements, with higher volumes corresponding to a hole in the tympanic membrane. Other types of tympanograms include As (shallow peak and low compliance at 0 mm H2O), indicating ossicular chain fixation or middle ear effusion, and Ad (very high peak and high compliance at 0 mm H2O), indicating ossicular chain discontinuity or a monomeric tympanic membrane.10

Speech Audiometry Commonly measured speech tests include the speech detection threshold (SDT), the speech reception threshold (SRT), and speech discrimination or word recognition. The SDT is the

Acoustic Reflex In acoustic reflex testing, acoustic immittance measures are used to assess the neural pathway surrounding the stapedial

chapter 25 examination of hearing and balance reflex, which occurs in response to a loud sound (70 to 90 dB above threshold).10 The afferent limb of the stapedial reflex is the ipsilateral eighth nerve, which leads to the brainstem. Complex pathways in the brainstem involving the ipsilateral ventral cochlear nucleus, trapezoid body, and bilateral medial superior olives lead from the eighth nerve on the ipsilateral (stimulated) side to the motor nucleus of the facial nerve on both sides of the brainstem.7,10-12 The efferent limb is the ipsilateral and contralateral facial nerves, which innervate the stapedius muscles. When the stapedius muscle contracts, the ossicular chain stiffens, causing a small change in compliance in the middle ear system that is detected by the probe.11 Patients with mild to moderate cochlear sensorineural hearing loss have reflexes bilaterally at about the same intensity level as those with normal hearing, but patients with severe or profound hearing loss have absent reflexes when the affected ear is stimulated.10 A conductive hearing loss results in absent reflexes when the affected ear is stimulated, as sound will not be loud enough to stimulate the reflex. Even when the normal ear is stimulated, the ear with the conductive loss does not have a reflex, as the middle ear condition prevents the stapedius from contracting.10 A lesion of the eighth nerve should result in absent reflexes bilaterally when the affected ear is stimulated, but reflexes should be present bilaterally when the nonaffected ear is stimulated. This can be confused with the reflex result associated with profound unilateral hearing loss (>70 dB) of cochlear origin. Lesions of the brainstem affecting the central crossed pathways may result in present ipsilateral reflexes when each ear is stimulated but absent contralateral reflexes. A facial nerve lesion results in an absent reflex on the affected side, no matter which side is stimulated, provided the lesion is proximal to the branching of the nerve to the stapedius muscle.10

Auditory Brainstem Response The auditory brainstem response (ABR) is an electrophysiological recording of responses of the distal auditory pathway (eighth nerve and brainstem) to sounds.11 The ABR involves placement of electrodes on the patient’s head and presentation of sound to the ear. When sound is presented to a normal ear, either in click form or frequency-specific tones, five to seven peaks occurring within 10 milliseconds make up the ABR.12 Usually only the first five peaks are considered. Wave I represents the action potentials from the eighth nerve near the cochlea. Wave II comes from the eighth nerve near the cochlear nucleus in the brainstem. Waves I and II are the only waves generated by ipsilateral structures. All subsequent waves represent bilateral crossed pathways. Wave III comes from the caudal pons with contributions from the cochlear nucleus, trapezoid body, and superior olive. Wave IV probably comes from the lateral lemniscus. Wave V, the most prominent wave, comes from the lateral lemniscus as it approaches the inferior colliculus.11 For audiological purposes, the latencies and amplitudes of waves I, III, and V are analyzed, and comparisons between sides are made. In normal hearing, the latencies of waves I, III, and V are within normal ranges and the latencies between ears are within 0.2 to 0.4 milliseconds of each other. In conductive hearing loss, the absolute latency of wave I is prolonged, but the latencies between waves and the amplitudes are not

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affected. In cochlear sensorineural loss, the wave I latency is slightly delayed and is small in amplitude, but the latencies between waves are not affected. In retrocochlear (neural) hearing loss, wave I tends to be normal, but latencies between waves I-III and I-IV are abnormally prolonged.10,11 In practice, the ABR is a good tool to definitively test hearing in uncooperative patients (newborns) and in suspected malingerers, and it can be used to evaluate the eighth nerve and brainstem structures in patients with suspected retrocochlear hearing loss. It is also used in neurotological surgical procedures, such as vestibular nerve section and acoustic neuroma removal.11

Electrocochleography Electrocochleography is a test of the electrical activity generated by the cochlea and eighth nerve. It is most often used to aid in the diagnosis of Ménière disease, but it can also be used for intraoperative monitoring of the cochlear and eighth nerve. An electrode is placed in the ear canal, on the tympanic membrane, or on the promontory of the cochlea in the middle ear. The three main signals detected by electrocochleography are the cochlear microphonic, the summating potential, and the action potential. The cochlear microphonic and summating potential reflect cochlear electrical activity, and the action potential reflects eighth nerve activity and is the same as wave I of the ABR. The calculation of interest is the summating potential/action potential ratio. An abnormally high ratio is suggestive of endolymphatic hydrops characteristic of Meniere’s disease.10,11

Otoacoustic Emissions Otoacoustic emissions (OAEs) represent auditory signals produced by the cochlear outer hair cells that can be picked up by a very sensitive microphone in the ear canal.12 Although they are a measure of cochlear function, abnormalities anywhere between the microphone and cochlea (e.g. middle ear) block any signals going from the cochlea to the microphone⎯they will not be detectable in the presence of conductive hearing loss.10 The three main types of OAEs are spontaneous, transient evoked, and distortion product. Spontaneous OAEs occur in the absence of a stimulus, but they only occur in less than one half to 60% of normal hearing individuals.10,11 Transient evoked OAEs (OAEs) are elicited by a brief click or tone burst. Distortion product OAEs (OAEs) are generated when two pure-tone stimuli of different frequencies are presented to the ear simultaneously. In response to these tones, the outer hair cells generate signals called distortion products that are related to the frequencies of the presented tones. Transient evoked OAEs are used to determine mainly if there is good cochlear function, whereas distortion product OAEs can be used to generate a curve resembling an audiogram based on frequency-specific responses of the cochlea.10-12 OAEs are useful in that they are specific to cochlear function. They are not present in conductive hearing loss or cochlear hearing loss greater than 25 to 30 dB HL. However, they can be present in retrocochlear (neural) hearing loss, which can help differentiate cochlear from retrocochlear lesions.10 OAEs are noninvasive and easy to perform⎯they can be used to screen hearing in infants, to confirm audiometric

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testing in young children, to monitor the effects of ototoxic medications, to detect cochlear abnormalities in patients with tinnitus and normal audiograms, and to help detect malingerers.10,11

Radiographic Testing Radiographic testing is indicated in certain patients with either conductive or sensorineural hearing loss. A CT scan of the temporal bones can be useful to detect the presence of congenital inner ear malformations, middle ear masses, erosive skull base neoplasms, and temporal bone fractures. It is also important in assessing the patient’s surgical anatomy and in planning for procedures such as cholesteatoma removal or cochlear implantation. Magnetic resonance imaging (MRI) of the internal auditory canals is extremely useful in the diagnosis of unilateral or asymmetric sensorineural hearing loss. It is more sensitive and specific than ABR for the detection of acoustic neuromas and is the gold standard in the diagnosis of acoustic neuromas as a cause of retrocochlear (neural) hearing loss.5,13 MRI with gadolinium enhancement is able to detect small tumors less than 1 cm in diameter, which results in better facial and hearing function after tumor removal.13 MRI should also be heavily considered in the face of sudden sensorineural hearing loss, even if it resolves with steroids, because as many as 19% of patients with acoustic neuromas can present with sudden hearing loss.14 Some reports state that as many as 47.5% of cases of sudden hearing loss may be caused by an acoustic neuroma.14,15

BALANCE EXAMINATION The diagnosis and treatment of patients with “dizziness” can be very challenging and frustrating for the patient, the neurologist, the otolaryngologist, and the audiologist. A huge variety of disorders can cause the patient to have a sensation of dizziness, and a huge variety of terms can be used to describe it (lightheadedness, spinning, “swimming sensation,” “things not being right in the head”).16 Often, the diagnosis is made by piecing together many different pieces of information. It is important to realize that not every case of dizziness can be completely cured or diagnosed exactly. An organized, systematic approach is necessary in order to make a reasonably accurate diagnosis and to avoid confusion. Key components in the evaluation of dizziness include the history, physical examination, electronystagmography, rotary chair testing, and computerized dynamic posturography testing.

History Obtaining a careful history is probably the most important step in the diagnosis of dizziness, but it often requires patience. Symptoms are often vague and difficult for the patient to describe. It may seem faster to begin by asking a lot of leading questions, but the physician will actually save time by allowing the patient to describe what he or she is feeling in the patient’s own words. Especially important is the patient’s description of the first episode of dizziness, although this may be difficult to elicit in patients who are so consumed by their dizziness that they cannot focus on the initial event and in patients who have already seen multiple specialists and/or lawyers.16

When the patient describes his or her symptoms, it is important to distinguish whether the patient is experiencing a sensation of movement, such as a spinning sensation or a falling sensation. Vertigo, a false sensation of movement, should be distinguished from dizziness, which is any kind of altered sense of orientation.17 Lightheadedness refers to a sensation characteristic of presyncope, which may include temporary blurred vision and pale facial color. It should be distinguished from vertigo and is usually caused by nonvestibular problems such as the cardiac or vasovagal reflex, both of which can result in cerebral hypoxia.17 A sense of imbalance refers to the inability to maintain the center of gravity, which causes the patient to feel unsteady and as if he or she is going to fall.17 This can be caused by both vestibular and nonvestibular disorders. When the patient describes vertigo, further information must be gathered in order to differentiate whether it is caused by a peripheral or central lesion. Vertigo can be caused by lesions anywhere from the vestibular end organs (utricle, saccule, and semicircular canals), the vestibular nuclei, the cerebellum, brainstem pathways, and the cortex (rarely).17 An important characteristic to ascertain is whether the vertigo is episodic or continuous. If episodic, how long the attacks last, how often they occur, and whether they occur with head movement or positioning are important points to know. Associated auditory symptoms, such as hearing loss, aural fullness, and tinnitus, are all important to ask about. Also important are associated neurological symptoms, such as headache with or without aura, visual changes, oscillopsia, numbness, weakness, ataxia, seizure, and loss of consciousness. Asking if the vertigo is more intense with a Valsalva maneuver is also helpful. A full otological history including history of infection, otalgia, otorrhea, and previous otological surgery is essential. In addition, it is imperative to obtain a full past medical history, past surgical history, history of head trauma, recent medications (with attention to ototoxic medications, blood pressure medications, stimulants, depressants, and illegal drugs), diet, allergies, social history, and family history of hearing loss or vestibular problems.16 Sorting out the history is important in suggesting possible diagnoses as well as recognizing more extensive and complex conditions. Episodic intense vertigo lasting up to one minute associated with head positioning or movement and not associated with other auditory symptoms is characteristic of benign paroxysmal positional vertigo (BPPV),17 but brief 5- to 10second episodes associated with head movement may also be a sign of vascular compression of the eighth nerve complex.2 Episodic vertigo lasting minutes to hours sometimes associated with fluctuating hearing loss, tinnitus, and/or aural fullness is suggestive of Meniere’s disease, but vertigo lasting 2 to 20 minutes may be associated with transient ischemic attacks, especially when associated with visual changes, ataxia, and other neurological findings.17 An isolated attack of continuous vertigo lasting longer than 24 hours with a sudden onset is suggestive of vestibular neuronitis when not associated with hearing loss and with viral labyrinthitis when associated with hearing loss.17 However, sudden-onset vertigo associated with hearing loss and tinnitus can also represent a brainstem stroke.18 Vertigo brought about by straining or other Valsalvalike maneuvers are associated with perilymphatic fistula, Chiari malformation, and superior semicircular canal dehiscence.17 There is also vertigo induced by sound, which is known as the Tullio phenomenon. This can be associated with perilymph

chapter 25 examination of hearing and balance fistula, Meniere’s disease, congenital inner ear malformations, Lyme disease, and superior semicircular canal dehiscence.19 Taking the history of the dizzy patient may be the most difficult part of the balance examination, but when done in an organized fashion, sometimes with the help of a questionnaire or preprinted template, it can be extremely useful in knowing what to look for in subsequent tests and examinations.

Physical Examination The physical examination of a patient with a balance disorder should contain a complete head and neck examination, including a detailed neurotological examination specifically using oculomotor function testing, positional testing, and postural control testing.

Head and Neck Examination The head and neck examination is similar to that described previously. Additional information can be found by performing a fistula test, which can be done by either tragal pressure or pneumatic otoscopy. The patient is instructed to look straight ahead, and continuous positive and negative pressure is applied. Normally, the eyes will not drift, but a positive fistula test (Hennebert’s sign) is manifest by the eyes drifting away from the tested ear with positive pressure and toward the tested ear with negative pressure. A positive fistula test is associated with a perilymph fistula, Meniere’s disease, or superior semicircular canal dehiscence.17,19 The cranial nerve examination should be as thorough as possible, as every cranial nerve may be potentially affected in disease processes that cause vertigo. Oculomotor examination documenting the function of cranial nerves III, IV, and VI should be performed. Internuclear ophthalmoplegia produced by lesions in the medial longitudinal fasciculus of the lower midbrain and pons is important to recognize, as vertigo may be one of the manifesting signs of multiple sclerosis.16 Subtle abnormalities in cranial nerves V, VII, and VIII may indicate a retrocochlear lesion. These can be tested by closely examining facial symmetry at rest and during movement, performing the corneal blink reflex test, and performing tuning fork testing. Usually, though, patients with retrocochlear lesions will present with hearing loss rather than tinnitus or vertigo.16 Finally, cranial nerves IX, X, XI, and XII should be thoroughly examined.

Oculomotor Function Testing The basis for nystagmus and oculomotor testing revolves around the vestibulo-ocular reflex (VOR). The VOR is a pathway that associates the activity of paired semicircular canals to a set of extraocular muscles.20 There are two main types of VOR: the angular reflex associated with the semicircular canals and the linear reflex associated with the utricle and saccule. The purposes of the reflex are to maintain binocular vision and to stabilize images on the fovea during head movement.2 The pathway involves the vestibule, the vestibular nuclei, and the oculomotor nuclei with modulation between cerebellar centers. The easiest reflex pathway to test is the paired horizontal semicircular canals with cranial medial and lateral recti muscles. For example, in a normal individual, there is an equal tonic

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firing rate of both vestibular nerves in the absence of head movement, but when the head turns to the left, the endolymph in the left horizontal canal moves to the right. This displaces the cupula and consequently the cilia toward the kinocilium, leading to an increased firing rate in the left superior vestibular nerve. The opposite effect occurs on the right side. Pathways in the brainstem then cause activation of the left medial rectus and the right lateral rectus, while the left lateral rectus and right medial rectus are inhibited. The eyes then move conjugately to the right in the exact opposing fashion to head rotation until they reach a limit. At this point, a saccade to the left brings the eyes back to the midline. When a patient has a unilateral left vestibular lesion, tonic input from the left vestibular nerve ceases, resulting in unopposed input from the right vestibular nerve. This leads to conjugate eye movements to the left (slow phase), followed by corrective saccades to the right (fast phase). The direction of nystagmus is defined by its fast phase. This is a right-beating spontaneous nystagmus. Right-beating torsional nystagmus would also occur from unopposed stimulation of the right superior and inferior canals. Upbeating or downbeating nystagmus is not characteristic of peripheral vestibular lesions and usually is caused by central lesions. Spontaneous peripheral nystagmus can be suppressed by visual fixation. The use of Frenzel lenses that do not allow visual fixation are useful to increase the examiner’s sensitivity to the patient’s nystagmus.2 Nystagmus can also be enhanced by having the patient look toward the intact side. Vestibular suppressants, alcohol, and antiepileptic medications decrease the amplitude of the nystagmus and can make evaluation difficult.16 Gaze nystagmus can be identified by having the patient look at the examiner’s index finger held at off-center positions. Gazeevoked nystagmus is often a side effect of drugs such as anticonvulsants, benzodiazepines, or alcohol, but when it is present in the absence of these drugs, it almost always indicates a central disorder involving the brainstem, cerebellum, or midbrain depending on its direction, and also tends to be direction changing.17,20 Head-shaking nystagmus is assessed by having the patient shake his or her head very rapidly back and forth in the horizontal plane while wearing Frenzel lenses. Shaking is abruptly stopped, and nystagmus is assessed. Normal individuals usually have just a beat or two of nystagmus, but individuals with a unilateral vestibular lesion show nystagmus with the fast phase toward the intact side.2 Patients with central lesions such as cerebellar dysfunction may also have post head-shaking nystagmus, often in the vertical direction.2 Nonlinearity testing, or head thrust testing, is performed by applying quick head thrusts about 15 degrees in the plane of each semicircular canal from the neutral position while the patient attempts to fix his gaze on the examiner’s nose. A normal patient is able to keep his or her gaze on the examiner’s nose, but a patient with a lesion affecting a semicircular canal demonstrates a corrective saccade after the head thrust toward the lesioned side.17

Positional Testing The first positional test that should be performed is the DixHallpike maneuver to detect the presence of benign paroxysmal positional vertigo of the posterior semicircular canal. In this

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test, the patient is sitting upright on an examination table and the head is turned 45 degrees to the side in question. The head is brought quickly down to a position where the head hangs off the edge of the table and the patient is instructed to look straight ahead with the eyes open (the patient may also wear Frenzel lenses if desired).2,17 This position is held for 30 seconds, and in the presence of BPPV, classically the patient has horizontorotary nystagmus with the fast phase beating toward the down ear (geotropic), which is delayed in onset and fatigable. Almost all persons with BPPV have a sensation of spinning.16 Nystagmus of central origin may also manifest itself during the Dix-Hallpike maneuver, but it usually lasts indefinitely while the patient is in the supine position.16

then with the eyes closed. Failure of this test can indicate an abnormality in the vestibulospinal pathway.2,17

Electronystagmography Electronystagmography is a combination of tests based on the VOR that provides important information about the vestibular and ocular systems. Results of the electronystagmographic battery should be used in conjunction with findings from the history, the physical examination, and other studies to arrive at a diagnosis.22

Electro-oculography Postural Control Testing Postural control testing is based on the vestibulospinal reflex. These pathways work in conjunction with visual and proprioceptive pathways to help the patient maintain balance. For example, if your body leans to the left, the left leg extensors are activated to counteract a change in the patient’s new center of gravity. With a perceived forward motion, the body sways forward to maintain the center of gravity. A simple way to think of this is that balance in gravity depends on three peripheral components: vision, proprioception, and the vestibular system. These three components are bilateral peripheral inputs to the brain, which integrates balance, whereas the cerebellum is considered a central input. Taking away one of the inputs places the burden of maintaining balance on the other two inputs, and taking away two of the inputs places all of the burden on the one remaining input. This is analogous to a person standing in darkness having to rely on vestibular inputs and proprioception to maintain balance.16 The Romberg test was originally described for tabes dorsalis and primarily tests proprioception.16,21 In this test, the patient stands with both feet together with the arms either folded in front or down at the sides. Then the patient closes his or her eyes and attempts to keep balance. Patients with a unilateral vestibular lesion tend to fall toward the lesioned side. The tandem Romberg test is a variant that requires patients to stand with one foot directly in front of the other. This increases its sensitivity.16 The Fukuda stepping test is performed with the patient’s arms straight out in front and the eyes closed. The patient then marches in place. A vestibular lesion is indicated if the patient is turned more than 30 degrees from the original position after approximately 50 steps. Usually, patients turn toward the diseased side. Patients with a vestibular lesion with a positive Fukuda stepping test are usually surprised by the result, as they do not sense that they are rotating during the test.16 Another test of vestibulospinal function is the tandem gait test, in which the patient is asked to step heel-to-toe with his/her eyes closed. Normal individuals can do this for at least 10 steps, but patients with vestibular disorders fail this test.17 The past pointing test is done by having the patient and examiner stand facing each other with arms extended forward and their index fingers in contact with one another. The patient then raises his or her arms up and brings his or her fingers into contact again with the examiner’s, first with the eyes open and

Electro-oculography is used to record eye movements during electronystagmographic testing. It is based on the corneoretinal potential (difference in electrical charge between the cornea and the retina), with the long axis of the eye acting as a dipole. Movements of the eye relative to the surface electrodes placed around the eye produce an electrical signal that corresponds to eye position. Recordings of eye movement are accurate to about 0.5 degree, but it is still less sensitive than visual inspection, which can perceive movements of about 0.1 degree.2 Therefore, visual inspection with Frenzel lenses is sometimes still necessary to document nystagmus of low amplitude. Another limitation of electro-oculography is that torsional eye movements cannot be monitored. Again, visual inspection with Frenzel lenses is sometimes necessary to document torsional nystagmus.2 Fortunately, new techniques have been developed to provide greater accuracy and breadth for oculomotor testing. The most clinically useful technique that has been developed is the infrared video electronystagmographic system. Here, the patient wears goggles that illuminate the eyes with infrared light (invisible to the patient), allowing a small video camera to pick up and project an image of the eyes onto a monitor. This can also assess eye movement in horizontal, vertical, and torsional directions and is more accurate than electrooculography.22

Oculomotor Testing Oculomotor testing measures the accuracy, latency, and velocity of eye movements in response to a stimulus (usually an LED light). The tests performed include tests for saccades, smooth pursuit, and optokinetic nystagmus. Saccades are rapid eye movements that bring objects from the peripheral visual fields onto the fovea. They are controlled by the occipitoparietal cortex, the frontal lobe, the basal ganglia, the superior colliculus, the cerebellum, and the brainstem.17 During saccade testing, the patient follows the LED, which flashes sequentially in positions 15 to 20 degrees to the right or left of center. The test is repeated vertically. The latency, peak eye velocity, and accuracy are then calculated. The latency is the time lag between presentation of the stimulus and the beginning of a saccade. Prolonged or shortened latency, as well as differences in latency between eyes, are usually indicative of neurodegenerative disease. Abnormally slow peak velocities can be caused by sedative drugs, drowsiness, cerebellar disorders, basal ganglia disorders, and brainstem lesions. Abnormally fast

chapter 25 examination of hearing and balance velocities are found with calibration errors and eye muscle restrictions. Asymmetrical velocities are caused by internuclear ophthalmoplegia, eye muscle restriction, and cranial nerves III and VI palsies. Poor accuracy, described as overshoot or undershoot dysmetria, usually indicates cerebellar, brainstem, or basal ganglia abnormalities.17 Smooth pursuit describes eye movements that are generated when tracking moving objects. In smooth pursuit testing, the patient follows an LED moving back and forth between two points at a constant velocity. The gain and phase are then calculated. Gain is the ratio of the eye velocity to the target velocity. Abnormally low gain is suggestive of a central disorder (brainstem or cerebellum).17 Phase is the difference in time between eye movement and target movement. Abnormalities here also indicate central nervous system disorders.17 The morphology of the smooth pursuit tracing can be analyzed. A saccadic pattern of smooth pursuit is associated with a cerebellar disorder.22 Acute peripheral vestibular lesions can also impair smooth pursuit when the eyes are trying to move opposite the slow phase of spontaneous nystagmus.17 Optokinetic nystagmus is tested by having the patient look ahead while seated in a rotating drum with black and white stripes on it. When the patient tries to look straight ahead, there will be small involuntary excursions of the eye (stare nystagmus). When the patient follows a target, smooth pursuit is tested (look nystagmus). Both types of nystagmus are probably responsible for eye movement during stimulation. However, when the lights go out, the patient with an intact optokinetic system will continue to have nystagmus for about 25 seconds⎯optokinetic after nystagmus (OKAN).22 The optokinetic system is distributed widely throughout the brainstem and cerebellum, so abnormalities are difficult to localize. However, absence or asymmetry of OKAN can occur with peripheral vestibular lesions. Bilateral lesions tend to greatly reduce or eliminate OKAN, whereas unilateral lesions can result in asymmetrical OKAN with prolonged nystagmus directed at the site of lesion.22,23

Spontaneous and Gaze Nystagmus The electronystagmogram can record eye movements associated with spontaneous and gaze-evoked nystagmus similar to that described earlier (see Physical Examination). An advantage of electronystagmography over physical examination is that eye movements can be monitored with the eyes closed. If during any part of the test nystagmus is identified with the eyes closed, the patient is then told to open the eyes so that changes in nystagmus can be detected. Patients with peripheral causes of nystagmus and a normal central pathway are able to suppress the nystagmus with the eyes open. This is called fixation suppression. A central lesion is suggested when there is no fixation suppression and the nystagmus continues with the eyes open.22

Positional and Positioning Tests Positional tests measure the response to changes in the direction of gravitational force. With the eyes closed, the patient is moved slowly into a series of stationary positions, and the presence of nystagmus is assessed, which can be fixed or direction changing. Positional nystagmus from a peripheral lesion can fatigue with repeated testing, is usually fixed in direction, and

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usually does not change independent of head movement. Nystagmus that changes in direction independent of head movement is suggestive of a central lesion.22 Positioning tests include the Dix-Hallpike maneuver, among others. The patient is positioned as described earlier (see Physical Examination), and the presence of nystagmus is noted. If the patient has nystagmus, the test is repeated to see if the response fatigues. If the response fatigues, it is suggestive of a peripheral disorder, but if it does not, it suggests a central lesion.22

Caloric Testing Caloric testing is a very important part of electronystagmography in that it is one of the few tests that allows one labyrinth to be examined independently of the other.2 Horizontal nystagmus is induced by stimulation of the horizontal semicircular canal using a cold and warm stimulus (air or water). The patient lies in the supine position with the head tilted 30 degrees upward to bring the horizontal canal into the vertical plane (direction of gravity), making it more sensitive to the flow of endolymph.17 The external canal is irrigated with 250 mL of water at 30ºC and 44ºC for about 30 seconds each. Alternatively, air at temperatures of 24ºC and 50ºC can be used. For example, a cold stimulus in the left ear causes the endolymph of the horizontal canal to fall (as if the head was turning right and the endolymph was moving left) and the cupula moves the cilia in an ampullofugal direction away from the kinocilium, causing a decreased firing rate in the left vestibular nerve and inhibition of the left medial rectus and the right lateral rectus via the VOR. The eyes then drift conjugately to the left (slow phase) and corrective saccades bring the eyes back to the right (fast phase)⎯this results in a right-beating nystagmus. The opposite occurs with warm stimulation. A mnemonic used to determine the direction of the fast phase of nystagmus in cold and warm stimulation is “COWS”: Cold Opposite, Warm Same. The measured value of the induced nystagmus for each stimulus is the peak slow-phase velocity averaged over a 10-second period.17 The difference between the sides is calculated, and any difference greater than 20% to 25% between sides is considered significant and indicates weakness of the vestibular labyrinth or nerve on the less active side. Directional preponderance, which compares the peak slow-phase velocities of eye movements to the right with the left, can also be calculated. A difference of 25% to 30% is considered significant and indicates an imbalance but is a nonlocalizing measure.16

Rotational Chair Testing Rotational chair testing measures the VOR response to small rotations of the body around an axis. It can be useful in monitoring changes in vestibular function over time (especially bilateral lesions or lesions from vestibulotoxic medications), monitoring compensation following acute injury, and identifying residual vestibular function in patients with no response during caloric testing.22 The easiest canal to test is the horizontal canal. The patient is fitted with electro-oculographic electrodes and rotated slowly around a vertical axis with the eyes covered. The patient then undergoes sinusoidal harmonic acceleration, during which the patient is rotated back and forth

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at gradually increasing frequencies to a peak angular velocity of about 50 degrees per second.16 The three values analyzed are phase, gain, and symmetry. Phase measures the timing of eye movement relative to head movement. In individuals with an intact VOR, the direction of slow phase eye velocity is exactly opposite head velocity, but patients with a vestibular or cerebellar lesion have an abnormal phase, with either a phase lead or lag. Gain is the ratio of the slow phase eye velocity to the head velocity. Abnormally low gain may indicate bilateral peripheral vestibular weakness, whereas abnormally high gain may be seen in cerebellar lesions.17 Symmetry measures the difference between slow phase velocities associated with rightward and leftward rotation and can suggest involvement of the central pathways or peripheral vestibular dysfunction.17

Other Testing Additional tests that may be useful in the balance evaluation are audiometric tests, radiographic tests, and blood tests. Audiometric tests are extremely important in the evaluation of dizziness. Every patient should at least have an audiogram and immittance testing. A unilateral hearing loss supports a peripheral cause of vertigo, and reduced speech discrimination scores may prompt a search for a retrocochlear abnormality such as an acoustic neuroma.16 Radiographic tests such as an MRI will be able to detect acoustic neuromas, multiple sclerosis, and brainstem strokes. CT scans may detect middle and inner ear anomalies such as a cholesteatoma eroding into the semicircular canals or a superior semicircular canal dehiscence. Finally, blood tests looking for thyroid function, glucose tolerance, syphilis, rheumatoid factor, and ANA may also be useful in helping to diagnose a dizzy patient.

Computerized Dynamic Posturography Posturography is a quantitative test of the vestibulospinal reflex. It has the same basis as the Romberg test, where three peripheral inputs of vision, the labyrinth, and proprioception are integrated for a patient to maintain balance. If one of these inputs is taken away, the patient has to rely on the remaining inputs to maintain balance. No one input can be measured by itself. Patients with cerebellar lesions and certain cortical lesions are characteristically ataxic and will have poor results on posturography.16 There are two tests in posturography: the sensory organization test and the motor control test. In the sensory organization test, the patient is subjected to six conditions. In condition 1, the patient stands on a fixed platform with the eyes open and looks at a fixed visual surround. In condition 2, the platform is fixed, but the eyes are covered, forcing the patient to rely on proprioceptive and vestibular cues. In condition 3, the platform is fixed and the eyes are open, but the visual surround moves in reference to body sway, forcing the patient to ignore the visual stimulus and rely on proprioceptive and vestibular cues. In condition 4, the eyes are open and the visual surround is fixed, but the platform sways, taking away proprioception, which forces the patient to rely on visual and vestibular cues. Patients with vestibular dysfunction still tend to do well in condition 4. In condition 5, the platform sways and the eyes are covered, forcing the patient to rely on vestibular cues alone⎯patients with vestibular dysfunction tend to fall here. In condition 6, the eyes are open, but both the platform and visual surround move, forcing the patient to rely on vestibular cues while ignoring inaccurate proprioceptive and visual cues.2 Patients with vestibular dysfunction tend to fall here as well. The parameter measured is the patient’s anterior and posterior body sway, and is measured on a 0-to-100 scale (fall = 0, no sway = 100).22 Motor control tests evaluate the automatic postural responses to forward and backward horizontal movements of the platform. The main parameter tested here is latency. A prolonged latency in both directions suggests a central lesion, whereas a prolonged latency in only one direction suggests either a peripheral or central lesion.17 Although posturography results tend not to localize lesions, they are useful for planning vestibular rehabilitation. Posturography may also aid in the detection of malingerers, who tend to have inconsistent results and may do more poorly on conditions 1 and 2 than on conditions 5 and 6.2

K E Y

P O I N T S

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Hearing loss and balance disorders are two of the most common reasons why patients visit their physicians.

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There are three main forms of hearing loss: conductive, sensorineural, and mixed. Each can be caused by a wide variety of conditions, ranging from benign conditions, such as cerumen impaction, to potentially life-threatening diseases, such as squamous cell carcinoma of the temporal bone.

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A thorough history is one of the most important aspects of a hearing evaluation.

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A complete head and neck examination can give many clues to the cause of a patient’s hearing loss.

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Audiological testing has been available for decades, but developments over the years have advanced the field of audiology to include tests and procedures that can determine the site of lesion with far greater accuracy than before. Otolaryngologists and audiologists often need to rely on one another to diagnose accurately the cause of a patient’s hearing loss using a combination of the history, physical examination, and results of various audiological tests.

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The diagnosis and treatment of patients with “dizziness” can be very challenging and frustrating for the patient, the neurologist, the otolaryngologist, and the audiologist. A huge variety of disorders can cause the patient to have a sensation of dizziness, and a huge variety of terms can be used to describe it (lightheadedness, spinning, “swimming sensation,” “things not being right in the head”).

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Often, the diagnosis is made by piecing together many different pieces of information. Not every case of dizziness can be completely cured or diagnosed exactly. An organized, systematic approach is necessary to make a reasonably accurate diagnosis and avoid confusion. Key components in the evaluation of dizziness include the history, physical examination, electronystagmography, rotary chair testing, and computerized dynamic posturography testing.

chapter 25 examination of hearing and balance Suggested Reading Chole RA, Cook GB: The Rinne test for conductive deafness. A clinical reappraisal. Arch Otolaryngol Head Neck Surg 1998; 114:399-403. Cueva RA: Auditory brainstem response versus magnetic resonance imaging for the evaluation of asymmetric sensorineural hearing loss. Laryngoscope 2004; 114:1686-1692. Kileny PR, Zwolan TA: Diagnostic and rehabilitative audiology. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3483-3502. Satar B: Vestibular testing. In Lalwani AK, ed: Current Diagnosis and Treatment in Otolaryngology⎯Head and Neck Surgery. New York: McGraw-Hill, 2004, pp 643-658.

References 1. McGee J, Walsh EJ: Cochlear transduction and the molecular basis of peripheral auditory pathology. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3402-3465. 2. Hullar TE, Minor LB, Zee DS: Evaluation of the patient with dizziness. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3160-3192. 3. Kroenke K, Arrington ME, Mangelsdorff AD: The prevalence of symptoms in medical outpatients and the adequacy of therapy. Arch Intern Med 1990; 150:1685-1689. 4. Kroenke K, Mangelsdorff AD: Common symptoms in ambulatory care: Incidence, evaluation, therapy, and outcome. Am J Med 1989; 86:262-266. 5. Arts HA: Sensorineural hearing loss: evaluation and management in adults. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3535-3561. 6. Diagnosis of ear disease. In Glasscock ME, Shambaugh GE, Johnson GD, eds: Surgery of the Ear. Philadelphia: WB Saunders, 1990. 7. Backous DD, Niparko JN: Evaluation and surgical management of conductive hearing loss. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3522-3534.

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8. Miltenburg DM: The validity of tuning fork tests in diagnosing hearing loss. J Otolaryngol 1994; 23:254-259. 9. Chole RA, Cook GB: The Rinne test for conductive deafness. A clinical reappraisal. Arch Otolaryngol Head Neck Surg 1998; 114:399-403. 10. Sweetow RW, Bold JM: Audiologic testing. In Lalwani AK, ed: Current Diagnosis and Treatment in Otolaryngology⎯Head and Neck Surgery. New York: McGraw-Hill, 2004, pp 631-641. 11. Hall JW, Antonelli PJ: Assessment of peripheral and central auditory function. In Bailey BJ, ed: Head and Neck Surgery⎯Otolaryngology. Philadelphia: Lippincott Williams and Wilkins, 2001, pp 1659-1672. 12. Kileny PR, Zwolan TA: Diagnostic and rehabilitative audiology. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3483-3502. 13. Cueva RA: Auditory brainstem response versus magnetic resonance imaging for the evaluation of asymmetric sensorineural hearing loss. Laryngoscope 2004; 114:1686-1692. 14. Nageris BI, Popovtzer A: Acoustic neuroma in patients with completely resolved sudden hearing loss. Ann Otol Rhinol Laryngol 2003; 112:395-397. 15. Chaimoff M, et al: Sudden hearing loss as a presenting symptom of acoustic neuroma. Am J Otolaryngol 1999; 20:157160. 16. Linstrom CJ: Office management of the dizzy patient. Otolaryngol Clin North Am 1992; 25:745-780. 17. Satar B: Vestibular testing. In Lalwani AK, ed: Current Diagnosis and Treatment in Otolaryngology⎯Head and Neck Surgery. New York: McGraw-Hill, 2004, pp 643-658. 18. Lee H, et al: Sudden deafness and anterior inferior cerebellar artery infarction. Stroke 2002; 33:2807-2812. 19. Mong A, et al: Sound- and pressure-induced vertigo associated with dehiscence of the roof of the superior semicircular canal. AJNR Am J Neuroradiol 1999; 20:1973-1975. 20. Brandt T, Strupp M: General vestibular testing. Clin Neurophysiol 2005; 116:406-426. 21. Moffat DA, et al: Unterberger’s stepping test in acoustic neuroma. J Laryngol Otol 1989; 103:839-841. 22. Driscoll CL, Green JD: Balance function tests. In Bailey BJ, ed: Head and Neck Surgery⎯Otolaryngology. Philadelphia: Lippincott Williams and Wilkins, 2001, pp 1652-1658. 23. Hain TC, et al: Localizing value of optokinetic afternystagmus. Ann Otol Rhinol Laryngol 1994; 103:806-811.

chapter 26 auditory system disorders

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Thomas O. Willcox and Gregory J. Artz

Hearing loss can be defined as an increase in the threshold of sound perception. Understanding speech and the general world around us depends on the accurate perception and processing of complex, multifrequency sounds. There are multiple areas along the auditory pathway for pathology to occur that can cause distorted, inefficient, or unperceived sound, resulting in hearing loss. Hearing loss affects nearly 28 million Americans, including 30% of adults over the age of 65 and 50% over the age of 85. Hearing loss is one of the most common chronic illnesses, and as the population ages and lives longer, it will increasingly affect the morbidity and quality of life of patients. Hearing loss is not just a disorder of adults. It also significantly affects children and their daily lives, as well as the lives of their parents and caregivers. Otitis media can cause a conductive hearing loss due to fluid accumulation that can take months to resolve. Otitis media is the most common reason for a child to visit the pediatrician. By 3 years of age, three of every four children will have had at least one episode of otitis media. This has a significant financial impact on the health care system, in addition to the financial impact on parents, who lose income when they miss work to care for their sick children. Children can also be afflicted with congenital causes of hearing loss; two or three of every 1000 children born today will be either deaf or hard of hearing. Hearing loss is a broad topic and first can be subdivided into hereditary and nonhereditary causes. Hereditary causes can be isolated genetic defects or associated with several childhood syndromes. Hereditary hearing impairment is not covered in depth in this chapter. Briefly, it is the cause of hearing impairment in more than 50% of children born with moderate to profound hearing loss. Of these children with genetic causes of their hearing loss, more than 75% will be determined to be nonsyndromic. More than 100 genetic loci have been implicated in causing nonsyndromic hereditary hearing loss, with defects in connexin 26 and connexin 30 being the most common. These causes are overwhelmingly autosomal recessive in approximately 75% of cases but also can be autosomal dominant or X-linked or even due to mitochondrial inheritance. Hereditary hearing loss usually manifests at birth, but some hearing disorders manifest as delayed onset or even adult onset in a nonprogressive or progressive fashion. Hearing loss can be subdivided into categories based on the site of pathology: conductive, sensorineural, or central hearing

loss. Conductive and sensorineural are the most common, whereas with central hearing loss is quite rare.

CONDUCTIVE HEARING LOSS Conductive hearing loss is caused by impairment in air transmission of sound waves to the inner ear. The impairment of function is due to pathology at the level of the external auditory canal, the tympanic membrane, or the ossicular chain, resulting in inefficient conversion of sound waves from air to the fluid medium of the endolymph in the membranous labyrinth. A rare cause of conductive hearing loss is the “third mobile window” of the inner ear, which is attributed to a dehiscent superior semicircular canal or an enlarged vestibular aqueduct. On bedside physical examination, a patient with a conductive hearing loss has a negative Rinne test, which means that the hearing threshold for bone conduction is less than air conduction in the tested ear. This test is performed by placing the 512-Hz tuning fork first on the mastoid tip, then approximately 2 to 3 inches from the entrance to the external auditory canal. Bone conduction surpasses air conduction when a conductive hearing loss reaches 25 to 30 decibels (dB). When performing the Weber test, the end of the tuning fork is placed in the middle of the patient’s forehead. If the patient has unilateral hearing loss, then the sound will lateralize to the bad ear, or the ear with the conductive hearing loss. The sensitivity of the Weber test can be increased by alternatively placing the tuning fork on the patient’s upper incisors.

SENSORINEURAL HEARING LOSS Sensorineural hearing loss is caused by damage to the cochlear sensory epithelium or, less commonly, the peripheral auditory neurons. The type of hearing loss a patient has can be quite different depending on whether the cochlea or the auditory nerve fibers are involved. When cochlear hair cell loss is the main reason for hearing difficulties, it often manifests as a sound threshold shift only. When the lesion involves the auditory nerve, or is called retrocochlear, a patient often has significant sound distortion that manifests as difficulty with word discrimination out of proportion to the associated hearing loss. On bedside evaluation, the Rinne test is positive, and if the

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hearing loss is unilateral, the Weber test lateralizes away from the side with the hearing loss, or toward the good ear. Sensorineural hearing loss is a challenge to physicians, as it progresses with age and causes significant reductions in quality of life and there are no treatments to reverse its effects, other than sound amplification with the use of hearing aids or direct auditory nerve stimulation via cochlear implantation.

CENTRAL HEARING LOSS Central hearing loss is caused by a lesion in the central auditory pathway or in the auditory cortex. The auditory cortex processes and interprets the sounds amplified and received by the ossicles and cochlear hair cells. The auditory cortex is located on the transverse temporal gyri of Heschl. It is divided into the primary auditory cortex (Brodmann’s areas 41 and 42) and the auditory association cortex (Brodmann’s areas 22 and 52). Lesions such as brain tumors and ischemic or embolic strokes in the region of the transverse temporal gyri affect speech discrimination more than they affect hearing threshold levels, as patients with central hearing loss often have normal audiograms. Types of central hearing loss include aphasia (Wernicke’s aphasia), pure word deafness, auditory agnosia, cortical deafness, and auditory hallucinations. Another more common form of central hearing loss is associated with presbycusis, or age-related hearing loss. In the elderly, speech discrimination is often worse than would be expected based on their pure-tone hearing thresholds. It is believed that this may be due to a combination of cochlear hair cell loss, neuronal loss, and age-related central auditory processing changes.

CAUSES OF CONDUCTIVE HEARING LOSS Suboptimal air conduction of sound waves to the cochlea can cause a hearing loss. This is referred to as a conductive hearing loss. There are several places that a conductive hearing loss can occur: the external auditory canal, the tympanic membrane, the middle ear space, and the inner ear. Most of the causes of conductive hearing loss are due to anatomical obstruction or damping of the transmitted sound waves on their way toward the sensory epithelium of the cochlea. Almost all of these causes are amenable to surgical or medical correction and, by definition, all patients with purely conductive hearing losses have normal eighth nerve function and can achieve normal hearing thresholds through hearing aid amplification.

Treatment is atraumatic cerumen removal. Irrigation should be performed with caution, as irrigation in a patient with a tympanic membrane perforation can cause vertigo and subsequent otitis media.

Cholesteatoma Cholesteatoma is normally associated with the middle ear and mastoid, but it can occasionally occur in the external auditory canal. Through inflammation and associated infection, it can cause a conductive hearing loss. Cholesteatomas of the external canal are usually unilateral and have associated symptoms of otalgia and otorrhea. On examination, there is narrowing or occlusion of the external auditory canal, abundant keratin debris, and sometimes granulation tissue. Treatment includes resolution of the external otitis infection with topical antibiotic eardrops and occasional systemic antibiotics, followed by surgical debridement and excision of the cholesteatoma.1

External Auditory Canal Tumors Tumors of the external auditory canal, benign or malignant, can cause a conductive hearing loss. The two most common benign bony tumors are exostoses and osteomas.1 Exostoses are broadbased lesions that are often multiple and bilateral. Patients usually give a long history of cold water exposure, such as swimming, diving, or surfing. Exostoses are found in the medial portion of the bony external auditory canal near the annulus and often along the tympanomastoid and tympanosquamous suture lines. Osteomas are solitary and unilateral and are not associated with any significant history such as that of patients with exostosis. They are found in the lateral portion of the external auditory canal at the bony-cartilaginous junction. Treatment of exostoses and osteomas is based on symptoms, as they are benign lesions with no known malignant conversion. Chronic or recurrent acute otitis externa is the most common reason patients undergo surgical excision. Care must be taken not to injure the mastoid segment of the facial nerve when removing these lesions, particularly when operating in the posteromedial external auditory canal. The most common malignant tumor of the external auditory canal is squamous cell cancer. Fortunately, these are rare head and neck tumors. They can arise from anywhere within the external auditory canal, and patients often have symptoms of otorrhea, otalgia, and occasionally hearing loss. Treatment is surgical excision with postoperative chemoradiation therapy depending on the stage of the tumor.

Cerumen Impaction One of the most common causes of hearing loss is cerumen impaction. The external auditory canal is one third cartilaginous and two thirds bony. The lateral one third of the canal is cartilaginous and has overlying skin containing subcutaneous tissue, hair follicles, cerumen, and sebaceous glands. The medial two thirds of the canal are bony, has thin skin, and lacks hair follicles or glandular tissue that are adherent to the bone. A conductive hearing loss can occur if cerumen completely obstructs the lumen of the external auditory canal. This often occurs suddenly, often after cotton swab manipulation or water exposure. Symptoms can include aural fullness and tinnitus.

External Auditory Canal Stenosis or Absence A rare cause of conductive hearing loss is stenosis or absence of the external auditory canal, as in congenital aural atresia. The incidence of aural atresia is 1 in 10,000 to 20,000 births.2 Aural atresia is usually associated with a large conductive hearing loss or air-bone gap, assuming that the cochlear function is normal. Varying degrees of external ear malformations (microtia), temporal bone atresia, ossicular deformities, and facial nerve anomalies are seen. Surgical treatment to repair the external ear, external auditory canal, and middle ear

chapter 26 auditory system disorders abnormalities can restore hearing to normal levels in favorable candidates.

Tympanic Membrane Pathology of the tympanic membrane includes perforations, atelectasis, and tympanosclerosis. Aside from its role in protecting the middle ear, the tympanic membrane is critical in receiving sound waves and efficiently transmitting them through the ossicular chain to the endolymph of the cochlea. Any pathological process that compromises the mobility or efficiency of the tympanic membrane results in a conductive hearing loss. Tympanic membrane perforations can be caused by acute and chronic infections, head trauma, or iatrogenic causes, such as after tympanostomy tube extrusion. Tympanostomy tube placement is common in infants with otitis media and is one of the most common surgical procedures performed today. The reported rate of tympanic membrane perforation depends on the type of tube placed; however, routine grommet-type tubes have a 1% to 3% incidence.3 Most perforations from tympanostomy tubes are small, causing a 10-dB hearing loss or less, and usually heal with time. However, larger perforations and total perforations of the tympanic membrane, usually seen in patients with a history of chronic otitis media, can result in a significant conductive hearing loss of 30 dB or more. A thin, atrophic, atelectatic tympanic membrane can also cause a conductive hearing loss, particularly if there is associated ossicular erosion. A retracted, atelectatic tympanic membrane is caused by eustachian tube dysfunction and the resultant chronic negative middle ear pressure. Hearing loss can be further affected in these patients by chronic middle ear fluid. Initial treatments consist of tympanostomy tube placement, tympanoplasty, and medical therapy, including decongestants and nasal steroid sprays. A common finding on otoscopy during routine physical examination is tympanosclerosis, a white discoloration of the tympanic membrane. Tympanosclerosis can be due to a prior history of tympanostomy tube placement and/or an associated history of otitis media. Unless the tympanic membrane involvement is particularly severe, it is rare for tympanosclerosis to cause an appreciable conductive hearing loss. The ratio of the tympanic membrane area to the stapes footplate area results in an 18-fold amplification of sound under normal physiological conditions.4 Any disruption or fixation of the ossicular movements impairs this efficient sound transmission. Therefore, any abnormalities of the ossicular chain manifest as a conductive hearing loss. Otosclerosis is a common cause of conductive hearing loss due to stapes footplate fixation. Otosclerosis is a disease of bone limited to the otic capsule. Classically, it causes a conductive hearing loss, but it must be mentioned that otosclerosis can also affect the cochlea, causing a mixed or even a purely sensorineural hearing loss. It is inherited in an autosomal dominant fashion with incomplete penetrance and is more often seen in white populations at a histological incidence of 7% to 10%. Only approximately 10% of patients with histological evidence of otosclerosis present with clinical symptoms.5 Two thirds of patients with otosclerosis are women. The disorder is often bilateral and classically manifests in the third and fourth decades of life as a conductive hearing loss. Otosclerosis in women has always been believed to worsen during pregnancy; however, clinical data

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have brought into question that premise.6 Treatment is often curative with stapedotomy or stapedectomy surgery. Middle ear and mastoid cholesteatoma is defined as an accumulation of keratin and desquamated debris from the squamous epithelial lining of the external auditory canal and lateral surface of the tympanic membrane. There are two types: congenital and acquired. Congenital cholesteatoma is an anteriorly based mass believed to be an embryological remnant. The more common type is the acquired cholesteatoma that results from otitis media. Squamous epithelium migrates into the middle ear and mastoid. Of the acquired type, cholesteatoma can occur in the setting of a tympanic membrane perforation or from chronic otitis media due to eustachian tube dysfunction causing persistent negative pressure and tympanic membrane retraction. Cholesteatoma manifests as a middle ear mass, often in close approximation to the ossicles, with or without bony erosion, and patients present with a conductive hearing loss. Other symptoms commonly include chronic otorrhea and rarely vertigo and facial nerve paresis or palsy. Treatment consists of treating any infection first and then surgical removal of the cholesteatoma with ossicular reconstruction if warranted. Ossicular reconstruction is sometimes delayed 6 to 12 months, during which time patients are observed for any signs of recurrence or recidivism. If the posterior external auditory canal wall is left intact, recurrence rates are slightly higher at 5% to 27% versus 2% to 10% when the posterior canal wall is removed.7 When treating cholesteatoma, the first priority is to create a dry, safe ear, as infectious complications of a cholesteatoma can have significant morbidity, such as meningitis and brain abscesses. Correcting the conductive hearing loss is a second priority only after antimicrobial and surgical treatments have been successful.

Otitis Media The most common cause of hearing loss in children is due to otitis media. Approximately 85% of children have at least one episode of acute otitis media. A decade ago, otitis media was estimated to cost the health care industry more than $5 billion annually.8 Factors that predispose children to otitis media include bottle feeding, crowded living conditions, day care, smoking at home, hereditary influences, and craniofacial abnormalities, such as cleft palate. Early treatment for children with chronic otitis media is critical to proper development. Lack of intervention can result in abnormal development of cognition, language, and general communicative skills.9 Otitis media with effusion or serous otitis media causes a conductive hearing loss by preventing normal mobility of the tympanic membrane as seen on pneumatic otoscopy and tympanometry examination. Audiometry in children with otitis media with effusion reveals an average air-conduction threshold of 28 dB.10 Guidelines from the Agency for Health Care Policy and Research (now called the Agency for Healthcare Research and Quality [AHRQ]) recommend treatment for chronic otitis media with effusion for any conductive hearing loss greater than 20 dB.11 Treatment for hearing loss from otitis media with effusion usually consists of tympanostomy tube placement. Antibiotic prophylaxis is generally not recommended due to the risk of promoting antimicrobial resistance. Other medications, such as antihistamines, decongestants, and corticosteroids, have not proved to be effective in clinical studies.

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Middle Ear Fluid or Masses There are several other causes of middle ear fluid or masses that can cause a conductive hearing loss. Chronic eustachian tube dysfunction can cause a persistent middle ear effusion that often requires myringotomy with or without placement of a tympanostomy tube. However, when an adult presents with a unilateral conductive hearing and physical examination reveals a middle ear effusion, the physician must rule out more serious causes, such as a spontaneous cerebrospinal fluid leak of the temporal bone or a nasopharyngeal mass causing obstruction of the eustachian tube orifice. Patients with cerebrospinal fluid leaks can have a conductive hearing loss that is exacerbated by a meningoencephalocele impinging directly on the ossicular chain. Cerebrospinal fluid leaks must be repaired surgically and nasopharyngeal masses are most commonly squamous cell cancers and are treated with chemoradiation. Other middle ear masses, such as paragangliomas (glomus tympanicum, glomus jugulare) and hemangiomas, can also manifest as a conductive hearing loss.

Superior Canal Dehiscence Syndrome Pathology of the inner ear has always been associated with sensorineural hearing loss. However, in 1998 superior canal dehiscence syndrome was described.12 In this syndrome, the bone overlying the semicircular canal on the floor of the middle cranial fossa is found to be dehiscent on computed tomography. Signs and symptoms may include vertical-torsional eye movements in response to loud sounds or middle ear pressure changes, autophony, and chronic disequilibrium, all of which can be disabling when severe.13,14 The symptoms and signs in this syndrome have been described as the dehiscence being a third window into the inner ear, with the other two being the oval and round windows. Intracranial pressure differences can exert pressure on this third window, creating the characteristic signs and symptoms. Other symptoms of this syndrome have been air-bone gaps and suprathreshold bone conduction hearing levels believed to be due to sound wave escape through the dehiscent superior semicircular canal. The dehiscence provides a low resistance alternative pathway for sound waves, thereby increasing air-conduction thresholds. There are several reports of patients undergoing unsuccessful stapes surgery for a conductive hearing loss only to be later diagnosed with superior canal dehiscence15 (personal communication, Michael Teixido, MD, Wilmington, DE, 2005). There have also been cases of patients having air-bone threshold gaps on audiometry with enlarged vestibular aqueducts, a possible alternative site contributing to the third mobile window theory. Treatment for superior canal dehiscence is surgical in those patients with severe debilitating symptoms. Surgical approaches include middle fossa craniotomy or transmastoid with varying success rates16 (personal communication, Michael Teixido, MD, Wilmington, DE, 2005).

CAUSES OF SENSORINEURAL HEARING LOSS Age-related hearing loss, or presbycusis, is a common diagnosis in the aging population. By strict definition, presbycusis is hearing loss specifically caused by aging. However, it has been nearly impossible to filter out other causes that can contribute to age-related hearing loss, such as genetic factors, accumu-

lated noise injury, acoustic trauma, and vascular and metabolic factors. Strictly speaking, there are four main physiological mechanisms that contribute to presbycusis. There can be loss of cochlear hair cells, predominantly in the high-frequency range, and the speech discrimination is usually preserved. There can be auditory neuronal loss that results in a generalized loss in all pure-tone averages but a disproportionate impairment in speech discrimination. The stria vascularis, which produces the endocochlear potential of the endolymph, can atrophy, and the result is a flat hearing loss on pure-tone averages with preservation of speech discrimination. And last, the basilar membrane can stiffen with age, which results in less sensitivity to sound waves, causing a cochlear conductive hearing loss.17 Cochlear implantation is a technological advance that can restore hearing to those adults with severe-profound hearing loss who have limited benefit from hearing aids. Success rates are high and can dramatically improve patients’ quality of life, particular the elderly.

Noise-induced Hearing Loss Noise-induced hearing loss is one of the most common causes of adult hearing impairment in the United States, second only to presbycusis. It is estimated that over 10 million people have noise-induced hearing loss.18 Noise exposure can be in the workplace, at home, or during recreational activities. Even the ambient noise level that Americans are exposed to on a daily basis is significantly higher now than it was one or two centuries ago prior to modern industrialization, which probably exacerbates noise-induced hearing loss as the population ages. Noise exposure causes a sensorineural hearing loss that affects both the cochlear hair cells and the auditory neurons. Most exposures result in what is called a temporary threshold shift that is reversible and recovers over a 24- to 48-hour period. Repeat exposures eventually result in a permanent threshold shift and subsequent hearing loss that can be documented by audiometry. Continuous noise exposure has been shown to be more damaging than intermittent noise exposure, due to limited recovery time during continuous exposure. A single episode of severe noise exposure or what is called acoustic trauma, if loud enough, can result in an immediate, permanent threshold shift. Noise damage to the cochlea typically affects the outer hair cells and is temporary; however, if the exposure persists, the outer hair cell damage becomes permanent and proceeds to affect the inner hair cells as well.19 The classic hearing loss seen on audiometry is in the 2-, 4-, and 6-kHz frequency ranges. An increase in the sensorineural hearing threshold at the 4-kHz frequency has been historically called the boilermakers notch and is classic for occupational noiseinduced hearing loss.20 Only in the past few decades has noiseinduced hearing loss been recognized as one of the most common causes of occupation-induced disability. As a result, noise exposure is now regulated by the Occupational Health and Safety Administration (OSHA). Current OSHA regulations require hearing protection for workers exposed to 90-dBA noise based on an 8-hour-per-day time-weighted average. Most industries require hearing conservation programs when noise levels are greater than or equal to 85 dBA. Treatment of noise-induced hearing loss consists of early identification and prevention of harmful noise exposure to prevent further deterioration in hearing threshold levels.

chapter 26 auditory system disorders Ototoxicity Ototoxicity is another common cause of sensorineural hearing loss and, with few exceptions, is usually irreversible. Nearly 100 pharmacological agents have been implicated as having potential ototoxic side effects. Among the types of drugs implicated are antibiotics, diuretics, salicylates, nonsteroidal antiinflammatory drugs, and chemotherapeutic medications. Aminoglycoside antibiotics are potent medications against gram-negative infections, and all have been found to have ototoxic side effects. Because of their low cost, they are commonly used worldwide.21 Streptomycin, discovered in 1940, was the first aminoglycoside. It was originally used to treat tuberculosis and, with these early treatment trials, reports of ototoxicity surfaced. Streptomycin and gentamicin are generally more vestibulotoxic, whereas tobramycin, amikacin, and neomycin are more cochleotoxic. The cochleotoxic effects manifest with tinnitus and then proceed with damage to the outer hair cells in the basal turn of the cochlea, giving a high-frequency sensorineural hearing loss. This hearing loss is often believed to be irreversible, but some recovery of hearing has been seen weeks after cessation of therapy.22 The risk of ototoxicity with aminoglycoside use is believed to be 10% to 15%, and this is increased in combination with certain other medications, such as loop diuretics and cisplatin.23,24 Factors that increase the risk of aminoglycoside-induced ototoxicity include renal disease, prolonged duration of therapy, and elevated peak and/or trough levels on serum blood testing. Occasionally, the vestibulotoxic effects of aminoglycosides are used therapeutically, such as in patients with episodic vertigo from Meniere’s disease. When patients are refractory to conventional treatments, gentamicin can be administered topically into the middle ear space to induce a chemical labyrinthectomy and relieve the disabling vertigo many of these patients experience. There are scant data on most other antibiotics in regard to hearing loss; however, there have been some reports of macrolide and vancomycin ototoxicities. The mechanism of macrolide-induced hearing loss is unknown, and the effects are generally reversible.25 Vancomycin-related ototoxicity has been more difficult to quantify due to multiple other medications and confounding comorbidities in the majority of patients receiving vancomycin therapy. The incidence of vancomycin ototoxicity has been estimated to be 3% and does not correlate to serum levels.26 The two most commonly implicated diuretic medications causing ototoxicity are furosemide and ethacrynic acid. Ototoxicity with these medications manifests as sensorineural hearing loss, as well as tinnitus and vertigo. These loop diuretics cause ototoxicity by injuring the stria vascularis, which is responsible for producing endolymph, and the endocochlear potential that allows for sound perception.27 The risk of sensorineural hearing loss caused by these medications has been reported to be approximately 1% to 6% and can be both temporary and permanent.28,29 Renal failure and rapid infusion can increase the ototoxic risks of these loop diuretics. A well-known reversible cause of ototoxicity is treatment with salicylates and, less commonly, with nonsteroidal anti-inflammatory drugs. These medications are routinely prescribed for common problems such as arthritis. The mechanism is believed to be due to reduced cochlear blood flow and alterations of the outer hair cell motility.30 The effects are dose dependent and reverse with cessation of therapy.31 Tinnitus can

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be consistently reproduced at doses of 6 to 8 g/day. Along with tinnitus, audiometric testing manifests a mild-to-moderate flat, bilateral sensorineural hearing loss that resolves in 48 to 72 hours after cessation of the medication.32 Other notable medications known for their ototoxic effects include the antimalarial medication quinine, which primarily causes transient hearing loss. Cisplatin, a common antineoplastic medication used to treat head and neck squamous cell cancers, is both ototoxic and nephrotoxic. The ototoxic effects are usually permanent and bilateral. At least some degree of hearing loss occurs in most treated patients. The effects are often dose dependent and affect the outer hair cells in the basal turn, yielding a highfrequency hearing loss.33

Sudden Sensorineural Hearing Loss Sudden sensorineural hearing loss (SSNHL) is a syndrome that has multiple etiologies. It is commonly defined as rapidly progressive hearing loss over 12 hours or less. Often these patients first present to their primary care physicians and the cause can be difficult to determine. The most common cause of SSNHL is believed to be a viral neuritis or cochleitis causing inflammation of the inner ear and subsequent hearing loss with or without vestibular symptoms. These patients are usually treated empirically with a high-dose prednisone steroid taper over 10 to 14 days. Antiviral therapy is also commonly prescribed, along with steroid therapy. The literature suggests that there is benefit with steroid therapy; however, the evidence supporting antiviral medication is less convincing. It is important for these patients to undergo evaluation by an otolaryngologist to monitor hearing levels through audiometry, as well as to rule out more serious etiologies such as an acoustic neuroma. Other causes of SSNHL include meningitis, syphilis, human immunodeficiency virus infection, autoimmune disorders, multiple sclerosis, and ischemic and thromboembolic events.

SUMMARY The initial differential diagnosis for hearing loss can be vast, ranging from cerumen impaction to cerebellar pontine angle tumors, such as acoustic neuromas. Based on history, physical examination, and audiometric testing, the clinician should be able to significantly narrow down the differential diagnosis. A conductive hearing loss is usually correctable with medical or surgical treatment to fix the anatomical obstruction to air conduction of sound waves. Sensorineural hearing loss, on the other hand, has proved to be more difficult to treat, and treatment is often in the form of prevention. Hearing aids are the mainstay for sound rehabilitation for patients with moderate degrees of hearing loss, although patients with severe-toprofound hearing losses and those with poor speech discrimination have had less success. Cochlear implantation has become the mainstay for those patients with severe-to-profound hearing losses who do not benefit from conventional hearing aid technology. Cochlear implants have a high success rate in postlingual adults and are a proved way to restore the sense of hearing and dramatically improve patient quality of life. Constant improvements in equipment, technology, and software enhance the perceptive experience of those who benefit from restoration of their sense of hearing.

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P O I N T S

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Hearing loss can be defined as an increase in the threshold of sound perception. It can be subdivided into hereditary and nonhereditary causes.

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Conductive hearing loss is caused by impairment in air transmission of sound waves to the inner ear. The impairment of function is due to pathology at the level of the external auditory canal, the tympanic membrane, or the ossicular chain, resulting in inefficient conversion of sound waves from air to the fluid medium of the endolymph in the membranous labyrinth.

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Sensorineural hearing loss is caused by damage to the cochlear sensory epithelium or the peripheral auditory neurons. The type of hearing loss can be quite different depending on whether the cochlea or the auditory nerve fibers are involved.

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Central hearing loss is caused by a lesion in the central auditory pathway or in the auditory cortex.

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The most common cause of hearing loss in children is otitis media.

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Age-related hearing loss, or presbycusis, is a common diagnosis in the aging population.

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Noise-induced hearing loss is one of the most common causes of adult hearing impairment in the United States, second only to presbycusis.

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When it comes to hearing loss, the initial differential diagnosis can be vast, ranging from cerumen impaction to cerebellar pontine angle tumors, such as acoustic neuromas. Based on history, physical examination, and audiometric testing, the clinician should be able to significantly narrow down the differential diagnosis.

Suggested Reading Gates GA: Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996; 114:525. Minor LB: Labyrinthine fistulae: pathobiology and management. Curr Opin Otolaryngol Head Neck Surg 2003; 11:340-346. Mikulec AA, Poe DS, McKenna MJ: Operative management of superior semicircular canal dehiscence. Laryngoscope 2005; 115:501-507. Riggs LC, Brummett RE, Guitjens SK, et al: Ototoxicity resulting from combined administration of cisplatin and gentamycin. Laryngoscope 1996; 106:401-406.

References 1. Tran LP, Grundfast KM, Selesnick SH: Benign lesions of the external auditory canal. Otol Clin North Am 1996; 5:807-825. 2. Jahrsdoefer RA: Congenital atresia of the ear. Laryngoscope 1978; 88(Suppl 13):1-46. 3. McLelland CA: Incidence of complications from use of tympanostomy tubes. Arch Otolaryngol Head Neck Surg 1980; 106:97.

4. Wever EG, Lawerence M: Physiological Acoustics. Princeton: Princeton University Press, 1954. 5. Morrison AW, Bundey SE: The inheritance of otosclerosis. J Laryngol Otol 1970; 84:921. 6. Lippy WH: Otosclerosis and pregnancy. Presented at the Triological Society Annual Meeting, May 15, 2005, Boca Raton, FL. 7. Karmaker S, et al: Cholesteatoma surgery: the individualized technique. Ann Otol Rhinol Laryngol 1995; 104:591. 8. Gates GA: Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996; 114:525. 9. Klein JO, et al: Otitis media with effusion during the first three years of life and development of speech and language. In Lim DL, et al, eds: Recent Advances in Otitis Media With Effusion. Philadelphia: Mosby, 1983. 10. Fria TJ, et al: Hearing acuity of children with otitis media with effusion. Arch Otolaryngol Head Neck Surg 1985; 111:10. 11. Stool SE, et al: Otitis Media With Effusion in Young Children. Rockville, MD: Agency for Health Care Policy and Research, U.S. Public Health Service, U.S. Department of Health and Human Services, 1994, Clinical Practice Guideline Technical Report No. 12, AHCPR Publication No. 94-0622. 12. Minor LB, Solomon D, Zinreich JS, et al: Sound- and/or pressure-induced vertigo due to bone dehiscence of the superior semicircular canal. Arch Otolaryngol Head Neck Surg 1998; 124:249. 13. Minor LB: Superior canal dehiscence syndrome. Am J Otol 2000; 21:9-19. 14. Minor LB: Labyrinthine fistulae: pathobiology and management. Curr Opin Otolaryngol Head Neck Surg 2003; 11:340346. 15. Minor LB: Dehiscence of bone overlying the superior canal as a cause of apparent conductive hearing loss. Otol Neurotol 2003; 24:270-278. 16. Mikulec AA, Poe DS, McKenna MJ: Operative management of superior semicircular canal dehiscence. Laryngoscope 2005; 115:501-507. 17. Schuknecht HF: Pathology of the Ear, 2nd ed. Philadelphia: Lea & Febiger, 1993. 18. Suter AH, Von Gierke HE: Noise and policy. Ear Hear 1987; 8:188. 19. Saunders JC, Cohen YE, Szymko YM: The structural and functional consequences of acoustic injury in the cochlea and peripheral auditory system: a five year update. J Acoust Soc Am 1991; 90:136. 20. Bunch CC: Nerve deafness of known pathology or etiology: the diagnosis of occupational or traumatic deafness; a historical an audiometric study. Laryngoscope 1937; 47:615. 21. Forge A, Schach J: Aminoglycoside antibiotics. Audiol Neurotol 2000; 5:3-22. 22. Matz GJ: Clinical perspectives on ototoxic drugs. Ann Otol Rhinol Laryngol Suppl 1990; 148:39. 23. Fee WE: Aminoglycoside ototoxicity in the human. Laryngoscope 1980; 90(Pt 2, Suppl 24):1-19. 24. Riggs LC, Brummett RE, Guitjens SK, et al: Ototoxicity resulting from combined administration of cisplatin and gentamycin. Laryngoscope 1996; 106:401-406. 25. Bizjak ED, Haug MT, Schilz RJ, et al: Intravenous azithromycin-induced ototoxicity. Pharmacotherapy 1999; 19:245-248. 26. Elting LS, Rubenstein EB, Kurtin D, et al: Mississippi mud in the 1990s. Risks and outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 1998; 83;2597-2606. 27. Rybak LP: Pathophysiology of furosemide ototoxicity. J Otolaryngol 1982; 11:127. 28. Tuzel IJ: Comparison of adverse reactions to bumetanide and furosemide. J Clin Pharmacol 1981; 21:615. 29. Boston Collaborative Drug Surveillance Program: Druginduced deafness. JAMA 1973; 224:515.

chapter 26 auditory system disorders 30. Boettcher FA, Salvi RJ: Salicylate ototoxicity: review and synthesis. Am J Otolaryngol 1991; 12:33. 31. Jung TT, et al: Ototoxicity of salicylates, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngol Clin North Am 1993; 26:791.

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32. Myers EN, Bernstein JN, Fostiropolous G: Salicylate ototoxicity. N Engl J Med 1965; 273:587. 33. Laurell G: Ototoxicity of the anticancer drug cisplatin. Clinical and experimental aspects. Scand Audiol Suppl 1991; 33:147.

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Linda M. Luxon and Doris-Eva Bamiou

Humans have developed a sophisticated and complex mechanism for maintaining balance that relies on the integration and modulation of sensory inputs from vision, the vestibular receptors within the labyrinth, and proprioception. Within the central nervous system, the cerebellum, the extrapyramidal system, the limbic system, and the cerebral cortex facilitate processing to enable the perception of head and body position in space, eye movement control, and appropriate static and dynamic postural function (Fig. 27–1). An alteration in any one of the three sensory inputs, or within the central vestibular pathways and their connections, may give rise to disordered eye movements, disequilibrium or instability, and the perception of dizziness or vertigo. The complexity of this system is such that pathology in almost all body systems may be associated with dizziness/disequilibrium; thus, affected patients present to many different specialist departments but most commonly to otology or neurology outpatient offices (Table 27–1). Despite these ubiquitous presentations, most clinicians do not have a clear diagnostic strategy, including knowledge of detailed neuro-otological examination, to enable them to accurately diagnose and appropriately manage vestibular symptoms. This chapter provides a broad overview of peripheral and central vestibular syndromes, together with an outline of an appropriate clinical assessment based on an understanding of vestibular pathophysiology, a discussion of management strategies, and specific points with regard to common vestibular disorders.

DEFINITIONS When the vestibular apparatus is damaged by any pathology, a number of typical clinical manifestations arise. Symptoms and signs of pathology are determined by the site of the lesion and not by the etiology. This in part compounds the diagnosis for the clinician. Nonetheless, the specific diagnosis is highly relevant in terms of appropriate management. The term peripheral vestibular disorders refers to pathology in the vestibular labyrinth and/or cranial nerve VIII, whereas pathology affecting the central nervous system pathways at or above the vestibular nuclei are referred to as central vestibular syndromes. For the purposes of this chapter, vertigo refers to an illusion of movement, whereas dizziness is a lay term variously covering a plethora of synonyms, including giddiness, light-

headedness, falling, “swimminess,” and mental disorientation. Ataxia is an inability to coordinate muscular movements; the terms falls and unsteadiness are self-explanatory. Oscillopsia refers to the rhythmic oscillation of the visual environment, often spontaneously as a consequence of a central eye movement disorder or in response to motion, as a consequence of bilateral vestibular failure.

EPIDEMIOLOGY Dizziness is an extremely common symptom, both in primary care and at the tertiary level. One in four healthy subjects in the community reports symptoms of dizziness, with significant effects on their daily living.1 By the age of 70, 36% of women and 29% of men have balance problems, whereas by the ages of 88 to 90, 45% to 50% of the population suffer symptoms of balance dysfunction.2 In the community, many cases of vestibular dysfunction resolve spontaneously, without recourse to medical care, although each year 5 per 1000 patients consult their general practitioners because of symptoms that are classified as vertigo, and a further 10 per 1000 are seen for dizziness or giddiness.3 In a tertiary setting, dizziness is associated with significant morbidity, and in the older population, falls and mortality are common sequelae.4 Vestibular symptoms after head/whiplash injury are the commonest cause of failure to return to work, and two thirds of patients in a tertiary neuro-otological clinic suffer psychiatric symptoms in association with vestibular pathology.5

VESTIBULAR ANATOMY AND PHYSIOLOGY The internal ear is a minute membranous structure within the bony labyrinth, buried in the temporal bone. Within the internal ear, the cochlea is the acoustic end-organ receptor, whereas, of the five vestibular end-organs, one lies within each of the three semicircular canals and one each in the utricle and saccule within the vestibule. The vestibular sensory epithelium is composed of type 1 and type 2 hair cells, covered with a gelatinous membrane that, in the saccule and utricle, contains calcium carbonate-rich crystals termed otoconia (Fig. 27–2). A force parallel to the surface of the sensory epithelium provides the maximal stimulus. Thus, the horizontal anterior and

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Cortex cerebellum Reticular formation Extra-pyramidal system

Cortical awareness of head/body/motion

Eye

Integrating/ data storage system Eye movement/ control of oculomotor activity

Joint position Proprioception Superficial sensation

posterior semicircular canals are stimulated by angular acceleration in the three planes of space but are insensitive to gravity or head position.6 The saccule, which lies approximately vertically, senses vertical linear head acceleration and gravity; the utricle, which is oriented approximately horizontally, senses horizontal linear head motion and head position in space. Physiologically, the vestibular apparatus can be considered in two halves, the right labyrinth and the left labyrinth, which are perfectly balanced and work in parallel. For example, when the head is turned to the right, the right horizontal semicircular canal increases its firing rate, whereas the left decreases its firing rate. This asymmetry in neural input is transmitted (1) to the vestibular nuclei and the cerebellum, which controls the amplitude and timing of movements, and (2) via the vestibular nuclei and the thalamus to the parietoinsular vestibular cortex. From birth, the vestibular, visual, and proprioceptive inputs associated with every type of movement are monitored, integrated, and stored in a “data bank,” which is considered to be the reticular formation of the brainstem.7 Subsequently, each movement generates signals that are then

Labyrinthine activity

Direction of view Control of posture Control of motor skills

■

Cupula movement generates nerve impulses

Cupula

Figure 27–1. Mechanisms of balance.

Crista

T A B L E 27–1. Causes of Disequilibrium General Medical Hematological Anemia Hyperviscosity Cardiovascular Mechanical (e.g., aortic stenosis) Postural hypotension Carotid sinus syndrome Dysrhythmia Metabolic Hypoglycemia Hyperventilation Otological Meniere’s syndrome Positional vertigo Viral Trauma Vascular Ototoxicity Tumor

Superior semicircular duct Lateral semicircular duct Utricle

Hair cell Supporting cells Nerve fibers

Ganglion of Sup. vestibular Inf. nerve Facial nerve Cochlear nerve

Posterior semicircular duct

Neurological Epilepsy Multiple sclerosis Vertebrobasilar insufficiency Infective disorders Degenerative disorders Tumors Foramen magnum anomalies Psychiatric disorders Miscellaneous Iatrogenic Cervical vertigo Visual vertigo Multisensory dizziness

Hair-like extensions

Ampullary crest

Otoliths

Sacculus

Otolithic membrane Hair process Hair cell Supporting cell

■

Macula

Figure 27–2. The vestibular end-organ and vestibular sensory epithelia.

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Corollary discharge

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Expected afferences

Re-afferences

Central store

Voluntary motion

Habituation Comparison

Space constancy

Mismatch Vertigo

■

Figure 27–3. Visual-vestibular mismatch. An active movement leads to stimulation of the sensory organs whose messages are compared with a multisensory pattern of expectation calibrated by earlier experience of motions (central store-data bank). The pattern of expectation is prepared either by the efference copy signal, which is emitted parallel to and simultaneously with the motion impulse, or by vestibular excitation during passive transportation in vehicles. If concurrent sensory stimulation and the pattern of expectation are in agreement, self-motion is perceived while “space constancy” is maintained. If, for example, there is no appropriate visual report of motion, as a result of the field of view being filled with stationary environmental contrasts (reading in the car), a sensory mismatch occurs. With repeated stimulation, motion sickness is induced through summation; the repeated stimulation leads to a rearrangement of the stored pattern of expectation, however, so that a habituation to the initially challenging stimulation is attained within a few days. An acute unilateral labyrinthine loss causes vertigo, because the self-motion sensation induced by the vestibular tone imbalance is contradicted by vision and the somatosensors. (Reprinted from Brandt T: Vertigo: Its Multisensory Syndromes. London: Springer, 2002, p 5, Fig. 1.2. Reprinted with kind permission of Springer Science and Business Media.)

compared with the information in the “data bank.” Integration of movement-induced neural asymmetry with other sensory input and comparison with the “data bank” template allow for awareness of head and body position in space, together with the generation of compensatory oculomotor (vestibulo-ocular reflex) and motor (vestibulospinal) activity. In addition to the motor control, the extensive convergence of vestibular and autonomic afferent information in the brainstem and cerebellum allows for coordination of appropriate motor and autonomic responses during movement or changes in posture. Thus, if there is any mismatch of the sensory input to the existing template, the patient senses disorientation, may develop an abnormal eye movement, frequently feels off balance, and may develop nausea lvomiting and other autonomic symptoms (Fig. 27–3). The classic physiological example of such a mismatch is motion sickness.8 However, any pathological lesion that results in a change in, for example, vestibular input to the central

nervous system, as may occur in Meniere’s disease or vestibular neuritis, produces similar symptoms of disorientation, nausea, vomiting, and malaise as a consequence of the change in the vestibular signal, with no corresponding changes in visual and proprioceptive inputs. In addition, connections at various levels of the central vestibular system with the locus ceruleus, the limbic system, and other brain regions that control affective responses, mood, and arousal may underlie the observed overlap between psychiatric and vestibular disorders.9,10

AGING AND THE VESTIBULAR SYSTEM Histopathological age-related changes in the human vestibular sensory organs include progressive hair cell degeneration, otoconial degeneration in the otolith organs, and decreasing numbers of vestibular nerve fibers,11,12 and age-dependent

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changes in both caloric and rotational test responses have been demonstrated.13,14 These changes alone are unlikely to generate vestibular symptoms, as they are symmetrical, and dizziness in elderly people is probably more multifactorial in origin.15 Thus, although older patients may be subject to the same common balance disorders as are younger patients, they have more problems with chronic disequilibrium and falls, and vertigo has been reported to rise with advancing age in parallel with the incidence of hearing loss.13 Correct diagnosis, prevention, and rehabilitation are particularly important in treating this group of patients.16

T A B L E 27–3. Vestibular Compensation Adaptation/Habituation/Plasticity Recalibration of the gain of vestibular reflexes Substitution Other sensory inputs Visual Somatosensory Proprioceptive Intact labyrinthine input Motor responses Strategies

PERIPHERAL VESTIBULAR DISORDERS Acute Unilateral Vestibular Deafferentation Acute pathology of one labyrinth manifests as an acute clinical syndrome with profound motor and sensory abnormalities17 and with the same symptoms and signs irrespective of the cause. A patient with an acute total right vestibulopathy has the following signs (Table 27–2): 1. A partial or complete ocular tilt reaction to the right. 2. Spontaneous horizontal nystagmus, with the fast phases directed to the left; nystagmus is enhanced by removal of optic fixation (e.g., with Frenzel glasses). 3. Rotation to the right when marching on the spot with eyes closed, or drift to the right when performing gait with eyes closed. 4. A positive horizontal head impulse test result to the right that remains when all other symptoms and signs improve. In most cases, the characteristic symptoms and signs of vestibular deafferentation abate, and the patient is rendered asymptomatic over a period of 2 weeks to several months. In this regard, the vestibular system has been shown to be extremely adaptable.18 The processes, which bring about the resolution of vestibular symptoms, are collectively known as cerebral compensation and are attributed to cerebral plasticity (Fig. 27–4; Table 27–3). The structures subserving compensation for vestibular dysfunction are unknown, but it has been shown that brain-

stem, cerebellar, and cortical structures are involved; the cerebellum is key to this recovery phenomenon,17,19,20 in addition to the requirement for all sensory inputs, including vision, somatosensory afferents, and remaining labyrinthine input.21-23 Furthermore, integrity of both the vestibular nerve24 and the central vestibular connections25 is required. The physiological mechanisms on which compensation depends include physical activity26,27 and vision28 (Fig. 27–5). Moreover, Fetter and coworkers29 demonstrated that occipital

Cerebral compensation

Viral labyrinthitis Peripheral vestibular dysfunction and symptoms

Vascular event

Physical or psychological stress

Trauma

■

Asymptomatic state

Figure 27–4. Natural history of peripheral vestibular dysfunction and symptoms.

Unilateral vestibular neurotomy

T A B L E 27–2. Consequences of Unilateral Peripheral Vestibular Destruction

Otolith Destruction or Deafferentation (Right-Sided) Vertical diplopia Deviation of the subjective visual vertical and horizontal to the right Skewed eye deviation (right eye down) Right head tilt Clockwise conjugate eye torsion

Clinical state of recovery

Semicircular Canal Destruction or Deafferentation (Right-Sided) Vertigo Nausea Vomiting Left beat horizontal-torsional nystagmus (increases with absence of optic fixation) Head impulse test result: positive to the right Unterberger test result: to the right

4

Unrestrained Restrained

3

2

1 0

2

7

14

21

30

Post-operative time (d) ■

Figure 27–5. Graph of clinical state of recovery in restrained versus unrestrained animals after unilateral vestibular neurotomy.

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lobectomy before labyrinthectomy impaired compensational recovery, and Schaefer and Meyer in 197330 also demonstrated that transsection of the cervical cord that led to loss of proprioception delayed vestibular compensation.

congenital nystagmus32 and oculomotor palsies.33 In general, patients with bilateral vestibular function recover significantly, although a proportion remain handicapped by oscillopsia and instability.

Chronic Unilateral Vestibular Deafferentation

Compensation/Decompensation

This situation is seen clinically in the presence of a slowly growing tumor, such as a vestibular schwannoma. The patient may report merely some mild instability or no sense of imbalance, although a unilateral peripheral abnormality may be detected on formal vestibular function testing. This relative lack of symptoms may be explained on the basis of such slow loss that no significant acute vestibular asymmetry occurs. Alternatively, adaptation occurs simultaneously with the loss, so that symptoms do not manifest.

The majority of cases of a unilateral peripheral vestibular deficit recover by means of cerebral compensation. However, some patients do not recover spontaneously and require vestibular rehabilitation with physiotherapy. The basis of physical therapy intervention relies on a structured approach in promoting recovery with visual, proprioceptive, and vestibular stimulation by means of a standard or customized range of exercises. A number of factors that predispose to failure of compensation (Fig. 27–6) or decompensation from a previously recovered state (Fig. 27–7) have been identified. There is some evidence that there exists a critical period in which stimuli must be provided to the adaptive mechanisms and recalibration of the vestibular function must begin, or else the rate of recovery and

Bilateral Vestibular Hypofunction If there is sequential loss of unilateral function with a period of 1 week or more between each event, then the clinical presentation is that of two episodes of acute unilateral loss, as outlined previously. If, however, both vestibular labyrinths are lost together, there may be no acute vertiginous symptoms, in the absence of any vestibular asymmetry. The long-term effects of bilateral vestibular failure are the same, irrespective of whether the loss has been simultaneous or sequential. The clinical features include the following:

Inadequate/inappropriate CNS activity Psychological dysfunction

Pure eye/head stabilisation

■ Sense of imbalance when standing or walking, especially

on uneven surfaces (e.g., sand) or in the absence of vision (e.g., at night). ■ Bobbing oscillopsia: that is, vertical bouncing or blurring of vision when the patient walks, runs, or moves, with degradation of visual acuity as a result of loss of the vestibuloocular reflex. ■ An inability to stand or walk when both vision and proprioception are removed (e.g., when standing on a foam pad with eyes closed or when attempting to walk across a foam pad with eyes closed). In these cases, the cervico-ocular reflex has been implicated in recovery of function31; other authorities have suggested that slippage of the retinal image in bilateral vestibular failure may be compensated for by central visual mechanisms, as occurs in

Balance

Impaired/inadequate musculoskeletal functions

Poor compensation

Fluctuating vestibular activity

Impaired/inappropriate balance strategies

Impaired sensory inputs ■

Figure 27–6. Factors that predispose to failure of compensation. CNS, central nervous system.

Balance Decompensation days to weeks

(Normal) 100%

Disordered perception of stability

(Normal) 100%

Recovery Periods of freedom weeks to months

(Severe impairment) 0% Recovery

(Severe impairment) 0%

Time

Time Labyrinthine insult

6/52–6/12 Labyrinthine insult ■

Figure 27–7. Vestibular decompensation.

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perhaps the ultimate degree of recovery may decrease.34 However, Shepard and colleagues35 did not identify duration of symptoms, or age, as a negative prognostic factor of a vestibular rehabilitation program, although financial compensation, head injury, and severe postural control abnormalities have all been reported to indicate poor outcome. Failure of compensation may follow an acute episode of vertigo and vomiting leaving the patient constantly disorientated and disabled, so that he or she cannot function occupationally or socially in an effective manner. Decompensation is often seen in a patient who has had a single acute episode of vertigo and vomiting with recovery over a period of 6 weeks to 6 months and then subsequent relapses, episodes usually becoming progressively less severe and more infrequent with the passage of time. Notwithstanding this, for the nonexpert in the field, such a presentation may be misdiagnosed as a recurrent condition or a new illness, as opposed to a previous labyrinthine event with repeated decompensation.

DIAGNOSIS OF VESTIBULAR DISORDERS The diagnosis of vertigo is critically dependent on a clear history that includes the following: ■ The exact character of the symptom (dizziness, vertigo,

ataxia). ■ The duration of both the illness and individual episodes. ■ The presence of associated symptoms: cochlear, neurologi-

cal, or general medical (Fig. 27–8). Vertigo of less than 1 minute’s duration is most commonly associated with benign paroxysmal positional vertigo (BPPV), whereas acute rotational vertigo of several hours’ duration is most commonly associated with migraine and Meniere’s disease. Vertigo lasting several days is common in viral vestibular neuritis and in ischemic and brainstem labyrinthitis. Pathology involving the labyrinth and cranial nerve VIII is commonly associated with hearing loss and/or tinnitus, whereas vertigo arising in the central vestibular pathways is

Outline of Diagnostic Strategy History Character Duration • episode • constant Associated symptoms • cochlear • neurological • general medical

General medical disorder ■

Examination General Medical Neurological Otological Neuro-otological • eye movement range and conjugacy • smooth pursuit • saccades • spontaneous nystagmus • positional nystagmus • optokinetic nystagmus • gait and stance

Neurological disorder

Neuro-otological disorder

Figure 27–8. Diagnosis of vertigo.

most commonly associated with disordered eye movements. In order to make a correct neuro-otological diagnosis, a clinical examination of the vestibular and oculomotor systems is key and requires a clear understanding of vestibular and oculomotor pathology, together with regular clinical practice at examination.36

COMMON PERIPHERAL VESTIBULAR DISORDERS Acute Vestibular Neuritis Single episodes of acute rotational vertigo associated with nausea and vomiting, with or without cochlear symptoms, are a common occurrence in all age groups. The attacks are usually unprecipitated and are commonly ascribed to a viral infection, termed vestibular neuritis, vestibular neuronitis, labyrinthitis, or acute vestibulopathy.37,38 The signs and symptoms are as described earlier for an acute unilateral vestibular disorder, and the natural history is resolution of symptoms within a few days or weeks. The majority of patients recover spontaneously, but it appears that early mobilization and vestibular rehabilitation reduce the incidence of disability from chronic vestibular symptoms, which develops in about 20% of patients with acute vestibular neuritis.39 Most cases of vestibular neuritis affect the superior vestibular nerve, with a marked canal paresis on caloric testing, which shows progressive recovery in about 50% of patients on repeat testing.40,41 Frequently, it is possible to obtain a normal saccular response, as judged by the vestibular evoked myogenic potential, which depends on normal inferior vestibular nerve function. In 25% of the patients with vestibular neuritis,43 BPPV (described later) of the posterior canal variant may develop subsequently. The differential diagnosis of acute vestibular neuritis includes perilymph fistula; vestibular neuritis with repeated decompensation and migrainous vertigo; cerebellar infarction; occlusion of a branch of the internal auditory artery in an elderly atherosclerotic patient or in a patient with risk factors for embolization; early Meniere’s disease with isolated episodes of vertigo; and autoimmune inner ear disease, either as an isolated phenomenon or as part of a systemic autoimmune disorder.

Ramsay-Hunt Syndrome The Ramsay-Hunt syndrome is the clinical presentation of herpes zoster oticus with facial palsy, auricular rash, and hearing loss, which are often associated with acute vertigo. Abramovich and Prasher44 reported vertigo in 85% of their series; conversely, vestibular dysfunction has also been described with Bell’s palsy or idiopathic facial palsy,45,46 at an incidence of between 20% and 92%. A number of mechanisms of vestibular involvement in this latter condition have been postulated, including compression of cranial nerve VIII by the edematous cranial nerve VII and involvement of both cranial nerves VII and VIII in the same disease process. Vertigo, imbalance, ataxia, and nausea have all been reported in human immunodeficiency virus infection, although it remains unclear whether the pathology is central or peripheral in type, and vestibular dysfunction is less common than auditory involvement.47

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Meniere’s Disease Meniere’s disease remains a clinical diagnosis characterized by fluctuating hearing loss, tinnitus, and vertigo, often associated with sensation of fullness or blockage in the ear. In 60% of patients affected, both vestibular and cochlear symptoms have developed within 6 months of the onset of the disease. The literature abounds with controversy on all aspects of this condition, and the diagnosis should be based on the strict American Academy of Otolaryngology—Head and Neck Surgery Committee on Hearing and Equilibrium Guidelines.48 The vertigo attacks usually last between 1 and 8 hours, but the tinnitus, hearing loss, and sensation of fullness in the ear may last for several days. Attacks tend to occur in clusters, with attackfree intervals. Initially, both vestibular function and cochlear function recover, so that the caloric test and audiometry may be normal between attacks. Later there is a progressive lowfrequency hearing loss, which, in the older patient, may be superimposed on presbycusis to yield a tent-shaped audiogram, and with continuing progression, a plateau hearing loss emerges. Moreover, with progressive attacks, interval disorientation may accompany loss of vestibular function. Clinical examination may show spontaneous nystagmus directed toward the affected ear (i.e., an irritative response), followed by an ablative phase, in which the nystagmus beats away from the affected ear, and a recovery phase, in which the nystagmus may again beat toward the affected side.49 Late in the disease, patients may develop drop attacks called Tumarkin or otolithic crises.50 The natural history of Meniere’s disease is variable, but in general there are clusters of episodes (relapses) with attack-free periods that may last several years (remission). Other patients, however, have a progressive course, with ultimate loss of auditory and vestibular function. Bilateral involvement is reported in 20% to 50% of cases.51 Electrocochleography with transtympanic recording at the promontory is the most sensitive and specific test for Meniere’s disease. Characteristically, there is broadening of the summating potential/action potential ratio; this ratio is often greater than 35%, in comparison with approximately 20% in normal subjects (Fig. 27–9). The underlying pathophysiology of Meniere’s disease is generally attributed to endolymphatic hydrops. In 75% of cases, the condition is considered idiopathic, whereas in 25%, a variety of other pathological conditions, including syphilis, trauma, infection, and otosclerosis, are reported to underlie the development of the condition. The disease may occur at any age, but the first attack most commonly occurs between the ages of 30 and 60. It is rare but not unknown in children and is uncommon as a presenting condition after the age of 60 years. About 10% of affected patients have a family history of this disease.52 A number of mechanisms have been hypothesized to predispose to a disorder of endolymph homeostasis, including a defect in normal endolymph absorption by the endolymphatic system. There may be hormonal factors53 or a viral etiology.54,55 Other hypotheses have been based on ischemia,56 and more complex disorders associated with autoimmune disease have been proposed.57 The differential diagnosis of Meniere’s disease includes perilymph fistula, vestibular neuritis with repeated decompensation, and vestibular migraine, which is a particularly difficult diagnosis in that there is a clear increased incidence of

N2

■

SP

N2

AP

N1

N1

Normal

Meniere’s disease

Figure 27–9. Electrocochleography. Left, Normal traces; right, findings in Meniere’s disease, with characteristic broadening of the summating potential/action potential (SP/AP) ratio. N1 and N2, first and second negative peaks of the action potential.

Meniere’s disease per se in migrainous subjects.58 Brief acute spells of dizziness may also occur in progressive bilateral vestibular failure of unknown etiology.59

Migrainous Vertigo Migraine affects approximately 4% to 6% of men and 11% to 18% of women in both Europe and the United States. The incidence and frequency of disequilibrium in association with migraine are reported to range between 50% and 70%.60 Vertigo may occur independently of headache, particularly in children (benign paroxysmal vertigo of childhood).61 Normally, there is a personal or family history of migraine, with troublesome motion sickness in childhood.62 In association with the vertigo, there may be classic symptoms of sensory hyperexcitability, including photophobia, phonophobia, and osmophobia. Visual symptoms are the symptoms most commonly associated with migraine with aura, but somatosensory and vestibular symptoms also occur frequently. Within this category are basilar migraine and migraine aura without headache, which are of particular neuro-otological relevance, although episodic vertigo without headache can prove difficult to diagnose etiologically. Frequently, such conditions are referred to as migraine equivalents or migraine accompaniments. Vertigo, tinnitus, and hearing impairment are common symptoms with basilar migraine, making the differential diagnosis between this condition and Meniere’s syndrome particularly difficult. Overall, episodic vertigo occurs in about 25% of unselected patients with migraine.58 In one study, nonspecific dizziness occurred approximately equally in patients with migraine (N = 200) and patients with tension-type headaches (N = 166), but vertigo occurred in 27% of patients with migraine, as opposed to 8% of patients with tension-type headache (a significant difference at the level of P > 0.001).28 Young children exhibit multiple and diverse manifestations of migraine, with headache frequently being absent.61 Children may present with cyclical vomiting or attacks of abdominal pain. Basser63 described an episodic disorder that occurs in young children younger than 4 years, termed benign paroxysmal vertigo. The affected child suddenly becomes frightened, cries out, clings to the caregiver, staggers, becomes pale, and often vomits. Typically, the attack is brief, lasting only several

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minutes, the symptoms are exacerbated by head movement, and nystagmus and/or torticollis may be observed. The child’s condition rapidly returns to normal, and although the attacks may occur up to several times a month before the age of 4, they gradually decrease in number and disappear by the age of 7 or 8. Characteristically, these children develop migraine with aura in adult life.64 Benign recurrent vertigo in adults was described by both Slater in 197965 and Moretti and coworkers in 1980,66 but subsequent consideration of their patients, who complained of episodic vertigo, nausea, and vomiting, worse around menses in women, with no auditory symptoms nor interval symptoms and strong personal or family histories of migraine, suggests that this condition also represents migraine equivalents. Rassekh and Harker67 followed up 38 patients with the diagnosis of “vestibular Meniere’s syndrome.” Of these, 8 developed characteristic Meniere’s disease, 7 became asymptomatic, and the remaining 21 failed to develop the classic triad of Meniere’s disease. Of this latter group, 81% had migraine, which highlights the diagnostic difficulty between early Meniere’s disease and migraine. It is currently believed that a specific pathophysiology underlines the association between vestibular and migrainous symptoms, termed migraine-related dizziness.68 Researchers have aimed to provide a diagnostic framework for this disorder on the basis of a combination of the International Headache Society criteria for migraine, the presence of specific other symptoms, and the exclusion of other pathology.69,70 Numerous studies have documented the familial pattern of migraine, although genetic studies to date have failed to define genetic abnormalities in the common forms of migraine. Familial hemiplegic migraine, a rare subtype of migraine with aura and autosomal dominant inheritance, is characterized by headache attacks that are preceded or accompanied by episodes of hemiplegia, usually lasting days. In about 50% of patients with familial hemiplegic migraine, mutations in a brainspecific P/Q-type calcium channel gene, CACNA1A,71 located on chromosome 19p, have been shown to produce this condition. Although the exact nature of the mutation has not been elucidated, certain features of migraine are compatible with ion channel dysfunction, including triggers, such as stress and menstruation. Research evaluating calcium channel genes in this population continues.

Benign Positional Paroxysmal Vertigo BPPV was characterized by Dix and Hallpike72 in their seminal work on patients with vertigo in 1952. This condition is the most common cause of vertigo in adults in virtually all reported series. Schuknecht73 defined degenerative changes in the superior vestibular nerve, the utricle, and the horizontal and anterior semicircular canals in the temporal bones of patients with BPPV and postulated ischemia of the anterior vestibular artery. He further74 identified basophilic deposits on the cupulae of the posterior semicircular canals in two patients with BPPV before death. On the basis of these findings, he proposed the hypothesis of cupulolithiasis (i.e., a heavy cupula) as the mechanism giving rise to positional nystagmus of the paroxysmal type (Fig. 27–10A). However, later workers75 proposed the hypothesis of canalithiasis, with free-floating debris from the otolith organ moving within the posterior

T A B L E 27–4. Positional Nystagmus BPPV Nystagmus direction Latent period Adaptation Fatigability Vertigo Incidence

Rotational to undermost ear 2-20 seconds Disappears in <50 seconds Disappears on repetition Strongly present Common

Central Positional Nystagmus Variable None Persists Persists Typically absent Uncommon

BPPV, benign paroxysmal positional vertigo.

canal and acting as a plunger, thus dragging the cupula (see Fig. 27–10B). Diagnosis is made by the Dix-Hallpike positioning test or roll tests. The typical features of BPPV (Table 27–4)76 are explained by free-floating otoconial debris, moving under the influence of gravity (so-called canalithiasis). In the upright position, a clot of calcium carbonate crystals is established around the most dependent portion of the posterior canal. As the patient moves backward and to the side, in the plane of the posterior canal (the movement induced by the Dix-Hallpike positioning test), the clot moves, producing an ampullar-fugal displacement of the cupula, as a result of a plunger effect within the narrow canal. The fatigability, which is characteristic of benign positional nystagmus of paroxysmal type, is explained by dispersion of the clot, making the plunger effect less marked on repeated maneuvers. The induced vertigo and nystagmus are brief, because once the clot settles in the lowest portion of the canal with regard to gravity, the cupula moves back to the primary position. Latency before the onset of nystagmus is best explained by a delay in the initial motion of the clot. Thus, BPPV is not a disease but a clinical manifestation that may result from a variety of different inner ear pathological processes, most commonly labyrinthine concussion secondary to trauma and vestibular neuritis. The condition may affect any of the semicircular canals (Table 27–5), but the posterior canal variant is the most common.76 Characteristically, the patient complains of brief, severe spells of vertigo induced by turning over in bed, tipping the head backward to look at something in the sky, or reaching for something on a high shelf (i.e., “top shelf vertigo”). Treatment is by an appropriate particle repositioning procedure (described later). Approximately 50% of patients suffer recurrence after resolution, and 15% of patients require a second attempt at this technique to clear the condition. In a very small number of intractable cases, a section of the ampullary nerve from the posterior semicircular canal or plugging of the posterior semicircular canal with bone is required. The majority of patients with BPPV show no abnormality on standard caloric testing, but 25% may demonstrate a canal paresis.

Autoimmune Inner Ear Disease Autoimmune inner ear disease is an uncommon but important cause of progressive bilateral loss of auditory and vestibular function.77 The condition commonly manifests with sequential stepwise loss of auditory and vestibular function. The disorder may be associated with systemic autoimmune phenomena,

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A

B ■

Figure 27–10. A, Cupulolithiasis: Otoconial debris on the cupula gives rise to positional nystagmus of paroxysmal type. B, Canalithiasis: free-floating debris from the otolith organ, moving within the posterior canal and acting as a plunger, drags the cupula and gives rise to positional nystagmus of paroxysmal type. (A reprinted from Brandt T, Vertigo: Its Multisensory Syndromes. London: Springer, 2002, p 259, Fig. 16.8. B reprinted from Brandt T, Vertigo: Its Multisensory Syndromes. London: Springer, 2002, page 260, Fig. 16.9.)

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T A B L E 27–5. Diagnostic Characteristics of Benign Paroxysmal Positional Vertigo (BPPV)

History Vertigo Latency Duration Nystagmus

Reversal Adaptation Fatigability

Posterior Canal BPPV

Horizontal Canal BPPV*

Anterior Canal BPPV

Vertigo on sitting up from supine position, lying down, rolling in bed, extending/flexing neck Present on testing 2-20 seconds after head tilt <40 seconds Linear-rotatory, geotropic (toward affected undermost ear) or upward when gaze is directed to uppermost ear On return to sitting position Yes Yes

Vertigo on rolling from side to side in bed

Onset of symptoms may follow a liberatory maneuver

Present on testing <5 seconds >20-60 seconds Geotropic toward undermost ear: beats stronger to affected ear

Present on testing Similar to that of posterior canal BPPV Similar to that of posterior canal BPPV Torsional toward unaffected undermost ear

On rolling to other side Yes No

Similar to that of posterior canal BPPV Yes Yes

*Atypical horizontal canal BPPV may beat toward the uppermost ear and last for minutes when the precipitating position is maintained. NS, not studied.

such as polyarthritis, Wegener’s granulomatosis, or otosclerosis; or it may be part of Cogan’s syndrome with associated interstitial keratitis or may occur in isolation as an inner ear organ-specific disorder.78 Initial symptoms may be suggestive of Meniere’s disease, with fluctuation of hearing and ear pressure, but unlike symptoms of Meniere’s disease, these symptoms progress rapidly over weeks or months to involve the opposite ear. Treatment requires high-dose steroids (60 to 80 mg of prednisolone for 10 days, tapering off, with or without the addition of cytotoxic drugs); plasmapheresis has also been advocated as treatment.

Labyrinthine Trauma Damage to the vestibular apparatus can occur as a result of barotrauma, acoustic trauma, and physical trauma.79 Scuba diving and flying in unpressurized aircraft are the commonest causes of otitic barotrauma, which, if sufficiently severe, may give rise to a perilymph fistula, in which there is disruption of the oval or round window, with acute loss of hearing and vertigo as a result of leakage of perilymph. Clinically, there may be a positive fistula sign with vertigo and nystagmus induced by pressure change in the external canal or by coughing or straining. Characteristically, audiometry shows a sensorineural hearing loss, and electronystagmography reveals a canal paresis on caloric testing. Management may be conservative, with bed rest, head elevation, and symptomatic treatment or surgical exploration if symptoms persist or there is a clear relationship to trauma. Acoustic trauma of sufficient severity to rupture the tympanic membrane may give rise to perilymph fistula, but vertigo usually does not result from noise exposure, which gives rise to a sensorineural hearing loss with a characteristic 4-kHz notch. Physical trauma to the head commonly gives rise to vestibular symptoms in three different presentations: 1. BPPV (discussed previously). 2. Labyrinthine concussion. 3. Vestibular failure. Labyrinthine concussion with or without unilateral hearing loss is common after mild, moderate, and severe head injuries.80 Acute vertigo with evidence of a canal paresis on caloric testing and spontaneous nystagmus in the direction opposite the affected ear are common.79,80 The natural history of the condition

is characteristic of that for any acute unilateral vestibular disorder, unless there is additional central vestibular dysfunction as a consequence of trauma, in which case recovery may be delayed. BPPV may also occur as an isolated late sequela of labyrinthine concussion—an important medicolegal consideration. Dizziness is reported in 75% to 93% of patients with temporal bone fractures. When a patient has a significant head injury, it may not be possible to identify post-traumatic vertigo immediately, because other problems correctly take priority. Nonetheless, evidence of a skull fracture should be sought as soon as possible. Nystagmus has been reported in 22% to 57% of patients with temporal bone fractures, although it has been suggested that the vestibular system is not as vulnerable to damage as the auditory system. Transverse fractures involve the labyrinth or cranial nerve VIII, with profound, irrecoverable hearing loss and severe vertigo, nausea, and vomiting. With the passing of time, the latter symptoms improve as a result of cerebral compensation, if there is no impairment of cerebral compensation. This type of fracture is commonly associated with involvement of the facial nerve. Longitudinal fractures result in less severe vestibular symptoms but commonly traverse the middle ear, giving rise to a conductive hearing loss that may or may not be associated with sensorineural loss. Labyrinthine concussion commonly occurs in this situation, with associated vestibular symptoms, including positional vertigo.

BILATERAL VESTIBULAR FAILURE Bilateral vestibular failure may result from genetic derangements, meningitis, trauma, autoimmune disease, or, most commonly, ototoxicity.59 Aminoglycoside antibiotics are well recognized as giving rise to vestibular (and auditory) toxicity, and the effect of the drug on a bedridden patient may not manifest until the patient begins to ambulate, at which point he or she develops ataxia and bobbing oscillopsia. The different aminoglycoside antibiotics vary in their predilection for the auditory or vestibular system, but gentamicin is relatively specific for the vestibular apparatus. None of the aminoglycosides is metabolized; they are excreted by glomerular filtration. Thus, patients with renal impairment cannot excrete these drugs, which accumulate in the blood and inner ear fluids. The ototoxic effect is on the hair cells of the inner ear.

chapter 27 vestibular system disorders Clinically, there may be no nystagmus, as there is bilateral vestibular loss, but the patient has degradation of visual acuity with head motion, is unable to walk across a firm mat with the eyes closed, and has absent or severely reduced caloric and rotational responses. Intensive vestibular rehabilitation is of value in rehabilitation.

Neoplasia In rare cases, both primary benign and malignant primary and secondary tumors involve the middle ear and temporal bone, but more rarely do they give rise to vertigo. Tumors of the cerebellopontine angle are also rare, but they are an important diagnostic entity in patients presenting with disequilibrium. A characteristic history is of a slowly progressive unilateral hearing loss, with tinnitus and instability, whereas only 10% to 20% of patients report vertigo. Together with the characteristic of the cranial nerve VIII, examination frequently reveals involvement of cranial nerve VII, followed by cranial nerve V, then the cerebellum, and, late in the disease process, the lower cranial nerves. Acoustic neuromata account for more than 90% of tumors in this region, but other tumors include meningiomas, epidermoid cysts, facial nerve schwannomas, cholesterol granulomas, and, in rare instances, secondary malignancies. Characteristically, there may be unidirectional horizontal nystagmus away from the affected ear, unless the tumor is compressing the brainstem, in which case Bruns bidirectional nystagmus is observed. The diagnosis should be suspected in all cases of progressive unilateral hearing loss and tinnitus and in unilateral hearing loss with an abnormal ipsilateral brainstem evoked response. The “gold standard” for diagnosis is magnetic resonance imaging (MRI) scan. Management may include watchful waiting, surgery, or radiotherapy.81

Acute Middle Ear Disorders Serous otitis media in childhood is well recognized to give rise to symptoms of disequilibrium and vertigo, although the underlying mechanism is poorly understood.82 Infections of the ear and temporal bone may give rise to acute pain, hearing loss, and disequilibrium, and in all cases of vertigo, a detailed otological examination must be undertaken to rule out erosive middle ear disease with serious intracranial complications, including meningitis, brain abscess, subdural effusion, lateral sinus thrombosis, otitic hydrocephalus, and subdural empyema. Such disorders are more common in immunosuppressed or otherwise debilitated patients.

CENTRAL VESTIBULAR DISORDERS Central vestibular disorders are associated with demyelination, degeneration, vascular events, or trauma and are commonly accompanied by disequilibrium, nausea, and eye movement disorders. Vertigo is much more commonly associated with peripheral vestibular disorders than with central disorders. Notwithstanding this, there are a number of central vestibular syndromes that require consideration. Vertebrobasilar transient ischemic attacks are characterized by brief episodes of vertigo, usually of minutes’ duration, in association with one or more of the constellation of brainstem symptoms and signs characteristic of ischemia in the posterior

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circulation.83 Recurrent vertigo that is not associated with additional neurological symptoms should not be diagnosed as ischemic events; however, in posterior circulation ischemia, vertigo is usually associated with additional neurological symptoms, although, in general, there are no neurological signs, and MRI scans are often normal. Nonetheless, vertigo in association with posterior circulation ischemia is common. The commonest cause is atherosclerosis of the subclavian, vertebral, and/or basilar arteries, but dissection, arteritis, emboli, polycythemia, and hyperviscosity syndromes may also manifest in this way. It should be emphasized that although cervical spondylosis is common in older patients, mechanical compression of the vertebral artery is extremely rare in this condition.84 Lateral medullary infarction (Wallenberg’s syndrome). This condition manifests with acute-onset vertigo, nausea, vomiting, imbalance, incoordination, facial numbness and weakness, diplopia, dysphagia, and dysphonia. This manifestation is commonly associated with ischemia of the posterior inferior cerebellar artery, although, in practice, it more commonly results from ipsilateral vertebral artery occlusion. Classic signs include ipsilateral Horner’s syndrome; ipsilateral paralysis of the palate, pharynx, and larynx; ipsilateral loss of pain and temperature sensation on the face with ipsilateral dysmetria, dysrhythmia, and dysdiadochokinesia; contralateral loss of pain and temperature sensation of the body; and spontaneous nystagmus. Classically, patients experience lateropulsion, a prominent, strong motor disturbance tending to push both the patient and the eyes to the side of the lesion. MRI reveals infarction in the dorsolateral medulla, with or without infarction of the posterior inferior cerebellum.85 Ischemia in the distribution of the anterior inferior cerebellar artery may result in infarction of the dorsolateral pontomedullary region and the anterior interior cerebellum.86 Because the labyrinthine artery arises from the anterior inferior cerebellar artery in about 85% of cases, there is commonly also infarction of the membranous labyrinth. This gives rise to a clinical syndrome characterized by both acute peripheral and central vestibular findings. Diagnosis of cerebellar infarction is crucial, because surgical decompression may be required if massive edema results. There is acute-onset vertigo with nausea and vomiting, together with severe imbalance and incoordination. Clinically, spontaneous or gaze-evoked nystagmus with truncal ataxia and limb dysmetria is common. MRI shows infarction in the territory of one of the cerebellar arteries or in the watershed area between territories. The condition must be differentiated from acute unilateral peripheral vestibular loss87; the key lies in the finding of spontaneous nystagmus that changes direction with gaze and profound ataxia. After a latent period of 24 to 96 hours, some patients develop progressive brainstem dysfunction caused by compression from a swollen cerebellum and hydrocephalus. Death is inevitable unless the compression is surgically relieved. Cerebellar hemorrhage is similar in presentation to cerebellar infarction, but frequently, in association with acute vertigo, nausea, and vomiting, there is headache and a complete inability to stand. In contrast to cerebellar infarction, in the early stages of examination there is frequently marked nuchal rigidity and prominent cerebellar signs, together with ipsilateral facial paralysis and ipsilateral gaze paralysis. Pupils are often small bilaterally but reactive. Approximately 50% of patients lose consciousness within 24 hours of the initial symptoms, and 75%

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become comatose within 1 week of onset. The condition is often fatal, unless surgical decompression is performed.88 In more than 50% of cases of brain tumors of the posterior fossa, vestibular and cochlear symptoms occur. In cerebellar tumors, positional vertigo, vomiting, headache, and gait imbalance are the norm. An MRI scan is diagnostic, and audiometry frequently shows normal pure-tone audiometry but abnormalities on brainstem evoked responses. Central gaze-evoked nystagmus with abnormalities of smooth pursuit, saccades, and visual-vestibular interaction are common.89 Such tumors are particularly common in children and adolescents when they are rapidly growing, whereas in adults, cerebellar secondary tumors are more common. Multiple sclerosis is characterized by plaques of demyelination disseminated in time and space, and it is commonly associated with disorientation and/or imbalance. Symptoms commonly include monocular visual loss, vertigo, diplopia, weakness, numbness, and ataxia. Both the auditory and vestibular systems may be involved. Acute vertigo may manifest in 5% of patients with multiple sclerosis, frequently mimicking an acute peripheral vestibular episode. However, careful oculomotor examination90 usually reveals central vestibular findings of gaze-evoked nystagmus, disconjugate vertical nystagmus, central positional nystagmus, and/or disorders of smooth pursuit; saccades; and visual-vestibular interactions. Brainstem evoked responses and otoacoustic emission suppression evaluations of efferent auditory function frequently identify central auditory disorders. As in the majority of central vestibular syndromes, however, MRI is the definitive investigation. Arnold-Chiari malformation is characterized by oscillopsia associated with downbeat nystagmus and gait unsteadiness. In addition to downbeat nystagmus, lower cranial nerve palsies and both gait and limb ataxia are typically noted on examination. Associated auditory disturbances caused by neural involvement may be present, and diagnosis is by means of MRI. Suboccipital decompression of the foramen magnum may alle-

viate progression of the neuro-otological abnormalities, but this procedure rarely brings about improvement.91

MANAGEMENT OF VESTIBULAR DISORDERS Successful management of the patient with vertigo depends on accurate diagnosis, an understanding of vestibular physiology and compensation, appropriate intervention strategies, and the physician’s awareness of the overlap between vestibular, autonomic, and psychological aspects of vestibular pathology (Fig. 27–11). The five main branches of management intervention are as follows:92 1. General medical evaluation with correction/amelioration of associated comorbid conditions. 2. Pharmacological intervention. 3. Vestibular rehabilitation with physiotherapy and specific physical maneuvers for the management of BPPV. 4. Psychological intervention. 5. Surgery. On the basis of the diagnosis, an appropriate rehabilitation plan (Table 27–6) should be constructed for each patient, and T A B L E 27–6. Rehabilitation Program Explanation to individual and family Correction of remediable problems General fitness program Physical exercise regimen Systematic Customized Psychological assessment Treatment for specific disorders Monitor progress Discharge

■

Vertigo

of vestibular disorders.

Full history and examination

Medical investigation

Neuro-otological investigation

Diagnosis and treatment

Specific diagnosis

Medical treatment

Neurological investigation

Diagnosis and treatment

Peripheral labyrinthine vertigo

Otological surgery

Medical treatment of acute attack

Medical treatment of chronic recurrent vertigo: • Physical exercise regimes or maneuvers • Psychological support • (Vestibular sedatives)

Therapeutic procedures Surgery Failure Destructive procedures

Figure 27–11. Management

chapter 27 vestibular system disorders it is important that the patient fully understands the aims and objectives of the rehabilitation package to ensure active compliance.

General Measures If appropriate treatment is not undertaken, systemic disorders such as hypertension, vascular disease, diabetes, autoimmune disorders, and psychological pathology may affect vestibular compensation in the dizzy patient. Specifically, ophthalmological and rheumatological/orthopedic problems should be addressed to ensure optimal visual and proprioceptive input and to enable optimal vestibular compensation.

Pharmacological Treatment Antiemetics and vestibular sedative drugs impair vestibular compensation and, therefore, should not be used in the longterm management of chronic vertigo of peripheral origin. Drug treatments of vestibular disorders include the following: 1. Treatment of acute vestibular symptoms. 2. Specific treatment of a condition that causes vestibular symptoms, such as migraine, epilepsy, or Meniere’s disease. 3. Nonspecific but empirical treatment of a chronic vestibular disorder, such as central vestibular dysfunction. Acute vestibular symptoms may be ameliorated by antiemetic and vestibular-suppressant drugs. Antiemetics may be administered intramuscularly, via the buccal membrane, or by suppository, if vomiting precludes oral administration. Hyoscine, prochlorperazine, promethazine, cyclizine, dimenhydrinate, and metoclopramide are the usual drugs of choice. Calcium channel antagonists, such as cinnarizine and funarizine, have vestibular suppressant effects, although both drugs may have extrapyramidal side effects and should be used cautiously by older patients. Diazepam has no specific action on the vestibular system, but it is widely used for its anxiolytic effect in acute vestibular crises. Specific treatment of vestibular disorders is appropriate for Meniere’s disease, migraine, and episodic ataxia. The treatment of Meniere’s disease remains controversial and empirical,93 with few double-blind randomized studies to assess treatment efficacy and an 80% placebo response in this condition. Medical treatment aims to influence the underlying pathology of endolymphatic hydrops or the postulated immunological pathogenesis of this disorder, whereas destructive procedures may be either medical (intratympanic injection of aminoglycosides) or surgical. A low-salt diet and diuretics (bendrofluazide, 10 mg/day), together with potassium supplements and regular serum potassium checks to avoid hypokalemia, appear to be highly effective. Betahistine, a histamine analog, is advocated for treatment of Meniere’s disease but is contraindicated in the presence of migraine. Steroids have been proposed both systematically and transtympanically, on the assumption of an autoimmune pathogenesis for Meniere’s disease. The treatment of migraine-associated dizziness parallels the treatment of migrainous headache. General measures, including dietary restriction, lifestyle adaptations, stress reduction techniques, and vestibular rehabilitation are of value in the presence of a fixed vestibular deficit. Treatment may include

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over-the-counter analgesics, in addition to triptans, ergot derivatives, and acetazolamide. Prophylactic medication includes β blockers, calcium channel blockers, serotonin reuptake inhibitors, and amitriptyline. Episodic ataxia, which is rare in comparison with migraine, may manifest with acute vertigo and ataxia. Both acetazolamide and 4-aminopyridine are effective in episodic ataxia type 2.94,95 Standard antiemetics and vestibular sedative drugs may be tried in maximal dosages to alleviate acute vestibular symptoms. On an empirical basis, nausea and disequilibrium associated with central eye movement disorders have reportedly been improved by a variety of drugs, including clonazepam, gabapentin, baclofen, flunarizine, and barbiturates. Each drug should be titrated against known side effects to obtain optimal suppression of symptoms.92 Ondansetron, a potent highly selective 5-hydroxytryptamine-3 receptor antagonist, has been effective in combating nausea, particularly in association with vertigo caused by brainstem stroke.96

Vestibular Rehabilitation Management of peripheral vertigo hinges on the facilitation of compensation through physical exercise regimens, such as the Cawthorne-Cooksey exercises and customized regimens,97 together with appropriate psychological support for patients who develop the common sequelae of avoidance behavior, anxiety, and depression.5 Treatment of BPPV is particularly rewarding, because particle repositioning procedures have been shown to be highly effective.97 In 1980, Brandt and Daroff98 proposed specific repetitive positional exercises that were based on the hypothesis of cupulolithiasis, and they claimed a 98% success rate. More recent studies in which both the Epley and the Semont maneuvers, based on the hypothesis of canalithiasis, were used reported success rates of between 80% and 95% after the first maneuver. Repeated maneuvers improve the success rate so much that fewer than 5% of patients appear to continue suffering persistent symptoms despite these treatments. It may be appropriate to consider surgical intervention such as plugging the posterior canal to bring about resolution of positional vertigo in this small subset of patients in whom medical management fails. There is some evidence to support the use of physiotherapy in central vestibular syndromes, and gait-retraining strategies may prove valuable in restoring confidence and optimizing available function.

Psychological Intervention The interaction of psychological factors and vestibular symptoms in recovery from peripheral vestibular disorders cannot be overemphasized. Many studies have highlighted the association of agoraphobia, avoidance behavior, anxiety states, panic attacks, and depression with vestibular pathology.99 When a patient is not recovering with physiotherapy intervention, such factors should always be considered.

Surgical Intervention It is now widely recognized that surgical intervention for vertigo is needed only in life-threatening complications of

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chronic middle ear disease, neoplasia involving otological structures (e.g., vestibular schwannoma), or trauma to the middle or inner ear, as may be seen in association with a perilymph fistula. Interventions such as endolymphatic sac decompression for Meniere’s disease have not been proved effective, and destructive surgical procedures such as labyrinthectomy or vestibular nerve section should be considered with caution in view of the reported incidence of bilateral pathology in this condition. Medical destruction of the inner ear with the aminoglycosides, through intratympanic instillation of gentamicin, remains an unproved therapeutic intervention in that although the episodes of vertigo may abate, there is a significant occurrence of sensorineural hearing loss, and the possible long-term consequence of bilateral disease must again be borne in mind.

Successful management of the patient with vertigo depends on accurate diagnosis, an understanding of vestibular physiology and compensation, appropriate intervention strategies, and the physician’s awareness of the overlap between vestibular, autonomic, and psychological aspects of vestibular pathology.

●

Management intervention is based on general medical evaluation with correction/amelioration of associated comorbid conditions; pharmacological intervention; vestibular rehabilitation with physiotherapy and specific physical maneuvers for the management of BPPV; psychological intervention; and rarely surgery.

Suggested Reading

CONCLUSION Balance disorders are common, and although the majority of peripheral vestibular disorders may resolve spontaneously, a significant proportion do not. This latter group, together with central vestibular syndromes, carries significant social and occupational morbidity. A clear diagnostic strategy, allowing accurate diagnosis and appropriate intervention, frequently facilitates a significant improvement in both patients’ symptoms and quality of life.

K E Y

●

P O I N T S

●

Balance relies on integration of movement-induced neural asymmetry with other sensory (visual and somatosensory) input and comparison with information in a central “data bank” template. If there is any mismatch between the sensory input and the existing template, or if there is a pathological lesion, the patient senses disorientation, may develop an abnormal eye movement, frequently feels off balance, and may develop nausea/vomiting and other autonomic symptoms.

●

Dizziness/disequilibrium is an extremely common symptom that may be associated with pathology in almost all body systems.

●

The diagnosis of vertigo is critically dependent on a clear history of the character of the symptom (dizziness, vertigo, ataxia), the duration of both the illness and individual episodes, and the presence of associated symptoms, in order to enable appropriate management.

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In most cases, the characteristic symptoms and signs of vestibular deafferentation abate over a period of weeks to months. The processes that bring about the resolution of vestibular symptoms are collectively known as cerebral compensation and are attributed to cerebral plasticity.

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A percentage of patients with a peripheral vestibular deficit do not recover spontaneously and require vestibular rehabilitation with physiotherapy, which promotes recovery with visual, proprioceptive, and vestibular stimulation.

●

Vertigo is much more commonly associated with peripheral vestibular disorders than with central neurological disorders. Notwithstanding this, there are a number of central vestibular syndromes that must be considered.

Baloh RW, Halmagyi GM: Disorders of the Vestibular System. Oxford, UK: Oxford University Press, 1996. Brandt T: Vertigo: Its Multisensory Syndromes, 2nd ed. London: Springer, 2003. Furman JM, Cass SP: Balance Disorders: A Case-Study Approach, 2nd ed. Oxford, UK: Oxford University Press, 2003. Herdman SJ: Vestibular Rehabilitation. Philadelphia: FA Davis, 2005. Luxon LM, Furman JM, Martini A, et al, eds: Textbook of Audiological Medicine. Martin Duritz London, 2003.

References 1. Yardley L, Owen O, Nazareth I, et al: Prevalence and presentation of dizziness in a general practice community sample of working age people. Br J Gen Pract 1998; 48:1131-1135. 2. Jonsson R, Sixt E, Landahl S, et al: Prevalence of dizziness and vertigo in an urban elderly population. J Vestib Res 2004; 14:47-52. 3. Royal College of General Practitioners and Office of Population Census and Surveys: Morbidity Statistics from General Practice. London: HMSO, 1986. 4. Downton JH: Falls in the Elderly. London: Edward Arnold, 1993. 5. Eagger S, Luxon LM, Davies RA, et al: Psychiatric morbidity in patients with peripheral vestibular disorder: a clinical and neuro-otological study. J Neurol Neurosurg Psychiatry 1992; 55:383-387. 6. Wuyts F: Physiology of Equilibrium. In Gleeson M, ed: ScottBrown’s Otolaryngology: Head & Neck Surgery, 7th ed. London: Hodder Arnold. In press. 7. Roberts TDM: Neurophysiology of Postural Mechanisms, 2nd ed. London: Butterworths, 1978. 8. Watt DG: Sensory and motor conflict in motion sickness. Brain Behav Evol 1983; 23(1-2):32-35. 9. Balaban CD: Neural substrates linking balance control and anxiety. Physiol Behav 2002; 77:469-475. 10. Furman JM, Balaban CD, Jacob RG, et al: Migraine-anxiety related dizziness (MARD): a new disorder? J Neurol Neurosurg Psychiatry 2005; 76:1-8. 11. Rauch SD, Velazquez-Villasenor L, Dimitri PS, et al: Decreasing hair cell counts in aging humans. Ann N Y Acad Sci 2001; 942:220-227. 12. Nadol JB Jr, Schuknecht HF: Pathology of peripheral vestibular disorders in the elderly. Am J Otolaryngol 1990; 11:213227. 13. Enrietto JA, Jacobson KM, Baloh RW: Ageing effects of auditory and vestibular responses: a longitudinal study. Am J Otolaryngol 1999; 20:371-378.

chapter 27 vestibular system disorders 14. Kazmierczak H, Pawlak-Osinski P: Visuoocular reflexes in presbyvertigo. Int Tinnitus J 2001; 7:112-114. 15. Drachman DA, Hart C: A new approach to the dizzy patient. Neurology 1972; 22:323-334. 16. Konrad H, Girardi M, Helfert R: Balance and aging. Laryngoscope 1999; 109:1454-1460. 17. Curthoys IS, Halmagyi GM: Vestibular compensation: a review of the oculomotor, neural and clinical consequences of unilateral vestibular loss. J Vestib Res 1995; 5:67-107. 18. Gonshor A, Melvill Jones G: Extreme vestibule-ocular adaptation induced by prolonged optical reversion of vision. J Physiol 1976; 256:381-414. 19. Ito M: The Cerebellum and Neural Control. New York: Raven Press, 1984. 20. Smith PF, Curthoys IS: Mechanisms of recovery following unilateral labyrinthectomy: a review. Brain Res Rev 1989; 14:155180. 21. Lacour M, Xerri C: Lesion induced neuronal plasticity in sensorineural systems. In Flohr H, Precht W, eds: Vestibular Compensation: New Perspectives. Berlin: Springer-Verlag, 1981, pp 240-253. 22. Halmagyi GM, Cremer PD, Curthoys IS: Peripheral vestibular disorders and diseases in adults. In Luxon LM, Furman JM, Martini A, et al, eds: Textbook of Audiological Medicine. London: Taylor & Francis, 2003, pp 797-818. 23. Luxon LM: Vestibular compensation. In Luxon LM, Davies RA, eds: Handbook of Vestibular Rehabilitation. London: Whurr, 1997, pp 17-29. 24. Cass SP, Goshgarian HG: Vestibular compensation after labyrinthectomy and vestibular neurectomy in cats. Otolaryngol Head Neck Surg 1991; 104:14-19. 25. Petrone D, De Benedittis G, De Candia N: Experimental research on vestibular compensation using posturography. Boll Soc Ital Biol Sper 1991; 67:731-737. 26. Lacour M, Roll JP, Appaix M: Modifications and development of spinal reflexes in the alert baboon (Papio papio) following an unilateral vestibular neurotomy. Brain Res 1976; 113:255269. 27. Igarashi M, Levy JK, O-Uchi T, et al: Further study of physical exercise and locomotor balance compensation after unilateral vestibular neurotomy. Acta Otolaryngol 1981; 92:101-105. 28. Courjon JH, Jeannerod M, Ossuzio I, et al: The role of vision in compensation of vestibulo-ocular reflex after hemilabyrinthectomy in the cat. Exper Brain Res 1977; 28:235-248. 29. Fetter M, Zee DS, Proctor LR: Effect of lack of vision and of occipital lobectomy upon recovery from unilateral labyrinthectomy in rhesus monkey. J Neurophysiol 1988; 59:394-407. 30. Schaefer KP, Meyer DL: Compensatory mechanisms following labyrinthine lesions in the guinea pig. A simple model of learning. In Zippel HP, ed: Memory and Transfer of Information. New York: Plenum, 1973, pp 203-232. 31. Bronstein AM, Hood JD: Oscillopsia of peripheral vestibular origin. Central and cervical compensatory mechanisms. Acta Otolaryngol 1987; 104:207-214. 32. Buchele W, Brandt T, Degner D: Ataxia and oscillopsia in downbeat-nystagmus vertigo syndrome. Adv Otorhinolaryngol 1983; 30:291-297. 33. Wist ER, Brandt T, Krafczyk S: Oscillopsia and retinal slip. Evidence supporting a clinical case. Brain 1983; 106(Part 1):153168. 34. Lacour M: Relearning and critical postoperative period in the restoration of nerve function. Example of vestibular compensation and clinical implications. Ann Otolaryngol Chir Cervicofac 1984; 101:177-187. 35. Shepard NT, Telian SA, Smith-Wheelock M, et al: Vestibular and balance rehabilitation therapy. Ann Otol Rhinol Laryngol 1993; 102:198-205.

351

36. Luxon LM: Evaluation and management of the dizzy patient. J Neurol Neurosurg Psychiatry 2004; 75(Suppl 4):iv45iv52. 37. Strupp M, Brandt T: Vestibular neuritis. Adv Otorhinolaryngol 1999; 55:111-136. 38. Strupp M, Arbusow V: Acute vestibulopathy. Curr Opin Neurol 1999; 14:11-20. 39. Strupp M, Arbusow V, Maag KP, et al: Vestibular exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology 1998; 51:838-844. 40. Herzog N, Allum JH, Probst R: [Follow-up of caloric test response after acute peripheral vestibular dysfunction]. HNO 1997; 45:123-127. 41. Schmid-Priscoveanu A, Bohmer A, Obzina H, et al: Caloric and search-coil head-impulse testing in patients after vestibular neuritis. J Assoc Res Otolaryngol 2001; 2:72-78. 42. Fetter M, Dichgans J: Vestibular neuritis spares the inferior division of the vestibular nerve. Brain 1996; 119:755-763. 43. Aw ST, Fetter M, Cremer PD, et al: Individual semicircular canal function in superior and inferior neuritis. Neurology 2001; 57:768-774. 44. Abramovich S, Prasher DK: Electrocochleography and brainstem potentials in Ramsay-Hunt syndrome. Arch Otolaryngol Head Neck Surg 1986; 112:925-928. 45. Koizuka I, Goto K, Okada M, et al: ENG findings in patients with Bell’s palsy. Relationship between visual suppression and clinical course. Acta Otolaryngol Suppl 1988; 446:85-92. 46. Yagi T, Yamaguchi J, Nonaka M: Neurotological findings in Bell’s palsy and Hunt’s syndrome. Acta Otolaryngol Suppl 1988; 446:97-100. 47. Pappas DG Jr, Roland JT Jr, Lim J, et al: Ultrastructural findings in the vestibular end-organs of AIDS cases. Am J Otol 1995; 16:140-145. 48. Committee on Hearing and Equilibrium, the American Academy of Ophthalmology and Otolaryngology: Committee on Hearing and Equilibrium guidelines for diagnosis and evaluation of therapy in Meniere’s disease. Otolaryngol Head Neck Surg 1995; 113:181-185. 49. Jacobson GP, Pearlstein R, Henderson J, et al: Recovery nystagmus revisited. J Am Acad Audiol 1998; 9:263-271. 50. Ishiyama G, Ishiyama A, Jacobson K, et al: Drop attacks in older patients secondary to an otologic cause. Neurology 2001; 57:1103-1106. 51. Conlon BJ, Gibson WP: Meniere’s disease: the incidence of hydrops in the contralateral asymptomatic ear. Laryngoscope 1999; 109:1800-1802. 52. Paparella MM, Djalilian HR: Etiology, pathophysiology of symptoms, and pathogenesis of Meniere’s disease. Otolaryngol Clin North Am 2002; 35:529-545, vi. 53. Brenner M, Hoistad DL, Hain TC: Prevalence of thyroid dysfunction in patients with Meniere’s disease. Arch Otolaryngol Head Neck Surg 2004; 130:226-228. 54. Pulec L, House WF: Meniere’s disease study: three-year progress report. Int J Equilib Res 1973; 3:156-165. 55. Selmani Z, Marttila T, Pyykko I: Incidence of virus infection as a cause of Meniere’s disease or endolymphatic hydrops assessed by electrocochleography. Eur Arch Otorhinolaryngol 2005; 262:331-334. 56. Friberg U, Rask-Andersen H: Vascular occlusion in the endolymphatic sac in Meniere’s disease. Ann Otorhinolaryngol 2002; 111:237-245. 57. Tomoda K, Suzuka Y, Iwai H, et al: Meniere’s disease and autoimmunity: clinical study and survey. Acta Otolaryngol Suppl 1993; 500:31-34. 58. Kayan A, Hood JD: Neuro-otological manifestations of migraine. Brain 1983; 107:1123-1142. 59. Bronstein A, Rinne T, Gresty M, et al: Bilateral loss of vestibular function. Acta Otolaryngol Suppl 1994; 520:247-250.

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60. Harker LA: Migraine associated vertigo. In Baloh RW, Halmagyi GM, eds: Disorders of the Vestibular System. Oxford, UK: Oxford University Press, 1996, pp 407-417. 61. Al-Twaijri WA. Shevell MI: Pediatric migraine equivalents: occurrence and clinical features in practice. Pediatr Neurol 2002; 26:365-368. 62. Cutrer FM, Baloh RW: Migraine associated dizziness. Headache 1992; 32:300-304. 63. Basser LS: Benign paroxysmal vertigo of childhood (a variety of vestibular neuronitis). Brain 1964; 87:141-152. 64. Lanzi G, Balottin U, Fazzi E, et al: Benign paroxysmal vertigo of childhood: a long-term follow-up. Cephalalgia 1994; 14:458460. 65. Slater R: Benign recurrent vertigo. J Neurol Neurosurg Psychiatry 1979; 42:363-367. 66. Moretti G, Manzoni GC, Caffarra P, et al: Benign recurrent vertigo and its connection with migraine. Headache 1980; 20:344-346. 67. Rassekh CH, Harker LA: The prevalence of migraine in Meniere’s disease. Laryngoscope 1992; 102:135-138. 68. Furman JM, Balaban CD, Jacob RG, et al: Migraine-anxiety related dizziness (MARD): a new disorder? J Neurol Neurosurg Psychiatry 2005; 76:1-8. 69. Furman JM, Marcus DA, Balaban CD: Migrainous vertigo: development of a pathogenetic model and structured diagnostic interview. Curr Opin Neurol 2003; 16:5-13. 70. Neuhauser H, Leopold M, von Brevern M, et al: The interrelations of migraine, vertigo and migrainous vertigo. Neurology 2001; 56:436-441. 71. Ophoff RA, Terwindt GM, Vergouwe MN, et al: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87:543-552. 72. Dix MR, Hallpike CS: Pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Proc R Soc Med 1952; 45:341-354. 73. Schuknecht HF: Positional vertigo: clinical and experimental observations. Trans Am Acad Ophthalmol Otolaryngol 1962; 66:319-331. 74. Schuknecht HF: Cupulolithiasis. Arch Otolaryngol 1969; 90:765-778. 75. Hall SF, Ruby RRF, McLure JA: The mechanics of benign paroxysmal vertigo. J Otolaryngol 1979; 8:151-158. 76. Honrubia V, Baloh RW, Harris MR, et al: Paroxysmal positional vertigo syndrome. Am J Otol 1999; 20:465-470. 77. Yu TJ, Yazawa Y: Immunology of cochlear and vestibular disorders. In Luxon LM, Furman JM, Martini A, et al, eds: Textbook of Audiological Medicine. London: Taylor & Francis, 2003, pp 61-88. 78. Agrup C, Luxon LM: Autoimmune inner ear disease. Curr Opin Neurol. 2006; 19(1):26-32. 79. Luxon LM: Post-traumatic vertigo. In Baloh RW, Halmagyi M, eds: Disorders of the Vestibular System. New York: Oxford University Press, 1996, pp 381-395. 80. Davies RA, Luxon LM: Dizziness following head injury: a neuro-otological study. J Neurol 1995; 242:222-230.

81. British Association of Otorhinolaryngologists—Head and Neck Surgeons: Clinical Effectiveness: Acoustic Neuroma (Vestibular Schwannoma) [Document 5]. London: ENT-UK, 2002. 82. Golz A, Netzer A, Angel-Yeger B, et al: Effects of middle ear effusion on the vestibular system in children. Otolaryngol Head Neck Surg 1998; 119:695-699. 83. Grad A, Baloh RW: Vertigo of vascular origin: clinical and electronystagmographic features in 84 cases. Arch Neurol 1989; 46:281-284. 84. Baloh RW, Honrubia V: Vascular disorders In Baloh RW, Honrubia V, eds: Clinical Neurophysiology of the Vestibular System, 3rd ed. New York: Oxford University Press, 2001, p 292. 85. Bjerner K, Silfverskold BJ: Lateropulsion and imbalance in Wallenberg’s syndrome. Acta Neurol Scand 1968; 44:91-98. 86. Osis JG, Baloh W: Vertigo and the anterior inferior cerebellar artery syndrome. Neurology 1992; 42:1274-1279. 87. Norrving B, Magnussen M, Holtas S: Isolated acute vertigo in the elderly: vestibular or vascular disease? Acta Neurol Scand 1995; 91:43-48. 88. Pollak L, Rabey JM, Gur R, et al: Indication to surgical management of cerebellar haemorrhage. Clin Neurol Neurosurg 1998; 100:99-103. 89. Hirose G, Halmagyi GM: Brain tumours and balance disorders. In Baloh RW, Halmagyi GM, eds: Disorders of the vestibular system. Oxford, UK: Oxford University Press, 1996, pp 446-460. 90. Williams NP, Roland PS, Yellin W: Vestibular evaluation in patients with early multiple sclerosis. Am J Otol 1997; 18:93100. 91. Crtistante L, Westphal M, Herrmann HD: Cranio-cervical decompression for Chiari I malformation: a retrospective evaluation of functional outcome with particular attention to the motor deficits. Acta Neurochir (Wien) 1994; 130(1-4):94-100. 92. Bamiou D-E, Luxon LM: Vertigo-clinical management and rehabilitation. In Gleeson M, Luxon LM, eds: Scott-Brown’s Otolaryngology: Head & Neck Surgery—Ear, Hearing and Balance, 7th ed, London: Hodder Arnold. In press. 93. Kim HH, Wiet RJ, Battista RA: Trends in the diagnosis and management of Meniere’s disease: results of a survey. Otolaryngol Head Neck Surg 2005; 132:722-726. 94. Jen J: Familial episodic ataxias and related ion channel disorders. Curr Treat Options Neurol 2000; 2:429-431. 95. Strupp M, Kalla R, Dichgans M, et al: Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004; 62:1623-1625. 96. Rice GP, Ebers GC: Ondansetron for intractable vertigo complicating acute brainstem disorders. Lancet 1995; 345:11821189. 97. Luxon LM, Davies RA, eds: Handbook of Vestibular Medicine. London: Whurr, 1997. 98. Brandt T, Daroff RB: Physical therapy for paroxysmal positional vertigo. Arch Otolaryngol 1980; 106:484-485. 99. Jacobs RG, Furman JM, Cass SP: Psychiatric consequences of vestibular dysfunction. In Luxon LM, Furman J, Martini A, et al, eds: Textbook of Audiological Medicine. London: Taylor & Francis, 2002, pp 869-887.

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ORTHOSTATIC HYPOTENSION ●

●

●

●

Horacio Kaufmann and Italo Biaggioni

Maintenance of upright posture is made possible by rapid cardiovascular adaptation that ensures blood flow to vital organs, including the brain, and depends primarily on an intact autonomic nervous system. When this system fails, as occurs in neurological disorders affecting autonomic neurons, orthostatic hypotension results. Severely affected patients are completely disabled, unable to stand for more than few seconds before syncope ensues. The incapacitating nature of orthostatic hypotension in autonomic failure underscores the importance of cardiovascular autonomic reflexes for normal life. Even though treatment remains suboptimal, orthostatic hypotension is arguably the symptom of autonomic impairment most amenable to treatment. These patients are hypersensitive to pressor agents because of baroreflex impairment and receptor upregulation, and clinicians can take advantage of these features in designing treatment.

PATHOPHYSIOLOGY When a normal individual stands, about 700 mL of blood pools in the legs and lower abdominal veins. Venous return decreases, resulting in a transient decline in cardiac output. The reduction in central blood volume and arterial pressure is sensed by pressure-sensitive cardiopulmonary volume receptors and arterial baroreceptors. This leads to baroreflex-mediated sympathetic activation with increases in stroke volume and peripheral vasoconstriction and parasympathetic withdrawal with increase in heart rate (Fig. 28–1). These rapid hemodynamic changes prevent blood pressure from falling; their failure causes orthostatic hypotension. When arterial blood pressure falls below a critical level, cerebral blood flow also decreases. When systolic blood pressure is around 50 mm Hg at brain level (which corresponds to a systolic blood pressure of approximately 70 mm Hg at cardiac level when a person is standing) (Fig. 28–1), the autoregulatory capacity of cerebral blood flow reaches maximum vasodilation and is unable to compensate for a further fall in blood pressure. In addition to these almost instantaneous changes in vascular tone and heart rate directly mediated by autonomic innervation, other longer term mechanisms that contribute to the maintenance of upright blood pressure are also influenced by the baroreflex. These mechanisms are impaired in patients with

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autonomic failure and contribute to their orthostatic hypotension. Increased sympathetic renal nerve activity induces tubular sodium reabsorption directly1 and by stimulating the secretion of renin from the juxtaglomerular apparatus.2 Renin and converting enzyme convert circulating angiotensinogen into angiotensin II, which is a vasoconstrictor and secretagogue of aldosterone from the adrenal medulla. Aldosterone retains sodium in the kidney, increasing extracellular fluid volume. Patients with autonomic failure have low renin and low aldosterone levels. In addition, unloading of thoracic baroreceptors releases the antidiuretic hormone from the neurohypophysis into the systemic circulation.3,4 Acting on specific receptors in vascular smooth muscle cells,5 vasopressin produces vasoconstriction, and in the kidney it causes water retention and expands extracellular fluid volume.6 Baroreflexmediated vasopressin release is blunted in some patients with autonomic failure. Two other circulating vasoactive peptides, atrial natriuretic factor (ANF) and endothelin, are involved in the regulation of blood pressure and extracellular fluid volume, and their secretion may also be controlled, at least in part, by autonomic reflexes. ANF is secreted from atrial myocites7 when atrial pressure increases. ANF produces natriuresis, relaxation of vascular smooth muscle, and inhibition of renin and aldosterone secretions.8-10 When right atrial pressure decreases, as during the upright posture, circulating levels of ANF quickly fall, contributing to vasoconstriction and expansion of extracellular fluid volume. Whether ANF is released by the direct effect of pressure on the cardiocytes or by a centrally mediated autonomic reflex is still unclear. Kaufmann and colleagues found that the response of circulating ANF to changes in atrial pressure is preserved in patients with baroreflex impairment, which suggests that a local intracardiac reflex regulates the secretion of the peptide.11 Endothelin, a powerful vasoconstrictor synthesized by endothelial cells,12 has an important role in the local control of the circulation.13 In addition, however, endothelin is synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus14 and is co-released with vasopressin from the neurohypophysis into the bloodstream when thoracic baroreceptors are unloaded.15 The physiological function of the endothelin released into plasma during baroreflex activation remains to be defined, but it is likely that circulating endothelin contributes to the vasoconstriction that maintains blood pressure in the upright posture.15

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T A B L E 28–1. Assessment of Autonomic Function: Bedside Physiological Tests Posture Test Measure blood pressure (BP) and heart rate (HR) after patient has been supine 15 minutes and standing 5 minutes. Express as supine – standing values. Normal response: systolic BP = 0-20 mm Hg, diastolic BP = 510 mm Hg, HR = 0-15 beats/minute. Sinus Arrhythmia (SA) Ratio Have patient breathe deeply 6 times/minute while HR is monitored. Measure longest R-R interval during expiration and shortest R-R interval during inspiration. Take average of R-R intervals in 6 breaths. SA ratio = R-Rexp/R-Rinsp; normal response: ≥1.2 (decreases with age). Valsalva Ratio Use 6- to 12-mL syringe barrel as mouthpiece connected to sphygmomanometer. Ask patient to blow mercury column to 40 mm Hg for 15 seconds while HR is monitored on continuous strip. Repeat four times. Make sure effort is barred by thorax and not mouth (e.g., by introducing a pin size leak in the mouthpiece). Measure shortest R-R interval during strain and longest R-R interval after release. Valsalva ratio = R-Rrelease/R-Rstrain; normal response: ≥1.4 (decreases with age). Cold Pressor Test Measure baseline BP and HR. Have patient place hand in ice water for 1 min. Measure BP and HR at end of minute. Normal response: rise in systolic BP > 15 mm Hg. R-R, R wave to R wave; R-Rexp, R-R interval during expiration; R-Rinsp, R-R interval during inspiration. ■

Figure 28–1. Effect of gravity on arterial and venous pressure in an upright posture. Below heart level, both arterial and venous pressures increase. Above heart level, pressures decrease. Within the cranium, the perfusion pressure (arterial-venous) remains relatively constant because of the subatmospheric pressure in cerebral sinuses. (From Hainsworth R: Pathophysiology of syncope. Clin Auton Res 2004; 14[Suppl 1]:18-24.)

DIAGNOSIS AND EVALUATION OF ORTHOSTATIC HYPOTENSION Orthostatic hypotension produces a characteristic clinical history. Symptoms of lightheadedness and tunnel vision occur on standing, never while the person is lying down, and are always relieved immediately on sitting or lying down, because cerebral blood flow is passively restored. Failure to meet these criteria suggests other causes of impaired consciousness (e.g., hypoglycemia, seizures, cardiac arrhythmias).16 In patients with diabetes or other peripheral neuropathies, proprioceptive abnormalities lead to feeling of unsteadiness that patients refer as dizziness, which may wrongly suggest orthostatic hypotension. In addition to the classic lightheadedness with blurred vision and syncope, symptoms of chronic orthostatic hypotension may include vague generalized weakness, fatigue, cognitive impairment, and pain in the shoulders and back of the neck (coat hanger pain). Many patients with chronic autonomic failure can tolerate very low orthostatic blood pressures with few symptoms of cerebral hypoperfusion, perhaps because their cerebral autoregulatory capacity is well preserved.17 However, physical

exercise, prolonged standing, the postprandial state, or mild volume depletion exacerbates orthostatic hypotension and invariably triggers symptoms of cerebral hypoperfusion, including presyncope or syncope. The diagnosis of orthostatic hypotension relies on simple measurements of blood pressure and heart rate after the patient has lain down for 5 to 10 minutes and after 1 to 3 minutes of standing. Orthostatic hypotension is arbitrarily defined as a decrease in systolic blood pressure of at least 20 mm Hg and in diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing, in association with symptoms of cerebral hypoperfusion.18 On occasion, the diagnosis of orthostatic hypotension may require repeated measurements of blood pressure throughout the day. In patients with autonomic impairment, the severity of orthostatic hypotension is worse early in the morning or about 30 minutes after a meal compared to the rest of the day. Concomitant measurements of heart rate are crucial for adequate interpretation of results. Side effects of medications are arguably the most common causes of orthostatic hypotension. The most common culprits are tricyclic antidepressants, diuretics, nitrates, and α blockers used to treat benign prostatic hypertrophy. In these cases, there is usually a compensatory increase in heart rate in association with orthostatic hypotension. In contrast, the presence of symptomatic orthostatic hypotension without an adequate compensatory increase in heart rate is sufficient clinical indication of autonomic failure (Fig. 28–3). The diagnosis can be easily confirmed with simple measurements of heart rate and blood pressure (Table 28–1). No single test completely differentiates patients with auto-

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Au to n o m i c N e rvo u s Syst e m D i s e as e s PVN

AVP

SON

NTS

NA Vagal outflow RVL

CVL

Baroreceptors IML Sympathetic outflow ■

Figure 28–2. Simplified outline of autonomic blood pressure regulation by the baroreflex. The baroreflex is a classic example of regulatory feedback control as exerted by the autonomic nervous system. Information is collected by pressure-sensitive receptors located in the walls of cardiopulmonary veins, the right atrium, and within almost every large artery of the neck and thorax, particularly within the carotid and aortic arteries. Venous and the aortic arch baroreceptors relay their information via fibers that course within the vagus nerve (cranial nerve X). Carotid sinus baroreceptor nerve activity is relayed centrally by the carotid sinus (Hering’s) nerve, then through the glossopharyngeal nerve (cranial nerve IX). Afferent fibers from baroreceptors have their first synapse in the nucleus tractus solitarii (NTS) of the medulla oblongata, a structure that also receives input from many other cardiovascular brain centers, such as the area postrema. The NTS provides excitatory input to the caudal ventrolateral (CVL) medulla, which in turn provides inhibitory influence on the rostral ventrolateral (RVL) medulla, where the pacemaker neurons that originate sympathetic tone are located. Axons from RVL neurons synapse with cell bodies of preganglionic sympathetic neurons in the intermediolateral column of the spinal cord, which send axons outside the central nervous system. These “preganglionic” axons synapse in peripheral ganglia with postganglionic efferent sympathetic neurons, which release norepinephrine at target organs; this results in an increase in heart rate and cardiac contractility, partial restoration of venous return and diastolic ventricular filling by venoconstriction, and an increase in peripheral resistance by arteriolar vasoconstriction. Parasympathetic activity is also modulated by the NTS, through projections to the nucleus ambiguus (NA), where preganglionic cardiac parasympathetic neurons are located. An increase in blood pressure stretches baroreceptors and increases firing of afferent fibers, which results in activation of the NTS and the caudal ventrolateral (CVL) medulla, which in turn inhibit the RVL to produce sympathetic withdrawal. Activation of the NTS also results in activation of the nucleus ambiguus, leading to parasympathetic activation. The end result is a decrease in vascular tone, myocardial contractility, and heart rate, which brings blood pressure back to “baseline” levels. In general, sympathetic activation is accompanied by parasympathetic withdrawal, and vice versa. This is probably explained by the central integration of both pathways, as exemplified by the role of the NTS in baroreflex responses. Sympathetic activation to the different organs is not homogeneously distributed and depends on the stimuli and afferent pathways involved. For example, mental stress induces sympathetic activation and increases blood pressure but causes vasodilation of the forearm vasculature. AVP, arginine vasopressin; IML, intermediolateral column; PVN, paraventricular nucleus; SON, supraoptic nucleus.

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A

*

* 0.16

0.12 800 0.08 400 0.04

0

0

B 90

200

30

100 50 Sleep

Nocturnal

C

BP (mm Hg)

150

Diurnal

200

140

150

50

HR (bpm)

Nocturnal

HR (bpm)

Diurnal

BP (mm Hg)

Na+/crea (mmol/mg)

Uvolume (mL/12 h)

1200

100 50 Sleep 0

0 13 15 17 19 21 23 1 3 5 7 9 11 13 15 Time ■

14 15 16 18 19 21 23 1 4 7 9 11 13 14 Time

Figure 28–3. A, Patients with autonomic failure have reversal of the normal diurnal variation in natriuresis, with about twice as much urine volume (Uvolume) (dark bars) and sodium excretion (lighter bars) during the night as during the day. Crea, creatinine. B and C, Patients with autonomic failure have reversed circadian rhythm of blood pressure (BP) and heart rate (HR). B, subject with autonomic failure; C, normal subject. bpm, beats per minute.

nomic failure from age-matched control subjects, but together these tests provide a reliable indicator of the presence and severity of cardiovascular autonomic impairment.

CAUSES OF AUTONOMIC FAILURE The most common cause of autonomic failure is autonomic neuropathy secondary to diabetes mellitus. Any systemic illness that causes peripheral neuropathies that affect somatic nerves may also affect autonomic fibers. Citetreeman (2005) lancet from suggested reading list in general, the primary condition is clinically apparent. Primary forms of autonomic failure are rarely the result of congenital deficiency of the enzyme dopamine β-hydroxylase. Affected patients cannot synthesize norepinephrine in sympathetic nerves.19 Most cases of primary autonomic failure are caused by degeneration of autonomic neurons.20 Autonomic failure is a prominent feature of two of the most prevalent neurodegenerative diseases: the Lewy body syndromes and multiple-system atrophy (MSA). The Lewy body syndromes, so named because of characteristic cytoplasmic eosinophilic neuronal inclusions (Lewy body, Lewy neuritis) found in the brain and peripheral autonomic nerves of affected patients, manifest with three different but overlapping phenotypes: pure auto-

nomic failure, with neuronal degeneration restricted mostly to peripheral autonomic neurons and autonomic failure as the sole clinical finding; Parkinson’s disease, with prominent degeneration of the substantia nigra and other brainstem nuclei, in addition to peripheral autonomic neurons, and clinical findings dominated by motor abnormalities with varying degrees of autonomic failure; and dementia with Lewy bodies, a disorder with extensive cortical involvement, in addition to degeneration of brainstem nuclei and peripheral autonomic neurons and, clinically, severe cognitive impairment associated with parkinsonism and autonomic dysfunction. The second type of neurodegeneration with prominent autonomic failure, MSA, affects neurons in basal ganglia, cortex, and spinal cord, sparing peripheral autonomic neurons, with characteristic glial cytoplasmic inclusions but no Lewy bodies. MSA has two phenotypes: parkinsonian and cerebellar, named MSAp and MSAc according to the predominant motor abnormality. Severe autonomic failure is prominent in both phenotypes.21 The differential diagnosis between primary neurodegenerative autonomic disorders can be difficult. There are three common diagnostic challenges. First, it is often very difficult to distinguish, early on in the disease process, between pure autonomic failure and MSA because patients with MSA can present initially with isolated autonomic failure. It may be impossible to rule out MSA and make a definitive diagnosis of

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pure autonomic failure during the first 1 to 2 years of disease onset. Follow-up may be required before a definitive diagnosis can be made. MSA has a more rapid progression, with disability resulting from worsening of the movement disorder, which commonly occurs 6 to 8 years after onset of symptoms. Another differential diagnosis challenge is that between MSA and Parkinson’s disease. Patients with otherwise classical Parkinson’s disease can have severe orthostatic hypotension. Patients with MSA rarely have the onset of unilateral resting tremor typical of Parkinson’s disease and, in general, respond poorly to levodopa. Third, studies suggest that autoimmune autonomic neuropathy can resemble pure autonomic failure clinically but with more prominent gastrointestinal abnormalities. Autonomic failure with an acute or subacute (less than 3 months) clinical onset is suggestive of an autoimmune autonomic neuropathy. In most cases, the precise cause is not known, but in some patients, ganglionic nicotinic acetylcholine receptor (nAChR) autoantibodies are found. Clinical autonomic impairment is more pronounced in patients with high antibody titers, which indicates a pathogenic role for the nAChR antibodies.22 In addition to orthostatic hypotension, patients have dry eyes and dry mouth, severe upper gastrointestinal motility impairment, large pupils that react poorly to light and accommodation, and neurogenic bladder.23 Autoimmune autonomic neuropathy with a subacute onset may also occur as a paraneoplastic syndrome.24 This is commonly associated with anti-Hu antibodies (also known as type 1 antineuronal nuclear antibody), most often in patients with small cell lung cancer but also in those with other malignancies.25 Other antibodies associated with paraneoplastic autonomic neuropathy include Purkinje cell cytoplasmic antibodies type 2 and antibodies to the neuron cytoplasmic protein collapsin response-mediator protein-5. The clinical onset is generally subacute; acute or chronic manifestations are unusual. As in autoimmune autonomic neuropathy, prominent clinical findings are orthostatic hypotension, bowel hypomotility, bladder dysfunction, pupillomotor and sudomotor dysfunction, and xerophthalmia.

T A B L E 28–2. Stepwise Approach to Management of Orthostatic Hypotension Aggravating Factors to Be Removed Volume depletion Prolonged bed rest/deconditioning Alcohol Diuretics Tricyclic antidepressants Venodilators (nitrates) Antihypertensives (α blockers, guanethidine) α Blockers used to treat prostatic hypertrophy Insulin in diabetic patients with autonomic neuropathy Medical Nonpharmacological Treatment Liberalize salt intake, salt supplements Head-up tilt during the night Waist-high support stockings Exercise as tolerated, preferable in a pool Pharmacological Treatment* Fludrocortisone Short-acting pressor agents *See Table 28–3.

150

mm Hg

358

100

50 SBP DBP 0 –15

0

15

30

45

60

Time (min) ■

MANAGEMENT In general, a stepwise approach to treatment according to the severity of the symptoms is preferable.26 Table 28–2 shows general management guidelines, but treatment should be individualized. Some recommendations may actually be contraindicated in a given patient. The initial approach is always to remove any of the conditions enumerated in Table 28–2 that may induce or aggravate orthostatic hypotension. The suggestions for management described as follows are relevant to patients with orthostatic hypotension caused by autonomic impairment.

Nonpharmacological Therapy In patients with persistent symptoms, conservative nonpharmacological therapy is indicated. Patients with autonomic failure are unable to conserve sodium, and liberalization of sodium intake is generally recommended. These patients have exaggerated nocturnal diuresis with relative hypovolemia and worsening of orthostatic hypotension early in the morning. Elevating the head of the bed with 6- to 9-inch blocks can

Figure 28–4. Example of the pressor response produced by 500 mL of tap water in a patient with multiple-system atrophy. DBP, diastolic blood pressure; SBP, systolic blood pressure.

reduce nocturnal diuresis by reducing nocturnal hypertension. This simple maneuver may ameliorate orthostatic hypotension the following morning. During the day, wearing waist-high custom-fitted elastic support stockings exerts pressure on the legs and reduces venous pooling. It is important to avoid wearing support stockings in the supine position because they may contribute to diuresis and supine hypertension. Support stockings, however, are difficult to wear, and compliance is low. Most of the pooling of blood, however, occurs in the abdomen.27 Therefore, patients can try using an abdominal binder as an alternative to support stockings (Table 28–3).28 It has been discovered that rapid intake of 500 mL of water results in an acute (within 30 minutes) and transient (lasting about 60 minutes) increase in blood pressure in patients with autonomic failure.29 This pressor effect can be substantial (Fig. 28–4) and can be used to alleviate orthostatic hypotension. It is commonly recommended that patients drink 500 mL of water

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T A B L E 28–3. Pharmacological Agents for the Treatment of Orthostatic Hypotension Agent

Dosage

Side Effects

Sodium chloride Fludrocortisone (Florinef)

1 g/meal 0.1-0.3 mg/day

Midodrine (ProAmatine) Yohimbine (Yocon) Indomethacin (Indocin) † L-Dihydroxyphenyl serine (DOPS)

5-10 mg* 5.4 mg* 25 mg

Nausea, diarrhea Hypokalemia, congestive heart failure, supine hypertension Scalp itching, goose bumps Nervousness, tremor Gastrointestinal discomfort, peptic ulcer Supine hypertension

Please refer to more detailed sources for complete list of side effects and contraindications. *A dose of these short-acting pressor agents, given before exertion, improves orthostatic symptoms for 2-3 hours. In general, administration of >3 doses/day is discouraged, to avoid side effects and development of tolerance. † Available only in Japan.

about 15 minutes before getting out of bed in the morning, when symptoms are at their worst.

Pharmacological Therapy In addition to nonpharmacological therapy, severely affected patients usually require the use of drugs. The goal of treatment is to minimize symptoms rather than to normalize an upright blood pressure. Therapy is often initiated with fludrocortisone acetate at a low dose (0.1 mg/day) and increased slowly up to 0.3 mg/day if needed.30 As an indication that volume expansion has occurred, a weight gain of 1 to 2 kg and mild ankle edema may be desirable in these patients. However, hypokalemia, supine hypertension, and pulmonary edema may occur, and patients must be monitored carefully. Fludrocortisone is not effective unless it is given in conjunction with increased salt intake (e.g., sodium chloride tablets, 1 g with meals), because its pressor effect is dependent on its ability to enhance renal sodium retention. A common mistake is to increase the dose of fludrocortisone without ensuring that patients have adequate salt supplementation. Fludrocortisone worsens supine hypertension, and its long-term safety in patients suffering from supine hypertension is not known. Patients with autonomic failure who receive fludrocortisone have target organ damage in the form of left ventricular hypertrophy, similar to that in patients with chronic arterial hypertension.31 Most patients with severe autonomic impairment also require short-acting pressor agents also cite Jordan et al., (1998).32 The goal in prescribing these drugs is to provide patients with periods when they can remain upright, rather than to try to keep severely afflicted patients symptom free throughout the day. Most of the agents listed in Table 28–4, if effective in a given patient, increase blood pressure for 2 to 3 hours. In general, these agents are best given before periods of exertion as needed, rather than at fixed (e.g., three-times-a-day) intervals. This approach may reduce the likelihood of side effects and the development of tolerance that reduces their long-term efficacy.33 Patients should also avoid lying down for 4 to 5 hours after taking these drugs, to prevent supine hypertension. These drugs have negligible effects in healthy subjects; the increase in blood pressure seen in patients with autonomic failure is a reflection of their extreme hypersensitivity to most pressor and depressor agents.34 For this reason, treatment should be started at very small doses and should be individualized. This is best done by measuring blood pressure at intervals

T A B L E 28–4. Stepwise Approach to Treat Supine Hypertension Education and Avoidance Instruct the patient about over-the-counter medication with pressor effects Avoid fluid intake at bedtime Avoid using elastic stocking when supine Avoid the use of pressor agents before bedtime Nonpharmacological Measures Raise the head of the bed by 6-9 inches Recommend rest on a semirecumbent chair with feet on floor during the day Encourage snack consumption before bedtime Allow minimal alcohol consumption before bedtime Pharmacological Measures Nitrates, transdermal nitroglycerin (0.1-0.2 mg/hour) Hydralazine (50 mg) Short-acting calcium blocker, nifedipine (10-30 mg) Minoxidil (2.5 mg) Clonidine (0.1 mg), early in the evening

for 2 to 3 hours after administration of the first dose of each drug. L-Threo-dihydroxyphenyl serine (the biologically active stereoisomer of the amino acid 3,4-dihydroxyphenyl serine) is a precursor of norepinephrine that has shown promise in the treatment of orthostatic hypotension in small clinical trials.35

Treatment of Related Conditions Autonomic failure can be associated with low-production anemia and inappropriately low serum erythropoietin levels. If other causes of anemia are ruled out, patients can be treated with recombinant erythropoietin (25 to 50 U/kg subcutaneously three times per week). Erythropoietin has been shown to improve upright blood pressure,36,37 and its use may be warranted for this reason alone, rather than as a treatment for anemia. Many patients may also have supine hypertension resulting from preexisting essential hypertension or as part of autonomic failure.38 In occasional patients, significant hypertension may be present even in the seated position. During the day, supine hypertension is best managed by simply avoiding the supine position. At night, it is necessary for many patients to take vasodilators at bedtime, after which they should be advised against getting up during the night without assistance.

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Hydralazine hydrochloride (25 to 100 mg) and low doses of nitrates as transdermal preparations (e.g., Nitro-Dur, 0.1 mg/hour, applied at bedtime and removed on arising) or short-acting calcium channel blockers (e.g., nifedipine, 10 mg) are often useful. A stepwise approach to the management of supine hypertension in the setting of orthostatic hypotension is included in Table 28–3 and discussed in detail elsewhere.39

K E Y

P O I N T S

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The autonomic nervous system is crucial for the regulation of blood pressure in general and for maintaining orthostatic hemodynamics in particular. Disorders associated with autonomic impairment are often characterized by disabling orthostatic hypotension.

●

Systemic illnesses producing peripheral neuropathy can cause secondary autonomic failure. Primary autonomic failure is caused by neurodegenerative disorders with neuronal or glial deposits of α-synuclein, including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure, and multiple-system atrophy (Shy-Drager syndrome).

●

Subacute onset of autonomic failure and rapid progression can be caused by an autoimmune autonomic disorder or may be a paraneoplastic syndrome.

●

The hallmark of autonomic failure is profound orthostatic hypotension without an appropriate compensatory increase in heart rate. Autonomic function tests are usually confirmatory, but the differential diagnosis can be challenging.

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There is currently no treatment to cure or delay the progression of disease. Symptomatic treatment of orthostatic hypotension is often successful and relies on a combination of nonpharmacological measures, blood and plasma volume enhancement, and short-acting pressor agents taken before upright activity rather than at fixed intervals.

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About half of the patients with autonomic failure paradoxically develop supine hypertension, which is managed during the day by simply avoiding the supine posture but may necessitate pharmacological treatment during the night.

Suggested Reading Freeman R: Autonomic peripheral neuropathy. Lancet 2005; 365:1259-1270. Jordan J, Shannon JR, Biaggioni I, et al: Contrasting actions of pressor agents in severe autonomic failure. Am J Med 1998; 105:116-124. Jordan J, Shannon JR, Grogan E, et al: A potent pressor response elicited by drinking water. Lancet 1999; 353:723. Shibao C, Gamboa A, Diedrich A, et al: Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension 2005; 45:469-476. Wright RA, Kaufmann H, Perera R, et al: A double-blind, doseresponse study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124.

References 1. Zambrasky E, DiBona G, Kaloyanides G: Specificity of neural effect on renal tubular sodium reabsorption. Proc Soc Exp Biol Med 1976. 151:543-546. 2. Ganong W, Reid I: Role of the sympathetic nervous system and central alpha and beta adrenergic receptors in regulation of renin secretion. In Onesti G, ed: Regulation of Blood Pressure by Central Nervous System. New York: Grune & Stratton, 1976, pp 261-273. 3. Segar W, Moore W: The regulation of antidiuretic hormone release in man. Effects of change in position and ambient temperature on blood ADH levels. J Clin Invest 1968; 47:21432151. 4. Leimbach WN Jr, Schmid PG, Mark AL: Baroreflex control of plasma arginine vasopressin in humans. Am J Physiol 1984 Oct; 247(4 Pt 2):H638-44. 5. Altura BM, Altura BT: Vascular smooth muscle and neurohypophyseal hormones. Fed Proc 1977; 36:1853-1860. 6. Jard S: Vasopressin receptors. In Czernichow P, Robinson A, eds: Diabetes Insipidus in Man. Basel: S. Karger, 1985, pp 89104. 7. de Bold AJ, Borenstein HB, Veress AT, et al: A rapid and potent natriuretic response to intravenous injections of atrial myocardial extract in rats. Life Sci 1981; 28:89-94. 8. Ledsome J, Wilson N, Courneya CA, et al: Release of atrial natriuretic peptide by atrial distension. Can J Physiol Pharmacol 1985; 63:739-742. 9. Garcia J, Thibault G, Cantin M, et al: Effect of a purified atrial natriuretic factor on rat and rabbit vascular strips and vascular beds. Am J Physiol 1984; 247:R34-R39. 10. Atarashi K, Mulrow PJ, Franco-Saenz R, et al: Inhibition of aldosterone production by an atrial extract. Science 1984; 224:992-994. 11. Kaufmann H, Oribe E, Pierotti AR, et al: Atrial natriuretic factor in human autonomic failure. Neurology 1990; 40:11151119. 12. Yanagisawa M, Kurihara H, Kimura S: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332:411-415. 13. Vane JR, Anggard EE, Botting RM: Regulatory functions of the vascular endothelium. N Engl J Med 1990; 323:27-36. 14. Yoshizawa T, Shinmi O, Giaid A, et al: Endothelin: a novel peptide in the posterior pituitary system. Science 1990; 247:462-464. 15. Kaufmann H, Oribe E, Oliver JA: Plasma endothelin during upright tilt: relevance for orthostatic hypotension? Lancet 1991; 338:1542-1545. 16. Kaufmann H: Syncope. A neurologist’s viewpoint. Cardiol Clin 1997; 15:177-194. 17. Horowitz DR, Kaufmann H: Autoregulatory cerebral vasodilation occurs during orthostatic hypotension in patients with primary autonomic failure. Clin Auton Res 2001; 11:363-367. 18. Kaufmann H: Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res 1996; 6(2):125-126. 19. Robertson D, Haile V, Perry SE, et al: Dopamine betahydroxylase deficiency. A genetic disorder of cardiovascular regulation. Hypertension 1991; 18:1-8. 20. Kaufmann H, Biaggioni I: Autonomic failure in neurodegenerative disorders. Semin Neurol 2003; 23:351-363. 21. Gilman S, Low P, Quinn N, et al: Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res 1998; 8(6):359-362. 22. Vernino S, Adamski J, Kryzer TJ, et al: Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 1998; 50:1806-1813.

chapter 28 orthostatic hypotension 23. Klein CM, Vernino S, Lennon VA, et al: The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003; 53:752-758. 24. Freeman R: Autonomic peripheral neuropathy. Lancet 2005; 365:1259-1270. 25. Winkler AS, Dean A, Hu M, et al: Phenotypic and neuropathologic heterogeneity of anti-Hu antibody- related paraneoplastic syndrome presenting with progressive dysautonomia: report of two cases. Clin Auton Res 2001; 11(2):115-118. 26. Kaufmann H: Treatment of patients with orthostatic hypotension and syncope. Clin Neuropharmacol 2002; 25:133141. 27. Diedrich A, Biaggioni I: Segmental orthostatic fluid shifts. Clin Auton Res 2004; 14(3):146-147. 28. Smit AA, Wieling W, Fujimura J, et al: Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction. Clin Auton Res 2004; 14(3):167175. 29. Jordan J, Shannon JR, Grogan E, et al: A potent pressor response elicited by drinking water [Letter]. Lancet 1999; 353:723. 30. Hickler R: Successful treatment of orthostatic hypotension with 9-alpha fluorohydrocortisone. N Eng J Med 1959; 261:788-791. 31. Vagaonescu TD, Saadia D, Tuhrim S, et al: Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet 2000; 355:725-726.

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32. Kaufmann H, Brannan T, Krakoff L, et al: Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology 1988; 38:951-956. 33. Wright RA, Kaufmann HC, Perera R, et al: A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124. 34. Jordan J, Shannon JR, Biaggioni I, et al: Contrasting actions of pressor agents in severe autonomic failure. Am J Med 1998; 105:116-124. 35. Kaufmann H, Saadia D, Voustianiouk A, et al: Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 2003; 108:724-728. 36. Biaggioni I, Robertson D, Krantz S, et al: The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994; 121:181-186. 37. Perera R, Isola L, Kaufmann H: Erythropoietin improves orthostatic hypotension in primary autonomic failure. Neurology 1994; 44(Suppl 2):A363. 38. Shannon JR, Jordan J, Diedrich A, et al: Sympathetically mediated hypertension in autonomic failure. Circulation 2000; 101:2710-2715. 39. Shibao C, Gamboa A, Diedrich A, et al: Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension 2005; 45:469-476. 40. Hainsworth R: Pathophysiology of syncope. Clin Auton Res 2004; 14(Suppl 1):18-24.

CHAPTER

29

BLADDER

AND SEXUAL FUNCTION AND DYSFUNCTION ●

●

●

●

Ronald F. Pfeiffer

The autonomic nervous system is sometimes perceived by neurologists as a somewhat mysterious, even miasmic, component of the nervous system. Consequently, when autonomic dysfunction accompanies a neurological disease process, neurologists often are reluctant to discuss the autonomic symptoms with their patients or to initiate specific evaluation or treatment, preferring to cede this to specialists in other disciplines such as cardiology, gastroenterology, and urology. However, autonomic dysfunction is an integral component of a number of neurological disease processes routinely managed by neurologists, and if attention to and assessment of autonomic dysfunction are inadequate, treatment of the disease and management of the patient may be inadequate. In this chapter, bladder and sexual dysfunction are addressed with the intent of providing practical information for the practicing neurologist.

BLADDER FUNCTION At a basic level, the bladder has two primary functions. First, it serves as an expandable storage vessel, collecting urine produced by the kidneys. Most of its time is spent in this storage mode. The second function of the bladder is to actively contract and eliminate the stored urine, typically at socially acceptable times that are consciously determined by the individual. To achieve these functions, a fine-tuned and well-orchestrated symphony of actions involving the urethral sphincter, bladder, peripheral nerves, spinal cord, brainstem, and cerebral centers must take place. Damage to any portion of this interconnected system can result in urinary dysfunction.

Brainstem Direct motor control of bladder function resides in the pons. The pontine micturition center, identified by Barrington in 19258,9 and now bearing his name, lies in the medial dorsal pons. Stimulation of this nucleus has the dual effect of producing both contraction of the detrusor muscle and relaxation of the urethral sphincter, the latter via inhibition of Onuf’s nucleus in the sacral spinal cord, with consequent micturition.10 A second, more lateral pontine region appears to tonically stimulate Onuf’s nucleus and to thus prevent micturition by inhibiting detrusor contraction and urethral relaxation.11 Sensory information regarding the state of bladder filling does not appear to come directly to these two pontine centers; rather, its path is coordinated through neurons in the periaqueductal grey matter in the mesencephalon.2,12

Neuroanatomy and Neurophysiology

Spinal Cord and Peripheral Nerves

Cortex

Control of bladder function at the spinal cord level is dependent on both autonomic and somatic mechanisms. Parasympathetic signals reach the bladder detrusor smooth muscle via pelvic nerves that originate in the intermediolateral column of the sacral cord at the S2-S4 levels, whereas sympathetic input arises from T11-L2 spinal cord levels and arrives at the smooth muscle of the bladder neck and urethra through the hypogastric nerves. The striated muscle of the urethral sphincter is innervated by a specialized group of anterior horn cells at the S2-S4 cord levels, first described by Onufrowicz in 1899 and

There is a tendency to focus on the spinal cord and sacral nerves when bladder function is assessed, but cortical and brainstem centers play active and very important roles in the control of bladder function.1,2 Early information regarding cerebral control of voiding was collected in studies of individuals with structural brain lesions.3-5 These studies demonstrated that lesions in the anterior frontal lobe may produce disturbances in bladder control. Affected individuals were noted to experi-

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ence severe, precipitous urgency without prior sensation of bladder fullness, but coordination of detrusor and sphincter muscle function during micturition remained normal. Studies of individuals after stroke have also implicated the anteromedial frontal lobe and its descending pathway, along with the basal ganglia in the production of urinary dysfunction.6 More recent elegant neuroimaging studies with single photon emission computed tomography (SPECT), positron emission tomography, and functional magnetic resonance imaging have revealed a more detailed pattern of a complex array of cortical centers involved with voluntary regulation and control of bladder function, including not only frontal cortex but also the cingulate cortex, parietal cortex, basal ganglia, hypothalamus, and even the cerebellum.2,7

chapter 29 bladder and sexual function and dysfunction now called Onuf’s nucleus.13 Their axons travel in the pudendal nerves to reach the sphincter. Parasympathetic stimulation results in contraction of the detrusor muscle (mediated by acetylcholine) and relaxation of urethral smooth muscle (mediated by nitric oxide) with the net result of micturition.14,15 Sympathetic stimulation has the opposite effect. Stimulation of Onuf’s nucleus produces contraction of the striated urethral sphincter.16 Sensory information from the bladder is transmitted by several different types of neurons.16,17 Small, unmyelinated, mechanosensitive Aδ fibers have a low activation threshold and are the principal conduit for transmitting information regarding the degree of bladder filling. Nociceptive, unmyelinated C fibers respond primarily to noxious stimuli rather than bladder distension. Finally, somatic afferents from the urethra transmit information regarding imminence of micturition.

BLADDER DYSFUNCTION A normally functioning bladder can expand to hold 400 to 500 mL of urine before detrusor contraction is triggered and bladder pressure increases, producing a sense of the need to void.14 Damage to the nervous system can produce three basic patterns of neurogenic bladder dysfunction, described in Table 29–1. As already noted, lesions affecting cerebral centers, both cortical and subcortical, may remove inhibitory influences on bladder function with consequent development of detrusor contractions at bladder volumes smaller than normal but without disturbing the coordinated contraction and relaxation of the detrusor and sphincter muscles. This has been labeled detrusor hyperreflexia, or neurogenic detrusor overactivity,18 and may prompt urinary frequency, often accompanied by a sense of urgency, that can lead to incontinence. In contrast, lesions involving neurons in the sacral cord or processes that damage the peripheral nerves emanating from this cord level result in reduced detrusor activity, with subsequent reduced urinary frequency and excessive bladder filling. The term hyporeflexic bladder is sometimes applied to this situation. This can also lead to incontinence, but of the overflow type. Lesions of the suprasacral spinal cord, by severing communication between pontine and sacral centers, may result in a loss of the normal coordinated reciprocal actions of the detrusor and sphincter muscles so that they contract simultaneously, producing a combination of increased pressure within the bladder and increased resistance to urine outflow from the bladder. This is called detrusor-sphincter dyssynergia. Obstruction of urine outflow from the bladder is usually caused by nonneurological processes (prostatic hypertrophy is an example), but on occasion, dystonic contractions of the urethral sphincter can cause similar difficulty in the setting of neurological disease. Symptoms of obstruction include hesitancy in initiating micturition, reduced urine flow, and dribbling.

T A B L E 29–1.

Patterns of Neurogenic Bladder Dysfunction

Detrusor overactivity (detrusor hyperreflexia) Detrusor underactivity (detrusor hyporeflexia) Detrusor-sphincter dyssynergia

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Diagnostic Tests Although diagnostic testing of bladder function is usually performed by a urologist, it is important for neurologists to be familiar with the types of testing employed and the significance of the findings. Therefore, several of the most frequently used tests are discussed briefly as follows (Table 29–2).

Urodynamic Testing Urodynamic testing actually entails a battery of tests, the exact complement of which can vary from urologist to urologist. Uroflowmetry is a screening study in which the patient urinates into a receptacle that measures the rate at which urine is voided. A urine flow curve is generated, and a variety of measurements, including mean and maximum flow rates, can be calculated. The normal flow curve has an unbroken bell shape, whereas obstructive lesions produce flattening and elongation of the curve. The flow curve in individuals with detrusorsphincter dyssynergia is characterized by intermittent, discontinuous flow.19 Cystometry measures detrusor pressure during both bladder filling and voiding. After catheterization, the bladder is filled at a set rate, while intravesical pressure and rectal pressure (as a measure of abdominal pressure) are continuously recorded. This recording is called a cystometrogram. Detrusor pressure is calculated by subtracting the abdominal (rectal) pressure from the intravesical pressure. In a normally functioning bladder, detrusor compliance allows filling of the bladder without a significant rise in detrusor pressure. Hyperreflexic detrusor muscle contractions produce rises in pressure that occur suddenly and involuntarily as the bladder is filling. If the pressure produced by the hyperreflexic contraction is high enough, it can overcome the urethral sphincter muscles, and incontinence ensues. If the elastic properties of the detrusor muscle and bladder wall are decreased, compliance is reduced and detrusor pressure rises as the bladder fills, triggering the need for what might be called “premature urination” before bladder filling is complete. Detrusor hyperreflexia and diminished bladder compliance reflect suprasacral neurological injury.

Electromyography Electromyography of the pelvic floor can be performed with either surface or needle electrodes. Surface electrodes are less invasive but record lower amplitude signals and are more prone to artifacts.20 The normal electromyographic sphincter pattern consists of continuous activity that ceases before detrusor contraction initiates micturition. Failure of this coordinated sphincter relaxation and detrusor contraction to occur is what constitutes detrusor-sphincter dyssynergia. Concentric needle electromyography of the urethral sphincter can also demonstrate a pattern of denervation and reinnervation. Evidence of this can be seen in structural lesions of the

T A B L E 29–2. Urodynamic testing Electromyography Ultrasonography

Diagnostic Testing of Bladder Function

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cauda equina and in degenerative processes that involve Onuf’s nucleus, such as multiple-system atrophy (MSA). Additional, more detailed, clinical neurophysiological testing can also be performed at specialized centers.20

Bladder Ultrasonography The measurement of the amount of urine remaining in the bladder after voiding can be accomplished noninvasively by means of ultrasonography. A postvoid residual amount of greater than 100 mL is considered abnormal.

Specific Neurological Diseases Stroke Bladder dysfunction after stroke is frequently described, although specific data about incidence are difficult to pinpoint.21 In a review of the topic of stroke and incontinence, Brittain and colleagues22 noted that in various studies, incontinence on hospital admission had been described in 32% to 79% of stroke patients and was still present in 25% to 28% at the time of discharge. Problems with incontinence persisted in 12% to 19% even months after discharge. The pattern of urinary difficulty differs between patients with hemispheric stroke and those with lesions in the brainstem. In individuals with hemispheric stroke, Sakakibara and colleagues6 documented nocturnal urinary frequency in 36%, urge incontinence in 29%, and difficulty voiding in 25%. Urinary symptoms were more frequent in persons with frontal lobe infarcts. Urodynamic testing in symptomatic patients demonstrated detrusor hyperreflexia in 68%, detrusorsphincter dyssynergia in 14%, and uninhibited sphincter relaxation in 36%. In a different group of patients after acute brainstem stroke, urodynamic studies showed detrusor hyperreflexia in 73%, low compliance bladder in 9%, atonic bladder in 27%, detrusorsphincter dyssynergia in 45%, and uninhibited sphincter relaxation in 27%.23 Lesions producing bladder dysfunction involved either the dorsolateral or medial pons. Thus, as expected, patients with stroke, whether hemispheric or brainstem, experience predominantly overactive or irritable bladder symptoms, although obstructive symptoms, including urinary retention, may also develop.23,24 Large infarct size, aphasia, cognitive impairment, and functional disability are associated with increased risk of urinary incontinence after stroke.25 Multiple infarcts, especially if bilateral, also predispose to urinary abnormalities after stroke.26 Because of the variability in urinary dysfunction that may appear after a stroke, urodynamic testing is invaluable in documenting the specific nature of the dysfunction. Specific treatment can then be tailored to the documented deficit.

Parkinson’s Disease Urinary symptoms are a frequent source of difficulty for individuals with Parkinson’s disease. Reported frequencies of urinary dysfunction in Parkinson’s disease show considerable variability, ranging from 36% to 90%.27-30 Hobson and colleagues,29 comparing a community-based sample of patients with Parkinson’s disease with a similar-aged healthy elderly control group,

discovered that the relative risk for bladder symptoms in the group with Parkinson’s disease was more than twice that of the control group. Some27,28,31-33 but not all29 studies have found a correlation between disease duration and severity and the presence of urinary symptoms. Irritative symptoms, such as frequency, urgency, and nocturia, are most common,27,28,30,34,35 but obstructive symptoms may also be reported. The most frequent finding on urodynamic testing in individuals with Parkinson’s disease is detrusor hyperreflexia. Studies have revealed detrusor hyperreflexia to be present in 45% to 100% of urologically symptomatic patients with Parkinson’s disease.33-36 It is important to remember, however, that obstructive uropathies, such as prostatic hypertrophy, can be superimposed on detrusor hyperreflexia. In these instances, urodynamic testing can be especially helpful. Urethral sphincter dysfunction may also develop in patients with Parkinson’s disease. Delayed relaxation of the sphincter on initiation of voiding, termed sphincter bradykinesia, has been reported in 11% to 42% of such patients.32,35,37 This phenomenon may create an obstructive pattern, characterized by a reduced flow rate. Inability to relax the perineal muscles on initiation of micturition has also been identified in the setting of Parkinson’s disease.38 The role of dopaminergic mechanisms in the production of urinary dysfunction in Parkinson’s disease has been the focus of research interest. In rats with unilateral 6-hydroxydopamine–induced lesions of the nigrostriatal pathway, bladder capacity was documented to be reduced and could be increased with administration of the dopamine D1/D5 receptor agonist SKF38393.39 In contrast, a D2/D3/D4 receptor agonist, quinpirole, reduced bladder capacity. In monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, the same pattern was evident in that the D2 agonist bromocriptine excited the micturition reflex, whereas the mixed D1/D2 agonist pergolide inhibited the reflex.40 Improvement in urinary symptoms has also been reported in humans whose treatment switched from bromocriptine to pergolide.41

Multiple-System Atrophy Autonomic dysfunction is one of the basic clinical features of MSA. Orthostatic hypotension and genitourinary dysfunction are especially likely to develop. In contrast to Parkinson’s disease, urinary dysfunction in MSA tends to develop earlier in the course of the disease process, sometimes appearing even before the motor features31,42; it is also more pervasively present. In a study by Stocchi and colleagues,38 100% of patients with MSA demonstrated some abnormality on urodynamic testing, whereas abnormalities were noted in only 63% of subjects with Parkinson’s disease. Urodynamic studies can be very useful in characterizing the nature of bladder dysfunction in MSA.43 A combination of detrusor hyperreflexia and impaired urethral sphincter function often produces a pattern of prominent urinary frequency and urgency, often accompanied by urge incontinence. Although this can also occur in Parkinson’s disease, it is typically a feature of only advanced Parkinson’s disease, whereas it can develop much earlier in the course of MSA. Urinary retention is also considerably more common in MSA than in Parkinson’s disease.31,44 Differentiating individuals with MSA from those with Parkinson’s disease is of very practical importance from the

chapter 29 bladder and sexual function and dysfunction urological standpoint, because patients with MSA who undergo surgery for prostatic hypertrophy are at especially high risk for developing urinary incontinence as a complication of the procedure. Thus, medical management is preferable to surgical management of prostatic hypertrophy in individuals with MSA.31

Multiple Sclerosis Symptoms of autonomic dysfunction may be present in almost 80% of patients with multiple sclerosis.45 Urinary symptoms are the most common, present in 65% of the 63 patients evaluated by McDougall and McLeod. In their study, urgency and frequency were especially common, and urinary incontinence was reported by more than 30% of patients. Detrusor-sphincter dyssynergia, as a consequence of spinal cord involvement, is the most common urodynamic finding in multiple sclerosis, reported in 15% to 20% of affected individuals.46 However, because multiple sclerosis can affect all levels of the central nervous system, some patients show evidence of detrusor hyperreflexia as a result of involvement of suprapontine cerebral pathways.46 Impaired voiding with hesitancy, interrupted urinary flow, and incomplete voiding can also be present.47 Urinary symptoms increase in frequency and severity in tandem with disease severity and duration.48-50 They are most evident in individuals with secondary progressive multiple sclerosis.45

Spinal Cord Injury The characteristics of urinary dysfunction after spinal cord injury depend on the timing of the injury and its location. During the period of spinal shock immediately after the trauma, reflexes below the level of the lesion are lost, including those associated with micturition. Detrusor areflexia with urinary retention is typically present. The duration of the spinal shock phase is variable; it may be present for only hours or may persist for weeks or even months. As spinal shock resolves, urinary function evolves into a pattern that reflects the level of the spinal cord injury. Detrusor hyperreflexia develops in individuals with suprasacral cord lesions. Because spinal cord injuries are typically labeled by the level of the vertebral bodies injured, it is important to remember that the spinal cord actually ends at the L1-L2 vertebral level. Therefore, lesions above a T10 vertebral level evolve into a pattern of detrusor hyperreflexia or detrusorsphincter dyssynergia, whereas the detrusor remains hyporeflexic with lesions below L2. If the injury is at vertebral levels T10-L2, either hyperreflexic or hyporeflexic bladder function may develop.51 If the spinal cord injury is complete in lesions above the T10 vertebral level, detrusor-sphincter dyssynergia is almost always present; with incomplete lesions, a pattern of detrusor hyperreflexia with maintained coordination of sphincter function is typically seen.52,53 Urodynamic testing is particularly valuable in assessing bladder function in patients with spinal cord injury at the thoracolumbar junction.54 When the vertebral injury is at the level of L2 or below, detrusor areflexia persists even after resolution of the period of spinal shock. The absence of detrusor function can be coupled with either intact sphincter function or with sphincter nonrelaxation.52

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Treatment of Urinary Dysfunction The treatment employed for urinary dysfunction depends on the character of the dysfunction that is present. Because treatment approaches to an overactive bladder are vastly different from those used in treating an areflexic bladder, it is vital that a correct assessment of the type of dysfunction present be made. This is not always readily apparent by clinical history and examination alone, inasmuch as incontinence can occur in both settings. Moreover, patients may display a combination of both types of dysfunction. Therefore, urodynamic testing can provide invaluable information and guidance in formulating treatment plans.

Neurogenic Detrusor Overactivity Anticholinergic drugs have long been, and still remain, the standard treatment for detrusor overactivity (Table 29–3). Their effects are mediated via blockade of muscarinic cholinergic receptors located on the detrusor muscle. Although muscarinic receptors in human detrusor muscle are primarily of the M2 and M3 subtypes, older anticholinergic drugs are generally nonselective and block all five muscarinic receptor subtypes.55 Numerous adverse effects of these drugs, such as dry mouth and cognitive impairment, are the consequence of this nonselective blockade. Although still older anticholinergic drugs, such as hyoscyamine, atropine, propantheline, and flavoxate, are still occasionally used, oxybutynin and tolterodine have been the mainstays of treatment for a number of years. Both immediate- and extended-release preparations of these two drugs are available; oxybutynin is also available in a transdermal patch preparation. Oxybutynin is reported to have a higher propensity to produce central nervous system toxicity than does tolterodine, presumably because it crosses the blood-brain barrier more readily.56 The antimuscarinic armamentarium has expanded considerably with the introduction of trospium,57 solifenacin,58,59 and darifenacin.60 Trospium binds to M1, M2, and

T A B L E 29–3. Treatment of Neurogenic Detrusor Overactivity Anticholinergic Drugs Older, nonselective Atropine Hyoscyamine Propantheline Flavoxate Newer, nonselective Oxybutynin Tolterodine Newer, selective Trospium Solifenacin Darifenacin Other Oral Drugs Gabapentin Desmopressin Other Approaches Capsaicin (intravesical) Resiniferatoxin (intravesical) Botulinum toxin (injection) Vesical pacing

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M3 receptors but does not cross the blood-brain barrier, whereas solifenacin and darifenacin are selective M3 receptor antagonists. These characteristics should diminish toxicity, but at increased expense. In individuals who have not responded to or have been intolerant of antimuscarinic drugs, various other experimental treatment approaches have been tried. Gabapentin has been reported to improve symptoms of overactive bladder.61 Desmopressin has also been employed as a means to reduce nocturia in individuals in whom anticholinergic drugs alone have not been adequate.47,62 A more radical treatment approach has been the intravesical instillation of drugs. Both capsaicin and resiniferatoxin have been used in this manner.47 Resiniferatoxin is a capsaicin analogue, derived from the Euphorbia species (Euphorbia resinifera) of cactus found in Morocco, and is 1000 times more potent than capsaicin.63 These compounds are presumed to act by means of their toxic effects on nonmyelinated C fiber afferent nerves.47,63,64 Botulinum toxin injections into the detrusor muscle under cystoscopic guidance have also been used successfully in treating detrusor overactivity.65,66 Vesical pacing has also been reported to be useful.67 Surgical treatment is rarely indicated.

Detrusor-Sphincter Dyssynergia In individuals with detrusor-sphincter dyssynergia, two problems must be attacked simultaneously. Anticholinergic drugs can reduce detrusor overactivity, but the failure of the urethral sphincter to relax during voiding must be addressed by other means. Intermittent self-catheterization remains the standard treatment approach for this problem,47 although botulinum toxin injections into the urethral sphincter have also been used.66 Incontinence is a potential complication of sphincter injections, but its incidence is low.66

Acontractile or Hypoactive Detrusor There really is no effective medical treatment for incomplete bladder emptying that results from an underactive or acontractile detrusor muscle. Intermittent self-catheterization is the best treatment option in this situation.47 If selfcatheterization is not possible, an indwelling catheter can be placed, but this increases the risk for recurrent urinary tract infections, bladder calculi, and urethral injury.47

SEXUAL FUNCTION Sexual function is a complex activity in which physiological and psychological aspects are inextricably intertwined. The psychological sphere, encompassing libido, is largely uncharted territory from an anatomical and physiological standpoint, whereas the physiological components of sexual function, such as erection, lubrication, ejaculation, and orgasm, have been more readily amenable to scientific inquiry. Considerably more attention has been focused on sexual function and dysfunction in men than in women, at least in part because of the greater ease in observing and quantifying many aspects of sexual functioning in men. Most neurologists are loathe to discuss sexual dysfunction with their patients even more than to discuss bladder dysfunction, but as with bladder dysfunction, sexual dysfunction is an integral component of the clinical pattern of a

considerable number of neurological disease processes, and familiarity with the features of this dysfunction is important for optimal patient care.

Neuroanatomy and Neurophysiology Cerebrum Although the cerebral cortex is presumed to be active in the realm of sexual desire, or libido, little is known about actual cortical localization of sexual function. Parasagittal primary sensory cortex receives sensory input from the genitalia, and the limbic cortex appears to play a role in sexual desire and behavior.68 Right frontal lobe activation during ejaculation has been identified in one study in which SPECT imaging was used.69 Additional evidence for frontal lobe involvement in sexual function comes from alterations in behavior, including sexual behavior, that have been observed in individuals with frontal lobe lesions.68 Temporal lobe dysfunction, especially in the setting of epilepsy, has also been implicated as a source of sexual dysfunction in both male and female patients; hypersexuality is occasionally seen, but sexual apathy is much more common.70,71 Hypothalamic involvement in sexual function and behavior has been clearly delineated. Hypothalamic injury can lead to a loss of sexual desire, as can occur in persons with pituitary tumors.68,72,73

Spinal Cord and Peripheral Nerves As with many aspects of sexual function, more detailed information regarding neuroanatomical and neurophysiological pathways and function is available for male patients than for female patients. Two distinct pathways have been identified for erectile function: psychogenic and reflexogenic. Psychogenic erections are triggered by visual or auditory stimuli or by fantasy thinking, whereas reflexogenic erections are induced by genital stimulation.74 Intact spinal cord pathways are necessary for psychogenic erections, whereas reflexogenic erections are mediated through the sacral spinal cord at the S2-S4 levels. The afferent pathway for reflexogenic erection is via the pudendal nerve; the efferent limb, through pelvic parasympathetic fibers. Thus, parasympathetic pathways are operative primarily in the generation of penile erection, although sympathetic function plays a role in psychogenic erection and also in detumescence.74 Ejaculation is a phenomenon separate from erection and involves parasympathetic, sympathetic, and somatic contributions.74 Parasympathetic fibers produce secretion by accessory glands during arousal; sympathetic fibers are responsible for producing bladder neck closure and contraction of smooth muscle within the seminal vesicles; somatic fibers induce actual ejaculation by triggering contraction of the bulbocavernosus and ischiocavernosus muscles.74,75

Diagnostic Tests Diagnostic testing for sexual dysfunction is more limited than that available for urological dysfunction, and it is limited primarily to the evaluation of erectile dysfunction (Table 29–4). Tests of both neurogenic and vascular integrity have been developed; vascular testing is not discussed here.

chapter 29 bladder and sexual function and dysfunction T A B L E 29–4. Diagnostic Testing of Sexual Function Nocturnal penile tumescence testing Sacral reflex testing Pudendal evoked responses

Nocturnal Penile Tumescence Testing Nocturnal penile tumescence testing has been used in the past as a means of separating neurogenic from psychogenic erectile dysfunction.76 If an individual with erectile dysfunction was documented to attain a full erection while sleeping, a psychogenic basis for the erectile dysfunction was presumed to be present. However, it has been recognized more recently that such test results can be unreliable and even misleading.77,78

Sacral Reflex Testing The bulbocavernosus reflex is the most frequently used sacral reflex test and typically involves electrical stimulation of the dorsal penile nerve with recording of the subsequent motor response in the bulbocavernosus muscle.20 Both the afferent and efferent responses of this reflex travel via the pudendal nerve. In patients with sacral cord (S2-S4) lesions or pudendal nerve lesions, latency of this reflex may be prolonged, or the reflex may be absent altogether. However, the sensitivity of this test is less than optimal,77 and its value in evaluating erectile dysfunction has been questioned.79

Pudendal Evoked Responses The pudendal somatosensory evoked potential is elicited by electrically stimulating the dorsal penile nerve and recording from the cerebrum.20 Latency may be prolonged in persons with spinal cord abnormalities, but the sensitivity and specificity of the test have been questioned, and its usefulness beyond the more frequently employed tibial somatosensory evoked potential testing is uncertain.77

Specific Neurological Diseases

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kibara and colleagues82 reported decreased libido in 84% of the women and 83% of the men; erectile dysfunction was present in 79% and impairment of ejaculation in 79% of the men. Other investigators have reported the presence of erectile dysfunction in 60% of individuals83 or a greater than twofold risk of developing erectile difficulty29 in men with Parkinson’s disease. Erectile dysfunction typically develops later in the course of Parkinson’s disease31; this is in sharp contrast with MSA, in which erectile dysfunction is often the initial clinical feature.84

Multiple Sclerosis Although it is rarely a presenting feature,85-87 sexual dysfunction eventually develops in the majority of persons with multiple sclerosis. More than 50% of women with multiple sclerosis experience impaired sexual functioning, including decreased libido, difficulty achieving orgasm, and reduced lubrication.88,89 Although erectile dysfunction was noted less frequently in older studies, more recent reports indicate that it is present in approximately 50% to 70% of men with multiple sclerosis.45,87 Impairment of ejaculation is also common in men with multiple sclerosis.90 Some86,91 but not all92 reports note a correlation between signs of pyramidal tract involvement in the legs and the presence of erectile dysfunction in men with multiple sclerosis. Sexual dysfunction in multiple sclerosis is closely associated with urinary dysfunction in both men and women.45,87

Spinal Cord Injury Erectile dysfunction can occur with both sacral and suprasacral spinal cord injury, but differences between the two manifestations are often evident. Men with clinically complete sacral cord injury are unable to achieve erection with genital stimulation but may be able to do so with psychogenic stimulation.74,93 In contrast, men with suprasacral cord injury can achieve erection with genital stimulation but are usually unable to do so with psychogenic stimulation if the spinal cord injury is at a cervical or thoracic level.74,93 Analogous abnormalities have been documented in women with spinal cord injuries. In women with complete upper motor neuron lesions, impaired vaginal lubrication during sexual excitation is typically evident, whereas vaginal lubrication may occur with psychogenic stimulation in women with sacral spinal cord injuries.94

Epilepsy Sexual dysfunction is more common in individuals with epilepsy than in the general population. However, studies have shown that it is not epilepsy itself but rather the location of the lesion responsible for the epilepsy that is the determining factor. Thus, individuals with focal temporal lobe epilepsy are more likely to experience sexual dysfunction than are persons with generalized epilepsy.1,70,71,80,81 Both hypersexuality and sexual apathy may occur, although the latter is much more frequent.1,68 Genital sensations or sexual behavior can also occur as ictal phenomena.68

Parkinson’s Disease Alterations in sexual function are common in patients with Parkinson’s disease. In a survey of 115 such patients, Saka-

Treatment of Sexual Dysfunction The treatment of sexual dysfunction in persons with neurological disease processes has largely centered on the treatment of erectile dysfunction in men; little attention has been devoted to the treatment of dysfunction in women. A discussion of treatment of the psychological aspects of sexual dysfunction is beyond the scope of this chapter. The emergence of orally administered drugs that can enhance erections has revolutionized the treatment of erectile dysfunction (Table 29–5). Sildenafil, now joined by tadalafil and vardenafil, has been shown to be effective in men with spinal cord injury, multiple sclerosis, and other neurological conditions.95-98 These drugs are inhibitors of type 5 cyclic guanosine monophosphate phosphodiesterase, which via nitric

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T A B L E 29–5. Treatment of Erectile Dysfunction Cyclic Guanosine Monophosphate Phosphodiesterase Inhibitors Sildenafil Vardenafil Tadalafil Dopamine Agonists Apomorphine Intracavernosal Injections Alprostadil Moxisylyte

K E Y ●

Neurological diseases at all levels of the nervous system— from cortex to brainstem to spinal cord to peripheral nerves—can produce bladder and sexual dysfunction.

●

Lesions affecting cerebral centers produce overactivity of the detrusor muscle, but coordination between the detrusor and sphincter muscles is retained.

●

Lesions affecting the sacral cord produce reduction in detrusor activity, but coordination between the detrusor and sphincter muscles is still retained.

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Lesions affecting the suprasacral spinal cord result in loss of coordination between detrusor and sphincter muscles; this is called detrusor-sphincter dyssynergia.

●

Various medications are useful in treating overactive bladder, but intermittent catheterization remains the most effective treatment for underactive or acontractile detrusor function; a combination of both may be necessary to treat detrusor-sphincter dyssynergia.

●

Treatment for sexual dysfunction has focused largely on erectile dysfunction, and a variety of therapeutic approaches are available.

Intraurethral Instillation Alprostadil Vacuum Devices

oxide–mediated mechanisms produces smooth muscle relaxation and increases corpora cavernosa blood flow, thus enhancing penile erection.14,99 Sildenafil and related drugs are generally well tolerated, but headache, flushing, gastrointestinal upset, changes in color vision, and rhinitis may occur. Lethal adverse reactions have occurred in individuals taking nitrates concomitantly, and these drugs should be used very cautiously by persons with neurological diseases, such as Parkinson’s disease, in which orthostatic hypotension may occur. In fact, use of these drugs by persons with MSA is probably ill advised. For individuals who cannot use or tolerate sildenafil and its analogues, other treatment approaches are available. Intracavernosal injections of alprostadil and moxisylyte are effective, but the requirement for injections, which are sometimes associated with significant pain, and the potential for development of fibrotic nodules within the corpora deter many individuals from using this form of treatment.94 Priapism may also occur. Intraurethral administration of alprostadil is also available. Vacuum devices, used in conjunction with constrictor bands, are also effective in inducing penile erection, but patient acceptance of the devices is low. Dopamine agonist drugs have been shown to induce penile erection in both animals100 and humans.14,101 There is evidence that this may be caused specifically by D4 receptor–mediated activation of oxytocinergic neurons within the paraventricular nucleus of the hypothalamus.100 A sublingual apomorphine preparation has been developed for use by humans.14,101

CONCLUSION The neurologist is neither a urologist nor a gynecologist and should not expect to be the primary source of treatment for urological and sexual dysfunction that may arise in the setting of neurological disease. However, familiarity with the nature and treatment of such problems and a willingness to discuss them with patients and family members are tremendously valuable and can immeasurably enhance patient care and satisfaction. Effective treatment measures are actually available for many of these problems, but they first must be identified, and it is in identification that the neurologist, who is often the primary treating physician for patients with chronic neurological diseases, must play a role.

P O I N T S

Suggested Reading Andersson KE: Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004; 3:46-53. Apostolidis AN, Fowler CJ: Evaluation and treatment of autonomic disorders of the urogenital system. Semin Neurol 2003; 23:443452. Fowler CJ: Neurological disorders of micturition and their treatment. Brain 1999; 122:1213-1231. Fowler CJ, ed: Neurology of Bladder, Bowel and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999. Singer C: Urinary dysfunction in Parkinson’s disease. In Ebadi M, Pfeiffer RF, eds: Parkinson’s Disease. Boca Raton, FL: CRC Press, 2005, pp 275-286.

References 1. Sakakibara R, Fowler CJ: Cerebral control of bladder, bowel, and sexual function and effects of brain disease. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 229-243. 2. Athwal BS, Berkley KJ, Hussain I, et al: Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001; 124:369-377. 3. Andrew J, Nathan PW: Lesions of the anterior frontal lobes and disturbances of micturition and defaecation. Brain 1964; 87:233-262. 4. Ueki K: Disturbances of micturition observed in some patients with brain tumor. Neurol Med Chir 1960; 2:2533. 5. Maurice-Williams RS: Micturition symptoms in frontal tumours. J Neurol Neurosurg Psychiatry 1974; 37:431-436. 6. Sakakibara R, Hattori T, Yasuda K, et al: Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI. J Neurol Sci 1996; 137:47-56.

chapter 29 bladder and sexual function and dysfunction 7. Zhang H, Reitz A, Kollias S, et al: An fMRI study of the role of suprapontine brain structures in the voluntary voiding control induced by pelvic floor contraction. Neuroimage 2005; 24:174-180. 8. Barrington FJF: The relation of the hindbrain to micturition. Brain 1921; 44:23-53. 9. Barrington FJF: The effect of lesions of the hind and midbrain on micturition in the cat. Q J Exp Physiol 1925; 15:81102. 10. Holstege G, Griffiths D, de Wall H, et al: Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J Comp Neurol 1986; 250:449-461. 11. Griffiths D, Holstege G, Dalm E, et al: Control and coordination of bladder and urethral function in the brainstem of the cat. Neurourol Urodyn 1990; 9:63-82. 12. Taniguchi N, Miyata M, Yachiku S, et al: A study of micturition inducing sites in the periaqueductal gray of the mesencephalon. J Urol 2002; 168:1626-1631. 13. Onufrowicz B: Notes on the arrangement and function of the cell groups in the sacral region of the spinal cord. J Nerv Mental Dis 1899; 26:498-504. 14. Apostolidis AN, Fowler CJ: Evaluation and treatment of autonomic disorders of the urogenital system. Semin Neurol 2003; 23:443-452. 15. Lundberg JM: Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 1996; 48:113-178. 16. Yoshimura N: Bladder afferent pathway and spinal cord injury: possible mechanisms inducing hyperreflexia of the urinary bladder. Prog Neurobiol 1999; 57:583-606. 17. Fowler CJ: Bladder afferents and their role in the overactive bladder. Urology 2002; 59(5, Suppl 1):37-42. 18. Abrams P, Cardozo L, Fall M, et al: The standardization of terminology in lower urinary tract function: report from the standardization sub-committee of the International Continence Society. Urology 2003; 61:37-49. 19. Swinn MJ: Urodynamics. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 97-107. 20. Vodusˇek DB, Fowler CJ: Clinical neurophysiology. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 109-143. 21. Korpelainen JT, Sotaniemi KA, Myllyla VV: Autonomic nervous system disorders in stroke. Clin Auton Res 1999; 9:325-333. 22. Brittain KR, Peet SM, Castleden CM: Stroke and incontinence. Stroke 1998; 29:524-528. 23. Sakakibara R, Hattori T, Yasuda K, et al: Micturitional disturbance and the pontine tegmental lesion: urodynamic and MRI analyses of vascular cases. J Neurol Sci 1996; 141:105110. 24. Kong KH, Young S: Incidence and outcome of poststroke urinary retention: a prospective study. Arch Phys Med Rehabil 2000; 81:1464-1467. 25. Gelber DA, Good DC, Laven LJ, et al: Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24:378382. 26. Arena MG, Di Rosa AE, Arcudi L, et al: Voiding disorders in patients with cerebrovascular disease. Funct Neurol 1992; 7:47-49. 27. Singer C: Urological dysfunction. In Pfeiffer RF, BodisWollner I, eds: Parkinson’s Disease and Nonmotor Dysfunction. Totowa, NJ: Humana Press, 2005, pp 139-148. 28. Singer C: Urinary dysfunction in Parkinson’s disease. In Ebadi M, Pfeiffer RF, eds: Parkinson’s Disease. Boca Raton, FL: CRC Press, 2005, pp 275-286.

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29. Hobson P, Islam W, Roberts S, et al: The risk of bladder and autonomic dysfunction in a community cohort of Parkinson’s disease patients and normal controls. Parkinsonism Relat Disord 2003; 10:67-71. 30. Campos-Sousa RN, Quagliato E, da Silva BB, et al: Urinary symptoms in Parkinson’s disease. Prevalence and associated factors. Arq Neuropsiquiatr 2003; 61:359-363. 31. Chandiramani VA, Palace J, Fowler CJ: How to recognize patients with parkinsonism who should not have urological surgery. Br J Urol 1997; 80:100-104. 32. Chandiramani VA, Fowler CJ: Urogenital disorders in Parkinson’s disease and multiple system atrophy. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 245-254. 33. Araki I, Kitahara M, Oida T, et al: Voiding dysfunction in Parkinson’s disease: urodynamic abnormalities and urinary symptoms. J Urol 2000; 164:1640-1643. 34. Murnaghan GF: Neurogenic disorders of the bladder in parkinsonism. Br J Urol 1961; 33:403-409. 35. Pavlakis AJ, Siroky MB, Goldstein I, et al: Neurourologic findings in Parkinson’s disease. J Urol 1983; 129:80-83. 36. Fitzmaurice H, Fowler CJ, Rickards D, et al: Micturition disturbance in Parkinson’s disease. Br J Urol 1985; 57:652-656. 37. Galloway NTM: Urethral sphincter abnormalities in parkinsonism. Br J Urol 1983; 55:691-693. 38. Stocchi F, Carbone A, Inghilleri M, et al: Urodynamic and neurophysiological evaluation in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 1997; 62:507-511. 39. Yoshimura N, Kuno S, Chancellor MB, et al: Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Br J Pharmacol 2003; 139:1425-1432. 40. Yoshimura N, Mizuta E, Yoshida O, et al: Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine– lesioned parkinsonian cynomolgus monkeys. J Pharmacol Exp Ther 1998; 286:228-233. 41. Kuno S, Mizuta E, Yamasaki S, et al: Effects of pergolide on nocturia in Parkinson’s disease: three female cases selected from over 400 patients. Parkinsonism Relat Disord 2004; 10:181-187. 42. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:93-103. 43. Kirby R, Fowler CJ, Gosling J, et al: Urethrovesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986; 49:554-562. 44. Bonnet AM, Pichon J, Vidailhet M, et al: Urinary disturbances in striatonigral degeneration and Parkinson’s disease: clinical and urodynamic aspects. Mov Disord 1997; 12:509513. 45. McDougall AJ, McLeod JG: Autonomic nervous system function in multiple sclerosis. J Neurol Sci 2003; 215:79-85. 46. Shah DK, Badlani GH: Urological symptoms. In Voltz R, Bernat JL, Borasio GD, et al, eds: Palliative Care in Neurology. Oxford, UK: Oxford University Press, 2004, pp 262-271. 47. Fowler CJ: Neurological disorders of micturition and their treatment. Brain 1999; 122:1213-1231. 48. Nortvedt MW, Riise T, Myhr KM, et al: Reduced quality of life among multiple sclerosis patients with sexual disturbance and bladder dysfunction. Mult Scler 2001; 7:231-235. 49. Giannantoni A, Scivoletto G, Di Stasi SM, et al: Lower urinary tract dysfunction and disability status in patients with multiple sclerosis. Arch Phys Med Rehabil 1999; 80:437441. 50. Barbalius GA, Nikiforidis G, Liatsikos EN: Vesicourethral dysfunction associated with multiple sclerosis: clinical and urodynamic perspectives. J Urol 1998; 160:106-111.

370

Section

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Au to n o m i c N e rvo u s Syst e m D i s e as e s

51. Wyndaele JJ: Correlation between clinical neurological data and urodynamic function in spinal cord injured patients. Spinal Cord 1997; 35:213-216. 52. Van Kerrebroeck PEV: Lower urinary tract dysfunction in spinal cord injury. In Corazziari E, ed: Neurogastroenterology. Berlin: Walter de Gruyter, 1996, pp 289-299. 53. Kaplan SA, Chancellor MB, Blaivas J: Bladder and sphincter behavior in patients with spinal cord lesions. J Urol 1991; 146:113-117. 54. Pesce F, Castellano V, Finazzi Agro E, et al: Voiding dysfunction in patients with spinal cord lesions at the thoracolumbar vertebral junction. Spinal Cord 1997; 35:37-39. 55. Andersson KE: Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004; 3:46-53. 56. Todorova A, Vonderheid-Guth B, Dimpfel W: Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J Clin Pharmacol 2001; 41:636-644. 57. Rovner ES: Trospium chloride in the management of overactive bladder. Drugs 2004; 64:2433-2446. 58. Chilman-Blair K, Bosch JL: Solifenacin: treatment of overactive bladder. Drugs Today (Barc) 2004; 40:343-353. 59. Brunton S, Kurtizky L: Recent developments in the management of overactive bladder: focus on the efficacy and tolerability of once daily solifenacin succinate 5 mg. Curr Med Res Opin 2005; 21:71-80. 60. Cardozo L, Dixon A: Increased warning time with darifenacin: a new concept in the management of urinary urgency. J Urol 2005; 173:1214-1218. 61. Kim YT, Kwon DD, Kim J, et al: Gabapentin for overactive bladder and nocturia after anticholinergic failure. Int Braz J Urol 2004; 30:275-278. 62. Dasgupta P, Haslam C: Treatment of neurogenic bladder dysfunction. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 163-183. 63. Palma PCR, Thiel M, Riccetto CLZ, et al: Resiniferatoxin for detrusor instability refractory to anticholinergics. Int Braz J Urol 2004; 30:53-58. 64. Kuo HC: Multiple intravesical instillation of low-dose resiniferatoxin is effective in the treatment of detrusor overactivity refractory to anticholinergics. BJU Int 2005; 95:10231027. 65. Hajebrahimi S, Altaweel W, Cadoret J, et al: Efficacy of botulinum-A toxin in adults with neurogenic overactive bladder: initial results. Can J Urol 2005; 12:2543-2546. 66. Smith CP, Nishiguchi J, O’Leary M, et al: Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005; 65:37-41. 67. Shafik A, El Sibai O, Shafik AA, et al: Vesical pacing: pacing parameters required for normalization of vesical electric activity in patients with overactive bladder. Front Biosci 2004; 9:995-999. 68. Lundberg PO: Physiology of female sexual function and effect of neurologic disease. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 33-46. 69. Tiihonen J, Kuikka J, Kupila J, et al: Increase in cerebral blood flow of right prefrontal cortex in man during orgasm. Neurosci Lett 1994; 170:241-243. 70. Shukla GD, Srivastava ON, Katiyar BC: Sexual disturbances in temporal lobe epilepsy: a controlled study. Br J Psychiatry 1979; 134:288-292. 71. Blumer D, Walker AE: Sexual behavior in temporal lobe epilepsy. A study of the effects of temporal lobectomy on sexual behavior. Arch Neurol 1967; 16:37-43. 72. Hulting AL, Muhr C, Lundberg PO, et al: Prolactinomas in men: clinical characteristics and the effect of bromocriptine treatment. Acta Med Scand 1985; 217:101-109.

73. Lundberg PO, Hulter B: Sexual dysfunction in patients with hypothalamo-pituitary disorders. Exp Clin Endocrinol 1991; 98:81-88. 74. Beck RO: Physiology of male sexual function and dysfunction in neurologic disease. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 47-56. 75. Hoyle CHV, Lincoln J, Burnstock G: Neural control of pelvic organs. In Rushton DN, ed: Handbook of Neuro-Urology. New York: Marcel Dekker, 1994, pp 1-54. 76. Karacan I, Williams RL, Thornby JI, et al: Sleep-related penile tumescence as a function of age. Am J Psychiatry 1975; 132:932-937. 77. Beck RO: Investigation of male erectile dysfunction. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 145-160. 78. Schmidt MH, Schmidt HS: Sleep-related erections: neural mechanisms and clinical significance. Curr Neurol Neurosci Rep 2004; 4:170-178. 79. Nogueira MC, Herbaut AG, Wespes E: Neurophysiological investigations of two hundred men with erectile dysfunction. Interest of bulbocavernosus reflex and pudendal evoked responses. Eur Urol 1990; 18:37-41. 80. Lundberg PO: Sexual dysfunction in patients with neurological disorders. Annu Rev Sex Res 1992; 3:121-150. 81. Lundberg PO, Brattberg A: Sexual dysfunction in selected neurologic disorders: hypothalamopituitary disorders, epilepsy, myelopathies, polyneuropathies, and sacral nerve lesions. Semin Neurol 1992; 12:115-119. 82. Sakakibara R, Shinotoh H, Uchiyama T, et al: Questionnairebased assessment of pelvic organ dysfunction in Parkinson’s disease. Auton Neurosci 2001; 92:76-85. 83. Singer C, Weiner WJ, Sanchez-Ramos JR: Autonomic dysfunction in men with Parkinson’s disease. Eur Neurol 1992; 32:134-140. 84. Beck RO, Betts CD, Fowler CJ: Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol 1994; 151:1336-1341. 85. Müller R: Studies on disseminated multiple sclerosis. Acta Med Scand 1949; 222:67-71. 86. Betts CD, Jones SJ, Fowler CG, et al: Erectile dysfunction in multiple sclerosis. Associated neurological and neurophysiological deficits, and treatment of the condition. Brain 1994; 117:1303-1310. 87. Betts CD: Bladder and sexual dysfunction in multiple sclerosis. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 289308. 88. Lundberg PO: Sexual dysfunction in female patients with multiple sclerosis. Int Rehabil Med 1981; 3:32-34. 89. Hulter BM, Lundberg PO: Sexual function in women with advanced multiple sclerosis. J Neurol Neurosurg Psychiatry 1995; 59:83-86. 90. Zorzon M, Zivadinov R, Bosco A, et al: Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups. Mult Scler 1999; 5:418-427. 91. Valleroy ML, Kraft GH: Sexual dysfunction in multiple sclerosis. Arch Phys Med Rehabil 1984; 65:125-128. 92. Minderhoud JM, Leemhuis JG, Kremer J, et al: Sexual disturbances arising from multiple sclerosis. Acta Neurol Scand 1984; 70:299-306. 93. Bors E, Comarr AE: Neurological disturbance of sexual function with special reference to 529 patients with spinal cord injury. Urol Surv 1960; 10:191-222. 94. Hatzichristou DG: Treatment of sexual dysfunction and infertility in patients with neurologic diseases. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 209-225.

chapter 29 bladder and sexual function and dysfunction 95. Derry F, Hultling C, Seftel AD, et al: Efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and spinal cord injury: a review. Urology 2002; 60(2, Suppl 2):49-57. 96. Langtry HD, Markham A: Sildenafil: a review of its use in erectile dysfunction. Drugs 1999; 57:967-989. 97. Sanchez Ramos A, Vidal J, Jauregui ML, et al: Efficacy, safety and predictive factors of therapeutic success with sildenafil for erectile dysfunction in patients with different spinal cord injuries. Spinal Cord 2001; 39:637-643. 98. Doggrell SA: Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction. Expert Opin Pharmacother 2005; 6:75-84.

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99. Hallén K, Gustafsson LE, Wiklund NP. Nerve-induced release of nitric oxide from the rabbit corpus cavernosum is modulated by cyclic guanosine 3′,5′-monophosphate. Neuroscience 2005; 133:169-174. 100. Melis MR, Succu S, Mascia MS, et al: PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats. Neurosci Lett 2005; 379:59-62. 101. Montorsi F, Salonia A, Dehò F, et al: Pharmacological management of erectile dysfunction. BJU Int 2003; 91:446454.

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PRIMARY AUTONOMIC FAILURE ●

●

●

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Felix Geser and Gregor K. Wenning

CLASSIFICATION A convenient approach to the syndromes of autonomic failure is to distinguish those of the primary variety, in which there is no clear etiological factor or specific disease association, from those with secondary autonomic failure, in which the lesion is defined (anatomically, as in spinal cord injuries, or biochemically, as in dopamine β-hydroxylase deficiency) or is linked to specific disease processes (as in diabetes mellitus). Furthermore, drugs form a major cause of autonomic dysfunction and merit separate categorization. Moreover, another group that probably warrants a separate entity is neurally mediated syncope, in which, between episodic autonomic disturbances, usually no abnormalities can be detected.1 Primary autonomic failure syndromes can be divided into a chronic subgroup and into a rarer subgroup with acute or subacute dysautonomia (Table 30–1). Furthermore, the chronic syndromes can be subdivided into those without (i.e., pure autonomic failure [PAF]) and those with associated neurological deficits. Clinically, the latter belong to at least three categories: Parkinson’s disease associated with autonomic failure, dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). Patients with parkinsonian features may be responsive to chronic levodopa (L-dopa) therapy, probable as part of treatment for Parkinson’s disease with autonomic failure. Alternatively, there may be no or poorly (transiently) L-dopa– responsive parkinsonism, probable as part of the parkinsonian variant of MSA, i.e. MSA-P. Other patients may have cerebellar features as the predominant motor disorder and may therefore be diagnosed as the cerebellar variant of MSA, i.e., MSA-C. Some patients present initially with autonomic abnormalities, including urogenital and cardiovascular dysfunction, and only later develop the additional neurological manifestations of MSA. Eventually, some patients present with parkinsonian features accompanied by dementia within the first year of disease onset, which leads to a diagnosis of DLB. Actually, it is important to classify patients or assign them to these different disease entities for a number of reasons, including prognosis. Indeed, analyses of two large series in the United Kingdom and the United States indicate that patients with PAF have a substantially better prognosis than those with additional neurological deficits.2 There are differences within this latter group as well, inasmuch as patients with Ldopa–responsive Parkinson’s disease and autonomic failure

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appear to live longer than do patients with MSA or DLB (personal observations). In this chapter, we discuss the clinical manifestation and its underlying neuropathological changes and the diagnostic workup and management of the primary autonomic failure disorders, including PAF, Parkinson’s disease with autonomic failure, MSA, and DLB. The rarer subgroups with acute or subacute primary autonomic failure are briefly considered. No further mention is made of the secondary forms, including drug-induced autonomic failure.

NEUROPATHOLOGY Degeneration of autonomic neurons with disabling dysautonomia is a prominent feature of the Lewy body syndromes and MSA. α-Synuclein is a major component of the Lewy bodies in Parkinson’s disease, DLB, and the glial and neuronal cytoplasmic inclusions of MSA. α-Synuclein also is a major component of Lewy bodies in the brain and peripheral autonomic ganglia in PAF.3 Therefore, these disorders are increasingly being referred to as “synucleinopathies.” Abnormalities in the expression or structure of α-synuclein or associated proteins may cause degeneration of catecholamine-containing neurons.4 However, the function of α-synuclein is not known, but interest in this protein derives from the finding that the gene encoding for α-synuclein is mutated in families with the autosomal-dominant form of Parkinson’s disease.5 To investigate the consequence of α-synuclein overexpression in glia, Stefanova and colleagues6 transfected U373 astrocytoma cells with vectors encoding wild-type human α-synuclein or C-terminally truncated synuclein fused to red fluorescent protein. α-Synuclein immunocytochemistry of transfected astroglial cells revealed diffuse cytoplasmic labeling associated with discrete inclusions within both cell bodies and processes. Susceptibility to oxidative stress was increased in astroglial cells overexpressing αsynuclein, particularly in the presence of cytoplasmic inclusions. However, whether the α-synuclein aggregation is induced by some other factor or factors or whether it is the primary trigger of MSA pathology is unknown. Impairment in the ability of oligodendrocytes to degrade α-synuclein, which they may normally produce at low levels, may promote abnormal subcellular aggregation in MSA.7 Alternatively, ectopic expression of oligodendroglial α-synuclein may result in glial

chapter 30 primary autonomic failure cytoplasmic inclusions. This scenario is supported by experimental studies demonstrating glial cytoplasmic inclusion–like inclusion pathology in transgenic mice overexpressing oligodendroglial α-synuclein.8 More work is necessary to elucidate the cascade of cell death in MSA and to determine exogenous and genetic susceptibility factors, both of which are likely to drive the disease process in this disorder. It is not known what determines whether α-synuclein precipitates in neurons (Parkinson’s disease, PAF) or glial cells (MSA) or on autonomic (PAF) or striatonigral neurons (Parkinson’s disease, MSA). Anyway, there are clear distinctions between the different αsynucleinopathies and little evidence of migration from one clinical form to the other.

Lewy Body Disorders The Lewy body syndromes are characterized by intracytoplasmic eosinophilic neuronal inclusions, so-called Lewy bodies or Lewy neurites, found in the brain, including brainstem, basal ganglia, and cortical neurons, and in the peripheral autonomic nerves of affected patients. Lewy bodies contain abnormally phosphorylated intermediate neurofilament proteins, αsynuclein, ubiquitin, and associated enzymes. There are three different but overlapping phenotypes. In PAF there is early and

T A B L E 3 0 – 1. Failure Disorders Acute/subacute primary autonomic failure disorders Chronic primary autonomic failure disorders

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Classification of Primary Autonomic Pure pandysautonomia Pandysautonomia with neurological features Pure cholinergic dysautonomia Acute noradrenergic autonomic neuropathy Pure autonomic failure Parkinson’s disease with autonomic failure Dementia with Lewy bodies Multiple system atrophy

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widespread neuronal degeneration restricted mostly to peripheral autonomic neurons; autonomic failure is the sole clinical finding.9 In fact, in patients with PAF, intracytoplasmic eosinophilic inclusion bodies with the histological appearance of Lewy bodies, similar to those found in Parkinson’s disease, are identified in neurons of the substantia nigra, locus ceruleus, thoracolumbar and sacral spinal cord, and sympathetic ganglia and in peripheral sympathetic and parasympathetic nerves.9,10 Neuropathological reports of patients with PAF showed αsynuclein–positive intraneuronal cytoplasmic inclusions (Lewy bodies) in brainstem nuclei and peripheral autonomic ganglia.3,9 In Parkinson’s disease, there is prominent degeneration of the substantia nigra (Fig. 30–1) and other brainstem nuclei, in addition to peripheral autonomic neurons; clinically, there are motor abnormalities with varying degrees of autonomic failure.11 In DLB there is extensive cortical involvement in addition to degeneration of brainstem nuclei and peripheral autonomic neurons; clinical findings are dominated by severe cognitive impairment in association with parkinsonism and autonomic dysfunction.12 It is likely that the clinical phenotype of Lewy body syndromes depends on the temporal formation and distribution of Lewy bodies and associated neurodegeneration. Individual differences in neuronal susceptibility may determine the manifesting phenotype. Patients with PAF, however, can progress to Parkinson’s disease or DLB, which suggests that phenotypes overlap and that neurodegeneration in the Lewy body syndromes may start in postganglionic autonomic neurons and later affect neurons in the central nervous system. As initially suggested by Oppenheimer,13 PAF may be a “forme fruste” of Parkinson’s disease, with early severe widespread degeneration of peripheral autonomic neurons.9,10

Multiple-System Atrophy The second type of neurodegeneration with prominent autonomic failure is MSA. The term multiple-system atrophy was introduced in 196914; however, cases of MSA were previously

Figure 30–1. Gross photograph of a coronal section through the midbrain of a normal person (left) and that of a patient with Parkinson’s disease (right). Note the pigmentation pattern of the substantia nigra in the normal specimen and the loss of pigmentation, resulting in a marked paleness, in the case of Parkinson’s disease.

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reported under the rubrics of striatonigral degeneration (SND),15-17 olivopontocerebellar atrophy (OPCA),18,19 ShyDrager syndrome,20 and idiopathic orthostatic hypotension. MSA is a sporadic neurodegenerative disorder characterized clinically by various combinations of parkinsonian, autonomic, cerebellar, or pyramidal symptoms and signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several brain and spinal cord structures. Indeed, this disorder affects neurons in the basal ganglia, cortex, and spinal cord, but spares peripheral autonomic neurons. Pathologically, cytoplasmic inclusions are located in glial cells and do not form Lewy bodies.21 Clinically, two major motor presentations can be distinguished. Parkinsonian features predominate in 66% of patients (MSA-P), and cerebellar ataxia is the major motor feature in 34% of patients (MSA-C), according to a European survey.22 Severe autonomic failure is prominent in both phenotypes.23 In MSA-P, the striatonigral system is the main site of pathology, but less severe degeneration can be widespread and usually includes the olivopontocerebellar system.24,25 The putamen is shrunken with gray-green discoloration. When putaminal pathology is severe, there may be a cribriform appearance. In early stages, the putaminal lesion shows a distinct topographical distribution with a predilection for the caudal and dorsolateral regions.24 Degeneration of pigmented nerve cells occurs in the substantia nigra pars compacta, whereas cells of the pars reticulata are reported as normal. The topographical patterns of neurodegeneration involving the motor neostriatum, efferent pathways, and nigral neurons reflect their anatomical relationship and suggest a common denominator or “linked” degeneration.24 In MSA-C, the brunt of pathology is borne by the olivopontocerebellar system; the involvement of striatum and substantia nigra is less severe. The basis pontis is atrophic, with loss of pontine neurons and transverse pontocerebellar fibers. In sections stained for myelin, the intact descending corticospinal tracts stand out against the degenerated transverse fibers and the atrophic middle cerebellar peduncles. There is a disproportionate depletion of fibers from the middle cerebellar peduncles in comparison with the loss of pontine neurons, an observation consistent with a “dying back” process. The location of the α-synuclein precipitates determines not only the presence or absence of movement disorders but also the characteristics of the autonomic cardiovascular abnormality. Autonomic failure in MSA is caused by dysfunction of (1) central and preganglionic efferent autonomic activity, (2) neuronal networks in the brainstem that control cardiovascular and respiratory function, and (3) the neuroendocrine component of the autonomic regulation via the hypothalamopituitary axis. In MSA, cell loss is reported in dorsal motor nucleus of the vagus.26 Catecholaminergic neurons in the rostral (C1 group) and caudal (A1 group) ventrolateral medulla, which are involved in the control of sympathetic outflow to the cardiovascular system and reflex control of vasopressin release, are also affected, as are neurons of the arcuate nucleus that are involved in cardiorespiratory interactions.27-30 Cell loss has also been described for the Edinger-Westphal nucleus and posterior hypothalamus,20 including the tuberomammillary nucleus.31 Papp and Lantos21 demonstrated marked involvement of brainstem pontomedullary reticular formation with glial cytoplasmic inclusions, which represented a supraspinal histological counterpart for impaired visceral function. Autonomic

neuronal degeneration affects the locus ceruleus, too.32 It is noteworthy that there is not always a strong correlation between nerve cell depletion or gliosis and the clinical degree of autonomic failure. It is estimated that more than 50% of cells within the intermediolateral column must decay before symptoms become evident.13 Degeneration of sympathetic preganglionic neurons in the intermediolateral column of the thoracolumbar spinal cord is considered contributory to orthostatic hypotension. On the basis of only the reports in which formal cell counts have been made, it is apparent, with very few exceptions, that all cases of MSA with predominant pathology in either the striatonigral or olivopontocerebellar system show loss of intermediolateral cells.33 Orthostatic hypotension in MSA is caused by blunted autonomic and neuroendocrine reflexes as a result of afferent and central neuronal loss; postganglionic autonomic fibers, however, are spared.34 Disordered bladder, rectal, and sexual function in MSA-P and MSA-C have been associated with cell loss in parasympathetic preganglionic nuclei of the spinal cord. These neurons are localized rostrally in Onuf’s nucleus between sacral segments S2 and S3 and more caudally in the inferior intermediolateral nucleus chiefly in the S3 to S4 segments.35 Loss of corticotrophin-releasing factor neurons in the pontine micturition area may contribute to neurogenic bladder dysfunction.30 In the peripheral component of the autonomic nervous system, Bannister and Oppenheimer36 described atrophy of the glossopharyngeal and vagus nerves. No pathology has been reported in the visceral enteric plexuses or in the innervation of glands, blood vessels, or smooth muscles. Sympathetic ganglia have not often been examined in pathological studies of autonomic failure and have seldom been described quantitatively. In MSA with autonomic failure, there are either no obvious or mild abnormalities in sympathetic ganglia. Any morphological changes reported in sympathetic ganglionic neurons in MSA have tended to be nonspecific,37 exhibiting the normal age-related range of appearances, and published micrographs and counts have indicated at least a moderate density, and sometimes quite a high density, of surviving neurons.38 Enteric and parasympathetic ganglia have been studied only in a few instances. A variety of other neuronal populations are noted to show cell depletion and gliosis with considerable differences in vulnerability from case to case. Varying degrees of abnormalities in the cerebral hemisphere, including Betz cell loss, were detected in pathologically proved MSA cases.32,33 Furthermore, anterior horn cells may show some depletion, but rarely to the same extent as that occurring in motor neuron disease.39

CLINICAL PRESENTATION Acute/Subacute Primary Autonomic Failure Disorders Pure Pandysautonomia and Pandysautonomia with Neurological Features There is a clinical spectrum of acute autonomic neuropathies. Acute panautonomic neuropathy (pandysautonomia), characterized by severe widespread sympathetic and parasympathetic failure, is at one extreme. Guillain-Barré syndrome is at the

chapter 30 primary autonomic failure other end of the spectrum, in which the brunt of the disorder is borne by the somatic nervous system. Pure acute panautonomic neuropathies are relatively rare. Actually, the majority of acute autonomic neuropathies have some minor somatic features. Dysautonomia may be restricted to the cholinergic system (acute cholinergic neuropathy), the adrenergic system, or other organ systems (e.g., motility disorders).40 In medical history, a definite entity of pure pandysautonomia involving both sympathetic and parasympathetic nervous systems with a subacute onset, monophasic course, and partial recovery without significant features of somatic peripheral neuropathy was first described by Young and colleagues in 1969. Actually, there had been some earlier reports of the condition in the literature, although it was not clearly defined.47 The disorder differs from other neurological causes of autonomic dysfunction in that normal function of the central nervous system is preserved. Furthermore, there are no or only minor features of peripheral somatic nervous system involvement. Since these first descriptions, a number of other cases of acute pandysautonomia have been reported, as well as some cases of pure cholinergic dysautonomia. Some cases of acute dysautonomia with significant sensory disturbances have been described; in some, but not all, there was electrophysiological and pathological evidence of loss of small-diameter myelinated and unmyelinated fibers.41 In 1994, Suarez and colleagues42 clarified the features of acute idiopathic autonomic neuropathy. Both sexes and all ages can be affected. The onset is acute or subacute. In approximately one half of affected patients, there is an antecedent viral infection. Several cases that followed EpsteinBarr virus infection have been described, in one of which Epstein-Barr virus DNA and antibody to the virus were found in the cerebrospinal fluid.43 The most common presenting features are symptomatic orthostatic hypotension (lightheadedness, dizziness, syncope) and symptoms of gastrointestinal dysfunction (nausea, vomiting, diarrhea, constipation, and postprandial bloating) or sudomotor dysfunction (failure to sweat, causing heat intolerance and flushing). Other symptoms include numbness, tingling, bladder disturbances, and impotence. Neurological examination findings are normal in about one half the patients; the remainder have depressed reflexes and distal sensory impairment. The clinical course is monophasic. Recovery tends to be gradual and frequently incomplete. The cerebrospinal fluid protein level may be mildly elevated. In rare cases, there may be evidence of sensory neuropathy with sensory symptoms of minimal intensity (mainly thermal and pain hypoesthesia in distal areas). In most cases, nerve conduction studies yield normal results. Sural nerve biopsy in some cases has demonstrated reduction of myelinated fiber density, predominantly of small fibers, and axonal degeneration. Actually, in some cases, there are minimal signs of distal denervation in electromyographic-electroneurographic studies.44 In some acute neuropathies, such as pandysautonomia, small-fiber impairment is relatively pure, but it may also appear in disorders with prominent somatic damage, such as Guillain-Barré syndrome, in which autonomic failure worsens the prognosis.45 The cause of the condition remains uncertain. Pathological features include the presence of a small inflammatory mononuclear cell infiltrate in the epineurium. It is probably a form of acute idiopathic polyneuritis restricted to autonomic nerves with an immune-mediated pathogenesis similar to that of the Guillain-Barré syndrome. Together, the acute onset, frequent

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antecedent viral infection, selectivity of involvement by fiber type and autonomic level, and presence of perivascular mononuclear cell infiltration suggest that the underlying mechanism is likely to be immune mediated. The following differential diagnoses have to be kept in mind: botulism, acute autonomic neuropathy associated with Guillain-Barré syndrome, porphyria, diabetes, toxic causes, systemic lupus erythematosus, and other connective tissue diseases.41

Pure Cholinergic Dysautonomia In pure cholinergic dysautonomia, clinical and laboratory features indicate only a cholinergic failure. A number of cases of pure cholinergic dysautonomia have been described in children. Clinical features include blurred vision, impaired lacrimation, dry mouth, constipation, urinary retention and incontinence, and absence of sweating. There is no postural hypotension. Excessive salivation and sweat secretion have been described in early disease stages. Cerebrospinal fluid findings are normal.41

Chronic Primary Autonomic Failure Disorders Primary Autonomic Failure Bradbury and Eggleston46 were the first to describe PAF in 1925. They used the term idiopathic orthostatic hypotension. Actually, the name pure autonomic failure was introduced by Oppenheimer as one of the primary autonomic failure syndromes. It is a sporadic, adult-onset, slowly progressive, neurodegenerative disorder of the autonomic nervous system.92 Clinically, it is characterized by an isolated impairment of the autonomic nervous system with no other neurological deficits.47 PAF affects men slightly more often than women, usually in their sixth decade. Its onset is slow, and symptoms begin developing insidiously for years as minimal impairment (nonspecific weakness and orthostatic intolerance). The patient may recall that symptoms first manifested several years before he or she sought medical treatment. Common symptoms causing the patient to seek medical advice include unsteadiness, lightheadedness, or faintness on standing. Questioning often elicits descriptions of aching in the neck or occiput only when standing; lying down relieves all symptoms. In general, orthostatic symptoms are more prominent after prolonged recumbency, as in the morning hours. Moreover, postural hypotension is exacerbated after mealtimes and physical exertion. Other contributory factors are heat, alcohol ingestion, coughing, and defecation.48,49 In fact, straining during evacuation or micturition elevates intrathoracic pressure and may result in symptomatic hypotension. Mathias and colleagues50 investigated the frequency of symptoms associated with orthostatic hypotension in PAF and MSA and found that more patients with PAF had syncope (91% vs. 45%), visual disturbances (75% vs. 53%), and suboccipital/paracervical “coat hanger” neck pain (81 vs. 53%) than did the patients with MSA. The reasons for this are unclear. Patients with PAF may also develop supine hypertension. Moreover, a decreased ability to sweat may be apparent, particularly in hot climates. Men found to have PAF may have sought advice about urinary tract symptoms (hesitancy, urgency, dribbling, and occasional incontinence). Other signs of dysautonomia, including erectile and

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ejaculatory dysfunction, an inability to appreciate orgasm, and retrograde ejaculation may be present, too. Women may experience urinary retention or incontinence as early symptoms. In patients with neurally mediated syncope, nausea and pallor, which are prominent signs of autonomic activation, occur before loss of consciousness. In contrast, in patients with PAF, these signs are noticeably absent, and consciousness is lost with little or no warning.51 Autonomic tests are abnormal: orthostatic hypotension, cardiovagal dysfunction, and hypo- or anhidrosis of the postganglionic type (see “Laboratory Assessment” section). A definitive diagnosis of orthostatic hypotension as the cause of symptoms is made when symptoms are reproduced while declines in systolic blood pressure of at least 20 mm Hg and diastolic pressure of at least 10 mm Hg are documented, within 3 minutes of standing. The diagnosis cannot be excluded with a single measurement of upright blood pressure that does not fulfill these criteria. Several measurements of orthostatic blood pressure, preferably early in the morning or after a meal, may be necessary. Patients with PAF also have decreased sinus arrhythmia and absent blood pressure overshoot during phase IV of the Valsalva maneuver, which indicates parasympathetic and sympathetic efferent dysfunction. PAF affects mainly efferent postganglionic neurons; afferent pathways and somatic neurons are not affected. Nevertheless, there is evidence of a preganglionic disorder in 22% of patients with PAF, which suggests that such patients actually may have some central component.44 In terms of differential diagnosis, PAF should be distinguished from other forms of neurogenic orthostatic hypotension, including peripheral somatic neuropathies with autonomic involvement (e.g., diabetes and amyloid), MSA, Parkinson’s disease, and DLB. There are no symptoms or signs of sensory, cerebellar, pyramidal, or extrapyramidal dysfunction in patients with PAF. In general, this allows a clinical distinction from other forms of neurogenic orthostatic hypotension. However, it cannot be determined whether a single patient with PAF will eventually develop more widespread, nonautonomic neuronal damage that leads to a diagnosis of MSA or, in rare cases, DLB. A number of warning signs, or “red flags,” for a clinical diagnosis of MSA have been operationally defined, and their frequency has been determined in a large cohort of European patients with MSA in a natural history study conducted by the European MSA-Study Group. Some of these features that are, if present, suggestive of MSA can be attributed, at least in part, to autonomic nervous system abnormalities. Abnormal respiration occurred in 42% to 60% of patients; its manifestations included inspiratory stridor (19% to 33%), involuntary deep sighs and/or gasps (34% to 37%), sleep apnea (13% to 18%), and excessive snoring (22% to 33%). Rapid eye movement (REM) sleep behavior disorder was present in 35% to 39%. Cold hands and/or feet were noted in 26% to 34%, whereas Raynaud’s phenomenon was recorded in only 6% to 7%.52,53 Although the specificity and positive predictive value of the red flags for a diagnosis of MSA have not been determined yet, they may serve as useful “soft signs” pointing toward a diagnosis of MSA. Because of the slow disease progression in PAF, most patients probably die before central nervous system involvement can become clinically evident. Apart from dysautonomia, these patients are otherwise normal and have a relatively good prognosis. Complications are usually related to falls and associated disorders.54

Parkinson’s Disease and Autonomic Failure In Parkinson’s disease, extrapyramidal motor problems are the presenting features. Later in the disease process, patients may also suffer severe autonomic failure, which makes the clinical distinction from MSA difficult. As in Parkinson’s disease, some patients with MSA display motor deficits before autonomic failure is apparent, which complicates the distinction further. However, dysautonomia in Parkinson’s disease is rarely as severe as that in MSA. The uncommonly encountered patients with both Parkinson’s disease and autonomic failure are usually older and are often responsive to L-dopa. Although in most cases autonomic failure occurs late, there is a subgroup of patients with Parkinson’s disease who have clinically significant autonomic failure early in the course of the disease. Orthostatic hypotension is often the key clinical feature suggestive of autonomic failure. However, there are many causes of orthostatic hypotension, including side effects of antiparkinsonian therapy (such as L-dopa or selegiline), coincidental disease causing autonomic dysfunction (e.g., diabetes mellitus), or concomitant administration of drugs for an allied condition (e.g., antihypertensives or α-adrenoceptor blockers).55 Studies on patients with Parkinson’s disease indicate that selegiline can cause orthostatic hypotension independently of autonomic failure through mechanisms that are not clearly defined.56 Together, the confounding effect of antiparkinsonian drugs that often worsens orthostatic hypotension and difficulties in the differential diagnosis (particularly between Parkinson’s disease and MSA) make it difficult to estimate accurately the prevalence of autonomic dysfunction in patients with Parkinson’s disease. Studies that mistakenly include patients with MSA-P may overestimate the frequency of autonomic dysfunction in Parkinson’s disease or underestimate it if patients with both Parkinson’s disease and autonomic dysfunction are diagnosed as MSA-P.54 In a retrospective study, almost one third of patients with Parkinson’s disease confirmed with post mortem examination had autonomic dysfunction documented in their clinical records.57 However, it has to be kept in mind that this retrospective method may underestimate the frequency of autonomic failure. Actually, bladder dysfunction (such as urgency, frequency, and incontinence) and decreased gastrointestinal motility represent the most frequent autonomic problems in Parkinson’s disease. Constipation is extremely common. Moreover, intestinal pseudo-obstruction and toxic megacolon may occur. Sexual dysfunction (loss of libido and erectile failure) is common in this disorder.54 In a study of patients whose Parkinson’s disease was diagnosed by means of clinical criteria, almost two thirds of subjects had orthostatic hypotension with symptoms of cerebral hypoperfusion, including syncope, when tested on a tilt table for 40 minutes or until symptoms developed.58 Because patients with normal responses and with orthostatic hypotension were taking similar drug regimens, antiparkinsonian medication was not the main cause of orthostatic hypotension. Senard and colleagues59 found a fall of at least 20 mm Hg of systolic blood pressure in almost 60% of patients with Parkinson’s disease. There was symptomatic orthostatic hypotension in 20% of the patients. It was related to duration and severity of the disorder, as well as with the use of higher daily L-dopa and bromocriptine dosages.59 A higher prevalence of symptomatic orthostatic hypotension (78%) was found in a retrospective study on

chapter 30 primary autonomic failure patients with neuropathologically confirmed Parkinson’s disease.60 In an earlier study, vagal control of the heart and hemodynamic response to standing were impaired and related to duration of the clinical features of Parkinson’s disease.61 Between 20% and 40% of patients with Parkinson’s disease become demented in the course of their illness.62 Operational criteria defining the clinical boundaries between Parkinson’s disease and Parkinson’s disease with dementia (PDD) are lacking, although this distinction may have profound clinical implications for prognosis and treatment strategies.63 The criteria in Diseases and Statistical Manual of Mental Disorders (Fourth Edition, DSM-IV™) are incomplete and descriptive and do not describe several core clinical features associated with dementia in Parkinson’s disease. Peralta and colleagues showed that orthostatic hypotension is more frequent and more severe in patients with PDD than in those with Parkinson’s disease. Attentional scores during tilt testing were also more reduced in patients with PDD in comparison with those with Parkinson’s disease, which suggests that orthostatic hypotension may exacerbate cognitive dysfunction in patients with PDD.64

Dementia with Lewy Bodies DLB is the most frequent cause of degenerative dementia after Alzheimer’s disease. Whether DLB and PDD are the same or different disorders is uncertain.65 Clinically, the central feature required for a diagnosis of DLB is progressive cognitive decline, severe enough to cause social and occupational functional impairment. Core features of DLB are fluctuating cognition, recurrent and persistent visual hallucinations, and extrapyramidal motor symptoms. Supportive features may increase diagnostic sensitivity. They include repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and hallucinations in other modalities. The two main differential diagnoses are Alzheimer’s disease and PDD. In order to improve the differential diagnosis of DLB, consensus criteria that establish possible and probable levels of diagnostic accuracy have been developed.12,66 In general, their sensitivity is variable and low, but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. With the use of operationally defined criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer’s disease or Parkinson’s disease. Autonomic failure is frequent in DLB. A retrospective analysis of autonomic symptoms in neuropathologically diagnosed DLB showed that 62% of affected patients had significant autonomic failure.67 Patients with DLB may suffer vocal cord palsy, which results in sudden death. However, autonomic function has not been well documented in patients with DLB. Some of the supportive features, including repeated falls, syncope, and transient loss of consciousness, can be attributed in part to autonomic nervous system abnormalities. Orthostasis, either asymptomatic or associated with syncope, may be observed in these patients, although symptomatic orthostatic hypotension has been found in a lower frequency (15%) than in other types of parkinsonism.60 Mean age at onset is 75 years; the age range is 50 to 80 years, with a slight male predominance.68 Although dementia is the

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most frequent presenting feature, psychiatric symptoms or transient alterations of consciousness are other early features. Indeed, affected patients may present with recurrent visual hallucinations even without exposure to dopaminergic antiparkinsonian agents and may have marked diurnal fluctuations in cognitive performance, which have been the most difficult feature of the disease to define but are often conspicuous in the environment. Although parkinsonism is common in DLB, occurring at some point during the course of the illness in 75% to 80% of cases,69,70 a minority of patients present with parkinsonism alone. In general, autonomic features occur later in the course of the disease, but some cases have been described in which dysautonomia was the initial and prominent feature, leading to an initial misdiagnosis of MSA.71 Fluctuating cognition, probably related to fluctuations in attention, is characteristic of DLB, occurring in 58% of cases at the time of presentation and observed during the disease course in 75%.72 The natural history of the neuropsychological changes in DLB is not well characterized, although differences with Alzheimer’s disease appear particularly pronounced in the early stages and lessen as the disease progresses. A rapidly progressive dementia, accompanied by aphasia, dyspraxia, and spatial disorientation suggestive of temporoparietal dysfunction can be seen as the disease progresses. Disability in DLB progresses at a rate similar to that in Parkinson’s disease (approximately 10% decline per year) or even at a significantly faster rate. The latency to onset of orthostatic hypotension in a postmortem series of the National Institute of Neurologic Disorders and Stroke were short in MSA patients, intermediate in patients with DLB, corticobasal degeneration, and progressive supranuclear palsy (PSP) and long in those with Parkinson’s disease.60 These data underpin the rapidly progressive nature of the disease process in DLB in comparison with that of Parkinson’s disease. As a result, mean length of survival in a series of patients with DLB confirmed with post mortem examination has been less than 10 years. It is similar to that for Alzheimer’s disease, although some patients with DLB show rapid symptom progression and die within 1 to 2 years of onset. Risk factors for increased mortality in DLB that are present at disease onset include older age, dementia, fluctuating cognition, and hallucinations.73 Strikingly, patients with DLB with neuroleptic sensitivity reactions show a twofold to threefold increase in mortality.

Multiple-System Atrophy This disease affects both men and women, usually starts in the sixth decade, and progresses relentlessly, with a mean survival length of 6 to 9 years.74-77 There is considerable variation in disease progression, with survival lengths of more than 15 years in some instances. Clinically, cardinal features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in various combinations. Previous studies suggest that 29% to 33% of patients with isolated late-onset cerebellar ataxia and 8% of patients with parkinsonism eventually develop MSA.78-80 Of importance, both motor presentations of MSA are associated with similar survival times.76 However, patients with MSA-P have a more rapid functional deterioration than do patients with MSA-C.74 MSA-P associated parkinsonism is characterized by progressive akinesia and rigidity. Jerky postural tremor and, less

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commonly, tremor at rest may be superimposed. Frequently, patients exhibit orofacial or craniocervical dystonia in association with a characteristic quivering, high-pitched dysarthria. Postural stability is compromised early on; however, recurrent falls at disease onset are unusual, in contrast to PSP. Differentiating between MSA-P and Parkinson’s disease may be exceedingly difficult in the early stages because of a number of overlapping features such as rest tremor or asymmetrical akinesia and rigidity. Furthermore, L-dopa–induced improvement of parkinsonism may be seen in 30% of MSA-P patients. However, the benefit is transient in most of these subjects, leaving 90% of the MSA-P patients unresponsive to L-dopa in the long term. L-Dopa–induced dyskinesias affecting orofacial and neck muscles occur in 50% of MSA-P patients, sometimes in the absence of motor benefit.81 In most instances, a fully developed clinical picture of MSA-P evolves within 5 years of disease onset, allowing a clinical diagnosis during follow-up.82 The cerebellar disorder of MSA-C comprises gait ataxia, limb kinetic ataxia, and scanning dysarthria, as well as cerebellar oculomotor disturbances. Patients with MSA-C usually develop additional noncerebellar symptoms and signs but, before doing so, may be indistinguishable from other patients with idiopathic late-onset cerebellar ataxia, many of whom have a disease restricted clinically to cerebellar signs and pathologically to degeneration of the cerebellum and olives.78 Dysautonomia is characteristic of both MSA motor presentations, comprising primarily urogenital and orthostatic dysfunction. During the early stages of MSA, autonomic deficits may be the sole clinical manifestation, thus resembling PAF, but after a variable period of time (sometimes 2 or 3 years, always less than 5), extrapyramidal or cerebellar deficits or both invariably develop. Early impotence (erectile dysfunction) is virtually universal in men with MSA, and urinary incontinence or retention, often early in the course or as presenting symptoms, are frequent.77 Disorders of micturition in MSA are caused by changes in the complex peripheral and central innervation of the bladder83 and generally occur more commonly, earlier, and to a more severe degree than in Parkinson’s disease. In fact, patients with MSA have early dysuria with or without chronic retention, frequently associated with a hypoactive detrusor muscle and low urethral pressure. In contrast, patients with Parkinson’s disease have urgency to void, with or without difficulty, but without chronic retention, in association with detrusor hyperreflexia and normal urethral sphincter function. Constipation occurs in equal percentages of patients in Parkinson’s disease and MSA. Symptomatic orthostatic hypotension is present in 68% of patients with clinical diagnoses of MSA, but recurrent syncope emerges in only 15%.77 LDopa or dopamine agonists may provoke or worsen orthostatic hypotension.

LABORATORY ASSESSMENTS In addition to the clinical presentation, several laboratory investigations have been used to distinguish among Parkinson’s disease, PAF, and MSA (Table 30–2). Basically, most of these tests exploit the anatomopathological distinction between Lewy body syndromes, which affect postganglionic autonomic neurons, and MSA, which affects preganglionic, central autonomic neurons.

Cardiovascular Function Testing A history of postural faintness or other evidence of orthostatic hypotension, such as neck ache on rising in the morning or posturally related changes of visual perception, should be sought in all patients in whom MSA is suspected. After a comprehensive history is documented, cardiovascular function should be tested according to consensus recommendations.47,84 A drop in systolic blood pressure of 20 mm Hg or more or in diastolic blood pressure of 10 mm Hg or more, in comparison with baseline within a standing time of 3 minutes, is defined as orthostatic hypotension and must lead to more specific assessment. This is based on continuous noninvasive measurements of blood pressure and heart rate during tilt-table testing.85-87 Although abnormal cardiovascular test results may provide evidence of sympathetic and/or parasympathetic failure, they do not differentiate autonomic failure associated with Parkinson’s disease from that associated with MSA.88 The autonomic abnormality of MSA can be distinguished biochemically from that of PAF. In MSA, during supine rest, norepinephrine (noradrenaline) levels (representing postganglionic sympathetic efferent activity) are normal,89,90 and there is no denervation hypersensitivity, which indicates a lack of increased expression of adrenergic receptors on peripheral neurons.90 In contrast to this normal or only slightly decreased plasma norepinephrine level during recumbency in MSA and varying levels in patients with Parkinson’s disease, patients with PAF have very low plasma norepinephrine levels when recumbent.90,91 On standing or tilt-table testing, patients with PAF, those with MSA, and some with Parkinson’s disease with autonomic failure do not have the expected increase in plasma norepinephrine levels, which indicates an inability to normally stimulate the release of catecholamines by baroreflex activation in all these disorders. When norepinephrine is infused into patients with PAF, there is an exaggerated increase in blood pressure. This reflects an excessive sensitivity of postsynaptic α-adrenergic receptors to exogenous catecholamines. In contrast, patients with MSA and Parkinson’s disease show only a mildly increased blood pressure response to infused norepinephrine, without leftward shift in the dose-response curve.92 Similarly, there is a greater degree of β-adrenergic receptor supersensitivity in PAF than in MSA, as shown by Baser and associates93 in a study with intravenous isoproterenol. Sympathetic cardiac innervation is selectively affected in Parkinson’s disease and PAF but is intact in MSA. Imaging studies that measure catecholamine uptake by cardiac sympathetic neurons have confirmed that peripheral sympathetic nerves are preserved in MSA but greatly reduced in PAF.94 Visualization of sympathetic cardiac neurons through scintigraphy with norepinephrine analogue iodine 123–meta-iodobenzylguanidine ([123I]MIBG) has revealed loss of binding in patients with Parkinson’s disease, regardless of disease severity, which reflects postganglionic sympathetic denervation; in comparison, cardiac binding is preserved in MSA95-100 and PSP.101 Pooled data from several studies showed that MIBG scintigraphy occurately discriminated a total of 246 cases of Parkinson’s disease from 45 of MSA with high sensitivity (90%) and specificity (95%).96 Similarly, (18F) fluorodopamine positron emission tomography (PET) is able to demonstrate cardiac sympathetic denervation in PAF and Parkinson’s disease in contrast with intact cardiac sympathetic innervation in MSA.94 6-[18F] Fluorodopamine is a catecholamine taken up by sympathetic post-

chapter 30 primary autonomic failure T A B L E 3 0 – 2. Examined Body Domain/Function Cardiovascular Physiological

Biochemical Pharmacological

Imaging Brain Imaging CSF studies Endocrine Sudomotor Gastrointestinal Renal function and urinary tract Sexual Respiratory Eye and lacrimal glands

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Laboratory Investigations in Primary Autonomic Failure Parameters/Techniques Head-up tilt (60 degrees); standing; Valsalva maneuver Pressor stimuli (isometric exercise, cutaneous cold, mental arithmetic) Heart rate responses-deep breathing, hyperventilation, standing, head-up tilt, 30 : 15 R-R interval ratio Liquid meal challenge Modified exercise testing Carotid sinus massage Plasma noradrenaline: supine and head-up tilt or standing; urinary catecholamines; plasma renin activity, and aldosterone Noradrenaline: α-adrenoceptors, vascular Isoprenaline: β-adrenoceptors, vascular and cardiac Tyramine: pressor and noradrenaline responses Edrophonium: noradrenaline response Atropine: parasympathetic cardiac blockade Cardiac [123I]MIBG SPECT, 6-[18F] fluorodopamine PET MRI (1.5 Tesla), diffusion-weighted imaging, voxel-based morphometry, [(123)I]β-CIT, [123I]iodobenzamide SPECT, 18Ffluorodopa PET, [11C]diprenorphine PET, 18F-fluorodeoxyglucose PET, 99mTc-hexamethylpropyleneamine oxime, [123I]FPCIT Neurofilament protein levels Clonidine–α2-adrenoceptor agonist: noradrenaline suppression; growth hormone stimulation Thermoregulatory sweat test Sweat gland response to intradermal acetylcholine, QSART, localized sweat test Sympathetic skin response External anal sphincter EMG, video-cinefluoroscopy, barium studies, endoscopy, gastric emptying studies, transit time, lower gut studies Day and night urine volumes and sodium/potassium excretion measurements Urodynamic studies, intravenous urography, ultrasonographic examination, sphincter electromyography Penile plethysmography Intracavernosal papaverine Laryngoscopy Sleep studies to assess apnea and oxygen desaturation Pupillary function, pharmacological and physiological Schirmer’s test

Modified from Mathias CJ: Autonomic diseases: clinical features and laboratory evaluation. J Neurol Neurosurg Psychiatry 2003; 74(Suppl 3):iii31-iii41. 11 C, carbon 11; β-CIT, 2β-carboxymethoxy-3β-(4-iodophenyl)tropane; CSF, cerebrospinal fluid; EMG, electromyography; 18F, fluorine 18; 123I, iodine 123; FP-CIT, 2βcarbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane; MIBG, meta-iodobenzylguanedine; MRI, magnetic resonance imaging; PET, positron emission tomography; QSART, quantitative sudomotor axon reflex test; SPECT, single photon emission computed tomography.

ganglionic neurons and handled similarly to norepinephrine. Together, these types of imaging of sympathetic cardiac neurons may turn out to be useful diagnostic tests to distinguish between Parkinson’s disease and MSA because sympathetic innervation of the heart is impaired in Parkinson’s disease and not in MSA. Moreover, in a patient with apparent PAF, finding normal sympathetic cardiac innervation should indicate a likely development of MSA.4 A caveat of this approach to be kept in mind is that published studies have compared patients with established diagnoses of MSA and PAF and, therefore, probably in later disease stages. It is not known whether these differences are apparent in patients during earlier stages of the disorder, when a diagnostic method would be more useful in the workup of patients in clinical practice.92 DLB affects peripheral postganglionic autonomic neurons (as with the other Lewy body syndromes). Actually, neuropathological studies on DLB associated with severe autonomic failure demonstrated—besides numerous Lewy bodies in the cortex and brainstem—sparse Lewy bodies in the intermediolateral columns of the spinal cord, as well as numerous Lewy bodies in autonomic ganglia and sympathetic neurons.71 These results suggests that, as in Parkinson’s disease,102 autonomic

dysfunction in DLB is, at least in part, caused by degeneration of peripheral autonomic neurons. This is supported by single photon emission computed tomography (SPECT) imaging of postganglionic sympathetic cardiac innervation with 123I-MIBG, which showed that postganglionic sympathetic neurons were nonfunctional.54 Indeed, 123I-MIBG SPECT has been shown to discriminate DLB from Alzheimer’s disease with severe denervation in the former and preserved sympathetic MIBG binding in the latter disorder.103-105

Bladder Function Testing Assessment of bladder function is a mandatory part of the diagnostic workup of parkinsonian patients and usually provides evidence of involvement of the autonomic nervous system already at an early stage of the disease (when bladder function is still normal in most patients with Parkinson’s disease). Urinary symptoms and studies of bladder function may help to distinguish between MSA-P and Parkinson’s disease. After documentation of a careful history regarding frequency of voiding, difficulties in initiating or suppressing voiding, and the

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presence of urinary incontinence, a standard urine analysis should be performed to rule out an infection. Postvoid residual volume needs to be determined sonographically or through catheterization to initiate intermittent self-catheterization in due course. In some patients, only cystometry can discriminate between hypocontractile detrusor function and hyperreflexic sphincter-detrusor dyssynergy. The nature of bladder dysfunction is different in MSA and Parkinson’s disease. Although frequency and urgency are common in both disorders, marked urge or stress incontinence with continuous leakage is not a feature of Parkinson’s disease, apart from very advanced cases. Urodynamic studies show a characteristic pattern of abnormality in patients with MSA.106 In the early stages, there is often detrusor hyperreflexia, often with bladder neck incompetence caused by abnormal urethral sphincter function, which results in early frequency and urgency, followed by urge incontinence. Later on, the ability to initiate a voluntary micturition reflex and the strength of the hyperreflexic detrusor contractions diminish, and the bladder may become atonic, which accounts for increasing postmicturition residual urine volumes.

Sphincter Electromyography As a matter of fact, the striated muscle of the external anal and urethral sphincter is innervated by fibers that originate in Onuf’s nucleus (see “Neuropathology” section). This nucleus is particularly vulnerable in MSA but not in Parkinson’s disease.54 Involvement of Onuf’s nucleus is much more frequent than that of anterior horn cells in the rest of the spinal cord in MSA, although there may be some depletion of anterior horn cells.39 Interestingly, the reverse occurs in patients with amyotrophic lateral sclerosis, in whom Onuf’s nucleus is selectively spared. On electromyography (EMG) of the anal and urethral sphincter muscle, neuronal loss in Onuf’s nucleus is reflected by signs of denervation and chronic reinnervation. An abnormal finding on sphincter EMG may be found in many patients with clinically definitive MSA, including those who as yet have no urological or anorectal problems. In at least 80% of patients with MSA, EMG of the external anal sphincter reveals signs of neuronal degeneration in Onuf’s nucleus with spontaneous activity and increased polyphasia.83,107,108 Schwarz and colleagues109 suggested that abnormal spontaneous activity on sphincter EMG, although difficult to detect, may be the most useful criterion for distinguishing between Parkinson’s disease and MSA. However, the prevalence of abnormalities in early stages of MSA remains unclear. These findings do not reliably differentiate between MSA and other forms of atypical parkinsonian disorders such as PSP.110 Furthermore, neurogenic changes of external anal sphincter muscle have also been demonstrated in advanced stages of Parkinson’s disease.111 Chronic constipation, previous pelvic surgery, or vaginal deliveries can also be confounding factors that induce nonspecific abnormalities.112 However, abnormalities on anal sphincter EMG appear to distinguish MSA from Parkinson’s disease in the first 5 years after disease onset and from PAF, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out.113

Neuroendocrine Testing In vivo studies in MSA, which involved testing of the endocrine component of the central autonomic nervous systems (the

hypothalamopituitary axis) with a variety of challenge procedures, provided evidence of impaired humoral responses of the anterior and the posterior parts of the pituitary gland with impaired secretion of adrenocorticotropic hormone,114 growth hormone,115 and vasopressin/antidiuretic hormone.34 Although these observations can be made in virtually all patients in an advanced stage of the disease, their prevalence during the early course of MSA is unknown. PAF selectively affects the efferent, mainly postganglionic autonomic neurons. Afferent pathways are not involved. Baroreceptor-mediated vasopressin release—a measurement of afferent baroreceptor function—is normal in patients with PAF, and presumably in those with Parkinson’s disease, but is blunted in patients suffering from MSA.34 Intravenous clonidine also tests the function of hypothalamic-pituitary pathways.92 Clonidine is a centrally active α2-adrenoceptor agonist that stimulates growth hormone secretion and lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. There is an ongoing debate about the diagnostic value of the growth-hormone response to clonidine, a neuropharmacological assessment of central adrenoceptor function, in Parkinson’s disease and MSA. In an early study, there was no increase in growth hormone levels after clonidine administration in patients with MSA in comparison with those with Parkinson’s disease or PAF.116 Kimber and colleagues115 confirmed a normal increase in serum growth hormone in response to clonidine in 14 patients with Parkinson’s disease (without autonomic failure) and in 19 patients with PAF, whereas there was no growth hormone rise in 31 patients with MSA. However, these findings were challenged subsequently.117-119 After clonidine administration, growth hormone rose in patients with PSP and controls, but not in patients with MSA.120 In patients with PSP, responses to both physiological and pharmacological tests provided evidence against widespread autonomic dysfunction; this differed markedly from patients with MSA. Stimulation of growth hormone release with growth hormone–releasing hormone plus arginine rather than clonidine may differentiate MSA from idiopathic Parkinson’s disease and idiopathic late-onset cerebellar ataxia,121 but this hypothesis would need to be confirmed by further investigations. In normal humans, clonidine reduces arginine-vasopressin secretion, probably by presynaptic inhibition of noradrenergic neuron terminals in the supraoptic nucleus. A lesion of noradrenergic pathways in animals abolishes this response to clonidine. Postmortem study in MSA reveals marked loss of hypothalamic noradrenergic innervation. After clonidine administration, there was a significantly greater fall of arginine-vasopressin levels in controls than in patients with MSA, which suggests that there is an abnormal arginine-vasopressin response to clonidine in MSA, which probably represents loss of functional noradrenergic innervation of the supraoptic nucleus.122 More studies in well-defined patient cohorts are needed before clonidine challenge tests can be recommended as helpful diagnostic tests in patients with suspected MSA. Neuroendocrine responses to hypotension or centrally acting adrenergic agonists are blunted in MSA but are preserved in Parkinson’s disease and PAF, inasmuch as brainstemhypothalamic-pituitary pathways are affected only in MSA.92 Hypothalamic dopaminergic pathways are involved in the regulation of growth hormone and prolactin release from the anterior pituitary. Neuroendocrine studies in patients with MSA, in whom there is a reported loss of hypothalamic

chapter 30 primary autonomic failure dopamine, are few and contradictory. In patients with MSA, the growth hormone–releasing hormone and growth hormone responses to L-dopa were preserved and were similar to responses in age-matched control subjects in a study by Kimber and colleagues.123 In contrast, there was impaired dopaminergic suppression of prolactin secretion. In patients with MSA, this may represent a selective dysfunction, rather than generalized loss, of tuberoinfundibular dopaminergic neurons. Besides orthostatic hypotension, supine hypertension, paradoxically, is present in about one half of patients with MSA or PAF.124 However, the mechanisms of supine hypertension differ between MSA and PAF. Eliminating residual sympathetic tone with the ganglionic blocker trimethaphan completely abolished hypertension in patients with MSA but not in those with PAF.125 Therefore, hypertension in MSA can be totally explained by the residual sympathetic tone unopposed by the absence of baroreflex mechanisms. However, patients with MSA are not able to engage and modulate sympathetic tone during upright posture. Therefore, they are suffering from orthostatic hypotension despite their supine hypertension. In patients with PAF, the cause of supine hypertension is not yet resolved.54

Brain Imaging Magnetic resonance imaging (MRI) of the brain and PET of the brain and heart (see previous discussion) may be helpful in the differential diagnosis of a patient with parkinsonism and autonomic failure, distinguishing among PAF, MSA, and Parkinson’s disease. In patients with PAF, MRI results of the brain are normal.92 In Parkinson’s disease, brain MRI reveals only mild putaminal abnormalities with few brainstem or cerebellar changes. In contrast, in patients with MSA, brain MRI shows severe putaminal abnormalities, frequently accompanied by brainstem and cerebellar changes. However, MRI abnormalities in MSA frequently occur late in the time course of the disorder, and the abnormalities reviewed in the following sections have been observed in patients with advanced rather than early disease. In these early disease stages, MRI is not very sensitive but has good specificity. The diagnosis of MSA still rests on the clinical history and findings of the neurological examination. According to the Consensus Conference on the Diagnosis of MSA,23 additional investigations such as neuroimaging (and autonomic function tests or sphincter EMG, described previously) may be used to support the diagnosis or to exclude other conditions. Therefore, the Consensus Conference considered it premature to incorporate the results of laboratory investigations into the diagnostic guidelines that were established.

Structural Imaging Routine 1.5-T MRI, including diffusion-weighted imaging, should be performed in all patients with suspected MSA, because basal ganglia and/or brainstem abnormalities suggestive of MSA may be observed even during early disease stages. These changes include an OPCA-like atrophy pattern indistinguishable from autosomal dominant cerebellar ataxia.126 MRI measures of basal ganglia pathology in MSA are less well established, and naked eye assessments are often unreliable. In advanced cases, putaminal atrophy may be detectable, and its extent may be correlated with severity of extrapyramidal symptoms.

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Abnormalities on MRI may include not only OPCA126 or putaminal atrophy127 but also signal abnormalities on T2-weighted images. Signal hyperintensities within the pons and middle cerebellar peduncles are believed to reflect degeneration of pontocerebellar fibers; these changes occasionally produce an appearance resembling a hot cross bun.127 Nonspecific putaminal hypointensities in patients with atypical parkinsonism, including MSA, were first reported in 1986 by two groups who used 1.5-T T2-weighted images.128,129 This change has subsequently been confirmed by other authors in cases of pathologically proved MSA.130-132 Similar MRI abnormalities may occur in patients with classic Parkinson’s disease.133 However, Kraft and colleagues demonstrated that hypointense putaminal signal changes were more frequent in MSA than in Parkinson’s disease, by using T2*-weighted gradient echo instead of T2-weighted fast-spin echo images; this indicates that T2*-weighted gradient echo sequences are of better diagnostic value for patients with parkinsonism.134 Increased putaminal hypointensities may be associated with a slitlike hyperintense band lateral to the putamen.134,135 This finding appears to be more specific for MSA than is putaminal hypointensity127,136; however, further studies in larger cohorts of patients are needed to confirm this. The hyperintense slit signal was correlated with reactive microgliosis and astrogliosis in a case of pathologically proved MSA.132 Diffusion-weighted imaging may represent a useful diagnostic tool that can provide additional support for a diagnosis of MSA-P. Diffusion-weighted imaging is able to discriminate patients with MSA-P from both patients with Parkinson’s disease and healthy volunteers on the basis of putaminal regional apparent diffusion coefficients (rADC) values.137 The increased putaminal rADC values in MSA-P probably reflect ongoing striatal degeneration, whereas most neuropathological studies reveal intact striatum in Parkinson’s disease. However, because rADCs were also significantly increased in both putamen and globus pallidus in PSP in comparison with Parkinson’s disease,138 increased putaminal rADC values do not discriminate MSA-P from PSP. Schulz and associates139 found significant reductions in mean striatal and brainstem volumes in patients with MSA-P, MSA-C, and PSP, whereas patients with MSA-C and MSA-P also showed a reduction in cerebellar volume. More recently, voxel-based morphometry confirmed previous region of interest–based volumetric studies139 showing basal ganglia and infratentorial volume loss in MSA-P patients.140 These data also revealed prominent cortical volume loss in MSA-P, comprising mainly the cortical targets of striatal projections such as the primary sensorimotor cortices, lateral premotor cortices, and the prefrontal cortex. MRI-based volumetry is a helpful tool to investigate the progression of cortical and subcortical atrophy patterns in MSA in comparison with other disorders; however, it cannot be applied for routine diagnostic workups of individual patients. Structural brain imaging with MRI reveals a relative preservation of the medial temporal lobes and the hippocampus in 40% of patients with DLB, in contrast to Alzheimer’s disease.141 There is no difference from Alzheimer’s disease in terms of degree of ventricular enlargement or presence of white matter changes on MRI.142 MRI shows atrophy of the putamen in DLB but not in Alzheimer’s disease.143 Additional features such as generalized atrophy141 and rates of progression of whole-brain atrophy144 are not helpful in differential diagnosis. In volumetric studies, frontal brain atrophy was described in DLB patients,

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which was correlated with increasing Lewy body densities.145 Voxel-based morphometry of gray matter revealed significant atrophy of the basal forebrain in DLB, which discriminates it from Alzheimer’s disease.146

Functional Imaging Functional imaging methods for the differential diagnosis of parkinsonian disorders can be divided into investigations of receptor binding and the investigation of glucose metabolism. In studies of receptor binding in disorders with parkinsonism, investigators examine the presynaptic nigrostriatal neurons by evaluating the dihydroxyphenylalanine decarboxylase activity and the dopamine transporter, and they examine postsynaptic dopaminergic function by evaluating the dopamine D2 receptor. Scintigraphic studies focus on the cardiac sympathetic innervation and are discussed previously. Despite the lack of comparative studies, iodobenzamide (IBZM) and MIBG SPECT, as well as fluorodeoxyglucose PET (when available), appear to be helpful functional imaging tools that may support an early clinical diagnosis of MSA. PET imaging in MSA reveals a generalized reduction in glucose utilization rate, which indicates hypometabolism, most prominently in the cerebellum, brainstem, striatum, and frontal and motor cortices. In contrast, none of these findings was present in PAF.92 In fact, the Hammersmith Cyclotron Unit, using PET, found that putaminal uptake of the presynaptic dopaminergic markers [18F]fluorodopa and S-[11C]nomifensine147,148 was similarly reduced in MSA and Parkinson’s disease; in approximately one half the patients with MSA, caudate uptake was also markedly reduced, as opposed to only moderate reduction in Parkinson’s disease. However, discriminant function analysis of striatal [18F]fluorodopa uptake distinguished patients with MSA from those with Parkinson’s disease poorly.149 Measurements of striatal dopamine D2 receptor densities with raclopride and PET failed to differentiate between Parkinson’s disease and atypical parkinsonian disorders, demonstrating a similar loss of densities in patients with advanced Parkinson’s disease, MSA, and PSP.150 PET studies with other ligands such as [11C]diprenorphine (nonselective opioid receptor antagonist)151 and [18F]fluorodeoxyglucose152-154 have proved more consistent in detecting striatal degeneration and in distinguishing patients with MSA-P from those with Parkinson’s disease, particularly when combined with a dopamine D2 receptor scan.155 Widespread functional abnormalities in MSA-C have been demonstrated through [18F]fluorodeoxyglucose and PET.156 Reduced metabolism was most marked in the brainstem and cerebellum, but other areas such as the basal ganglia and cerebral cortex were also involved, which is evidence of its nosological status as the cerebellar subtype of MSA. Furthermore, assessing nigrostriatal dopaminergic function with 18F-fluorodopa PET may be a useful diagnostic aid in cases of DLB, inasmuch as there is a pronounced reduction of striatal dopamine uptake.157 PET examination of the cerebral glucose metabolism with 18F-fluorodeoxyglucose demonstrated that among widespread cortical regions showing glucose hypometabolism in patients with DLB, the metabolic reduction was most pronounced in the visual association cortex, in comparison with that in patients with Alzheimer’s disease.158 Therefore, among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the

occipital cortex may be an informative diagnostic aid to distinguish DLB from Alzheimer’s disease.158,159 SPECT evaluation of the dopamine transporter with 2β-carboxymethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT) reflects the disruption of the nigrostriatal pathway, and therefore MSA and PSP cannot be distinguished from Parkinson’s disease with this method alone.160 However, dopamine transporter SPECT may be useful in differentiating parkinsonism from controls.161 In another SPECT study, striatal [123I]β-CIT uptake was markedly reduced in both the patients with Parkinson’s disease and those with MSA,162 but patients with MSA showed a more symmetrical dopamine transporter loss, consistent with the more symmetrical clinical motor dysfunction observed in this condition. SPECT studies using [123I]IBZM as D2 receptor ligand have revealed significant reductions of striatal IBZM binding in subjects with clinically probable MSA in comparison with patients with Parkinson’s disease or controls.163-165 However, striatal IBZM binding is also reduced in other atypical parkinsonian disorders such as PSP,164 which limits its predictive value for an early diagnosis of MSA. IBZM SPECT imaging in patients with early parkinsonism seems to distinguish between L-dopa–responsive and Ldopa–unresponsive parkinsonism in patients not previously treated with dopaminergic drugs.166 A good response to apomorphine challenge and subsequent benefit from chronic dopaminergic therapy was observed in subjects with normal IBZM binding, whereas subjects with reduced binding failed to respond. Some of these patients developed other atypical clinical features suggestive of MSA during follow-up.167 Functional neuroimaging with technetium 99m–hexamethylpropyleneamine oxime and SPECT reveals occipital hypoperfusion in DLB, differentiating it from Alzheimer’s disease.168,169 In DLB, as well as in PDD, bilateral temporal and parietal perfusion deficits have been reported. Dopamine transporter loss in the caudate and putamen, a marker of nigrostriatal degeneration, can be detected by dopaminergic SPECT.170 [123I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) and SPECT reveal significant reduction in striatal uptake of a ligand for the presynaptic dopamine transporter site (FP-CIT) in DLB but not in Alzheimer’s disease, and this may prove to be a highly specific and widely applicable diagnostic test.171,172

THERAPY The complex manifestations of primary autonomic failure syndromes generate multiple therapeutic needs, many of which are still unmet. Unfortunately, there are no causal therapies available. Therefore, the therapeutic strategies are defined by clinical symptoms and impairment of health-related quality of life in these patients.

Acute/Subacute Primary Autonomic Failure Patient education is an important aspect of treatment. Sympathomimetic drugs and 9-α-fluorohydrocortisone have been of value in treating postural hypotension in cases of pandysautonomia. Correcting anemia improves orthostatic tolerance, if necessary by hemopoietin. Because the underlying mechanism is likely to be immune mediated, plasma exchange or other

chapter 30 primary autonomic failure immunosuppressive modalities as early therapeutic intervention in patients with progressive disability may be justified. In fact, corticosteroids are frequently used, and plasmapheresis and intravenous immunoglobulin may be effective.173-175 Carbachol may be helpful for the management of urinary retention and impaired gastrointestinal motility associated with acute cholinergic neuropathy.

Chronic Primary Autonomic Failure Because of the chronic or progressive course of primary autonomic failure syndromes, a regular review of treatment is mandatory to adjust measures according to clinical needs. Guidelines for the practical management of chronic PAF syndromes are shown in Table 30–3.

Motor Disorder Treatment of the motor abnormalities is fairly successful in Parkinson’s disease but remains dismal in MSA patients. These patients often do not respond to antiparkinsonian medications and fail to benefit from current surgical treatments for Parkinson’s disease. Although less effective than in Parkinson’s disease, L-dopa replacement represents the mainstay of antiparkinsonian therapy in MSA. However, a sufficiently powered double-blind controlled trial has never been performed. Results of open-label studies suggest that, in contrast to patients with Parkinson’s disease, most patients with MSA fail to benefit from treatment with L-dopa in the long run, although a transient response may occur in some cases. However, the assumption that patients with MSA are generally not responsive or poorly responsive to L-dopa is certainly misleading. L-Dopa responsiveness should be tested by administering escalating doses (with a peripheral decarboxylase inhibitor) over a 3-month period up to at least 1000 mg per day (if necessary and if tolerated).23 Reports of open-label L-dopa therapy in MSA have documented L-dopa efficacy in up to 80% of patients with clinical diagnoses.75,77,81,176-184 Data obtained from series with pathological confirmation are more variable, with rates of beneficial L-dopa response ranging between 30% and 70%.32,77,179,185-188 On occasion, a beneficial effect is evident only when seemingly unresponsive patients deteriorate after Ldopa withdrawal.179 Whatever response there is usually declines after a few years of treatment.189 The effectiveness of L-dopa on motor symptoms in DLB has not been established but is probably less than in uncomplicated Parkinson’s disease, possibly because there is additional intrinsic striatal pathology and dysfunction.190 But, although this limited L-dopa responsiveness has generally been reported in DLB, it may reflect either a failure to treat or underdosing, because of concerns about exacerbating psychotic symptoms. In fact, there are reports showing that 70% to 100% of patients with DLB do have a good response.191-193 In comparison with Parkinson’s disease, Ldopa–related motor complications appear to be less common in DLB. L-Dopa is the preferred antiparkinsonian drug in DLB because dopamine agonists may increase the occurrence of hallucinations.194 Reviews of the therapeutic values of both dopaminergic and nondopaminergic drugs for the management of the motor disorder in Parkinson’s disease, MSA, and DLB are covered in more detail elsewhere.195-198

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Orthostatic Hypotension The concept to treat symptoms of orthostatic hypotension is based on the increase of intravasal volume and the reduction of volume shift to lower body parts when a patient changes to an upright position. The selection and combination of the following options, including both nonpharmacological and pharmacological measures, depend on the severity of symptoms and their practicability in the single patient, but not on the extent of blood pressure drop during the tilt-table test. Nonpharmacological options include sufficient fluid intake, high-salt diet, more frequent but smaller meals per day to reduce postprandial hypotension by spreading the total carbohydrate intake, and as the ultima ratio custom-made elastic body garments. During the night, head-up tilt increases intravasal volume up to 1 L within a week, which is particularly helpful in improving hypotension early in the morning. This is achieved by an increased secretion of renin as a result of reduced renal perfusion pressure and by reduced atrial natriuretic hormone levels because of lower atrial filling pressure. This approach is successful, particularly in combination with the mineralocorticoid fludrocortisone, which further supports sodium retention. Indeed, medical treatment begins with attempting to increase blood volume by increasing sodium intake unless the patient is at risk for congestive heart failure or has renal insufficiency. The next group of drugs to use is the sympathomimetics. They include ephedrine (with both direct and indirect effects), which is often valuable in central autonomic failure as occurs in MSA. In fact, ephedrine can be helpful through its peripheral vasoconstrictor effects. With high doses, side effects include tremulousness, loss of appetite, and in men, urinary retention. Orthostatic hypotension is often successfully treated with midodrine,199-202 an adrenergic agonist activating α1 receptors on arterioles and veins. Midodrine increases peripheral resistance, thereby significantly reducing orthostatic hypotension. Side effects are usually mild and only rarely lead to discontinuation of treatment because of urinary retention or pruritus predominantly on the scalp. Furthermore, L-threo-3,4-dihydroxyphenyl serine has been used with some success in short clinical trials.203 It represents a precursor of norepinephrine and has been used for this indication in Japan for years. Mathias and associates showed its efficacy in an open-label, dose-finding trial in patients with MSA and PAF.204 If the above drugs do not produce the desired effect, then selective targeting is needed. The somatostatin analogue octreotide is often beneficial in postprandial hypotension,205 presumably because it inhibits release of vasodilatory gastrointestinal peptides;206 of importance, it does not enhance nocturnal hypertension.205 The vasopressin analogue desmopressin, which acts on renal tubular vasopressin-2 receptors, reduces nocturnal polyuria and improves morning postural hypotension.207 Recombinant erythropoietin, used to reverse the anemia common in MSA, increases upright blood pressure and ameliorates symptoms of orthostatic hypotension208-211 by secondarily improving cerebral oxygenation.209,211,212

Supine Hypertension In more than one half of patients with PAF or MSA, supine hypertension is present, complicating their management. Actually, the treatment of patients with primary autonomic failure is aimed primarily at improving orthostatic hypotension, and

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T A B L E 3 0 – 3.

Practical Management of Chronic Primary Autonomic Failure Syndromes

Feature

Pharmacological Measures

Nonpharmacological Measures

Orthostatic hypotension

Starter drug Fludrocortisone (0.1-0.3-0.4 mg/day) Sympathomimetics Ephedrine (15-45 mg t.i.d.) Midodrine (2.5-10 mg t.i.d.) L-Threo-DOPS (300 mg b.i.d.) Specific targeting For postprandial hypotension: Octreotide (25-50 μg subcutaneously, 30 min before a meal) For nocturnal polyuria: Desmopressin (spray: 10-40 μg/night or tablet: 100-400-600 μg/night) Increasing red cell mass: Erythropoietin (25-50 U/kg body weight subcutaneously three times a week) In individual cases Vasoconstriction: Phenylephrine, noradrenaline, clonidine, tyramine with monoamine oxidase inhibitors, yohimbine, dihydroergotamine, terlipressin Preventing vasodilatation: Indomethacin (cave: gastric ulceration and hemorrhage), flurbiprofen, metoclopramide, domperidone, propanolol, caffeine Increasing cardiac output: Pindolol (cave: cardiac failure), xamoterol, ibopamine Nitroglycerin (transdermal, 0.1-0.2 mg/hour) Short-acting calcium antagonists (e.g., nifedipine, 30 mg) Hydralazine (50-100 mg) For urinary incontinence Oxybutynin for detrusor hyperreflexia (2.5-5 mg b.i.d-t.i.d., or 5 to 10 mg at bedtime) Trospium chloride (15-20 mg b.i.d.-t.i.d.) Tolterodine (1-2-4 mg b.i.d) For incomplete bladder emptying Prazosin (1 mg t.i.d.) Moxisylyte (10 mg t.i.d.) Tamsulosine (0.4 mg o.i.d.) Alfuzosine (5 mg b.i.d) Erectile dysfunction Yohimbine (2.5-5 mg t.i.d.) Sildefanil (50-100 mg) Intracavernosal papaverine, prostaglandin E1 Bulk agents, laxatives, and suppositories Macrogol 3350/electrolyte Avoid Botulinum toxin A

To be avoided Sudden head-up postural change (especially on waking) Prolonged recumbency Straining during micturition and defecation High environmental temperature (including hot baths) “Severe” exertion Large meals (especially with refined carbohydrates) Alcohol Drugs with vasodepressor properties To be introduced Head-up tilt during sleep Small frequent meals High salt intake Judicious exercise (including swimming; delay physical exertion until the afternoon; exercise caution on arising in the morning and immediately after meals or physical exertion) Body position and maneuvers—elevation of the legs periodically during the day To be considered Elastic stockings or tights Abdominal binders Water ingestion Cardiac pacing

Supine hypertension

Urinary difficulties

Sexual dysfunction

Constipation Inspiratory stridor

REM sleep behavior disorder Sialorrhea

Clonazepam 0.5-1.5 mg shortly before bedtime (cave: lower initial dose in a patient older than 70 years) Anticholinergics Botulinum toxin A: Parotid gland: Botox®, 10-40 MU Submandibular gland: Botox®, 5-15 MU

Nocturnal snacks Head-up tilt at night Treatment of concurrent prostatism in men or pelvic floor muscle laxity in women Treatment of concurrent urinary tract infection Urinary acidification Intermittent (residual volume>100 mL) or permanent urethral or suprapubic catheterization Penile implant/prosthesis

Dietary fiber and liquid intake Physical activity Continuous positive airway pressure Tracheostomy Anchoring one vocal cord in abduction/cord lateralization procedures Laser cricoarytenoidectomy Nasotracheal intubation Tissues

Modified from Wenning GK, Geser F, Poewe W: Therapeutic strategies in multiple system atrophy. Mov Disord 2005; 20(Suppl 12):S67-S76. DOPS, dihydroxyphenyl serine; REM, rapid eye movement.

chapter 30 primary autonomic failure the need to treat supine hypertension in these patients is disputed. As a matter of fact, all antihypertensive agents may worsen orthostatic hypotension and trigger symptoms of cerebral hypoperfusion. However, the finding of left ventricular hypertrophy in hypertensive patients with primary autonomic failure suggests that this question should be reconsidered.213 Effective treatment of supine hypertension can be easily accomplished simply by avoiding the supine position, at least during daytime. Sleeping in the head-up tilt position reduces nocturnal sodium loss, which improves orthostatic hypotension in the morning (see previous discussion).214,215 Although head-up tilt may reduce hypertensive cerebral perfusion pressure, it is often not sufficient to treat supine hypertension. Theoretically, a result similar to that with head-up tilt at night could be obtained pharmacologically by reducing blood pressure with antihypertensive agents. An ideal agent would decrease blood pressure and natriuresis during the night. Furthermore, it would have a short half life, in order to avoid worsening of orthostatic hypotension in the morning.54 In any case, supine hypertension does not necessitate drug treatment if systolic blood pressure is below 200 mm Hg. Patients with primary autonomic failure are particularly sensitive to transdermal nitroglycerin.124 It can be applied at bedtime and removed on arising in the morning. Short-acting calcium antagonists216 such as nifedipine given at nighttime have also been used in PAF. However, nifedipine increased the nocturnal sodium loss in a study by Jordan and colleagues,217 and nifedipine but not nitroglycerin worsened orthostatic hypotension in the morning. Oral hydralazine can also be used.54

Bladder Dysfunction Nocturnal voiding frequency can be lessened by curtailing fluid intake after the evening meal. If this is not effective, and if there is no significant postmicturition residual, peripherally acting anticholinergics (oxybutynin, propantheline, or tolterodine) are the initial pharmacological therapeutics to be administered.54 Anticholinergic agents alleviate detrusor hyperreflexia or sphincter-detrusor dyssynergy, but commonly at the expense of inducing urinary retention.83 Muscarinic receptors of the detrusor muscle are the common target of anticholinergics, and their M1, M2, or M3 subreceptor profile seems to have little influence on their clinical efficacy. Several anticholinergics are available, but for most cases, clinical use is based on the results of open-label trials. Propantheline bromide is nonselective for muscarinic receptor subtypes and has low bioavailability. It was a first-choice agent for detrusor overactivity in the 1980s but has been largely supplanted by newer agents since. Trospium chloride is a very efficacious nonselective quaternary ammonium compound showing tissue selectivity for the bladder over the salivary glands. Oxybutynin has antimuscarinic, muscle relaxant, and local anesthetic actions. It has been demonstrated to have a higher affinity for muscarinic M1 and M3 receptors than for M2 receptor, but the clinical significance of this is unclear. Side effects are typically antimuscarinic, including dry mouth, constipation, blurred vision, and drowsiness. The administration of desmopressin at night may improve nocturia (see previous discussion). In patients with MSA and incomplete bladder emptying, clean intermittent catheterization three to four times per day is a widely accepted approach to prevent myogenic overdistension and secondary consequences from failure to micturate. In the advanced stages of MSA, a

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permanent urethral or transcutaneous suprapubic catheter may become necessary, when motor symptoms of MSA or mechanical obstruction in the urethra prevent uncomplicated catheterization. Pharmacological options with cholinergic or adrenergic substances are usually not successful to adequately reduce postvoid residual volume in MSA. However, α-adrenergic receptor antagonists (prazosin and moxisylyte) have been shown to improve voiding with reduction of residual volumes in patients with MSA.218 Urological surgery must be avoided in these patients because worsening of bladder control postoperatively is most likely.83

Erectile Dysfunction The necessity of a specific treatment of sexual dysfunction needs to be evaluated individually in each MSA patient. Sildenafil is an orally active inhibitor of the type V cyclic guanosine monophosphate–specific phosphodiesterase (the predominant isoenzyme in the human corpus cavernosum) and has shown remarkable success in clinical trials.219-221 In fact, preliminary evidence in patients with Parkinson’s disease220 suggests that sildenafil citrate may also be successful in treating erectile failure in patients with MSA. A double-blind, placebo-controlled trial confirmed the efficacy of this compound in MSA but also suggested caution because of the frequent cardiovascular side effects.221 Erectile failure in MSA may also be improved by oral yohimbine, by intracavernosal injection of papaverine, or by a penile implant.83 Moreover, erectile dysfunction can be treated with intracavernosal injections or transurethral suppositories of alprostadil, a synthetic prostaglandin E1.222 Dopaminergic agents may also help with sexual dysfunction, probably by alleviating bradykinesia, as well as increasing desire. On high doses of antiparkinsonian medication, some patients may become hypersexual—even despite their inability to perform.54

Constipation Constipation affects overall well-being and can be managed with dietary changes, adequate liquid intake, exercise, and pharmacotherapy. In fact, at least two meals per day should include high-fiber raw vegetables. Furthermore, increasing physical activity can also be helpful. Constipation can be relieved by increasing the intraluminal volume, which may be achieved with a macrogol-water solution. Indeed, it is already shown that macrogol 3350 plus electrolytes improves constipation in Parkinson’s disease and MSA.223 Stool softeners given with meals can be helpful. Lactulose may be beneficial for some patients. Bowel motility may be increased by discontinuing anticholinergic agents.

REM Sleep Behavior Disorder In many patients, REM sleep behavior disorder is responsive to low-dose clonazepam. In patients with DLB, precipitation or aggravation of hallucinations with dopaminergic agents may occur. L-Dopa has less of a propensity to cause hallucinations and somnolence and is therefore preferred over dopamine agonists.54 Although clonazepam may be regarded as the treatment of choice for REM sleep behavior disorder, an alternative treatment is desirable for affected patients whose condition is refractory to clonazepam, who experience intolerable side effects with clonazepam, or in whom clonazepam precipitates

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or aggravates obstructive sleep apnea. In a series by Boeve and colleagues,224 a persistent benefit with melatonin beyond 1 year of therapy occurred in most patients, which suggests that melatonin may be considered as a possible sole or add-on therapy in selected patients with REM sleep behavior disorder.

Cognitive and Psychiatric Problems In patients with DLB, cholinesterase inhibitor drugs are commonly used for the treatment of cognitive dysfunction. These drugs may reduce hallucinations and other neuropsychiatric symptoms of DLB, too. According to a Cochrane Database review,225 DLB patients who suffer from behavioral disturbances or psychiatric problems may benefit from rivastigmine if they tolerate it. However, the evidence is weak, and further trials with rivastigmine or other cholinesterase inhibitors in DLB are needed.54 Another important issue that has to be kept in mind is that about one third to one half of patients with DLB develop severe side effects when treated with typical or atypical neuroleptics.191,226,227 The reported side effects include increased rigidity, immobility, confusion, sedation, and postural falls.191,226-232 It is not possible to predict these neuroleptic sensitivity reactions in an individual patient before treatment starts. Severe neuroleptic sensitivity probably also occurs in about 25% of PDD patients, and caution in their use is also urged.233 Selective serotonin reuptake inhibitors have shown some effectiveness for the management of depression and for behavioral and psychological disorders in patients with dementia (particularly in Alzheimer’s disease).54

tive bladder drainage, it is not an ideal long-term solution. Erosion of the urethra may occur in both men and women, whereas men are also prone to developing urethral stricture disease. Most urologists agree that a suprapubic catheter is the preferred route for long-term bladder drainage if an indwelling catheter is required. A reduction in maximal detrusor pressure, improvement in bladder structure, and a resolution of reflux have been reported. Complications common to both urethral and suprapubic catheterization include urine bypassing the catheter, leading to incontinence, and recurrent infections and catheter blockage. Expert uroneurological advice is invaluable. Occupational therapy helps to limit the handicap resulting from the patient’s disabilities and should include a home visit. Gait training and timely provision of a walking aide or assistive devices to prevent falling help avoid further debilitation of the patient. Provision of a wheelchair is usually dictated by the liability to falls because of postural instability and gait ataxia but not by akinesia and rigidity per se. Psychological support for patients and partners needs to be stressed. Until primary autonomic failure can be effectively treated or prevented, it will continue to present neurologists with a major challenge: that of providing the rapport, empathy, trust, and compassion necessary to support patients and family in the presence of progressive and incurable disease.

K E Y ●

Pure autonomic failure (PAF) is a rare neurodegenerative disorder that is characterized by Lewy bodies in the autonomic nervous system.

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PAF may evolve into Parkinson’s disease with autonomic failure, dementia with Lewy bodies (DLB), or multiplesystem atrophy (MSA)

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In PAF, Parkinson’s disease with autonomic failure, and DLB, the Lewy bodies stain positive for a-synuclein, whereas in MSA, a-synuclein immunoreactivity is found in glial cytoplasmic inclusions.

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Postganglionic lesions predominate in PAF, Parkinson’s disease with autonomic failure, and DLB, whereas preganglionic lesions predominate in MSA.

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The practical management of these disorders is based on alleviating patients’ individual symptoms.

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New neuroprotective or neurorestorative treatment concepts to slow down, halt, or reverse disease progression are urgently required.

Palliative Care Patients with PAF should be assured that their disease has a relatively benign nature. MSA patients continue to suffer from this malignant and distressing condition. Because the results of drug treatment for MSA are generally poor in the long term, other therapies are all the more important. Palliative management decisions should be based on careful clinical judgment, with the expectations of both patient and caregivers taken into account. It is most crucial that patients have maximum access to speech, occupational, and physical therapists; social workers; wheelchair clinics; and continence advisers. In fact, physiotherapy helps maintain mobility and prevent contractures. Speech therapy can improve speech and swallowing and provide communication aids. Dysphagia may necessitate feeding via a nasogastric tube or even percutaneous endoscopic gastrostomy. Continuous positive airway pressure may be helpful in some affected patients with inspiratory stridor.234,235 Tracheostomy, after all the ethical issues related to this procedure have been considered, is only rarely (about 4%) needed in mobile patients with inspiratory stridor; it should be avoided in preterminal stages of the disease. The advisability of either gastrostomy or tracheostomy should be approached on an individual basis with a realistic appraisal of the patient’s general quality of life. In advanced disease, long-term indwelling catheters become the mainstay of urinary control. Many factors, including neurological, urological, sexual, psychological, and social factors, may complicate or affect the choice of bladder management. Indeed, sometimes the preservation of quality of life for caretakers or lack of adequate nursing may dictate the use of indwelling catheters. Although urethral catheterization does provide effec-

P O I N T S

Suggested Reading Kaufmann H, Schatz IJ: Pure autonomic failure. In Robertson D, ed: Primer on the Autonomic Nervous System, 2nd ed. Amsterdam: Elsevier, 2004, pp 309-311. Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford, UK: Oxford University Press, 1999.

chapter 30 primary autonomic failure Mathias CJ, Polinsky RJ: Separating the primary autonomic failure syndromes, multiple system atrophy, and pure autonomic failure from Parkinson’s disease. Adv Neurol 1999; 80:353-361. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:293-103. Wenning GK, Stampfer M: Dementia with Lewy Bodies. In Robertson D, ed: Primer on the Autonomic Nervous System, 2nd ed. Amsterdam: Elsevier, 2004, pp 293-294.

References 1. Mathias CJ: The classification and nomenclature of autonomic disorders—ending chaos, resolving conflict and hopefully achieving clarity. Clin Auton Res 1995; 5:307-310. 2. Bannister R, Mathias CJ, Polinsky R: Clinical features of autonomic failure. B. Autonomic failure: a comparison between UK and US experience. In Bannister R, ed: Autonomic Failure. A Textbook of Disorders of the Autonomic Nervous System, 2nd ed. Oxford: Oxford University Press, 1988, pp 281-288. 3. Kaufmann H, Hague K, Perl D: Accumulation of alphasynuclein in autonomic nerves in pure autonomic failure. Neurology 2001; 56:980-981. 4. Kaufmann H: Primary autonomic failure: three clinical presentations of one disease? Ann Intern Med 2000; 133:382-384. 5. Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276:2045-2047. 6. Stefanova N, Klimaschewski L, Poewe W, et al: Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 2001; 65:432-438. 7. Tu PH, Galvin JE, Baba M, et al: Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998; 44:415-422. 8. Kahle PJ, Neumann M, Ozmen L, et al: Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 2002; 3:583-588. 9. Hague K, Lento P, Morgello S, et al: The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol (Berl) 1997; 94:192-196. 10. van Ingelghem E, van Zandijcke M, Lammens M: Pure autonomic failure: a new case with clinical, biochemical, and necropsy data. J Neurol Neurosurg Psychiatry 1994; 57:745747. 11. Hughes AJ, Daniel SE, Blankson S, et al: A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol 1993; 50:140-148. 12. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1113-1124. 13. Oppenheimer DR: Lateral horn cells in progressive autonomic failure. J Neurol Sci 1980; 46:393-404. 14. Graham JG, Oppenheimer DR: Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 1969; 32:28-34. 15. van der Eecken H, Adams R, van Bogaert L: Striopallidalnigral degeneration: a hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 1960; 19:159-161. 16. Adams R, Van Bogaert L, Van der Eecken H: [Nigro-striate and cerebello-nigro-striate degeneration. Clinical uniqueness and pathological variability of presenile degeneration of the extrapyramidal rigidity type]. Psychiatr Neurol (Basel) 1961; 142:219-259. 17. Adams RD, Vanbogaert L, Van der Eecken H: Striatonigral degeneration. J Neuropathol Exp Neurol 1964; 23:584608.

387

18. Dejerine J, Thomas A. L’atrophie olivo-ponto-cerebelleuse. Nouv Iconogr Salpetr 1900; 13:330-370. 19. Stauffenberg W: Zur Kenntnis des extrapyramidalen motorischen Systems und Mitteilung eines Falles von sog. Atrophie olivo-pontocerbelleuse. Zeitschr Ges Neurol Psychiatrie 1918; 39:1-55. 20. Shy GM, Drager GA: A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol 1960; 2:511-527. 21. Papp MI, Lantos PL: The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994; 117(Pt 2):235243. 22. Geser F, Stampfer-Kountchev M, Seppi K, et al: The clinical presentation of multiple system atrophy (MSA) in Europe: An interim analysis of the EMSA-SG (European MSA-Study Group) Registry. Mov Disord 2004; 19(Suppl 9):347. 23. Gilman S, Low P, Quinn N, et al: Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res 1998; 8:359-362. 24. Kume A, Takahashi A, Hashizume Y: Neuronal cell loss of the striatonigral system in multiple system atrophy. J Neurol Sci 1993; 117:33-40. 25. Wenning GK, Tison F, Elliott L, et al: Olivopontocerebellar pathology in multiple system atrophy. Mov Disord 1996; 11:157-162. 26. Sung JH, Mastri AR, Segal E: Pathology of Shy-Drager syndrome. J Neuropathol Exp Neurol 1979; 38:353-368. 27. Benarroch EE, Smithson IL, Low PA, et al: Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998; 43:156-163. 28. Benarroch EE, Schmeichel AM, Parisi JE: Depletion of cholinergic neurons of the medullary arcuate nucleus in multiple system atrophy. Auton Neurosci 2001; 87:293-299. 29. Benarroch EE, Schmeichel AM, Parisi JE: Depletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy. Neurology 2002; 59:944946. 30. Benarroch EE: Brainstem in multiple system atrophy: clinicopathological correlations. Cell Mol Neurobiol 2003; 23:519526. 31. Nakamura S, Ohnishi K, Nishimura M, et al: Large neurons in the tuberomammillary nucleus in patients with Parkinson’s disease and multiple system atrophy. Neurology 1996; 46:1693-1696. 32. Wenning GK, Tison F, Ben Shlomo Y, et al: Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997; 12:133-147. 33. Daniel S: The neuropathology and neurochemistry of multiple system atrophy. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 321-328. 34. Kaufmann H, Oribe E, Miller M, et al: Hypotension-induced vasopressin release distinguishes between pure autonomic failure and multiple system atrophy with autonomic failure. Neurology 1992; 42:590-593. 35. Konno H, Yamamoto T, Iwasaki Y, et al: Shy-Drager syndrome and amyotrophic lateral sclerosis: cytoarchitectonic and morphometric studies of sacral autonomic neurons. J Neurol Sci 1986; 73:193-204. 36. Bannister R, Oppenheimer DR: Degenerative diseases of the nervous system associated with autonomic failure. Brain 1972; 95:457-474. 37. Spokes EG, Bannister R, Oppenheimer DR: Multiple system atrophy with autonomic failure: clinical, histological and

388

38.

39. 40. 41.

42.

43. 44.

45. 46. 47. 48. 49. 50.

51. 52.

53.

54. 55.

56.

57.

Section

VI

Au to n o m i c N e rvo u s Syst e m D i s e as e s

neurochemical observations on four cases. J Neurol Sci 1979; 43:59-82. Matthews M: Autonomic ganglia and preganglionic neurons in autonomic failure. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 329-339. Sima AA, Caplan M, D’Amato CJ, et al: Fulminant multiple system atrophy in a young adult presenting as motor neuron disease. Neurology 1993; 43:2031-2035. Low PA: Autonomic neuropathies. Curr Opin Neurol 1994; 7:402-406. McLeod JG: Autonomic dysfunction in peripheral nerve disease. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 367-377. Suarez GA, Fealey RD, Camilleri M, et al: Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology 1994; 44:16751682. Bennett JL, Mahalingam R, Wellish MC, et al: Epstein-Barr virus—associated acute autonomic neuropathy. Ann Neurol 1996; 40:453-455. Santiago S, Ferrer T, Espinosa ML: Neurophysiological studies of thin myelinated (A delta) and unmyelinated (C) fibers: application to peripheral neuropathies. Neurophysiol Clin 2000; 30:27-42. Santiago S, Espinosa ML, Perez-Conde MC, et al: Small fiber dysfunction in peripheral neuropathies. Rev Neurol 1999; 28:543-554. Bradbury S, Eggleston C: Postural hypotension: a report of three cases. Am Heart J 1925; 1:75-86. Kaufmann H: Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res 1996; 6:125-126. Mathias CJ: Orthostatic hypotension: causes, mechanisms, and influencing factors. Neurology 1995; 45:S6-S11. Robertson D, Davis TL: Recent advances in the treatment of orthostatic hypotension. Neurology 1995; 45:S26-S32. Mathias CJ, Mallipeddi R, Bleasdale-Barr K: Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. J Neurol 1999; 246:893898. Schatz IJ: Orthostatic hypotension. I. Functional and neurogenic causes. Arch Intern Med 1984; 144:773-777. Geser F, Stampfer-Kountchev M, Seppi K, et al: Warning signs (“red flags”) in multiple system atrophy (MSA): a preliminary cross-sectional analysis of 79 European MSA-P patients. Mov Disord 2004; 19(Suppl 9):346-347. Geser F, Stampfer-Kountchev M, Seppi K, et al: Warning signs (“red flags”) in possible MSA: a preliminary cross-sectional analysis of the European MSA-Study Group (EMSA-SG). Funct Neurol 2004; 19:144. Kaufmann H, Biaggioni I: Autonomic failure in neurodegenerative disorders. Semin Neurol 2003; 23:351-363. Mathias CJ, Polinsky RJ: Separating the primary autonomic failure syndromes, multiple system atrophy, and pure autonomic failure from Parkinson’s disease. Adv Neurol 1999; 80:353-361. Churchyard A, Mathias CJ, Boonkongchuen P, et al: Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 63:228-234. Magalhaes M, Wenning GK, Daniel SE, et al: Autonomic dysfunction in pathologically confirmed multiple system atrophy and idiopathic Parkinson’s disease: a retrospective comparison. Acta Neurol Scand 1995; 91:98-102.

58. Kaufmann H, Nouri S, Olanow W, et al: Orthostatic intolerance in Parkinson’s disease. Neurology 1997; 48: 149. 59. Senard JM, Rai S, Lapeyre-Mestre M, et al: Prevalence of orthostatic hypotension in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 63:584-589. 60. Wenning GK, Scherfler C, Granata R, et al: Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed parkinsonian syndromes: a clinicopathological study. J Neurol Neurosurg Psychiatry 1999; 67:620-623. 61. Orskov L, Jakobsen J, Dupont E, et al: Autonomic function in parkinsonian patients relates to duration of disease. Neurology 1987; 37:1173-1178. 62. Mayeux R, Denaro J, Hemenegildo N, et al: A populationbased investigation of Parkinson’s disease with and without dementia: relationship to age and gender. Arch Neurol 1992; 49:492-497. 63. Aarsland D, Larsen JP, Karlsen K, et al: Mental symptoms in Parkinson’s disease are important contributors to caregiver distress. Int J Geriatr Psychiatry 1999; 14:866-874. 64. Peralta CM, Stampfer M, Karner E, et al: Orthostatic hypotension and attention in Lewy body disorders. Mov Disord 2004; 19(Suppl 9):331-332. 65. Geser F, Wenning GK, Poewe W, et al: How to diagnose dementia with Lewy bodies: state of the art. Mov Disord 2005, 20(Suppl 12):S11-S20. 66. McKeith IG, Perry EK, Perry RH: Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999; 53:902-905. 67. Horimoto Y, Matsumoto M, Akatsu H, et al: Autonomic dysfunctions in dementia with Lewy bodies. J Neurol 2003; 250:530-533. 68. Ransmayr G: Dementia with Lewy bodies: prevalence, clinical spectrum and natural history. J Neural Transm Suppl 2000; (60):303-314. 69. Del Ser T, McKeith I, Anand R, et al: Dementia with Lewy bodies: findings from an international multicentre study. Int J Geriatr Psychiatry 2000; 15:1034-1045. 70. Aarsland D, Ballard C, McKeith I, et al: Comparison of extrapyramidal signs in dementia with Lewy bodies and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:374-379. 71. Pakiam AS, Bergeron C, Lang AE: Diffuse Lewy body disease presenting as multiple system atrophy. Can J Neurol Sci 1999; 26:127-131. 72. McKeith I, Burn D: Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. In DeKosky S, ed: Neurologic Clinics: Dementia. Philadelphia: WB Saunders, 2000, pp 865-883. 73. Wenning GK, Seppi K, Jellinger K, et al: Survival of patients with dementia with Lewy bodies: a meta-analysis of 236 postmortem confirmed cases. Neurology 2000; 54(Suppl 3):391392. 74. Watanabe H, Saito Y, Terao S, et al: Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 2002; 125:1070-1083. 75. Testa D, Monza D, Ferrarini M, et al: Comparison of natural histories of progressive supranuclear palsy and multiple system atrophy. Neurol Sci 2001; 22:247-251. 76. Ben-Shlomo Y, Wenning GK, Tison F, et al: Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology 1997; 48:384-393. 77. Wenning GK, Ben Shlomo Y, Magalhaes M, et al: Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 1994; 117(Pt 4):835845.

chapter 30 primary autonomic failure 78. Abele M, Burk K, Schols L, et al: The aetiology of sporadic adult-onset ataxia. Brain 2002; 125:961-968. 79. Gilman S, Little R, Johanns J, et al: Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy. Neurology 2000; 55:527-532. 80. Schwarz J, Tatsch K, Gasser T, et al: 123I-IBZM binding compared with long-term clinical follow up in patients with de novo parkinsonism. Mov Disord 1998; 13:16-19. 81. Boesch SM, Wenning GK, Ransmayr G, et al: Dystonia in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 72:300-303. 82. Wenning GK, Ben-Shlomo Y, Hughes A, et al: What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000; 68:434-440. 83. Beck RO, Betts CD, Fowler CJ: Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol 1994; 151:1336-1341. 84. Braune S, Elam M, Baron R, et al: Assessment of blood pressure regulation. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999; 52:287-291. 85. Bannister R, Mathias C: Investigation of autonomic disorders. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 169195. 86. Braune S, Auer A, Schulte-Monting J, et al: Cardiovascular parameters: sensitivity to detect autonomic dysfunction and influence of age and sex in normal subjects. Clin Auton Res 1996; 6:3-15. 87. Braune S, Schulte-Monting J, Schwerbrock S, et al: Retest variation of cardiovascular parameters in autonomic testing. J Auton Nerv Syst 1996; 60:103-107. 88. Riley DE, Chelimsky TC: Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003; 74:56-60. 89. Ziegler MG, Lake CR, Kopin IJ. The sympathetic-nervoussystem defect in primary orthostatic hypotension. N Engl J Med 1977; 296:293-297. 90. Polinsky RJ, Kopin IJ, Ebert MH, et al: Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981; 31:1-7. 91. Goldstein DS, Polinsky RJ, Garty M, et al: Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 1989; 26:558-563. 92. Kaufmann H, Schatz IJ: Pure autonomic failure. In Robertson D, ed: Primer on the Autonomic Nervous System. Amsterdam: Elsevier, 2004, pp 309-311. 93. Baser SM, Brown RT, Curras MT, et al: Beta-receptor sensitivity in autonomic failure. Neurology 1991; 41:11071112. 94. Goldstein DS, Holmes C, Cannon RO 3rd, et al: Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 1997; 336:696-702. 95. Braune S, Reinhardt M, Schnitzer R, et al: Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999; 53:1020-1025. 96. Braune S: The role of cardiac metaiodobenzylguanidine uptake in the differential diagnosis of parkinsonian syndromes. Clin Auton Res 2001; 11:351-355. 97. Orimo S, Ozawa E, Nakade S, et al: 123I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67:189-194. 98. Takatsu H, Nagashima K, Murase M, et al: Differentiating Parkinson disease from multiple-system atrophy by measuring cardiac iodine-123 metaiodobenzylguanidine accumulation. JAMA 2000; 284:44-45.

389

99. Taki J, Nakajima K, Hwang EH, et al: Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 2000; 27:566-573. 100. Hirayama M, Hakusui S, Koike Y, et al: A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[123I]iodobenzylguanidine in neurological patients with autonomic failure. J Auton Nerv Syst 1995; 53:230-234. 101. Yoshita M: Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 1998; 155:60-67. 102. Goldstein DS, Holmes C, Li ST, et al: Cardiac sympathetic denervation in Parkinson’s disease. Ann Intern Med 2000; 133:338-347. 103. Watanabe H, Ieda T, Katayama T, et al: Cardiac123I-metaiodobenzylguanidine (MIBG) uptake in dementia with Lewy bodies: comparison with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2001; 70:781-783. 104. Yoshita M, Taki J, Yamada M: A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer’s-type and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2001; 71:583-588. 105. Oide T, Tokuda T, Momose M, et al: Usefulness of [123I]metaiodobenzylguanidine ([123I]MIBG) myocardial scintigraphy in differentiating between Alzheimer’s disease and dementia with Lewy bodies. Intern Med 2003; 42:686690. 106. Kirby R, Fowler C, Gosling J, et al: Urethro-vesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986; 49:554562. 107. Pramstaller PP, Wenning GK, Smith SJ, et al: Nerve conduction studies, skeletal muscle EMG, and sphincter EMG in multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:618-621. 108. Palace J, Chandiramani VA, Fowler CJ: Value of sphincter electromyography in the diagnosis of multiple system atrophy. Muscle Nerve 1997; 20:1396-1403. 109. Schwarz J, Kornhuber M, Bischoff C, et al: Electromyography of the external anal sphincter in patients with Parkinson’s disease and multiple system atrophy: frequency of abnormal spontaneous activity and polyphasic motor unit potentials. Muscle Nerve 1997; 20:1167-1172. 110. Valldeoriola F, Valls-Sole J, Tolosa ES, et al: Striated anal sphincter denervation in patients with progressive supranuclear palsy. Mov Disord 1995; 10:550-555. 111. Giladi N, Simon ES, Korczyn AD, et al: Anal sphincter EMG does not distinguish between multiple system atrophy and Parkinson’s disease. Muscle Nerve 2000; 23:731-734. 112. Colosimo C, Inghilleri M, Chaudhuri KR: Parkinson’s disease misdiagnosed as multiple system atrophy by sphincter electro-myography. J Neurol 2000; 247:559-561. 113. Vodusek DB: Sphincter EMG and differential diagnosis of multiple system atrophy. Mov Disord 2001; 16:600-607. 114. Polinsky RJ, Brown RT, Lee GK, et al: Beta-endorphin, ACTH, and catecholamine responses in chronic autonomic failure. Ann Neurol 1987; 21:573-577. 115. Kimber JR, Watson L, Mathias CJ: Distinction of idiopathic Parkinson’s disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet 1997; 349:1877-1881. 116. Zoukos Y, Thomaides T, Pavitt DV, et al: Beta-adrenoceptor expression on circulating mononuclear cells of idiopathic Parkinson’s disease and autonomic failure patients before and after reduction of central sympathetic outflow by clonidine. Neurology 1993; 43:1181-1187.

390

Section

VI

Au to n o m i c N e rvo u s Syst e m D i s e as e s

117. Clarke CE, Ray PS, Speller JM: Failure of the clonidine growth hormone stimulation test to differentiate multiple system atrophy from early or advanced idiopathic Parkinson’s disease. Lancet 1999; 353:1329-1330. 118. Tranchant C, Guiraud-Chaumeil C, Echaniz-Laguna A, et al: Is clonidine growth hormone stimulation a good test to differentiate multiple system atrophy from idiopathic Parkinson’s disease? J Neurol 2000; 247:853-856. 119. Strijks E, van’t Hof M, Sweep F, et al: Stimulation of growth-hormone release with clonidine does not distinguish individual cases of idiopathic Parkinson’s disease from those with striatonigral degeneration. J Neurol 2002; 249:12061210. 120. Kimber J, Mathias CJ, Lees AJ, et al: Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy. Brain 2000; 123(Pt 7):1422-1430. 121. Pellecchia MT, Salvatore E, Pivonello R, et al: Stimulation of growth hormone release in multiple system atrophy, Parkinson’s disease and idiopathic cerebellar ataxia. Neurol Sci 2001; 22:79-80. 122. Kimber J, Watson L, Mathias CJ: Abnormal suppression of arginine-vasopressin by clonidine in multiple system atrophy. Clin Auton Res 1999; 9:271-274. 123. Kimber J, Watson L, Mathias CJ: Neuroendocrine responses to levodopa in multiple system atrophy (MSA). Mov Disord 1999; 14:981-987. 124. Shannon J, Jordan J, Costa F, et al: The hypertension of autonomic failure and its treatment. Hypertension 1997; 30:10621067. 125. Shannon JR, Jordan J, Diedrich A, et al: Sympathetically mediated hypertension in autonomic failure. Circulation 2000; 101:2710-2715. 126. Wullner U, Klockgether T, Petersen D, et al: Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology 1993; 43:318-325. 127. Schrag A, Good CD, Miszkiel K, et al: Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 2000; 54:697-702. 128. Drayer BP, Olanow W, Burger P, et al: Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 1986; 159:493-498. 129. Pastakia B, Polinsky R, Di Chiro G, et al: Multiple system atrophy (Shy-Drager syndrome): MR imaging. Radiology 1986; 159:499-502. 130. O’Brien C, Sung JH, McGeachie RE, et al: Striatonigral degeneration: clinical, MRI, and pathologic correlation. Neurology 1990; 40:710-711. 131. Lang AE, Curran T, Provias J, et al: Striatonigral degeneration: iron deposition in putamen correlates with the slit-like void signal of magnetic resonance imaging. Can J Neurol Sci 1994; 21:311-318. 132. Schwarz J, Weis S, Kraft E, et al: Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60:98-101. 133. Schrag A, Kingsley D, Phatouros C, et al: Clinical usefulness of magnetic resonance imaging in multiple system atrophy. J Neurol Neurosurg Psychiatry 1998; 65:65-71. 134. Kraft E, Trenkwalder C, Auer DP: T2*-weighted MRI differentiates multiple system atrophy from Parkinson’s disease. Neurology 2002; 59:1265-1267. 135. Konagaya M, Konagaya Y, Iida M: Clinical and magnetic resonance imaging study of extrapyramidal symptoms in multiple system atrophy. J Neurol Neurosurg Psychiatry 1994; 57:1528-1531. 136. Kraft E, Schwarz J, Trenkwalder C, et al: The combination of hypointense and hyperintense signal changes on T2-weighted

137.

138.

139.

140.

141. 142.

143. 144. 145. 146. 147.

148.

149.

150.

151.

152. 153.

magnetic resonance imaging sequences: a specific marker of multiple system atrophy? Arch Neurol 1999; 56:225228. Schocke MF, Seppi K, Esterhammer R, et al: Diffusionweighted MRI differentiates the Parkinson variant of multiple system atrophy from PD. Neurology 2002; 58:575580. Seppi K, Schocke MF, Esterhammer R, et al: Diffusionweighted imaging discriminates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple system atrophy. Neurology 2003; 60:922-927. Schulz JB, Skalej M, Wedekind D, et al: Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson’s syndrome from multiple system atrophy and progressive supranuclear palsy. Ann Neurol 1999; 45:6574. Brenneis C, Seppi K, Schocke MF, et al: Voxel-based morphometry detects cortical atrophy in the Parkinson variant of multiple system atrophy. Mov Disord 2003; 18:1132-1138. Barber R, Ballard C, McKeith IG, et al: MRI volumetric study of dementia with Lewy bodies: a comparison with AD and vascular dementia. Neurology 2000; 54:1304-1309. Barber R, Scheltens P, Gholkar A, et al: White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer’s disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry 1999; 67:66-72. Cousins DA, Burton EJ, Burn D, et al: Atrophy of the putamen in dementia with Lewy bodies but not Alzheimer’s disease: an MRI study. Neurology 2003; 61:1191-1195. O’Brien JT, Paling S, Barber R, et al: Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology 2001; 56:1386-1388. Cordato NJ, Halliday GM, Harding AJ, et al: Regional brain atrophy in progressive supranuclear palsy and Lewy body disease. Ann Neurol 2000; 47:718-728. Brenneis C, Wenning GK, Egger KE, et al: Basal forebrain atrophy is a distinctive pattern in dementia with Lewy bodies. Neuroreport 2004; 15:1711-1714. Brooks DJ, Ibanez V, Sawle GV, et al: Differing patterns of striatal 18F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28:547-555. Brooks DJ, Salmon EP, Mathias CJ, et al: The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson’s disease, studied with PET. Brain 1990; 113 (Pt 5):1539-1552. Burn DJ, Sawle GV, Brooks DJ: Differential diagnosis of Parkinson’s disease, multiple system atrophy, and SteeleRichardson-Olszewski syndrome: discriminant analysis of striatal 18F-dopa PET data. J Neurol Neurosurg Psychiatry 1994; 57:278-284. Brooks DJ, Ibanez V, Sawle GV, et al: Striatal D2 receptor status in patients with Parkinson’s disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann Neurol 1992; 31:184-192. Burn DJ, Rinne JO, Quinn NP, et al: Striatal opioid receptor binding in Parkinson’s disease, striatonigral degeneration and Steele-Richardson-Olszewski syndrome, a [11C]diprenorphine PET study. Brain 1995; 118(Pt 4):951-958. De Volder AG, Francart J, Laterre C, et al: Decreased glucose utilization in the striatum and frontal lobe in probable striatonigral degeneration. Ann Neurol 1989; 26:239-247. Perani D, Bressi S, Testa D, et al: Clinical/metabolic correlations in multiple system atrophy: a fluorodeoxyglucose F 18

chapter 30 primary autonomic failure

154. 155.

156.

157. 158. 159. 160. 161.

162.

163.

164.

165. 166. 167. 168.

169. 170. 171. 172.

positron emission tomographic study. Arch Neurol 1995; 52:179-185. Antonini A, Kazumata K, Feigin A, et al: Differential diagnosis of parkinsonism with [18F]fluorodeoxyglucose and PET. Mov Disord 1998; 13:268-274. Ghaemi M, Hilker R, Rudolf J, et al: Differentiating multiple system atrophy from Parkinson’s disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging. J Neurol Neurosurg Psychiatry 2002; 73:517523. Gilman S, Koeppe RA, Junck L, et al: Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol 1994; 36:166-175. Hu XS, Okamura N, Arai H, et al: 18F-fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia with Lewy bodies. Neurology 2000; 55:1575-1577. Higuchi M, Tashiro M, Arai H, et al: Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol 2000; 162:247-256. Ishii K, Imamura T, Sasaki M, et al: Regional cerebral glucose metabolism in dementia with Lewy bodies and Alzheimer’s disease. Neurology 1998; 51:125-130. Brucke T, Djamshidian S, Bencsits G, et al: SPECT and PET imaging of the dopaminergic system in Parkinson’s disease. J Neurol 2000; 247(Suppl 4):IV/2-7. Kim YJ, Ichise M, Ballinger JR, et al: Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord 2002; 17:303-312. Varrone A, Marek KL, Jennings D, et al: [123I]Beta-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson’s disease and multiple system atrophy. Mov Disord 2001; 16:1023-1032. Schulz JB, Klockgether T, Petersen D, et al: Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 57:1047-1056. van Royen E, Verhoeff NF, Speelman JD, et al: Multiple system atrophy and progressive supranuclear palsy: diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM single photon emission computed tomography. Arch Neurol 1993; 50:513-516. Brucke T, Wenger S, Asenbaum S, et al: Dopamine D2 receptor imaging and measurement with SPECT. Adv Neurol 1993; 60:494-500. Schwarz J, Tatsch K, Arnold G, et al: 123I-iodobenzamideSPECT predicts dopaminergic responsiveness in patients with de novo parkinsonism. Neurology 1992; 42:556-561. Schwarz J, Tatsch K, Arnold G, et al: 123I-iodobenzamideSPECT in 83 patients with de novo parkinsonism. Neurology 1993; 43:S17-S20. Donnemiller E, Heilmann J, Wenning GK, et al: Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD and 123Ibeta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease. Eur J Nucl Med 1997; 24:320-325. Lobotesis K, Fenwick JD, Phipps A, et al: Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001; 56:643-649. Ransmayr G, Seppi K, Donnemiller E, et al: Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson’s disease. Eur J Nucl Med 2001; 28:1523-1528. Walker Z, Costa DC, Ince P, et al: In-vivo demonstration of dopaminergic degeneration in dementia with Lewy bodies. Lancet 1999; 354:646-647. Walker Z, Costa DC, Walker RW, et al: Differentiation of dementia with Lewy bodies from Alzheimer’s disease using a

173. 174. 175.

176. 177. 178.

179. 180. 181.

182. 183.

184. 185. 186. 187.

188. 189. 190. 191.

192. 193.

391

dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 2002; 73:134-140. Heafield MT, Gammage MD, Nightingale S, et al: Idiopathic dysautonomia treated with intravenous gammaglobulin. Lancet 1996; 347:28-29. Smit AA, Vermeulen M, Koelman JH, et al: Unusual recovery from acute panautonomic neuropathy after immunoglobulin therapy. Mayo Clin Proc 1997; 72:333-335. Ramirez C, de Seze J, Stojkovic T, et al: Pure subacute pandysautonomia: an assessment of treatment with intravenous polyvalent immunoglobulins. Rev Neurol (Paris) 2004; 160:939-941. Goetz CG, Tanner CM, Klawans HL: The pharmacology of olivopontocerebellar atrophy. Adv Neurol 1984; 41:143-148. Hughes AJ, Lees AJ, Stern GM: Apomorphine test to predict dopaminergic responsiveness in parkinsonian syndromes. Lancet 1990; 336:32-34. Staal A, Meerwaldt JD, van Dongen KJ, et al: Non-familial degenerative disease and atrophy of brainstem and cerebellum: clinical and CT data in 47 patients. J Neurol Sci 1990; 95:259-269. Hughes AJ, Colosimo C, Kleedorfer B, et al: The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry 1992; 55:1009-1013. Parati EA, Fetoni V, Geminiani GC, et al: Response to L-DOPA in multiple system atrophy. Clin Neuropharmacol 1993; 16:139-144. Albanese A, Colosimo C, Bentivoglio AR, et al: Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria. J Neurol Neurosurg Psychiatry 1995; 59:144-151. Gouider-Khouja N, Vidailhet M, Bonnet AM, et al: “Pure” striatonigral degeneration and Parkinson’s disease: a comparative clinical study. Mov Disord 1995; 10:288-294. Fetoni V, Soliveri P, Monza D, et al: Affective symptoms in multiple system atrophy and Parkinson’s disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 1999; 66:541-544. Rossi P, Colosimo C, Moro E, et al: Acute challenge with apomorphine and levodopa in Parkinsonism. Eur Neurol 2000; 43:95-101. Fearnley JM, Lees AJ: Striatonigral degeneration: a clinicopathological study. Brain 1990; 113(Pt 6):1823-1842. Rajput AH, Rozdilsky B, Rajput A, et al: Levodopa efficacy and pathological basis of Parkinson syndrome. Clin Neuropharmacol 1990; 13:553-558. Colosimo C, Albanese A, Hughes AJ, et al: Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson’s disease. Arch Neurol 1995; 52:294-298. Wenning GK, Ben-Shlomo Y, Magalhaes M, et al: Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:160-166. Quinn N: Multiple system atrophy. In Marsden CD, Fahn S, eds: Movement Disorders 3. London: Butterworth-Heinemann, 1994, pp 262-281. Duda JE, Giasson BI, Mabon ME, et al: Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 2002; 52:205-210. Gnanalingham KK, Byrne EJ, Thornton A, et al: Motor and cognitive function in Lewy body dementia: comparison with Alzheimer’s and Parkinson’s diseases. J Neurol Neurosurg Psychiatry 1997; 62:243-252. Louis ED, Goldman JE, Powers JM, et al: Parkinsonian features of eight pathologically diagnosed cases of diffuse Lewy body disease. Mov Disord 1995; 10:188-194. Louis ED, Klatka LA, Liu Y, et al: Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse

392

194. 195.

196.

197. 198. 199.

200. 201.

202. 203. 204.

205.

206.

207.

208. 209. 210. 211.

Section

VI

Au to n o m i c N e rvo u s Syst e m D i s e as e s

Lewy body disease and 34 pathologically confirmed cases of Parkinson’s disease. Neurology 1997; 48:376-380. Zesiewicz TA, Baker MJ, Dunne PB, et al: Diffuse Lewy body disease. Curr Treat Options Neurol 2001; 3:507-518. Poewe W, Granata R, Geser F: Pharmacologic treatment of Parkinson’s disease. In Watts RL, Koller WC, eds: Movement Disorders: Neurological Principles and Practice, 2nd ed. New York: McGraw-Hill, 2004, pp 247-271. Lees A: The treatment of the motor disorder of multiple system atrophy. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford: Oxford University Press, 1999, pp 357-363. Wenning GK, Geser F, Poewe W: Therapeutic strategies in multiple system atrophy (MSA). Mov Disord 2005; 20(Suppl 12):S67-S76. Poewe W: Treatment of dementia with Lewy bodies and Parkinson’s disease dementia. Mov Disord 2005; 20(Suppl 12):S77-82. Kaufmann H, Brannan T, Krakoff L, et al: Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology 1988; 38:951-956. Wright RA, Kaufmann HC, Perera R, et al: A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124. Low PA, Gilden JL, Freeman R, et al: Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997; 277:1046-1051. Jankovic J, Gilden JL, Hiner BC, et al: Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993; 95:38-48. Kaufmann H, Saadia D, Voustianiouk A, et al: Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 2003; 108:724-728. Mathias CJ, Senard JM, Braune S, et al: L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001; 11:235242. Alam M, Smith G, Bleasdale-Barr K, et al: Effects of the peptide release inhibitor, octreotide, on daytime hypotension and on nocturnal hypertension in primary autonomic failure. J Hypertens 1995; 13:1664-1669. Raimbach SJ, Cortelli P, Kooner JS, et al: Prevention of glucose-induced hypotension by the somatostatin analogue octreotide (SMS 201-995) in chronic autonomic failure: haemodynamic and hormonal changes. Clin Sci (Lond) 1989; 77:623-628. Mathias CJ, Fosbraey P, da Costa DF, et al: The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br Med J (Clin Res Ed) 1986; 293:353-354. Perera R, Isola L, Kaufmann H: Erythropoietin improves orthostatic hypotension in primary autonomic failure. Neurology 1994; 44(Suppl):A363. Biaggioni I, Robertson D, Krantz S, et al: The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994; 121:181-186. Hoeldtke RD, Streeten DH: Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 1993; 329:611-615. Perera R, Isola L, Kaufmann H: Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clin Auton Res 1995; 5:211213.

212. Winkler AS, Marsden J, Parton M, et al: Erythropoietin deficiency and anaemia in multiple system atrophy. Mov Disord 2001; 16:233-239. 213. Vagaonescu TD, Saadia D, Tuhrim S, et al: Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet 2000; 355:725-726. 214. Maclean A, Allen E: Orthostatic hypotension and orthostatic tachycardia, treatment with the “head up” bed. JAMA 1940; 115:2162-2167. 215. Ten Harkel AD, Van Lieshout JJ, Wieling W: Treatment of orthostatic hypotension with sleeping in the head-up tilt position, alone and in combination with fludrocortisone. J Intern Med 1992; 232:139-145. 216. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:93-103. 217. Jordan J, Shannon JR, Pohar B, et al: Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol 1999; 10:35-42. 218. Sakakibara R, Hattori T, Uchiyama T, et al: Are alphablockers involved in lower urinary tract dysfunction in multiple system atrophy? A comparison of prazosin and moxisylyte. J Auton Nerv Syst 2000; 79:191-195. 219. Goldstein I, Lue TF, Padma-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338:1397-1404. 220. Zesiewicz TA, Helal M, Hauser RA: Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson’s disease. Mov Disord 2000; 15:305308. 221. Hussain IF, Brady CM, Swinn MJ, et al: Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71:371-374. 222. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al: Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336:1-7. 223. Eichhorn TE, Oertel WH: Macrogol 3350/electrolyte improves constipation in Parkinson’s disease and multiple system atrophy. Mov Disord 2001; 16:1176-1177. 224. Boeve BF, Silber MH, Ferman TJ: Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4:281-284. 225. Wild R, Pettit T, Burns A: Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database Syst Rev 2003; (3):CD003672. 226. McKeith I, Fairbairn A, Perry R, et al: Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992; 305:673-678. 227. Ballard C, Grace J, McKeith I, et al: Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer’s disease. Lancet 1998; 351:1032-1033. 228. Sechi G, Agnetti V, Masuri R, et al: Risperidone, neuroleptic malignant syndrome and probable dementia with Lewy bodies. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24:1043-1051. 229. McKeith IG, Ballard CG, Harrison RW: Neuroleptic sensitivity to risperidone in Lewy body dementia. Lancet 1995; 346:699. 230. Rich SS, Friedman JH, Ott BR: Risperidone versus clozapine in the treatment of psychosis in six patients with Parkinson’s disease and other akinetic-rigid syndromes. J Clin Psychiatry 1995; 56:556-559. 231. Burke WJ, Pfeiffer RF, McComb RD: Neuroleptic sensitivity to clozapine in dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci 1998; 10:227-229.

chapter 30 primary autonomic failure 232. Walker Z, Grace J, Overshot R, et al: Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychiatry 1999; 14:459-466. 233. Aarsland D, Ballard C, Larsen JP, et al: Marked neuroleptic sensitivity in dementia with Lewy bodies and Parkinson’s disease. Nord J Psychiatry 2003; 57:94. 234. Iranzo A, Santamaria J, Tolosa E: Continuous positive air pressure eliminates nocturnal stridor in multiple system

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atrophy. Barcelona Multiple System Atrophy Study Group. Lancet 2000; 356:1329-1330. 235. Iranzo A, Santamaria J, Tolosa E, et al: Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 2004; 63:930-932.

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ORGANIZATION: PYRAMIDAL AND EXTRAPYRAMIDAL SYSTEM ●

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Glenda M. Halliday and Simon C. Gandevia

The large brains of primates have afforded remarkable behavioral adaptability. In humans, this adaptability is manifested in many ways, including the capacity for movements generated volitionally or somewhat automatically. Such movements include those required for speech and communication, for independent hand use, and for locomotion. Furthermore, these movements can be engaged in simultaneously, a feat that requires extraordinary adaptive control of the motoneuronal outputs to muscles. This occurs, for example, when a person talks and uses a mobile phone when walking or bicycling. This performance of skilled and complex movements can be generated by all components of the body’s musculature. Motoneuronal output to generate movements under volitional control is achieved by descending neural drive from socalled motor cortical centers that generate corticospinal and corticobulbar outputs, as well as corticoreticulospinal outputs.1 Since work in the late 19th and early 20th centuries on stimulation of motor cortex to elicit movements and on sectioning of the pyramidal tract to impair them, the important role of motor cortical outputs with axons in the medullary pyramids has been recognized. This emphasis has fitted with observations of paralysis and weaknesses after development of lesions of this system and with evidence for evolution of the size and terminations of the corticospinal system in primates. There are corticospinal outputs not only to interneurons within the spinal cord but also directly to motoneurons (termed corticomotoneuronal connections). The pyramidal tract itself, so named from the pyramidal decussation in the medulla, contains the bulk of direct corticofugal outputs destined to recruit spinal motoneurons.1 A primary role for the motor cortex in movement control has been paralleled by recognition that subcortical nuclei are also critically involved. Two subcortical systems appear crucial for adequate volitional movement: cortical interactions with the motor thalamus and the integration of information through the basal ganglia.2 The basal ganglia comprise a large number of integrated regions (see later discussion) that affect the motor system at the level of the thalamus and brainstem. Just as lesion and stimulation studies show the importance of motor cortical outputs, comparable approaches to study of the basal ganglia and thalamus have revealed that they profoundly gate and modify movements. Depending on the location of lesions or stimulation, there can be extreme poverty of all movements, abnormal postures, and uncontrollable rhythmic motor outputs.3

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THE EXTRAPYRAMIDAL MOTOR SYSTEMS The basal ganglia and thalamus comprise a number of anatomically integrated regions involved in motor control.4,5 They also play important roles in emotional, motivational, associative, and cognitive functions. Basal ganglia regions include the caudate nucleus, putamen, internal and external segments of the globus pallidus, subthalamic nucleus, and substantia nigra. These regions have complex anatomical interconnections that are not fully characterized electrophysiologically. Thalamic regions participating in motor control include specific ventral, posterior, and intralaminar nuclei.6 The understanding of how these regions integrate motor information is based largely on knowledge of their relationship to the corticospinal pyramidal system. There are three types of subcortical extrapyramidal regions to consider: those that receive direct information from pyramidal or cortical regions with major influences on pyramidal regions; those with projections to pyramidal or directly related regions; and those that perform internal monitoring and regulation of extrapyramidal regions.

Subcortical Regions Receiving Pyramidal Input and Their Influence on the Pyramidal System The largest subcortical extrapyramidal region receiving pyramidal input from both supragranular and infragranular regions of the motor cortices is the putamen (Figs. 31–1 and 31–2).4 Together with the caudate nucleus, this striatal area receives an information from all cortical regions. The putamen passes on processed information through both a direct activating and an indirect inactivating pathway to the basal ganglia output nuclei, the internal globus pallidus, and the substantia nigra pars reticulata.4 These basal ganglia regions are small in comparison with the striatum (100-fold fewer neurons) and contain large nonspiny γ-amino butyric acid–ergic (GABAergic) inhibitory projection neurons. Striatal neurons also receive excitatory thalamic input from the ventral anterior, ventrolateral nuclei, and caudal intralaminar nuclei; receive inhibitory input from the external globus pallidus; and are modulated by dopamine from the substantia nigra pars compacta and mesencephalic tegmentum.4,7 Overall dopamine enhances activity in the direct pathway and decreases activity in the indirect pathway.8 The striatum con-

chapter 31 organization: pyramidal and extrapyramidal system

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Cortical-cortical Premotor Pre-SMC 1˚ motor

Internal circuits

Throughput circuits

Dopamine GABA Glutamate ■

Figure 31–1. Basal ganglia internal feedback circuits (left) and throughput circuits (right). Projections from pyramidal neurons in the motor cortex innervate the putamen (red), the subthalamic nucleus (green), and the ventrolateral (gray) and caudal intralaminar (brown) thalamic nuclei. The basal ganglia output nuclei, the substantia nigra pars reticulata, and the internal globus pallidus (yellow), project to the motor thalamus (gray/brown) with information passing through a hyperdirect pathway from the subthalamus (green) or a direct pathway from the putamen (red) or an indirect pathway from the putamen (red) through the external globus pallidus (orange). Several feedback systems exist with information regulated within the putamen by γamino butyric acid–ergic (GABAergic) and cholinergic interneurons, by dopamine from the substantia nigra pars compacta (gray), and by glutamate from the caudal intralaminar thalamus (mauve). The subthalamic nucleus (green) and external globus pallidus (yellow) are strongly coupled.

tains mainly GABAergic spiny projection neurons and a small population of GABAergic and cholinergic interneurons (≈3% of striatal neurons). Striatal spiny neurons project to the globus pallidus and substantia nigra, as well as giving rise to dense local arbors that contact other spiny neurons.4 They are usually silent and discharge only when cortical information is received. The GABAergic interneurons establish contacts with the dendritic shafts of neighboring spiny neurons and form the structural basis for feedforward striatal surround inhibition. Striatal cholinergic interneurons, in contrast, are tonically active and play a major role in the learning of reward behavior. The smallest subcortical extrapyramidal region receiving pyramidal input from layer V neurons of the motor cortices is the subthalamic nucleus.9 This is the only cortical input to this nucleus, and this hyperdirect pathway conveys powerful excitatory effects from the motor cortices to the globus pallidus and substantia nigra pars reticulata, bypassing the striatum, with shorter conduction times than in the direct striatal pathway.9 It also receives significant inhibitory input from the globus pallidus and striatum.10 The subthalamic nucleus contains nonspiny excitatory glutamatergic neurons that conduct shortlatency excitatory responses to the globus pallidus and substantia nigra after cortical excitation.

Corticothalamic

Thalamocortical

Fast transmission Slow transmission ■

Figure 31–2. Pyramidal input to the thalamus (left) and thalamocortical pathways (right). Some corticocortical pathways are also indicated. Information from the presupplementary motor cortex (or area) is relayed to the supplementary and premotor cortices through the ventrolateral anterior (purple) and caudal intralaminar (brown) nuclei, as well by direct corticocortical connections. Feedback from the premotor cortices to the pre-SMC occurs via the mediodorsal thalamus (blue), whereas reciprocal feedback between the primary (1°) motor cortex and the ventrolateral posterior thalamus (purple).

Specific regions of the thalamus also receive pyramidal input from motor cortices.5 There is a reciprocal excitatory component from small layer VI neurons to the ventrolateral thalamus and a fast-conducting nonreciprocal excitatory component from layer V neurons that allows the synchronization of thalamocortical oscillations and information flow across functionally related cortical fields. Cortical regions associated with executive function (such as dorsolateral prefrontal cortex) have nonreciprocal connections to thalamic regions that project to premotor cortices (ventral anterior thalamus), whereas premotor cortices have nonreciprocal connections with thalamic regions that project to the primary motor cortex (ventrolateral thalamus).11 The thalamus contains nonspiny excitatory glutamatergic neurons that conduct short-latency excitatory responses after appropriate cortical excitation. These interconnections between the cortex and thalamus largely determine cortical activity, facilitating information transfer from one cortical region to another through a feedforward mechanism. The output nuclei of the basal ganglia inhibit thalamocortical activity in the ventral anterior, anterior ventrolateral, and caudal intralaminar nuclei.11

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Subcortical Regions Participating in the Internal Regulation of Extrapyramidal Systems There is significant internal modulation of the hyperdirect, direct, and indirect basal ganglia pathways (see Fig. 31–1). One of the basal ganglia regions that most influence striatal processing is the dopaminergic substantia nigra pars compacta, as discussed previously, although pallidal and thalamic projections also significantly modify striatal output. The large, tonically active, nonspiny dopaminergic neurons of the substantia nigra pars compacta receive input directly from striatal spiny projection neurons, which modifies their firing rate and patterns.8 This reinforces wanted behaviors and suppresses unwanted behaviors. These dopaminergic neurons also receive significant innervation from cortical, limbic, and brainstem regions and play a role in shifting attentional sets. The basal ganglia region with the most internal connections is the external segment of the globus pallidus.4 These pallidal neurons receive most input from the striatum and the subthalamic nucleus, as well as a small dopaminergic projection from the substantia nigra. Individual neurons in the external globus pallidus innervate the output nuclei, the subthalamic nucleus, and the substantia nigra pars compacta.4 About 25% of them also innervate the striatal GABAergic spiny neurons. These neurons provide the anatomical substrate for the synaptic integration of functionally diverse cortical information within the basal ganglia and appear to work in parallel with the subthalamic nucleus and striatum to set up appropriate oscillatory activity within the basal ganglia.10 They are therefore in a position to provide level-setting control of the activity through virtually the whole of the extrapyramidal basal ganglia system.

corresponds to the lower part of Brodmann’s area 6 and may be functionally subdivided into two or three regions. An alternative nomenclature derived by Matelli and colleagues15 refers to these areas as F4 and F5, F1 being the traditional primary motor cortex. The ventral premotor cortex areas are likely to be involved in the transformation of information about peripersonal space and visual space into motor commands for movements, particularly of the upper limb. The dorsal premotor cortex corresponds to the superior part of area 6, which also can be subdivided on functional grounds (F2 and F7). The precise role of F2 is debated, but it is involved in reaching and visual signaling. The F7 area is involved in eye movement control and perhaps also in stimulus-response associations for movements.16 The mesial part of area 6, once considered to be a single area, the supplementary motor area, is now subdivided into the supplementary motor area proper (F3) and the presupplementary motor area (F6). The supplementary motor area was originally defined in humans by Penfield and Welch.17 The main supplementary motor area is involved in preparation and selection of movements and perhaps in the initial learning of motor sequences.18 Finally, there are motor cortical areas within the cingulate sulcus (Brodmann areas 23 and 24), termed the rostral, dorsal, and ventral cingulate motor areas. The motor function of these nonprimary motor cortical areas has been discerned by a mixture of methods, including electrical stimulation and neurophysiological mapping, neuroanatomical tracing, and functional neuroimaging in primates. These areas not only contain some somatotopic organization (e.g., face, arm, and leg separations) but also have some direct projections of varying strength to the primary motor cortex and to the brainstem and spinal cord.1,19,20

Primary Motor Cortex THE MOTOR CORTICES AND PYRAMIDAL SYSTEM Pyramidal neurons in the somatomotor cortices send corticospinal and corticobulbar axons through the pyramidal tract. The primary motor cortex is usually known as area 4, defined according to Brodmann’s classic analysis of the cytoarchitecture of the human brain.12 In addition to its own local circuitry, it contains a topographically organized motor output to the bulbar muscles and to the trunk and extremities. The precise borders of this and other areas have been disputed partly because it is difficult to depict the areas precisely on maps of the cortical surface, which cannot reveal the borders in the depths of sulci (for review, see Zilles13). The caudal border of the primary motor cortex is clearly demarcated in the fundus of the central sulcus with its rostral border close to the anterior of the central sulcus. Hence, laterally over the hemisphere, the main part of area 4 lies in the central sulcus rather than on the external cortical surface. This delineation of the rostral edge of the primary motor cortex varies between individuals and relies on several architectural and cytoarchitectural features (see later discussion), and its existence is supported by highresolution imaging and cytoarchitectonic mapping.14 Before some of the specific features of the primary motor cortex are described, other cortical areas that have a motor function must be recognized. Although several nomenclatures exist for these areas, there is broad agreement that the following cortical areas are involved. The ventral premotor cortex

Certain anatomical features are unusual for this cortical region. First, it has the greatest cortical thickness (≈3.8 mm, the adjacent sensory cortex being narrowest at ≈1.8 mm), and it has a relatively low density of neuronal cell bodies.13 Presumably this allows substantial synaptic integration for flexible selection of motor outputs. Second, the area is agranular, lacking an obvious layer IV, and it contains giant Betz cells. These pyramidal neurons are characterized by large and variable size and the presence of many dendrites originating from their cell bodies, in addition to their major apical and basal dendrites.21 Pyramidal cells with output to subcortical and cortical regions are distributed throughout layers II to VI, with the majority in layers III and V. Layer V has a low density of neuronal packing, and approximately 15% of cells have projections through the pyramidal tract and are thus corticospinal cells. Such projections probably make up about 30% of the descending pyramidal tract (see later discussion). The projecting axons are largely myelinated with a range of conduction velocities. The intrinsic connectivity of the primary motor cortex, as in most of the cortex, is arranged radially in columns. Intrinsic nonpyramidal neurons (including stellate and basket cells) have radially oriented dendrites and make largely local connections. Basket cells exert GABAergic inhibition of pyramidal cell output, part of a recurrent, laterally spreading inhibitory circuit from local corticofugal cells.22 About a third of local pairs of primary cortical cells show evidence of correlated drive during tasks, which indicates that they are receiving common inputs.23,24

chapter 31 organization: pyramidal and extrapyramidal system Cortical and Thalamic Input to the Pyramidal System According to findings with various neuroanatomical techniques and electrophysiological mapping, many cortical areas project directly to the primary motor cortex (see Fig. 31–2).15 These include the ventral and dorsal premotor areas (both subfields of area 6), supplementary motor areas, and cingulate (rostral, dorsal, and ventral) motor areas. Some degree of somatotopic organization is maintained in these projections to the primary motor cortex. Sensory information from parietal areas also project either directly or indirectly through sensory cortex to the motor cortex.25 Corticocortical projection neurons are usually derived from the small supragranular pyramidal neurons and provide excitatory drive to supragranular neurons in nearby cortical regions. Within the cortical columns, these supragranular neurons provide strong excitatory drive to the large layer V pyramidal output neurons, thus reinforcing the thalamic input to these neurons. As discussed previously, a number of thalamic nuclei assist in determining cortical activity by facilitating information transfer from one cortical region to another through a feedforward mechanism.11 In particular, the ventral anterior thalamus feeds forward executive information to premotor cortices

(under basal ganglia influence), the ventrolateral anterior thalamus feeds forward premotor information to the primary motor cortex (under basal ganglia and cerebellar influence), and the ventrolateral posterior thalamus provides feedback from primary motor cortex (under cerebellar influence). These reciprocal and nonreciprocal corticothalamocortical connections form cohesive integrated circuits for the control of movement.11

Corticospinal Outputs and Their Origin In addition to major corticofugal outputs to the medullary motor nuclei and the spinal cord from the lower part of layer V in the primary motor cortex, the upper part of its layer V has outputs to the striatum, red nucleus, pons, and reticular formation (Fig. 31–3). The focal outputs to the principal relay nuclei of the thalamus originate in layer VI, whereas corticocortical, corticostriate, and corticocallosal fibers arise from layer III.26,27 Evolution of mammals and ultimately primates appears to have shaped the outputs to the medulla and spinal cord similarly, with a progressive shift away from projections to sensory nuclei and toward the motor nuclei. The most direct projections—that is, monosynaptic corticomotoneuronal

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Motor cortices Planning of voluntary movements

Motor cortical and other corticospinal outputs

Input from muscle and other afferents

Other supraand propriospinal outputs

Spinal cord α and γ motoneurons

Muscle

Corticospinal tract

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Figure 31–3. Pyramidal pathway through the corticospinal tract (left) and the influences most directly affecting the motoneurons innervating muscle (right).

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connections—arise largely from the caudal part of area 4. These outputs diverge at the motoneuronal level in such a way that one corticospinal axon can supply more than one motoneuron pool monosynaptically, and it probably synapses on many motoneurons within each pool.28 The primary motor cortex is concerned not with contraction of single muscles but with the actions of whole groups of functionally related muscles. Its function is to bring them to action both in specific movements and when a more static posture is maintained.29 The divergence of primary motor cortical output and the presence of multiple motor cortical areas allows for parallel control of muscle activity. The densest projections to the motoneuron pools arise in the primary motor cortex.19

COMMENTS ON FUNCTION AND CONCLUSIONS The following points deal with some of the complications of pyramidal and extrapyramidal functional anatomy as discussed in this chapter: 1. There is no comprehensive model of the motor cortical system that takes into account the range of inputs reaching the primary motor cortex or its multiple output paths, many of which are effectively “upstream” of the final common path at the motoneuron pool. Although description of the anatomical complexity promotes physiological insight, the special microcircuitry of the primary motor cortex and its increasing monosynaptic projection to motoneurons in primates emphasize its pivotal role in volitional movement. At a more fine-grained level, defining the anatomical convergent and divergent projections of the major motor cortical area is only one step in generating a comprehensive model, because it will ultimately be necessary to incorporate synaptic function. 2. There is increasing recognition of the importance of the different cortical areas that project to the motoneuron pool. Many of these premotor and cingulate regions receive a specific dominant set of projections from the thalamus, prefrontal cortices, and parietal lobe, and they are thus likely to have a more specialized role in shaping the final motor output. This implies that any functional “units” of cortical control of movement must include both its sensory input (through parietal projections) and its higher order motor role (through prefrontal projections) relating to, for example, motivation, planning, and skill acquisition. However, studies based on clinical lesions, electrical stimulation, and neuroimaging reveal the capacity of the different motor cortical areas to “take over,” at least partially, the functions of others. Hence, properties of ipsilateral corticospinal projections are altered after a middle cerebral artery stroke or when one motor cortical region is temporally depressed.30 3. Although the human corticospinal system can exert its actions on the motoneuron pool through direct monosynaptic input, less direct routes are important and numerically predominant. The corticospinal system is heavily engaged in fine motor tasks, but some of this motor command reaches motoneurons via less direct routes, including an important set of propriospinal premotoneurons.31,32 One function for the corticospinal system is the appropriate recruitment of these spinal premotor circuits.

K E Y

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The corticospinal pyramidal system arises from frontal motor cortical regions, which differ in their organization and function. Corticospinal neurons from primary motor cortex directly innervate motoneurons; corticospinal neurons from other motor cortices largely innervate excitatory and inhibitory spinal interneurons.

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Interconnections between the cortex and thalamus largely determine cortical activity, facilitating information transfer from one cortical region to another through feedforward and feedback mechanisms.

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The basal ganglia extrapyramidal system consists of three intersecting pathways (hyperdirect, direct, and indirect) that innervate the inhibitory output nuclei of the basal ganglia and process cortical information that modulates thalamocortical motor activity and drive.

Suggested Reading 1. Matelli M, Luppino G, Geyer S, et al: Motor cortex. In Paxinos G, ed: The Human Nervous System. New York: Academic Press, 2004, pp 973-996. 2. Rizzolatti G, Luppino G: The cortical motor system. Neuron 2001; 31:889-901. 3. Porter R, Lemon RN: Corticospinal Function and Voluntary Movement. Oxford, UK: Clarendon, 1993. 4. Nambu A: A new dynamic model of the cortico-basal ganglia loop. Prog Brain Res 2004; 143:461-466. 5. Bolam JP, Hanley JJ, Booth PA, et al: Synaptic organization of the basal ganglia. J Anat 2000; 196:527-542.

References 1. Dum RP, Strick PL: Motor areas in the frontal lobe of the primate. Physiol Behav 2002; 77:677-682. 2. Sherman SM, Guillery RW: On the actions that one nerve cell can have on another: distinguishing “drivers” from “modulators.” Proc Natl Acad Sci U S A 1998; 95:7121-7126. 3. Vilensky JA, Gilman S: Integrating the work of D. DennyBrown and some of his contemporaries into current studies of the primate motor cortex. J Neurol Sci 2001; 182:83-87. 4. Bolam JP, Hanley JJ, Booth PA, et al: Synaptic organisation of the basal ganglia. J Anat 2000; 196:527-542. 5. Guillery RW, Sherman SM: The thalamus as a monitor of motor outputs. Philos Trans R Soc Lond B Biol Sci 2002; 357:1809-1821. 6. Darian-Smith C, Darian-Smith I: Thalamic projections to areas 3a, 3b, and 4 in the sensorimotor cortex of the mature and infant macaque monkey. J Comp Neurol 1993; 335:173199. 7. Smith Y, Raju DV, Pare JF, et al: The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 2004; 27:520-527. 8. Onn SP, West AR, Grace AA: Dopamine-mediated regulation of striatal neuronal and network interactions. Trends Neurosci 2000; 23:S48-S56. 9. Hamani C, Saint-Cyr JA, Fraser J, et al: The subthalamic nucleus in the context of movement disorders. Brain 2004; 127:4-20.

chapter 31 organization: pyramidal and extrapyramidal system 10. Bevan MD, Magill PJ, Terman D, et al: Move to the rhythm: oscillations in the subthalamic nucleus–external globus pallidus network. Trends Neurosci 2002; 25:525-531. 11. Haber S, McFarland NR: The place of the thalamus in frontal cortical-basal ganglia circuits. Neuroscientist 2001; 7:315-324. 12. Brodmann K: Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth, 1909, p 324. 13. Zilles K: Architecture of the human cerebral cortex: regional and laminar organization. In Paxinos G, ed: The Human Nervous System. New York: Academic Press, 2004, pp 9971055. 14. Geyer S, Ledberg A, Schleicher A, et al: Two different areas within the primary motor cortex of man. Nature 1996; 382:805-807. 15. Matelli M, Luppino G, Geyer S, et al: Motor cortex. In Paxinos G, ed: The Human Nervous System. New York: Academic Press, 2004, pp 973-996. 16. Passingham RE: The Frontal Lobe and Voluntary Action. Oxford, UK: Oxford University Press, 1993. 17. Penfield W, Welch K: The supplementary motor area of the cerebral cortex; a clinical and experimental study. AMA Arch Neurol Psychiatry 1951; 66:289-317. 18. Tanji J: New concepts of the supplementary motor area. Curr Opin Neurobiol 1996; 6:782-787. 19. Lemon RN, Maier MA, Armand J, et al: Functional differences in corticospinal projections from macaque primary motor cortex and supplementary motor area. Adv Exp Med Biol 2002; 508:425-434. 20. Miyachi S, Lu X, Inoue S, et al: Organization of multisynaptic inputs from prefrontal cortex to primary motor cortex as revealed by retrograde transneuronal transport of rabies virus. J Neurosci 2005; 25:2547-2556. 21. Scheibel ME, Scheibel AB: The dendritic structures of the human Betz cell. In Braxier AAB, Pets H, eds: Architectonics

22. 23. 24. 25. 26. 27. 28. 29. 30.

31. 32.

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of the Cerebral Cortex. New York: Raven Press, 1978, pp 4357. Hendry SH, Houser CR, Jones EG, et al: Synaptic organization of immunocytochemically identified GABA neurons in the monkey sensory-motor cortex. J Neurocytol 1983; 12:639-660. Fetz EE, Shupe LE: Neural network models of the primate motor system. In Eckmiller R, ed: Advanced Neural Computers. Amsterdam: Elsevier, 1991, pp 43-50. Baker SN, Olivier E, Lemon RN: An investigation of the intrinsic circuitry of the motor cortex of the monkey using intracortical microstimulation. Exp Brain Res 1998; 123:397-411. Jones EG: Ascending inputs to, and internal organization of, cortical motor areas. Ciba Found Symp 1987; 132:21-39. Jones EG, Wise SP: Size, laminar and columnar distribution of efferent cells in the sensory-motor cortex of monkeys. J Comp Neurol 1977; 175:391-438. Jones EG: Laminar distribution of cortical efferent cells. In Peters A, Jones EG, eds: Cerebral Cortex. New York: Plenum Press, 1984. Lemon RN, Baker SN, Davis JA, et al: The importance of the cortico-motoneuronal system for control of grasp. Novartis Found Symp 1998; 218:202-218. Kurtzer I, Herter TM, Scott SH: Random change in cortical load representation suggests distinct control of posture and movement. Nat Neurosci 2005; 8:498-504. Strens LH, Fogelson N, Shanahan P, et al: The ipsilateral human motor cortex can functionally compensate for acute contralateral motor cortex dysfunction. Curr Biol 2003; 13:1201-1205. Pierrot-Deseilligny E: Propriospinal transmission of part of the corticospinal excitation in humans. Muscle Nerve 2002; 26:155-172. Fetz EE, Perlmutter SI, Prut Y, et al: Roles of primate spinal interneurons in preparation and execution of voluntary hand movement. Brain Res Brain Res Rev 2002; 40:53-65.

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Ramón C. Leiguarda

Apraxia is one of the more frequent consequences of brain damage and can lead to severe disabilities in daily life. The term apraxia covers a wide spectrum of higher order motor disorders caused by acquired brain disease that affects the performance of skilled, learned movements with or without preservation of the ability to perform the same movement outside the clinical setting in the appropriate situation or environment. The disturbance of purposive movements cannot be termed apraxia, however, if it results from a language comprehension disorder or from dementia or if the patient suffers from any elementary motor or sensory deficit (i.e., paresis, dystonia, ataxia) that could fully explain the abnormal motor behavior.1-3 Apraxia is found mostly in patients with stroke, but the disorder can result from a wide variety of other focal lesions (i.e., trauma, tumors) or from diffuse brain damage as observed in Alzheimer’s disease or corticobasal degeneration.2 Praxic disorders may affect various body parts, such as the eyes, face, trunk, or limbs, and may involve both sides of the body (i.e., ideational and ideomotor apraxias), one side preferentially (i.e., limb-kinetic apraxia [LKA]), or, alternatively, interlimb coordination, as in the case of apraxia of gait.

LIMB APRAXIAS Hugo Liepmann originally posited that the idea of the action, or movement formula, containing the space-time picture of the movement, was stored in the left parietal lobe and that in order to carry out a skilled movement, the space-time plan must first be retrieved and associated via cortical connections with the innervatory pattern stored in the left sensorimotorium— mainly the premotor cortex—which in turn conveys the information on formula to the left primary motor areas. When the left limb performs the movement, the information must be transmitted from the left to the right sensorimotorium through the corpus callosum to activate, thereafter, the right motor cortex. Liepmann conceived of ideational apraxia as a disruption of the space-time plan or its proper activation, so that it was impossible to construct the idea of the movement; the patient would not know what to do. In contrast, in ideomotor apraxia, the space-time plan was intact but it could no longer guide the innervatory engrams that implemented the movement because it was disconnected from them; the patient knew

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what to do but not how to do it. Finally, LKA appeared when the disruption of the innervatory engrams interfered with the selection of the muscle synergies necessary to perform the skilled movement.4,5 Liepmann’s initial description and classification of these three types of apraxia have such clarity and influence that they still underlie the most widely used existing schemes of apraxic disturbances. In 1985, Roy and Square6 advanced a model for the organization of action that was based on the operation of a two-part system involving both conceptual and production components. The conceptual system involves knowledge of objects and tools in terms of the actions and functions they serve and knowledge of actions independent of tools or objects but in which the use of tools and objects may be incorporated. On the other hand, the production system incorporates a sensorimotor component of knowledge, as well as encompassing the perceptual motor processes for organizing and executing action. According to this model, dysfunction of the praxis conceptual system would give rise to conceptual or ideational apraxia, whereas impairment of the praxis production system would induce ideomotor apraxia.6 Thereafter, an influential cognitive neuropsychological model, also mapped onto the model of language processing, was introduced by Rothi and colleagues.7 They proposed to separate input pathways for verbal and visual stimuli to explain the dissociation between the ability to perform an action on command versus on imitation; to separate semantic and nonsemantic pathways to account for dissociations in the ability to represent meaningful versus meaningless actions; and to separate input and output lexicons to allow for differences in the ability to conceptualize actions and to perform them.7 More recently, Buxbaum and associates8 proposed an interplay between a dynamic body-centered representation of actions and stored representation of learned actions in order to explain the different forms of ideomotor apraxia, and Leiguarda and Marsden9 suggested that the most common form of ideomotor apraxia as well as of LKA can be interpreted as caused by disruption of multiple parallel parietofrontal circuits involved in sensorimotor transformations.

Evaluation of Limb Praxis A systematic evaluation of limb praxis is crucial in order to (1) identify the presence of apraxia, (2) classify correctly the nature

chapter 32 apraxia T A B L E 3 2 – 1.

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Assessment of Limb Praxis

Intransitive movements Transitive movements Tool* selection tasks Alternative tool selection tasks Mechanical problem-solving task Multiple-step tasks Gesture recognition and discrimination tasks

Nonrepresentational (e.g., touch your nose, wiggle your fingers). Representational (e.g., wave goodbye, hitchhike) (e.g., use a hammer or use a screwdriver) under verbal, visual, and tactile modalities Imitation of meaningful and meaningless movements, postures, and sequences To select the appropriate tool to complete a task, such as a hammer for a partially driven nail To select an alternative tool such as pliers to complete a task such as pounding a nail, when the appropriate tool (i.e., hammer) is not available (e.g., to select the appropriate one of three novel tools for lifting a wooden cylinder out of a socket). (e.g., to prepare requiring actions such as prepare a letter for mailing) To assess the capacity to comprehend gestures, either verbally (to name gestures performed by the examiner) or nonverbally (to match a gesture performed by the examiner with cards depicting the tool/object† corresponding to the pantomime); and to assess the ability to discriminate a well from a wrongly performed gesture

From Leiguarda R: Apraxias as traditionally defined. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 303-338. *Tool: implement with which an action is performed (e.g., hammer, screwdriver). † Object: the recipient of the action (e.g., nail, screw).

of limb praxis deficit according to the errors committed by the patient and the modality through which these errors are elicited, and (3) gain an insight into the underlying mechanism of the patient’s abnormal motor behavior (Table 32–1). A patient’s performance should be assessed in both forelimbs if an elementary sensorimotor deficit does not preclude testing the limb contralateral to the damaged hemisphere. Several types of intransitive and transitive movements must be evaluated because apraxic patients commonly perform some but not all movements in a particularly abnormal manner and/or because individual differences appear in some but not all components of a given movement. Therefore, the dissimilar complexity and particular features of each skill movement should be considered in order to analyze and interpret praxic errors accurately. For instance, (1) movements may or may not be repetitive in nature (e.g., hammering versus using a bottle opener to remove a cap); (2) an action may be composed of sequential movements (e.g., reaching for a glass and raising it to one’s lips to drink); (3) a movement may primarily reflect proximal limb control (transport) (e.g., transporting the wrist when carving a turkey), proximal and distal limb control (e.g., reaching for and grasping a glass of water), or primarily distal control (e.g., manipulating a pair of scissors); and (4) movements may be performed in the peripersonal space (e.g., carving a turkey) or in a body-centered space (e.g., brushing teeth) or require the integration of both (e.g., drinking). Transitive movements should be assessed under different modalities, including verbal, visual (seeing the tool or the object on which the tool works), and tactile (using actual tools and/or objects), as well as on imitation, because impairment can be seen under some performance conditions but not others. Nevertheless, the most sensitive test for apraxia is to ask patients to pantomime to verbal commands, because actions must be performed without guidance through visual or tactile feedback from the object and thus are almost entirely dependent on stored movement representations. In addition to the specific praxis assessment tasks listed in Table 32–1, it is important to carry out a complete cognitive evaluation, because findings may contribute to an understanding of the neural mechanisms of some praxic deficits. Analysis of a patient’s performance is based on both accuracy and error patterns (Table 32–2). Detailed error analysis is

crucial both for unveiling and for properly classifying an apraxic disorder; patients with ideational apraxia have difficult mainly with sequencing actions (e.g., making coffee) and exhibit content errors or semantic parapraxias (e.g., mimicking use of a hammer when requested to use a knife). Patients with ideomotor apraxia show primarily temporal and spatial errors, which are more evident when they perform transitive rather than intransitive movements. Errors in LKA represent slowness, coarseness, and fragmentation of finger and hand movements.2,3 Three-dimensional motion analysis of different types of movements has provided a better and more accurate method of objectively capturing the nature of the praxis errors observed in clinical examination. Patients with ideomotor apraxia caused by focal left hemisphere lesions, by different asymmetrical cortical degenerative syndromes, and by basal ganglion disease have shown several kinematic abnormalities of dissimilar complexity, such as slow and hesitant build up of hand velocity, irregular and nonsinusoidal velocity profiles, abnormal amplitudes, alterations in the plane of motion and in the directions and shapes of wrist trajectories, decoupling of hand speed and trajectory curvature, and loss of interjoint coordination (Fig. 32–1).10,11 The study of manipulating finger movements in patients with LKA also disclosed severe abnormalities that unveiled the nature of the motor deficit. The workspace is highly irregular and of varying amplitude, there is breakdown of the temporal profiles of the scanning movements, and, overall, severe lack of coordination between fingers has been found (Fig. 32–2).12

Lateralization of Praxic Functions Apraxia, as tested by the imitation of gestures and object use pantomime, has been found in about 50% of patients with left hemisphere damage and in fewer than 10% of those with right hemisphere damage,1 which means that some praxic functions or some specific components of learned skilled movement are bilaterally represented or are preferentially processed in the right hemisphere. Nevertheless, most of the errors exhibited by patients with ideomotor apraxia are seen equally in patients with left or right hemisphere damage when they pantomime

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T A B L E 3 2 – 2. Types of Praxis Errors Temporal S = sequencing: Some pantomimes require multiple positionings that are performed in a characteristic sequence. Sequencing errors involve any perturbation of this sequence, including addition, deletion, or transposition of movement elements as long as the overall movement structure remains recognizable. T = timing: This error reflects any alterations from the typical timing or speed of a pantomime and may include abnormally increased, decreased, or irregular rate of production or searching or groping behavior. O = occurrence: Pantomimes may involve either single (i.e., unlocking a door with a key) or repetitive (i.e., screwing in a screw with a screwdriver) movement cycles. This error type reflects any multiplication of single cycles or reduction of a repetitive cycle to a single event. Spatial A = amplitude: Any amplification, reduction, or irregularity of the characteristic amplitude of a target pantomime. IC = internal configuration: When pantomiming, the fingers and hand must be in specific spatial relation to one another to reflect recognition and respect for the imagined tool. This error type reflects any abnormality of the required finger/hand posture and its relationship to the target tool. For example, when asked to pretend to brush teeth, the subject’s hand may close tightly into a fist with no space allowed for the imagined toothbrush handle. BPO = body-part-as-object: The subject uses his/her finger, hand, or arm as the imagined tool of the pantomime. For example, when asked to smoke a cigarette, the subject might puff on his or her index finger. ECO = external configuration orientation: When pantomiming, the fingers/hand/arm and the imagined tool must be in a specific relationship to the “object” receiving the action. Errors of this type involve difficulties orienting to the “object” or in placing the “object” in space. For example, the subject might pantomime brushing teeth by holding his/her hand next to his/her mouth without reflecting the distance necessary to accommodate an imagined toothbrush. Another example would be when asked to hammer a nail, the subject might hammer in differing locations in space, reflecting difficulty in placing the imagined nail in a stable orientation or in a proper plane of motion (abnormal planar orientation of the movement). M = movement: When acting on an object with a tool, a movement characteristic of the action and necessary to accomplish the goal is required. Any disturbance of the characteristic movement reflects a movement error. For example, a subject, when asked to pantomime using a screwdriver, may orient the imagined screwdriver correctly to the imagined screw but instead of stabilizing the shoulder and wrist and twisting at the elbow, the subject stabilizes the elbow and twists at the wrist or shoulder. Content P = perseverative: The subject produces a response that includes all or part of a previously produced pantomime. R = related: The pantomime is an accurately produced pantomime associated in content with the target. For example, the subject might pantomime playing a trombone for a target of a bugle. N = nonrelated: The pantomime is an accurately produced pantomime not associated in content with the target. For example, the subject might pantomime playing a trombone for a target of shaving. H = the patient performs the action without benefit of a real or imagined tool: For example, when asked to cut a piece of paper with scissors, he or she pretends to rip the paper. Other NR = no response. UR = unrecognizable response: The response shares no temporal or spatial features of the target. From Rothi LJG, Heilman KM, eds: Apraxia: The Neuropsychology of Action. East Sussex, UK: Psychology Press, 1997.

nonrepresentative and representative/intransitive gestures, but they are observed predominantly in patients with left hemisphere damage when they pantomime transitive movements, because this action is performed outside the natural context. Moreover, it has been suggested that, whereas either hemisphere would be able to process both intransitive movements and transitive movements with tools/objects, the left hemisphere would be dominant not only for the “abstract” performance (pantomiming to verbal command) of transitive movements but also for learning and reproducing novel movements such as meaningless movements and sequences.3 The left hemisphere also seems to be specialized for the selection of limb movements that are appropriate for the use of an object and for the retrieval of action knowledge in general, including knowledge related to tools.3 Most functional neuroimaging studies in which researchers have evaluated pantomiming tool-use gestures have revealed activation of parietofrontal areas predominantly in the left hemisphere, regardless of which hand was used.13-15 Frydman and colleagues16 specifically studied the lateralization of praxis assessed through pantomiming transitive gestures. They found that transitive gestures involving mainly distal muscles when pantomimed with the right hand activated frontoparietal asso-

ciation areas in the left hemisphere. When the same movement was performed with the left hand, activation also predominated on the left hemisphere, with the exception of the premotor cortex, which showed bilateral activation in most subjects. In turn, transitive gestures involving proximal limb movements performed with either the right or the left hand caused bilateral parietofrontal activation. Thus, transitive gestures, when pantomimed in response to verbal command, are differentially represented interhemispherically and intrahemispherically, depending on whether the movement involves predominantly proximal or distal musculature and whether it is performed with the right or the left hand.16

Types of Limb Apraxia Ideational or Conceptual Apraxia Liepmann defined ideational apraxia as an impairment in performing tasks that required a sequence of several acts with tools and objects (e.g., prepare a letter for mailing).5 However, other authors use the term to denote a failure to use single tools appropriately.2 To overcome this confusion, Ochipa and associ-

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Figure 32–1. Kinematic correlates of ideomotor praxis errors. A, Lateral and frontal views of reconstructed trajectories of limb segments during a slicing gesture performed by a control subject and by a patient with ideomotor apraxia (IMA). In the control, wrist trajectories (top left and right) follow a path perpendicular to the target/object and are aligned along the sagittal plane with slight vertical and horizontal displacement, whereas the patient (bottom left and right) exhibits abnormal lateral wrist displacement and incorrect movement axis orientation. B, Superior, lateral, and frontal views of wrist paths in a control subject (left) and in patients with ideomotor apraxia (right). C, Interjoint coordination in a control subject (top left and right) and in a patient with ideomotor apraxia (bottom left and right). The control subject shows a smooth and linear relationship between elbow flexion/extension and upper arm yaw; as the elbow extends, the upper arm moves laterally across the body in a well-coordinated pattern. The patient, in contrast, shows distorted angle/angle relationships as a result of poor coordination between elbow flexion/extension and upper arm yaw, as well as asynchronous intersegmental joint velocities. Continued

ates17 suggested restricting the term ideational apraxia to a failure to conceive a series of acts leading to an action goal, and they introduced the term conceptual apraxia to denote a loss of knowledge of how objects are used. However, a strict difference between ideational and conceptual apraxia is not always feasible, inasmuch as patients with ideational apraxia not only fail on tests of multiple object use but may also perform abnormally when using a single object. Thus, ideational apraxia or conceptual apraxia could be defined as a deficit in the conception of a single movement or of a sequence of them, so that the patient does not know what to do.3

Patients with ideational or conceptual apraxia exhibit primarily content errors or semantic parapraxias (e.g., using a comb as a toothbrush) in the performance of transitive movements (see Table 32–2). They are unable to associate tools with the objects that receive their action; thus, when a partially driven nail is shown, the patient may select a pair of scissors rather than a hammer from an array of tools to complete the action and may also fail to describe the function of a tool or be unable to point out a tool when its function is described by the examiner. In addition, a patient may have difficulties in matching objects for shared purposes: for example, when asked to

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Figure 32–2. Kinematic analysis of manipulative finger movements. Spatial and temporal characteristics of manipulative finger movements in a control subject (top left and right) and in a patient with LKA (bottom left and right). In A and C, three-dimensional views of fingertips are displayed. In B and D, the temporal variation of movement trajectories is shown. The movements of the patient with limb-kinetic apraxia (LKA) showed highly disrupted spatial organization and deranged temporal characteristics, distinctly different from those of the control subject.

complete an action and the appropriate tool is not available (e.g., a hammer to drive a nail), the patient may select not the most adequate tool for that action (e.g., a wrench) but rather one that is inadequate (e.g., a screwdriver).18 Patients with ideational apraxia are impaired in the sequencing of tool/object use, exhibiting many types of errors including deletion, addition, omission, misuse, substitution, and perseveration and are disabled in everyday life, because they use tools/objects improperly, select the wrong tools/objects for an intended activity, perform a complex sequential activity (e.g., making espresso) in a wrong order, or cannot complete the task at all.19 Ideational

apraxia has been traditionally allocated to the left parietooccipital and parietotemporal regions, although left frontal and frontotemporal lesions may also cause ideational apraxia or conceptual apraxia.5,18,19 Nevertheless, semantic or conceptual errors are observed particularly in patients with temporal lobe pathology (e.g., semantic dementia).20

Ideomotor Apraxia Ideomotor apraxia has been defined as “an impairment in the timing, sequencing, and spatial organization of gestural

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movements.”7 Patients with ideomotor apraxia exhibit mainly temporal and spatial errors. The movements are incorrectly produced, but the goal of the action can usually be recognized. Transitive movements are more affected than intransitive ones when patients pantomime in response to commands, and patients usually do better on imitation than when responses are elicited through verbal commands. Acting with tools/objects is performed better than pantomiming their use, but even so, movements may not be entirely normal. Ideomotor apraxia is commonly associated with damage to the parietal association areas surrounding the intraparietal sulcus, less frequently with lesions of the premotor and prefrontal cortices and supplementary motor area, and usually with disruption of the intrahemispheric white matter bundles that interconnect parietal and frontal areas. Small lesions of the basal ganglia and thalamus may cause ideomotor apraxia, but in the majority of patients, the pathology extends to the internal capsule, as well as to the periventricular and peristriatal white matter.2,9

Callosal Apraxia

Limb-Kinetic Apraxia

Modality-specific or dissociation apraxias are praxic deficits exhibited by patients who commit errors only, or predominantly, when the movement is evoked by one but not all modalities.7,29 Thus, some patients may perform abnormally only under verbal commands; this deficit has been attributed to a left hemispheric lesion probably located in the parietal lobe, which disrupts the lexicomotor transformation process, or in the corpus callosum.28,30,31 Investigators have also described patients who performed poorly in response to seeing an object but performed considerably better when given the object tactile input or when asked to gesture to the name of the object.32 As an exception, some patients may be unable to use tool/objects but can correctly pantomime their use on commands.33 Furthermore, investigators have described patients who, unlike those with ideomotor apraxia who improved on imitation, were more impaired when imitating than when pantomiming in response to command (conduction apraxia)34 or could not imitate but performed flawlessly under other modalities; this situation is termed visuoimitative apraxia.35 Deficits may be restricted solely to the imitation of meaningless gestures with preserved imitation of meaningful gestures36,37 (see later discussion).

Many clinicions do not consider LKA a true apraxia but merely the expression of a basic motor (corticospinal) deficit. However, studies performed since 2000 clearly demonstrated— as Kleist and Liepmann originally suggested5,21,22—that LKA is a higher order motor disorder over and above a corticospinal or basal ganglia deficit.9,12 The deficit in LKA is confined mainly to finger and hand movements contralateral to the lesion, regardless of the affected hemisphere, with preservation of power and sensation. Manipulative finger movements are predominantly affected. However, in most cases, all movements, either complex or routine and independently of the modality needed to evoke them, are involved. There is a delay in the initiation of movements, as well as slowing in their execution, but what is especially striking is the temporal disordering of cooperative muscle action and loss of selective muscle activation; the fingers no longer act in concert, and there is lack of interfinger coordination. Simultaneous and sequential actions of individual fingers are distorted, and the resulting movement becomes coarse, fragmented, and mutilated. Fruitless attempts usually precede wrong movements, which in turn are frequently contaminated by extraneous movements. Imitation of finger postures is also abnormal, and some patients use the less affected or normal hand to reproduce the requested posture. The severity of the deficit is consistent, exhibited to the same degree in everyday activities as in the clinical setting; not presenting therefore voluntary-automatic dissociation.5,3,12,23 Performance with the limb-kinetic apraxic hand may superficially resemble tactile apraxia caused by posterior parietal lesions, inasmuch as both are unilateral finger and hand apraxias, with gross disturbances of object exploration and manipulation. However, intransitive and expressive movements are preserved, and imitation of hand and finger movements is normal in tactile apraxia. Tactile apraxia is a unimodal somatosensorimotor transformation disorder characterized by a specific inability to engender adequate finger movements required for the exploration of an object held in the hand. No apraxia is present when the patient sees the object; it appears only when he or she is blindfolded and starts actively touching it. Somatosensory functions, particularly tactile recognition, may be normal or moderately disturbed.3

Damage to the body of the corpus callosum (with or without associated genu involvement) may induce a unilateral apraxia deficit of the nondominant limb, the characteristics of which may vary according to the type of test given and the lateralization pattern of praxic skills present in each patient, although the most enduring defect is demonstrated when verbal-motor tasks, such as pantomiming in response to command, are used.24-27 Some patients cannot correctly pantomime in response to verbal commands with their left hands but perform normally on imitation and object use,28 whereas others cannot use their left hands on command, by imitation or while holding the object.25,27 Moreover, a few patients cannot pantomime in response to verbal commands or while holding the object, but they perform fairly well on imitation or improve over time on imitation and object use.26

Modality-Specific or Dissociation Apraxias

Neural Processes Underlying Limb Praxis Neural Representation of Gestures and the Selection of Actions Skillful and competent conventional use of objects and tools requires a normal prehension system, intact representations of functional actions for an adequate utilization behavior, and an intact semantic knowledge.3 Visually guided reaching, grasping, and object manipulation are paramount components in any task-related movement. Such object-oriented action implies a cerebral interface set up to align sensory information concerning position and shape of both object and limb, with specific motor commands encoding distance, velocity, direction, and grip.38 Research on primates has identified a series of segregated parietofrontal circuits that work in parallel, each one involved in a specific sensorimotor transformation process. The proposed functions of the main

chapter 32 apraxia parietofrontal circuits are as follows: (1) visual and somatosensory transformation for reaching; (2) somatosensory transformation for posture, as well as transformation of body part location data into information necessary to control body part movements; (3) visuomotor transformation for grasping and manipulation; (4) coding peripersonal space for limb and neck movements; (5) internal representation of actions; and (6) visual transformation for eye movements.39 Several functional brain imaging studies on reaching, grasping, and object manipulation in humans have demonstrated activation of the parietal (Brodmann areas 7, 39, and 40) and frontal areas (dorsal premotor, ventral premotor, and supplementary motor areas), as well as of the primary sensorimotor cortex, corresponding to those involved in the circuits described in monkeys. In addition, activation has been documented in the caudate and putamen, globus pallidus, thalamus, and cerebellum.40-43 Grasping specifically activates the lateral bank of the anterior intraparietal sulcus, whereas during grasping and manipulation, the ventral premotor cortex is involved.43 Most studies investigating tool and action knowledge have shown activation in posterior left superior and middle temporal gyri. The left posterior temporal areas are usually activated together with neural systems associated with semantic retrieval (left inferior and middle temporal gyri/Brodmann areas 20 and 21); left inferior frontal cortex (Brodmann areas 44, 45, and 47), and left premotor and left frontomarginal gyri (Brodmann areas 10 and 12).44-47 The generation of action verbs related to tool/object use also activates the left angular gyrus, which indicates that the system mediating access to verbs is anatomically close to those the system that supports concepts of movements and space-time relationships.48 Functional brain imaging studies on tool use skills have demonstrated activation, predominantly in the left hemisphere, of an extensively distributed control network made up of the inferior and superior parietal lobules, the posterior superior and middle temporal areas, the premotor (dorsal and ventral) and dorsolateral prefrontal cortices, and the supplementary motor area. The dorsolateral prefrontal cortex and posterior temporal areas are preferentially involved during action planning, whereas parietal, premotor, and supplementary motor areas are engaged during action execution in addition to action planning.15 The only brain region activated during manipulation with the tool, in comparison with the fingers, is the lateral edge of the intraparietal sulcus.49 In conclusion, skillful and competent use of tool/object depends on tool-/object-specific conceptual knowledge, as well as on several sensorimotor transformation processes involved in reaching, grasping, and manipulation; it is therefore subserved by an extensive temporoparietofrontal system that integrates tool/object knowledge with the ideation and generation of actions. A putative temporoparietal route may constitute an intermediate and necessary step for integrating objects’ functional properties into adequate movement patterns such as those required for utilization behavior.3 To date, there have been no studies designed to evaluate the representation of intransitive gestures. Intransitive gestures are usually much less complex than transitive movements, are geared to sociocultural contexts, and are stimulated by environmental cues (e.g., salute) rather than constrained by the shape and function of tools/objects, as in the case of transitive movements. It has therefore been suggested that intransitive

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movements and postures are subserved by a more widely and differently distributed intrahemispheric network and/or that they are bilaterally represented.3 Neurophysiological, neuroimaging, and clinical studies have delineated at least two well-distributed neural systems essential for the selection of limb movement responses and for the selection of object-oriented responses. The first system consists of the lateral premotor (Brodmann area 6) and parietal cortices, basal ganglia, thalamus, and white matter fascicles participating in the selection of limb movement responses. The other is an adjacent system made up of lateral area 8 and interconnected parietal regions, thalamus, striatum, and white matter fascicles and is concerned with the selection of object-oriented responses.50

Pathophysiology of Limb Apraxia Ideational or conceptual types of praxic deficits Competent conventional use of objects and tools depends primarily on an intact semantic knowledge. Two possible models of semantic system functioning have been postulated. According to the model based on a multimodal distributed semantic architecture, objects of all types are represented by visual, tactile, and motor/proprioceptive nodes in proportion to the degree to which these various sensory and motor systems are involved as the representation is acquired and elaborated. In the case of tools and body parts, the dominant “channel” of experience involves sensorimotor (i.e., how the tool is held and used/manipulated) and functional information (i.e., knowing the usage context).51 According to the second model, a verbal, propositional semantic system operates by “reading” the sensorimotor representations or gestural engrams20; thus, skill and appropriate object use require the combination of dorsal stream processing (“how” system) with the product of ventral pathway processing (“what” system), which provides access to semantics.52 Therefore, ideational apraxia or conceptual apraxia may result from disruption of normal integration processes between the system subserving the functional knowledge of action and those involved in object knowledge, or it may result from damage to the putative conceptual system involving in toolaction knowledge.6,9 On the basis of studies of patients with semantic dementia syndrome, however, it has been alternatively proposed that patients with conceptual apraxia are impaired in the use of objects for which they have lost conceptual knowledge (e.g., naming and object descriptions). Their ability to select and use novel tools normally (mechanical problem solving), which unveils the capacity to infer function from structure, is usually preserved.20 The finding that some patients with ideational apraxia or conceptual apraxia may use some objects normally may be ascribed to degraded but partially retained conceptual knowledge about such objects, enhanced by sensorimotor information53 or, more precisely, to reliance on visual/tactile affordance, together with good problem-solving skills, because patients may be able to efficiently manipulate novel tools.20 Finally, the impairment in carrying out sequences of actions requiring the use of various objects (i.e., the original definition of ideational apraxia) may be the consequence of disruption of the subsystem involved in short-term script ordering31 (see later discussion).

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Ideomotor types of praxic deficits There are two major subtypes of ideomotor apraxia. The largest subtype results from disruption at the movement execution stage of gesture performance (anterior or dynamic ideomotor apraxia) and has been attributed to dysfunction of parietofrontal circuits involved in sensorimotor transformation. The second subtype, posterior or representational ideomotor apraxia, has been suggested to be caused by the inability to store or access representational memories of complex body posture and movements or by a deficit in the selection of actions.2

Dysfunction of frontoparietal circuits involved in sensorimotor transformation A subgroup of patients with ideomotor apraxia usually commit spatial and temporal errors when performing both transitive and intransitive symbolic or communicative movements under all modalities of elicitation (i.e., verbal command, imitation, seeing and handling the object), although performance usually improves on imitation and with object use. These patients also exhibit errors when imitating meaningless postures and novel motor sequences. It was originally suggested that the crucial underlying neural mechanism in this group of patients with ideomotor apraxia was a disruption of multiple parietofrontal circuits and their subcortical connections, which subserve the computations necessary to translate an action goal into movements by integrating sensory input with central representation of actions that is based on prior experience.9,54 Whereas damage to specific circuits causes unimodal deficit, such as tactile apraxia, involvement of several circuits by a larger lesion or disruption of their integration in supramodal reference frames causes ideomotor apraxia. Thus, damage to circuits devoted to sensorimotor transformation for grasping, reaching, and posture; for transformation of body part location into information required to control body part movements; and for coding extrapersonal space would produce incorrect finger and hand postures and abnormal orientation of the tool/object, inappropriate arm configuration and faulty movement orientation (with regard to both the body and the target of the movement in extrapersonal space), and movement trajectory abnormalities. Patients select the correct movements but have difficulties in translating the selected response into action because of an “execution” disturbance; the online guidance of movements may be defective, and patients may complain of disability in everyday activities.3

Disruption of action selection Another subgroup of patients with ideomotor apraxia exhibits spatial and temporal errors predominantly when pantomiming in response to verbal command with either hand (i.e., outside the appropriate context). They improve on imitation and when handling the object. These patients do not complain of difficulties in everyday activities; there is an automatic voluntary dissociation. Their online guidance of movements is normal, and they have no pointing and/or grasping deficits; thus, pragmatic representations for object-oriented actions are not directly affected, inasmuch as this is a higher level deficit involving a premovement neural process. The deficits arise when the subject has to shift from a strategy in which objectoriented actions are processed automatically to a more cogni-

tive mode, because of inability to select the appropriate motor schemas from stored motor representations and organize them into purposive action. They may also have deficits in mentally evoking (imaging) the action and may be unable to discriminate correct from incorrect gestures.3 In the study conducted by Rushworth and associates,50 all patients with deficits in the selection of learned actions and apraxia had lesions in the left hemisphere, predominantly in the parietal lobe, but in many, lesions also involved the lateral premotor cortex, as well as interconnecting white matter fascicles and basal ganglia and the thalamus. Therefore, patients in whom performance is impaired predominantly when pantomiming in response to verbal commands may be those with lesions involving systems subserving movement selection; circuits devoted to sensorimotor transformation are preserved. As a matter of fact, it has been possible to distinguish in monkeys an impairment in movement selection from an impairment in kinematics.3 The improvement in performance that patients may show when seeing and handling the object may be explained by the affordance provided by the visual/tactile cues from the tool/ object, which in addition provides a more natural context and facilitates the correct hand/limb position for the gesture. Finally, some patients with the ideomotor type of apraxia have deficits in forming correct hand configuration appropriate for object use only; this means they show inadequate hand grasp when the object has to be manipulated with the intention to use it, but neither during visually guided (“on-line”) reaching and grasping movements nor when grasping novel objects. These patients can correctly name and recognize fingers and objects and can also define their functions verbally, but they are unable to discriminate between normal and abnormal hand postures, and they exhibit deficits in the perception of self-generated movements and in mentally simulating hand gestures. These types of deficits have been associated with left inferior parietal cortex lesions; damage to these regions may degrade the storing of or interrupt the access to representations of learned complex body postures and/or movements associated with familiar objects.55

Limb-kinetic type of praxic deficit Proper grasping and manipulation require the integrity of the corresponding sensorimotor transformation circuit, the capacity to generate independent finger movements, and the capacity to perform and to exert a delicate somatosensory control process.38 On the basis of the anatomical connections and functional properties of F5 and anterior intraparietal areas, a sensorimotor circuit for grasping has been proposed in which parietal neurons represent the entire hand action and frontal neurons encode particular segments of the action. In turn, direct corticomotoneural projection systems underpin the ability to perform relatively independent finger movements. However, movements of individual digits require activation of a complex set of muscles; this muscular activity must not only generate the digit movement required but also stabilize the bony chain and prevent unwanted digit movements. Both cortical inhibition and corticospinal inhibition seem to be essential for the selection and control of hand muscle activity. When the object is finally grasped, a delicate somatosensory control of finger movement is necessary for precise manipulation to be performed.

chapter 32 apraxia Leiguarda and Marsden9 proposed that the most typical examples of LKA, such as those seen in corticobasal degeneration, are caused by disruption of the frontoparietal circuits devoted to grasping and manipulation, combined with impaired generation and control of independent finger movements caused by disruption of intracortical inhibitory circuits, as well as dysfunction of somatosensory control of manipulation. However, because patients with corticobasal degeneration and LKA have neither clinical signs of corticospinal deficit nor involvement of fast-conducting corticomotoneural projections, as evaluated with transcranial magnetic stimulation, and a defect in somaesthesis may not be present, this distinctive apraxic disorder may basically result from dysfunction of the nonprimary cortical motor areas, as previously suggested.9 In support, transcranial magnetic stimulation of Brodmann area 44 produces slowing and clumsiness of fine finger movements without paresis.56 All pathologically confirmed cases of LKA suffered a degenerative process such as corticobasal degeneration and Pick’s disease, involving frontal and parietal cortices or, predominantly, the premotor cortex.9

Imitation of Actions Imitation is an important component of nonverbal communication. Testing the ability to imitate is an essential aspect of apraxia assessment, particularly in patients with aphasia. Defective performance in gesture imitation has been found in patients with lesions in several cortical regions but essentially with parietofrontal damage. These patients tend to exhibit more errors when imitating transitive than intransitive and meaningless movements.54 Moreover, patients with left parietal lobe damage seem to have more difficulties when imitating meaningful transitive gestures on their own bodies than when imitating movements with reference to external objects.57 Imitation of meaningless hand and finger postures discloses differential susceptibility to right- and left-brain damage. Patients with leftbrain damage have more difficulties imitating hand than finger postures, whereas patients with right-brain damage commit more errors with finger postures.58,59 Thus, imitation seems to be body part specific; the gesture’s visual appearance is mentally transformed into categories of body part relationships. Difference in action imitation between meaningful and meaningless action/postures can be predicted on the basis of a cognitive imitation model, which postulates disparate processing routes to the motor system. Imitation of meaningless actions/postures would be processed through a nonsemantic route from visual analysis, including mental transformation of another person’s body part and temporary holding in working/short-term memory of the observed movement/ posture, to the motor system for actual execution. Imitation of meaningful actions/postures, in turn, can be achieved by either a nonsemantic or a semantic route through a longterm/semantic memory station. This model has received support from functional neuroimaging studies that showed involvement of the dorsal pathway when a meaningless action/posture is imitated and of the dorsal together with the ventral pathway when a meaningful action/posture is perceived with the aim to be imitated.45,46

Representation of sequential movements and actions Functional brain imaging has shown that different neural systems are actively engaged in planning and executing sequen-

411

tial movements, depending on whether the sequence has been relearned or is a new one and contingent on the complexity of the movement sequence. The supplementary motor area, the primary sensorimotor cortex, the midposterior putamen, and the cerebellum are involved primarily in the execution of automatic, overlearned sequential movements, whereas the prefrontal, premotor, and parietal association cortices and the anterior part of the caudate/putamen are specifically recruited—in addition to such areas engaged in the execution of simple movement sequences—when a complex or newly learned sequence, which requires attention, integration of multimodal information, and working memory processing for its appropriate selection and monitoring, has to be performed.3 Patients with ideomotor apraxia may exhibit several types of errors such as omissions, deletions, additions, transpositions, and perseverations when performing sequencing limb movements and have been found to be particularly impaired in planning and implementing sequences of various hand movements. Abnormalities in movement sequencing have been reported most commonly in patients with left parietal lobe lesions but also with left frontal and basal ganglion involvement.60-63 Thus, different neural systems would be engaged, depending on the characteristics of movement sequences needed to be executed during praxis evaluation. Most of the sequences used to test praxis are new (e.g., sequencing of movements in the movement imitation test) or part of an otherwise well-learned sequence that has to be represented explicitly. In any case, the system comprising the prefrontal, premotor, and parietal cortices and the caudate would be specifically engaged. When the sequence is well known, automated, or overlearned, the supplementary motor area–putamen would be preferentially recruited. Interestingly, activation shifts back to caudateanterior putamen when attention was paid to the overlearned action. In addition, it might be possible that within this system, there are many different subsystems subserving functionally separate cognitive computations involved in motor sequencing (i.e., working memory, attention, selection of limb movements), which, in turn, may be selectively damaged by the pathological process and so produce different types of sequencing impairment in apraxic patients.9 The sequential organization of actions, rather than movements, has been studied with the use of script event ordering to address the cognitive activity that occurs during action planning at a covert level.31 A script consists of a goal-oriented sequence of events that typically occur in a specific and systematic order. Functional imaging studies have shown that short-term scripts as those used in testing ideational apraxia (e.g., peeling, opening, and eating an orange) cause activation in the left hemisphere of the dorsolateral prefrontal cortex, supramarginal gyrus, inferior temporal gyrus, and middle occipital gyrus. Patients with ideational apraxia caused by damage of the left parietotemporal region or damage of the frontal lobe fail on naturalistic, multiple object tests requiring a sequential structuring of common everyday actions (shortterm script ordering, such as making coffee).5,18-20

Recognition of actions and perception of self-generated movements A subset of neurons in area F5 have been found to discharge during the time a monkey observes meaningful hand movements made by the experimenter, particularly when interacting

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with objects; these were called mirror neurons and were considered to belong to an observation/execution matching system involved in understanding the meaning of motor events, as well as in action imitation.39 Neurons with properties similar to those of mirror neurons in area F5 are also found in the superior temporal sulcus in monkeys. Two other types of neurons that may contribute to the recognition and imitation of postures and actions have also been found in the superior temporal sulcus. One type encodes the visual appearance of particular parts of the body (i.e., fingers, hands, arms), which combine in such a way that the collection of components can specify a particular meaningful posture or action. The second type encodes specific body movements, such as walking and turning. Cells responding to hand-object interaction are also present in the rostral part of the inferior parietal lobe, which sends its cortical output to the F5 area; in turn, the inferior parietal lobe receives projection from the superior temporal sulcus region, and the latter is interconnected with the frontal lobe, thus completing a cortical circuit involved in the perception of handobject interaction. The crucial cognitive role of the superior temporal sulcus—inferior parietal lobe—F5 network would be the internal representation of actions that, when evoked by an action made by other people, would be involved in two related functions: namely, action recognition and action imitation. Findings of functional neuroimaging studies in humans parallel neurophysiological findings in monkeys.64 Action recognition deficits have been observed in patients with parietal, temporal, frontal, and basal ganglion lesions predominantly in the left hemisphere.65,66 However, Halsband and colleagues57 compared gesture comprehension and imitation in patients with parietal and frontal lesions and found that when lesions affected the left parietal cortex, sparing temporal lobe structures, gesture comprehension was slightly disturbed, although action imitation was severely impaired. The lack of consistent gesture comprehension deficits in these patients could result from preservation of the left temporal cortex, which seems to be crucial for the knowledge of actions.57 Apraxic patients with left parietal damage may also have difficulties when they are required to discriminate from their own hand an external hand that performs the same movement. The impairment in correctly attributing the ownership of the movement may result from the inability to evaluate and compare internal and external feedback about movements.67

Treatment of Limb Apraxia Apraxic impairments are ecologically significant because communicative gestures can compensate for inadequate verbal expression in patients with aphasia and because the improper use and selection of tools/objects and the inability to perform a routine, naturalistic action, directly interfere with activities of daily living. Studies of spontaneous recovery from apraxia have concentrated on imitation of gestures and performance of meaningful gestures, such as pantomiming of object use on command. On these tests, only about one half of the patients who were apraxic in the first week after a stroke were still apraxic 3 months later, and only 20% continued to be apraxic after 1 year. Two different approaches can be used to rehabilitate apraxia. A top-down approach would be characterized by teaching the

patients general principles of tool and object use, which they can then deliberately apply to novel and difficult activities. A bottom-up approach, by contrast, could be established through gradual shaping and subsequent rehearsal of one particular activity until a routine is established, which will occur automatically when the trained activity is to be performed. In one study, investigators used a cross-over design to compare the efficacy of top-down and bottom-up training for the same activities in the same patients. Their top-down approach, “exploration training,” was aimed at teaching patients to infer possible functions of tools and objects from their structural properties. Patients were told to compare tools with similar or different function with regard to their structural properties (e.g., contrasting the teeth of a cutting knife and of a saw with the plain edge of a knife used for spreading) or to make drawings of them that emphasized these structural details. In contrast, “direct training” was intended to establish a routine through performing the task and may hence be classified as being bottom-up. Direct training led to a significant reduction of errors and of the need for assistance, whereas exploration training had no significant practical effects.68

DISTRIBUTION OF THE APRAXIAS IN OTHER BODY PARTS Although face apraxia has been generally equated with oral nonverbal apraxia—that is, the inability to perform skilled movements of the lips, checks, and tongue1—early reports of patients with facial apraxia described eye and/or eyebrow movement deficits.69 Therefore, face apraxia should refer to a disturbance of upper and lower face movements not explained by elementary motor or sensory deficits. Patients exhibit spatial and temporal errors of similar quality to those observed in limb apraxia when performing representational and nonrepresentational movements such as sticking out the tongue, blowing out a match, smiling, blowing a kiss, showing the teeth, blinking the left or right eye, looking down, or sucking on a straw. Face apraxia often co-exists with Broca’s aphasia and thus is more frequently observed with left hemisphere lesions, particularly those involving the frontal and central operculum, insula, centrum semiovale, and basal ganglia; however, it can also be seen with lesions confined to left posterior cortical regions, as well as with right hemisphere damage.3,69 Trunk movement impairments, labeled trunk apraxia, were originally reported as part of a syndrome associated with bilateral frontal lobe lesions encompassing stance and gait apraxia. However, in some patients, trunk apraxia is overwhelming; they experience difficulties in dancing or turning around and may even be unable to adapt their body in order to use furniture; they have difficulty sitting down in a chair, showing hesitation, sitting in the wrong position (e.g., on the edge of the chair) and in incorrect directions (e.g., facing the back of the chair). When lying in bed, their bodies are not aligned parallel along the major axis of the bed, or they place the pillow in an unusual position. Patients may have minimal or no difficulty in standing or getting up, in contrast to features of some basal ganglion disorders such as parkinsonism.3 It is still controversial whether trunk apraxia results from only left hemisphere damage or whether bilateral hemispheric lesions are necessary. It is often observed in cortical degenera-

chapter 32 apraxia tive syndromes such as progressive apraxia and corticobasal degeneration, in which parietofrontal involvement is prominent, but it has also been found in patients with left hemisphere damage, particularly in those with cortical and subcortical vascular lesions confined to the territory of the middle cerebral artery. Trunk apraxia in these patients can be found without association with limb apraxia.70 The precise nature and localization of gait apraxia still defy exact identification. Gerstmann and Schilder71 described apraxia of gait as a genuine disturbance of walking caused by frontal lesions; more recently, however, it has been considered not as a disorder but a spectrum of higher order walking syndromes.72 Nevertheless, apraxia of gait may be defined as the loss of ability to use the lower limbs properly in the act of walking, a loss that cannot be accounted for by demonstrable sensory impairment or motor weakness.73 Such patients’ gait is characterized by slowness of initiation; loss of balance; “magnetic attraction of the foot to the ground”; counterproductive parasitic movements; difficulty in stopping and turning; and inability to pedal, to kick, or to trace a circle with the foot, as well as increased tone and brisk reflexes in the lower limbs with grasping foot responses. The disorder is caused by bilateral damage mainly to the medial frontal lobes or by white matter lesions that interrupt the connections between premotor cortex, supplementary motor area, and cerebellum and basal ganglia.74

K E Y

P O I N T S

●

Apraxias are common but poorly recognized disorders that can result from a wide variety of focal (e.g., stroke) or diffuse (i.e., corticobasal degeneration, Alzheimer’s disease) brain damage.

●

Limb apraxias all bear ecological significance because communicative gestures can compensate for inadequate verbal expression in patients with aphasia, and because improper use and selection of tools/objects, as well as inability to perform routine movements in a natural manner, significantly affect activities of daily living.

●

Limb apraxias are attributable to disruption of a large neural network, which is distributed both intrahemispherically and interhemispherically, although mainly lateralized to the left, and is made up of many interrelated systems pertaining to dissimilar levels of action representation.

●

Damage to one or more of these systems, depending on the location and extension of the pathological process involved, would cause different types of apraxic disorders and would explain the clinical dissociations commonly observed.

●

Therefore, a battery of tests is necessary to identify and categorize apraxic deficits appropriately.

●

Precise identification of abnormal motor behaviors and a better understanding of their underlying neural mechanisms will help clinicians design rehabilitation strategies targeting specific apraxic deficits.

413

Suggested Reading Jeannerod M, Leiguarda R, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press 2005, pp 303-338. Johnson-Frey S, Newman-Norlund R, Grafton S: A distributed left hemisphere networks active during planning of everyday tooluse skills. Cereb Cortex 2005; 15:681-695. Leiguarda R: Apraxias as traditionally defined. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 303-338. Leiguarda R, Merello M, Nouzeilles MI, et al: Limb-kinetic apraxia in corticobasal degeneration: clinical and kinematic findings. Mov Disord 2003; 18:49-59. Nutt J: Higher-order disorders of gait. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 237-248. Rossetti I, Rode G, Goldenberg G: Perspectives on higher-order motor deficit rehabilitation. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 475-498.

References 1. De Renzi E: Apraxia. In Boller F, Grafman J, eds: Handbook of Neuropsychology, vol 2. Amsterdam: Elsevier Science, 1989, pp 245-263. 2. Rothi LJG, Heilman KM, eds: Apraxia: the Neuropsychology of Action. East Sussex, UK: Psychology Press, 1997. 3. Leiguarda R: Apraxias as traditionally defined. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 303-338. 4. Liepmann H: Die linke hemisphare und das handeln [The left hemisphere and action]. Munch Med Wochenschr 1907; 49:2322-2326, 2375-2378. [Translations from Liepmann’s essays on apraxia. In Research Bulletin 506, Department of Psychology, University of Western Ontario, 1980.] 5. Liepmann H: Apraxie. Ergenbnisse der Gesamten Medizin 1920; 1:516-543. 6. Roy EA, Square PA: Common considerations in the study of limb, verbal, and oral apraxia. In Roy EA, ed: Neuropsychological Studies of Apraxia and Related Disorders. Amsterdam: North-Holland, 1985, pp 111-161. 7. Rothi LJG, Ochipa C, Heilman KM: A cognitive neuropsychological model of limb praxis. Cogn Neuropsychol 1991; 8:443458. 8. Buxbaum LJ, Giovannetti, Libon D: The role of the dynamic body schema in praxis: evidence from primary progressive apraxia. Brain Cogn 2000; 44:166-191. 9. Leiguarda R, Marsden CD: Limb apraxias: higher-order disorders of sensorimotor integration. Brain 2000; 123:860879. 10. Poizner H, Mack L, Verfaellie M, et al: Three-dimensional computer graphic analysis of apraxia. Brain 1990; 113:85101. 11. Leiguarda R, Merello M, Balej J, et al: Disruption of spatial organization and interjoint coordination in Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy. Mov Disord 2000; 15:627-640. 12. Leiguarda R, Merello M, Nouzeilles MI, et al: Limb-kinetic apraxia in corticobasal degeneration: clinical and kinematic findings. Mov Disorder 2003; 18:49-59. 13. Moll J, de Oliveira-Souza R, Passman LJ, et al: Functional MRI correlates of real and imagined tool-use pantomimes. Neurology 2000; 54:1331-1336. 14. Choi SH, Na DL, Kang E, et al: Functional magnetic resonance imaging during pantomiming tool-use gestures. Exp Brain Res 2001; 139:311-317.

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15. Johnson-Frey S, Newman-Norlund R, Grafton S: A distributed left hemisphere networks active during planning of everyday tool-use skills. Cerebral Cortex 2005; 15:681-695. 16. Fridman E, Carpintiero S, Amengual A, et al: Hemispheric lateralization of pantomiming tool-use gestures: a fMRI study. Manuscript in preparation. 17. Ochipa C, Rothi LJG, Heilman KM: Conceptual apraxia in Alzheimer’s disease. Brain 1992; 115:1061-1071. 18. Heilman KM, Maher LH, Greenwald L, et al: Conceptual apraxia from lateralized lesions. Neurology 1997; 49:457464. 19. De Renzi E, Lucchelli F: Ideational apraxia. Brain 1988; 113:1173-1188. 20. Hodges J, Bozeat S, Lambon Ralph M, et al: The role of conceptual knowledge in object use evidence from semantic dementia. Brain 2000; 123:1913-1925. 21. Kleist K: Kortikale (innervatorische) Apraxie. Jahrb Psychiat Neurol 1907; 28:46-112. 22. Kleist K: Gehirnpathologische und lokalisatorische Ergebnisse: das Stirnhirn im engeren Sinne und seine Störungen. Z ges Neurol Psychiatry 1931; 131:442-448. 23. Faglioni P, Basso A: Historical perspectives on neuroanatomical correlates of limb apraxia. In Roy EA, ed: Neuropsychological Studies of Apraxia and Related Disorders. Amsterdam: North-Holland, 1985, pp 3-44. 24. Liepmann H, Maas O: Eie Fall von linksseitiger Agraphie und Apraxie bei rechtsseitiger Lähmung. Monatsschrift fur Psychiatrie und Neurologie 1907; 10:214-227. 25. Watson RT, Heilman KM: Callosal apraxia. Brain 1983; 106:391-403. 26. Graff-Radford NR, Welsh K, Godersky J: Callosal apraxia. Neurology 1987; 37:100-105. 27. Leiguarda R, Starkstein S, Berthier M: Anterior callosal haemorrhage: a partial interhemispheric disconnection syndrome. Brain 1989; 112:1019-1037. 28. Geschwind N, Kaplan E: A human cerebral disconnection syndrome. Neurology 1962; 12:675-685. 29. De Renzi E, Faglioni P, Sorgato P: Modality-specific and supramodal mechanisms of apraxia. Brain 1982; 105:301-312. 30. Heilman KM: Ideational apraxia: a re-definition. Brain 1973; 96:861-864. 31. Ruby P, Sirigu A, Decety J: Distinct areas in the parietal cortex involved in long-term and short-term action planning: a PET investigation. Cortex 2002; 38:321-339. 32. Pilgrim E, Humphreys GW: Impairment of action to visual objects in a case of ideomotor apraxia. Cogn Neuropsychol 1991; 8:459-473. 33. Motomura N, Yamadori A: A case of ideational apraxia with impairment of object use and preservation of object pantomime. Cortex 1994; 30:167-170. 34. Ochipa C, Rothi LJ, Heilman KM: Conduction apraxia. J Neurol Neurosurg Psychiatry 1994; 57:1241-1244. 35. Merians AS, Clark M, Poizner H, et al: Visual-imitative dissociation apraxia. Neuropsychologia 1997; 35:1483-1490. 36. Mehler MF: Visuo-imitative apraxia [Abstract]. Neurology 1987; 34(Suppl 1):129. 37. Goldenberg G, Hagmann S: The meaning of meaningless gestures: a study of visuo-imitative apraxia. Neuropsychologia 1997; 35:333-341. 38. Jeannerod M, Arbid MA, Rizzolatti G, et al: Grasping objects: the cortical mechanisms of visuomotor transformation. Trends Neurosci 1995; 18:314-320. 39. Rizzolatti G, Luppino G, Matelli M: The organization of the cortical motor system: new concepts. Electroencephalogr Clin Neurophysiol 1998; 106:283-296. 40. Grafton ST, Arbid MA, Fadiga L, et al: Localization of grasp representation in humans by PET: 2. Observation compared with imagination. Exp Brain Res 1996; 112:103-111.

41. Rizzolatti G, Fadiga L, Matelli M, et al: Localization of grasp representations in humans by positron emission tomography. 1. Observation versus execution. Exp Brain Res 1996; 111:246252. 42. Faillenot I, Toni I, Decety J, et al: Visual pathways for objectoriented action and object recognition: functional anatomy with PET. Cereb Cortex 1997; 7:77-85. 43. Binkofski F, Phil M, Posse S, et al: Human anterior intraparietal area subserves prehension: a combined lesion and functional MRI activation study. Neurology 1998; 50:1253-1259. 44. Martin A, Haxby JV, Lalonde FM, et al: Discrete cortical regions associated with knowledge of color and knowledge of action. Science 1995; 270:102-105. 45. Decety J, Grezes J, Costes N, et al: Brain activity during observation of action: influence of action content and subject’s strategy. Brain 1997; 120:1763-1777. 46. Grèzes J, Costes N, Decety J: The effects of learning and intention on the neural network involved in the perception of meaningless actions. Brain 1999; 122:1875-1887. 47. Phillips JA, Noppeney U, Humphreys GW, et al: Can segregation within the semantic system account for category-specific deficits? Brain 2002; 125:2067-2080. 48. Grèzes J, Decety J: Functional anatomy of execution, mental simulation, observation, and verb generation of actions: a meta-analysis. Hum Brain Mapp 2001; 12:1-19. 49. Inoue K, Kawashima R, Sugiura M, et al: Activation in the ipsilateral posterior parietal cortex during tool use: a PET study. Neuroimage 2001; 14:1469-1475. 50. Rushworth MFS, Nixon PD, Wade DT, et al: The left hemisphere and the selection of learned actions. Neuropsychologia 1998; 36:11-24. 51. McCarthey RA, Warrington EK: Evidence for modality specific meaning systems in the brain. Nature 1988; 334:428-430. 52. Milner AD, Goodale MA: The Visual Brain in Action. Oxford, UK: Oxford University Press, 1995. 53. Buxbaum LJ, Schwartz MF, Carew TG: The role of semantic memory in object use. Cogn Neuropsychol 1997; 14:219-254. 54. Haaland KY, Harrington DL, Knight RT: Neural representations of skilled movement. Brain 2000; 123:2306-2313. 55. Sirigu A, Cohen L, Duhamel JR, et al: A selective impairment of hand posture for objects utilization in apraxia. Cortex 1995; 31:41-55. 56. Vozumi T, Tamagawa A, Hashimoto T, et al: Motor hand representation in cortical area 44. Neurology 2004; 62:757761. 57. Halsband U, Schmitt J, Weyers M, et al: Recognition and imitation of pantomimed motor acts after unilateral parietal and premotor lesions: a perspective on apraxia. Neuropsychologia 2001; 39:200-216. 58. Goldenberg G: Matching and imitation of hand and finger postures in patients with damage in the left or right hemispheres. Neuropsychologia 1999; 37:559-566. 59. Goldenberg G, Straus S: Hemisphere asymmetries for imitation of novel gestures. Neurology 2002; 59:893-897. 60. De Renzi E, Faglioni P, Lodesani M, et al: Performance of left brain-damaged patients on imitation of single movements and motor sequences: frontal and parietal-injured patients compared. Cortex 1983; 19:333-343. 61. Harrington DL, Haaland KY: Motor sequencing with left hemisphere damage: are some cognitive deficits specific to limb apraxia? Brain 1992; 115:857-874. 62. Benecke R, Rothwell JC, Dick JPR, et al: Disturbance of sequential movements in patients with Parkinson is disease. Brain 1987; 110:361-379. 63. Luria AR: Higher Cortical Function in Man, 2nd ed. New York: Basic Books, 1980. 64. Rizzolatti G, Craighero L: The mirror-neuron system. Annu Rev Neurosci 2004; 27:169-192.

chapter 32 apraxia 65. Ferro J, Martins I, Mariano G, et al: CT scan correlates of gesture recognition. J Neurol Neurosurg Psychiatry 1983; 46:943-952. 66. Varney N, Damasio H: Locus of lesion in impaired pantomime recognition. Cortex 1987; 23:699-703. 67. Sirigu A, Daprati E, Pradat-Diehl P, et al: Perception of selfgenerated movement following left parietal lesion. Brain 1999; 122:1867-1874. 68. Rossetti I, Rode G, Goldenberg G: Perspectives on higher-order motor deficit rehabilitation. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 475-498. 69. Bizzozero I, Costato D, Della Sala S, et al: Upper and lower face apraxia: role of the right hemisphere. Brain 2000; 123:22132230.

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70. Spinazzola L, Cubelli R, Della Sala S: Impairment of trunk movements following left or right hemisphere lesions: dissociation between apraxic errors and postural instability. Brain 2003; 126:2656-2666. 71. Gerstmann J, Schilder P: Über eine besondere Gangstörung bei Stirnhirner krankung. Wien Med Wochenschr 1926; 76:97102. 72. Nutt J: Higher-order disorders of gait. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 237-248. 73. Meyer JS, Barron DW: Apraxia of gait: a clinico-physiological study. Brain 1960; 83:261-284. 74. Della Sala S, Francescani A, Spinnler H: Gait apraxia after supplementary motor area lesions. J Neurol Neurosurg Psychiatry 2002; 72:77-85.

CHAPTER

33

TREMOR ●

●

●

●

Günther Deuschl and Jan Raethjen

Tremor is the most common movement disorder encountered in clinical neurology. It denotes a rhythmic involuntary movement of one or several regions of the body.1 Although most tremors are pathological, a low-amplitude physiological action tremor can also be detected in healthy subjects and may even be of functional relevance for normal motor control.2 Pathological tremor is visible to the naked eye and mostly interferes with normal motor function. The disabilities caused by these tremors are as diverse as their clinical appearance, pathophysiology, and etiologies. Although there are numerous medical treatment options, their efficacy is limited, and therefore refined stereotactic surgical approaches have become increasingly important. Here, we provide some general clinical definitions and then describe all these aspects for each of the most important pathological tremor syndromes separately.

CLINICAL DEFINITIONS The clinical examination of tremor patients should focus on certain aspects of the tremor that form the basis for the differential diagnosis (Tables 33−1 and 33−2) and should always be documented: Topography: Tremors can occur in any joint or muscle that is free to oscillate. The patient should be examined carefully under different conditions (see later) to be able to detect all the affected body parts. By far the most common locations are the arms and hands, but they can be spared and are typically combined with tremor in other regions. The degree of symmetry between the two sides of the body can be an important hint (see Tables 33−1 and 33−2). Activation: Different states of muscle innervation can lead to an activation that is the appearance or marked increase of tremor. Resting tremor occurs when the muscles of the affected body part are not voluntarily activated (ideally completely relaxed, e.g., resting on a couch); its amplitude typically increases during mental stress (e.g., counting backward, Stroop test, etc.) and markedly decreases during voluntary activation, especially when moving the affected limb. Action tremor is any tremor that is produced by voluntary contraction of muscles. Its subgroups are clinically meaningful and always need to be defined: Postural tremor is present while voluntarily maintaining a position against gravity or additional weight. Kinetic tremor occurs during

any voluntary movement and can again be subdivided into a simple kinetic tremor that is present during simple voluntary movements that are not goal directed (e.g., slow up and down movements of the hands) and a tremor during goal-directed movements (intention tremor) that only occurs during movements directed at a certain target (e.g., target reaching movements). Classic intention tremor typically increases as the target is approached and the amplitude and velocity may fluctuate from beat to beat. These tremors must be separated from rarer forms of action tremor that occur only during certain positions or certain tasks (e.g., task-specific or position-specific tremor or isometric tremor). Frequency: For exact frequency measurement, a signal analysis of accelerometric or electromyographic recordings of the affected body part is necessary. However, with some experience the three main frequency ranges can be separated on inspection: high (>7 Hz), medium (4 to 7 Hz), and low (<4 Hz). Additional symptoms: Although not strictly related to the tremor syndrome itself, additional signs and symptoms are almost equally important. For example, a parkinsonian syndrome, cerebellar ataxia, and dystonia in the region of the tremor are important diagnostic and etiological hints (see later).

ENHANCED PHYSIOLOGICAL TREMOR Normal physiological tremor is an action tremor and usually not visible. It can only be measured with sensitive accelerometers. An increase of the amplitude leads to enhanced physiological tremor (EPT). The pathological tremor amplitudes are typically short lived and reversible once the cause (see Etiology) is removed. Other neurological symptoms or diseases that could cause tremor must be excluded.1

Epidemiology There are no studies available on the epidemiology of EPT as a whole. The short-lived transient form is very likely the most common form of tremor; most people have experienced this on stressful or frightening occasions. Some of the causes (side effect of drugs, endogenous intoxication, etc.) of EPT are

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T A B L E 33-1. Clinical Presentation of Tremors Diagnosis

Topography

Activation

Enhanced physiological tremor Essential tremor syndromes: Classic essential tremor

Arms (head); bilateral symmetrical

Posture/movement

6 to 13 Hz

None

Arms/head/tongue/voice bilateral, often asymmetrical Legs (trunk, arms, facial muscles); bilateral Task specific

Posture/movement/intention

4 to 11 Hz

Mild ataxia (when advanced)

Primary orthostatic tremor Task- and position-specific tremor Dystonic tremor

Standing

Frequency

13 to 18 Hz

Additional Symptoms

Main symptom: postural instability None

Task/position specific

5 to 10 Hz

Head/arm or other limbs; unilateral, often monomelic

Posture/movement

5 to 10 Hz

Dystonic posturing of affected region

Parkinsonian tremor Rest/re-emergent (types I and II) Action (types II and III)

Arm/leg/face; unilateral begin, asymmetrical Arms; often more symmetrical

Rest/posture

4 to 7 Hz

Posture/movement

6 to 13 Hz

Holmes tremor

Arm (leg); unilateral

3 to 6 Hz

Neuropathic tremor

Arms (legs); bilateral, usually symmetrical Arms/head/leg + other limbs, bilateral, usually symmetrical Arm/leg/head /trunk; often unilateral or asymmetrical

Rest/posture/movement/ intention Posture/movement

Akinesia, rigidity, postural instability Akinesia, rigity, postural instability Akinesia, rigidity, postural instability/ataxia Symmetrical distal sensory loss, paresis Very diverse depending on etiology Other somatizations

Toxic and drug-induced tremor Psychogenic tremor Palatal tremor Essential Symptomatic

Soft palate Soft palate/facial muscles/(arm)

common, so it is likely one of the most common forms of tremor.

Pathophysiology EPT relies on the same physiological mechanism as normal physiological tremor, and the physiology of normal tremor is meanwhile well defined. Two different physiological tremor mechanisms have been established. The first is based on simple mechanical properties. Any movable limb can be regarded as a pendulum with the capability to swing rhythmically, that is to oscillate. These oscillations automatically assume the resonant frequency of this limb, which is dependent on its mechanical properties⎯the greater its weight, the lower is its resonant frequency, and the greater the joint stiffness, the higher is this frequency. Any mechanical perturbation can activate such an oscillation. In the case of the hands, which are most often affected by tremors, the main and most direct mechanical influence comes from the forearm muscles. Indeed, it has been shown that the tremor measured in normal subjects during muscle activation mainly emerges from an amplification of the muscles’ effect on the hand at its resonant frequency.3-5 Thus, although the muscles show normal nonrhythmic isometric activity, they contribute to these resonant oscillations, which account for most of the tremor seen in the physiological situation.6 Such a pure resonant phenomenon does not produce pathological tremors as its amplitude is typically quite low. However, as this low-amplitude oscillation leads to rhythmic activation of muscle receptors, it activates segmental (spinal) or long (e.g., transcortical) reflex loops that can greatly

5 to 10 Hz

Posture/movement/ (rest/intention) Rest/posture/(movement)

3 to 10 Hz 4 to 9 Hz

Rest Rest/(posture/movement)

2 to 5 Hz 2 to 7 Hz

Rhythmic ear click Brainstem/cerebellar symptoms

enhance this oscillation. Such a reflex enhancement of the physiological mechanical oscillation is one well-established pathophysiological basis for the emergence of pathological tremor amplitudes in the case of EPT.7 The second less frequent mechanism in physiological tremor is a transmission of oscillatory activity within the central nervous system to the peripheral muscles. The rhythmic activity of the muscles then leads to tremor. In contrast to the mechanical-reflex oscillations, central oscillations occur at the centrally determined frequency and are independent of the limbs’ mechanics.8,9 It has been shown that such a central tremor component is present in a small proportion of normal subjects in parallel to the more common mechanical reflex oscillations.6,10-12 An enhancement of this component is another basis for EPT.13 Such central oscillations generally are the most common pathophysiological mechanism in pathological tremors4,9,14 (see later). Accelerometric tremor recordings with different weight loads in combination with the electromyogram recorded from the driving muscles can distinguish between such central and peripheral resonant (possibly reflex enhanced) tremors.

Etiology The causes of an enhancement of one or both of the physiological tremor components are diverse. The well-known trembling with excitement, fear, or anxiety is the most common form of EPT. It is believed to be mediated through an increased sympathetic tone that results in a β-adrenergically driven sensitization of the muscle spindles increasing the gain in the

chapter 33 tremor

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T A B L E 33-2. Differential Diagnosis of Tremors Diagnosis

Clinical Clues

Neurophysiology

Brain Imaging

Essential tremor (ET) versus enhanced physiological tremor (EPT) ET versus asterixis (AS) ET versus orthostatic tremor (OT) ET versus parkinsonian tremor (type I)

Family history (ET), duration of tremor (ET > EPT), medical history (ET), concomitant medication (EPT) Jerky tremor (AS) Tremor only during stance (OT)

Frequency under loading conditions, frequency below 8 Hz in early ET

Not useful

Polygraphic EMG (pathognomic) Polygraphic EMG (pathognomic)

Not useful Not useful

Subclinical low-frequency rest tremor (PD) on accelerometric or EMG spectrum Inhibition (PD) versus activation (ET) of tremor amplitude during movement

DAT-scan (PD), MIBG-scintigraphy (PD)

Frequency (DT ≤ ET), Quantified effect of a geste maneuver (DT)

Rarely lesions on MRI (DT)

Frequency (CT < ET)

CT/MRI: cerebellar lesions or degeneration (CT)

Frequency (HT < CT)

MRI: lesions/degeneration (CT) DAT-Scan: positive (HT),

Entrainment (PsT) Quant. distract. (PsT) Coherence l.-r. (PsT) Variable frequency (PsT)

Maybe useful depending on the cause of OrT

Burst duration (Mcl < Tr), Spectral peak width (Tr < Mcl), Synchronous bursts in different muscles (Mcl > Tr)

MRI depending on the cause of Mcl

ET versus dystonic tremor (DT)

ET versus cerebellar tremor (CT) CT versus Holmes tremor (HT)

Organic tremor (OrT) versus psychogenic tremor (PsT)

Tremor (Tr) versus myoclonus (Mcl)

Rest tremor (PD), unilateral beginning (PD), other PD symptoms (PD), alcohol responsivity (ET), kinetic tremor (ET), family history (ET), leg tremor (PD > ET), face tremor (PD > ET), head tremor (ET > PD), voice tremor (ET > PD), Family history (ET), Alcohol response (ET), Geste antagonistique (DT), Focal (DT), Further dystonic symptoms (DT), Alcohol response (ET), Intention tremor (CT > ET), Ataxia (CT > ET), Eye movements (CT) Rest tremor (HT), Low frequency (HT), Irregularity (HT), Parkinsonian symptoms (HT), Ataxia (CT > HT), Distractibility (PsT), Variable presentation (PsT > OrT), Selective disabilities (PsT), Entrainment (PsT), Coactivation (PsT > OrT), Somatizations (PsT > OrT), Rhythmic (Tr), More irregular (Mcl),

reflex loops.7 A similar origin via the sympathetic nervous system has been proposed for the tremor in reflex sympathetic dystrophy.15 The majority of other causes for EPT are related to drugs or toxins that can enhance the peripheral and the central component of physiological tremor (see Toxic Tremors).

Differential Diagnosis As both EPT and early essential tremor are not accompanied by any other neurological symptoms, they can be difficult to distinguish. The positive family history in essential tremor, its chronic course, and the lack of an overt cause for the tremor are important hints. Sometimes the diagnosis can only be made after having observed the tremor for some time. EPT is usually bilateral and thus any tremor manifesting unilaterally, even with a high frequency and a pure postural component, must be suspected of being a symptomatic tremor (see Table 33−2). Electrophysiology (spectral analysis of accelerometry and electromyography) can be helpful in cases where EPT emerges from a reflex enhancement of physiological tremor, as essential tremor is a centrally driven tremor.14,16 Electromyographic bursts below 8 Hz seem to be in favor of essential tremor rather than EPT.17

Treatment The short-lived emotional trembling in certain situations usually does not require any treatment. A single dose of a βblocking agent (e.g., propranolol 30 to 100 mg) just before a stressful situation can usually help to suppress this transient tremor that may interfere with important (e.g., professional) functions. Treatment of thyreotoxic tremor is recommended with propranolol (<160 mg daily) but other β blockers (atenolol [<200 mg daily], metoprolol [<200 mg daily]; acebutolol [<400 mg daily], oxprenolol [<160 mg daily], nadolol [<80 mg daily], and molol [<20 mg daily]) have a similar effect. This finding is at variance with the effects of β blockers other than propranolol in essential tremor.

ESSENTIAL TREMOR Essential tremor is a slowly progressive tremor disorder that causes severe disability but is not life limiting. It is defined by the following core criteria:1,18 ■ Bilateral tremor of the hands or forearms with predominant

kinetic tremor and resting tremor only in advanced stages of the disease

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■ Or isolated head tremor without evidence of abnormal

posture (e.g., dystonic signs) ■ And absence of other neurological signs with the exception of cogwheel phenomenon and slight gait disturbances Experts believe that the following criteria are supporting the diagnosis, although prospective studies on their diagnostic value are not yet available: ■ Duration longer than 3 years ■ Alcohol responsiveness ■ Family history

Some criteria involve the severity of the tremor,19 which are falling short when applied to a slowly developing condition. But the criteria mentioned here also have difficulties as the differential diagnosis to enhanced physiological tremor is not yet clear enough. Essential tremor usually starts with a postural tremor but can still be suppressed during goal-directed movements. In advanced stages an intention tremor can develop. This has been found in roughly 50% of an outpatient population and is accompanied by signs of cerebellar dysfunction of hand movements like movement overshoot and slowness of movements.20 In more advanced stages a tremor at rest can develop. Also, a mild gait disorder prominent during tandem gait is frequently found.21 Oculomotor disturbances are found with subtle electrophysiological techniques but cannot be detected by means of clinical assessment. The condition may begin very early in life and the incidence is increasing above 40 years with a mean onset of 35 to 45 years in different studies and an almost complete penetrance at the age of 60.22,23 The topographic distribution shows hand tremor in 94%, head tremor in 33%, voice tremor in 16%, jaw tremor in 8%, facial tremor in 3%, leg tremor in 12%, and tremor of the trunk in 3% of the patients.22-24 In some of the topographic regions (e.g., head, voice, and chin), tremor may occur in isolation.25 About 50% to 90% of the patients improve with ingestion of alcohol, which can be used as an important feature of medical history. So far only few data are available on the progression of the condition and have shown a decrease of tremor frequency and a tendency to develop larger amplitudes.26 Intention tremor develops at various intervals between 3 and 30 years after the onset of postural tremor.20 The disease-related disability varies significantly and is dependent on the severity of intention tremor.27 For a generic quality of life questionnaire (SF-36), essential tremor patients scored worse in all eight SF-36 domains. Tremor severity correlated with some of the physical domains as well as with social function of the mental domains.28 An essential tremor-specific quality of life questionnaire has been validated.29 Up to 25% of the patients seeking medical attention must change jobs or retire from work.30 Nontremor symptoms have been described as a mild frontal dysexecutive syndrome31 and slight personality changes,28,32 which have both been interpreted to reflect a cerebellar dysfunction. Furthermore, a deficit of hearing33 and olfaction was found independent from disease duration and severity.34

Epidemiology The prevalence of essential tremor has been assessed in many studies to be between 1.3% and 5.1% when only studies with

convincing methodological approaches are taken into account.35 Such methodological problems are the lack of a test for the validation of the diagnosis as many other conditions may manifest with a slowly progressive action tremor. Convincing studies on the incidence are not available. Patients with essential tremor were found in retrospective studies to live longer than those without essential tremor,36 but other studies failed to find this. There is at least no evidence for a shortening of life span due to essential tremor.

Etiology The majority of cases are hereditary. The families that have been described hitherto have shown an autosomal dominant inheritance with an almost complete penetrance at the age of 60 years. Twin studies allow to estimate the heritability, which was estimated to be low in a relatively small study37 but almost 100% in a larger study of twins of old age (>70 years).38 Thus, in families with familial essential tremor, the heritability seems to be extremely high and the role of environmental factors is probably limited. However, there is a proportion of approximately 20% to 40% of the patients who have no family history of essential tremor and therefore may not be genetic. Linkage has been found for two chromosomes, 3q1339 and 2p22.40 For the latter locus, a rare variant of the HS1-BP3 protein has been described,41 which binds to motor neurons and Purkinje cells and regulates the Ca2+/calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase. Further confirmation is needed. On chromosome 3, a gain of function-mutation of the DRD3-gen is considered to be responsible. The environmental factors that may cause tremor are also understudied. β-Carboline alkaloids are known to cause tremor in animals and humans42 and were found to be elevated in the blood of patients with essential tremor.43 Also, the lead concentration was found to be elevated in essential tremor.44 Controlled epidemiological studies are necessary.

Pathophysiology The pathophysiology of essential tremor was reviewed45,46 and is covered only briefly here. Essential tremor is likely enhanced by peripheral reflex mechanisms, but its main origin must be within the central nervous system for various reasons: either a preformed mechanism in the brain that is producing rhythmic movements is overactive or pathology has created a system to oscillate, which is usually stable. The oscillator is most likely located within the olivocerebellorubral triangle. The cerebellum shows some mild to moderate signs of malfunction demonstrated in a number of motor tests. The rhythmic movement is obviously mediated through different channels of both hemispheres for the different extremities as the trembling is independent in the four extremities.47 It is assumed that the rhythmic discharges are mediated through the thalamus to the premotor and motor cortex projecting down to the motor neurons. At both locations, tremor-related activity can be detected with electrophysiological techniques. Alternative pathways, mainly from the cerebellar nuclei through reticulospinal pathways to the spinal cord, have been proposed.

chapter 33 tremor Differential Diagnosis The following criteria are considered red flags for the diagnosis (see also Table 33−2): ■ Isolated tremor in the voice, tongue, chin, or legs ■ Unilateral tremor or leg tremor ■ Presence of known causes of enhanced physiological tremor ■ ■ ■ ■ ■ ■ ■ ■

(e.g., drugs, anxiety, depression, hyperthyroidism) History of recent trauma preceding the onset of tremor History or presence of psychogenic tremor Sudden onset or stepwise progression Isolated head tremor with abnormal postures (e.g., dystonia) Drugs Other systemic disorders (e.g., endocrine, renal) Primary orthostatic tremor Isolated position-specific or task-specific tremors, including occupational tremors and primary writing tremor

Treatment Tremor of the Hands Propranolol and primidone are the drugs of first choice for this indication, and both have been carefully studied (for review, see Findley48). Propranolol was introduced in 197149 as a treatment for essential tremor. Drugs with predominant β1 effects have been shown to be less effective than those acting on the β2 receptor, and none has proved superior to propranolol. Only 25% maintain their initial good response for 2 years. Contraindications are cardiac insufficiency or arrhythmia and diabetes. As propranolol acts on the peripheral (reflex) enhancement of tremors, it is helpful for many other tremors like parkinsonian or cerebellar tremor.50,51 Primidone is efficient for essential tremor52 but tachyphylaxia may occur. The major problems are early adverse effects with nausea, dizziness, sedation, and headache. The combination of propranolol and prinidone is recommended whenever one of the drugs is insufficient. Arotinolol has been tested in a crossover study with a similar effect as propranolol.53 Gabapentin is also effective

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following two double-blind studies,54 but another double-blind study showed no convincing effect.55 Topiramate was shown to be effective in a small double-blind study.56 Levetiracetam is just beginning to be explored for the treatment of essential tremor and single-dose studies are promising.57,58 Acetazolamide (and methazolamide) are not significantly better than placebo.59 Alprazolam is helpful in essential tremor.60 Clonazepam is recommended for patients with predominant action and intention tremor in essential tremor61 but not effective in uncomplicated essential tremor.62 Botulinum toxin at a dosage of 50 units or 100 U of Botox has a significant but clinically limited effect and carries a high risk of a clinically meaningful but completely reversible paresis63 (Table 33−3 and, for drug dosages, Table 33−4). Surgery is the accepted treatment for patients resistant to medical treatment and severe disability. Multicenter studies have shown that thalamic deep-brain stimulation is effective,64-67 and one study has shown that deep-brain stimulation of the Vim has a better effect than Vim-thermocoagulation and even fewer side effects.68 The selection of patients for surgery is a crucial point for a good therapeutic effect. Each patient should test the treatments of first choice before surgery and each patient proposed for surgery must have a significant handicap. Gamma knife surgery for the treatment of tremors is proposed in some centers, but prospective studies are lacking and the risks are not yet fully clear.69-71

Head and Voice Pharmacological treatment of essential head and voice tremor is less efficient than the one of hand tremor. Propranolol and primidone, each alone or both combined, have been recommended72,73 for essential head tremor. Clonazepam is often recommended for this indication, but careful studies are not available. One of the promising therapies for head tremor is the local injection of botulinum toxin.74 Deep brain stimulation is also effective for head and voice tremor. As bilateral thalamotomies carry a high risk of dysarthria and bilateral interventions show better effects on these “midline” tremors,75,76 mostly Vim stimulation is applied.66,77 An evidence-based medicine-

T A B L E 33-3. Drugs and Dosages for Essential Tremor Choice

Drug

Dosage

Remarks

First choice

Propranolol

First choice

Primidone

First choice

Contraindications: cardiac, pulmonary, diabetes, etc. Hand and head tremors Hand and head tremors Preferentially for patients with age >60 years Try always before using second- and third-choice drugs

Second choice Second choice

Combination: propranolol/ primidone Arotinolol Gabapentine

30 to 320 mg, 3 doses (standard or long-acting) 62.5 to 500 mg, single dose in the evening Maximum dosage for each 10 to 30 mg 1800 to 2400 mg daily

Second choice Second choice Third choice

Topiramate Clonazepam Botulinum toxin

<400 mg 0.75 to 6 mg

Third choice

Clozapine

Test: 12.5 mg, 30 to 50 mg daily

If drug therapy fails

Surgery

Crossover study with propranolol Conflicting results of three double-blind studies: one without, two with benefit! So far, small double-blind study only For predominant kinetic tremor Double-blind study with a significant result, but weakness as a significant side effect Less well documented effect than for Parkinson’s disease. Often ineffective Vim stimulation or thalamotomy

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T A B L E 33-4. Dosages of Various Substances Applied for the Treatment of Tremor Initial Dose

Increase in Steps of

High Dose

62.5 mg 50 mg

62.5 mg/d 50 mg/d

750 mg 600 mg

Dopamine agonists Bromocriptine Lisuride α-Dihydroergocryptin Pergolide Pramipexole Ropinirole Cabergoline

5 mg 0.1 mg 10 mg 0.15 mg 1.5 mg 3 mg 2 mg

5 mg/wk 0.1 mg/wk 10 mg/wk 0.10 mg/d 0.5 mg/wk 1.5 mg/d 1 mg/wk

20 mg 1.2 mg 90 mg 3.0 mg 4.5 mg 15 mg 6 mg

Anticholinergics Bornaprine Biperiden Metixen Trihexyphenidyl

3 mg 1 mg 7.5 mg 1 mg

3 mg/wk 2 mg/wk 7.5 mg/wk 2 mg/wk

12 mg 12 mg 60 mg 10 mg

b Blockers Propranolol Nadolol

30 mg 10 mg

30mg/wk 30 mg/wk

240 mg 120 mg

Miscellaneous Clozapine Amantadine Primidone Clonazepam Alprazolam

12.5 mg 100 mg 62.5 mg 0.5 mg 0.75 mg

12.5 mg/d 100 mg/d 125 mg/d 0.5 mg/d 0.75 mg/d

75 mg 300 mg 500 mg 6 mg 4 mg

L-Dopa L-Dopa L-Dopa

+ benserazid + carbidopa

For some substances (e.g., anticholinergics), a slow titration is strictly recommended. Treatment for parkinsonian tremor must be customized to the individual patient, and we have indicated which dosages we consider to be high for the indication tremor.

Etiology and Pathophysiology Orthostatic tremor is considered an idiopathic condition. However, other movement disorders often occur simultaneously: Parkinson’s disease, vascular parkinsonism, and Restless legs syndromes (RLS) have all been described in orthostatic tremor, but there is no convincing evidence that any of these conditions are pathophysiologically related. It is of special interest that dopaminergic terminals are significantly reduced in this condition82 but clinical trials with L-dopa and dopamine agonists are usually unsuccessful. Surface electromyography (e.g., from the quadriceps femoris muscle) while standing shows a typical (pathognomic) 13- to 18-Hz burst pattern. All of the leg, trunk, and arm muscles show this pattern, which is in many cases absent during tonic innervation when sitting and lying.83-85 Besides asterixis, orthostatic tremor is the only tremulous condition for which electromyography is mandatory for the diagnosis. Arm tremor may occur in roughly one half of the patients and is usually more evident during stance.86,87 The high-frequency electromyographic pattern is coherent in all the muscles of the body,88 leading to the hypothesis that a bilaterally descending system must underlie orthostatic tremor. Such projections originate only from the brainstem and not from the hemispheres. Therefore, the generator for this tremor is assumed to be located within the brainstem or cerebellum.89

Differential Diagnosis Other idiopathic tremors like essential tremor and also cerebellar tremors can manifest with similar complaints. The most important test to separate them is electromyography.

Treatment based review on treatments for essential tremor was published.78

ORTHOSTATIC TREMOR Primary orthostatic tremor is a unique tremor syndrome79,80 characterized by a subjective feeling of unsteadiness during stance but only in severe cases during gait. Some patients show sudden falls. None of the patients has problems when sitting and lying. The only clinical finding is sometimes visible but mostly only palpable fine-amplitude rippling of leg muscles. This tremor is suspected mainly based on the complaints of the patients rather than on clinical findings.

Epidemiology Orthostatic tremor is a relatively rare condition (only small case series have been published adding up to fewer than 200 cases), but epidemiological data are lacking. Other movement disorders are common in orthostatic tremor. The condition occurs only in patients older than 40 years, and in the series of Gerschlager and colleagues,81 the mean age at onset was lower for women (50 years) compared with men (60 years). So far, it is not considered a hereditary disease.

Orthostatic tremor has been documented to be responsive to clonazepam and primidone.90 Valproate and propranolol were applied in single cases with varying success. Abnormalities of dopaminergic innervation of the striatum have been described, although L-dopa has not consistently shown efficiency.82,91 According to small double-blind studies92,93 and our experience, gabapentin seems to have an excellent and most consistent beneficial effect.94 We use it as the drug of first choice for orthostatic tremor (1800 to 2400 mg daily). The drug of second choice, in our hands, is clonazepam.

PARKINSONIAN TREMORS Parkinsonian tremor has been defined as tremor that occurs in Parkinson’s disease.1 The most common forms are the following: Classic parkinsonian tremor (type I) is defined as tremor at rest (ideally resting on a couch) that increases in amplitude under mental stress and is suppressed during initiation of a movement and often during the course of a movement. Tremor frequency is 4 to 6 Hz but can be as high as 6 Hz, especially in early Parkinson’s disease. It may also be seen in the hands during walking or when sitting as a typical pill-rolling tremor of the hand. The postural/kinetic tremor (with similar frequencies for rest and postural/kinetic tremors) seems to be a

chapter 33 tremor continuation of the resting tremor under postural and action conditions. The frequencies for resting and postural/action tremor can be considered to be equal if they do not differ by more than 1.5 Hz. Unilateral tremor or leg tremor are often seen and are typical for type I tremor. A clinically important specific variant of Parkinson’s disease is the monosymptomatic tremor at rest or benign tremulous parkinsonism. This is defined as a classic Parkinson’s disease type I tremor without other symptoms sufficient to diagnose Parkinson’s disease.1 In some patients, a second form of postural and action tremor with a different frequency from resting tremor (>1.5 Hz) may occur, which is labeled type II tremor. This postural/action tremor can be extremely disabling. Some patients have a predominant postural tremor in addition to their resting tremor. The postural/action tremor has a higher and non−harmonically related frequency to the resting tremor. This form is rare (<15% of patients with Parkinson’s disease) and has often been described as a combination of an essential tremor with Parkinson’s disease.95 Some of these patients had their postural tremor long before the onset of other symptoms of Parkinson’s disease. A high-frequency action tremor also described as “rippling” is often found in Parkinson’s disease and has been described as type III tremor in Parkinson’s disease.1

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but that there are no clear-cut differences in the positron emission tomography imaging of the presynaptic or postsynaptic dopaminergic terminals in patients with monosymptomatic tremor at rest compared with classic Parkinson’s disease patients.104,105 Interestingly, reduction in 5-hydroxytryptamine1A binding in the midbrain raphe region is correlating with tremor severity but not with rigidity or bradykinesia.106 Thus, degeneration of transmitter systems other than dopamine may be responsible for the erratic behavior of tremor as a symptom in Parkinson’s disease. Nevertheless, L-dopa and dopamine agonists are potent drugs to treat Parkinson’s disease tremor. Beyond all of these unsolved problems, animal experiments and human data converge to suggest that parkinsonian tremor is generated within the basal ganglia.107 In the 1-methyl 4phenyl 1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease it has been shown that the cells within the basal ganglia loop are topographically organized through the whole loop and well segregated for the different muscle groups and functional regions. In MPTP animals, these cells become abnormally synchronized, and this may be the reason for synchronized activity leading to peripheral tremor.108 Recordings in humans are compatible with this view.109

Treatment Epidemiology Tremor at rest is common in Parkinson’s disease. It is estimated that 90% of all patients with Parkinson’s disease have a classic rest tremor at any time of their disease and that 75% of all parkinsonian syndromes are idiopathic. Thus, the occurrence of the classic tremor at rest in a patient with parkinsonism has a likelihood of more than 95% to reflect idiopathic Parkinson’s disease.

Etiology and Pathophysiology It is one of the mysteries of Parkinson’s disease that the typical type I tremor is a symptom with such a high specificity for Parkinson’s disease but that the symptom of tremor does not correlate with disease progression96,97 nor does tremor severity correlate with the amount of dopaminergic degeneration measured with positron emission tomography or single-photon emission computed tomography imaging.98-100 Pathology suggests that in patients with predominant tremor the retrorubral Aδ part of the substantia nigra is specifically degenerating101-103

T A B L E 33–5.

Drug treatments differ for the different forms of tremor in Parkinson’s disease (for drug dosages, see Table 33−4). Our personal approach to the treatment of patients is included in Table 33−5. L-Dopa is the most effective treatment for the majority of symptoms in Parkinson’s disease. Among the tremors in Parkinson’s disease, mainly the resting tremor is improved, but other forms may also respond. Generally, the effect on tremor is highly variable in patients with Parkinson’s disease, and the tremor may even worsen, especially for the action tremor with frequencies different from the resting tremor frequency. All of the available double-blind studies of different dopamine agonists failed to demonstrate a superior effect of one or the other agonist on tremor, although all of them obviously have a significant effect. For pramipexol, a double-blind-study has shown a favorable effect on tremor.110 Although the treatment of tremors with anticholinergics is often recommended, there are only a few double-blind studies. The anticholinergic bornaprine has been found to be effective in two double-blind studies.111,112 Trihexyphenidyl has been tested alone and compared with amantadine and L-dopa.113 Possible side effects are dry mouth,

Suggestions for the Treatment of Tremors in Parkinson’s Disease

Tremor type

step 1.

step 2.

step 3.

Classic parkinsonian tremor or monosymptomatic rest tremor

L-Dopa Dopamine agonists Anticholinergics Propranolol Primidone

Amantadine Propranolol Clozapine Dopamine Dopamine agonists Anticholinergics Clozapine Amantadine

STN-stimulation

Rest and postural tremor with different frequencies Isolated action tremor

Propranolol Anticholinergics

STN-stimulation

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visual disturbances, constipation, glaucoma, disturbance of micturition, and memory deficits. Especially in elderly subjects, confusional states can occur, which are reversible after cessation of the drug. Discontinuation may induce a severe rebound effect. A study has provided ample evidence that patients treated with anticholinergics have a higher incidence of Alzheimer pathology.114 The favorable effect of clozapine on rest tremor has been confirmed in several studies,115,116 which have shown a good effect on resting tremor—even when other drugs failed.117 No tolerance has been observed over 6 months. The dosage was 18 to 75 mg. Major side effects are sedation and leukopenia as a serious, even lethal complication in some patients. Functional neurosurgery is a useful treatment for some patients who cannot be treated otherwise. Thalamic thermocoagulation or deep brain stimulation (DBS) of the Vim improves tremor but does not improve akinesia. Lesional surgery cannot be applied bilaterally due to speech disturbances (but DBS can) and therefore is no longer the surgical treatment of first choice.68 Pallidotomy, as well as stimulation of the pallidum, also improves tremor. Subthalamic nucleus (STN) stimulation improves tremor118,119 as well as akinesia and rigidity and is the preferred surgery. Further controlled studies are necessary.

DYSTONIC TREMOR SYNDROMES Different forms of tremor can be associated with dystonia. Typical dystonic tremor occurs in the body region affected by dystonia. It is defined120 as a postural/kinetic tremor usually not seen during complete rest. Usually, these are focal tremors with irregular amplitudes and varying frequencies (mostly below 7 Hz). Some patients exhibit focal tremors even without overt signs of dystonia. These tremors have been included with dystonic tremors121 because in some of them, dystonia develops later. Tremor associated with dystonia is a more generalized form of tremor in extremities that are not affected by the dystonia. This is a relatively symmetrical, postural, and kinetic tremor usually showing higher frequencies than actual dystonic tremor, often seen in the upper limbs in patients with spasmodic torticollis.122

Epidemiology The prevalence of dystonic tremor is not known. In one Brazilian cross-sectional study, it was estimated that around 20% of patients with dystonia present with postural tremor.123 This proportion does not differ between primary and secondary dystonia but seems to be more common in cervical dystonia than in other locations.124 In a large survey among patients from a large Indian movement disorder center, dystonic tremor constituted about 20% of all patients presenting with non-parkinsonian and noncerebellar tremors (essential tremor, 60%).125

Pathophysiology and Etiology Dystonic tremor is still an entity that is under debate, and different definitions have been proposed by clinicians.126-128 Its pathophysiology is largely unknown but is likely related to the central nervous system (basal ganglia) abnormality postulated

for dystonia itself.120 Tremor associated with dystonia may be a “forme fruste” of essential tremor.127 However, it is not yet clear if they share common genes (the DYT1 locus is already excluded), and the pathophysiological mechanisms seem to be different in some of the patients.122

Differential Diagnosis In many patients with dystonic tremors, antagonistic gestures lead to a reduction of the tremor amplitude. This is well known for dystonic head tremor in the setting of spasmodic torticollis. A reduction in tremor is seen when the patient touches the head or only lifts the arm.129 As this sign is absent in essential head tremor, it can be an important differential diagnostic hint in unclear head tremors in which the dystonic posture is not obvious. The effect of these maneuvers can be difficult to observe clinically, and it can be helpful to record surface electromyography from the affected muscles and look for electromyographic suppression.129 Other important but less specific differential diagnostic clues are the focal nature and relatively low frequency of dystonic tremor (see Table 33−2). The tremor associated with dystonia is more difficult to separate from essential tremor, especially when the accompanying dystonia has not evolved completely.

Treatment A positive effect of propranolol has been described earlier in studies of dystonic head tremor. The effectivity of botulinum toxin for dystonic head130 tremor and in tremulous spasmodic dysphonia is well documented. A double-blind study has also documented the efficacy of botulinum toxin for hand tremor,63 but the use of this drug for this indication is limited because of the paresis associated with this treatment. Severe cases in the setting of a generalized dystonia have been successfully treated with deep brain stimulation of the pallidum.131 Stimulation of the ventrolateral thalamus can also alleviate the tremor drastically but can occasionally lead to worsening of the dystonia itself. Tremor associated with dystonia often responds to the medication for classic essential tremor (for drug dosages, see Table 33−4).

CEREBELLAR TREMOR SYNDROMES The classic cerebellar tremor is an intention tremor that may occur unilaterally or bilaterally depending on the underlying cerebellar abnormality. The tremor frequency is almost always below 5 Hz. Simple kinetic and postural tremor may also be present. Some patients with a mild cerebellar ataxia present with an isolated postural and simple kinetic tremor above 5 Hz resembling essential tremor. Titubation is another tremor manifestation of cerebellar disease and is a low-frequency oscillation (around 3 Hz) of the head and trunk depending on postural innervation. If the low-frequency action tremor is severe, it may sometimes be seen in a seemingly resting position because the patient is unable to completely relax.

Epidemiology and Etiology This type of tremor can be caused by insults of various etiologies and degenerations, so no epidemiological data are avail-

chapter 33 tremor able. One of the most common causes of cerebellar tremor certainly is demyelinating lesions in multiple sclerosis.132 Cerebellar strokes can also manifest with tremor, especially when the brainstem is involved.133 Degenerations of cerebellar neurons of various etiologies often produce tremor. Whereas the hereditary ataxias are rare syndromes, toxic cerebellar degeneration due to alcohol abuse predominantly of the anterior lobe is common and often manifest with low-frequency (2 to 3 Hz) stance tremor in the anteroposterior direction.134

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symptomatic improvement can be obtained with stereotactic high-frequency stimulation or thalamotomy in select patients.68,144,145 Functional outcome after surgery, however, greatly varies and depends on the presence of other motor symptoms of the disease; patients with tremor in Multiple Sclerosis (MS) with a frequency above 3 Hz and significant tremorrelated disabilities were found to respond favorably.144 Accelerometric tremor recordings and frequency analysis may help to distinguish patients with predominant MS tremor from those with tremor and ataxia. The long-term follow-up in a larger cohort has not yet been assessed.

Pathophysiology The pathophysiology of the classic cerebellar intention tremor seems to be distinct from the mechanisms underlying most of the other central tremors in that it most likely does not emerge from oscillating groups or loops of neurons but is due to altered characteristics of feedforward or feedback loops. It is meanwhile well established in animals and humans135-137 that one of the striking abnormalities in cerebellar dysfunction is a delay of the second and third phases of the triphasic electromyographic pattern in ballistic movements138 or a delay of the reflexes regulating stance control.139 During goal-directed movements or sway during stance, this causes the breaking movement to occur late and thereby produce an overshoot, in turn producing a quasi-rhythmic movement that is compatible with intention tremor during goal-directed movements or the low-frequency body tremor during stance. However, the higher-frequency postural and action tremors in some patients with cerebellar disease most likely reflect the existence of a separate central oscillator.

Differential Diagnosis Intention tremor is a unique form of tremor that can usually be separated from other tremor forms clinically. However, the fact that intention tremor can also occur in advanced essential tremor45 can make the differentiation difficult. The most important clinical clue in this situation is the degree to which ataxia is present and the absence of clinically detectable oculomotor abnormalities in essential tremor. whereas in essential tremor only a mild dysmetria45 and tandem gait disturbance21 have been described, these dominate the cerebellar syndrome, in which lesions or atrophy can often be seen in brain imaging studies (see Table 33−2).

HOLMES’ TREMOR This is a rare symptomatic tremor due to a lesion in the region of the midbrain. It has been labeled under different names in the past (rubral tremor, midbrain tremor, myorhythmia, Benedikt’s syndrome). It is the only tremor with resting, postural, and intentional components. It typically shows low frequencies (<4.5 Hz) and often manifests as irregular, not as rhythmic as are other tremors. If the date of the lesion is known (e.g., in case of a cerebrovascular accident), a variable delay between the lesion and the first occurrence of the tremor is typical (usually 2 weeks to 2 years). This is among the most disabling forms of tremor because it disturbs rest and all kinds of voluntary and involuntary movements. It mainly affects the hands and proximal arm and is mostly unilateral.

Pathophysiology and Etiology It is generally accepted that this unique tremor form is caused by lesions that seem to be centered in the brainstem/cerebellum and the thalamus. The pathophysiological basis of Holmes tremor is a combined lesion of the cerebellothalamic and nigrostriatal systems as suggested by autopsy data,146 positron emission tomography data,147 and clinical observations.148,149 Any lesion involving fiber tracts from both systems can produce this tremor. The exact location of the lesions seen in these patients may vary. Because of these lesions the tremors can be accompanied by a cerebellar as well as parkinsonian syndrome. Central oscillators are causing this tremor. It seems likely that the rhythm of resting tremor is usually blocked during voluntary movements by the cerebellum. If this cerebellar compensation is absent, the rhythm of rest tremor spills into movements,148 thereby producing the low-frequency intention (action) tremor.

Treatment Cerebellar tremors are difficult to treat and good results are rare. Double-blind studies are lacking. Studies with cholinergic substances (physostigmine, lecitine [a precursor of choline]) have shown improvement in some patients but failed in the majority. Isoniazid failed to show significant results.140 5-HTP has been found to be effective in some patients.141,142 Another proposal has been to administer amantadine. Open studies or single-case observations have shown favorable results with propranolol, clonazepam, carbamazepine, tetrahydrocannabiol, and trihexyphenidyl. Limited improvements have been observed after loading of the shaking extremity, but most clinicians do not use it because the patients adapt rapidly to the new weight. Cannabis is not effective.143 Probably the best

Differential Diagnosis A specific tremor syndrome associated with thalamic lesions can be difficult to differentiate from Holmes tremor. It has been presented often in the past but was further analyzed with modern imaging techniques. The label thalamic tremor150 has been used for this entity. A more detailed study has shown that this tremor is part of a specific dystonia-athetosis-chorea-action tremor following lateral-posterior thalamic strokes.151,152 The combination of tremor, dystonia, and a severe sensory loss following this stroke seems to be the important clue for the diagnosis. The “thalamic” tremor itself is a mixture of action tremor with an intentional component and dystonia in the setting of a

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well-recovered severe hemiparesis. Proximal segments are often involved. This tremor syndrome is also developing with a certain delay after the initial insult. Cerebellar tremor that continues under seemingly resting conditions due to a lack of relaxation can be mistaken for Holmes tremor. The irregularity, the lower frequency, and an accompanying parkinsonian syndrome can help to recognize Holmes tremor in this situation (see Table 33−2).

Treatment No generally accepted therapy is available. Nevertheless, treatment is successful in a higher percentage than for patients with cerebellar tremor. Some patients respond to L-dopa, anticholinergics, or clonazepam (for drug dosages, see Table 33−4). The effect of functional neurosurgery for this tremor syndrome is poorly documented. Such patients have been operated on but they are diagnosed as having post-traumatic tremors or poststroke tremors and the clinical features are not described in detail. Several patients received thalamic surgery (lesion or DBS153-155) with some improvement.

PALATAL TREMOR SYNDROMES Palatal tremors are rare tremor syndromes that were earlier classified among the myoclonias (palatal myoclonus).156 Because they are rhythmic, they have been reclassified among the tremors. Palatal tremor can be separated into two forms.157,158 Symptomatic palatal tremor (SPT) is characterized by rhythmic movements of the soft palate (levator veli palatini). This is clinically visible as a rhythmic movement of the edge of the palate. Other brainstem-innervated (leading to oscillopsia in case of eye muscle involvement) or extremity muscles can also be involved.146 It typically follows a brainstem/cerebellar lesion with a variable delay159,160 and is often associated with a cerebellar syndrome.161 Essential palatal tremor occurs without any overt central nervous pathology and is characterized by rhythmic movements of the soft palate (tensor veli palatini), usually with an ear click. The tensor contraction is visible as a movement of the roof of the palate. Extremity or eye muscles are not involved.158,161,162

Pathophysiology and Etiology Although the pathophysiological basis of essential palatal tremor is unknown, the emergence of SPT has been studied in detail and carries important implications for central mechanisms of tremors in general. After the cerebellar/brainstem lesion, an inferior olivary pseudohypertrophy (which can be demonstrated on MRI) develops most likely as a consequence of an interruption of inhibitory GABAergic fibers terminating in the inferior olive.158 It is well established that inferior olivary neurons are prone to oscillate spontaneously and can be easily synchronized through gap junctions.163 The disinhibition and hypertrophy lead to enhanced synchronized oscillations and build the basis for the rhythmic movement disorder. Interestingly, this rhythm is also reflected in rhythmic electromyographic inhibition in extremity muscles, sometimes leading to a mild postural tremor.158,164 Therefore, it has been postulated that the inferior olive (and the olivocerebellar system) may be

a key structure in producing postural tremors8 and that these tremors are characterized by a rhythmic inhibition of ongoing contractions rather than rhythmic activation, which may be the basis of the etiologically different resting tremors.158

Treatment The disability of patients with SPT is mostly due to other clinical symptoms of the underlying cerebellar lesion. The rhythmic palatal movement in SPT does not cause discomfort or disability for the patient except when the eyes are involved or when there is an extremity tremor. Oscillopsia is difficult to treat. Single cases have been described with a favorable response to clonazepam. Other oral drugs that have been proposed are trihexyphenidyl and valproate. Botulinum toxin has been used for the treatment of oscillopsia. The toxin can be injected into the retrobulbar fat tissue, or specific muscles can be targeted selectively.165,166 So far no controlled studies are available. In our hands, this treatment is helpful for some patients but is not always accepted for long-term use. For the treatment of extremity tremors, only single case reports have described a response to clonazepam167 or trihexiphenidyl.168 The only complaint of patients with essential palatal tremor is the ear click. A number of medications have been reported to be successful: valproate,169 trihexyphenidyl,168 and flunarizine.170 Sumatriptane has been found to be effective in a few patients171,172 but was unsuccessful in others.173 The antagonism of 5-hydroxytryptamine receptors may thus play a role at least for some of the patients. As a long-term therapy, this drug is not applicable for various reasons. The most established therapy is the treatment of the click by injection of botulinum toxin into the tensor veli palatini.174 Low dosages of botulinum toxin (e.g., 4 to 10 units of Botox) are injected under electromyographic guidance. The critical point is to ascertain by endoscopy and electromyography with an electromyography injection needle (isolated up to the tip) that the toxin is definitely injected in the tensor muscle. Spread of botulinum toxin in the soft palate or too large dosages can otherwise cause severe side effects. Although we have never seen any such complications in our patients, it must be mentioned that the injection of botulinum toxin into the palatal muscles in rabbits has been introduced as an animal model for middle ear infections (for drug dosages, see Table 33−4).

TREMOR SYNDROMES IN PERIPHERAL NEUROPATHY Several peripheral neuropathies regularly manifest with tremors (Table 33-1). The tremors are mostly postural and action tremors. The frequency in hand muscles can be lower than in proximal arm muscles. Abnormal position sense need not be present.

Epidemiology Dysgammaglobulinemia and chronic Guillain-Barré syndrome are the acquired neuropathies manifesting most frequently with tremor. In a series of 62 patients with dysgammaglobu-

chapter 33 tremor linemic polyneuropathy, postural and action tremor of the hands was present in 70% to 80% of the cases.175 However, it only rarely represents the dominant source of disability in these patients.176 A similar type of tremor can be observed in around 40% of patients with hereditary polyneuropathy. Many of these patients have a family history of tremor.177

Pathophysiology and Etiology The tremor in dysimmune neuropathies seems to be somewhat related to the severity of the peripheral neuronal damage,178 and it has been postulated that an abnormal peripheral feedback to central tremor generating structures could be the basis for the tremor enhancement in this situation.179 The tremor in hereditary polyneuropathy seems to be largely unrelated to the severity of neuropathic syndromes, and it may also occur in family members without a neuropathy. Thus, it has been suggested that it is pathogenetically related to essential tremor.177 There is an ongoing debate as to whether the combination of a hereditary neuropathy with postural tremor (Roussy-Lévy syndrome) actually constitutes a distinct disease entity.180

Treatment No convincing therapies are reported for this type of tremor. Successful treatment of the underlying neuropathy can improve the tremor in some of the patients.178 In our hands, propranolol and primidone have been helpful for some patients at similar dosages as for essential tremor. One patient was successfully implanted with DBS electrodes.181

PSYCHOGENIC TREMOR Psychogenic tremors have very diverse clinical manifestations. Most of them are action tremors but many also remain during rest and often show very unusual combinations of rest/postural and intention tremors.182 Typical clinical features are a sudden onset and sometimes spontaneous remissions, decrease of tremor amplitude or variable frequency during distraction, selective disability, and a positive “coactivation sign.” (This is tested as with rigidity testing, at the wrist. Variable, voluntarylike force exertion can be felt in both movement directions.183) Some of the patients have a history of somatizations in the past or additional, unrelated (psychogenic) neurological symptoms and signs.183

Epidemiology In a large series of 842 patients presenting with a movement disorder, only 3.3 % were diagnosed with a psychogenic movement disorder. Among those, psychogenic tremor was the most common diagnosis (50%).184

Pathophysiology and Etiology Two pathogenetic mechanisms seem to play a role in psychogenic tremor. Voluntary-like rhythmic movements can be

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detected by a coupled (coherent) tremor oscillations in different limbs. This resembles the situation in voluntarily sustained rhythmic movements in normal subjects, as it is extremely difficult to keep up two completely independent rhythms in different limbs.185,186 In pathological, organic tremor (clearly involuntary rhythmic movements), the oscillations are typically independent between different limbs.47,187 Such independent rhythms can also be found in psychogenic tremor patients.188 They most likely represent physiological but involuntary oscillations, such as clonus-like mechanisms, which are enhanced by the ongoing co-contraction of antagonistic muscles detected as the coactivation sign.183 These findings may easily explain the motor control mechanisms underlying these tremors. They do not allow conclusions to be drawn on the underlying psychological mechanisms.

Differential Diagnosis Psychogenic tremors manifest very variably and can mimic virtually all organic tremors. The tremor phenomenology does not help to differentiate them. The typical conditions of tremor appearance or disappearance, enhancement or attenuation described earlier are important clinical clues. The coupling between the oscillations in both arms, which is present only in psychogenic tremor and is absent in organic tremors, can be used as an electrophysiological diagnostic tool. The surface electromyography from both arm muscles can be analyzed using “coherence,” which is a reliable mathematical measure of the oscillatory coupling. If the patients show only unilateral tremor, a voluntarily sustained rhythmic hand movement on the unaffected side is related to the tremor on the affected side (“coherence entrainment test”).189 This test is very specific, and the entrainment of psychogenic tremor by a contralateral rhythmic movement can sometimes be visible even clinically. However, it is not very sensitive; some psychogenic tremor patients show unrelated rhythms in different limbs resembling organic tremors.188 An accelerometric quantification of the distractibility can also be helpful.190

Treatment No studies on the treatment effects in psychogenic tremor are available.191 Psychotherapy is helpful only in the minority of patients. We recommend physiotherapy aiming at a decontraction of the muscles during voluntary movements. Additionally, we administer propranolol at medium or high dosages to desensitize the muscle spindles, which are necessary to maintain the clonus mechanism in these patients. Conclusive data on the prognosis and long-term outcome in these patients are lacking, but the prognosis is generally believed to be poor.192

DRUG-INDUCED AND TOXIC TREMORS Drug-induced tremors can manifest with the whole range of clinical features of tremors depending on the drug and probably on individual predisposition of the patients. The most common form is enhanced physiological tremor following, for example, sympathomimetics or antidepressants. Another frequent form is parkinsonian tremor following neuroleptic or, more generally, antidopaminergic drugs (dopamine receptor

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blockers, dopamine-depleting drugs such as reserpine, flunarizin, etc). Intention tremor may occur following lithium intoxication and ingestion of some other substances. The withdrawal tremor from alcohol or other drugs has been characterized as enhanced physiological tremor with tremor frequencies mostly above 6 Hz. However, this has to be separated from the intention tremor of chronic alcoholism, which is most likely related to cerebellar damage following alcohol ingestion. A specific variant is tardive tremor associated with longterm neuroleptic treatment.193,194 The risk factors to develop this tremor are not well known, but many clinicians believe that patients with essential tremor, older age, and females represent a higher risk to develop this tremor. Its frequency range is 3 to 5 Hz, it is most prominent during posture but is also present at rest and during goal-directed movements. The tremor in Wilson’s disease can also be regarded a toxic tremor as it results from copper toxicity. All kinds of movement disorders, including cerebellar syndromes, can be observed.195 Tremor is one of the most common neurological manifestations and occurs in around 30% to 50% of the patients. Resting, postural, and kinetic tremors have all been described. The treatment of these tremors is usually to stop the medication or toxin ingestion. If this is not possible, propranolol may be tried in action tremors if it does not have negative interactions with the causative drug. It has been shown to be effective in a small open series of valproate-induced tremors.196 Treatment attempts for tardive tremor have been with trihexyphenidyl or clozapine. The treatment of Wilson’s disease with copper chelators (D-penicillamine) also improves the tremor and other neurological manifestations.197,198 In patients with very severely disabling neurological symptoms (tremor), a liver transplantation may be considered even with normal liver function.199

MYOCLONUS Myoclonus is defined as a sudden, brief, shocklike involuntary movement caused by muscle contractions or inhibitions. It can be of cortical, subcortical, or spinal origin and occurs in different neurodegenerative diseases, in focal structural lesions of the respective region of the central nervous system, and as idiopathic diseases.200 It can be difficult to differentiate from tremor when the myoclonic jerks occur repetitively with only short intervals sometimes looking rhythmically. This type of rhythmic myoclonus is not well defined but has been described as low frequency (usually below 5 Hz) muscle jerks topographically limited to segmental levels. A similar picture can be seen in asterixis in which an ongoing contraction is repetitively interrupted by inhibitions of different duration (‘negative myoclonus’). It can manifest as “flapping tremor” and typically results from focal lesions of the contralateral hemisphere (unilateral form) or endocrine dysfunction, intoxication, and liver disease (bilateral form). Both myoclonus and asterixis should be diagnosed on the basis of polymyographic recordings revealing irregular short bursts or inhibitions occurring synchronously in different muscles. Cortical tremor is considered a specific form of rhythmic myoclonus201,202 manifesting with high-frequency, irregular tremor-like postural and action myoclonus. On electrophysiological analysis, they show the typical features of cortical myoclonus with a related electroencephalographic spike pre-

ceding the electromyographic jerks and often enhanced longloop-reflexes and/or giant SEP. This form is mostly hereditary but has also been described in corticobasal degeneration203,204 and even after focal lesions205 or celiac disease.206 There is an overlap between these cortical myoclonias and epileptic phenomena, being most obvious in epilepsia partialis continua (EPC), a focal epilepsy producing (mostly lowfrequency) rhythmic jerks of an extremity. Resting and rarely postural/intention tremors (e.g., Holmes tremor) can be mimicked by EPC. A medical history for epilepsy and presence of electroencephalographic spikes, short electromyographic bursts, and jerk-locked averaging are diagnostically helpful. Clonus also is a rhythmic movement mostly around one joint elicited through the stretch reflex loop and increasing in strength (or amplitude) by maneuvers affecting the stretch reflex.207 Passive stretching of the muscles increases the force of clonus and serves as a diagnostic criterion. According to the clinical definition (see earlier), all of those myoclonic syndromes can manifest as tremors when they are rhythmic; however, they often show more irregular or even arrhythmic bursts, and most of them show pathophysiological features that are distinct from all the other pathological tremors described earlier. Thus, it seems justified and diagnostically useful to separate them from the tremor syndromes.

CONCLUSIONS Tremor or tremulous phenomena are so common in neurology that this chapter could not give a full account of all the diseases manifesting with tremor and instead concentrated on the clinical characteristics and distinctive features of the most important tremor syndromes. An exact diagnostic classification of tremors can be an important hint in the differential diagnosis of the neurological syndrome as a whole and is indispensable to the correct treatment decisions. Based on our current knowledge of the pathophysiology of tremors, good hypotheses exist as to which brain structures are involved in the generation of the tremor oscillation. This has stimulated the development or refinement of a number of new therapies, the most prominent of which is the extremely effective stereotactic deep brain stimulation. However, the underlying causes that trigger the enhanced oscillatory activity are far from being understood in the majority of tremors, and most of our treatment options are purely symptomatic. Future progress in this field will undoubtedly lead to an improvement and increasingly causal approaches in the rational therapy of tremor.

K E Y

P O I N T S

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Tremor is commonly encountered in clinical neurology. It can manifest as an isolated symptom or as a sign of another neurological disease.

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Each tremor form is characterized clinically by the conditions of activation (rest, posture, and goal-directed movements), its topographic distribution, the frequency, and additional neurological symptoms.

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The most common tremors are enhanced physiological, essential, and parkinsonian tremor.

chapter 33 tremor ●

The following tremors are less frequent but important: orthostatic tremor, cerebellar tremor, Holmes tremor, tremor in neuropathies, drug-induced tremor, and psychogenic tremor.

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The differential diagnosis mainly relies on clinical characteristics, but additional tests, including recordings of the limb oscillations or the underlying electromyographic activity or special brain imaging techniques, can help to differentiate the various forms of tremor.

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The pathophysiological background seems to be different for the different forms of tremor, and thus different tremors respond to different medical treatments.

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For some tremors, well-established therapies are available. For uncommon tremors, only small studies exist.

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Developments in the field of stereotactic deep brain operations have added an important new and very effective second-line option to the treatment of severe tremors.

Suggested Reading Deuschl G, Bain P, Brin M, Ad Hoc Scientific Committee: Consensus statement of the Movement Disorder Society on Tremor. Mov Disord 1998; 13:2-23. Findley LJ, Koller WC, eds: Handbook of Tremor Disorders. New York: Marcel Dekker, 1995. Pahwa R, Lyons KE, eds: Handbook of Essential Tremor and Other Tremor Disorders. Philadelphia: Taylor & Francis, 2005.

References 1. Deuschl G, Bain P, Brin M, Ad Hoc Scientific Committee: Consensus statement of the Movement Disorder Society on Tremor. Mov Disord 1998; 13:2-23. 2. Vallbo AB, Wessberg J: Organization of motor output in slow finger movements in man. J Physiol Lond 1993; 469:673-691. 3. Elble RJ, Randall JE: Mechanistic components of normal hand tremor. Electroencephalogr Clin Neurophysiol 1978; 44:72-82. 4. Hömberg V, Hefter H, Reiners K, et al: Differential effects of changes in mechanical limb properties on physiological and pathological tremor. J Neurol Neurosurg Psychiatr 1987; 50:568-579. 5. Timmer J, Lauk M, Pfleger W, et al: Cross-spectral analysis of physiological tremor and muscle activity. I. Theory and application to unsynchronized electromyogram. Biol Cybern 1998; 78:349-357. 6. Raethjen J, Pawlas F, Lindemann M, et al: Determinants of physiologic tremor in a large normal population. Clin Neurophysiol 2000; 111:1825-1837. 7. Marsden CD, Gimlette TM, McAllister RG, et al: Effect of betaadrenergic blockade on finger tremor and Achilles reflex time in anxious and thyrotoxic patients. Acta Endocrinol (Copenh) 1968; 57:353-362. 8. Deuschl G, Raethjen J, Lindemann M, et al: The pathophysiology of tremor. Muscle Nerve 2001; 24:716-735. 9. Elble RJ: Central mechanisms of tremor. J Clin Neurophysiol 1996; 13:133-144. 10. Elble RJ: Characteristics of physiologic tremor in young and elderly adults. Clin Neurophysiol 2003; 114:624-635.

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11. Elble RJ, Randall JE: Motor-unit activity responsible for 8- to 12-Hz component of human physiological finger tremor. J Neurophysiol 1976; 39:370-383. 12. Lyons KE, Pahwa R, Comella CL, et al: Benefits and risks of pharmacological treatments for essential tremor. Drug Saf 2003; 26:461-481. 13. Raethjen J, Lemke MR, Lindemann M, et al: Amitriptyline enhances the central component of physiological tremor. J Neurol Neurosurg Psychiatry 2001; 70:78-82. 14. Deuschl G, Krack P, Lauk M, et al: Clinical neurophysiology of tremor. J Clin Neurophysiol 1996; 13:110-121. 15. Deuschl G, Blumberg H, Lücking CH: Tremor in reflex sympathetic dystrophy. Arch Neurol 1991; 48:1247-52. 16. Raethjen J, Lauk M, Koster B, et al: Tremor analysis in two normal cohorts. Clin Neurophysiol 2004; 115:2151-2156. 17. Elble RJ, Higgins C, Elble S: Electrophysiologic transition from physiologic tremor to essential tremor. Mov Disord 2005; 20:1038-1042. 18. Bain P, Brin M, Deuschl G, et al: Criteria for the diagnosis of essential tremor. Neurology 2000; 54:S7. 19. Louis ED, Ford B, Lee H, et al: Diagnostic criteria for essential tremor: a population perspective. Arch Neurol 1998; 55:823-828. 20. Deuschl G, Wenzelburger R, Loffler K, et al: Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain 2000; 123(Pt 8):1568-1580. 21. Stolze H, Petersen G, Raethjen J, et al: The gait disorder of advanced essential tremor. Brain 2001; 124:2278-2286. 22. Bain PG, Findley LJ, Thompson PD, et al: A study of hereditary essential tremor. Brain 1994; 117(Pt 4):805-824. 23. Lou JS, Jankovic J: Essential tremor: clinical correlates in 350 patients. Neurology 1991; 41:234-238. 24. Koller WC, Busenbark K, Miner K: The relationship of essential tremor to other movement disorders: report on 678 patients. Essential Tremor Study Group. Ann Neurol 1994; 35:717-723. 25. Jankovic J: Essential tremor: clinical characteristics. Neurology 2000; 54: S21-S25. 26. Elble RJ: Essential tremor frequency decreases with time. Neurology 2000; 55:1547-1551. 27. Louis ED, Ford B, Wendt KJ, et al: Clinical characteristics of essential tremor: data from a community-based study. Mov Disord 1998; 13:803-808. 28. Lorenz D, Schwieger D, Moises H, et al: Quality of life and personality in essential tremor. Mov Disord 2006. 29. Troster AI, Pahwa R, Fields JA, et al: Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord 2005; 11:367-373. 30. Louis ED, Barnes L, Albert SM, et al: Correlates of functional disability in essential tremor. Mov Disord 2001; 16:914920. 31. Troster AI, Woods SP, Fields JA, et al: Neuropsychological deficits in essential tremor: an expression of cerebellothalamo-cortical pathophysiology? Eur J Neurol 2002; 9:143151. 32. Chatterjee A, Jurewicz EC, Applegate LM, et al: Personality in essential tremor: further evidence of non-motor manifestations of the disease. J Neurol Neurosurg Psychiatry 2004; 75:958-961. 33. Ondo WG, Sutton L, Dat Vuong K, et al: Hearing impairment in essential tremor. Neurology 2003; 61:1093-1097. 34. Louis ED, Bromley SM, Jurewicz EC, et al: Olfactory dysfunction in essential tremor: a deficit unrelated to disease duration or severity. Neurology 2002; 59:1631-1633. 35. Louis ED, Ottman R, Hauser WA: How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998; 13:5-10.

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36. Jankovic J, Beach J, Schwartz K, et al: Tremor and longevity in relatives of patients with Parkinson’s disease, essential tremor, and control subjects. Neurology 1995; 45:645-648. 37. Tanner CM, Goldman SM, Lyons KE, et al: Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology 2001; 57:1389-1391. 38. Lorenz D, Frederiksen H, Moises H, et al: High concordance for essential tremor in monozygotic twins of old age. Neurology 2004; 62:208-211. 39. Gulcher JR, Jonsson P, Kong A, et al: Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997; 17:84-87. 40. Higgins JJ, Loveless JM, Jankovic J, et al: Evidence that a gene for essential tremor maps to chromosome 2p in four families. Mov Disord 1998; 13:972-977. 41. Higgins JJ, Lombardi RQ, Pucilowska J, et al: A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005; 64:417-421. 42. Lucotte G, Lagorde JP, Funalot B, Sokoloff P: Linkage with the SergGly DRD3 polymorphism in essential tremor families. Clin Genet 2006; 69:437-440. 43. Louis ED, Zheng W, Jurewicz EC, et al: Elevation of blood beta-carboline alkaloids in essential tremor. Neurology 2002; 59:1940-1944. 44. Louis ED, Applegate L, Graziano JH, et al: Interaction between blood lead concentration and delta-amino-levulinic acid dehydratase gene polymorphisms increases the odds of essential tremor. Mov Disord 2005; 20:1170-1177. 45. Deuschl G, Elble RJ: The pathophysiology of essential tremor. Neurology 2000; 54: S14-S20. 46. Raethjen J, Deuschl G: Pathophysiology of essential tremor. In Lyons KE, Pahwa R, eds: Handbook of Essential Tremor and Other Tremor Disorders. Boca Raton, FL: Taylor & Francis, 2005, pp 27-50. 47. Raethjen J, Lindemann M, Schmaljohann H, et al: Multiple oscillators are causing parkinsonian and essential tremor. Mov Disord 2000; 15:84-94. 48. Findley LJ: The pharmacological management of essential tremor. Clin Neuropharmacol 1986; 9(Suppl 2): S61-S75. 49. Winkler GF, Young RR: The control of essential tremor by propranolol. Trans Am Neurol Assoc 1971; 96:66-68. 50. Koller WC: Long-acting propranolol in essential tremor. Neurology 1985; 35:108-110. 51. Meert TF: Pharmacological evaluation of alcohol withdrawalinduced inhibition of exploratory behaviour and supersensitivity to harmine-induced tremor. Alcohol Alcohol 1994; 29:91-102. 52. Findley LJ, Cleeves L, Calzetti S: Primidone in essential tremor of the hands and head: a double blind controlled clinical study. J Neurol Neurosurg Psychiatry 1985; 48:911915. 53. Lee KS, Kim JS, Kim JW, et al: A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor. Parkinsonism Relat Disord 2003; 9:341-347. 54. Gironell A, Kulisevsky J, Barbanoj M, et al: A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol 1999; 56:475-480. 55. Pahwa R, Lyons K, Hubble JP, et al: Double-blind controlled trial of gabapentin in essential tremor. Mov Disord 1998; 13:465-467. 56. Connor GS: A double-blind placebo-controlled trial of topiramate treatment for essential tremor. Neurology 2002; 59:132134. 57. Bushara KO, Malik T, Exconde RE: The effect of levetiracetam on essential tremor. Neurology 2005; 64:1078-1080. 58. Sullivan KL, Hauser RA, Zesiewicz TA: Levetiracetam for the treatment of essential tremor. Mov Disord 2005.

59. Busenbark K, Pahwa R, Hubble J, et al: Double-blind controlled study of methazolamide in the treatment of essential tremor. Neurology 1993; 43:1045-1047. 60. Huber SJ, Paulson GW: Efficacy of alprazolam for essential tremor. Neurology 1988; 38:241-243. 61. Biary N, Koller W: Kinetic predominant essential tremor: successful treatment with clonazepam. Neurology 1987; 37:471474. 62. Thompson C, Lang A, Parkes JD, et al: A double-blind trial of clonazepam in benign essential tremor. Clin Neuropharmacol 1984; 7:83-88. 63. Brin MF, Lyons KE, Doucette J, et al: A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology 2001; 56:1523-1528. 64. Kolek M, Mrozek V, Schenk P: [Cardiac manifestations of Friedreich’s ataxia]. Cas Lek Cesk 2004; 143:48-51. 65. Koller W, Pahwa R, Busenbark K, et al: High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997; 42:292-299. 66. Limousin P, Speelman JD, Gielen F, et al: Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry 1999; 66: 289-296. 67. Pahwa R, Lyons KL, Wilkinson SB, et al: Bilateral thalamic stimulation for the treatment of essential tremor. Neurology 1999; 53:1447-1450. 68. Schuurman PR, Bosch DA, Bossuyt PM, et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000; 342:461468. 69. Ohye C, Shibazaki T, Sato S: Gamma knife thalamotomy for movement disorders: evaluation of the thalamic lesion and clinical results. J Neurosurg 2005; 102(Suppl):234-240. 70. Siderowf A, Gollump SM, Stern MB, et al: Emergence of complex, involuntary movements after gamma knife radiosurgery for essential tremor. Mov Disord 2001; 16:965-967. 71. Young RF, Jacques S, Mark R, et al: Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg 2000; 93(Suppl 3):128-135. 72. Calzetti S, Sasso E, Negrotti A, et al: Effect of propranolol in head tremor: quantitative study following single-dose and sustained drug administration. Clin Neuropharmacol 1992; 15:470-476. 73. Massey EW, Paulson GW: Essential vocal tremor: clinical characteristics and response to therapy. South Med J 1985; 78:316-317. 74. Pahwa R, Busenbark K, Swanson-Hyland EF, et al: Botulinum toxin treatment of essential head tremor. Neurology 1995; 45:822-824. 75. Koller WC, Lyons KE, Wilkinson SB, et al: Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential head tremor. Mov Disord 1999; 14:847-850. 76. Ondo W, Almaguer M, Jankovic J, et al: Thalamic deep brain stimulation: comparison between unilateral and bilateral placement. Arch Neurol 2001; 58:218-222. 77. Pollak P, Benabid AL, Gervason CL, et al: Long-term effects of chronic stimulation of the ventral intermediate thalamic nucleus in different types of tremor. Adv Neurol 1993; 60:408413. 78. Zesiewicz TA, Elble R, Louis ED, et al: Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005; 64:2008-2020. 79. Heilman KM: Orthostatic tremor. Arch Neurol 1984; 41:880881. 80. Pazzaglia P, Sabattini L, Lugaresi E: [On an unusual disorder of erect standing position (observation of 3 cases)]. Riv Sper Freniatr Med Leg Alien Ment 1970; 94:450-457.

chapter 33 tremor 81. Gerschlager W, Munchau A, Katzenschlager R, et al: Natural history and syndromic associations of orthostatic tremor: a review of 41 patients. Mov Disord 2004; 19:788-795. 82. Katzenschlager R, Costa D, Gerschlager W, et al: [123I]-FPCIT-SPECT demonstrates dopaminergic deficit in orthostatic tremor. Ann Neurol 2003; 53:489-496. 83. Deuschl G, Lucking CH, Quintern J: [Orthostatic tremor: clinical aspects, pathophysiology and therapy]. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb 1987; 18:13-19. 84. McManis PG, Sharbrough FW: Orthostatic tremor: clinical and electrophysiologic characteristics. Muscle Nerve 1993; 16:1254-1260. 85. Thompson PD, Rothwell JC, Day BL, et al: The physiology of orthostatic tremor. Arch Neurol 1986; 43:584-587. 86. Boroojerdi B, Ferbert A, Foltys H, et al: Evidence for a nonorthostatic origin of orthostatic tremor. J Neurol Neurosurg Psychiatry 1999; 66:284-288. 87. McAuley JH, Britton TC, Rothwell JC, et al: The timing of primary orthostatic tremor bursts has a task-specific plasticity. Brain 2000; 123(Pt 2):254-266. 88. Britton TC, Thompson PD: Primary orthostatic tremor. BMJ 1995; 310:143-144. 89. Wu YR, Ashby P, Lang AE: Orthostatic tremor arises from an oscillator in the posterior fossa. Mov Disord 2001; 16:272279. 90. Poersch M: Orthostatic tremor: combined treatment with primidone and clonazepam. Mov Disord 1994; 9:467. 91. Wills AJ, Brusa L, Wang HC, et al: Levodopa may improve orthostatic tremor: case report and trial of treatment. J Neurol Neurosurg Psychiatry 1999; 66:681-684. 92. Evidente VG, Adler CH, Caviness JN, et al: Effective treatment of orthostatic tremor with gabapentin. Mov Disord 1998; 13:829-831. 93. Onofrj M, Thomas A, Paci C, et al: Gabapentin in orthostatic tremor: results of a double-blind crossover with placebo in four patients. Neurology 1998; 51:880-882. 94. Rodrigues JP, Edwards DJ, Walters SE, et al: Gabapentin can improve postural stability and quality of life in primary orthostatic tremor. Mov Disord 2005. 95. Koller WC, Vetere-Overfield B, Barter R: Tremors in early Parkinson’s disease. Clin Neuropharmacol 1989; 12:293297. 96. Jankovic J, McDermott M, Carter J, et al: Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 1990; 40:1529-1534. 97. Louis ED, Tang MX, Cote L, et al: Progression of parkinsonian signs in Parkinson disease. Arch Neurol 1999; 56:334-337. 98. Brooks DJ: PET and SPECT studies in Parkinson’s disease. Baillieres Clin Neurol 1997; 6:69-87. 99. Leenders KL, Oertel WH: Parkinson’s disease: clinical signs and symptoms, neural mechanisms, positron emission tomography, and therapeutic interventions. Neural Plast 2001; 8:99-110. 100. Tissingh G, Bergmans P, Booij J, et al: Drug-naive patients with Parkinson’s disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta-CIT SPECT. J Neurol 1998; 245:1420. 101. Hirsch EC, Mouatt A, Faucheux B, et al: Dopamine, tremor, and Parkinson’s disease. Lancet 1992; 340:125-126. 102. Jellinger KA: Post mortem studies in Parkinson’s disease—is it possible to detect brain areas for specific symptoms? J Neural Transm Suppl 1999; 56:1-29. 103. Paulus W, Jellinger K: The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol 1991; 50:743-755.

431

104. Brooks DJ, Playford ED, Ibanez V, et al: Isolated tremor and disruption of the nigrostriatal dopaminergic system: an 18Fdopa PET study. Neurology 1992; 42:1554-1560. 105. Ghaemi M, Raethjen J, Hilker R, et al: Monosymptomatic resting tremor and Parkinson’s disease: a multitracer positron emission tomographic study. Mov Disord 2002; 17:782788. 106. Doder M, Rabiner EA, Turjanski N, et al: Tremor in Parkinson’s disease and serotonergic dysfunction: an 11C-WAY 100635 PET study. Neurology 2003; 60:601-605. 107. Bergman H, Deuschl G: Pathophysiology of Parkinson’s disease: from clinical neurology to basic neuroscience and back. Mov Disord 2002; 17(Suppl 3): S28-S40. 108. Bergman H, Raz A, Feingold A, et al: Physiology of MPTP tremor. Mov Disord 1998; 13 Suppl 3:29-34. 109. Hurtado JM, Rubchinsky LL, Sigvardt KA, et al: Temporal evolution of oscillations and synchrony in GPi/muscle pairs in Parkinson’s disease. J Neurophysiol 2005; 93:15691584. 110. Pogarell O, Gasser T, van Hilten JJ, et al: Pramipexole in patients with Parkinson’s disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study. J Neurol Neurosurg Psychiatry 2002; 72:713-720. 111. Cantello R, Riccio A, Gilli M, et al: Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30 patients. Ital J Neurol Sci 1986; 7:139-143. 112. Piccirilli M, D’Alessandro P, Testa A, et al: [Bornaprine in the treatment of parkinsonian tremor]. Rev Neurol 1985; 55:3845. 113. Koller WC: Pharmacologic treatment of parkinsonian tremor. Arch Neurol 1986; 43:126-7. 114. Perry EK, Kilford L, Lees AJ, et al: Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann Neurol 2003; 54:235-238. 115. Fischer PA, Baas H, Hefner R: Treatment of parkinsonian tremor with clozapine. J Neural Transm Park Dis Dement Sect 1990; 2:233-238. 116. Pakkenberg H, Pakkenberg B: Clozapine in the treatment of tremor. Acta Neurol Scand 1986; 73:295-297. 117. Jansen EN: Clozapine in the treatment of tremor in Parkinson’s disease. Acta Neurol Scand 1994; 89:262-265. 118. Krack P, Benazzouz A, Pollak P, et al: Treatment of tremor in Parkinson’s disease by subthalamic nucleus stimulation. Mov Disord 1998; 13:907-914. 119. Sturman MM, Vaillancourt DE, Metman LV, et al: Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson’s disease. Brain 2004; 127:2131-2143. 120. Deuschl G: Dystonic tremor. Rev Neurol (Paris) 2003; 159:900-905. 121. Rivest J, Marsden CD: Trunk and head tremor as isolated manifestations of dystonia. Mov Disord 1990; 5:60-65. 122. Munchau A, Schrag A, Chuang C, et al: Arm tremor in cervical dystonia differs from essential tremor and can be classified by onset age and spread of symptoms. Brain 2001; 124:1765-1776. 123. Ferraz HB, De Andrade LA, Silva SM, et al: [Postural tremor and dystonia. Clinical aspects and physiopathological considerations]. Arq Neuropsiquiatr 1994; 52:466-470. 124. Bartolome FM, Fanjul S, Cantarero S, et al: [Primary focal dystonia: descriptive study of 205 patients]. Neurologia 2003; 18:59-65. 125. Shukla G, Behari M: A clinical study of non-parkinsonian and non-cerebellar tremor at a specialty movement disorders clinic. Neurol India 2004; 52:200-202. 126. Jedynak CP, Bonnet AM, Agid Y: Tremor and idiopathic dystonia. Mov Disord 1991; 6:230-236.

432

Section

VII

Motor System and Motor Diseases

127. Marsden CD: Dystonia: the spectrum of the disease. Res Publ Assoc Res Nerv Ment Dis 1976; 55:351-367. 128. Vidailhet M, Jedynak CP, Pollak P, et al: Pathology of symptomatic tremors. Mov Disord 1998; 13 Suppl 3:49-54. 129. Masuhr F, Wissel J, Muller J, et al: Quantification of sensory trick impact on tremor amplitude and frequency in 60 patients with head tremor. Mov Disord 2000; 15:960964. 130. Jankovic J, Schwartz K: Botulinum toxin treatment of tremors. Neurology 1991; 41:1185-1188. 131. Coubes P, Roubertie A, Vayssiere N, et al: Treatment of DYT1generalised dystonia by stimulation of the internal globus pallidus. Lancet 2000; 355:2220-2221. 132. Alusi SH, Worthington J, Glickman S, et al: A study of tremor in multiple sclerosis. Brain 2001; 124:720-730. 133. Louis ED, Lynch T, Ford B, et al: Delayed-onset cerebellar syndrome. Arch Neurol 1996; 53:450-454. 134. Neiman J, Lang AE, Fornazzari L, et al: Movement disorders in alcoholism: a review. Neurology 1990; 40:741-746. 135. Flament D, Hore J: Movement and electromyographic disorders associated with cerebellar dysmetria. J Neurophysiol 1986; 55:1221-1233. 136. Flament D, Hore J: Comparison of cerebellar intention tremor under isotonic and isometric conditions. Brain Res 1988; 439:179-186. 137. Hore J, Flament D: Evidence that a disordered servo-like mechanism contributes to tremor in movements during cerebellar dysfunction. J Neurophysiol 1986; 56:123-136. 138. Hallett M, Shahani BT, Young RR: EMG analysis of patients with cerebellar deficits. J Neurol Neurosurg Psychiatry 1975; 38:1163-1169. 139. Mauritz KH, Schmitt C, Dichgans J: Delayed and enhanced long latency reflexes as the possible cause of postural tremor in late cerebellar atrophy. Brain 1981; 104:97-116. 140. Hallett M, Ravits J, Dubinsky RM, et al: A double-blind trial of isoniazid for essential tremor and other action tremors. Mov Disord 1991; 6:253-256. 141. Rascol A, Clanet M, Montastruc JL, et al: L5H tryptophan in the cerebellar syndrome treatment. Biomedicine 1981; 35:112-113. 142. Trouillas P, Xie J, Getenet JC, et al: [Effect of buspirone, a serotonergic 5-HT-1A agonist in cerebellar ataxia: a pilot study. Preliminary communication]. Rev Neurol (Paris) 1995; 151:708-713. 143. Fox P, Bain PG, Glickman S, et al: The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004; 62:1105-1109. 144. Alusi SH, Aziz TZ, Glickman S, et al: Stereotactic lesional surgery for the treatment of tremor in multiple sclerosis: a prospective case-controlled study. Brain 2001; 124:15761589. 145. Lozano AM: VIM thalamic stimulation for tremor. Arch Med Res 2000; 31:266-269. 146. Masucci EF, Kurtzke JF, Saini N: Myorhythmia: a widespread movement disorder. Clinicopathological correlations. Brain 1984; 107:53-79. 147. Remy P, de Recondo A, Defer G, et al: Peduncular ‘rubral’ tremor and dopaminergic denervation: a PET study [see comments]. Neurology 1995; 45:472-477. 148. Deuschl G, Wilms H, Krack P, et al: Function of the cerebellum in Parkinsonian rest tremor and Holmes’ tremor. Ann Neurol 1999; 46:126-128. 149. Krack P, Deuschl G, Kaps M, et al: Delayed onset of “rubral tremor” 23 years after brainstem trauma. Mov Disord 1994; 9:240-242. 150. Miwa H, Hatori K, Kondo T, et al: Thalamic tremor: case reports and implications of the tremor-generating mechanism. Neurology 1996; 46:75-79.

151. Kim JS: Delayed onset mixed involuntary movements after thalamic stroke: clinical, radiological and pathophysiological findings. Brain 2001; 124:299-309. 152. Lehericy S, Grand S, Pollak P, et al: Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology 2001; 57:1055-1066. 153. Kim MC, Son BC, Miyagi Y, et al: Vim thalamotomy for Holmes’ tremor secondary to midbrain tumour. J Neurol Neurosurg Psychiatry 2002; 73:453-455. 154. Kudo M, Goto S, Nishikawa S, et al: Bilateral thalamic stimulation for Holmes’ tremor caused by unilateral brainstem lesion. Mov Disord 2001; 16:170-174. 155. Nikkhah G, Prokop T, Hellwig B, et al: Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. Report of two cases. J Neurosurg 2004; 100:10791083. 156. Lapresle J: Palatal myoclonus. Adv Neurol 1986; 43:265273. 157. Deuschl G, Mischke G, Schenck E, et al: Symptomatic and essential rhythmic palatal myoclonus. Brain 1990; 113:16451672. 158. Deuschl G, Toro C, Valls SJ, et al: Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain 1994:775-788. 159. Deuschl G, Wilms H: Clinical spectrum and physiology of palatal tremor. Mov Disord 2002; 17(Suppl 2):S63-S66. 160. Samuel M, Torun N, Tuite PJ, et al: Progressive ataxia and palatal tremor (PAPT): clinical and MRI assessment with review of palatal tremors. Brain 2004; 127:12521268. 161. Deuschl G, Jost S, Schumacher M: Symptomatic palatal tremor is associated with signs of cerebellar dysfunction. J Neurol 1996; 243:553-556. 162. Deuschl G, Toro C, Hallett M: Symptomatic and essential palatal tremor. 2. Differences of palatal movements. Mov Disord 1994; 9:676-678. 163. Llinas R, Volkind RA: The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res 1973; 18:69-87. 164. Elble RJ: Inhibition of forearm EMG by palatal myoclonus. Mov Disord 1991; 6:324-329. 165. Leigh RJ, Averbuch HL, Tomsak RL, et al: Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology. Ann Neurol 1994; 36:129-141. 166. Repka MX, Savino PJ, Reinecke RD: Treatment of acquired nystagmus with botulinum neurotoxin A. Arch Ophthalmol 1994; 112:1320-1324. 167. Bakheit AM, Behan PO: Palatal myoclonus successfully treated with clonazepam [letter] [see comments]. J Neurol Neurosurg Psychiatry 1990; 53. 168. Jabbari B, Scherokman B, Gunderson CH, et al: Treatment of movement disorders with trihexyphenidyl. Mov Disord 1989; 4:202-212. 169. Borggreve F, Hageman G: A case of idiopathic palatal myoclonus: treatment with sodium valproate. Eur Neurol 1991; 31:403-404. 170. Cakmur R, Idiman E, Idiman F, et al: Essential palatal tremor successfully treated with flunarizine. Eur Neurol 1997; 38:133-134. 171. Gambardella A, Quattrone A: Treatment of palatal myoclonus with sumatriptan [letter]. Mov Disord 1998; 13:195. 172. Scott BL, Evans RW, Jankovic J: Treatment of palatal myoclonus with sumatriptan. Mov Disord 1996; 11:748-751. 173. Pakiam AS, Lang AE: Essential palatal tremor: evidence of heterogeneity based on clinical features and response to Sumatriptan. Mov Disord 1999; 14:179-180.

chapter 33 tremor 174. Deuschl G, Lohle E, Heinen F, et al: Ear click in palatal tremor: its origin and treatment with botulinum toxin. Neurology 1991; 41:1677-1679. 175. Yeung KB, Thomas PK, King RH, et al: The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol 1991; 238:383-391. 176. Busby M, Donaghy M: Chronic dysimmune neuropathy. A subclassification based upon the clinical features of 102 patients. J Neurol 2003; 250:714-724. 177. Cardoso F, Jankovic J: Movement disorders. Neurol Clin 1993; 11:625-638. 178. Dalakas MC, Teravainen H, Engel WK: Tremor as a feature of chronic relapsing and dysgammaglobulinemic polyneuropathies. Incidence and management. Arch Neurol 1984; 41:711-714. 179. Bain PG, Britton TC, Jenkins IH, et al: Tremor associated with benign IgM paraproteinaemic neuropathy. Brain 1996; 119:789-799. 180. Plante-Bordeneuve V, Guiochon-Mantel A, Lacroix C, et al: The Roussy-Lévy family: from the original description to the gene. Ann Neurol 1999; 46:770-773. 181. Ruzicka E, Jech R, Zarubova K, et al: VIM thalamic stimulation for tremor in a patient with IgM paraproteinaemic demyelinating neuropathy. Mov Disord 2003; 18:1192-1195. 182. Kim YJ, Pakiam AS, Lang AE: Historical and clinical features of psychogenic tremor: a review of 70 cases. Can J Neurol Sci 1999; 26:190-195. 183. Deuschl G, Koster B, Lucking CH, et al: Diagnostic and pathophysiological aspects of psychogenic tremors. Mov Disord 1998; 13:294-302. 184. Factor SA, Podskalny GD, Molho ES: Psychogenic movement disorders: frequency, clinical profile, and characteristics. J Neurol Neurosurg Psychiatry 1995; 59:406-412. 185. Brown P, Thompson PD: Electrophysiological aids to the diagnosis of psychogenic jerks, spasms, and tremor. Mov Disord 2001; 16:595-599. 186. McAuley JH, Rothwell JC, Marsden CD, et al: Electrophysiological aids in distinguishing organic from psychogenic tremor. Neurology 1998; 50:1882-1884. 187. Lauk M, Koster B, Timmer J, et al: Side-to-side correlation of muscle activity in physiological and pathological human tremors. Clin Neurophysiol 1999; 110:1774-1783. 188. Raethjen J, Kopper F, Govindan RB, et al: Two different pathogenetic mechanisms in psychogenic tremor. Neurology 2004; 63:812-815. 189. McAuley J, Rothwell J: Identification of psychogenic, dystonic, and other organic tremors by a coherence entrainment test. Mov Disord 2004; 19:253-267.

433

190. Zeuner KE, Shoge RO, Goldstein SR, et al: Accelerometry to distinguish psychogenic from essential or parkinsonian tremor. Neurology 2003; 61:548-550. 191. Koller W, Lang A, Vetere OB, et al: Psychogenic tremors. Neurology 1989; 39:1094-1099. 192. Feinstein A, Stergiopoulos V, Fine J, et al: Psychiatric outcome in patients with a psychogenic movement disorder: a prospective study. Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:169-176. 193. Ebersbach G, Tracik F, Wissel J, et al: Tardive jaw tremor. Mov Disord 1997; 12:460-462. 194. Stacy M, Jankovic J. Tardive tremor. Mov Disord 1992; 7:5357. 195. Oder W, Grimm G, Kollegger H, et al: Neurological and neuropsychiatric spectrum of Wilson’s disease: a prospective study of 45 cases. J Neurol 1991; 238:281-287. 196. Karas BJ, Wilder BJ, Hammond EJ, et al: Treatment of valproate tremors. Neurology 1983; 33:1380-1382. 197. Starosta-Rubinstein S, Young AB, Kluin K, et al: Clinical assessment of 31 patients with Wilson’s disease. Correlations with structural changes on magnetic resonance imaging. Arch Neurol 1987; 44:365-370. 198. Takahashi W, Yoshii F, Shinohara Y: Reversible magnetic resonance imaging lesions in Wilson’s disease: clinicalanatomical correlation. J Neuroimaging 1996; 6:246-248. 199. Schumacher G, Platz KP, Mueller AR, et al: Liver transplantation: treatment of choice for hepatic and neurological manifestation of Wilson’s disease. Clin Transplant 1997; 11:217-224. 200. Caviness JN: Myoclonus and neurodegenerative disease— what’s in a name? Parkinsonism Relat Disord 2003; 9:185192. 201. Ikeda A, Kakigi R, Funai N, et al: Cortical tremor: a variant of cortical reflex myoclonus. Neurology 1990; 40:1561-1565. 202. Toro C, Pascual LA, Deuschl G, et al: Cortical tremor. A common manifestation of cortical myoclonus. Neurology 1993; 43:2346-2353. 203. Chen R, Ashby P, Lang AE: Stimulus-sensitive myoclonus in akinetic-rigid syndromes. Brain 1992; 115:1875-1888. 204. Thompson PD, Day BL, Rothwell JC, et al: The myoclonus in corticobasal degeneration. Evidence for two forms of cortical reflex myoclonus. Brain 1994; 44:578-591. 205. Wang HC, Hsu WC, Brown P: Cortical tremor secondary to a frontal cortical lesion. Mov Disord 1999; 14:370-374. 206. Fung VS, Duggins A, Morris JG, et al: Progressive myoclonic ataxia associated with celiac disease presenting as unilateral cortical tremor and dystonia. Mov Disord 2000; 15:732-734. 207. Jung R: Physiologische Untersuchungen über den Parkinsontremor und andere Zitterformen beim Menschen. Zsch Neurol Psychiat 1941; 173:263-332.

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34

MYOCLONUS ●

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Hiroshi Shibasaki

The term myoclonus originates from report of a case by Friedreich in 1881 with the title of “paramyoclonus multiplex.” The patient was a 50-year-old man manifesting involuntary small muscle jerks mostly in the resting state. Myoclonus is defined as involuntary shocklike movements associated with sudden contraction of skeletal muscles ( positive myoclonus), sudden interruption of the ongoing muscle contraction (negative myoclonus), or a combination of the two.

CLASSIFICATION Myoclonus can originate from either the central nervous system or the peripheral nervous system, but most of myoclonic jerks occur in association with disorders of the central nervous system.1 It can originate from the motor cortex, brainstem, and spinal cord, and there are some other forms of myoclonus whose source has not been clarified completely (Table 34–1). Cortical myoclonus occurs either spontaneously or through a reflex mechanism in response to external stimulus (cortical reflex myoclonus). Epilepsia partialis continua is a focal, continuous form of cortical myoclonus, usually involving the distal part of the upper or lower limb. Cortical myoclonus is often epileptic in nature and thus is also called epileptic myoclonus. Palatal tremor, reticular reflex myoclonus, and startle syndrome are known to originate from brainstem structures. There are two forms in spinal myoclonus: segmental and propriospinal. Periodic myoclonus and dystonic myoclonus are easily recognized from their unique clinical features, but their underlying mechanisms have not been elucidated precisely.

CLINICAL FEATURES Myoclonic jerks are usually detectable by visual observation without much difficulty. However, when the jerks are small, palpation of the corresponding muscles helps in identifying the myoclonus. Because most myoclonic jerks are associated with co-contraction of agonist and antagonist muscles, it is useful to palpate, in the case of hand myoclonus, the wrist flexors and extensors simultaneously. Cortical myoclonus appears as brisk, shocklike movements involving fingers, hands, arms, facial muscles, and/or legs, and sometimes trunk muscles, independently (Fig. 34–1). When

hand intrinsic muscles are involved, it appears as small twitches of each individual finger or a group of fingers. When, in contrast, proximal muscles of an extremity are involved, it appears as big jerks. When the jerks rapidly spread from proximal to distal muscles of an extremity, it appears as if the whole extremity is involved almost simultaneously. Moreover, a jerk of one hand can be followed by another jerk in the other hand by a very short time interval: in fact, as short as 10 milliseconds, corresponding to the transcallosal conduction time. In this case, it appears as if both upper extremities are almost simultaneously involved. Cortical myoclonus appears rhythmic when it repeats in the same muscle groups at a fast rate (7 to 8 Hz), and thus it often resembles tremor (cortical tremor) (Fig. 34–2). Rhythmic cortical myoclonus is commonly seen in corticobasal ganglionic degeneration, familial adult myoclonic epilepsy, postanoxic myoclonus, and Angelman’s syndrome. Cortical myoclonus is induced or enhanced when the patient attempts to move or actually moves the corresponding part of the body or other parts of the body (action myoclonus). Furthermore, it is often stimulus-sensitive; for example, jerks are elicited by tendon tap during neurological examination. In this case, it appears as if the deep tendon reflex is exaggerated, but the cortical reflexmyoclonus occurs slightly later than the expected time for the monosynaptic spinal reflex. In addition, it can be differentiated from the enhanced deep tendon reflex in that cortical reflex myoclonus spreads to other parts of the corresponding extremity (e.g., from distal to proximal muscles) and even to the contralateral extremity. In patients with spastic paraparesis, the deep tendon reflex in response to the patellar tendon tap may be recognized also in the contralateral leg; a typical example is the crossed adductor reflex. This phenomenon, however, is the result of simultaneous mechanical activation of the proprioceptive input to the contralateral spinal segment by the knee tap, which causes a visible reflex in the contralateral leg as a result of the hyperactive state of the contralateral anterior horn cells. Furthermore, cortical myoclonus is elicited or enhanced when the corresponding limb is passively moved or when its posture is changed. These maneuvers are thought to induce a kind of proprioceptive reflex myoclonus. Cortical reflex myoclonus is sometimes elicited by flash stimulus and is noticed when the pupillary light reflex is tested (photic cortical reflex myoclonus). Typical examples have been reported in the advanced stage of Creutzfeldt-Jakob disease (CJD).

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F3’

Figure 34–1. Electroencephalographic (EEG)– electromyographic (EMG) polygraph recorded from a patient with progressive myoclonus epilepsy. EMG discharges associated with cortical myoclonus are abrupt and very brief in duration, involving one or more muscles of the right (Rt) upper extremity almost synchronously. There are frequent sharp spikes or multiple spikes on EEG, some of which are associated with the myoclonus. EEG electrode placement is in approximate accordance with the International 10-20 System as indicated by a prime symbol (′). ECR, extensor carpi radialis muscle; 1stDI, first dorsal interosseous muscle.

Fz’ F4’ C3’ C1’ Cz’ C2’ C4’ P3’ Pz’ 100 ␮V

P4’ Rt thenar Rt 1stDI Rt ECR Rt biceps 1s

■

Lt biceps br.

Figure 34–2. Electromyographic (EMG) polygraph obtained from a patient with clinical diagnosis of corticobasal ganglionic degeneration. Repetitive discharges are seen in the right (RT) biceps and triceps muscles almost synchronously at an approximate rate of 7 to 8 Hz. br., brachii; Lt, left.

Triceps br.

Rhomboid

Rt biceps br. Triceps br.

Rhomboid 500 ␮V 1 sec

Cortical myoclonus sometimes manifests as negative myoclonus, which is caused by sudden interruption of the ongoing muscle contraction (silent period of the electromyogram [EMG]). Most of the negative myoclonus are either immediately preceded or immediately followed by abrupt muscle contraction (positive myoclonus), but on occasion, the isolated form of negative myoclonus is seen. Thus, the pure negative myoclonus can be easily overlooked unless the extremity is examined during sustained muscle contraction: for example, while the wrists are kept in an extended posture. When the trunk muscles are suddenly involved by negative myoclonus, the patient may fall down abruptly (drop attack). On occasion, negative myoclonus is induced by somatosensory or photic

stimulus through a transcortical reflex mechanism (cortical reflex negative myoclonus). Epilepsia partialis continua manifests as continuous, repetitive focal muscle jerks at the rate of 1 to 6 Hz, localized unilaterally to one finger, several fingers, or a foot. Palatal tremor used to be called palatal myoclonus, but the name was changed after the first International Congress of Movement Disorders, held in Washington, D.C., in 1990, because of the lack of shocklike features and its resemblance to tremor, especially when other skeletal muscles are also involved. Essential palatal tremor is characterized by repetitive elevation of the soft palate at a rate of 2 to 3 Hz, often associated with ear click. Familial cases of essential palatal tremor

chapter 34 myoclonus T A B L E 34–1. Classification of Myoclonus Cortical Myoclonus Spontaneous cortical myoclonus Cortical reflex myoclonus Epilepsia partialis continua Brainstem Myoclonus Palatal tremor (“palatal myoclonus”) Reticular reflex myoclonus Startle syndrome Spinal Myoclonus Segmental spinal myoclonus Propriospinal myoclonus Unclassified Periodic myoclonus Dystonic myoclonus

have been reported. The movement may be associated with repetitive, brisk muscle contractions of other cranial muscles, which are approximately synchronous with the palatal movement. Symptomatic palatal tremor consists of rhythmic vertical oscillation of the soft palate and is frequently associated with rhythmic vertical oscillation of eyes (ocular myoclonus). This condition is commonly associated with organic lesions of brainstem or cerebellum and often involves other cranial and extremity muscles. In this condition, the movement of extremities is not very shocklike and may resemble real tremor. This form of palatal tremor may be persistent even during sleep. Reticular reflex myoclonus is a rare form of reflex myoclonus, characterized by shocklike jerks first appearing in the sternocleidomastoid and/or trapezius muscles and then spreading rostrally to the masseter, orbicularis oris, and orbicularis oculi muscles in this order, as well as caudally from proximal to distal muscles of extremities. Diagnosis of this condition requires demonstration of the characteristic spread of jerks by polygraphic recording of surface EMG from different muscles. Startle syndrome is a group of diseases characterized by exaggerated startle responses to sudden unexpected acoustic or tactile stimuli. Physiologically, this condition is considered to be an exaggerated form of physiological startle reaction. Familial startle disease, or hyperexplexia, is mostly an autosomal dominant disorder characterized by muscular rigidity in the neonatal period and the exaggerated startle responses. This condition has drawn special attention in relation to the discovery of heterogeneous mutation of genes encoding inhibitory glycine receptors. Segmental spinal myoclonus is seen as brisk contraction of muscles innervated by a certain spinal segment. It is often quasi-rhythmic or periodic and may be stimulus-sensitive. Propriospinal myoclonus involves mainly trunk muscles. Each jerk starts at a certain segmental level, most commonly at the thoracic segments, and spreads rostrally as well caudally at a slow speed of approximately 5-10 m/second. Within each individual patient, the jerk starts always from the same segment, although it may shift one or two segments during the course of illness. The term propriospinal is derived from the propriospinal tract, which connects successive spinal segments. The causative lesion in spinal myoclonus, either segmental or propriospinal,

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is often difficult to be identified even by extensive laboratory investigation. Underlying mechanisms have not been disclosed for other kinds of myoclonus, including periodic myoclonus and dystonic myoclonus. There are two representative forms of periodic myoclonus; one seen in CJD and the other seen in subacute sclerosing panencephalitis. Periodic myoclonus seen in CJD is quasi-periodic repetition of shocklike, quasi-synchronous jerks involving extremities and facial muscles at a rate of about 1 Hz. It might shift from one extremity to others and continue during sleep, although the rate and the periodicity might change from time to time. It is often associated with periodic synchronous discharge (PSD) on electroencephalographic (EEG) recording, but there is no fixed time relationship between PSD and periodic myoclonus in this condition (Fig. 34–3). In contrast, periodic myoclonus seen in subacute sclerosing panencephalitis is really periodic, with almost constant interval of 6 to 8 seconds, and associated with PSD with a fixed time relationship. The muscle contraction in this condition is rather slow and is characterized by twisting nature of the movement, resembling dystonia rather than myoclonus. Therefore, the involuntary movement in this condition might be called periodic dystonic myoclonus. Myoclonus can be seen in association with other involuntary movements, such as tremor and/or dystonia, either concurrently or independently. For example, patients with writer’s cramp, as a typical example of focal hand dystonia, might exhibit a combination of muscle cramp, tremor, and myoclonic jerks. The term dystonic myoclonus is used when myoclonus has a twisting feature. In this regard, periodic dystonic myoclonus seen in patients with subacute sclerosing panencephalitis is a representative form of dystonic myoclonus. The term myoclonic dystonia is used to indicate almost the same condition as dystonic myoclonus. However, inherited myoclonus-dystonia syndrome is characterized by independent occurrence of myoclonus and dystonia in the same patient. In this case, myoclonic jerks commonly involve the proximal limb muscles and trunk, and they respond to ethanol in just the same way as essential tremor. Autosomal dominant trait with mutation of the gene encoding ε-sarcoglycan is one of the diseases that causes this condition.

UNDERLYING DISEASES Myoclonus can be caused by a number of different diseases. Representative diseases causing cortical myoclonus are listed in Table 34–2. Progressive myoclonus epilepsy is a group of diseases manifesting postural/action myoclonus and generalized convulsive seizures. Most of them are hereditary, and gene abnormalities have been identified for many of these diseases (Table 34–3).2 Among other diseases, postanoxic myoclonus (Lance-Adams syndrome) is most commonly encountered. In this condition, myoclonus develops in patients who survived the acute phase of anoxic encephalopathy, and it is often refractory to various drug treatments. Most jerks are of cortical origin, although reticular reflex myoclonus has been described in this condition. In contrast with progressive myoclonus epilepsy, generalized convulsive seizures are rather rare in this condition. It is noteworthy that cortical myoclonus can be present in metabolic encephalopathy, such as the disease caused by

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F3 C3 CP3 P3 F4 C4 CP4 P4 Fz A1 EOG1 EOG2 Lt FDI Lt FCR Lt FCU

128 ␮V

100 ␮V

500 ms ■

Figure 34–3. Electroencephalographic (EEG)–electromyographic (EMG) polygraph recorded from a patient with Creutzfeldt-Jakob disease. The rectified EMG discharge associated with jerks involving the left upper limb is relatively long in duration and varies from one to the other jerk in its waveform. The myoclonus is associated with periodic synchronous discharge on the EEG, but their time relationship is not fixed.

T A B L E 34–2. Diseases Causing Cortical Myoclonus Progressive myoclonus epilepsy (PME) Unverricht-Lundborg disease Lafora’s disease Neuronal ceroid lipofuscinosis Myoclonus epilepsy associated with ragged-red fibers (MERRF) Lipidosis Dentatorubral-pallidoluysian atrophy (DRPLA) Familial adult myoclonic epilepsy Angelman’s syndrome Celiac disease Progressive myoclonus epilepsies of unknown cause Progressive myoclonic ataxias Juvenile myoclonic epilepsy Postanoxic myoclonus (Lance-Adams syndrome) Alzheimer’s disease Creutzfeldt-Jakob disease (advanced stage) Metabolic encephalopathy Corticobasal ganglionic degeneration Olivopontocerebellar atrophy Rett’s syndrome

uremia. Thus, this condition is not necessarily associated with organic brain lesions and is reversible when the underlying cause is successfully treated. In relation to this, hepatic encephalopathy characteristically shows rhythmic negative myoclonus (asterixis), although the mechanism of this condition is not known. The diagnosis of essential myoclonus is made when myoclonus is not found to be associated with generalized convulsive seizures or other neurological deficits in spite of clinical observation over a long period of time. It is often familial and may be related to the inherited dystonia-myoclonus syndrome (see previous discussion). The physiological mechanism

of essential myoclonus has not been elucidated, but at least some of them might be of cortical origin. Many drugs can cause myoclonus as a side effect (druginduced myoclonus). Myoclonus of this category is often of negative form, associated with the EMG silent period (Fig. 34–4). Thus, whenever negative myoclonus develops in a patient who takes anticonvulsants, this possibility has to be considered. In other words, some cases of negative myoclonus in patients with cortical myoclonus may be, in fact, a side effect of anticonvulsants that they are taking. The physiological mechanisms underlying drug-induced myoclonus may not be homogeneous. It is most likely that some of them may be of cortical origin and the others subcortical.

PHYSIOLOGICAL MECHANISMS As far as cortical myoclonus is concerned, its physiological mechanisms have been elucidated to some extent. This is because most activities of the sensorimotor cortex are remarkably exaggerated in this condition, which makes it easier to assess those activities physiologically by EEG or magnetoencephalographic recording from the head surface. Cortical myoclonus is characterized by increased excitability of the primary motor cortex, extreme enhancement of cortical response to somatosensory stimulus, and enhanced long-loop, transcortical reflex (Fig. 34–5). When a part of the primary motor cortex is suddenly involved by epileptic activity, the muscles innervated by that particular cortical area show sudden contraction at a latency of about 20 milliseconds for a hand and 40 milliseconds for a foot. The cortical activity related to myoclonus may be actually recognized as a spike on EEG recording. In this condition, the somatosensory cortex reacts to tactile or proprioceptive input with magnitude of 10 times

chapter 34 myoclonus

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T A B L E 34–3. Major Forms of Progressive Myoclonus Epilepsy and Their Gene Abnormality Disorder

Locus/Chromosome

Gene Product

Unverricht-Lundborg disease Lafora’s disease

EPM1/21q22.3 EPM2A/6q24 EPM2B/6p22.3 MTTK/mtDNA NEU1/6p21 DRPLA/12p13

Cystatin B Laforin (dual-specificity phosphatase) Malin tRNALys Neuraminidase 1 Atrophin 1

CLN1/1p32 CLN2/11p15 CLN3/16p12

Palmitoyl-protein thioesterase 1 Tripeptidyl peptidase 1 CLN3 (membrane protein of unknown function)

MERRF Sialidosis DRPLA Neuronal ceroid lipofuscinosis Infantile Late infantile Juvenile

Modified from Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:34733478, with help from Dr. Lehesjoki. DRPLA, dentatorubral-pallidoluysian atrophy; MERFF, myoclonic epilepsy associated with ragged-red fibers.

■

Figure 34–4. Polygraphic record consisting of accelerometer (Acceler.), electromyographic (EMG), and electroencephalographic (EEG) recordings from a patient with anticonvulsant-induced negative myoclonus. There are frequent interruptions of EMG discharges of the right extensor carpi radialis (RECR) muscle, associated with the wrist drop as shown in the accelerometer record. The longer the EMG silent period, the more conspicuous is the asterixis. There is no special EEG activity associated with the negative myoclonus. R-FCR, right flexor carpi radialis.

Acceler. R–ECR EMG R–FCR F3 F4 C3 EEG C4 P3 100 ␮V

P4 1 sec

or more in comparison with the physiological reaction. This activity can be recorded as an enormously enhanced (giant) somatosensory evoked potential (SEP). Furthermore, tapping of a hand, for example, elicits reflex muscle contraction in that hand at a latency of about 45 milliseconds. This response can be recorded as an EMG response (long-loop reflex or C reflex) through the use of the surface electrodes.

LABORATORY TESTS The main laboratory test is aimed at confirming and classifying the myoclonus and understanding its pathophysiology, by using a battery of electrophysiological tests (Table 34–4).3,4 The most essential test for any kind of myoclonus is the EMG recording of myoclonic jerks with the surface electrodes. In order to find the distribution and spread of myoclonus, it is

more effective to record simultaneously from as many muscles as possible. This is also useful for finding the most appropriate muscle for carrying out other physiological studies as described later. For recording EMG from a large muscle, a pair of disk electrodes are placed on the skin overlying the muscle belly about 3 cm apart from each other; for recording from a small muscle such as hand intrinsic muscles, one electrode is placed over the muscle, and the other electrode on the skin covering the adjacent bone. A band-pass filter of 30 to 1000 Hz is adequate. Application of low-frequency filter (high-pass filter) is mainly for eliminating movement artifacts. Cortical myoclonus is associated with an EMG discharge of abrupt onset and of short duration, lasting less than 50 milliseconds (see Fig. 34–1). Usually, agonist and antagonist muscles contract simultaneously. The contraction may spread from proximal to distal muscles at the speed of about 50

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Cortical Reflex Myoclonus

Cortical Myoclonus Spike

Giant SEP

Stim.

T A B L E 34–4. Essential Physiological Tests of Myoclonus Technique

Purpose

Surface electromyography

Confirmation of myoclonus and its classification To know the relationship with cortical activity Detection of myoclonus-related cortical activity, and to know its temporal and spatial relationship to myoclonus To confirm giant SEPs

Jerk-locked back averaging of electroencephalogram Somatosensory evoked potential (SEP) Long-loop reflex

Figure 34–5. Schematic diagrams illustrating the hypothesized impulse flow for cortical reflex myoclonus and spontaneous cortical myoclonus. In the latter case (right), excessive discharge arising from the hand area of the motor cortex, seen as a spike on electroencephalographic (EEG) recording, causes abrupt muscle contraction in the corresponding hand in 20 milliseconds via the fast conducting corticospinal tract. In cortical reflex myoclonus (left), the somatosensory input (Stim.) generates giant somatosensory evoked potential (SEP) at a latency of 20 to 25 milliseconds in the sensorimotor cortex, which then gives rise to a reflex muscle contraction (C reflex) at a latency of 45 milliseconds.

Myoclonus

C reflex

EEG-EMG polygraphy

■

To confirm the reflex nature of myoclonus

EEG, electroencephalogram; EMG, electromyogram.

m/second, which corresponds approximately to the conduction velocity of α motor fibers. In case of hand myoclonus, it may be seen in the homologous muscles of the contralateral upper extremity 10 to 15 milliseconds later. Simultaneous EEG recording with the surface EMG is especially useful for the confirmation of cortical myoclonus. EEG recording is accomplished by placing electrodes in accordance with the International 10-20 System recommendations. Referential derivation with ipsilateral earlobe reference or bipolar derivation is used. Usually a band-pass filter of 1 to 500 Hz is used. When the number of EEG channels, the recording time, or both are limited, EEG may be recorded from a limited number of electrodes: for example, from C3, Cz, and C4 of the International 10-20 System in reference to the ipsilateral earlobe. Demonstration of spikes or multiple spikes on EEG is highly suggestive of the cortical origin of myoclonus. The spikes may or may not be associated with myoclonic jerks (see Fig. 34–1). Absence of EEG spikes, however, does not rule out the cortical myoclonus, because small spikes may not be

detected by the scalp recording as a result of attenuation of the electric potential by the skull. Demonstration of PSD is almost pathognomonic of either CJD or subacute sclerosing panencephalitis, depending on the waveform. EEG findings similar to the CJD type of PSD are sometimes encountered in anoxic encephalopathy, but PSD in this condition is not persistent. The technique of jerk-locked back averaging can be used for detecting spikes associated with myoclonus that are not detectable on the conventional EEG-EMG polygraph and for investigating the time and spatial relationship between the EEG spikes and myoclonus. EEG and EMG are recorded simultaneously, just as for the conventional polygraph, and the onset of EMG discharges associated with myoclonus is used as a fiducial point for back averaging the EEG (Fig. 34–6). The EMG may be rectified to avoid the canceling effect of averaging, and integrated. The onset of the rectified, integrated EMG waveform is used as a fiducial point for back averaging, as well as for obtaining the averaged EMG waveforms. Averaging of 100 sweeps is usually sufficient, but it is important to confirm the reproducibility of the results. In order to obtain a record of high quality, it is important to choose the most appropriate muscle for obtaining the fiducial point, to distinguish the myoclonic discharges from the background EMG activities, and to avoid artifacts such as head movements. When the myoclonic jerks occur infrequently in the resting condition, passive or active movement of the corresponding limb might help increase the number of jerks. In case of hand myoclonus, the positive peak or the onset of the negative peak of the EEG spike precedes the myoclonus by 20 milliseconds, on average, and it is localized to the central region of the contralateral head. SEPs are recorded by stimulating the median nerve at wrist by electric shock of 0.2 to 0.3 milliseconds duration with the stimulus intensity 10% above the motor threshold delivered at a frequency of 1 Hz. Averaging of 100 sweeps is usually sufficient, but it is important to confirm the reproducibility of the results. The initial peak of the cortical SEP, N20/P20, is not significantly enlarged, but the subsequent peaks (P25, N30/P30,

chapter 34 myoclonus

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EEG Correlates of Myoclonus (Jerk–locked back averaging)

Back Averaging

Myoclonus

Fiducial point ■

Figure 34–6. Diagram showing the method of jerk-locked back averaging for demonstrating an electroencephalographic (EEG) correlate of myoclonus. The electromyogram (EMG) associated with myoclonus is recorded simultaneously with EEG, and the onset of the rectified EMG is used as a fiducial point for back averaging the EEG as well as the rectified EMG.

N35) are extremely enlarged in the majority of patients with cortical reflex myoclonus. It is convenient to record the long-loop reflex at the time of SEP recording. When the median nerve is electrically stimulated for recording SEP, the surface EMG can be recorded from the thenar muscle of that hand by a pair of surface electrodes. The transcortical reflex (C reflex) is seen at the latency of about 45 milliseconds. In case of severe cortical reflex myoclonus, the reflex EMG response is seen not only in the thenar muscle but also in other muscles of the same limb and also in the thenar muscle of the contralateral hand. In this case, the C reflex of the contralateral hand occurs 10 to 15 milliseconds later than that of the stimulated hand. When the patient is likely to have reflex myoclonus that is sensitive to visual stimulus, it is worthwhile to record photic evoked responses and photically evoked long-loop reflex, just as in the case of SEP and somatosensory evoked long-loop reflex. In addition to these electrophysiological tests, other tests such as magnetic resonance imaging and chemical tests of blood should be performed, depending on the underlying diseases that are possible according to the history and physical findings in each case.

EXPERIMENTAL MODEL The rat model of posthypoxic myoclonus has been extensively studied by Truong’s group.5 They observed auditory stimulusinduced myoclonus in the rats that survived the acute stage of coma and seizures caused by mechanically induced cardiac arrest. The myoclonus was thought to be of brainstem origin, but in contrast to startle response, the acoustic reflex

myoclonus did not show habituation. It was maximal about 4 days after the anoxic insult, and it subsided in 3 to 4 weeks. Histologically, neuronal degeneration was seen extensively in the motor cortex, somatosensory cortices, thalamic reticular nucleus, hippocampus, and cerebellum. Hypofunction of serotonergic system in the frontal cortex was found in this experimental condition, and clonazepam, sodium valproate, and piracetam were found to reduce the myoclonus. Most human cases of posthypoxic myoclonus are of cortical origin, although reticular reflex myoclonus is occasionally encountered. Dichlorodiphenyltrichloroethane (p,p′-DDT) causes spontaneous myoclonus in rats, but in this condition, hyperfunction of 5-hydroxyindole acetic acid (5-HIAA) was demonstrated. Injection of picrotoxin, a γ-amino butyric acid type A (GABAA) antagonist, into the reticular nucleus of the thalamus in rats induces rhythmic, spontaneous myoclonus, which is also evoked by acoustic stimulus. Complex neuropharmacological abnormalities seem to be involved in these experimental conditions, mainly involving serotonergic and GABAergic systems.

TREATMENT Symptomatic treatment of cortical myoclonus is achieved by anticonvulsants such as clonazepam, sodium valproate, and, on occasion, primidone to a variable degree, depending on the patient (Table 34–5). In addition, piracetam or levetiracetam may be effective for cortical myoclonus. This can be given either in combination with those anticonvulsants or alone. L-5-hydroxytryptophan (5-HTP) has been reported to be effective, especially for posthypoxic myoclonus. Other forms of myoclonus also respond to clonazepam.

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T A B L E 34–5. Treatment of Cortical Myoclonus Drug Clonazepam Sodium valproate Piracetam Levetiracetam Primidone L-5-Hydroxytryptophan (5-HTP)

Initial Dosage

Maintenance Dosage

0.5-1.0 mg/day 200 mg/day 12 g/day 1000 mg/day 125 mg/day 100 mg/day

2-6 mg/day 600-1200 mg/day 12-21 g/day 3000 mg/day 375-750 mg/day 500-1500 mg/day

Prepared with help from Dr. Akio Ikeda.

K E Y ●

Suggested Reading Caviness JN, Brown P: Myoclonus: current concepts and recent advances. Lancet Neurol 2004; 3:598-607. Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:3473-3478. Shibasaki H, Hallett M: Electrophysiological studies of myoclonus. Muscle Nerve, 2005; 31:157-174. Shibasaki H: Myoclonus and startle syndromes. In Jankovic J, Tolosa E, eds: Parkinson’s Disease and Movement Disorders, 5th ed. Philadelphia: Lippincott Williams & Wilkins. In press. Truong DD, Kirby M, Kanthasamy A, et al: Posthypoxic myoclonus animal models. In Fahn S, Frucht SJ, Truong DD, et al, eds: Advances in Neurology, vol 89: Myoclonus and Paroxysmal Dyskinesias. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 295-306.

P O I N T S

Myoclonus is a group of involuntary movements characterized by a shocklike appearance.

●

Myoclonus is associated with brisk muscle contraction (positive myoclonus), brisk interruption of ongoing muscle contraction (negative myoclonus), or a combination of the two.

●

It is important to distinguish myoclonus from other involuntary movements, especially for finding its most appropriate treatment.

●

It is important to recognize cortical myoclonus because it is often epileptic in nature.

●

Electrophysiological studies are useful for the confirmation and classification of myoclonus and for the understanding of its pathophysiology.

References 1. Caviness JN, Brown P: Myoclonus: current concepts and recent advances. Lancet Neurol 2004; 3:598-607. 2. Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:3473-3478. 3. Shibasaki H, Hallett M: Electrophysiological studies of myoclonus. Muscle Nerve, 2005; 31:157-174. 4. Shibasaki H: Myoclonus and startle syndromes. In Jankovic J, Tolosa E, eds: Parkinson’s Disease and Movement Disorders, 5th ed. Philadelphia: Lippincott Williams & Wilkins. In press. 5. Truong DD, Kirby M, Kanthasamy A, et al: Posthypoxic myoclonus animal models. In Fahn S, Frucht SJ, Truong DD, et al, eds: Advances in Neurology, vol 89: Myoclonus and Paroxysmal Dyskinesias. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 295-306.

CHAPTER

35

DYSTONIA ●

●

●

●

T. T. Warner

The dystonias are an unusual group of movement disorders whose main feature is involuntary muscle contraction or spasm. The term dystonia was originally introduced by Hermann Oppenheim in 1911 to describe alterations in muscle tone and postural abnormalities that are seen in this condition. The concept of dystonia can be confusing because the term has been used to describe a symptom (e.g., a dystonic arm posture), a disease (primary torsion dystonia), or a syndrome. The dystonias constitute a relatively common group of movement disorders that encompass a wide range of conditions from those in which the only manifestation is dystonic muscle spasms to those in which dystonia is one part of a more severe neurological condition.

DEFINITION AND CLASSIFICATION Dystonia is characterized by involuntary sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures.1 The movements range from slower twisting athetosis to rapid, shocklike jerky movements. They are repetitive and sometimes rhythmic and can be accompanied by tremor. Dystonic movements can be aggravated by movement (action dystonia) that can be nonspecific or task-specific (e.g., writing). Over time the dystonia can occur with less specific movements and eventually can be present at rest, leading to sustained abnormal postures. Three basic approaches are used to classify dystonia: age at onset, distribution of affected body parts, and etiology. The categories of age at onset and affected body distribution (Table 35–1) are important in describing clinical signs and have clinical implications for prognosis and treatment.

Age at Onset Dystonia can develop at any age, although those with earlier age at onset are more likely to have a more severe course affecting more of the body. The ages at onset were initially divided into childhood (0 to 13 years), adolescence (13 to 21 years) and adulthood (>21 years), but a more pragmatic division into early (<26 years) and late (>26 years) onset is now used.

Distribution The distribution distinguishes patients on the basis of whether dystonia is localized to a single body region (focal), whether it has spread to contiguous (segmental) or noncontiguous (multifocal) regions, or whether the legs are affected along with other body regions (generalized). The age at onset and the body distribution are related: The earlier the age at onset, the more likely dystonia is to be severe, spreading to a generalized distribution. In addition, the body region first affected is also important: Onset in the legs is most frequent during childhood, and with increasing age, the site of onset ascends to the arms/hands, neck, and then cranial muscles. Thus, childhood limb onset dystonia usually generalizes; writer’s cramp occurs with a mean onset in the 30s and can spread to become segmental dystonia; cervical dystonia has a mean onset in the 40s, and blepharospasm usually starts in the sixth decade, and both usually remain focal.

Etiology The third approach to classification is by etiology. Dystonia can be divided into primary and secondary or symptomatic dystonia. Primary torsion dystonia (PTD) comprises a group of dystonias with predominantly genetic causes. Phenotypically, in PTD, dystonia must be the only clinical feature (except for tremor of the arms or head and neck), and there must be no evidence of neuronal degeneration or acquired cause. Secondary dystonias make up all other causes and are divided into inherited, complex, and acquired causes. Among the inherited causes are the dystonia-plus syndromes, which are characterized by the presence of dystonia plus other neurological features and have a genetic basis without evidence of neurodegeneration. Dystonia can also be part of a more widespread neurological disorder in which there is underlying neurodegeneration (such as Wilson’s disease), and these are referred to as heredodegenerative causes.

EPIDEMIOLOGY The true population incidence and prevalence of dystonia are unknown. The prevalence data available are usually based on studies of diagnosed cases only and therefore are under-

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T A B L E 35–1. Classification of Dystonia Age at Onset Early: <26 years Late: >26 years Distribution: Focal: Single body part affected Neck: cervical dystonia (spasmodic torticollis) Eyelids: blepharospasm Mouth: oromandibular dystonia Larynx: laryngeal dystonia Hand or arm: writer’s cramp and other limb dystonias Segmental: two or more contiguous body parts Cranial: head and/or neck Axial: neck and trunk Brachial: one arm and axial; both arms ± neck ± trunk Crural: one leg and trunk, both legs ± trunk Generalized: segmental crural and any other segment Multifocal: two or more noncontiguous parts Hemidystonia: ipsilateral arm and leg Etiology Primary Dystonia is only sign, plus tremor; no acquired or degenerative cause Secondary Inherited Dystonia-plus syndromes Heredodegenerative disorders Acquired Structural lesions, drugs, toxins, etc. Complex/unknown Dystonia associated with parkinsonism ±, with or without.

estimates of the real numbers. This is particularly the case with dystonia, which can manifest in a variety of ways, and a significant number of cases of focal dystonia are undiagnosed or even misdiagnosed. In an early study in the United States that was based on case note review, the prevalence for PTD was estimated to be 329 per million population. In more recent studies of diagnosed cases in Japan and Europe, the prevalence was estimated to be between 101 and 150 per million. The most reliable estimate is from an ongoing study in the northeast of England, where ascertainment was more complete, and some previously undiagnosed cases were identified. This finding has implied a prevalence rate of 485 per million. The prevalence of secondary dystonia is unknown, although it is estimated from case series that it may be less than 20% to 25% the rate for PTD. The most prevalent form of PTD is focal dystonia, of which cervical dystonia is the commonest, with prevalence rates reported between 57 and 290 per million population. Rates for blepharospasm are 17 to 80 per million, and for writer’s cramp, 14 to 61 per million. In a study in South Tyrol in Austria, a random sample of the population older than 50 years was examined.2 Primary dystonia was diagnosed in 6 of the 707 individuals studied, implying a prevalence of 7320 per million in this age-selected population, although 95% confidence intervals were very wide, at 3190 to 15,640, because of the small sample. However, this indicates that in the aging population, dystonia is a relatively common neurological disorder.

T A B L E 35–2. Clinical Features Suggestive of Secondary Dystonia Abnormal birth/perinatal history Developmental delay Seizures Exposure to drugs (e.g., dopamine blockers) Continuous progression of symptoms Prominent bulbar involvement Unusual distribution (e.g., hemidystonia) Additional neurological symptoms Pyramidal, cerebellar, cognitive decline Signs of other system involvement (e.g., organomegaly)

CLINICAL FEATURES The diagnosis of dystonia is based on clinical findings. Primary dystonia has no other neurological features apart from dystonia and tremor.3 Features suggestive of a secondary cause of dystonia are listed in Table 35–2. Investigations are usually performed to help rule out a secondary cause of dystonia.

Primary Dystonia Early-Onset Primary Torsion Dystonia (Dystonia Musculorum Deformans, Oppenheim’s Dystonia) The commonest cause of early onset PTD is mutation in the DYT1 gene on chromosome 9q34, which is inherited as an autosomal dominant trait with reduced penetrance (30% to 40%). The disorder typically manifests in childhood or adolescence (mean age at onset, 12 years) with dystonia causing posturing of a foot, leg, or arm. Dystonia is usually first apparent with specific actions (e.g., writing or walking) but becomes evident with less specific actions over time and spreads to other body regions. No other neurological abnormalities are present apart from postural arm tremor. Disease severity varies considerably even within the same family, and isolated writer’s cramp may be the only sign. However, approximately 60% to 70% of individuals have progression to generalized or multifocal dystonia involving at least a leg and an arm, and often axial muscles. In 10% of cases, segmental dystonia develops, and only 25% remain focal. The cranial muscles are involved in about 10% of affected patients. Key investigations are to exclude treatable differential diagnoses, such as Wilson’s disease and dopa-responsive dystonia (DRD). DYT1 dystonia is diagnosed through molecular genetic testing of the TOR1A gene, which reveals a three–base pair deletion in all affected individuals. There is a higher prevalence of DYT1 PTD in the Ashkenazi Jewish population, which is the result of a founder mutation that appeared about 250 years ago. Most forms of early-onset PTD are genetic in origin, and Table 35–3 lists the genetic forms that have been identified to date. Most are autosomal dominant, some reported only in single families. The existence of autosomal recessive forms (DYT2) is controversial.

Focal Primary Torsion Dystonia These are by far the commonest forms of dystonia. Usually sporadic, they have onset in adult life and remain focal in distri-

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T A B L E 35–3. Genetic Forms of Primary Dystonia Type

Clinical Features

Frequency

Age at Onset

Genetics

DYT1

Limb onset, generalizes, can manifest as focal

50% cases early onset in nonJews, 90% in Ashkenazi Jews

Childhood; most present by 26 years

DYT2

Focal and generalized

Childhood to adult

DYT4

Laryngeal and cervical, some generalize Focal or generalized; cranial, cervical, or limb

Spanish Gypsy families and a single Iranian Single Australian family Two families: one Mennonite, one Amish

Mean age at onset: 19 years

AD TOR1A on chromosome 9q34 Protein torsin A AR Locus and gene unknown AD Locus and gene unknown AD DYT6 Chromosome 8p21-q22 AD DYT7 Chromosome 18p AD DYT13 Chromosome 1p36

DYT6

13-37 years

DYT7

Focal dystonia, cervical and laryngeal

Single German family

28-70 years

DYT13

Cranial or cervical; some generalize

Single Italian family

Childhood to adult

AD, autosomal dominant; AR, autosomal recessive.

bution. Families with autosomal dominant forms have been described, and it is believed that a proportion of the apparently sporadic cases may represent manifestation of a dominant gene with very low penetrance (estimated at 12% to 15%). The individual types are discussed as follows.

Cervical dystonia (spasmodic torticollis) Cervical dystonia is a focal dystonia that affects cervical muscles, leading to abnormal postures and movements of the head, neck, and shoulders. It is the most common form of dystonia, usually with onset in the fifth decade (mean age at onset, 42 years) and affects women more than men (ratio, 1.4 : 1 to 1.6 : 1). The dystonic muscle activity can be tonic, phasic, or tremulous and leads to symptoms of neck pain, head posturing, or repetitive jerking, producing tremor of the head. Cervical dystonia symptoms tend to worsen over the first 5 years and then stabilize. Twisting of the head around the horizontal axis (torticollis) is the most common movement, present in 80% of patients and caused by overactive contralateral sternomastoid and ipsilateral splenius capitis muscles. Laterocollis (head sideways) is seen in 10% to 20% and caused by overactivity in the ipsilateral splenius, sternomastoid, and levator scapulae muscles. Retrocollis (head back) and antecollis (head forward) are less frequent. Many patients, however, present with combinations of torticollis and laterocollis. Pain is present in 75% of patients and can cause significant disability. Many patients with cervical dystonia have sensory tricks (geste antagoniste) that can alleviate symptoms. These can involve touching the back of the head, cheek, or temple and lead to reduction in abnormal dystonic muscle spasm. Spontaneous remission of symptoms occurs in less than 20% of patients; unfortunately for most of these patients, there will be a subsequent relapse. Focal cervical dystonia can spread to other body parts, including the face and arms, but rarely generalizes. The long-term complications of cervical dystonia include cervical spine degeneration, which leads to radicular or myelopathic symptoms. Cervical dystonia also has a significant effect on quality of life and is associated with a higher incidence of anxiety and depression.

Blepharospasm and other cranial dystonias Blepharospasm is the second commonest form of dystonia and is caused by dystonic muscle spasms of the orbicularis oculi muscles. Like cervical dystonia, it is more common in women, with female-to-male ratios of between 1.8 : 1 and 2.5 : 1. Onset usually occurs in the sixth or seventh decade and is insidious, often with soreness or dryness of the eyes, followed by excessive blinking, especially with bright light or reading. This can worsen over months to years, leading to sustained muscle spasms and eye closure, and, when severe, can render a patient functionally blind for significant periods of time. The spasms are sometimes accompanied by perioral muscle involvement. Oromandibular dystonia can manifest with predominant jaw opening (lateral pterygoid muscles, muscles of the floor of the mouth, and infrahyoid muscles), jaw closing (masseter and medial pterygoid muscles), or a mixed type. There can also be involvement of the tongue, facial, and pharyngeal muscles. Oromandibular dystonia can be present at rest but often worsens on eating or talking, with dysarthria and dysphagia. It is an extremely visible form of dystonia and can be very distressing and stigmatizing for patients. Complications include temporomandibular joint impairment and muscular pain.

Writer’s cramp and task-specific limb dystonias Writer’s cramp is the most common form of task-specific dystonia and, in contrast to craniocervical dystonia, is more common in men than in women. Onset usually occurs between the ages of 30 and 50 years and often starts with a feeling of tension in fingers and forearms that interferes with writing fluency. The pen is held abnormally forcefully as a result of dystonic contraction of hand and/or forearm muscles. This commonly involves excessive flexion of the thumb and index finger with pronation of the hand and ulnar deviation of the wrist. Affected individuals may also experience lifting of the thumb or index finger off the pen or isolated extension of fingers. Up to 50% of patients also experience upper limb tremor, either on writing or a postural tremor. Strain and aching, particularly in

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affected forearm muscles, is common on writing, but pain is an uncommon feature. Writing difficulty is often intermittent at onset but usually progresses so that cramping starts soon after starting writing. In a minority of patients, dystonia occurs on performing other manual tasks, and this can be a feature that develops with time. Spontaneous remission is rare. Many patients whose writing has become illegible therefore learn to write with their nondominant hands. Unfortunately, in up to 10% of cases, writer’s cramp can develop in that hand as well. Dystonic patterns of involuntary muscle contractions are also seen in the context of other highly learned motor skills. These are most commonly seen in professional musicians, craftsmen, and sportsmen whose work involves frequent, repetitive movements of particular muscle groups. They have been reported in fewer than 1% of professional musicians, more frequently men. In pianists, for instance, the fourth and fifth fingers of the right hand are most commonly involved, whereas for guitarists, the third finger of the right hand is affected. For wind instrument players, the hand supporting the instrument and doing fingering at the same time is most involved. Less commonly, lip or orofacial dystonia can develop. Tremor can accompany task-specific dystonias in less than 40% of cases. Other manual tasks associated with task-specific dystonia include typing, painting, and sports such as golf, tennis, and snooker.

Laryngeal dystonia Laryngeal dystonia is relatively rare and can be divided into cases in which the predominant problem is spasm of the adductor muscles and spasms involving abductor muscles. It can occur in isolation or sometimes as part of a segmental craniocervical dystonia. In one family with autosomal dominant inheritance (DYT3 locus), it is the presenting feature in individuals who developed generalized dystonia. Adductor spasmodic dysphonia is the commonest form and is characterized by intermittent voice stoppages, particularly with vowels. This is caused by hyperadduction of the vocal cords caused by involuntary spasm of thyroarytenoid and/or lateral cricoarytenoid muscles. Abductor spasmodic dysphonia occurs in about 15% of patients and manifests with breathy breaks in speech, especially with consonants. In some cases, this is caused by involvement of vocal fold opening muscles, such as the posterior cricoarytenoid and cricothyroid muscles. Spasmodic dysphonia is task specific and occurs only during speech. Laughter, crying, and breathing are unaffected. Voice tremor often occurs with both types of spasmodic dysphonia and is also speech specific. Other laryngeal disorders that can be confused with laryngeal dystonia can occur in other neurological conditions, but the presence of additional neurological signs should alert the clinician to alternative diagnoses. Examples are vocal fold paralysis in motor neuron disease, airway obstruction in multiple-system atrophy, hypophonia in Parkinson’s disease, and abductor vocal fold paralysis in hereditary motor neuronopathy.

Secondary/Symptomatic Dystonias Dystonia-Plus Syndromes Dystonia-plus syndromes describe a group of conditions that can be distinguished from PTD on the basis of clinical charac-

teristics found in addition to dystonia, or specific pharmacological responses. They usually have a genetic etiology but do not have underlying neurodegeneration. The group comprises three distinct conditions: DRD, myoclonus dystonia syndrome, and rapid-onset dystonia parkinsonism (RDP).

Dopa-responsive dystonia DRD was first described in Japan in 1977 by Masaya Segawa. Patients typically present in childhood with gait disturbance caused by foot dystonia. The dystonia frequently worsens as the day goes on (diurnal variation) and is relieved by rest or sleep. Progression is variable; some patients develop severe generalized dystonia, whereas others develop features suggestive of lower limb spasticity. Parkinsonian features such as bradykinesia and rigidity can develop in later life in some affected individuals but can also be the presenting features in adult life in a minority of cases. On occasion, DRD can manifest with adultonset limb dystonia (e.g., writer’s cramp), with cranial or cervical dystonia, or with signs resembling spastic paraplegia. In most cases, DRD is inherited as an autosomal dominant trait with reduced penetrance. The key feature in DRD is a dramatic and sustained response to small doses of levodopa (L-dopa), often as low as 50 to 200 mg. Benefit is usually apparent within days to weeks, and the motor complications of L-dopa treatment seen with Parkinson’s disease rarely develop, even with long-term treatment. Anticholinergic drugs also can be beneficial. The principal considerations in the differential diagnosis for childhood DRD are early-onset PTD, spastic paraplegia and cerebral palsy, and early-onset parkinsonism, especially when it is caused by mutations in the parkin gene. The patients thought to have early-onset parkinsonism often present with dystonia and show good initial response to L-dopa. However, clues to the diagnosis come from the inheritance pattern (usually autosomal recessive for the parkin gene) and the occurrence of motor fluctuations and dyskinesias with L-dopa treatment. Positron emission tomography (PET) with markers for presynaptic dopaminergic terminals (18F–dopa) or single photon emission computed tomography can also differentiate between the two conditions. The gene for dominant DRD has been mapped to chromosome 14 (DYT5) and mutations within the gene for guanosine triphosphate (GTP) cyclohydrolase 1 have been identified. Numerous mutations have been identified in all five exons, which makes genetic testing laborious. Other extremely rare forms of DRD have been reported, including a recessive form with genetic deficiency of tyrosine hydroxylase and defects in other enzymes involved in pterin synthesis. The diagnosis can usually be confirmed by an excellent response to L-dopa treatment in dosages slowly increasing up to 400 mg a day. Alternatively detecting reduced levels of pterins in the cerebrospinal fluid or an abnormal oral phenylalanine loading test can substantiate the diagnosis.

Myoclonus-dystonia syndrome Myoclonus-dystonia syndrome (MDS) is characterized by the presence of dystonia in combination with brief lightning-like myoclonic jerks. It is frequently inherited as an autosomal dominant trait, caused by mutations in the gene for εsarcoglycan (DYT11), although sporadic cases also occur. A further autosomal dominant locus (DYT14) has been mapped to chromosome 18.

chapter 35 dystonia MDS usually has onset in childhood or early adolescence, with myoclonic jerks affecting the upper limbs and axial muscles (trunk and neck). The myoclonus can occur on rest and also be precipitated by action. Dystonia occurs in approximately two thirds of patients; cervical dystonia and writer’s cramp are the most common forms. On occasion, dystonia affects the legs. Several reports have identified psychiatric features associated with MDS, including obsessive-compulsive disorder, panic attacks, and anxiety. Most affected patients note significant relief of symptoms with alcohol or benzodiazepines and can have marked rebound of symptoms after administration of these drugs. This can often lead to abuse of these substances.

Rapid-onset dystonia parkinsonism Rapid-onset dystonia parkinsonism (RDP) is a rare autosomal dominant movement disorder with reduced penetrance. It is characterized by abrupt or subacute onset of both dystonia and parkinsonism with prominent bulbar involvement. Symptoms, including dystonic posturing of the limbs, bradykinesia, dysarthria, and dysphagia, and postural instability, develop over hours to days, followed by little or no progression. Onset is usually in adolescence or young adulthood, and the subacute extrapyramidal storm can be preceded by stable mild limb dystonia for a number of years. Potential triggers in some families include emotional trauma, extreme heat, or physical exertion. Investigation with magnetic resonance imaging (MRI), computed tomography, and PET of the presynaptic dopamine uptake sites has yielded normal results. In some patients, reduced levels of cerebrospinal fluid dopamine metabolites have been detected. The current assumption is that RDP is caused by neuronal dysfunction rather than neurodegeneration. The condition is rare, and only a small number of families with evidence of autosomal dominant inheritance with reduced penetrance have been described. The gene was mapped to chromosome 19q13.2 (DYT12), and mutations in the gene for the Na+/K+–adenosine triphosphatase α3 subunit (ATP1A3) have been identified in seven unrelated kindreds with RDP. This finding implicates the Na+/K+ pump, which is crucial for maintaining the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

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T A B L E 35–4. Secondary Causes of Dystonia Cause

Examples

CNS lesion

Brain tumor, stroke, hypoxia, intracranial hemorrhage, CNS trauma, congenital malformations, cervical cord lesions Cerebral palsy, delayed-onset dystonia, perinatal hypoxia, kernicterus Subacute sclerosing panencephalopathy, Reye’s syndrome, viral encephalitis, Creutzfeld-Jakob disease, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren’s syndrome

Perinatal cerebral injury Infectious, postinfectious, and inflammatory

Peripheral nerve injury Drug-induced Dopaminergic agents (L-dopa, dopamine agonists), dopamine receptor–blocking drugs (neuroleptics, prochlorperazine, metoclopramide), selective serotonin reuptake inhibitors, MAO inhibitors, antiepileptic drugs, ergots, flecainide, cocaine, ranitidine, calcium antagonists, anesthetic agents Toxin-induced Manganese, carbon monoxide, carbon disulfide, cyanide, methanol, disulfiram, wasp sting venom Metabolic Hypoparathyroidism CNS, central nervous system; L-dopa, levodopa; MAO, monoamine oxidase.

been described for a number of drugs, including dopamine receptor–blocking (DRB) agents, antidepressants (selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), calcium antagonists, general anesthetic agents, anticonvulsants (carbamazepine, phenytoin), L-dopa, ranitidine, 3,4methylenedioxymethamphetamine (“ecstasy”), and cocaine. Tardive dystonia is usually seen with use of dopamine receptor–blocking drugs and is defined as dystonia present for at least 1 month and occurring either during or within 3 months of discontinuation of a dopamine receptor–blocking drug. It most commonly affects the face and neck but can spread and even generalize in some cases. Toxins such as manganese and carbon monoxide that can directly affect the basal ganglia also result in secondary dystonia.

Secondary Dystonia The term secondary implies that an identifiable cause for the dystonia can be found. Many of these directly involve the basal ganglia and lead to contralateral hemidystonia. Table 35–4 summarizes the most common causes of secondary dystonia. Strokes, tumors, vascular malformations, and traumatic injuries to the basal ganglia are well-described causes of dystonia, but dystonia also, more rarely, occurs after injury to cortical or brainstem structures, the spinal cord, and even peripheral nerves. Perinatal injury may cause dystonia at the time of brain injury (dystonic or choreoathetoid cerebral palsy) or can lead to delayed-onset dystonia, which can begin years after the injury and progress. Infectious, postinfectious, and inflammatory syndromes associated with dystonia usually manifest in combination with other movement disorders, such as parkinsonism, chorea, athetosis, and tics. Drugs may also cause transient or chronic (tardive) dystonia. Acute dystonic reactions occur shortly after the introduction of a drug and have

Heredodegenerative Disorders Dystonia also occurs in a wide range of heredodegenerative disorders in which there is progressive neuronal loss with a mixture of neurological symptoms and signs, sometimes with systemic involvement. Table 35–5 lists the various heredodegenerative disorders that can be divided into those with disorders of metabolism, mitochondrial disease, trinucleotide repeat diseases, parkinsonian disorders, and other degenerative processes without defined causes.

Psychogenic Dystonia The concept of psychogenic dystonia is difficult because in the first half of the 20th century many cases of organic dystonia were thought to be psychiatric in origin as a result of the unusual and variable nature of the symptoms. Psychogenic dystonia does exist, often resulting in profound disability, but is a

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T A B L E 35–5. Heredodegenerative Disorders That Can Cause Dystonia Metabolic Disorders Metal and mineral metabolism Lysosomal storage disorders Inborn errors of metabolism Amino and organic acidurias

Wilson’s disease, neurodegeneration with brain iron accumulation type I, neuroferritinopathy, idiopathic basal ganglia calcification (Fahr’s disease) Niemann-Pick disease type C, GM1 and GM2 gangliosidoses, metachromatic leukodystrophy, Krabbe’s disease, Pelizaeus-Merzbacher disease, fucosidosis Lesch-Nyhan syndrome, triosephosphate isomerase deficiency, glucose transport defects Glutaric aciduria type I, homocystinuria, propionic acidemia, methylmalonic aciduria, 4-hydroxybutyric aciduria, 3-methylglutaconic aciduria, 2-oxoglutaric aciduria, Hartnup’s disease

Mitochondrial Disorders Leigh’s disease Leber’s hereditary optic neuropathy Mohr-Tranebjaerg syndrome (dystonia/deafness) Trinucleotide Repeat Disorders Huntington’s disease Spinocerebellar ataxias Parkinsonian Disorders Parkinson’s disease (especially familial young-onset forms) Progressive supranuclear palsy Multiple-system atrophy Corticobasal ganglionic degeneration X-linked dystonia–parkinsonism (“Lubag”) Others Ataxia-telangiectasia Chorea-acanthocytosis Rett’s syndrome Infantile bilateral striatal necrosis Ataxia with vitamin E deficiency Progressive pallidal degeneration Sjögren-Larsson syndrome Ataxia–amyotrophy–mental retardation–dystonia syndrome

rare form of dystonia. As with organic dystonias, it is difficult to diagnose with certainty, and the assessment should be undertaken only by a neurologist with considerable experience with organic dystonias. One reason for this is the absence of a specific diagnostic test for dystonia. The diagnosis is based on the presence of clinical inconsistencies and incongruities with organic dystonia. The pathophysiology is poorly understood. Prompt diagnosis and treatment are necessary, in view of the poor prognosis of conversion disorders when there has been considerable delay between symptom onset and diagnosis, and treatment often involves a combination of psychotherapy, physical therapy, and psychopharmacologic therapy.

accumulation type 1 (Fig. 35–1), typical changes in the midbrain of a patient with Wilson’s disease, or basal ganglia calcification in Fahr’s disease. If MRI appearance is normal, further tests should be performed to exclude Wilson’s disease as it is potentially treatable. Slit-lamp examination for Kayser-Fleischer rings (Fig. 35–2), serum ceruloplasmin measurement, and 24-hour urinary copper excretion measurement are required. For cases of possible secondary dystonics, futher investigations for metabolic and heredodegenerative disorders are required, with testing for serum amino and organic acids and investigation for specific enzymatic disorders in white blood cell or fibroblast cultures.

INVESTIGATIONS

PATHOPHYSIOLOGY OF DYSTONIA

Table 35–6 list potential investigations. However, the clinical presentation determines which of these are appropriate. For instance, a woman aged 60 presenting with blepharospasm alone may need no investigation, whereas a child with dystonia and other neurological features would need extensive tests to identify a potential secondary cause. A history of birth injury, a family history of other neurological disorders, and exposure to dystonia-inducing drugs are important. Hemidystonia is highly suggestive of a contralateral lesion of the basal ganglia, and cranial imaging with MRI is mandatory. For young-onset generalized dystonia, imaging may also aid in diagnosis, such as revealing the “eye of the tiger” sign in brain iron

Neurophysiological Studies The hallmark of dystonia is involuntary sustained muscle contractions, which are characterized by an abnormal pattern of EMG activity: excessive co-contraction of antagonist muscles during an action and overflow into extraneous muscles. Other findings include prolongation of EMG bursts. These findings have been described in patients with primary focal hand dystonia, and it was also noted that there was loss of selectivity to perform independent finger movements, occasional failure of willed activity, and tremor. These features emphasize that in

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T A B L E 35–6. Investigation of Dystonia Dystonia Phenotype Primary torsion dystonia Early onset (<28 years)

Late onset (>28 years)

Secondary dystonia

Investigation Copper studies, slit-lamp examination Brain MRI DYT1 gene analysis Trial of L-dopa Copper studies, slit-lamp examination if younger than 50 years Brain MRI Spine MRI if dystonia fixed or painful EMG if painful axial muscle spasm Brain/spine MRI Nerve conduction studies Copper studies, slit-lamp examination, liver biopsy Genetic test for neurodegenerative disorders (e.g., Huntington’s disease) White blood cell enzymes α-Fetoprotein, immunoglobulins Lactate, pyruvate, mtDNA analysis; muscle biopsy Blood film for acanthocytes Urine amino acid, organic acid, oligosaccharide measurements Bone marrow biopsy Phenylalanine loading test, CSF pterin measurement ERG, retinal examination

CSF, cerebrospinal fluid; EMG, electromyography; ERG, electroretinogram; MRI, magnetic resonance imaging; mtDNA, mitochondrial deoxyribonucleic acid.

■

Figure 35–2. Typical Kayser-Fleischer ring (arrow) in a patient with Wilson’s disease.

■

Figure 35–1. Cranial magnetic resonance image from a patient with brain iron accumulation type 1, showing the “eye of the tiger” sign.

dystonia, there is excessiveness of movements and lack of fine control. The problem of excessive co-contraction of agonist and antagonist muscles appears to be caused in part by loss of reciprocal inhibition, a mechanism present at many levels in the central nervous system that has been shown to be impaired in generalized dystonia, writer’s cramp, cervical dystonia, and blepharospasm. Studies of other spinal and brainstem inhibitory reflexes have also confirmed that a common theme in various forms of primary dystonia is the reduction in inhibitory processes within the motor system. However, it has become clear that dystonia is not a pure motor disorder and that individuals with dystonia have sensory abnormalities that play an important role in causing motor dysfunction. Studies have demonstrated evidence of abnormalities in both somatosensory spatial discrimination and temporal

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discrimination (the shortest time two successive stimuli are perceived as separate). The importance of the sensory system in dystonia is also evident from study of the sensory tricks (geste antagoniste), which are various maneuvers used by patients with focal dystonia to temporarily relieve the dystonic spasms; for example, a finger placed on the face of an individual with cervical dystonia can eliminate neck muscle spasm. There is also evidence to suggest that abnormal sensory input can trigger dystonia, such as trauma to a body part before the dystonia. Another line of evidence comes from study of processing of muscle spindle input. In patients with hand cramps, vibration can induce the patient’s dystonia, and cutaneous input similar to that which produces the sensory trick can reverse this vibration-induced dystonia. Studies of intracortical inhibition with transcranial magnetic stimulation paradigms have shown that there is motor cortex hyperexcitability in dystonia. This has been shown to result from deficient intracortical inhibition in the cortical hand muscle representation, not only in focal hand dystonia but also in blepharospasm, in which hand muscles are clinically normal. This defect in inhibition appears to occur specifically during dystonic muscle contraction and not during more normal movements, which implies that the contraction is dystonic because of the deficient inhibition. These findings of reduced intracortical inhibition, shorter silent period, and abnormal spinal reciprocal inhibition have also been demonstrated in patients with DYT1 generalized dystonia. It is therefore believed that the excessive muscle contractions that occur in dystonia are generated by loss of inhibition, particularly loss of “surround inhibition”: the suppression of unwanted movements when a specific motor task is performed. Surround inhibition is believed to be essential for the production of precise, functional movement, just as surround inhibition in the visual system leads to more precise perceptions. Studies with transcranial magnetic stimulation and PET/ functional MRI have supported the view that deficient intracortical inhibition leads to hyperexcitability of the motor cortex, which in turn could lead to the excessive movement seen in dystonia. Most of the clinical evidence points to the basal ganglia as the site of the pathology in dystonia. There is experimental evidence that the basal ganglia output can influence cortical inhibition and also that the basal ganglia are anatomically organized to work in a center-surround mechanism, which would allow surround inhibition.

Molecular Genetic Studies Dopa-responsive dystonia is the best characterized genetic form of dystonia. Mutations within the GTP cyclohydrolase 1 gene lead to marked reduction in the activity of the enzyme it encodes. GTP cyclohydrolase 1 is the rate-determining enzyme in the synthesis of tetrahydrobiopterin, a key cofactor in the monoamine synthesis pathway. Reduced levels of tetrahydrobiopterin lead to reduced dopamine synthesis, which appears to play a key role in the production of dystonia in this condition. The central role of abnormal dopaminergic neurotransmission in dystonia is supported by the finding that dopamine-blocking drugs can produce both acute and tardive dystonia. In DYT1 dystonia, the protein product torsin A, which normally resides

in the endoplasmic reticulum, becomes mislocated to the nuclear envelope and abnormal inclusions that also contain proteins involved in dopaminergic transport. Whether mutant torsin A affects neurotransmission, however, is unclear.

Summary Evidence therefore suggests that dystonia is characterized pathophysiologically by abnormal sensory processing and deficient cortical inhibition.4 The current model implicates abnormal surround inhibition as the substrate that leads to generation of uncontrolled dystonic movements. Dystonia could result from lesions in the basal ganglia, which disrupt intricate pathways and push normal movements to abnormal. Genetic defects (such as those found in DYT1 dystonia) may also affect these pathways, possibly through abnormal dopaminergic neurotransmission. Repetitive movements or use of a body part may also lead to dystonia. Thus, a combination of factors may lead to the cortical abnormality that results in the production of dystonic movements.

TREATMENT OF DYSTONIA Treatment options for dystonia have increased dramatically since the mid-1980s. This has been the result of the use of botulinum toxin and a renewed interest in functional neurosurgery for dystonia. Drug treatment has some use, particularly for DRD and MDS and the more severe childhoodonset primary dystonias. Table 35–7 lists the treatment options for various forms of dystonia.

Drug Therapy Drug treatment of dystonia has changed little since the mid1980s. Although many forms of dystonia are relatively unresponsive to drugs, there is still an important role for drug therapy for primary generalized dystonia, dystonia-plus conditions, and some forms of secondary dystonia.

Dopaminergic Agents Patients with DRD show dramatic response to low doses of Ldopa (with decarboxylase inhibitor) and all patients with youngonset dystonia should undergo an L-dopa trial. The mean daily dose effective in DRD is 250 mg, although higher doses are sometimes required. Symptoms of DRD may also respond to dopamine agonists and anticholinergic drugs. The role of dopaminergic agents in the treatment of primary dystonia is less clear. Reviews of small treatment trials suggest that improvement with these drugs was rarely dramatic. Twenty percent of patients believed that they actually deteriorated, but on occasion there was benefit.

Anticholinergic Drugs Trihexyphenidyl can be useful for childhood-onset primary dystonia. One prospective placebo-controlled trial revealed that 67% of treated patients showed improvement and 68% continued to benefit after 2.4 years at a mean daily dose of 40 mg. It appears to be less useful for adult-onset primary focal dystonia. In both children and adults, the dose of anticholinergic must

chapter 35 dystonia

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T A B L E 35–7. Treatment Options for Dystonia Therapy

Agent/Procedure

Uses

Drugs

Dopaminergic agents

DRD, sometimes primary and secondary dystonia Primary and secondary dystonia and DRD Childhood primary dystonia

Anticholinergics Baclofen (oral or intrathecal) Benzodiazepines Antidopaminergic agents Botulinum toxin

Type A and B

Destructive neurosurgery

Selective peripheral denervation Myectomy/myotomy Intradural rhizotomy/ nerve sectioning Pallidotomy, thalamotomy

Functional stereotactic neurosurgery

Deep brain stimulation

Primary and secondary dystonia, MDS Occasional primary/secondary dystonia Main treatment of focal and segmental dystonia Cervical dystonia Cervical dystonia/blepharospasm Cervical dystonia (rarely used) Primary and secondary generalized or hemidystonia Primary generalized and segmental dystonia

DRD, dopa-responsive dystonia; MDS, myoclonus-dystonia syndrome.

be titrated up gradually to minimize side effects, particularly of dry mouth, gastrointestinal upset, and confusion.

Baclofen Baclofen is a derivative of γ-amino butyric acid that reduces spinal cord interneuron and motor neuron excitability. A retrospective study showed it to have useful benefit, especially in childhood-onset primary dystonia, but only in a minority of adult cases. It appeared to be better tolerated by the younger patients, but significant side effects of lethargy, dizziness, and confusion have been reported. Intrathecal baclofen has also been used with benefit, particularly for secondary generalized dystonia and in patients with dystonia and spasticity. Intrathecal baclofen is administered through an implanted infusion pump connected to an intrathecal catheter, which is inserted at approximately the L2-L3 level and advanced to C7-T1.

Benzodiazepines Benzodiazepines have been frequently used, although there are no data from controlled trials. They appear to be effective, although use is limited by sedation, ataxia, and habituation. Diazepam and clonazepam are the benzodiazepines most frequently used.

Other Drugs Numerous other drugs have been used to treat various forms of dystonia. Paradoxically, some patients with dystonia appear to improve with use of antidopaminergic drugs, such as tetrabenazine and haloperidol. The concern with dopamineblocking drugs is the development of tardive dystonia and dyskinesia. Other drugs that have been used to treat dystonia in single cases include carbamazepine, propranolol, phenytoin, clonidine, tizanidine, lithium, and cannabidiol.

Botulinum Toxin Botulinum toxin injections are the first line of treatment for focal and segmental dystonias.5 Botulinum toxin consists of a number of serotypes of a potent neurotoxin that acts by inhibiting neurotransmitter release at the neuromuscular junction, which leads to temporary weakness of the muscle. Botulinum toxin types A and B are most commonly used in clinical practice. Its principal mode of action in dystonia is to cause denervation of motor end plates, although there is evidence that its effect on sensory symptoms may also be important, possibly by modulating muscle spindle input to the central nervous system. Local injection of botulinum toxin type A into overactive dystonic muscles can provide very effective relief of symptoms. Double-blind placebo-controlled trials have shown botulinum toxin type A to be efficacious in treating cervical dystonia and blepharospasm (60% to 70% patients showed improvement), and retrospective and open-label studies have also demonstrated its efficacy for laryngeal dystonia, writer’s cramp, and limb dystonias and for selected cases of oromandibular dystonia. Botulinum toxin has a temporary effect; patients require repeat injections at intervals, usually every 12 to 16 weeks. For uncomplicated cases of blepharospasm and cervical dystonia, muscles to receive injection are usually selected clinically. For more complex cases and other types of dystonia, EMG guidance is often required. The most common side effects are of unwanted weakness, which is related to the dose used and local spread of toxin. Thus, for cervical dystonia, transient dysphagia can occur, especially when the sternocleidomastoid muscles have received injections. Ptosis is a common complication of injections for blepharospasm. Another problem is the development of resistance to botulinum toxin as a result of the formation of neutralizing antibodies, which occurs in up to 10% of patients. The development of neutralizing antibodies is a serious problem because it essentially prevents further response to that type of toxin, although the patient may respond to a different serotype of botulinum toxin.

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Surgery Surgical treatment options for patients with medically refractory dystonia have gained increasing acceptance.

Peripheral Surgery Peripheral surgery for cervical dystonia and blepharospasm has been used for patients who do not respond to botulinum toxin injections and involves either destruction of nerves supplying the dystonic muscles, myotomy/myectomy, or sometimes a combination of procedures. One of the commonest procedures, selective peripheral denervation, involves sectioning of the peripheral branch of the spinal accessory nerve to the sternocleidomastoid muscle in combination with posterior ramisectomy from C1 to C6. Beneficial results have been reported in 70% to 90% of patients, although there is risk of recurrence, and in a retrospective long-term study at a mean of 5 years after surgery, there was a reduction in dystonia by 30% in about one third of patients. For blepharospasm the most frequently used operations are limited or full myectomies of the orbicularis muscles and sometimes corrugator superficialis.

Functional Stereotactic Surgery Current functional stereotactic options include lesion induction and deep-brain stimulation (DBS) of the globus pallidus internus and the thalamus. Because of the relatively small numbers of patient series, variations in surgical technique, and inconsistent use of outcome measures, no definite recommendations about ideal surgical targets or optimal methods can be made. In general, however, the globus pallidus internus appears to be the preferred target in primary dystonias. The pallidal target is located in the posteroventral lateral globus pallidus internus, which is the same site as that used in Parkinson’s disease. Pallidotomy has been reported to be effective in various forms of dystonia, including primary generalized and segmental dystonia and hemidystonia, with a number of studies reporting 50 to 80% improvement in symptoms. In general, patients with primary dystonia (especially DYT1) had a better response than did those with secondary dystonia.6 The focus of stereotactic surgery for dystonia is now on DBS because there is a lower risk in bilateral surgery than in lesion induction. Pallidal DBS is the most frequent stereotactic procedure for dystonia and involves implanting quadripolar electrodes within the globus pallidus internus and applying continuous stimulation. In contrast to DBS in Parkinson’s disease, it may take months before full benefit of pallidal DBS is seen with dystonia. However, the dystonia may recur within hours of switching off the implantable pulse generators. DBS has advantages over lesion-induction surgery in that it is reversible and adaptable, avoids the concerns over the effects of lesions in the developing brain in childhood, and has lower morbidity in bilateral surgery. However, problems with DBS include hardware and battery failure, high costs and timeconsuming follow-up, and perioperative risks of infection and possible hemorrhage. The most striking results for DBS are found for children with primary (notably DYT1) dystonia. One case series demonstrated a mean improvement in the Burke-Fahn-Marsden Dystonia Rating Scale motor score of 71% in 15 patients with DYT1

generalized dystonia 1 year after pallidal DBS. Other case series have demonstrated lesser or no effect, and it has become clear that case selection is critical; secondary cases usually show much less response. There is also some evidence for improvement in primary segmental and focal dystonias, particularly for medically refractory cervical dystonia.

Dystonic Crisis (Status Dystonicus) A rare but potentially fatal development is the dystonic storm or crisis. This usually occurs in patients with more severe generalized forms of dystonia, often secondary, in which they develop increasingly frequent and relentless episodes of devastating generalized dystonia that can lead to respiratory compromise that necessitates ventilation. It can be precipitated by infection or drugs changes or even failure of DBS (e.g., battery failure). Treatment is difficult but involves a combination of drugs, including benzodiazepines, anticholinergic drugs, and sometimes antidopaminergic drugs. Pallidotomy has been reported as a potential treatment option for this condition.

PAROXYSMAL DYSKINESIAS These are a rare group of conditions that manifest with abnormal involuntary movements that occur episodically and are of brief duration. The abnormal movements are mixed but include dystonia, chorea, and ballism. They can be acquired or genetic in origin, and between attacks, the patient is normal.

Paroxysmal Kinesigenic Dyskinesia (PKD) In this condition, the dyskinetic movements are precipitated by sudden movement. Onset is usually in childhood, the disease is more common in boys, and it is often familial, exhibiting autosomal dominant inheritance. Attacks frequently are of dystonia or chorea-dystonia induced by sudden change in position or running. Often they affect one side of the body, which can alternate, and are brief, lasting seconds or, on occasion, minutes. Numerous attacks can occur in a day. For idiopathic or genetic forms, the prognosis is good, and frequency of attacks decreases with age and often abates in adulthood. A genetic locus for PKD has been mapped to chromosome 16, which may be allelic with a locus found for families with infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome), although there is also evidence for genetic heterogeneity. PKD responds well to antiepileptic drugs, particularly carbamazepine in low doses. Reports also suggest benefit with gabapentin, lamotrigine, topiramate, and levetiracetam.

Paroxysmal Nonkinesigenic Dyskinesia (PKND) PKND is characterized by attacks of dyskinesia that are frequently precipitated by alcohol ingestion, caffeine ingestion, stress, or fatigue. The episodes are often dystonic or choreic and have longer duration (minutes to hours) and are less frequent (on to three per day) than those in PKD. There may be longer attack-free intervals, and, again, boys are more often affected than girls. It is often familial, showing autosomal dominant inheritance, with onset in childhood and attacks diminishing

chapter 35 dystonia in adulthood. A locus on chromosome 2q31-36 has been mapped in a number of families. Most patients with PKND do not benefit from antiepileptic drugs, but some response to clonazepam or clobazam has been reported. In general, it is more difficult to treat than PKD, and patient often learn to avoid precipitants.

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Treatment can be difficult, but the use of botulinum toxin can be very successful for focal dystonias, and there is increasing evidence of the efficacy of DBS for medically refractory cases of dystonia. The underlying pathogenesis of dystonic movements is not fully understood but appears to involve basal ganglia defects that lead to abnormal sensory processing and reduced inhibition within the motor system at many levels.

Paroxysmal Exercise-Induced Dyskinesia In this condition, episodes of involuntary movements occur after exercise such as walking or swimming. These usually take the form of dystonia, which resolves 10 to 15 minutes after the patient ceases exercising. The dystonic movements take longer to begin and last longer than those in PKD. Cold exposure may also bring on an attack. Sporadic cases have been described, but it is frequently familial with autosomal dominant inheritance. As with PKND, the control in paroxysmal exercise-induced dyskinesia are often difficult to treat, although some response to antiepileptic drugs has been reported. If the dystonia is unilateral and severe, stereotactic surgery may be an option.

K E Y ●

The dystonias are a relatively common group of movement disorders, with primary focal dystonia being the most prevalent.

●

Diagnosis is clinical, and investigations are used to rule out secondary causes.

●

The underlying pathogenesis of the abnormal movements is thought to be abnormal sensory processing and deficient motor cortex inhibition.

●

Genetic factors are important to the development of primary dystonia.

●

Treatment is tailored to the individual type of dystonia, with the use of botulinum toxin injections for focal and segmental dystonia and of medication or surgery for more severe forms.

Paroxysmal Hypnogenic Dyskinesias Paroxysmal hypnogenic dyskinesia is a term used to describe brief episodes of involuntary dystonic or ballistic limb movements that waken the patient from sleep and can occur frequently during the night. The majority of these cases, particularly familial forms, have been found to be due to mesial frontal lobe seizures, now described as autosomal dominant nocturnal frontal lobe epilepsy. To date, mutations in two genes, the α4 subunit of neuronal acetylcholine receptor (CHRNA4) and the β subunit of the nicotinic acetylcholine receptor subunit genes, have been described in some families.

Secondary Paroxysmal Dyskinesias Secondary or symptomatic paroxysmal dyskinesias are notable for variability of age at onset, the presence of both kinesigenic and nonkinesigenic symptoms in some patients, the prevalence of sensory precipitants, and the reversal of symptoms if the underlying condition can be treated. The presence of other neurological symptoms and signs also points to a secondary cause. The association of PKD and PKND with multiple sclerosis is well described. Other causes include stroke, antiphospholipid syndrome, central and peripheral nervous system trauma, human immunodeficiency virus infection, hypoglycemia and hyperglycemia, hypoparathyroidism, pseudohypoparathyroidism, basal ganglia calcification, and kernicterus.

CONCLUSIONS The dystonias represent a relatively common group of movement disorders whose diagnosis is predominantly clinical. They have diverse causes with both primary (genetic) and secondary causes. The most common forms in clinical practice are the primary focal dystonias.

P O I N T S

Suggested Reading Albanese A: The clinical expression of primary dystonia. J Neurol 2003; 250:1145-1151. Comella CL, Pullman SL: Botulinum toxin in neurological disease. Muscle Nerve 2004; 29:628-644. Fahn S, Bressman S, Marsden CD: Classification of dystonia. Adv Neurol 1998; 78:1-10. Hallett M: Abnormal movements result from loss of inhibition. Adv Neurol 2004; 94:1-11. Vidailhet M, Vercueil L, Houeto JL, et al: Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005; 352:459-500.

References 1. Fahn S, Bressman S, Marsden CD: Classification of dystonia. Adv Neurol 1998; 78:1-10. 2. Muller J, Kiechl S, Wenning GK, et al: The prevalence of primary dystonia in the general community. Neurology 2002; 59:941943. 3. Albanese A: The clinical expression of primary dystonia. J Neurol 2003; 250:1145-1151. 4. Hallett M: Abnormal movements result from loss of inhibition. Adv Neurol 2004; 94:1-11. 5. Comella CL, Pullman SL: Botulinum toxin in neurological disease. Muscle Nerve 2004; 29:628-644. 6. Vidailhet M, Vercueil L, Houeto JL, et al: Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005; 352:459-500.

CHAPTER

36

GAIT DISTURBANCES ●

●

●

AND FALLS

●

Nir Giladi, Bastiaan R. Bloem, and Jeffrey M. Hausdorff

Gait, the action of walking from one place to another on two legs, is one of the most fundamental human motor tasks. Unlike all other mammals, it takes about 1 year for a human baby to start walking independently on two legs and 2 to 3 additional years until gait is fully coordinated and the response to external restrictions is well developed. Many congenital or perinatal psychomotor disturbances first manifest as a delayed initiation of walking, and this underscores how much normal gait depends on mature and intact central and peripheral nervous systems. Furthermore, gait also requires intact musculoskeletal and cardiovascular systems, from the very first year of life. For the next six or seven decades of their lives, humans generally walk independently and largely automatically, without any apparent need for paying special attention to this essential daily task. Remarkably, healthy adults fall only rarely, despite multiple and often unexpected challenges in the everyday environment, such as slippery floors or doorsteps. At around the seventh to ninth decade of life, walking again becomes an issue of concern that is often related to fear and anxiety about falls. Falls are the most serious and dangerous complications of gait disturbances. The fear from this terrifying experience alone can keep an elderly person at home in selfimposed house arrest. Furthermore, loss of independent locomotion and abnormal balance are two major causes for institutionalization. This chapter describes the basic requirements for locomotion and the ways of characterizing normal gait and classifying, assessing, and quantifying gait disturbances. We also highlight the close relationship of gait to abnormalities in balance and to falls. The last part of the chapter discusses interventional modalities for improving gait, reducing the incidence of falls, and preventing deterioration in mobility.

LOCOMOTION, EQUILIBRIUM, AND THE SUPPORT SYSTEMS Multiple support systems are required to rise up on both legs, maintain balance, initiate the first step, and maintain rhythmic and effective stepping while interacting with the environment and internal restrictions. The first essential ones are the musculoskeletal and cardiovascular systems that provide the ability to safely stand erect and move without collapsing because of weakness or hemodynamic deprivation. The visual, vestibular,

and proprioceptive senses play a major role as support systems that provide the central nervous system (CNS) with essential feedback about ongoing movements and environmental constraints. Similarly, the ability to learn, memorize, retrieve, plan, and execute walking as a sensorimotor integrated task is critical to gait and requires cognitive abilities. Locomotion starts with the first shift of the center of mass over the support foot and tilting of the pelvis in order to lift and swing the first leg. This first step—which is based on preplanning and execution of a complex motor task—is especially challenging because all the supporting and executive systems are activated. The next step is the beginning of synchronized, rhythmic, and largely automatic motor planning that leads to continuous stepping. Stepping is done while responding to internal (personal) factors, such as the purpose and goal of the walk, as well as the chosen motor plan for each specific walk, such as walking fast to catch a bus or marching in the army. In addition, one has to take into account the external (environmental) factors, such as the route, the surface, and the possible obstacles on the way, as well as the walker’s physical state. All these factors act together, and so the responses or modifications of the walking motor plan have to take place in a coordinated manner. Disharmony in the integration of the multiple systems involved in locomotion obviously has a devastating effect on gait and may also increase the likelihood of falls. Balance is the other major player in locomotion. The ability not only to stand erect on two feet but also to stand on one leg for about one third of the gait cycle is a precondition to locomotion. Again, the support systems are critical enablers of safe, forward movement. Afferent sense of limb and trunk position, vestibular and visual information, and judgment of fall risk during specific circumstances will influence the choice of a strategic plan at any given time. Both locomotion and postural responses must be fully integrated to plan and to instantly respond to any unexpected event in real time. The fact that healthy people fall so rarely while functioning in a constantly changing internal and external environment reflects the extraordinarily harmonic integration of all the systems involved in normal walking. Not surprisingly, any defect in this orchestration can lead to gait disturbances, insecurity, and falls. Clinical syndromes, however, depend on the corrective mechanisms that are called into action in response to a mismatch or defect in the normal physiology. An efficient corrective system can mask major pathology and maintain normal function.

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Central Locomotion Generators Locomotion is controlled by several centers at different levels of the CNS. There is strong evidence that the most basic rhythmic, bipedal, synchronized stepping of mammalian quadrupeds originates in centers in the spinal cord referred to as the central pattern generators. Indeed, decerebrate cats can produce a rhythmic stepping pattern if they are put on a treadmill. Although anatomical demonstration of the existence of such centers is lacking in humans, central pattern generator–like centers probably exist in humans as well. The human central pattern generator also controls the timed coupling between arm and leg movements during normal walking.1 In primates, including humans, the central pattern generator is probably located within the spinal cord, as is suggested by the production of gaitlike movements in paraplegic patients who, when placed with support on a moving treadmill, can also produce rhythmic stepping. Such spinal central pattern generators are under the influence of brainstem control mechanisms, which are most probably situated at the level of the mesencephalon in the brain. In humans, the caudal cholinergic mesencephalic nucleus, also referred to as the pedunculopontine nucleus (PPN), is considered as the human mesencephalic locomotion center. It is believed to control spinal pattern generators or to play a similar role as the spinal central pattern generator in animals and is considered the human mesencephalic locomotion center.2 The PPN receives afferent GABAergic projections (secreting the neurotransmitter gamma-amino-butyric acid [GABA]) from the internal globus pallidus, subthalamic nucleus, and the substantia nigra pars reticulata. It sends efferent cholinergic and glutamatergic projections (secreting the neurotransmitters acetylcholine and glutamic acid) to the substantia nigra pars compacta and downward to the brainstem and spinal cord. The PPN is the only nucleus associated with the basal ganglia that has a direct connection with the spinal cord and, as such, it is believed to play a major role in motor control of gait and posture. PPN stimulation can induce stepping in primates while a lesion at the PPN causes severe akinesia and parkinsonism in primates that is reversed by blocking GABAergic stimulation of the PPN. Furthermore, a focal stroke within the dorsal mesencephalon (presumably involving the PPN) has been shown to cause severe gait initiation problems in a human patient. Higher centers at the level of the basal ganglia, thalamus, and cortex are parts of the locomotion network that controls walking as a motor behavior, and they constantly interact with the internal and external environments. The frontal lobe and its premotor area are of special importance for planning, initiating, and continuous adjustment of the walking motor plan. The visual cortex produces information about the space where walking takes place, and this information is interpreted in other cortical areas in terms of visuospatial orientation, danger, and significance. The basal ganglia pass on information needed for the generation of a rhythmic gait pattern (i.e., internal cueing of gait) and play an especially critical role when there is a need for constant alertness and focused attention to the motor task or to a changing environment. Cortical and subcortical white matter and basal ganglionic lesions can lead to complete inability to initiate locomotion (akinesia), severe unsteady gait (disequilibrium), unorganized and dysfluent locomotion, and pathological interaction with the environment. Altogether, these types of lesions often lead to loss of mobility and a high risk for falls.

Walking is dependent heavily on the musculoskeletal system for its execution. Strong bones with flexible joints and elastic feet and spine are essential for effective gait. Similarly, strong muscles are responsible for maintaining the correct posture and moving the bones in harmonic fashion to create motion in space. The peripheral nervous system executes the motor plan of walking at the level of the spinal cord through the motor neurons and provides online information from the sensory receptors about the internal (e.g., sense of position) and the external environments. The centrally generated gait motor plan is tested by the degree of scaling and synchronized activation of multiple muscle groups at multiple levels of the spinal cord. Walking is not possible if muscle weakness or activation dyssynchronization exceeds a certain threshold. Similarly, an abnormal sensory input from the periphery leads to instability and frequent falls because balance is heavily dependent on data from the environment.

The Gait Cycle Walking can be regarded as a composite of numerous small and similar gait cycles, each based on an alternating single step accomplished by both legs. A full cycle can be calculated from any given point because of the rhythmic and stereotypic manner of locomotion. Classically, spatial description of the gait cycle starts when the right heel touches the ground while the right knee is stretched (locked) and the right foot is dorsiflexed. The foot rolls on the ground and carries most or all of the body mass as part of the stance phase. As the body mass moves forward, the heel leaves the ground. After a forced plantar flexion that pushes the body center of mass forward, the toes also leave the ground. When the toes of the right foot leave the ground, the swing phase of the right leg starts. In the swing phase, the right leg swings forward after the right hip is pulled up (flexed) while the knee initially will be flexed and later extended to reach the ground in a locked position. During the swing phase, the foot is dorsiflexed to avoid any contact of the toes with the ground. The cycle ends when the right heel again comes in contact with the ground (Fig. 36–1). The gait cycle can also be characterized temporally. The right foot normally touches the ground for about 60% to 65% of the gait cycle. Only one leg is in contact with the ground (single support time) during 30% to 40% of the cycle, and both legs touch the ground in the double support phase during one third of that time or 20% to 25% of the whole cycle. Based on this time frame, the swing phase of the right leg and the stance phase of the left leg (single support time of the left leg), which, by definition are equal in time, take place during 35% to 40% of the gait cycle. The proportion of each phase of the gait cycle is changed in relation to the speed of walking, as well as in relation to the individual’s physical state, security, and equilibrium. Accelerated walking is associated with shortening of all phases, but proportionally more of the double-limb support time shrinks. Aging, physical weakness, and disequilibrium lead to slower gait speed and increased double-limb support time. Three additional spatiotemporal features of locomotion are stride length, cadence, and step width. Stride length is the distance between the places where the right heel first touches the ground at the initiation of one gait cycle to the place where it touches the ground again at the beginning of the next gait cycle. Stride length is also the summation of the distances of two steps (left plus right). Cadence is the step rate or the

chapter 36 gait disturbances and falls

Right initial contact

Left terminal contact

Left initial contact

Right terminal contact

Right initial contact

Right stance

Right swing

Left swing

Left stance

Right double support

457

Left terminal contact

Left double support

Left step

Right step ■

Figure 36–1. The gait cycle.

number of steps in a given time (e.g., steps per minute), and step width describes the distance between the two feet along the perpendicular axis to the walking direction for a given step.

ASSESSMENT OF GAIT The quantitative assessment of gait and balance can be stratified into three levels: no tech, low tech, and high tech.3 Each has an appropriate time and place. The decision to use one or the other of these approaches partly depends on the purpose of the evaluation, the degree of sensitivity and specificity required, and trade-offs of cost, time, and convenience. Many volumes have been written on each of these approaches.4 Here, we briefly describe some of the more salient features of each of them and common approaches.

Clinical Assessment The “bedside examination” of gait and balance involves taking a careful history and a detailed physical examination.

History Taking Interviewing patients about their problems with gait or balance can be a challenge. When asking about gait problems, the clinician has to understand the amount of walking a person does in daily life. In addition, the nature of the questions themselves should try to help the patient describe his difficulties in terms of walking speed, amount of effort required, confidence or degree of fear from falling, and whether any assistance or walking aids are used. It is informative to look at the patient’s step length as a good general marker and to note if one can hear the soles dragging on the floor during each step as a practical marker for the height and duration of the swing phase. For patients presenting with gait disorders, try to distinguish between consistently present walking difficulties versus an episodic gait disorder, such as freezing of gait, festination, or sensory ataxia in the dark. When asking about possible freezing of gait, one must specifically inquire about the characteristic subjective feeling of the feet “being glued to the ground.”

A specific Freezing of Gait Questionnaire has been developed that may assist in screening for and rating the severity of freezing of gait.5 To make sure that the patient understands what is meant by freezing of gait, it may be useful to demonstrate an imitation of a typical freezing of gait episode. Falls are one of the most serious complications of gait disturbances and should receive special attention. Many elderly persons tend to forget their falls, particularly when there is concurrent cognitive impairment, as is often the case. Some persons may even purposely deny the occurrence of falls because they fear being admitted to a nursing home or another form of sheltered care. Many elderly persons find it extremely difficult to indicate under which circumstances their falls occur. Nevertheless, obtaining a careful fall history is important, because the presence of a prior fall in the preceding 6 to 12 months consistently emerges as an excellent, simple predictor for repeated falls in the future.6 Patients should be asked not only about falls but also about the presence of “near-falls.” These are at least as common and can be debilitating in their own right. In light of the characteristic amnesia for falls, eyewitness reports are often indispensable, and every effort must be made to retrieve the accounts of bystanders who witness falls. Table 36–1 can serve as a guideline for the interview. Several important elements of this clinical approach are discussed in more detail next. For any patient presenting with falls, the first thing to do is to clarify the circumstances surrounding the fall and, in particular, to identify any specific pattern, because this may reveal the underlying pathophysiology and offer opportunities for prevention. The second step involves a distinction between single versus recurrent (two or more) falls and between “internal” and “external” falls, features that are important for secondary prevention. One should therefore evaluate whether any environmental factors were obviously responsible for the falls. When the role of environmental factors is unclear or frankly denied, the fall can then be classified as “intrinsic” (usually defined as a fall that was caused by gait or balance disorders or misperception of the environment). The third step is to inquire whether any transient loss of consciousness preceded the fall. The absence of a preceding transient loss of consciousness indicates a probable involvement of an underlying gait disorder

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T A B L E 36–1. Elements of History Taking in Persons With Gait Disorders or Falls Continuous or episodic gait disorder? Walking worse in the dark? Relationship between walking and falls? Frequency of prior (near-) falls Specific fall pattern distinguishable? Apparent cause of the falls: None (“spontaneous”) Environment (e.g., slippery floor)* (Sudden) change of posture Performing several activities simultaneously Hazardous behavior Inappropriate footwear Symptoms preceding the fall: Loss of consciousness “Funny turn” (vertigo; presyncope) Palpitations/chest pain/breathlessness Sudden weakness of the legs Symptoms after the fall: Inability to stand up Loss of consciousness Physical injury Fear of falling Use of walking aids: Difficulties in use If none: why not? Medical history: Prior/current diseases (Psychoactive) medication and drug combinations Intoxications (alcohol) Protective factors: Exercise level Adaptation of behavior/activities

Physical Examination Table 36–2 lists several important elements of the physical examination. The examination should include a battery of functional tests to capture the full repertoire of gait and balance abnormalities. Ideally, physicians should examine the patients in the environment where they walk and function in daily life (i.e., home and surroundings), but this is not practical. A homemade video can sometimes be extremely informative, especially for episodic gait disturbances. Similarly, examining the patient immediately after a fall can help with the identification of its cause(s) and consequences, but this is rarely possible. A problem with the inevitably “interictal” examinations is that the observed abnormalities may not be causally related to the gait disturbance or the fall. Physical examinations can appear to be entirely normal in between freezing of gait or fall episodes.

General Physical Examination This should include measurements of height and weight, because a low body mass index increases the risk of major injury and indicates frailty. Examination of the musculoskeletal system should mainly include “functional” tests. Rating the strength of individual muscles is less informative than asking a patient to stand up from a chair (a measure of, among others, proximal leg strength). Measurements of blood pressure in both the recumbent and standing positions can detect orthostatic hypotension.

Gait *If needed, evaluate domestic situation by community nurse, physiotherapist, or occupational therapist.

and/or balance deficit. This will become evident during physical examinations between falling episodes. If the gait or balance disorder is severe enough, even small movements can be destabilizing and the patient may start to fall almost spontaneously. In patients with apparently unprovoked falls, care must be taken not to miss a possible preceding transient loss of consciousness. Explicit inquiry into the use of medication is vitally important, because this is one of the most common risk factors for gait disorders, falls, and hip fractures in elderly persons. In particular, benzodiazepines and antidepressants are associated with falls in the elderly, but other psychotropic medications (e.g., neuroleptics) and drugs causing orthostatic hypotension or arrhythmia also increase the risk of falls. Dopaminergic medication may paradoxically increase the fall frequency of patients with Parkinson’s disease by causing excessive dyskinesias, orthostatic hypotension, or confusion. The risk of falls increases dramatically if different drugs are used at the same time (Fig. 36–2). The psychological consequences of falls can be severe. Thus, it is important to assess whether a patient has a fear of falls and whether this fear is reasonable (in persons with extremely poor balance) or if it is inappropriate (a pathological fear induced by a single but otherwise innocent fall). “Self-confidence” (confidence in not falling) should also be evaluated as this provides valuable complementary information about the impact of falls on activities of daily living and independence. Some patients feel overly confident despite marked balance deficits, and they have a high risk of falling.

Most examination rooms are too small to assess gait properly. It is therefore helpful to monitor the patient while walking to and from the examination room or even follow him down the corridor. The reduced step height observed in mildly affected patients such as those with mild spasticity or parkinsonism may be better heard than seen. Inspecting their shoes may reveal excessive wear on the medial and anterior side of the sole on the side of a spastic leg. A reduced support phase on one leg suggests an antalgic gait (e.g., that of someone with a twisted ankle). Dystonic gait disorders can be task specific (e.g., evident during regular walking but disappearing during walking backward or running). Freezing of gait is particularly difficult to elicit in the physician’s examination room and is best examined as patients walk along a specifically developed trajectory, periodically passing through narrow paths and performing turns of 180 or 540 degrees. Abnormalities to be noted during turning movements include the “pivoting” strategy, where the trunk rotates stiffly (“en bloc”) with the legs, shuffling of the feet with multiple small steps or even overt freezing of gait. Providing patients with one or more secondary “distracting” tasks while walking can be informative because impaired multiple task performance may detect balance problems that might otherwise remain unnoticed. Furthermore, multiple task performance provides insight into actual falling risks because falls in daily life commonly occur when subjects attempt to do more than one thing at the same time. Cognitively impaired patients may try to perform all tasks equally well, but pay a price in terms of poor gait or balance. The simplest test is to start a routine conversation while walking beside the patient. An inability to walk and talk at the same time (usually manifested by a stop in the conversation) has a good predictive value for falls in cognitively

chapter 36 gait disturbances and falls

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Falls Single

Obvious extrinsic cause

Recurrent

Insufficient extrinsic cause

Treating injuries suffices

Stereotypical pattern? → If multiple: analyze each pattern separately!

Review medical notes

Search for risk factors “Spontaneous” (*)

Identified risk factors Interaction? “Intrinsic” (patient-related)

“Extrinsic” (environmental) No preceding TLC

Preceding TLC

Preceding “funny turn”

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Presyncope? (**)

Gait or balance disorder?

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• Vertigo

• Neurological • Orthopedic • Others

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• Drop attacks • Cataplexy • Hyperexplexia

• Syncope • Epilepsy • Others

Figure 36–2. The clinical work-up of falls. An “obvious extrinsic cause” refers to an overwhelming external hazard, which would make almost every person fall (e.g., a pedestrian being knocked down by an automobile). Medical notes provide a wealth of easily accessible information about relevant risk factors (age, sex, medical history, and medication) that could serve to guide the selection of patients at risk for falls. TLC, transient loss of consciousness. *In patients with seemingly spontaneous falls, consider one of the following three possibilities: TLC that was apparently forgotten or misperceived by the patient; a mimic of TLC (drop attacks, cataplexy, or hyperexplexia); or a seemingly spontaneous fall that was in fact caused by a severe underlying gait or balance disorder. (Modified from Bloem BR, Boers I, Cramer M, et al: Falls in the elderly. I. Identification of risk factors. Wien Klin Wochenschr 2001; 113:352-362, with permission.)

impaired elderly persons, but probably not in patients without cognitive impairment. Other examples of secondary tasks include avoiding obstacles or carrying objects such as a tray while walking. Various different tasks can be combined to challenge balance and gait even further.

Balance This must be reviewed not only during slowly performed tasks, but also during more abrupt movements (e.g., turning around quickly on command), because they more closely resemble everyday fall circumstances. The Functional Reach test is a commonly used measure of dynamic balance control that evaluates the individual’s limits of postural stability in standing. With outstretched arms, subjects are instructed to reach forward as far as possible, while keeping their feet in place. This test may identify fallers in the general elderly population, but

not in a high-risk population such as patients with Parkinson’s disease. The retropulsion test (pull test) measures protective responses by delivering an external disturbance in motion— usually a sudden shoulder pull from behind and sometimes a push to the chest. Drawbacks include the difficulty in standardizing test execution and the lack of a generally accepted scoring system. Assessment of the patient’s tandem stance and/or single leg standing abilities may also be useful.

Timed Tests Some clinicians advocate the use of timed tests because they produce a quantifiable result. One example is the Timed Up and Go test (TUaG), which is a reliable measure of functional performance that captures transfers, gait, and turning movements.7 In this test, the subject is asked to rise from a chair, walk 3 m, turn around, return to the chair, and sit down. In its

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T A B L E 36–2. Elements of Physical Examination in Patients With Gait Disorders or Falls General Body mass index Cardiovascular examination Joints (ankles, knees, hips) Orthostatic hypotension Depression Neurological examination, including: Cognition Vision (with/without correction) Strength of the legs Proprioception of the legs Vestibular tests Walking* Gait ignition Gait speed† Arm swing Festination Step height and length Stance width Instability while turning‡ Freezing§ Circumstances (e.g., turning or narrow passages) Effect of cues Dual tasking “Stops walking when talking” Avoiding obstacles Carrying object in hands Combinations of the above Posture¶¶ Seated and standing Frontal and lateral views Balance Transfers Righting reactions (rising from chair or bed) Sitting or lying down Supporting reactions (quiet stance, eyes open/closed) Anticipatory reactions (lifting object from floor; arm raising) Reactive/protective postural responses (retropulsion test)¶ Tandem gait Romberg test Climbing stairs Quantifiable Tests Functional reach test Timed Up and Go test Walking distance (e.g., in 6 minutes)** Standardized Rating Scales Generic Tinetti Mobility Index Berg Balance Scale Disease specific†† *Use sufficient space! †Speed of performance less important than safety. ‡Instruct to execute slowly and abruptly; note occurrence of freezing. §Often difficult to assess during routine clinical examination; preferentially use standardized trajectory (from Schaafsma JD, Balash Y, Gurevich T, et al: Characterization of freezing of gait subtypes and the response of each to levodopa in Parkinson’s disease. Eur J Neurol 2003; 10:391-398.) ¶Elements to be noted include the trunk (stooped; marked lateroflexion, or Pisa syndrome) and neck (retrocollis, anterocollis, or laterocollis). ¶¶Difficult to standardize and score. **As a measure of cardiopulmonary condition. ††Specific rating scales are available for some disorders, but there is a general lack of validated measures for posture, balance, and gait. Modified from Bloem and Bhatia 2004, with permission.

original form, this was a subjective test in which the performance of this task was assessed qualitatively. It has since become timed, however, to lessen its subjective nature. The TUaG test predicts falls and may be used to screen for fall risk. Part of the reason that the TUaG test is used so widely is that it evaluates different important mobility functions (e.g., transfers, gait, and turning), it takes only a very short time to complete, and it requires minimal expertise or training. Subjects who perform the TUaG test in more than 13.5 seconds are believed to have an increased risk of falls.8 The TUaG test could be classified as a low-tech measure of gait. Another measurement is stance duration on one leg, which may predict falls. Judging the safety of gait and balance maneuvers, however, may be more important than measuring timing: indeed, emphasizing the aspect of timing deleteriously influences the quality of the movements.

Rating Scales Standardized rating scales are comprised of combinations of different tests and this helps to systematically rate most aspects of gait and balance. A widely used example is the standardized version of Tinetti’s test9 (also known as the Performance Oriented Mobility Assessment [POMA]). It includes an evaluation of balance under challenging conditions (e.g., while rising from a chair, after a nudge to the sternum, standing with eyes closed, and while turning) and an evaluation of gait characteristics (including gait initiation, step height, length, continuity and symmetry, trunk sway, and path deviation). Scoring is based on clinical judgement and takes only about 15 minutes. Poor performance on this scale is associated with an increased risk of falls in the elderly population. One disadvantage is that very unstable patients cannot (or refuse to) perform all the elements of these rating scales. Another disadvantage is that the rating scales lack validity in general and have never been validated for specific disorders of balance or gait.

Quantitative Assessment of Gait Gait mats provide another increasingly popular method for quantifying gait. Subjects walk across an instrumented carpet or walkway that is sensitive to the pressure changes caused by walking. A major advantage of this type of system is that the subject is not required to wear any special shoes, markers, or inserts. The instrumented walkway quantifies stride length, stride width, stride time, and the timing of the gait cycle, typically as averaged over 5 to 10 strides (depending on the size of the walkway). A number of studies have demonstrated the validity, reliability, and clinical usefulness of these types of systems in various clinical populations. Ambulatory monitoring systems enable the quantitative measurement of the timing of gait. The subject might be equipped with accelerometers, foot switches, or other wearable sensors. A key advantage of such systems is that they are not tethered to any computer or stationary system and therefore allow the measurement of multiple strides in almost any environment. This, in turn, enables evaluation of gait rhythmicity and the stride-to-stride fluctuations of gait timing (Fig. 36–3). Several studies have shown that such measures of gait variability or dynamics are sensitive to subtle changes that occur with aging and neurodegenerative diseases, such as Parkinson’s

chapter 36 gait disturbances and falls ■

RECORD DKTESTO Signal O 0:00 Signal I

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Figure 36–3. Continuous recording of the vertical ground reaction force by an ambulatory gait analysis system. Such a long-term (several minutes) recording is the basis for assessment of gait dynamics and stride-to-stride variation (fluctuation). Signals 0 and 1 represent data from left and right feet.

Parkinson’s disease (PD)

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Huntington’s disease (HD)

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disease, Huntington’s disease, and Alzheimer’s disease10-13 (see, for example, Fig. 36–4). Stride-to-stride fluctuations reflect the consistency or steadiness of gait and the ability of the locomotor system to regulate gait from one stride to the next. Thus, it is easy to understand how such measures have clinical efficacy in the identification and prospective prediction of elderly fallers14 (see, for example, Fig. 36–5). Gait laboratories offer the most comprehensive means of quantifying gait. Typically, a modern gait laboratory includes a camera or marker-based system to measure the movement of various body segments (termed “kinematics”), force-platforms to measure the ground reaction forces, (i.e., the forces exerted by the foot on the ground [termed “kinetics”]), and electromyographic equipment to measure muscle activity. Such systems provide a highly detailed assessment of walking, including the position, velocity, and acceleration of different joint segments and angles and muscle forces and timing. This combination can provide insightful information into changes in gait mechanics. Studies of children with cerebral palsy, especially when they are candidates for surgery, probably represent the most popular applications of a full-scale gait laboratory. For many clinical purposes, however, some of the simpler approaches described earlier may be sufficient.

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Etiology and Pathophysiology Gait disturbances can be the result of a lesion or functional derangement at any level, from the toes to all areas of the cortex. In many instances, it is easy and straightforward to identify the etiology of a gait disturbance just by observing the patient walking and by performing physical and neurological

1

■

Figure 36–4. Example of time series of patients with three neurodegenerative diseases and a healthy control subject. The stride-to-stride fluctuations of the stride time are much larger in the patients; this reflects an irregular and unsteady gait. (Adapted from www.physionet.org. For more information, see Hausdorff et al.10,13)

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84-year-old Non-faller

T A B L E 36–3. System-Oriented Classification of Gait Syndromes

1.5

Peripherally Originating Gait Syndromes Musculoskeletal Joints, bones, ligaments, tendons, muscles, peripheral nerves Sensory Proprioceptive, vestibular, visual

Stride time (sec)

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1.3 *The etiology of many gait syndromes is not always readily attributable to a single cause. For example, fear of falling may be due to changes in frontal and/or extrapyramidal function.

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Centrally Originating Gait Syndromes Spinal Spastic paraparesis Sensory ataxia Pyramidal Spastic Paretic Cerebellar Ataxic Extrapyramidal Bradykinetic/hypokinetic Rigid Dyskinetic Episodic High Level Disequilibrium “Apratic” Unclassified Cautious/fear of falling*

Figure 36–5. Stride-to-stride fluctuations in the stride time, were much larger in this subject who subsequently experienced a fall during the 12-month follow-up period than in the non-faller. Group results were similar. Measures of the stride-to-stride variability prospectively predicted falls; older adults with increased variability were more likely to fall during the 12-month follow-up period compared with those with a lower variability. (See Hausdorff et al.14 for further details.)

examinations. The origin of gait disturbances in a person with orthopedic problems as seen in feet, joint, or spinal diseases can be easily diagnosed similar to the way that visual, vestibular, cardiovascular, respiratory, or muscular disturbances can often be readily identified. The effect of those and other peripheral neuropathies on gait is secondary. As a result, any therapeutic intervention should be focused on the primary etiology. Due to the critical role of gait in normal daily function, however, a compensatory approach frequently has to be taken, even before solving the primary problem, simply in order to promote mobility and independence. Due to the complex nature of the central gait network, different lesions at multiple levels of the CNS can cause gait disturbances. In some instances, such as stroke and hemiparesis or cerebellar disease and ataxia, the association between focal brain dysfunction and a distinct gait disturbance is clear-cut and easily diagnosed. When it comes to disturbances in the extrapyramidal-limbic-prefrontal locomotion network, the clinical-pathological relationships may be less clear. The gait

disturbance also becomes more difficult to describe, even from a phenomenological perspective. The pathophysiology of those disturbances, which were first described by Nutt and colleagues as “high level gait disturbances,”15 is not completely defined. Nonetheless, there is justification for associating those gait disturbances with the frontal lobe in general and, more specifically, with the prefrontal-limbic-anterior basal ganglia network. (See Table 36–3 for gait classification.) Frequently, the patient complains about a gait disturbance or fear of falling but the formal examination may not detect any specific cause. As a result, frontal gait disturbances are often mistakenly associated with the normal aging process or with parkinsonism just because the patient walks slowly and with a stooped posture. In addition, the frontal gait disorders may look bizarre and be suggestive of “apraxia” of gait. A major symptomatic aspect of the frontal gait disorders is a feeling of insecurity and of disequilibrium associated with anxiety, fear, and depression that might not be associated with a history of falls or proportional to the degree of imbalance or postural disturbances.16 This group of gait disturbances poses a real challenge from the diagnostic and therapeutic points of view. General atrophy with enlarged lateral ventricles may be seen on brain imaging. Many such patients undergo surgery in which a ventriculoperitoneal shunt is inserted, occasionally with partial and transient improvement. Based on clinical and neuroimaging techniques, it is very difficult to differentiate between normal pressure hydrocephalus and frontal gait disorders: only those cases with a very long-term and clear-cut response to ventriculoperitoneal shunting can be diagnosed—retrospectively—as having typical normal pressure hydrocephalus. From the functional point of view, one of the most important features of gait disturbances is that it has a characteristic time course. Abnormal gait that develops slowly over a period

chapter 36 gait disturbances and falls T A B L E 36–4. Examples of Episodic Gait Disturbances Freezing of gait Start/turning hesitation Tight quarters hesitation Hesitation while reaching destination Hesitation during mental overload or stressful situations Festinating gait Paroxysmal disequilibrium—vestibular Psychogenic gait (Pre-)syncope Drop attacks Sensory ataxia It is helpful to distinguish between those gait disturbances that occur continuously, whenever walking occurs (e.g., bradykinetic gait) and those that are transient and episodic in nature. Examples of the latter are listed in this table.

of weeks or months can be incorporated into the daily routine with a relatively low risk of falls. For example, a person who develops continuous locomotion disturbances, such as slow gait, unsecured gait, hemiparetic gait, or even spastic gait, can use a walking aid, compensate for the difficulty by slowing the walking speed, and, very often, broaden the walking base. In contrast, the episodic gait disturbances (Table 36–4) are characterized by their unexpected and transient appearance. As a result, episodic gait disturbances often lead to falls or fear of falling and are associated with self-imposed restrictions of daily activities. As mentioned earlier, freezing of gait refers to the phenomenon where patients experience brief and sudden moments where the feet subjectively become “glued to the floor.” Freezing of gait most commonly appears when patients make turns (thereby explaining why patients with Parkinson’s disease frequently fall while turning), but it may also occur spontaneously during straight walking, while crossing narrow spaces, when trying to initiate gait (“start hesitation”), or when reaching a target. Freezing of gait is a particularly common source of falls, because the legs fail to follow through with the forward motion of the trunk. An objective demonstration of freezing of gait episode is demonstrated in Figure 36–5 using the ambulatory gait assessment technique. It may be difficult to distinguish freezing of gait from festination, another episodic gait disorder that commonly leads to falls. Festination is characterized by a sudden change in locomotion rhythm because of an inability to maintain the base of support (the feet) beneath the forward moving trunk during gait, forcing the patient to rapidly take increasingly small steps (hastening) to avoid a fall. Festination leads to propulsion when patients walk forward or to retropulsion when patients lose their balance and take corrective steps backward. Festination or freezing of gait can also be embarrassing due to their unusual and bizarre nature, leading to the avoidance of situations in which they might occur. For example, patients may try to avoid crowds, walking in the street, crossing through doorways, or entering elevators. These episodic gait disturbances may be especially responsive to external cues like rhythmic auditory stimulation, lines on the floor, or changing the normal gait pattern to marching or walking sideway.17

Classification There are many ways to classify gait disturbances. It is, however, important to have a common understanding of terms when

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describing changes in walking patterns, to facilitate communication between clinicians and investigators. Classification of gait should give phenomenological information to form a faithful picture of the nature of the individual’s gait, as well as temporal data about its course and linkage to possible etiologies. Table 36–5 was developed to provide a practical stepwise classification of gait disturbances. The classification moves from phenomenology to examination to etiological options. Gait disturbances are divided into six general categories that are based on observation of a patient walking and should help describe gait at a given moment. It is important to note that a patient might have one or more types of general gait disturbances. For example, a parkinsonian patient can have bradykinetic, dyskinetic, and episodic (freezing) gait disturbances, with each type probably reflecting a different pathophysiology; each type should therefore be discussed (and treated) separately. The second column of Table 36–5 presents a more detailed but again observational characterization of gait. The observational description is followed by the physical and neurological examination. Based on the results of detailed and focused observation and examination (with or without the help of more advanced methods, such as motion analysis imaging, etc.), one can move to etiological categorization. The last column of Table 36–5 provides examples of the different types of gait disturbances in the different categories. The main reason for classifying a patient’s gait is the need to understand the pathophysiology behind the gait disturbance to plan appropriate therapeutic strategies.

GAIT AND MENTAL FUNCTION Traditionally, the first lessons of controlling gait comprise a hierarchical system with control taking place on many levels in the CNS. For example, central pattern generators (putatively) exist at multiple levels of the spinal cord, and their output is regulated at several levels, including feedback by the brainstem that contains the mesencephalic locomotor region and the premotor and dorsolateral-prefrontal cortex. The basal ganglia may also be included in this picture as a regulator of motor control, but gait is typically viewed first and foremost as an automatic process with little or no input from higher-level cognitive function. The result is that we tend to blame deficits in muscle function, balance, and motor control when we think about gait disturbances and falls. Although these factors are, indeed, essential for successful and safe walking, it is also important to keep in mind that cognitive functions may play a strong role. In other words, gait is much more than automated muscles and reflexes. Epidemiological evidence indicates that among older adults, fall risk increases in those with impaired cognitive function.8 This highlights the importance of cognitive function in gait and walking steadiness. In addition, the stability of gait and balance declines in certain populations when subjects are asked to walk and perform a second task (dual tasking).18 If gait were really automatic, one would anticipate that the performance of an additional task would have no influence on gait. An exacerbated dual-task decrement in walking ability has, however, been observed in idiopathic elderly fallers, in patients with Parkinson’s disease (primarily a motor disorder) (Fig. 36–6), and in patients with Alzheimer’s disease (primarily a cognitive disorder).19-23 Moreover, patients with dementia have an

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T A B L E 36–5. Gait Disorders Classified by Phenomenology and Examination, 2005 General Category

Gait Characteristics

On Examination

Etiology Categories

Examples

I

Paretic/Hypotonic Gait (Weakness of one or two legs or the pelvis girdle)

Symmetrical/asymmetrical Dropped foot with or without high pull-up of the knee while swinging Dragging one or two feet on the ground Exaggerated pelvic tilt or swing (waddling gait) Hyperextension or locking of the knee Short strides Weak “push off” (from the ground)

True leg(s) weakness, proximal or distal Reduced or absent tendon reflexes Decreased or normal muscle tone

1. Neurogenic a. Peripheral nervous system b. Central nervous system 2. Myopathic 3. Neuromuscular junction 4. Mixed

Lower motor neuron lesion Acute upper motor neuron lesion Motor neuropathy Radicular lesion Myopathy Myasthenic syndromes

II

Stiff Gait (Increased muscle tone in legs or trunk)

Symmetrical or asymmetrical Hyperadduction of thighs with or without scissoring

Increased tone: rigidity, dystonia, spasticity

Upper motor neuron lesion Parkinsonism Fear of falling

Circumduction while swinging Plantar flexion on swinging Decreased knee flexion Stiffed spine Dragging feet on the ground Low swing of legs

Inability to fully relax the muscles Decreased joint range of motion Flexors and feet extensors Joint disease

1. Neurogenic a. Upper motor neuron disturbance b. Extrapyramidal disorder c. Frontal paratonia 2. Nonneurogenic a. Musculoskeletal b. Secondary to pain c. (Lump this with musculoskeletal) 3. Psychogenic (see above)

Symmetrical/asymmetrical Slow speed Short or normal stride

Parkinsonism Turning “en bloc” Compensatory

Parkinson’s disease Parkinson plus syndromes Secondary parkinsonism

Dragging feet on the ground Pain while walking

Exercise intolerance Fatigue

Poor physical state (in particular cardiopulmonary function!)

Lack of internal drive to walk

1. Neurogenic a. Parkinsonism b. Mental lack of drive c. Visual insecurity d. Balance difficulties 2. Non-neurogenic a. Exercise intolerance b. Peripheral vascular disease c. Pain syndromes associated with walking d. Psychogenic 3. Mixed

III Bradykinetic/ Hypokinetic Gait (Mainly slow)

Musculoskeletal pain

II

Stiff Gait (Increased muscle tone in legs or trunk)

III Bradykinetic/ Hypokinetic Gait (Mainly slow)

Disequilibrium Dystonia Pain while walking Joint disease (e.g., arthritis) Stiff muscles

Poor cardiovascular/respiratory condition General weakness Depression Cognitive changes

Decreased arm swing Lack of motivation Increased cadence with shorter strides Slow initiation or response

Poor leg blood supply Visual disturbances Physiological Disequilibrium

Symmetrical/asymmetrical Hyperadduction of thighs with or without scissoring Circumduction while swinging Plantar flexion on swinging Decreased knee flexion Stiff spine Springy steps Dragging feet on the ground Feet are plantar flexed while swinging Low swing of legs

Increased tone: rigidity, dystonia, spasticity Inability to fully relax the muscles Decreased joint range of motion Weakness of hip flexors and feet extensors Joint disease

1. Neurogenic a. Upper motor neuron disturbance b. Extrapyramidal disorder c. Frontal paratonia 2. Non-neurogenic a. Skeletal b. Secondary to pain c. Fibromuscular 3. Psychogenic

Upper motor neuron lesion Parkinsonism Fear of falling Disequilibrium Dystonia Arthropathy Pain while walking Arteritis. joint disease Stiff muscles

Slow speed Short or normal stride Dragging feet on the ground Pain while walking Poor physical state Decreased arm swing Lack of motivation Increased cadence with shorter strides Slow initiation or response

Parkinsonism Compensatory Exercise intolerance Fatigue Lack of internal drive to walk Musculoskeletal pain Poor leg blood supply Visual disturbances Physiological Disequilibrium

1. Neurogenic a. Parkinsonism b. Mental lack of drive c. Visual insecurity d. Balance difficulties 2. Non-neurogenic a. Exercise intolerance b. Peripheral vascular disease c. Pain syndromes associated with walking d. Psychogenic

Parkinson’s disease Parkinson plus syndromes Secondary parkinsonism Poor cardiovascular/ respiratory condition

Intermittent claudications Pain related to walking Blindness Normal aging Insecurity/disequilibrium

General weakness Depression Cognitive changes Intermittent caudications Pain related to walking Blindness Normal aging

chapter 36 gait disturbances and falls

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T A B L E 36–5 Gait Disorders Classified by Phenomenology and Examination, 2005—cont’d General Category

Gait Characteristics

On Examination

IV

Ataxic Gait (Unsteadiness)

Wide base Short stride, slow speed Dragging feet on the ground Hesitancy, looking for support Increased double support Constant deviation to one side (particularly with eyes closed) Aggravation of unsteadiness with eye closure (in case of sensory ataxia or vestibular problems) Often a tendency to lock the knees

1. Objective balance 1. Peripheral problem a. Peripheral sensory Abnormal sense of neuropathy position b. Musculoskeletal Abnormal disturbances cerebellar function c. Vestibular Disturbed postural disturbance responses d. Visual disturbances Severe visual 2. Central disturbances Cerebellar Vestibular Vestibular disturbances Frontalsubcortical Fear of falling Psychogenic 2. Only subjective 3. Mixed balance problems

V

Dyskinetic Gait (Extra movements that affect gait)

Extra movement of legs, trunk, or head while walking Can be task specific Dystonic gait Choreic gait Dysrhythmic locomotion

Continuous dyskinesia Only during 1. Involuntary walking a. Extrapyramidal Legs or general syndrome dystonia b. Psychogenic Chorea Compensatory movements to improve security or confidence or to decrease pain

Episodic Gait Disturbances (freezing, festination, intermittent disequilibrium)

Normal locomotion between episodes Abnormal locomotion between episodes “FREEZING” Feet get “glued” to the ground with transient akinesia or legs shaking in place or forward motion with very small and fast steps: Start hesitation, turning hesitation, hesitation at tight quarters, stressful situations or in open runway FESTINATION Uncontrolled tendency to increase walking speed with small steps and a tendency to fall forward Episodic disequilibrium Episodic weakness

Parkinsonism Orthostatic hypotension Vestibulopathy Psychogenic syndrome

VI

impaired gait and an extremely high, not fully explained, risk of falls,24 despite only minimal involvement of their disease in the classic motor control systems. Walking and the maintenance of upright balance during gait clearly require more than “auto-pilot” control. Instead, walking and the proper integration of the many steps that are involved in walking should be viewed as a complex motor task that needs higher-level cognitive input. With this in mind, one can better appreciate the groundbreaking study by Lundin-Olson and associates.25 They investigated “stops walking when talking” in a mixed group of community-dwelling older adults, some of whom had dementia or depression or were poststroke or a combination. About 80% of the subjects who were unable to walk and talk fell at least once during a 6-month follow-up period, whereas about 80% of the subjects who were able to walk and talk did not fall. In other words, subjects who were unable to coordinate walking

Etiology Categories

Examples

3. Mixed

Insecurity/disequilibrium

1. With parkinsonism 2. No other significant neurological abnormality 3. Frontal gait disorders 4. Psychogenic

Peripheral sensory neuropathy Stiff and distorted feet Spinocerebellar ataxia Parkinsonism Hydrocephalus Multiple cerebral lesions mainly in white matter Basal ganglia, thalamus, (lacunar state, demyelination, etc.) Blindness Vestibulopathy Previous falls Anxiety Huntington’s disease Primary or secondary dystonia/chorea Tourette’s syndrome Pain syndromes Weakness Drug induced

Parkinsonism primary/ secondary Normal pressure hydrocephalus Primary freezing of gait Vestibular disorder Frontal gait disorders Dysautonomia

and talking such that they had to completely stop one task in order to perform the second task were at increased risk of falls, a further demonstration of the reliance of safe walking and falls on cognitive function. This idea that higher-level cognitive function is critical to walking also partially accounts for the intriguing results of prospective studies that reported impaired mobility that was not attributable to a specific disease predicts future dementia as much as 6 years into the future.26,27 If walking is a complex task that requires harmonic function of multiple brain networks, one can understand why even minor changes in locomotion reflect brain dysfunction, which may predict the future development of dementia. Furthermore, this concept suggests the possibility that interventions designed to improve cognitive function28 might enhance gait and reduce the fall risk of certain patient populations. To ensure that gait disturbances are truly minimized and that walking and safety are optimized, it is

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Figure 36–6. Effects of “dual tasking,” performance of a cognitively challenging task, on stride variability in a subject with Parkinson’s disease. Note the large stride-to-stride fluctuation and instability during dual tasking. (Adapted from Yogev G, Giladi N, Peretz C, et al: Dual tasking, gait rhythmicity, and Parkinson’s disease: which aspects of gait are attention demanding? Eur J Neurosci 2005; 22:1248-1256.)

essential to keep in mind that there is much more to gait than automated musculoskeletal movements.

Therapeutic Interventions Gait disturbances can be treated by physical therapy, exercise, and medical or surgical approaches. Many gait disorders can lead to a significant decrease in mobility in daily activities. As a result, muscle weakness stemming from the atrophy of disused muscles can further exacerbate the functional disturbance and decrease daily mobilization. The first step in any intervention designed to improve gait is to get the patients back on their feet and start walking again. This can be achieved by instructions for an individual exercise routine or by a physical therapy program. One important aspect of the intervention program should be the assessment for a need of a walking aid. A walking stick, a walker or, if nothing can keep a patient on his/her feet, a wheelchair should always be considered and used according to clinical judgment. The ultimate goal is always to give a patient the tools to mobilize himself or herself independently, but maintenance of mobilization by a wheelchair is frequently the only or preferred solution.

Rehabilitation Strategies Physical Therapy and Exercise Exercises, strength training, and gait or balance rehabilitation can help to improve the subject’s fitness and reduce the number of falls (Table 36–6). There is good evidence to suggest that a home exercise program can prevent injuries in older people.29 Because leg weakness is associated with falls in the elderly, fall prevention programs often include strength training. Balance training using Tai Chi Quan techniques may also help to reduce fall risk in this population. Gait or balance training will not cure

the underlying neurological deficits, but patients can be taught to cope better with existing mobility problems. For example, patients can learn to make safer transfers by using alternative motor strategies. Physiotherapists could also play a role in restoring balance confidence and reduce the fear of falls. Furthermore, physiotherapists can train patients to avoid hazardous activities, such as sudden changes of posture or the performance of simultaneous tasks. By training and promoting regular exercise, physical therapy can lead to improvement of general fitness and reduce cardiovascular comorbidity and mortality.30 Regular exercises also help to arrest the development or progression of osteoporosis and increase bone mass, density, and strength. When exercise, such as daily walking, is combined with oral bisphosphonates, the risk of bone fracture as the result of a fall can be decreased. Although the effects of exercise on bone strength are most prominent when initiated at a young age, beneficial effects can also be seen in elderly persons.

CUEING One of the most powerful modes of intervention to improve gait initiation and walking is the cueing technique. Despite even severe locomotion disturbances, patients (classically those with Parkinson’s disease) can walk almost normally by adopting special behavioral techniques, by being exposed to special sensory stimulations, or by using learned cognitive tricks.17 The challenge lies in enabling patients to access this ability at will and to apply it in their normal, daily function. Different cueing techniques have been used, and the population that most dramatically benefits from them are patients with Parkinson’s disease. All cueing techniques, in essence, intervene with the automatic walking brain network through behavioral sensory or cognitive techniques. The rationale behind these powerful behavioral modification techniques is that the normal locomotion network is dysfunctional and the

chapter 36 gait disturbances and falls T A B L E 36–6. Gait and Balance Rehabilitation A. Physiotherapy Exercise therapy (e.g., daily walks; home trainer) Improve cardiopulmonary fitness Prevention/arrest of: Osteoporosis Constipation Venous thrombosis Airway infections (pneumonia!) Pressure sores Contractures Improve sleep quality Increase self-respect Better feeling of control Interaction with others Split complex movements into simple components (“chaining”) Practice everyday routines Climbing stairs Transfer training Rising from chair, sitting down Getting out of bed, lying down Gait training Increase step height Practice safe turns Maneuvers to rise from floor after a fall Strength training (particularly legs) Anti-orthostatic maneuvers B. Home Visits Remove domestic hazards Training in own environment C. Treatment of Secondary Complications Reduce fear of falls Fall training* Prevention of injuries Hip or wrist protectors Protective helmets Shock-absorbing floors Restriction of unsupervised activities D. Assistive Devices Choose optimal walking aid Train proper use Replace unsafe footwear Heightened heels (to reduce backward falls) Optimize vision *For example, learning to direct the fall toward bed or chair.

cues “force” the brain to use other alternative locomotion programs by partly bypassing the primary network. Two common examples of behavioral cues are marching and climbing stairs. Lifting the knees and thinking about each step can enable a patient to walk almost normally when a regular walking pattern is impossible due to severe freezing of gait. Although stairs may pose a challenge to many older adults, patients (mainly those with Parkinson’s disease) who struggle to put together continuous steps on level ground can easily manage stair climbing. This is because the stairs act as an external cue. Another powerful external cue is rhythmic auditory stimulation, which intervenes with a deficient internal gait rhythm system. Rhythmic auditory stimulation has been shown to be very effective, not only for improving general walking but also for enhancing internal gait rhythmicity and stride-to-stride fluctuations (gait dynamics).17 When walking with rhythmic auditory stimulation, patients with Parkinson’s disease are able to match their cadence to a beat set at 10% faster than their baseline values,

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thereby significantly improving their velocity, cadence, and stride length.31-33 These improvements remained evident in the immediate short term even after the cues were removed. The fact that the improvements persisted suggests that rhythmic auditory stimulation may also provide some sort of rhythmic training mechanism. Walking on a treadmill can also be considered an external pacemaker for providing an external cue and enhancing gait.34 Another commonly used and very effective group of external cues is that of working through the visual system to set the proper stride length, thus providing external information to help augment the defective scaling motor set, which is commonly downregulated in extrapyramidal disorders.35 Placement of floor markers is one technique that can be very effective in regulating stride length and demonstrating to the patient the potential value of cues. Floor markers were reported to be effective for improving gaits of patients with Parkinson’s disease as early as 1967.36 Some studies found that these patients retained a positive “carryover” effect even after the visual cues were removed.37,38 This suggests that a certain degree of training had taken place, even with only a short exposure to the visual cues. Visual cues have also been found to be helpful in alleviating freezing of gait episodes. The cognitive tricks are all attentional cues that have been used to focus attention on walking and thus remove it from the automatic mode of action. As a clinical tool, patients with deficient internal pacing mechanisms should be taught about the different cueing options. Repeated demonstration accompanied by the appropriate integration of cueing into the daily routine may go a long way toward enhancing mobility and quality of life.

Walking Aids Promoting the use of walking aids is important. Too few elderly persons use walking aids, partly because physicians fail to recommend them and partly because many elderly persons are ashamed to revert to them. Others who do try to use a walker or wheeled rollator fail to do so properly and so give up. On the other hand, many persons who are properly instructed are very pleased with their renewed mobility and independence. A wheeled rollator is usually more effective than a frame, which is often merely carried rather than used for support. The use of well-fitting and sturdy footwear with leather soles can help to reduce accidental trips or slips. Narrow high heels must be discouraged. Persons who are prone to sustain backward falls can be prescribed adaptive footwear with slightly heightened heels to reduce retropulsion. Ankle braces can be recommended for patients who trip by “catching their toe.”

Medical Treatment Drugs can sometimes improve gait dramatically to the extent of freeing a person from the use of a wheelchair. Drugs can be given orally, parenterally (subcutaneous, intramuscular, or intravenous), or intrathecally (directly into the spinal subarachnoid space). In general, drugs that can improve gait can be subdivided into the following six categories: Antispastic drugs—to decrease spasticity. One drawback is the reduction in muscle tone, which may aggravate the supportive abilities of the legs and thereby aggravate the gait

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disorder. Another problem is that adequate relief of spasticity often calls for high dosages, which may cause some sedation: one possible solution is focal treatment with botulinum toxin. Dopaminomimetic drugs—to improve parkinsonian and hypokinetic gait disorders. In patients with Parkinson’s disease, the hypokinetic elements of gait often improve with dopaminergic medication. Freezing of gait usually occurs during OFF periods (i.e., when the antiparkinson medication has lost its efficacy), and this OFF-period freezing usually responds well to dopaminergic medication. However, less often freezing of gait is actually caused by dopaminergic medication, and this ON-period freezing improves when the dosage of antiparkinson medication is reduced. Balance impairment and falls in Parkinson’s disease are usually resistant to (and sometimes aggravated by) dopaminergic medication. Antidyskinetic drugs—to improve dystonic or choreatic gait. The same concerns mentioned for the antispastic drugs apply here as well. Neuroleptics prescribed for choreatic gait may reduce excessive involuntary movements, but this often comes at the price of increased bradykinesia (which often accompanies the chorea in patients with Huntington’s disease). Vestibular stabilization drugs—to improve vestibular disturbances associated with disequilibrium. Although these are frequently prescribed, no drug has shown convincing efficacy in properly designed studies. Psychostimulants—to improve fatigue, somnolence, and general weakness. An example of such an approach is the recent use of methylphenidate (Ritalin) in patients with Parkinson’s disease.39 Pain-relieving drugs—to improve antalgic gait. Drugs should always be prescribed with caution because of possible side effects and may paradoxically exacerbate the gait disturbance. In general, however, medical treatment should always be considered because of its significant potential therapeutic benefit.

Surgical Interventions Surgery can have a dramatic therapeutic effect in keeping patients on their feet and maintaining mobility and independence. Surgical interventions can be divided into musculoskeletal orthopedic interventions, peripheral nerve surgery, and functional surgeries at the level of the CNS.

by treating compressive neuropathies, such as by releasing entrapments or adhesions, disc herniations, and other compressive causes. As a result, muscles can become reinnervated and regain strength. Similarly, treating a cause for compression can alleviate pain, which is frequently the cause of abnormal gait. Causing loss of function is mainly used for the treatment of spasticity. Dorsal rhizotomy has been used for many years as a potential antispasticity intervention with some benefit in very resistant cases.

Functional Intervention Functional interventions at the level of the CNS can be divided into manipulation of cerebrospinal fluid flow or drainage and electrical stimulations at the level of the spinal cord or the basal ganglia. Ventriculoperitoneal or lumboperitoneal drainage (shunt) have varying and usually temporary efficacy for the treatment of gait disturbances associated with hydrocephalus. A ventriculoperitoneal shunt is commonly used for the treatment of normal pressure hydrocephalus. which classically present with the triad of gait disturbance, urinary incontinence, and cognitive decline. It is not easy to predict who will benefit from a ventriculoperitoneal shunt, but a subgroup of patients with normal pressure hydrocephalus often experience dramatic improvement that can last for years. The other functional surgical intervention is high-frequency deep-brain stimulation. This approached has recently gained much interest when it was discovered that high-frequency (60 to 185 Hz) and low-voltage (0 to 10 μA) continuous electrical stimulation of the internal globus pallidum or the subthalamic nucleus via deeply implanted electrodes can significantly improve parkinsonian and dystonic gait. This approach is now under investigation and, in the future, electrodes might be implanted at the human locomotion network/center for further intervention in the locomotion network.

SUMMARY Gait disturbances and falls are commonplace and debilitating. Identification of the underlying causes and the recommendation of appropriate interventions may help patients regain mobility abilities, a key to independence.

K E Y ●

Gait disturbances and falls are commonplace and debilitating. Identification of the underlying causes and the recommendation of appropriate interventions may help patients regain mobility abilities, a key to independence.

●

Musculoskeletal and cardiovascular support systems, along with visual, vestibular, and proprioceptive senses, are required to stand, maintain balance, and walk while interacting with the environment.

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For any patient presenting with falls, the first thing to do is to clarify the circumstances surrounding the fall and, in particular, to identify any specific pattern, because this may reveal the underlying pathophysiology and offer opportunities for prevention.

Peripheral Surgical Interventions Orthopedic interventions are made at the levels of the feet, ankle, knee, hip, and spine for improvement of joint or spine position and to improve function while walking. The classic surgeries are those for children with cerebral palsy or chronic joint diseases. Tendon transfer or elongations, replacement of joints, and discectomies with spine stabilization have been used for many years and can preserve a person’s ability to walk. Similarly, stabilization of unstable joints can improve stabilization and balance to the degree of regaining secure mobility. Peripheral nerves can be manipulated surgically for gain of function or loss of function. Gain of function can be achieved

P O I N T S

chapter 36 gait disturbances and falls Suggested Reading Bloem BR, Visser JE, Allum JH: Posturography. In Hallett M, ed: Handbook of Clinical Neurophysiology. Amsterdam: Elsevier Science BV, 2003, pp 295-336. Emere M, Aarsland D, Albanese A, et al: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509-2518. Herman T, Giladi N, Gurevich T, et al: Gait instability and fractal dynamics of older adults with a “cautious” gait: why do certain older adults walk fearfully? Gait Posture 2005; 21:178185. Nutt JG, Carter JH, Sexton GJ: The dopamine transporter: importance in Parkinson’s disease. Ann Neurol 2004 ;55:766773.

References 1. Wannier T, Bastiaanse C, Colombo G, et al: Arm to leg coordination in humans during walking, creeping and swimming activities. Exp Brain Res 2001; 141:375-379. 2. Pahapill PA, Lozano AM: The pedunculopontine nucleus and Parkinson’s disease. Brain 2000; 123:1767-1783. 3. Alexander NB: Clinical evaluation of gait disorders: no-tech and low-tech. In Hausdorff JM, Alexander NB, eds: Evaluation and Management of Gait Disorders. New York: Marcel Dekker Inc, 2005. 4. Bloem BR, Visser JE, Allum JH: Posturography. In Hallett M, ed: Handbook of clinical neurophysiology. Amsterdam: Elsevier Science BV, 2003, pp 295-336. 5. Giladi N, Shabtai H, Simon ES, et al: Construction of Freezing of Gait Questionnaire for patients with parkinsonism. Parkinson Relat D 2000; 6:165-170. 6. Tinetti ME: Clinical practice. Preventing falls in elderly persons. N Engl J Med 2003; 348:42-49. 7. Podsiadlo D, Richardson S: The timed “Up & Go:” a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991; 39:142-148. 8. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopedic Surgeons Panel on Falls Prevention: Guideline for the prevention of falls in older persons. J Am Geriatr Soc 2001; 49:664-672. 9. Tinetti ME: Performance-oriented assessment of mobility problems in elderly persons. J Am Geriatr Soc 1986; 34:119126. 10. Hausdorff JM, Cudkowicz M, Firtion R, et al: Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson’s disease and Huntington’s disease. Mov Disord 1997; 13:428-437. 11. Herman T, Giladi N, Gurevich T, et al: Gait instability and fractal dynamics of older adults with a “cautious” gait: why do certain older adults walk fearfully? Gait Posture 2005; 21:178185. 12. Nakamura T, Meguro K, Sasaki H: Relationship between falls and stride length variability in senile dementia of the Alzheimer type. Gerontology 1996; 42:108-113. 13. Hausdorff JM, Schaafsma JD, Balash Y, et al: Impaired regulation of stride variability in Parkinson’s disease subjects with freezing of gait. Exp Brain Res 2003;149:187194. 14. Hausdorff JM, Rios D, Edelberg HK: Gait variability and fall risk in community-living older adults: a 1-year prospective study. Arch Phys Med Rehabil 2001; 82:1050-1056. 15. Nutt JG, Marsden CD, Thompson PD: Human walking and higher-level gait disorders, particularly in the elderly. Neurology 1993; 43:268-279.

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16. Giladi N, Herman T, Rieder I, et al: Clinical characteristics of the idiopathic gait disorders of the elderly: evidence suggestive of a distinct neurodegenerative syndrome. J Neurol 2005; 252:300-306. 17. Rubenstein TC, Giladi N, Hausdorff JM: The power of cueing to circumvent dopamine deficits: a review of physical therapy treatment of gait disturbances in Parkinson’s disease. Mov Disord 2002; 17:1148-1160. 18. Woollacott M, Shumway-Cook A: Attention and the control of posture and view of an emerging area of research. Gait Posture 2002; 16:1-14. 19. Shumway-Cook A, Brauer S, et al: Predicting the probability for falls in community-dwelling older adults using the timed Get Up and Go test. Phys Ther 2000; 80:896-903. 20. Bloem BR, Valkenburg VV, Slabbekoorn M, et al: The multiple tasks test. Strategies in Parkinson’s disease. Exp. Brain Res 2001; 137:478-486. 21. Sheridan PL, Solomont J, Kowall N, et al: Influence of executive function on locomotor function: divided attention increases gait variability in Alzheimer’s disease. J Am Geriatr Soc 2003; 51:1633-1637. 22. Yogev G, Giladi N, Peretz C, et al: Dual tasking, gait rhythmicity, and Parkinson’s disease: which aspects of gait are attention demanding? Eur J Neurosci 2005; 22:1248-1256. 23. Hausdorff J M, Balash J, Giladi N: Effects of cognitive challenge on gait variability in patients with Parkinson’s disease. J Geriatr Psychol Neurol 2003; 16:53-58. 24. Shaw FE, Bond J, Richardson DA, et al: Multifactorial intervention after a fall in older people with cognitive impairment and dementia presenting to the accident and emergency department: randomised controlled trial. BMJ 2003; 326: 73. 25. Lundin-Olsson L, Nyberg L, et al: “Stops walking when talking” as a predictor of falls in elderly people. Lancet 1997; 349:617. 26. Verghese J, Lipton RB, Hall CB, et al: Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med 2002; 347:1761-1768. 27. Marquis S, Moore MM, Howieson DB, et al: Independent predictors of cognitive decline in healthy elderly persons. Arch Neurol 2002; 59:601-606. 28. Emere M, Aarsland D, Albanese A, et al: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509-2518. 29. Robertson MC, Campbell AJ, Gardner MM, et al: Preventing injuries in older people by preventing falls: a metaanalysis of individual-level data. J Am Geriatr Soc 2002; 50:905-911. 30. Hakim AA, Petrovitch H, Burchfiel CM, et al: Effects of walking on mortality among nonsmoking retired men. N Engl J Med 1998; 338:94-99. 31. Cunnington R, Iansek R, Bradshaw J, et al: Movementrelated potentials in Parkinson’s disease: presence and predictability of temporal and spatial cues. Brain 1995; 118: 935-950. 32. McIntosh GC, Brown SH, Rice RR, et al: Rhythmic auditorymotor facilitation of gait patterns in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 62:22-26. 33. McIntosh G, Thaut M, Rice R, et al: Stride frequency modulation in Parkinsonian gait using rhythmic auditory stimulation. Ann Neurol 1994; 36:316. 34. Frenkel-Toledo S, Giladi N, Peretz C, et al: Treadmill walking as an external cue to improve gait rhythm and stability in Parkinson’s disease. Mov Disord 2005; 20:1109-1114. 35. Morris ME, Iansek R, Matyas TA, et al: Ability to modulate walking cadence remains intact in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1994; 57:1532-1534.

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36. Stern GM, Lander CM, Lees AJ. Akinetic freezing and trick movements in Parkinson’s disease. J Neural Transm Suppl 1980; 16:137-141. 37. Morris ME, Iansek R, Matyas TA, et al: Stride length regulation in Parkinson’s disease. Normalization strategies and underlying mechanisms. Brain 1996; 119:551-568.

38. Bagley S, Kelly B, Tunnicliffe N, et al: The effect of visual cues on the gait of independently mobile Parkinson’s disease patients. Physiotherapy 1991; 77:415-420. 39. Nutt JG, Carter JH, Sexton GJ: The dopamine transporter: importance in Parkinson’s disease. Ann Neurol 2004; 55:766773.

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37

RESTLESS LEGS SYNDROME ●

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Wolfgang H. Oertel and Karin Stiasny-Kolster

Restless legs syndrome (RLS) is the most common neurological sleep disorder. It was first described in 1672 and was rediscovered in 1945 by K. A. Ekbom,1 who extensively studied this disorder and contributed important findings that are still relevant today. Major advances in the clinical definition of RLS, in understanding the basic mechanisms, the discovery of genetic factors, and the successful treatments of RLS have increased medical attention in the field of neurology. However, awareness of the disorder among general physicians is still low, despite its high prevalence and significant morbidity. RLS is often misdiagnosed, underdiagnosed, or undiagnosed. One survey showed that the rate of correct diagnosis of RLS by general physicians is less than 7% of that of correct diagnosis by specialists. Even when diagnosed, RLS is often not appropriately treated.2 However, the prevalence of individuals whose symptoms of RLS are sufficiently severe for them to seek medical advice is estimated at approximately 3% of general practice populations.2 Increased awareness will improve the rate of recognition and treatment of RLS, which most often dramatically improves patients’ lives.

CLINICAL FEATURES AND DEFINITION OF RESTLESS LEGS SYNDROME RLS is a distressing neurological sensorimotor disorder characterized by an almost irresistible urge to move the limbs that is most often but not necessarily accompanied by uncomfortable sensations in the legs. RLS symptoms are evoked by rest, such as lying down or sitting, and are worse in the evening or night. Patients describe the sensations, most commonly deep in the legs, as “creepy-crawly,” “like an electric current,” “pulling,” “tearing,” “itching bones,” “aching,” or “throbbing.” Because the symptoms are unfamiliar, patients often find them extremely difficult to describe. The regions between the knees and the ankles are especially affected, whereas the feet are frequently spared. In response to the discomfort, patients often rub or stretch and flex their legs, turn in bed, or pace the floor, because passive or active movement characteristically provides temporary relief. The arms may also be involved, particularly in patients with severe RLS. Because the symptoms of RLS occur predominantly in the evening or during the night, RLS has a significant effect on sleep, and patients often present with a sleep problem. In addition to difficulty initiating sleep, many

patients with RLS have problems maintaining sleep, with frequent awakenings or short arousals that result in poor sleep efficiency. Patients with moderate to severe RLS may sleep on average less than 5 hours per night and may chronically have less sleep time than do patients with almost any other persistent disorder of sleep.3 In many patients with RLS, quality of life is poor, and these patients are at increased risk for depressive and anxiety disorders.4,5 Approximately 80% to 90% of the patients with RLS have associated nocturnal, involuntary periodic limb movements (PLMs)—during sleep (PLMSs) or during wakefulness (PLMWs)—which are usually present in the legs.6 PLMs are mostly rhythmic extensions of the big toe and dorsiflexion of the ankle that resemble the Babinski reflex, with occasional flexion of the knee and hip.7 Movements are often bilateral, involving both legs, but may be predominant in one leg or alternate between legs. The quantification of PLMs is routinely performed in the sleep laboratory by recording both anterior tibialis muscles with surface electrodes. Polysomnographic recordings show that they tend to occur every 20 to 40 seconds and are frequently associated with arousals or complete awakenings. Thus, PLMs further contribute to sleep fragmentation, especially in advanced cases in which the PLMS arousal index (number of PLMS-associated arousals per hour total sleep time) may be very high. PLMs may be assumed if bed partners of patients with RLS report nocturnal kicking of the leg or sometimes if patients themselves experience involuntary jerks of the legs while lying in bed.

EPIDEMIOLOGY Well-performed epidemiological studies have concordantly shown that the prevalence of RLS in the general population is between 5% and 10%8-13 and that RLS prevalence is higher in women with more births.2,9,12-15 In addition, one study showed that the frequency of RLS in women increases by the number of births.13 The time of onset varies between early childhood and 80 years of age or even older. In retrospective surveys, 23%16 and 13%6 of adult patients with RLS reported the onset of RLS before the age of 10 and 25% between 10 and 20 years.6,16 Although valid data about the prevalence of RLS in adults exist, respective data for the adolescent population or children are lacking. However, existing data suggest that RLS and sleep disturbances caused by RLS are a frequent but undiagnosed

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problem in this younger age group. RLS varies in severity, and the prevalence of adults in a general practice population whose RLS is severe enough to seek medical advice has been shown to be about 3.4%.2 Despite the prevalence, there is a lack of awareness of RLS among health care providers. One epidemiological study showed that only 12.9% of cases were accurately diagnosed by the general practitioner, although patients explicitly reported their symptoms. The rate of correct diagnosis of RLS by general practitioners is less than 7% that by specialists. Even when diagnosed, RLS is often not appropriately treated.2

Primary Restless Legs Syndrome Most affected individuals suffer from primary RLS, which shows a familial association in more than 50% of cases.17-19 Patients with familial RLS have an earlier onset of symptoms than do those suffering from the sporadic type, and the progression is slower. The relevant age at onset of the disease at which to subdivide patients with RLS into early- and late-onset groups remains to be investigated. One study revealed that patients who were younger than 45 years at onset have a greater probability of having an affected first-degree relative than do those who were older than 45 years at onset.20 In another study, earlyonset RLS (with onset at younger than 30 years) has been found to be genetically different from late-onset RLS: In early-onset RLS, it was suggested that a major gene is segregating in an autosomal dominant mode of inheritance with an additional multifactorial component.19 Genome-wide studies have been conducted to map genes that play a role in the vulnerability to RLS. So far, linkage was found to a chromosomal locus on 12q,21 which was not confirmed in four other families; on 14q,22 which was replicated in one family23; and on 9p.24 Inspection of huge pedigrees indicates anticipation and variable penetrance.25,26 Investigations of candidate gene coding for receptors and enzymes related to dopaminergic transmission27,28 revealed no differences in the genotypic or allelic distributions between RLS and control subjects.

with attention deficit/hyperactivity disorder may have PLMS or in fact suffer from RLS.43-45

PATHOPHYSIOLOGY Although RLS pathophysiology is still unknown, knowledge about it has developed significantly, which has led to diverse hypotheses.46 The medication responses indicate that RLS results from abnormal functioning in the nervous system.47 Overall, the central nervous system areas involved in RLS pathophysiology are unknown, and the role of the peripheral nervous system, if any, is uncertain.48 Several studies have provided evidence that RLS is associated with peripheral neuropathy; therefore, it is possible that peripheral nerve lesions are a trigger for RLS.

Dopaminergic Function in Restless Legs Syndrome Dopaminergic mechanisms are supposed to play an important role, particularly inasmuch as dopaminergic drugs have shown to be especially beneficial in RLS. In addition, the circadian manifestation of RLS symptoms coincides with lower levels of central dopamine activity.49 However, several investigations, including positron emission tomography and single photon emission computed tomography studies of the dopaminergic nigrostriatal system,50 cerebrospinal fluid analysis of dopaminergic metabolites,51,52 and even histopathological studies, have not provided evidence of a primary dopaminergic deficit or neurodegeneration in the basal ganglia53 that favors a functional impairment or a modulating effect of the dopaminergic system. The fact that melatonin secretion, which is increased at night, is correlated with the severity of RLS symptoms54 supports the dopamine hypothesis, inasmuch as melatonin exerts an inhibitory effect on central dopamine secretion. Daytime and nighttime melatonin excretion per se is normal in patients with RLS.55

Iron Metabolism in Restless Legs Syndrome Secondary Restless Legs Syndrome Although most RLS cases may be idiopathic, RLS is often linked to other medical or neurological disorders. The most important associations of RLS are with end-stage renal disease29,30 and with iron deficiency.31,32 RLS may also develop during pregnancy33,34 or may intensify after treatment with various drugs. In many reports, RLS has been linked to dopamine antagonists, such as typical and atypical neuroleptics and metoclopramide, or to antidepressants, such as tricyclic and tetracyclic antidepressants, serotonin reuptake inhibitors, and lithium. Although supporting data are limited, peripheral neuropathies, such as axonal neuropathy,35 cryoglobulinemic neuropathy,36 familial amyloid polyneuropathy,37 Charcot-Marie-Tooth disease type 2,38 and small-fiber neuropathies39 may be associated with RLS. Because the prevalence of RLS among patients with peripheral polyneuropathies has been shown to be only 5.2%40 and thus does not exceed that in the general population, this association is of unclear significance. Other neurological diseases that have been reported to be linked with RLS are radiculopathies41 and myelopathies, such as multiple sclerosis or syringomyelia.42 It has also been shown that some children who were diagnosed

A strong negative correlation between serum ferritin levels and RLS severity,31,32 the therapeutic effect of iron in RLS,56 the reduction of iron in the substantia nigra as shown by magnetic resonance imaging,57 and reduced cerebrospinal fluid ferritin levels and increased cerebrospinal fluid transferrin levels58 in patients with RLS indicate that an impaired iron metabolism may be another important factor in the pathophysiology of RLS. Neuropathological investigations have shown that iron and heavy-ferritin staining was markedly decreased (and lightferritin staining was strong) in the substantia nigra. In addition, transferrin receptor staining on neuromelanin-containing cells was decreased in brains of patients with RLS, whereas transferrin staining in these cells was increased.59 These data suggest that iron acquisition is compromised in neuromelanin cells, which may interfere with dopaminergic mechanisms.

Role of the Nociceptive System Stiasny-Kolster and colleagues (2004)60 showed that the nociceptive system is involved in RLS pathophysiology. Patients with RLS exhibited a profound static mechanical hyperalgesia

chapter 37 restless legs syndrome in response to punctate stimuli. This type of hyperalgesia improved significantly after long-term treatment with dopaminergic drugs. These findings suggests that RLS may be associated with central sensitization of spinal neurons, such as that in chronic neuropathic pain resulting from abnormal peripheral input and/or from altered descending inhibition (i.e., involving the supraspinal dopaminergic system). Thus, in addition to being a motor and sleep disorder, RLS may also be a pain disorder. These findings may also explain why substances that are well accepted for the treatment of neuropathic pain, such as opioids or anticonvulsants, alleviate RLS symptoms.

Localization of the Dysfunction Regardless of the neurotransmitter systems and neurophysiological mechanisms involved in RLS pathophysiology, the site of the underlying neurological alteration is still unclear. Cortical involvement was previously considered unlikely because of the absence of cortical activity in functional magnetic resonance imaging (fMRI) studies and the absence of a Bereitschaftspotential61 associated with the involuntary movements in RLS. Spectral power analysis of electroencephalographic studies, however, provides evidence that characteristic involuntary leg movements in RLS are preceded by a preparatory cortical activation. In addition, several neurophysiological studies with single or paired pulse stimulation showed a reduced intracortical inhibition62 and a shortened cortical silent period in patients with RLS.63,64 This cortical disinhibition may result from a shift in the balance of excitatory and inhibitory mechanisms toward either more excitability or less inhibition (e.g., as a result of increased sensory input or impaired subcortical mechanisms). Interestingly, levodopa (Ldopa) leads to a prolongation of the silent period and thus to an improvement of impaired inhibitory mechanisms.64 Some studies have suggested the involvement of subcortical areas in RLS pathophysiology. Lesions in the dopaminergic diencephalospinal tract (A11 neurons) have been proposed as an animal model for RLS65 and are discussed as potential underlying cause of RLS in humans.66 The effects of acute dopaminergic treatment on RLS symptoms and long-term dopaminergic treatment on static mechanical hyperalgesia support this suggestion. Thus, the dopaminergic system is either directly or indirectly involved in the central sensitization in RLS.60 The only fMRI investigations in patients with RLS conducted so far67 revealed a bilateral activation of the cerebellum and a contralateral activation of the thalamus during sensory symptoms. During the occurrence of PLMs and sensory symptoms, the patients showed additional activation in the red nuclei and brainstem close to the reticular formation. These results support aforementioned neurophysiological studies that suggested that subcortical cerebral generators are involved in the pathogenesis of RLS. During the combined condition (PLMs and sensory symptoms), the activation was still larger in the cerebellum than during each condition alone, which points to a neuronal participation of the cerebellum in the motor and sensory process as well. This finding is in agreement that in healthy subjects, the cerebellum is involved in sensory processing. When the distribution of the fMRI-activated cerebellar areas (subcortical in both hemispheres) were compared with histological autoradiographical studies of the human cerebellum, a similar distribution of opioid μ receptors could be detected. Thus, the cerebellum could be another possible site

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of interaction of opioidergic agents. The spinal cord may also play a major role in the pathophysiology of RLS. Patients with spinal cord lesions, particularly those with transsection of the spinal cord, often have PLMs, which suggests that PLMs are generated in the spinal cord.68-71 In these cases, however, the number of PLMs is lower and the circadian rhythmicity and the response to dopaminergic agents are less pronounced than in patients with RLS.69,72,73 Flexor reflex studies showed an increased spinal cord excitability during sleep in patients with RLS, which indicates that signal processing in the spinal cord is altered. In addition, the presence of mechanical hyperalgesia in RLS indicates central sensitization of spinal neurons. However, the central sensitization in RLS may also be based on afferent input–induced plasticity of spinal nociceptive transmission,74 and long-standing abnormal peripheral input may explain various kinds of secondary RLS: for example, RLS triggered by polyneuropathies. Thus, it is conceivable that at least in a subgroup of patients with RLS, peripheral lesions may represent a pathophysiological factor for the development or aggravation of RLS.

DIAGNOSTIC CRITERIA FOR RESTLESS LEGS SYNDROME RLS is a clinical diagnosis that relies entirely on the patient’s symptoms. According to international diagnostic criteria75 (Walters, 1995) and a consensus established by the International Restless Legs Syndrome Study Group76 (Allen et al, 2003) RLS is characterized by four essential criteria (Table 37–1). To make a definite diagnosis of RLS, all four diagnostic criteria must be established. In some cases, these criteria may be inadequate for ruling out conditions mimicking RLS, such as peripheral neuropathy, leg cramps, positional discomfort, or parkinsonian symptoms, inasmuch as these conditions may sometimes lead to positive answers referring to different problems. If these features are comorbid with RLS, it can, in turn, also be difficult to recognize RLS. The following supportive features that are not necessary to make the diagnosis RLS but may, especially in doubtful cases, help to diagnose or exclude RLS have been established.76

T A B L E 37–1. Essential Diagnostic Criteria of the International Restless Legs Syndrome Study Group An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (sometimes the urge to move is present without the uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs) The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues The urge to move or unpleasant sensations are worse in the evening or night than during the day or occur only in the evening or at night (when symptoms are very severe, the worsening at night may not be noticeable but must have been previously present) From Allen R, Picchietti D, Hening WA, et al: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from The Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health. Sleep Med 2003; 4:101-119.

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Positive Family History A positive family history is present in more than 50% of patients with RLS. The prevalence of RLS among first-degree relatives of people with RLS is three to five times greater than in people without RLS.

Positive Response to Dopaminergic Treatment Several controlled studies have shown that most patients with RLS have a positive therapeutic response to dopaminergic drugs. According to clinical experience, more than 90% of patients report some relief of their symptoms when treated with these agents.

Periodic Limb Movements in Sleep PLMSs are reported to occur in 80% to 90% of patients with RLS. However, PLMS also commonly occur in other disorders and in the elderly. A PLMS index (number of PLMSs per hour of sleep) of greater than 5 is considered pathological, although data supporting this feature are very limited. The occurrence of PLMs during nocturnal periods of wakefulness (PLMW) is considered to be more specific for RLS.77 Thus, the presence of a high number of PLMs is supportive for RLS, but the absence of PLMs does not exclude RLS. In addition to the essential and supportive criteria, the natural clinical course, the presence and character of sleep disturbances, and the physical examination findings are other features that may be helpful for diagnosis of RLS.76

Natural Clinical Course RLS is usually a chronic disease, and symptoms typically increase over time. As mentioned, the age at onset of RLS varies widely, from childhood to 80 years of age and even older. Patients with early-onset RLS are more likely to have affected family members than are those with late-onset RLS.19 When RLS symptoms appear at a young age, the onset is more often insidious. RLS symptoms may be present intermittently for many years with fluctuating severity. Initially, mild RLS may occur in single nights, sometimes with or without sleep disturbances, or in aggravating situations during the day, such as during a long overseas flight. There may be long periods of remission, but the severity and frequency typically increase over time. Many patients with RLS experience their RLS as nightly events with difficulty falling asleep and several awakenings with walking around or other actions that may lead to temporary relief, such as taking a cold foot bath. Other patients progress to daily symptoms within several years. Many of these patients have disease onset in late adult life and have secondary RLS. The natural clinical course may be influenced by the development of augmentation as a result of medication side effects (see following discussion).

Sleep Disturbances Because of the nocturnal appearance of the disease, sleep disturbances caused by RLS are very frequent. In some patients, sleep is already affected in the very beginning, during single

nights when RLS symptoms show up occasionally. In others, sleep disturbances develop when RLS severity increases to a certain degree. In RLS, the underlying alerting motor activity and, even more, the methods to relieve sensory and motor symptoms of RLS interfere with the conditions needed to initiate sleep. This applies not only for the start of sleep but also for the time after an awakening that is caused mostly by PLMS. Prolonged sleep onset and several awakenings with brief or agonizing periods of wakefulness caused by RLS symptoms often result in reduced total sleep time and poor sleep efficiency. In addition, numerous PLMS associated with short-lasting arousals frequently contribute to a fragmented and unrestorative sleep. The number of PLMS arousals or PLMWs rather than the PLMSs, which does not necessarily indicate an interference with sleep, may be considered as an indicator for the severity of RLS. For patients with mild RLS, sleep disturbances may be less of a problem.

Medical Examination The physical examination and medical evaluation findings are generally normal and do not contribute to the diagnosis except for conditions that may be comorbid or secondary forms, such as end-stage renal disease, pregnancy, and iron deficiency. The presence of peripheral neuropathy, radiculopathy, or myelopathy should be determined because these conditions have a possible, although uncertain, association and may necessitate different treatment.

EVALUATION OF RESTLESS LEGS SYNDROME Medical History When a patient meets the four essential diagnostic criteria and when mimicking conditions can be ruled out, the evaluation of RLS (Table 37–2) is minimal. In any case, however, a thorough medical history should be obtained with special attention to the time course, the appearance of symptoms during the 24-hour day, type and severity of sleep disturbances, and daytime vigilance. An atypical course of the disease with an abrupt onset and daily symptoms from the beginning may be suggestive of secondary forms of RLS. The time of RLS symptom onset during the day is important to know because medication intake should be individually tailored. Patients in whom severe RLS symptoms are already present in the late afternoon must take medication earlier than do patients with late-evening symp-

T A B L E 37–2.

Evaluation of Restless Legs Syndrome

Basic Evaluation Medical history, including sleep history, family history, drug history General medical and neurological examination Measurement of serum iron and ferritin Other Studies Sometimes Necessary Electrophysiological studies Cardiorespiratory polysomnography (with electromyography of both tibialis anterior muscles) Levodopa test

chapter 37 restless legs syndrome toms. Patients with problems initiating sleep may require other medication or another time of medication intake, in comparison with those who have problems maintaining sleep. It is also important to figure out why a patient’s sleep is disturbed. Even if RLS symptoms are adequately treated, sleep disturbances may remain if back pain or depression additionally interferes with sleep. A careful drug history should detect substances that may aggravate RLS or sleep disturbances. Thus, it is worthwhile to invest some time in a detailed history, particularly in the initial contact with an RLS patient.

Blood Tests When evaluating patients with RLS, the clinician must look for factors that may exacerbate symptoms of RLS, because these may alter the treatment plan or make effective treatment more difficult to establish. With regard to laboratory findings, not only low iron but also low-normal serum ferritin levels (<50 μg/L) have been related to increased severity of RLS and may be associated with an increased risk of RLS even in patients with normal hemoglobin levels.31,32 Therefore, evaluation of serum iron and ferritin levels is strongly recommended as part of the medical evaluation for RLS, because these patients may benefit from iron supplements. When iron therapy is initiated, patients need to be routinely monitored to check the response to iron and to avoid iron overload. The iron storage disease hemochromatosis, which can coexist with RLS, requires special attention because it would be aggravated by iron supplementation.51,78 Other blood tests should be conducted, depending on the clinician’s reasonable suspicion, although it should be clear that patients are not in renal failure.

Electrophysiological Studies Nerve conduction studies or electromyography (EMG) may be necessary if peripheral neuropathy is suspected. If peripheral neuropathy exists, it has to be determined by an even more detailed history and possibly by further tests (e.g., L-dopa test, polysomnography) if it is comorbid with RLS or if the complaints are completely explained by the peripheral neuropathy and RLS does not even exist. Although symptoms of peripheral neuropathy are usually present throughout the day, they may increase or are experienced as more intense at night. However, complete and persistent relief while walking is rarely obtained in peripheral neuropathy. The report of frequent involuntary movements in resting positions during the day (indicative of PLMW) may be a hint for a marginal affection of the spinal cord even if neurological examination findings are unremarkable. In these cases, transcranial magnetic stimulation studies with assessment of the central motor conduction time is recommended.

Polysomnographic Recordings Sleep studies may be helpful in uncertain or complicated cases and if another sleep disorder such as sleep apnea is suspected. The presence of PLMs and, even more, of PLMSs associated with arousals supports the diagnosis of RLS.77 However, for the interpretation of polysomnographic recordings, it is important to consider that not all patients with RLS have PLM, that the

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presence and frequency of PLMs varies between nights, and that even patients with advanced RLS may have nights with nearly undisturbed sleep. Thus, the absence of PLMs does not preclude RLS. In addition, PLMSs can occur in a variety of disorders or even in normal individuals and are not specific for RLS. In the majority of these cases, however, PLMs are less frequent and less often associated with arousals. Although a higher number of PLMs are sometimes detected in sleep apnea, the arousals are caused mostly by the respiratory event. A sensitive technique must be used to monitor breathing during polysomnography, such as pressure transducer airflow monitoring or esophageal manometry, to reasonably rule out sleep-disordered breathing as the direct cause of the PLMSs.79 When PLMSs are independently present in a patient with sleep-disordered breathing and without a history of RLS, then a separate diagnosis of periodic limb movement disorder (PLMD) may be considered if the PLMSs are still seen with adequate continuous positive airway pressure and if clinical sleep-wake disturbance that is not otherwise explained remains. In RLS, the number of PLMS arousals may be considered as a marker for the severity of the disease, which can be used for monitoring treatment effects. In general, polysomnographic recordings should be performed without drugs known to either suppress PLMs (e.g., dopaminergic drugs, opioids, anticonvulsants, benzodiazepines) or enhance PLMs (e.g., neuroleptics, antidepressants). Withdrawal of such medication, however, is often not possible and may also lead to a PLM rebound. In these cases, the significance of polysomnography is limited. Polysomnography during treatment may be helpful for optimizing therapy, for determining the reason for nonresponse, or if other sleep disturbances are suspected. PLMs can also be detected with actigraphic monitoring. Accelerometers that record movements and not electrical potentials, as in EMG, are generally placed on the ankle or foot. In comparison of technologies, it remains uncertain whether the more important phenomenon is the electrical potential or the actual movement. It has been suggested that EMG can overcount PLMs by counting potentials that do not result in any appreciable movement. The disadvantage of actigraphy is that it provides less or no information about the context of movements to sleep and sleep-related respiratory disturbances. For differential diagnosis, PLMs can be examined not only during polysomnography but also in a provocative test called the suggested immobilization test.77,80 In this test, the subject is asked to sit quietly, typically for an hour, while leg movements, usually determined by EMG and subjective complaints, are monitored. Most patients with RLS experience greater sensory discomfort than do normal persons and have a fair number of movements, which fulfill criteria for PLMWs.80 A combination of increased discomfort during the suggested immobilization test and PLMWs during polysomnography (using optimal thresholds) has been reported to provide a better discrimination from control subjects than does any single measure, with a sensitivity of 82% and a specificity of 100%.80

Levodopa Test The response to a single oral dose of L-dopa can be used in clinical practice to support the diagnosis RLS. This is of particular value in untreated patients, in patients in whom the initial

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therapeutic effect of dopaminergic substances is not reliably assessable (e.g., dosage unknown, inappropriate time of drug intake, no accurate statement from the patient), and particularly in patients with mild RLS in whom polysomnography frequently fails to detect PLMs. A combined dose of 100 mg of L-dopa with 25 mg of dopa decarboxylase inhibitor is taken after onset of the leg symptoms, independently of the time of day. The severity of the symptoms in the legs is rated by the patient before medication intake and afterwards for a period of about 1 to 2 hours on a visual analog scale (0 = no symptoms to 100 = very severe symptoms). A positive test result is defined as a 50% improvement at any time within 2 hours after administration. The L-dopa test has a sensitivity of 88% and a specificity of 100%; this means that 88% of patients with RLS have a positive test result (>50% improvement) and that all patients with leg symptoms that are not caused by RLS, such as peripheral neuropathy, have a negative test result (<50% improvement) with L-dopa. On the basis of this 50% cutoff criterion, 90% of cases can be correctly diagnosed with the L-dopa test. However, a negative test result, defined as less than 50% improvement, does not preclude RLS, inasmuch as some patients report only mild improvement with 100 mg of L-dopa. Complete nonresponse, particularly in hitherto untreated patients, strongly argues against RLS (Stiasny-Kolster et al).81

Severity Assessment The severity of RLS may be quantified by the validated 10-item International Restless Legs Syndrome Study Group Rating Scale (IRLS) (Fig. 37–1)82 (International Restless Legs Syndrome Study Group, 2003) or the RLS-6 rating scales (Fig. 37–2).83 These scales are used in treatment trials to assess the therapeutic efficacy of drugs referring to the severity of RLS symptoms and sleep disturbances. The IRLS additionally addresses the frequency of RLS symptoms and the effect of RLS on quality of life. Both scales are easy to use in clinical practice.

DIFFERENTIAL DIAGNOSIS OF RESTLESS LEGS SYNDROME Various conditions that may be similar to RLS need to be considered in the differential diagnosis (Table 37–3). However, most of them do not fulfill all four essential criteria for RLS or

T A B L E 37–3. Legs Syndrome

Differential Diagnosis of Restless

Nocturnal cramps Peripheral neuropathy, especially small-fiber neuropathy Painful legs and moving toes Myelopathy (spinal cord compression, spinal vascular malformation) Chronic pain disorders Positional discomfort or ischemia Habitual limb shaking Arthritic, muscular, or vascular disorders Nonspecific restlessness Neuroleptic-induced akathisia Depression with somatic symptoms Periodic limb movement disorder Sensorimotor symptoms of Parkinson’s disease

do not have a circadian variation with nocturnal accentuation. Restriction to rest may also be absent, and relief with movement may be either not present or only temporary with continued movement. Nocturnal leg cramps and polyneuropathy may meet all four diagnostic criteria of RLS. Nocturnal leg cramps are often unifocal; are associated with a contracted, indurated muscle; often occur in single attacks with subsequent relief; and are usually extremely painful. In peripheral neuropathy, particularly in small-fiber neuropathy, symptoms may be noticed more intensely in resting positions in the evening or during the night and may be experienced less with movement. However, these symptoms usually include the feet and are persistently present from the beginning, being mild initially and gradually increase in severity over time. Complete relief of pronounced symptoms is almost never reported. Peripheral neuropathy and sometimes somatic features of depression may be most difficult to delimit. Of course, it is possible that RLS could coexist with any mimicking conditions. Therefore, the presence of a mimicking disorder does not necessarily rule out RLS. Patients with PLMD have sleep fragmentation caused by PLM and consecutively have complaints of daytime sleepiness. To diagnose PLMD other causes of PLMS or associated disorders such as sleep apnea syndrome or RLS have to be ruled out. Sensory complaints and akathisia are fairly common in Parkinson’s disease,84 and lower limb restlessness may accompany wearing-off episodes in patients with motor fluctuations, thus mimicking RLS.85

TREATMENT Nonpharmacological treatment consists of good sleep hygiene. Patients should be advised to avoid caffeine, alcohol, and heavy meals before going to bed. Bedtime hours should be regular and activity gradually reduced in the evening. Patients should sleep in a bedroom that should be used only for sleep or intimacy and not for watching television. In a next step, secondary causes of RLS should be excluded and/or associated disorders be primarily treated. The clinician should consider whether antidepressants, neuroleptic agents, or dopamine-blocking antiemetics such as metoclopramide may be contributing and whether discontinuation is possible without causing the patient harm. Successful kidney transplantation may lead to a complete remission in patients with RLS with renal insufficiency.17,86 Complete loss of all RLS symptoms in affected pregnant women after delivery is also frequently observed.33,87,88 The most important underlying cause may be iron deficiency. Iron supplementation has been shown to improve RLS in patients with iron deficiency31 but not in patients with normal iron levels.89 A common regimen is 325 mg of ferrous sulfate three times a day in combination with 100 to 200 mg of vitamin C with each dose to enhance absorption. Oral iron therapy can cause obstipation and abdominal discomfort, and the dosage may need to be reduced in some patients. Iron tablets are ideally taken on an empty stomach to enhance absorption, but if gastrointestinal symptoms develop, they should be taken with food. Iron should not be prescribed empirically because it may result in iron overload. Magnesium supplements may be beneficial in patients with mild RLS.90 Taking 12.4 mmol of magnesium in the evening has been shown to be beneficial in patients with a postulated magnesium deficiency in an open trial.91 There are no Text continued on p. 48.

chapter 37 restless legs syndrome

International Restless Legs Syndrome (IRLS) Study Group Rating Scale (Investigator Version 2.2)

Have the patient rate his/her symptoms for the following ten questions. The patient and not the examiner should make the ratings, but the examiner should be available to clarify any misunderstandings the patient may have about the questions. The examiner should mark the patient’s answers on the form.

In the past week. . . (1) Overall, how would you rate the RLS discomfort in your legs or arms? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

In the past week. . . (2) Overall, how would you rate the need to move around because of your RLS symptoms? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

In the past week. . . (3) Overall, how much relief of your RLS arm or leg discomfort did you get from moving around?

■

4

No relief

3

Mild relief

2

Moderate relief

1

Either complete or almost complete relief

0

No RLS symptoms to be relieved

Figure 37–1. International Restless Legs Syndrome Study Group Rating Scale (IRLS). Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, Trenkwalder C; International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003 Mar; 4(2):121-32. Copyright IRLS Study Group 2001. How to obtain the IRLS: Please contact the Information Resources Centre of Mapi Research Trust, 27 rue de la Villette, 69003 Lyon, FRANCE – Tel: +33(0)472 13 65 75 – Fax: +33(0)472 13 66 82 – Email: [email protected] – Internet: www.mapi-trust.org (conditions of use and (User)-agreement are provided). Useful information about the IRLS (such as references, translations available, scoring and others) is available on the Quality of Life Instrument Database (QOLID), available on the Internet at www.Qolid.org. Continued

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In the past week. . . (4) How severe was your sleep disturbance due to your RLS symptoms? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

In the past week. . . (5) How severe was your tiredness or sleepiness during the day due to your RLS symptoms? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

In the past week. . . (6) How severe was your RLS as a whole? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

In the past week. . . (7) How often did you get RLS symptoms? 4

Very often (This means 6 to 7 days a week)

3

Often (This means 4 to 5 days a week)

2

Sometimes (This means 2 to 3 days a week)

1

Occasionally (This means 1 day a week)

0

Never ■

Figure 37–1, cont’d.

chapter 37 restless legs syndrome In the past week. . . (8) When you had RLS symptoms, how severe were they on average? 4

Very severe (This means 8 hours or more per 24-hour day)

3

Severe (This means 3 to 8 hours per 24-hour day)

2

Moderate (This means 1 to 3 hours per 24-hour day)

1 0

Mild (This means less than 1 hour per 24-hour day) None

In the past week. . . (9) Overall, how severe was the impact of your RLS symptoms on your ability to carry out your daily affairs, for example, carrying out a satisfactory family, home, social, school, or work life? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

In the past week. . . (10) How severe was your mood disturbance due to your RLS symptoms—for example, angry, depressed, sad, anxious, or irritable? 4

Very severe

3

Severe

2

Moderate

1

Mild

0

None

The sum of the item scores serves as the global score for the scale. Higher scores indicate more impairment/higher severity.

1 – 10 = mild RLS 11 – 20 = moderate RLS 21 – 30 = severe RLS 31 – 40 = very severe RLS ■

Figure 37–1, cont’d.

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RLS-6 Rating Scales

■

Figure 37–2. RLS-6 Rating Scales. (Copyright R. Kohnen, W. H. Oertel, K. Stiasny-Kolster, H. Benes, and C. Trenkwalder [Version 06, May 2003]. The RLS-6 may not be used without written confirmation of the authors [e-mail [email protected]].)

chapter 37 restless legs syndrome controlled studies that have shown a beneficial effect of other supplements such as zinc, vitamin B1, vitamin B12, vitamin E, or vitamin C. Pharmacological therapy should be restricted to patients who meet the specific diagnostic criteria and suffer from clinically relevant RLS symptoms. Several factors—such as the frequency and severity of symptoms, the temporal appearance of symptoms, the kind of sleep disturbances, and the degree to which RLS interferes with the quality of life—influence treatment strategies.

Levodopa According to Hening and colleagues (2004), if pharmacological therapy is initiated, dopaminergic agents are considered the first-line agents for treatment of RLS.92 In September 2000, L-Dopa/benserazide (Restex and Restex retard) became the first drug licensed for RLS, in two European countries, Germany and Switzerland.93-95 Doses of 50/12.5 to 100/25 mg of standard L-dopa/dopadecarboxylase inhibitor improve RLS symptoms about 1 hour after drug intake, resulting in an improved quality of sleep. In correlation to the plasma half-life of L-dopa (1 to 2 hours), the beneficial effect decreases, and RLS may persist into the second half of the night. If so, an additional dose of slowrelease L-dopa/dopadecarboxylase inhibitor (100/25 mg given in combination with standard L-dopa/benserazide 1 hour before or at bedtime) is recommended.94 In general, L-dopa is best used by patients with mild RLS. The immediate response to L-dopa without a long titration period is appreciated by the patient and indicates to the treating physician that the diagnosis is correct. In patients with sporadic RLS, L-dopa can be given on demand. Pills are generally taken at bedtime, perhaps supplemented by a dose earlier in the day to control evening or daytime symptoms. For maximal absorption, L-dopa should not be taken with high-protein foods. In more severely affected patients, RLS symptoms may not be adequately controlled for the whole night even with the combination of standard and slow-release preparations. These patients benefit from a dopamine agonist. In others, RLS symptoms may shift to the early evening or daytime, become more intense, or involve other body parts after L-dopa therapy has been started. This phenomenon has been called augmentation.96 Consequently, these patients are frequently treated with multiple and higher dosages of L-dopa throughout the 24 hours to control RLS symptoms. If L-dopa therapy is complicated by augmentation, L-dopa should be completely substituted by a dopamine agonist. Because augmentation seems to be more frequent in patients with higher L-dopa dosages, maximum dosages of 300 to 400 mg should not be exceeded. It is also possible that augmentation may be triggered if patients are treated with higher L-dopa dosages than are needed or if daily L-dopa therapy is recommended although symptoms appear only intermittently. Therefore, in some patients with mild symptoms, 50 mg L-dopa, perhaps on demand, may be sufficient.

Dopamine Agonists Because of their longer half-lives and fewer problems (at least according to current clinical observations) with augmentation, dopamine agonists are preferred especially in patients with advanced daily RLS. Given once in the early evening—in

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dosages that are usually lower than those for Parkinson’s disease—dopamine agonists cover sensory and motor symptoms of RLS throughout the night. As a consequence, sleep and quality of life markedly improve in most patients. To date, several large-scale placebo-controlled trials with dopamine agonists with the goal of approval by the European Medicines Agency or the U.S. Food and Drug Administration have been performed. Convincing data are available for the dopamine agonists cabergoline,97-99 pergolide,100-102 ropinirole,102,103 and pramipexole104,105 and the dopamine agonist patch rotigotine.106 Apart from general considerations, several factors determine the physician’s decision about a certain substance and its dosage, such as the half-life, the duration of upward titration, the structure (nonergot or ergot), individual efficacy and tolerability, and, the physician’s experience with regard to a single dopamine agonist. Shorter-acting dopamine agonists may necessitate twice-daily doses, with an earlier dose in the late afternoon and a second dose in the evening. With longer acting dopamine agonists, a single evening dose (2 to 3 hours before bedtime) is sufficient. If insomnia remains to a considerable degree even though sensorimotor symptoms are well controlled by the dopaminergic drug, other factors and possibly other treatment options must be considered. Characteristics of various dopamine agonists are given in Table 37–4.

Other Substances Opioids have shown to be effective in RLS, and their analgesic or sedative effect may be advantageous in individual patients, but data from placebo-controlled trials are very limited and available for only oxycodone.107 Opioids may be highly effective particularly in advanced RLS and should not be withheld from appropriate patients because of fear of potential development of tolerance or dependence. Escalation of dosage is rare, as is dependence in the absence of a history of substance abuse. If opioids are used, treatment regimens like those for in chronic pain syndromes should be applied. Severely affected patients in particular may profit from opioid patch applications. To avoid constipation, lactulose should be added to the regimen from the beginning. Gabapentin may be an alternative choice, particularly for less intense RLS, for RLS perceived as painful, for RLS in combination with a painful peripheral neuropathy, or for an unrelated chronic pain syndrome. Gabapentin should be used in once- or twice-daily doses in the late afternoon or evening (one third of the dose) or before sleep (two thirds of the dose). Treatment should commence with 300 mg per dose or even less because of the possible tendency to cause somnolence and gait unsteadiness, especially in elderly patients. A controlled trial has shown that a mean dosage of 1800 mg/day is needed for efficacy.108 The anticonvulsants carbamazepine and valproic acid seem to be less effective against RLS than gabapentin. Other anticonvulsants with antinociceptive effect are currently under investigation in patients with RLS. Benzodiazepines are sometimes employed for residual insomnia but should be used with caution, particularly in older patients. Better alternatives are zaleplon (5 to 10 mg), zolpidem (5 to 10 mg), and zopiclone (3.75 to 7.5 mg). In some patients, combination therapies with dopaminergic agents, opioids, anticonvulsants, and benzodiazepines may be a necessary option, but this has not been formally studied.

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T A B L E 37–4. Characteristics of Dopamine Agonists in the Treatment of Restless Legs Syndrome Half-Life (Hours) α-Dihydroergocryptine Bromocriptine Cabergoline Lisuride Pergolide Pramipexole HCl*† (nonergot) Ropinirole (nonergot) Rotigotine (nonergot)

Initial Dosage

Titration

Dosage in Restless Legs Syndrome

Maximal Dosage

10-15 3-8 >65 2-3 7-16

5 mg 1.25 mg 0.5 mg 0.1 mg 0.05 mg

5 mg/3 days 1.25 mg/week 0.5 mg/week 0.1 mg/week 0.05 mg/3 days

10-40 mg 2.5-5 mg 0.5-2 mg 0.1-2 mg 0.1-0.75 mg

80 mg 7.5 mg 4 mg 4 mg 1.5 mg

8-12 3-10 5 (constant plasma levels because of patch application)

0.125 mg 0.25 mg 1.25 mg (2.5 cm2) or 2.5 mg (5 cm2)

0.125 mg/3 days 0.25 mg/3 days 1.25 mg/day More than 4.5 mg: 2.25 mg/day

0.125-0.75 mg 0.5-6 mg 1.25-6.75 mg (2.5-15 cm2)

1.5 mg 8 mg 9 mg

*In some European countries, it is declared that free base 0.088 mg pramipexole = 0.125 mg pramipexole HCl. † At least two randomized, placebo-controlled clinical trials with a sufficient number of patients have been conducted.

K E Y

P O I N T S

●

With a prevalence of 5% to 10%, RLS is one of the most common neurological disorders with a significant impact on the patient’s sleep.

●

The key feature is an irresistible urge to move the legs which appears during periods of rest predominantly in the evening hours and is relieved by movement at least as long as the activity continues. Sleep complaints due to RLS are often the main reason for the patient to seek medical advice.

●

Diagnosis can usually be based exclusively on the patient history, and the positive response to dopaminergic therapy strongly supports the diagnosis. In unclear cases polysomnography may be helpful but can be negative especially in early diagnosis.

●

The dopaminergic system and iron metabolism–related components have been extensively investigated and contribute to the pathophysiology of RLS. New findings point toward an underlying role of the nociceptive system.

●

Not all patients require treatment, but for those that do there is a range of therapies available for effective management. Dopaminergic agents in dosages usually much lower than those prescribed in Parkinson’s disease are considered the first-line treatment in RLS.

Selected Reading Allen R, Picchietti D, Hening WA, et al: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4:101-119. Hening WA, Allen RP, Earley CJ, et al: An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine interim review. Sleep 2004; 27:560-583. The International Restless Legs Syndrome Study Group: Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs. Sleep Med 2003; 4:121132.

Stiasny-Kolster K, Kohnen R, Möller JC, Trenkwalder C, et al: Validation of the “L-dopa test” for diagnosis of restless legs syndrome. MOV Disord in press. Stiasny-Kolster K, Magerl W, Oertel WH, et al: Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 2004; 127:773-782. Walters AS: Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995 10:634-642.

References 1. Ekbom KA: Restless legs syndrome. Acta Med Scand 1945; 158(Suppl):4-122. 2. Hening W, Walters AS, Allen RP, et al: Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004; 5:237-246. 3. Allen RP, Earley CJ: Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurol 2001; 18:128-147. 4. Winkelmann J, Prager M, Lieb R, et al: “Anxietas tibiarum.” Depression and anxiety disorders in patients with restless legs syndrome. J Neurol 2005; 252:67-71. 5. Sevim S, Dogu O, Kaleagasi H, et al: Correlation of anxiety and depression symptoms in patients with restless legs syndrome: a population based survey. J Neurol Neurosurg Psychiatry 2004; 75:226-230. 6. Montplaisir J, Boucher S, Poirier G, et al: Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997; 12:61-65. 7. Smith RC: Relationship of periodic movements in sleep (nocturnal myoclonus) and the Babinski sign. Sleep 1985; 8:239243. 8. Ulfberg J, Nystrom B, Carter N, et al: Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001; 16:1159-1163. 9. Rothdach AJ, Trenkwalder C, Haberstock J, et al: Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology 2000; 54:1064-1068. 10. Phillips B, Young T, Finn L, et al: Epidemiology of restless legs syndrome in adults. Arch Intern Med 2000; 160:21372141.

chapter 37 restless legs syndrome 11. Ulfberg J, Nystrom B, Carter N, et al: Restless legs syndrome among working-aged women. Eur Neurol 2001; 46:17-19. 12. Högl B, et al: Prevalence of restless legs syndrome in the central European alpine region of South Tyrol. Sleep 2003; 26:A344. 13. Berger K, Luedemann J, Trenkwalder C, et al: Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004; 164:196-202. 14. Kageyama T, Kabuto M, Nitta H, et al: Prevalences of periodic limb movement–like and restless legs–like symptoms among Japanese adults. Psychiatry Clin Neurosci 2000; 54:296-298. 15. Ohayon MM, Roth T: Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002; 53:547-554. 16. Walters AS, Hickey K, Maltzman J, et al: A questionnaire study of 138 patients with restless legs syndrome: the “NightWalkers” survey. Neurology 1996; 46:92-95. 17. Stautner A, Stiasny K, Collado-Seidel V, et al: Comparison of idiopathic and uremic restless legs syndrome: results of a database of 134 patients [Abstract]. Mov Disord 1996; 11(Suppl):98. 18. Ondo W, Jankovic J: Restless legs syndrome: clinicoetiologic correlates. Neurology 1996; 47:1435-1441. 19. Winkelmann J, Muller-Myhsok B, Wittchen HU, et al: Complex segregation analysis of restless legs syndrome provides evidence for an autosomal-dominant mode of inheritance in early age at onset families. Ann Neurol 2002; 52:279-302. 20. Allen, RP, Earley CJ: Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med 2000; 1:11-19. 21. Desautels A, Turecki G, Montplaisir J, et al: Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet 2001; 69:1266-1270. 22. Bonati MT, Ferini-Strambi L, Aridon P, et al: Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 2003; 126(Pt 6):1485-1492. 23. Levchenko A, Montplaisir JY, Dube MP, et al: The 14q restless legs syndrome locus in the French Canadian population. Ann Neurol 2004; 55:887-891. 24. Chen S, Ondo WG, Rao S, et al: Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004; 74:876885. 25. Trenkwalder C, Seidel VC, Gasser T, et al: Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996; 11:389-394. 26. Lazzarini A, Walters AS, Hickey K, et al: Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord 1999; 14:111-116. 27. Desautels A, Turecki G, Montplaisir J, et al: Dopaminergic neurotransmission and restless legs syndrome: a genetic association analysis. Neurology 2001; 57:1304-1306. 28. Dichgans M, Walther E, Collado-Seidel V, et al: Autosomaldominant restless legs syndrome: genetics model and evaluation of 22 candidate genes. Mov Disord 1996; 11:87. 29. Collado-Seidel V, Kohnen R, Samtleben W, et al: Clinical and biochemical findings in uremic patients with and without restless legs syndrome. Am J Kidney Dis 1998; 31:324328. 30. Gigli GL, Adorati M, Dolso P, et al: Restless legs syndrome in end-stage renal disease. Sleep Med 2004; 5:309-315. 31. O’Keeffe ST, Gavin K, Lavan JN: Iron status and restless legs syndrome in the elderly. Age Ageing 1994; 23:200-203. 32. Sun ER, Chen CA, Ho G, et al: Iron and the restless legs syndrome. Sleep 1998; 21:371-377. 33. McParland P, Pearce JM: Restless legs syndrome in pregnancy. Case reports. Clin Exp Obstet Gynecol 1990; 17:5-6.

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34. Manconi M, Govoni V, De Vito A, et al: Restless legs syndrome and pregnancy. Neurology 2004; 63:1065-1069. 35. Iannaccone S, Zucconi M, Marchettini P, et al: Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995; 10:2-9. 36. Gemignani F, Marbini A, Di Giovanni G, et al: Cryoglobulinaemic neuropathy manifesting with restless legs syndrome. J Neurol Sci 1997; 152:218-223. 37. Salvi F, Montagna P, Plasmati R, et al: Restless legs syndrome and nocturnal myoclonus: initial clinical manifestation of familial amyloid polyneuropathy. J Neurol Neurosurg Psychiatry 1990; 53:522-525. 38. Gemignani F, Marbini A, Di Giovanni G, et al: Charcot-MarieTooth disease type 2 with restless legs syndrome. Neurology 1999; 52:1064-1066. 39. Polydefkis M, Allen RP, Hauer P, et al: Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000; 55:1115-1121. 40. Rutkove SB, Matheson JK, Logigian EL: Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996; 19:670-672. 41. Walters AS, Wagner M, Hening WA: Periodic limb movements as the initial manifestation of restless legs syndrome triggered by lumbosacral radiculopathy [Letter]. Sleep 1996; 19:825-826. 42. Winkelmann J, Wetter TC, Trenkwalder C, et al: Periodic limb movements in syringomyelia and syringobulbia. Mov Disord 2000; 15:752-755. 43. Chervin RD, Archbold KH, Dillon JE, et al: Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep 2002; 25:213218. 44. Walters AS, Mandelbaum DE, Lewin DS, et al: Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group. Pediatr Neurol 2000; 22:182-186. 45. Picchietti DL, Underwood DJ, Farris WA, et al: Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord 1999; 14:1000-1007. 46. Trenkwalder C, Paulus W: Why do restless legs occur at rest?—Pathophysiology of central and peripheral structures in RLS. Neurophysiology of RLS (part 2). Clin Neurophysiol 2004; 115:1975-1988. 47. Winkelmann J, Schadrack J, Wetter TC, et al: Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients. Sleep Med 2001; 2:57-61. 48. Happe S, Zeitlhofer J: Abnormal cutaneous thermal thresholds in patients with restless legs syndrome. J Neurol 2003; 250:362-365. 49. Sowers JR, Vlachakis N: Circadian variation in plasma dopamine levels in man. J Endocrinol Invest 1984; 7:341-345. 50. Garcia-Borreguero D, Odin P, Schwarz C: Restless legs syndrome: an overview of the current understanding and management. Acta Neurol Scand 2004; 109:303-317. 51. Earley CJ, Hyland K, Allen RP: CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome. Mov Disord 2001; 16:144-149. 52. Stiasny-Kolster K, Moller JC, Zschocke J, et al: Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients. Mov Disord 2004; 19:192-196. 53. Pittock SJ, et al: Neuropathology of primary restless legs syndrome: Absence of specific tau- and alpha-synuclein pathology. Mov Disord 2004; 19(6):695-699. 54. Michaud M, et al: Circadian rhythm of restless legs syndrome: relationship with biological markers. Ann Neurol 2004; 55:372-380.

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55. Tribl SJ, Waldhauser F, Sycha T, et al: Urinary 6-hydroxymelatonin-sulfate excretion and circadian rhythm in patients with restless legs syndrome. J Pineal Res 2003; 35:295-296. 56. Earley CJ, Heckler D, Allen RP: The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 2004; 5:231-235. 57. Allen RP, Barker PB, Wehrl F, et al: MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001; 56:263-265. 58. Earley CJ, Connors JR, Allen RP: RLS patients have abnormal reduced CSF ferritin compared to normal controls. Neurology 1999; 52(Suppl 2):A111-A112. 59. Connor JR, Wang XS, Patton SM, et al: Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 2004; 62:1563-1567. 60. Stiasny-Kolster K, Magerl W, Oertel WH, et al: Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 2004; 127:773782. 61. Trenkwalder C, Bucher SF, Oertel WH, et al: Bereitschaftspotential in idiopathic and symptomatic restless legs syndrome. Electroencephalogr Clin Neurophysiol 1993; 89:95-103. 62. Tergau F, Wischer S, Paulus W: Impaired motor cortex excitability in patients with restless legs syndrome. Neurology 1998; 50:A223. 63. Entezari-Taher M, Singleton JR, Jones CR, et al: Changes in excitability of motor cortical circuitry in primary restless legs syndrome. Neurology 1999; 53:1201-1205. 64. Stiasny-Kolster K, Haeske H, Tergau F, et al: Cortical silent period is shortened in restless legs syndrome independently from circadian rhythm. Suppl Clin Neurophysiol. 2003; 56:381-389. 65. Ondo W: Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000; 15:154-158. 66. Akpinar S: The primary restless legs syndrome pathogenesis depends on the dysfunction of EEG alpha activity. Med Hypotheses 2003; 60:190-198. 67. Bucher SF, Seelos KC, Oertel WH, et al: Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1997; 41:639-645. 68. de Mello MT, et al: Incidence of periodic leg movements and of the restless legs syndrome during sleep following acute physical activity in spinal cord injury subjects. Spinal Cord 1996; 34(5):294-296. 69. de Mello MT, Poyares DL, Tufik S: Treatment of periodic leg movements with a dopaminergic agonist in subjects with total spinal cord lesions. Spinal Cord 1999; 37:634-637. 70. Dickel MJ, Renfrow SD, Moore PT, et al: Rapid eye movement sleep periodic leg movements in patients with spinal cord injury. Sleep 1994; 17:733-738. 71. Yokota T, Hirose K, Tanabe H, et al: Sleep related periodic leg movements (nocturnal myoclonus) due to spinal cord lesion. J Neurol Sci 1991; 104:13-18. 72. Culpepper WJ, Badia P, Shaffer JI: Time-of-night patterns in PLMS activity. Sleep 1992; 15:306-311. 73. Pollmächer T, Schulz H: Periodic leg movements (PLM): their relationship to sleep stages. Sleep 1993; 16:572-577. 74. Sandkühler J: Learning and memory in pain pathways. Pain 2000; 88:113-118. 75. Walters AS: Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995; 10:634-642. 76. Allen R, Picchietti D, Hening WA, et al: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4:101-119.

77. Montplaisir J, Boucher S, Nicolas A, et al: Immobilization tests and periodic leg movements in sleep for the diagnosis of restless leg syndrome. Mov Disord 1998; 13:324-329. 78. Barton JC, Wooten VD, Acton RT: Hemochromatosis and iron therapy of restless legs syndrome. Sleep Med 2001; 2:249-251. 79. Exar EN, Collop NA: The association of upper airway resistance syndrome. Sleep 2001; 24:188-192. 80. Michaud M, Lavigne G, Desautels A, et al: Effects of immobility on sensory and motor symptoms of restless legs syndrome. Mov Disord 2002; 17:112-115. 81. Stiasny-Kolster K, Kohnen R, Möller JC, Treukwalder C, et al: Validation of the “L-dopa test” for diagnosis of restless legs syndrome. MOV Disord in press. 82. The International Restless Legs Syndrome Study Group: Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs. Sleep Med 2003; 4:121132. 83. Kohnen R, Oertel WH, Stiasny-Kolster K, et al: Severity rating of restless legs syndrome: review of ten years experience with the RLS-6 scales in clinical trials. Sleep 2003; 26:A342. 84. Lang AE, Johnson K: Akathisia in idiopathic Parkinson’s disease. Neurology 1987; 37:477-481. 85. Poewe W, Högl B: Akathisia, restless legs and periodic limb movements in sleep in Parkinson’s disease. Neurology 2004; 63(Suppl 3):S12-S16. 86. Yasuda T, Nishimura A, Katsuki Y, et al: Restless legs syndrome treated successfully by kidney transplantation—a case report. Clin Transpl 1986; 12:138. 87. Goodman JD, Brodie C, Ayida GA: Restless leg syndrome in pregnancy. BMJ 1988; 297:1101-1102. 88. Lee KA, Zaffke ME, Baratte-Beebe K: Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend Based Med 2001; 10:335-341. 89. Davis BJ, Rajput A, Rajput ML, et al: A randomized, doubleblind, placebo-controlled trial of iron in restless legs syndrome. Eur Neurol 2000; 43:70-75. 90. Silber MH, Ehrenberg BL, Allen RP, et al: An algorithm for the management of restless legs syndrome. Mayo Clin Proc 2004; 79:916-922. 91. Hornyak M, Voderholzer U, Hohagen F, et al: Magnesium therapy for periodic leg movements–related insomnia and restless legs syndrome: an open pilot study. Sleep 1998; 21:501-505. 92. Hening WA, Allen RP, Earley CJ, et al: An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine interim review. Sleep 2004; 27:560-583. 93. Trenkwalder C, Stiasny K, Pollmacher T, et al: L-Dopa therapy of uremic and idiopathic restless legs syndrome: a doubleblind, crossover trial. Sleep 1995; 18:681-688. 94. Collado-Seidel V, Kazenwadel J, Wetter TC, et al: A controlled study of additional SR-L-dopa in L-dopa responsive RLS with late night symptoms. Neurology 1999; 52:285-290. 95. Benes H, Kurella B, Kummer J, et al: Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep 1999; 22:10731081. 96. Allen RP, Earley CJ: Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996; 19:205-213. 97. Stiasny K, Robbecke J, Schuler P, et al: Treatment of idiopathic restless legs syndrome (RLS) with the D2-agonist cabergoline—an open clinical trial. Sleep 2000; 23:349-354. 98. Stiasny-Kolster K, Benes H, Peglau I, et al: Effective cabergoline treatment in idiopathic restless legs syndrome (RLS). Neurology 2004; 63:2272-2279. 99. Oertel WH, Benes H, Happe S, et al: Efficacy of cabergoline for the treatment of sensori-motor symptoms and sleep

chapter 37 restless legs syndrome

100. 101. 102.

103.

disturbances in restless legs syndrome: A placebo-controlled, 5-week, double-blind, randomized, multicenter, polysomnographic study. Mov Disord 2004; 19(Suppl. 9):S425. Wetter TC, Stiasny K, Winkelmann J, et al: A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999; 52:944-950. Stiasny K, Wetter TC, Winkelmann J, et al: Long-term effects of pergolide in the treatment of restless legs syndrome. Neurology 2001; 56:1399-1402. Trenkwalder C, Garcia-Borreguero D, Montagna P, et al: Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004; 75:92-97. Walters AS, Ondo WG, Dreykluft T, et al: Ropinirole is effective in the treatment of restless legs syndrome: TREAT RLS 2: a 12-week double-blind, randomized, parallelgroup, placebo-controlled study. Mov Disord 2004; 19:14141423.

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104. Montplaisir J, Nicolas A, Denesle R, et al: Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999; 52:938-943. 105. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al: Efficacy of Pramipexole in restless legs syndrome: a 6-week, multicenter, randomize, double-blind study. Submitted for publication. 106. Stiasny-Kolster K, Kohnen R, Schollmayer E, et al: Patchapplication of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome— a double-blind placebo-controlled pilot study. Mov Disord 2004; 19:1432-1438. 107. Walters AS, Wagner ML, Hening WA, et al: Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993; 16:327-332. 108. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al: Treatment of restless legs syndrome with gabapentin: a doubleblind, cross-over study. Neurology 2002; 59:1573-1579.

CHAPTER

38

SPINE

AND SPINAL CORD: DEVELOPMENTAL DISORDERS ●

●

●

●

Valerie S. Tay, Andrew Kornberg, and Mark Cook

Developmental disorders of the spine and spinal cord occur because of defects in the development and maturation of the nervous system. A basic understanding of embryology is therefore important in appreciating the nature and scope of these disorders. There are various ways of approaching and thinking about the developmental disorders: 1. Clinicoanatomical: This is a logical viewpoint because the anatomical defect is correlated with the neurological impairment, disabilities experienced, and overall functional outcome. Disorders can be classified anatomically on the basis of the structures (e.g., bony elements, supporting soft tissues, or neural elements) or the level of the neuraxis involved. Clinically, the developmental disorders of the spine and spinal cord can manifest in various domains, and clinical features can generally be thought of as neurological or myelopathic, as orthopedic and biomechanical, or as multisystem features of a widespread developmental disorder. 2. Molecular genetics: In the area of developmental disorders, research into the molecular genetics is increasingly important in advancing knowledge of the mechanisms underlying these disorders, in reclassifying the syndromes, and in providing a common link between some of the disorders. As knowledge and understanding of these disorders continue to expand, the most reasonable approach is to integrate advances in genetic and etiological models within the traditional phenotypic clinicoanatomical framework. Developmental disorders can be classified anatomically, depending on whether they affect primarily the spinal cord and neural tissues or the spine and supporting structures (Table 38–1). There is a wide spectrum of developmental disorders affecting the spine and spinal cord, ranging in age at presentation, in clinical manifestations, and in severity. Although more likely to manifest in the pediatric population, some milder forms may manifest later in life as well. Neurologists for both pediatric and adult populations should have an awareness and appreciation of the range and manifestations of these disorders. The aim of this chapter is to provide a broad overview and appreciation of the developmental disorders affecting the spine and spinal cord, with a few select disorders covered in greater depth. A host of vascular malformations and metabolic conditions may affect the spine and spinal cord; they remain, however, beyond the scope of this chapter and are not discussed.

488

NORMAL DEVELOPMENT OF THE NERVOUS SYSTEM The human embryonic period spans the first 8 postfertilization weeks and is classified on the basis of a morphological system. There are 23 distinct Carnegie stages, each stage covering a period of 2 to 3 days. This staging system facilitates an understanding of the timing and sequence of embryonic development. The fetal period spans the 9th week after fertilization to birth. Fetal age is thought of mainly as measurements, inasmuch as a similar morphological staging system is not available. The great majority of congenital malformations begin during the embryonic period.1-3 The neural tube is the embryonic structure that develops into the brain and spinal cord. Primary neurulation refers to the development of the neural tube from the neural plate. Complete development and closure of the neural tube occurs from days 17 to 30 after conception and spans Carnegie stages 8 to 12 in the embryonic period (Table 38–2). The caudal eminence is the continuation of the primitive streak and develops into the terminal portions of the notochord, somites, vertebrae, and hindgut. The neural cord arises from the caudal eminence and forms the caudal portion of the spinal cord. This process is secondary neurulation. The level of the junction between primary and secondary neurulation is at the level of the future second sacral vertebra. There is elongation of the previous neural tube together with formation of the lower sacral and coccygeal segments. This part of the development of the nervous system commences in stage 12 at 4 weeks and ends approximately at stage 20.2-6 The vertebral bodies of the spine are generated from the mesenchymal cells. The process of gastrulation occurs at day 14 in embryonic life to generate the mesenchymal cells that will in turn develop into the head, cardiac, and the paraxial and lateral mesoderm. At 20 to 30 days in embryonic life, the paraxial mesoderm, in a process of somatogenesis, subdivides into spherical somite segments on each side of the spinal cord in a rostral-tocaudal direction. The somites first appear in stage 9; differentiation commences at stage 10. The somites mature and further subdivide into the sclerotome to form the vertebral bodies, the myotome to form the musculature, and the dermatome to form the dermis. The sclerotome undergoes a resegmentation process in which the caudal end of one somite links with the rostral end of the next somite to form a vertebral body.7-9

chapter 38 spine and spinal cord: developmental disorders

489

T A B L E 38–1. Developmental Disorders That Can Affect Vertebrospinal Structures Disorders Affecting the Spine

Disorders Affecting the Spinal Cord and Neural Tissues

Disorders of the craniovertebral junction, including: Klippel-Feil anomaly Basilar invagination and platybasia Occipitalization of the atlas Congenital atlantoaxial dislocation

Chiari malformation Syrinx Neural tube defects Split cord malformations Sacral agenesis Tethered cord syndrome Lipomas Tight filum terminale Dural bands Congenital sinus tracts and intraspinal dermoid, epidermoid Developmental cysts

Scoliosis

Vascular Malformations A variety of vascular malformations can affect the spine and spinal cord

T A B L E 38–2. Important Stages in Primary Neurulation and the Formation and Closure of the Neural Tube Development Stage No.

Days in Embryonic Life

8 9 10

17-19 19-21 22-23

11 12

23-26 26-30

Nervous System Development Development of the neural plate Development of the neural folds First steps in the fusion of the neural folds: There are two initial sites of fusion: fusion proceeds bidirectionally from the lower medullary rhombencephalic site and in a caudal direction from the higher prosencephalic site. The fusions terminate in two neuropores: the rostral and caudal neuropores. Closure of the rostral neuropore Closure of the caudal neuropore

Based on a table from Lemire RJ: Neural tube defects. JAMA 1988; 259:558-562 Copyright © 1988 American Medical Association. All rights reserved; and on information from O’Rahilly R, Muller F: The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology 2002; 65:162-170.

DEVELOPMENTAL DISORDERS AFFECTING THE SPINE The developmental disorders affecting the spine that are covered in this chapter include scoliosis and a cluster of disorders originating primarily at the craniocervical junction. Some of the other generalized spinal disorders, including metabolic disorders, are covered in other chapters.

Klippel-Feil Anomaly Definition The Klippel-Feil anomaly comprises a heterogeneous spectrum of conditions with the unifying feature of congenital synostosis of some or all of the cervical vertebrae. There have been many classification systems put forth for Klippel-Feil, including those based on anatomy and the extent of cervical fusion and on genetic transmission.

Epidemiology The Klippel-Feil anomaly occurs in 1 per 40,000 to 1 per 42,000 births, with a female-to-male ratio of 3:2.8

Clinical Features Individuals with Klippel-Feil anomaly may be asymptomatic. Clinical manifestations can range from pain, through orthopedic or neurological manifestations, to a more widespread malformation disorder. The initial description was of a classical triad of shortening of the neck, limited range of neck movement, and a low posterior hairline. Affected individuals may complain of cervical pain and present with cosmetic deformities. The Klippel-Feil anomaly may be associated with spinal instability. This occurs if there are unstable fusion patterns or if stenosis and arthritis develop at the interspaces between the fused joints. The associated axial and spine anomalies include cervical or fused ribs, cleft vertebrae or hemivertebrae, and kyphoscoliosis.8 Neurological impairment depends on the presence and degree of neurocompression. For instance, a cervical rib can cause neurocompression with upper limb numbness and pain. Cervical cord compression can lead to a myelopathic picture. A traditional observation is the presence of mirror movements. This can be demonstrated by asking the patient to supernate/pronate a single arm. Mirror movements are those in which the other limb supernates/pronates at the same time. The Klippel-Feil anomaly may be associated with other spinal developmental disorders, including syrinx, tethered cord, and split cord malformations (SCMs). Alternatively, the Klippel-

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Feil anomaly could be part of a widespread multisystem developmental disorder as well, in which other features include hearing deficits, congenital heart disease, and genitourinary manifestations.8

lize the spine is indicated if there is neurological impairment or symptomatic cervical instability. Surgical options include occipitocervical arthrodesis and combined atlantoaxial and subaxial arthrodesis.8

Etiology and Pathophysiology

Basilar Impression

The Klippel-Feil anomaly results from failure of normal segmentation of the vertebral column in early embryonic life. The exact cause and mechanism behind this syndrome are unclear; the Klippel-Feil anomaly may result from disruptions in isolated genes that govern segmentation, or it may result from complex gene-gene or gene-environment interactions.8

Definition

Management Diagnostic investigations center on imaging studies. Goodquality radiographs and computed tomographic (CT) scans of the cervical spine are necessary to show the extent of cervical fusion and to evaluate potential instability (Fig. 38–1). Magnetic resonance imaging (MRI) studies, including flexion and extension views, are useful for evaluating instability or stenosis in the cervical spine and for assessing neurocompression of the spinal cord. MRI should be performed on the whole neuraxis in order to look for the associated developmental anomalies. Further evaluation is targeted at the associated conditions, including audiology assessments and cardiac and renal investigations.8 Management depends on the symptoms and the presence of other malformations. Treatment modalities may include simple measures of modifying activities and the use of traction and bracing to alleviate deformities. Surgical intervention to stabi-

Basilar impression (or basilar invagination) occurs when there is an abnormal upward displacement of the basilar and condylar portions of the occipital bone. This leads to invagination of the foramen magnum into the posterior cranial fossa with associated translocation of the upper cervical vertebrae into this depression. We believe the terms basilar impression and basilar invagination are interchangeable, but some authors differentiate basilar impression from basilar invagination on the basis of differences in anatomical definitions and causation (e.g., acquired or primary).10,11 Some texts include platybasia in the spectrum of basilar impression. Platybasia is an abnormal flattening of the base of the skull with an abnormally obtuse angle between the plane of the clivus and the plane of the anterior fossa. This may occur together with basilar impression but is of no real clinical significance. Basilar impression has traditionally been defined on the basis of a deviation from set anatomical and radiological parameters: 1. Chamberlain’s line is drawn from the dorsal edge of the hard palate to the dorsal lip of the foramen magnum. 2. McGregor’s line is from the upper surface of the posterior edge of the hard palate to the lowest level of the occipital bone.

■

Figure 38–1. Computed tomographic image of a Klippel-Feil anomaly. The coronal image (A) shows fusion of C2 and C3 and a large block fusion from C5 to T2. B, A three-dimensional reconstruction in the same patient.

A

B

chapter 38 spine and spinal cord: developmental disorders 3. McRae’s line is a line from the anterior to the posterior border of the foramen magnum. 4. Bull’s angle is an angle at the intersection of the plane of the hard palate and the plane of the atlas (line formed by joining the midpoints of the anterior and posterior arches of the atlas). The normal upper limit for this angle is 13 degrees. For instance, if Chamberlain’s line is the defining parameter, basilar impression is present when more than one third of the odontoid process lies above this line.10,12

Epidemiology Basilar impression is the most common of the craniocervical malformations; clinical manifestations usually occur from the second decade onward.11 The true incidence is unclear.

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modalities for symptomatic basilar impression include cervical traction and surgical intervention. Cervical traction has been reported to cause vertebral artery dissection, as well as potentially causing infection, cranial fractures, and hemorrhage. Anterior compression is managed with an anterior surgical approach; posterior or circumferential compression is managed with a posterior approach. The role of prophylactic surgery or prolonged immobilization with asymptomatic lesions is unclear.10,12

Occipitalization of the Atlas Definition This is a congenital disorder in which the atlas either is completely or incompletely fused to or is incorporated into the occiput.

Clinical Features Basilar impression may be asymptomatic or may manifest with deformities, including a shortened neck. Movement or exerciseinduced occipital headache is a common feature. Oculomotor features include horizontal and upward-beat or downward-beat nystagmus. Other cranial nerve symptoms include facial nerve spasm, trigeminal sensory symptoms, and trigeminal neuralgia. Pontomedullary compression can lead to pyramidal tract signs, with the lower limbs typically more affected than the upper limbs. Sleep apnea and respiratory depression have been described.11,12 Primary basilar impression is often associated with other developmental anomalies, including occipitalization of the atlas, the Klippel-Feil anomaly, the Arnold-Chiari malformation, and syringomyelia or syringobulbia.12

Epidemiology Occipitalization of the atlas occurs in 1% of the population.13

Clinical Features This condition may be asymptomatic. However, atlantoaxial dislocation can occur in up to 60% of affected patients. In this condition, there is excessive compensatory stress on the atlantoaxial joint as a result of the decreased movement of the atlantooccipital joint. This situation increases the possibility of developing traumatic dislocation or cervical degenerative joint disease. Occipitalization of the atlas is associated with other developmental disorders as well, including basilar impression, Klippel-Feil anomaly, and Chiari malformations.13

Etiology and Pathophysiology Neurological manifestations occur in basilar impression as a result of direct compression on the brainstem and of vascular abnormalities. Basilar impression can be classified on the basis of etiology into two categories: 1. Primary basilar impression, a primary developmental defect with a familial tendency in which there is no underlying bone abnormalities. 2. Secondary basilar impression, in which an underlying generalized bone disorder leads to bone softening. Secondary basilar impression has been described with achondroplasia, osteogenesis imperfecta, osteomalacia, hyperparathyroidism, Paget’s disease, Hurler’s syndrome, and HajduCheney syndrome.11,12

Management Imaging studies are necessary to fully evaluate basilar impression and associated anomalies. CT scans are useful in reviewing the bony anatomy, whereas MRI is particularly useful in evaluating neural structures for neurocompression, cerebellar tonsillar herniation, and syrinx. Other investigations for an underlying systemic disorder include measurements of calcium, phosphate, and alkaline phosphatase. The treatment goal is to relieve current compression, and to prevent future compression, of the neuraxis. The treatment

Atlantoaxial Dislocation Definition A variety of congenital anomalies can affect the atlantoaxial junction and cause atlantoaxial dislocation. These anomalies include the following: 1. Congenital C1 anomalies, which may include partial or complete agenesis or dysgenesis of the posterior arch and hypoplasia of the atlas with an intact arch.14 2. Abnormalities of the dens, including hypoplasia, bifid dens, and tripartite dens. 3. Os odontoideum, in which the odontoid process fails to fuse to the body of the axis.

Epidemiology The various degrees of C1 malformations have a quoted prevalence rate of 4%, which is based on autopsy studies.14

Clinical Features Abnormalities in this region may be asymptomatic and found incidentally, or they may manifest with pain. The vertebral anomalies may lead to atlantoaxial instability and dislocation.

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This may result in cervicomedullary compression, which may manifest either spontaneously or after trauma. Affected individuals are especially prone to cord compression during extension injuries: for instance, with intubation or after neck injuries. These anomalies should be considered when a child presents with a neurological deficit or neck pain after minor trauma.14,15 Congenital atlantoaxial instability may be seen in association with Down’s syndrome. Other congenital craniovertebral junction and spinal disorders may occur in tandem as well, including Chiari type I and SCMs. It is important to be aware that atlantoaxial instability may not be congenital in nature but may be caused by an underlying condition, such as rheumatoid arthritis.14,15

Etiology and Pathophysiology The craniovertebral junction malformations arise from defects during the ossification process. The malformations lead to instability in the atlantoaxial joint with subsequent dislocation. Subluxation usually occurs in the horizontal plane, with C1 moving anteriorly to C2. In other settings, progressive cervical myelopathy rarely occurs above C2; the usual scenario of a myelopathy is in the context of acquired degenerative change and usually occurs below C3. The risk of neurocompression depends on the underlying malformation and the joint stability. The actual degree of neurocompression depends on the extent of the subluxation and the width of the spinal canal. The normal sagittal diameter of the spinal canal is 16 to 25 mm at the level of the atlas; the spinal cord is at risk when the canal diameter is less than 14 mm.14

Management The use of high-quality imaging with plain radiographs, CT scans (including fine cuts), and MRI is necessary in the evaluation of atlantoaxial dislocation and craniocervical anomalies. Flexion and extension views are especially useful for assessing joint stability. MRI is crucial in the assessment of the neural structures, especially with regard to cord compression. Surgery is indicated in order to decrease the possibility that significant neurological deficits may develop and should be considered when there is neurocompression or when the individual is symptomatic. Surgery for atlantoaxial and craniocervical instability is a challenging field, especially because surgeons have to work with abnormal anatomy while taking into account the ongoing growth potential for the child. Depending on the underlying malformation, surgical management consists of decompression procedures and joint fusion and stabilization.14-17

Scoliosis

Epidemiology Idiopathic scoliosis affects 2% to 4% of children aged 10 to 16 years. The incidence is equal in boys and girls for curves of less than 20 degrees. Girls, however, significantly outnumber boys, at 5:1, for curves of more than 20 degrees. Secondary neurogenic scoliosis is more common in the younger population. For instance, of patients with the Chiari malformation and syringomyelia, 82% younger than 20 years have scoliosis, as opposed to only 16% of those older than 20 years.18,19

Clinical Features Individuals with scoliosis may present with back pain or, more obviously, with the spinal curvature deformity. In evaluating scoliosis, it is imperative to be aware that the spinal deformity may be the presenting feature of an underlying spinal cord or brainstem anomaly in 4% to 58% of affected patients. Individuals with scoliosis may present with the neurological or orthopedic features of the underlying developmental disorder.18,19

Etiology and Pathophysiology Secondary scoliosis is thought to arise from a generalized paresis of truncal musculature or congenital changes in the vertebrae. In addition, scoliosis in the Chiari-syringomyelia complex may be caused by the abnormal intramedullary pressures within the spinal cord that interfere with the postural tonic reflexes.18,19

Management It is important to treat or rule out an underlying spinal cord or brainstem disorder in a young patient with scoliosis. Evaluation includes the use of radiographs (Fig. 38–2) to chart the pattern of scoliosis and MRI to look for associated anomalies in the neural elements. Posterior fossa decompression for the Chiari-syringomyelia malformation can lead to an improvement in the scoliosis, especially if done early in the patient’s life. Initial treatment may involve use of a spinal orthotic brace as well. Spinal fusion surgery may ultimately be required for surgical correction of the scoliosis.18,19

DEVELOPMENTAL DISORDERS AFFECTING THE SPINAL CORD AND NEURAL TISSUES The developmental disorders affecting the spinal cord and neural tissues broadly includes the craniospinal anomalies, including the Chiari malformation and syringomyelia, and a diverse range of spinal cord abnormalities, including NTDs and the various causes of spinal dysraphism.

Definition Scoliosis is diagnosed on the basis of a 10-degree lateral curve with associated vertebral rotation. Scoliosis may be either primary (idiopathic scoliosis) or secondary. Neurogenic scoliosis is usually secondary to a developmental disorder, including the Chiari malformation, hydrosyringomyelia, and neural tube defects (NTDs).

Chiari Malformation Definition In 1891, Hans Chiari first described the disorder that now bears his name as cerebellar tonsillar herniation below the plane of the foramen magnum into the spinal canal. Further contribu-

chapter 38 spine and spinal cord: developmental disorders

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Figure 38–2. Plain radiograph of scoliosis in a patient with spina bifida. The radiograph is best done in a standing position. The radiograph shows a C-shaped scoliosis of the spine centered at L1 with the convexity toward the patient’s left. There is a windswept appearance to the pelvis, with the right iliac crest sitting higher than the left as a result of the underlying scoliosis.

tions and observations were made by Julius Arnold and John Cleland. Chiari malformations are also known as cerebellar ectopy and are classified into four types: 1. Type I: Herniation of the cerebellar tonsils. This may be associated with elongation of the medulla. Tonsillar herniation is deemed to be pathological if it extends more than 5 mm below the foramen magnum. 2. Type II: Herniation of the caudal part of the cerebellum, the fourth ventricle, the pons, and the medulla. Chiari type II malformation is often associated with a lumbar myelomeningocele. 3. Type III: Rare condition with cerebellar herniation associated with a cervical or occipital encephalocele. 4. Type IV: Severe cerebellar and brainstem hypoplasia.20-22

Epidemiology Chiari type I malformations have a prevalence of 0.6% to 0.9% in studies based on MRI. Symptomatic Chiari type I malformations are slightly more common in girls and women, with a female-to-male ratio of 1.3:1 to 1.7:1.22,23

Clinical Features As with the other developmental disorders, the Chiari malformation may be asymptomatic or, alternatively, may be symptomatic with a wide spectrum of clinical manifestations. A very common manifestation is headaches with or without

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cervical pain. The headache is typically a protracted occipitalsuboccipital headache and is exacerbated by the Valsalva maneuver, postural changes, and coughing or straining. Another common complaint is of weakness and altered sensation, including paresthesia and dysesthesias. A myelopathy may manifest with the sensorimotor or sphincter disturbances. Individuals with Chiari malformations may present with ataxia and other cerebellar signs. Downward-beating nystagmus and other oculomotor disturbances may occur. Other features of brainstem dysfunction may result, including cranial neuropathies, neuro-otological symptoms, sleep apnea, and dysphagia.21-24 Syringomyelia occurs in 32% to 74% of individuals with Chiari type I malformations. A cervical syrinx may manifest with upper limb neurological deficits, whereas a thoracic syrinx may lead to scoliosis. In addition, osseous anomalies of the base of skull, including basilar impression, may be seen with Chiari type I malformations. Chiari type II malformations are often associated with an NTD, other brainstem deformities, and hydrocephalus. Features of raised intracranial pressure are commonly the clinical manifestations of the associated hydrocephalus. The Chiari type I malformation is usually asymptomatic in childhood and tends to manifest in the second to third decade of adulthood. The Chiari type II malformation, however, is usually evident in childhood.21,23,24

Etiology and Pathophysiology The Chiari malformation probably arises from underdevelopment of the occipital enchondrium, which leads to an undeveloped occipital bone with a small and shallow posterior fossa. This in turn leads to overcrowding of the posterior fossa and a downward herniation of the brain. The occipital enchondrium originates from the occipital somite, which in turn is derived from paraxial mesoderm. If the occipital enchondrium is more severely affected, basilar impression may result as well. The degree of tonsillar herniation is thought to be correlated to some extent with the severity of symptoms.21,24

Management The main investigation for a suspected Chiari malformation is MRI of the neuraxis. Sagittal views are particularly important in confirming the diagnosis and demonstrating the degree of cerebellar and brainstem herniation and compression (Fig. 38–3). MRI is also useful for identifying the associated hydrocephalus or syrinx and identifying other developmental disorders, including NTDs, although these are usually obvious clinically. If there are neurological symptoms or signs, surgical intervention is usually indicated, to stabilize or ameliorate symptoms. The goal of surgery is to relieve brainstem and cerebellar compression. Ventral compression can be surgically treated with a transoral clivus odontoid resection. If there is no ventral compression, posterior fossa decompression is usually undertaken. A ventriculoperitoneal shunt may be inserted for associated hydrocephalus. The syrinx usually improves after recovery of cerebrospinal fluid (CSF) flow dynamics. If indicated, especially if the syrinx persists despite decompression, a shunt procedure for the syrinx can be undertaken as well.18,19

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Etiology and Pathophysiology

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Figure 38–3. Magnetic resonance image of a Chiari type I malformation. This sagittal T2 image shows tonsillar herniation and narrowing of the space around the foramen magnum.

Syrinx

The source of fluid in syringomyelia has been postulated to be CSF itself. The exact mechanism for the formation of syringomyelia in a Chiari malformation is unclear. There are two initial principal theories that rely on a patent communication between the fourth ventricle and the syrinx: According to the “water-hammer” theory, the pulsatile transmission of CSF from the choroid plexus is transmitted via an abnormal fourth ventricle to hammer out a dilatation within the spinal cord. The abnormal communication is considered to result from a delayed and incomplete embryonic opening of the outlet of the fourth ventricle. According to the “one-way-valve” theory, there are intermittent high pressures generated in the spinal cord, as a result of an uneven pressure gradient during the Valsalva maneuver. During the Valsalva maneuver, high intrathoracic pressures are transmitted to the epidural spinal veins, leading to an ascending pressure wave pushing CSF from the spinal column to the cranial subarachnoid space. Because there is a downward obstruction to the flow of CSF, this pressure is then translated into CSF movement from the fourth ventricle through the patent central canal into the syrinx. Investigators have reexamined the mechanism of syringomyelia formation, in which magnetic resonance images did not demonstrate a patent communication between the fourth ventricle and syrinx. Instead, it was postulated that during systole, the brain expands with blood. This imparts a systolic pressure wave that moves the cerebellar tonsils downward and acts on the spinal CSF along the surface of the cord to compress the cord and propel fluid in the syrinx longitudinally with each pulse.18,19,25,28

Definition

Management

Hydromyelia is an abnormal dilatation of the central spinal canal, which usually communicates with the fourth ventricle. A syrinx is a fluid-filled cavity either within the spinal cord (syringomyelia) or within the brainstem (syringobulbia). A syrinx is described as either communicating or noncommunicating, depending on whether there is a connection to the CSF pathways.

MRI is crucial in the evaluation of a syrinx because it shows the syrinx itself and the associated neurological disorders, including malformations at the craniocervical junction (Fig. 38–4).27 Surgical management consists mainly of either drainage or posterior fossa decompression. Traditionally, surgical intervention involved drainage with syringostomy and aspiration of the intramedullary fluid. There was later a paradigm shift with foramen magnum decompression, with or without plugging of the obex. More recently, there has been increasing interest in drainage procedures again, mainly because of the advent of microsurgical techniques and better shunt materials. Currently, surgery is indicated for a symptomatic syrinx and can be done either with posterior fossa decompression or as a shunt procedure. Shunts inserted in a syringosubarachnoid, syringopleural, or syringoperitoneal position are potentially associated with many complications, including shunt obstruction, dislocation or infection, spinal cord tethering, and septation within the syrinx cavity.27,29

Clinical Features A syrinx may occur in isolation or may be associated with an abnormality in the craniocervical junction. A common association is with the Chiari type I malformation. The level of the syrinx is variable and may in fact be several levels below the foramen magnum. Syringes may also be secondary to either trauma or focal spinal cord pathology, including tumors.25 The clinical picture in syringomyelia can be variable. The typical description is of a dissociated suspended sensory loss of compromised pain and temperature sensation with intact vibration and joint position sense, in a capelike distribution over the arms and trunk. Associated motor features include myelopathy, leading to spasticity and weakness with lower motor neurone signs at the level of the lesion and upper motor neuron signs below the level of the syrinx. A syrinx can manifest with pain, including radicular pain, neck pain, and headaches. Involuntary movements were characterized in 22% of patients with syringomyelia and syringobulbia, including torticollis, myoclonus, tremors, dystonia, myokymia, respiratory synkinesis, and inverse masticatory muscle activity.26,27

Neural Tube Defects Definition NTDs result either from a failure of fusion of the neural tube in early postconceptional life or from a reopening of a previously closed neural tube.3,6 NTDs can be classified according to the following:

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■ Encephalocele or cranial meningocele is an unfused

midline defect in the skull that results in a closed lesion with eventration of the brain tissue and its coverings (encephalocele) or filled with only cerebrospinal fluid (cranial meningocele). These defects are classified by location into occipital, parietal, and anterior lesions.3,6 3. Level of the spinal neural tube: Terminology in this area can be confusing. Some authors refer to this defect in the spinal neural tube as spina bifida. There is incomplete fusion of the caudal neural tube, which leads to lesions affecting the spinal cord, vertebrae, and skin. Other authors, however, consider spina bifida to encompass a more wide-ranging spectrum involving the whole central nervous system. In this chapter, we refer to the former definition of spina bifida. In addition, the terms rachischisis and myelodysplasia are occasionally used as well to define a spinal NTD.3,6,30 Within the spine and spinal cord itself, spina bifida can span a wide range of anomalies, from mild defects with absent spinous processes to the huge defects seen with a myelomeningocele. There are two major working classification systems for spina bifida. Spina bifida can be classified depending on the pattern of the defect (Fig. 38–5):

A ■

B

Figure 38–4. Magnetic resonance images of a thoracic syrinx. There is a syrinx of the cord, largest at the midthoracic level, where it occupies 60% of the cord width. A syrinx is usually central within the cord and has a fusiform appearance. The signal characteristic of a syrinx is isointensity of cerebrospinal fluid on both T1 and T2. For instance, the syrinx appears hypointense on the T1 sequence (A) and hyperintense on the T2 sequence (B).

1. The level at which they occur within the nervous system. 2. The timing of the defect: Neurulation defects occur during the neurulation process, whereas postneurulation defects occur later. 3. Whether they are open or closed: In an open lesion, the neural tissues are exposed, whereas in a closed lesion, the defect is covered by skin. Open lesions occur as neurulation defects and closed lesions as postneurulation defects. The postneurulation defects are closed lesions because the embryonic ectoderm covers the surface of the embryo, this coverage having occurred with earlier closure of the neural tube. Clinically, it is best to consider NTDs according to the level at which they occur within the neuraxis: 1. Level of both the cranial and spinal portions of the neural tube ■ Craniorachischisis is an open lesion in which there is total dysraphism, with the brain and spinal cord exposed to the surface. Craniorachischisis occurs from failures in the very initial stages of neurulation. ■ Iniencephaly is a closed lesion with significant abnormalities of the brain, spinal cord, skull, and vertebrae. Dysraphia in the occipital region is accompanied by severe retroflexion of the neck and trunk.3,6 2. Level of the cranial neural tube ■ Anencephaly consists of partial or total absence of the brain, with the undeveloped brain exposed to the surface through a defect in the skull and scalp.

1. Closed spina bifida is a defect is covered by normal skin. There can be a visible herniation covered by normal skin, or there may be no external sac or other visible stigmata, such as subcutaneous lipomata and cutaneous manifestations. 2. Open spina bifida is a failure of fusion of the posterior vertebral arches with secondary herniation of exposed neural tissue and meninges that is not covered by skin or that is covered only by a membrane in a visible cystic mass. The other classification system categorizes spina bifida as follows: 1. Spina bifida occulta refers to a concealed form of spina bifida with few cutaneous clues to the underlying spinal disorder. 2. Spina bifida aperta refers to lesions that communicate with the environment. 3. Spina bifida cystica refers to either a meningocele or a myelomeningocele: ■ Meningocele is a protrusion of the dura and arachnoid through the defect in the vertebral laminae, leading to a cystic swelling. The spinal cord remains within the spinal canal. This normally occurs in the lumbosacral region. ■ Myelomeningocele is a defect in which the spinal cord and/or the cauda equina, together with the meninges, are extruded within an externalized lumbosacral sac. This is the most common form of spina bifida and occurs mainly in the lumbar region (Figs. 38–6 and 38–7).3,6,30

Epidemiology In the United States, NTDs occur in 1 per 1000 pregnancies. Rates of NTDs are higher in Mexico and northern China. NTDs are more common in girls than in boys.5,6

Clinical Features It is important to recognize the cutaneous manifestations of a closed NTD in the caudal regions. These can include lipomas,

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Spina Bifida Occulta and Spina Bifida Cystica Conus Lumbar vertebral body

Filum terminale Spinous processes Absent spinous process

Sacrum

A. Spina Bifida Occulta. This is a closed defect and can be relatively minor. Conus

Filum terminale

Meningocele pouch

B. Meningocele. This is an outpouching of the meninges without the neural elements.

■

Figure 38–6. A large myelomeningocele. The neural elements are visible within this membrane-covered protrusion.

Thin membrane

C. Myelomeningocele. This is an outpouching of the meninges with the neural elements within and may be covered by only a thin membrane. ■

Figure 38–5. Diagrammatic representation of spina bifida occulta (A) and spina bifida cystica with a meningocele (B) and with a myelomeningocele (C).

epidermoid sinus, dermoid cysts, hemangiomas, cutaneous nevi, and a deep sacral dimple. Clinicians must maintain a high index of suspicion when they see these cutaneous lesions and not dismiss them merely as isolated benign lesions.3 The actual clinical manifestations and functional outcomes in spina bifida depend mainly on the level of the defect and the severity of the lesion. Neurological dysfunction results from sensory abnormalities and manifests through leg weakness and paralysis to bladder and bowel dysfunction. Spina bifida most commonly occurs in the lumbosacral region: 1. Spina bifida in the sacral region commonly affects bladder and bowel function and results in sexual dysfunction. The lower limbs may not be affected. 2. A lesion affecting the lower lumbar and sacral regions affects the lower limbs, with the lower legs and the feet more affected than the more proximal hip flexors or quadriceps. The buttocks tend to be involved as well. 3. Spina bifida in the upper lumbar region affects the hip flexors and knee extensors and occasionally spares the feet and lower legs. Urological abnormalities are common; most affected individuals lack sphincter control, and 80% have a neurogenic

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including sleep apnea, swallowing difficulties, stridor, headache, quadriparesis, scoliosis, and balance and coordination difficulties. Hydromyelia occurs in approximately 40% of individuals with myelomeningocele and manifests as progressive scoliosis, weakness of the upper limbs, spasticity, and an ascending motor loss in the lower limbs. Meningitis and serious nervous system infections cause significant morbidity as well.3,5,32 Individuals with spina bifida have a normal overall IQ score. Despite this, they have selective cognitive disabilities, including distractibility, a short attention span, and difficulties with perceptual organization and visual-motor integration. Practitioners involved in the care of individuals with spina bifida must monitor for the psychosocial complications of having a chronic disorder that is potentially disabling and deforming. All these factors have a significant effect on an individual’s ability to participate in education and employment opportunities and to engage in independent living.31

Prognosis

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Figure 38–7. Magnetic resonance image of a myelomeningocele. This sagittal T2 image shows a well-defined myelomeningocele sac with the filum terminale extending into the sac.

bladder. Although mainly in the lumbosacral region, spina bifida can also affect the thoracic region and, in rare cases, the cervical region. A lesion affecting the thoracic level significantly compromises lower limb strength.5,31 Orthopedic abnormalities, including clubfoot, contractures, and dislocated hips, can occur as well. Of all children with spina bifida, 90% have spinal curvature problems as well, including kyphosis, scoliosis, and kyphoscoliosis. Community ambulation is defined as the ability to move about the community without using a wheelchair. This can be achieved by 100% of patients with sacral and lower lumbar lesions and by 63% of patients with higher-level lesions. Other than the neurological level of the lesion and musculoskeletal deformities, other important factors influencing mobility and ambulation include balance disturbances, spasticity in the knees and hips, and the number of shunt revisions made.32,33 A host of late complications can occur in spina bifida, either as a consequence of the disorder and the deficits or as a consequence of the surgical intervention. The extent and severity of the neurological deficit itself can lead to severe medical complications as well. For instance, a neurogenic bladder can lead to recurrent urinary tract infections and chronic renal dysfunction. Severe sensorimotor deficits can lead to decubitus pressure sores and ulcers and other consequences of reduced mobility. Other late neurological complications include progressive hydrocephalus and the Chiari type II malformation, spinal cord tethering, and hydromyelia. Of individuals with myelomeningocele, 75% have an associated Chiari type II malformation that can be identified radiologically. Up to a third have clinically symptomatic lesions with manifestations,

Spina bifida is a complex developmental disorder that is associated with relatively longer survival. Approximately 78% of all individuals with spina bifida survive to 17 years, and approximately 52% to 68% with spina bifida survive to the third decade. Survival depends significantly on the availability and delivery of optimal medical and surgical care. For instance, the early infant mortality rate in spina bifida is 10% in the United States and nearly 100% in northern China. The prognosis in spina bifida is relatively good, in contrast to anencephaly (affected children either are stillborn or die shortly after birth) and craniorachischisis (most affected fetuses are lost in early spontaneous abortion, or infants die after birth).3,5,6 The overall long-term prognosis in spina bifida, however, is not good in that there is significant morbidity associated with the condition. Survivors of spina bifida can have a multitude of problems ranging from the neurological deficits to the medical complications to the emotional and psychological scars. There is a significant burden of care on the community as well. The average monetary cost of medical care over a lifetime for an infant born in 1988 with spina bifida was $294,000 (in 1992 monetary terms).6

Etiology and Pathophysiology The causes of spina bifida are heterogenous and consist of genetic and environmental factors. Spina bifida is likely to be the culmination of an interplay of genetic susceptibility and environmental factors. The combination of environmental and genetic triggers for spina bifida is supported by the geographical variation in the incidence rates.5,6 A genetic basis for NTDs is suggested by the racial differences in incidence and by the familial recurrence patterns. For instance, NTDs are more common in Hispanic and nonHispanic white persons than in black persons in the United States. In addition, there is a degree of disease aggregation in families. The siblings of affected individuals have a 3% to 8% chance of having spina bifida, anencephaly, or both. There is also an increased risk of spina bifida in second- and third-degree relatives of affected individuals.5,6 The exact etiological factors remain unknown for the majority of cases of spina bifida. In a minority, there are recognized

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syndromes causing the spina bifida. Of all children with NTDs, 20% have additional congenital malformations. Genetic abnormalities, including chromosomal abnormalities and single gene mutations, and teratogenic causes are identified in 10% of affected children.5,6 Of all the environmental factors studied, inadequate maternal intake of either natural folate or synthetic folic acid before conception and during the early stages of pregnancy has the most robust association with the development of NTDs. The exact mechanism of protection from folic acid is unclear but is likely to be mediated by genes that regulate folate transport and metabolism. Various genetic defects in the folate-homocysteine metabolism and folate transport have been identified as being associated with NTDs.5 Only a few specific environmental factors, including maternal diabetes and maternal use of anticonvulsants, have been identified in the causation of NTDs. A history of pregestational diabetes in women is associated with a twofold to tenfold increase in the risk of malformations of the central nervous system, including spina bifida, in their children. The risk is related to the level of maternal metabolic control. Use of valproic acid or carbamazepine by women is associated with a 1% to 2% risk of spina bifida in their children. Other factors shown to lead to an increased risk of NTDs include maternal obesity and maternal hyperthermia.5,6

Prevention Maternal folic acid supplementation before conception and during early pregnancy has been shown to prevent at least half the cases of NTDs and up to 70% of the cases of spina bifida. In 1991, a British study demonstrated that recurrent NTDs could be reduced by taking 4000 μg/day of folic acid. This was followed in 1992 by a Hungarian study that demonstrated that 800 μg/day of folic acid reduced the first occurrence of a neural tube defect. In a later (1999) study, a daily dose of 400 μg/day of folic acid was sufficient to prevent NTDs in an area of China with a high incidence of NTDs.5,6 The recommended dose is 400 μg/day of folic acid in women of childbearing age, especially if they are contemplating or planning a pregnancy. This is most consistently achieved through nutritional supplements. Other sources of folic acid include foods fortified with folic acid, including cereals and grains, and foods naturally rich in folate, including fruits and vegetables. There has been some concern that universal fortification of common foods may mask vitamin B12 deficiency.5,6

Management There are four phases in the management of spina bifida, described as follows.

Prenatal diagnosis and management considerations Prenatal management centers on diagnosis of the NTD and discussions about subsequent management. NTDs can be screened with maternal serum α-fetoprotein measurements and ultrasonography. The maternal serum α-fetoprotein level can be tested at the 16th week of pregnancy. False-positive results can arise from other malformations, the presence of multiple fetuses, and incorrect calculation of gestation dates. Ultrasonography is useful in diagnosing the NTD and in providing

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Figure 38–8. Magnetic resonance image of a Chiari malformation and a neural tube defect in a 35-week-old fetus. This scan demonstrates hydrocephalus and a Chiari malformation with tonsillar herniation. In addition, there is a neural tube defect in the lumbar region.

useful information about the overall growth of the fetus. It may, however, miss small myelomeningoceles. Once an NTD is diagnosed, ultrasonography is used to assess for other associated malformations and general limb movement, deformity, and paralysis. The use of fetal MRI is increasingly studied in this area as well (Fig. 38–8). Such prenatal imaging may have a bearing in predicting neurological deficit and functional outcome.3,5 Amniocentesis is a more invasive investigation that can be used to follow up positive screening test results. The αfetoprotein levels in the amniotic fluid at the 15th or 16th week of gestation are elevated in cases of an open NTD. Similarly, acetylcholinesterase levels are also elevated in cases of an open NTD. Fetal karyotype studies can be undertaken as well to investigate for chromosomal anomalies.3,5 Elective abortion for NTDs is an area of medicine fraught with ethical dilemmas and questions. Each situation must be dealt with on an individual basis within the foundations of a sound therapeutic relationship, with all the intertwined psychosocial factors and religious, moral, and ethical considerations taken into account. Damage to the neural tissue can occur either in utero, as a result of exposure to toxic substances in the amniotic fluid or mechanical damage from contact with the uterine wall, or during delivery, as a result of contact with the birth canal. Despite this, there is currently insufficient medical evidence to

chapter 38 spine and spinal cord: developmental disorders support any particular mode of delivery in minimizing the neurological impairments from spina bifida. The elective use of cesarean section, however, may be warranted to minimize trauma if there is a large lesion and to reduce the risk of dehiscence after in utero surgical treatment.5,6

Perinatal surgical considerations The next stage in management involves exploring the various surgical and therapeutic treatment options available. There is the choice of either in utero fetal surgery or the more traditional postnatal surgery. Postnatal surgical closure of a spinal lesion is usually undertaken within the first 48 hours after birth. If there is associated hydrocephalus, a ventricular shunt is usually inserted as well.5 There have been various studies exploring the role of in utero surgical repair of NTDs in fetuses as young as 22 weeks of gestational age. Studies have shown complete reversal of hindbrain herniation and a lower proportion of cases of hydrocephalus necessitating shunting (43% versus 85%). Initial reports have shown resolution of the associated Chiari type II malformations and a lower incidence of moderate to severe hindbrain herniation and hydrocephalus necessitating shunting. The urodynamic and leg function, however, remain similar in comparison with that in infants who are treated postnatally. The exact role of in utero surgery is unclear, especially with regard to the overall fetal and maternal risk-benefit ratio.5,6

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monitoring and judicious management of complications that can arise. This is best achieved through a multidisciplinary approach and within a primary prevention framework. Throughout the life of such a patient, it is important to monitor for psychological manifestations as well and to consider neuropsychological assessments as appropriate. Approximately 47% of hospital admissions for spina bifida result from potentially preventable secondary complications, including recurrent urinary tract infections and skin ulceration.6 Careful urological monitoring and advice are important. This is especially so in providing techniques for complete bladder emptying and in ensuring adequate catheter management, balanced with judicious use of pharmacological agents and surgical intervention. Skin care is of prime importance, with strategies to minimize skin friction and to ensure early attention to skin irritation and ulcers. Approximately 43% of people with spina bifida have a latex allergy. Latex-containing products should be avoided in the care of patients with spina bifida.6

Tethered Cord Syndrome Definition The tethered spinal cord is a syndrome complex in which there is progressive neurological deterioration as a result of pathological tethering of the spinal cord to an abnormal caudal position. The syndrome can be caused by a group of congenital vertebrospinal conditions, including the following:

A multidisciplinary setting is of critical importance in the ongoing early childhood assessment and management of spina bifida. The core participants in medical care include the primary care physician, the pediatrician, the pediatric neurosurgeon, the urologist, the orthopedic surgeon, a nurse clinician, the physiotherapist, and the social worker. Assessing and optimizing ambulation and mobility are of prime importance in the management of spina bifida. The orthopedic deformities can be treated with early surgical intervention. If left untreated, orthopedic deformities, including scoliosis, kyphosis, and hip dysplasias, can compromise mobility and functional outcomes. Supportive aids, including braces, canes, and walkers, can be used to maintain erect posture to achieve effective community ambulation. Wheelchair assessment is also important, especially if the combination of deficits weigh against successful independent ambulation.5,6 The potential complications must be considered and sought. For instance, the medical team should watch for progressive hydrocephalus with baseline imaging studies and serial head circumference measurements. Children who have had shunt surgery need to be evaluated on a regular basis for potential markers of shunt malfunction, including the development of seizures. Urodynamic studies and renal tract ultrasonography are important in assessing urological function.5 Growth is affected in spina bifida. Growth hormone has been successfully used in improving the growth of children with spina bifida. The overall long-term outcomes, however, are unknown at this stage.6

1. Thickened, tight filum terminale, which is one of the commonest causes of a tethered cord and occurs as the cord is pinned down to the sacrum by the thickened filum. 2. Intradural fibrous adhesions. 3. Intradural lipomas (Figs. 38–9 and 38–10): There are various classification systems for spinal lipomas according to either location in relation to the neural elements (e.g., caudal, dorsal, or transitional lipoma) or degree of herniation (e.g., lipomyelomeningocele). 4. Myelomeningocele, including occult lesions. 5. SCMs. 6. Dermal sinus tracts, which may be connected with an intraspinal dermoid cyst. 7. Developmental cysts.

Lifelong management and considerations

There are four modes of presentation of TCS:

The ongoing lifelong phase in the management of spina bifida essentially involves regularly scheduled evaluation for

1. Cutaneous stigmata: Affected individuals may be asymptomatic and present with only a cutaneous marker, including

All these causative conditions are sometimes grouped under the umbrella term spinal dysraphism, despite the clear structural and anatomical differences. The term refers broadly to this assorted group of congenital anomalies affecting the spine and spinal cord that have similarities in clinical manifestation and the consequent neurological deficits and deformities.34-36 Tethered cord syndrome (TCS) may also occur as a secondary condition as a result of surgical treatment for these disorders. For instance, the syndrome has been reported in 15% of patients with a previously repaired myelomeningocele, in whom surgical closure has led to posterior attachment of the neural placode at the site of repair.34,36

Clinical Features

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Figure 38–9. Magnetic resonance image of an intradural lipoma and tethered cord. This sagittal T2 image shows a low-lying spinal cord tethered to the intradural lipoma (in black, as opposed to the surrounding white cerebrospinal fluid). The spinous processes are not visualized in the sacral region.

a subcutaneous lipoma, hypertrichosis, or a nevus. Cutaneous features are more likely to occur in patients who present in childhood (Fig. 38–11). 2. Pain in the back, lower limbs, or anorectal region. This is less common in affected children but is a common feature in affected adults, occurring in 78%. The lower limb pain can be either unilateral or bilateral and may be diffuse, in a nondermatomal distribution. The pain tends to occur after prolonged sitting or bending forward. A radicular pattern of pain is rare in TCS. There have been reports of a Lhermittetype effect as well, with shocklike sensations traveling up and down the spine upon forward bending. 3. Progressive neurological deficits: Sensorimotor deficits localize to the lumbosacral region, may be mild, and manifest with minimal sensory disturbance and slight walking difficulties, or they may be severe with diffuse sensory disturbance and progressive weakness. Multiple cord segments or nerve root lesions may be affected bilaterally, in a combination of upper and lower motor neuron signs. Although the distal muscles are usually the most severely affected, the whole lower limb may be involved. Affected individuals may also present with rapidly progressive calf atrophy. Sensory disturbance is likely to occur in a saddle distribution. Neurogenic bladder and bowel dysfunction may occur. The bladder dysfunction may occur in either an upper or a lower motor neuron pattern, with either overactive or underactive detrusor function. Affected individuals may have an upper motor neuron pattern with a spastic, small-capacity bladder

B

Figure 38–10. Magnetic resonance images of an intradural lipoma associated with a lumbar syrinx. The lipoma lies dorsal to the tethered cord, with the conus at the level of L5/S1. The lipoma follows the subcutaneous fat signal; it is brighter and hyperintense on the sagittal T1 image (A) and relatively hypointense and less visible on the T2 image (B). In contrast, the syrinx has signal characteristics similar to those of the cerebrospinal fluid, appearing hypointense on the T1 image and hyperintense on the T2 image. The syrinx extends from T11-T12 to L4-L5 and occupies 75% of the cord diameter.

and voiding frequency and urgency. Alternatively, there may be a hypotonic large-capacity bladder with dribbling incontinence and a patulous anus with fecal incontinence. Infants may present with fewer dry diapers, whereas young children may also present with enuresis and problems with toilet training. Individuals may present with complications may arise from these neurological deficits, including trophic ulceration and urinary tract infections. 4. Progressive orthopedic deformities of the lower limb and spine, including equinovarus deformities and worsening scoliosis. This is more common as a presenting feature in children (Fig. 38–12).34,37 TCS tends to present in childhood. The age at symptom onset depends on the actual [VT1][VT2] degree of cord traction. The causative pathology itself does not appear to be correlated with either time of symptom onset or particular clinical manifestations. The milder lesions may manifest later in adulthood either as a result of the accumulated effects over time of tension on the conus during normal head and neck flexion or in the setting of an aggravating factor. Circumstances that have precipitated or worsened symptoms have included the following: 1. Activities that stretch the conus: lithotomy position for childbirth, prolonged sitting, straight-leg raising exercises. 2. Conditions that narrow the spinal canal: lumbar spondylosis, heavy lifting.

chapter 38 spine and spinal cord: developmental disorders

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C

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B

3. Direct trauma to the back, further compromising the neural tissues. Spinal cord tethering may occur after surgery for spinal dysraphism; hence, neurological deterioration or progression must be carefully evaluated after surgery. A history of myelomeningocele repair in childhood is an important clue to underlying TCS if an adult presents with clinical features suggestive of the syndrome.34,36

Etiology and Pathophysiology The spinal cord reaches the sacral-coccygeal region in early embryonic life. After 16 weeks of gestation, there is then a growth differential in which the bony vertebral column lengthens and grows beyond the spinal cord itself. This leads to ascension of the spinal cord to the level of L3 at 30 weeks of

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Figure 38–11. Patients with obvious midline cutaneous manifestations of underlying spinal dysraphism. The images show patients with a subcutaneous lipoma (A), a nevus (B), and a midline area of hypertrichosis overlying a patch of hyperpigmentation (C).

gestation and to the adult level of L1 or L2 by 2 months after birth.34,37 In embryonic life, the normal pattern of ascent is compromised if the conus is hinged to an abnormally low level by any of the underlying causative pathological entities responsible for TCS. In addition to the low-lying position, the neural tissues are abnormally stretched vertically. Studies have shown that, when placed under traction, the lumbosacral cord is vulnerable to hypoxic stress, with neuronal dysfunction resulting from mitochondrial oxidative derangement. Over time, neuronal dysfunction leads to neuronal damage. Other contributory factors include impairment of blood supply and problems with glucose metabolism. In essence, the TCS results from abnormal longitudinal traction that causes cord injury. There may be an additional factor with a compressive element from the underlying pathology: for instance, with a lipoma.34-36,38

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Management

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Figure 38–12. Patient with spinal dysraphism showing scoliosis, a visible lumbar region lipoma, and a left foot equinovarus deformity.

With normal growth and development—for instance, during the growth spurts—there is further stretching of the spinal cord, causing increasing neuronal damage. This leads to the onset of neurological features in early childhood in individuals with more severe cord tethering. Alternatively, symptoms may emerge later in milder cases, either in the setting of aggravating features as discussed previously or over time after repeated normal day-to-day stretching of the spinal cord from head and neck flexion. The sudden tension may lead to irreversible neuronal damage in an already chronically tethered cord. The tension from the tethered spinal cord can be transmitted up the cord, with neural elements stretched at levels away from the site of the tethering. This is one of the factors explaining the combination of upper and lower motor neuron signs that may be seen.34,35,38

MRI is of critical importance in the evaluation of TCS. MRI is useful for assessing conus position and thickness of the filum terminale and in looking for associated vertebrospinal anomalies. The conus is low-lying when the tip is abnormally located below the lower border of the L2 vertebral body, and the filum is thickened if it appears wider than 1.5 to 2.0 mm on MRI. The other clues of TCS include posterior placement of the spinal cord, thickened filum terminale, and the sacral roots’ running in a lateral or cephalic course, as opposed to the usual cephalocaudal orientation. Plain radiographs and CT scans are useful in delineating the associated bony vertebral abnormalities. Although the advent of MRI has rendered most of the older procedures obsolete, including the use of hyperbaric and gas myelography, there is occasionally a role for myelography in further defining the nerve root anatomy and pathways.34,36 Evaluation of TCS is incomplete without urodynamic studies, because neurogenic bladder dysfunction may occur even in the absence of symptoms. It is therefore important to refer individuals with TCS for urodynamic assessment. It is especially useful to perform assessments both preoperatively and postoperatively.37 Surgical management is aimed at untethering the spinal cord and neural elements and leads to good neurological outcomes and improvement in symptoms. Compressive lesions, if present, should be removed as well. Improvement after untethering surgery is especially convincing if the deficits are mild or treated early. In an analysis of TCS in adults, 83% experienced relief of significant pain and 67% experienced an improvement in sensorimotor deficits. Improvement in sphincter disturbance, however, is more variable. In one study, for instance, only 39% of patients with sphincter disturbance experienced an improvement. There have been occasional reports as well of bladder dysfunction occurring after surgery. Although there are no differences in the clinical presentation for the different pathologies, there are differences in ease of surgical management, depending on causative etiology. Complex lipomas and adhesions from previous operations prove to be the most challenging. Despite this, the overall rate of complications from surgery is low, with reported immediate postoperative neurological morbidity rates of 0% to 5%. Postoperative CSF fistula is a possible complication that should be treated early with further surgery and dural repair.34,36,37 Together, all these factors positively support the role of surgical intervention. Early surgery is particularly crucial for preventing further neuronal damage. Surgery is recommended in infants upon diagnosis of a tethered cord, to prevent neurological deficits. Surgery is also advocated in later presentations with progressive neurological deterioration. Retethering may occur after surgery and must be differentiated from incomplete untethering during the initial operation. There is a range of operative options for retethered cords.34,36-38

Split Cord Malformations Definition The traditional terms used for double spinal cord malformations were diplomyelia, for a twinning and doubling of the cord within a single dural sac, and diastematomyelia, for two hemicords in separate dural sacs separated by a midline spur. These

chapter 38 spine and spinal cord: developmental disorders terms were derived from Greek words: myelos, meaning marrow or cord; diplous, meaning double; and diastema, meaning cleft. These malformations have been categorized as SCMs. They are rare disorders with complete or incomplete division of the spinal cord by an osseocartilaginous or fibrous septum, leading to double spinal cords. In type I SCM, there are two hemicords separated by a rigid dura-sheathed osseocartilaginous septum, each hemicord housed within its own dural tube. In type II SCM, the spinal cord sits within a single dural tube and is split into two independent segments for a variable vertical extent by a nonrigid fibrous median septum.39,40

Clinical Features SCMs can be either asymptomatic or symptomatic. Affected children are more likely than affected adults to be asymptomatic. Both affected adults and children may present with cutaneous manifestations, the most common being hypertrichosis. Other cutaneous signs include capillary hemangiomas, a lipoma, and dermal sinus openings. SCMs may manifest with pain. This is a common feature in adulthood, and the pain may be localized to the spine at the site of the split cord, or it may be diffuse with a dysesthetic component. Neurological deficits, including progressive gait disturbance, worsening sensorimotor disturbance, and bladder or bowel dysfunction, may occur. SCMs most commonly affect the lumbar region; they also can occur in the cervical and thoracic regions. A cervical region SCM involves the upper limbs as well. Neurological decline is independent of SCM pattern and location type; neurological features occur equally in type I and type II SCMs, and progression rates are similar for cervical and thoracolumbar lesions. Trophic changes and nonhealing ulcers may eventuate in SCM. Urinary tract manifestations may include features of a neurogenic bladder, renal impairment, recurrent urinary tract infections, or incontinence. Urinary tract dysfunction, however, may be asymptomatic and must be carefully evaluated with urodynamic studies. Children can also present with orthopedic deformities, including scoliosis and foot deformities.30,40 SCMs may occur in conjunction with other vertebrospinal anomalies. The incidence of an coexisting myelomeningocele is 26% to 39% in individuals with SCM and is more common with type I SCM. The neural placode may involve both hemicords or only one of the hemicords as a hemimyelocele. Alternatively, involvement may be more limited with strands of neural tissue flowing from the hemicords to enter the myelomeningocele sac. SCMs may be associated with a low-lying conus and other tethering lesions, including tight filum terminale and lipomas. Abnormalities in the vertebral bodies adjacent to the SCM, including a bifid body, a widened body, and vertebral fusion, may be seen. Individuals with a cervical SCM may have an associated Klippel-Feil anomaly, with torticollis, a short neck, and webbed trapezii.30,40 Overall, the clinical manifestations are similar to those of TCS. There is one notable difference: Individuals with SCM may have a significant left-right differential with regard to lower limb neurology. This occurs either in the setting of a hemimyelocele, in which the side with the hemicord involved with the myelocele has much reduced function, or in the setting of an asymmetrical split within the spinal cord. In the latter situation, there is a large, major hemicord and a smaller, minor hemicord, with reduced function on the minor side.40

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Epidemiology There may be a slight female preponderance for SCM. The average age at diagnosis ranges from 3.9 to 5.7 years.30

Etiology and Pathophysiology The exact cause of SCMs is unknown. Initially, diastematomyelia was thought to be a developmental disorder resulting from abnormal tissue protrusions splitting the spinal cord. Diplomyelia, on the other hand, was postulated to result from an abnormal twinning response in early embryonic development. Later work, however, has shown the two entities to be the same and suggests that SCMs arise from a common embryogenetic mechanism. In the early embryonic period, adhesions are formed between the ectoderm and endoderm. These adhesions develop into an accessory neurenteric canal, which subsequently condenses into the endomesenchymal tract. This abnormal tract splits the notochord and neural plate into two hemineural plates.39

Management Investigations in SCMs are twofold. The first is to characterize the malformation, especially as part of an extensive presurgical workup. Plain radiographs are often unhelpful, although they occasionally show the bone abnormalities involved. CT scans and MRI have complementary roles. MRI is particularly valuable in demonstrating spinal cord anatomy and in defining the level and extent of the hemicord (Fig. 38–13). The number of vertebral bodies crossed is used to define the length of the split segment. In addition, it is important to perform MRI of the whole neuraxis to look for associated anomalies, including NTDs and lipomas. The high-resolution CT scan with finecut slices is especially useful in defining the spur characteristics and the bony vertebral body and posterior arches. The second role of investigations is to map out complications that may arise. Urodynamic studies are particularly important in this regard, especially if there are no overt renal tract features.40 Most surgeons advocate prompt identification and early surgical intervention for SCMs to either improve outcomes or prevent further functional deterioration. The pain component responds the best to surgical management; improvement occurs within a month. With neurological deficits, surgery may improve symptoms or may prevent further progression. Neurological recovery is inversely proportional to the duration of symptoms before surgical intervention. Results with sphincter dysfunction, however, are generally less encouraging, with an overall 40% improvement rate. Surgery involves excision of the midline spur, together with the dural sheath encasing the spur and any associated soft tissue bands that may be attached to the hemicord. The surgical morbidity rate is slightly higher in type I SCM. Complications may include wound complications and CSF leakage. Coexisting anomalies can be surgically treated as well. Orthopedic deformities can occasionally be managed with appropriate operations, including tendon transfer and joint arthrodesis. Management of bladder dysfunction with monitoring of renal function and judicious use of catheterization is also important. There have been reports in the literature of SCMs’ being diagnosed prenatally with ultrasonography.40

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Spine and Spinal Diseases 4. Type IV: total sacral agenesis with the lumbar vertebrae lying superior to the fused ilia. Some authors make a further distinction, with sacral agenesis referring to a symmetrical absence and sacral dysgenesis referring to an asymmetrical deformity. The syndrome of caudal regression encompasses a constellation of malformations in which multiple embryological defects of the caudal region occur in addition to sacral agenesis. The term caudal dysplasia refers to the anomalies of the spine and lower extremities that may be seen in infants of diabetic mothers.41-43

Epidemiology Sacral agenesis is a rare congenital malformation. A maternal history of diabetes mellitus is strongly associated with sacral agenesis; 16% to 64% of individuals with caudal vertebral deformity or sacral agenesis have a diabetic mother.42,43

A

Clinical Features

B ■

Figure 38–13. Magnetic resonance images of a split cord malformation. A, Two hemicords are shown enclosed in a single dural sac. B, The septum separating the two hemicords is visible. (Courtesy of Dr. Rachel Evans.)

Sacral Agenesis Definition In sacral agenesis, there is partial or complete absence of the sacral and coccygeal bones. Lumbosacral agenesis is a more severe point of the spectrum: complete sacral agenesis, together with variable lumbar agenesis. Sacral agenesis and lumbosacral agenesis are occasionally referred to together as distal spinal agenesis. This spectrum of anomalies was classified by Renshaw as follows: 1. Type I: unilateral sacral agenesis, partial or total. 2. Type II: partial and symmetrical bilateral defects. 3. Type III: total sacral agenesis with the lumbar vertebrae articulating with the ilia.

The features of sacral agenesis depend on the severity and extent of the lesion. Minor defects in the sacrum and coccyx may be asymptomatic, or typical cutaneous stigmata (e.g., lipoma, nevus) may be exhibited. Affected individuals may complain of back pain or may present with orthopedic and musculoskeletal features, including lower limb deformities and contractures, scoliosis, spine instability, and hip dislocations. Complete sacral agenesis, especially if affecting the lumbar region as well, leads to completely thin and flaccid lower limbs. The neurological deficit tends to correlate with the level of the vertebral abnormality and is often associated with bladder or bowel dysfunction. Ambulatory capacity is correlated with the type of sacral agenesis.41-43 Two distinct subgroups have been identified. Individuals with high agenesis have high blunt conus termination and tend to present with the typical features of flat buttock cheeks and prominent iliac crests. Such morphological changes are less pronounced with low agenesis and a low-lying conus. The recurring theme of multiple developmental defects applies to sacral agenesis as well; other congenital vertebrospinal deformities, including syrinx, myelomeningocele, and lumbosacral lipoma, may be present.41-43 The features of the syndrome of caudal regression may be more variable and span a wider range of potential problems, including cleft lip or palate and gastrointestinal and genitourinary malformations. Gastrointestinal tract abnormalities include imperforate anus and malrotation of the bowel. Genitourinary malformations include a pelvic or solitary kidney, a urogenital sinus, a perineal urethra, labial abnormalities, and penile atrophy. A combination of orthopedic and neurological problems may lead to a “Buddha” position, with marked flexion and overlapping of the lower limbs and equinovarus. The most severe end of the spectrum includes the dramatic sirenomelia malformation, in which the “mermaid” fusion of the lower limbs is accompanied by extreme malformations of lower gastrointestinal and genitourinary tracts, including total agenesis of the kidneys, renal tract, anus, and rectum.41,43

Etiology and Pathophysiology The exact cause of sacral agenesis is unclear but appears to be a defect either late in or after the neurulation stage of embryo-

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tomatic; typical clinical features involve cutaneous lesions, pain, neurological deficits, and orthopedic deformities. Most of the disorders do not occur in isolation and tend to be associated with the other vertebrospinal anomalies. Imaging techniques, including CT scans and MRI, are useful in the delineation and characterization of these disorders. Clinicians need to be aware of the whole spectrum of disorders and the manifestations that may occur, in order to facilitate early diagnosis and appropriate management within a multidisciplinary health care team to improve neurological and functional outcomes.

K E Y

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An understanding of the basic aspects of the embryology and development of the nervous system is necessary to appreciate the spectrum and severity of developmental disorders affecting the spine and spinal cord.

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There are many developmental disorders that can affect the spine and spinal cord. In approaching the treatment of these disorders, it is important to clarify definitions in order to avoid confusion, and it is useful to have a working classification system within which to approach treatment.

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Many developmental disorders and malformations coexist rather than being isolated. In addition, the clinical manifestations of the developmental disorders are varied and can manifest during both childhood and adulthood. For clinicians, it is important to recognize the whole range of developmental disorders and the myriad of clinical features in order to optimize investigation and treatment of the primary disorder and coexisting malformations.

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The neural tube defects are particularly important because they are among the more common serious malformations affecting the spine and spinal cord for which there is relative success in prevention and treatment.

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Imaging modalities, including computed tomographic and magnetic resonance imaging techniques, are essential for the diagnosis of many developmental disorders. It is vital for clinicians to understand the role and interpretation of these techniques.

Figure 38–14. Sagittal T2 magnetic resonance image of sacral agenesis. Only the first two sacral segments are identified. In addition, there is an abrupt termination of the conus at T12 with a blunt end, rather than the usual tapering structure.

genesis. This view is derived from the observation that sacral agenesis is a closed defect. An insult to the caudal eminence may be the cause of high agenesis, whereas a milder or later insult affecting differentiation may be the cause of the low agenesis.43

Management As with the other vertebrospinal conditions, evaluation with MRI is necessary to delineate the neural structures and associated anomalies (Fig. 38–14). Bony definition may be improved on CT scanning. The primary aim of orthopedic intervention is to improve mobility or sitting and standing balance. This may be achieved through the use of orthotics and a range of surgical measures, including soft tissue releases, osteotomies, and open reduction of hip dislocations. Limb amputation has been undertaken for severe deformities that cannot be corrected or ameliorated with simpler operations. The role of neurosurgery is not as well defined, inasmuch as there are conflicting accounts of benefit in sacral agenesis. There have been reports favoring early preemptive neurosurgery for the low-lying variant.41,43

P O I N T S

Suggested Reading Botto LD, Moore CA, Khoury MJ, et al: Neural-tube defects. N Engl J Med 1999; 341:1509-1519. Lemire RJ: Neural tube defects. JAMA 1988; 259:558-562. Mitchell LE, Adzick NS, Melchionne J, et al: Spina bifida. Lancet 2004; 364:1885-1895. Pang D, Dias MS, Ahab-Barmada M: Split cord malformation: Part I: a unified theory of embryogenesis for double spinal cord malformations. Neurosurgery 1992; 31:451-480. Pang D, Wilberger JE Jr: Tethered cord syndrome in adults. J Neurosurg 1982; 57:32-47.

CONCLUSION The developmental disorders of the spine and spinal cord encompass a wide spectrum of anomalies with variable clinical manifestations. The disorders may be asymptomatic or symp-

References 1. O’Rahilly R, Muller F: Prenatal ages and stages—measures and errors. Teratology 2000; 61:382-384.

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2. O’Rahilly R, Muller F: Minireview: summary of the initial development of the human nervous system. Teratology 1999; 60:39-41. 3. Lemire RJ: Neural tube defects. JAMA 1988; 259:558-562. 4. O’Rahilly R, Muller F: The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology 2002; 65:162-170. 5. Mitchell LE, Adzick NS, Melchionne J, et al: Spina bifida. Lancet 2004; 364:1885-1895. 6. Botto LD, Moore CA, Khoury MJ, et al: Neural-tube defects. N Engl J Med 1999; 341:1509-1519. 7. O’Rahilly R, Muller F: Somites, spinal ganglia, and centra. Enumeration and interrelationships in staged human embryos, and implications for neural tube defects. Cells Tissues Organs 2003; 173:75-92. 8. Tracy MR, Dormans JP, Kusumi K: Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res 2004; (424):183-190. 9. Muller F, O’Rahilly R: Segmentation in staged human embryos: the occipitocervical region revisited. J Anat 2003; 203:297-315. 10. Dickinson LD, Tuite GF, Colon GP, et al: Vertebral artery dissection related to basilar impression: case report. Neurosurgery 1995; 36:835-838. 11. Hayes M, Parker G, Ell J, et al: Basilar impression complicating osteogenesis imperfecta type IV: the clinical and neuroradiological findings in four cases. J Neurol Neurosurg Psychiatry 1999; 66:357-364. 12. Bhangoo RS, Crockard HA: Transmaxillary anterior decompressions in patients with severe basilar impression. Clin Orthop Relat Res 1999; (359):115-125. 13. Jain VK, Takayasu M, Singh S, et al: Occipital-axis posterior wiring and fusion for atlantoaxial dislocation associated with occipitalization of the atlas. Technical note. J Neurosurg 1993; 79:142-144. 14. May D, Jenny B, Faundez A: Cervical cord compression due to a hypoplastic atlas. Case report. J Neurosurg Spine 2001; 94:133-136. 15. Lowry DW, Pollack IF, Clyde B, et al: Upper cervical spine fusion in the pediatric population. J Neurosurg 1997; 87:671676. 16. Dickman CA, Sonntag VK: Surgical management of atlantoaxial nonunions. J Neurosurg 1995; 83:248-253. 17. Gluf WM, Brockmeyer DL: Atlantoaxial transarticular screw fixation: a review of surgical indications, fusion rate, complications, and lessons learned in 67 pediatric patients. J Neurosurg Spine 2005; 2:164-169. 18. Eule JM, Erickson MA, O’Brien MF, et al: Chiari I malformation associated with syringomyelia and scoliosis: a twenty-year review of surgical and nonsurgical treatment in a pediatric population. Spine 2002; 27:1451-1455. 19. Muhonen MG, Menezes AH, Sawin PD, et al: Scoliosis in pediatric Chiari malformations without myelodysplasia. J Neurosurg 1992; 77:69-77. 20. Koehler PJ: Chiari’s description of cerebellar ectopy (1891). With a summary of Cleland’s and Arnold’s contributions and some early observations on neural-tube defects. J Neurosurg 1991; 75:823-826. 21. Nishikawa M, Sakamoto H, Hakuba A, et al: Pathogenesis of Chiari malformation: a morphometric study of the posterior cranial fossa. J Neurosurg 1997; 86:40-47.

22. Meadows J, Kraut M, Guarnieri M, et al: Asymptomatic Chiari Type I malformations identified on magnetic resonance imaging. J Neurosurg 2000; 92:920-926. 23. Wu YW, Chin CT, Chan KM, et al: Pediatric Chiari I malformations: do clinical and radiologic features correlate? Neurology 1999; 53:1271-1276. 24. Pascual J, Oterino A, Berciano J: Headache in type I Chiari malformation. Neurology 1992; 42:1519-1521. 25. Oldfield EH: Syringomyelia. J Neurosurg Spine 2001; 95:153155. 26. Nogues MA, Leiguarda RC, Rivero AD, et al: Involuntary movements and abnormal spontaneous EMG activity in syringomyelia and syringobulbia. Neurology 1999; 52:823-834. 27. Vaquero J, Martinez R, Arias A: Syringomyelia-Chiari complex: magnetic resonance imaging and clinical evaluation of surgical treatment. J Neurosurg 1990; 73:64-68. 28. Oldfield EH, Muraszko K, Shawker TH, et al: Pathophysiology of syringomyelia associated with Chiari I malformation of the cerebellar tonsils. Implications for diagnosis and treatment. J Neurosurg 1994; 80:3-15. 29. Batzdorf U, Klekamp J, Johnson JP: A critical appraisal of syrinx cavity shunting procedures. J Neurosurg 1998; 89:382388. 30. Kumar R, Bansal KK, Chhabra DK: Occurrence of split cord malformation in meningomyelocele: complex spina bifida. Pediatr Neurosurg 2002; 36:119-127. 31. Simeonsson RJ, McMillen JS, Huntington GS: Secondary conditions in children with disabilities: spina bifida as a case example. Ment Retard Dev Disabil Res Rev 2002; 8:198-205. 32. Bartonek A, Saraste H: Factors influencing ambulation in myelomeningocele: a cross-sectional study. Dev Med Child Neurol 2001; 43:253-260. 33. McLone DG: Spina bifida today: problems adults face. Semin Neurol 1989; 9:169-175. 34. Pang D, Wilberger JE Jr: Tethered cord syndrome in adults. J Neurosurg 1982; 57:32-47. 35. Yamada S, Zinke DE, Sanders D: Pathophysiology of “tethered cord syndrome.” J Neurosurg 1981; 54:494-503. 36. Kirollos RW, Van Hille PT: Evaluation of surgery for the tethered cord syndrome using a new grading system. Br J Neurosurg 1996; 10:253-260. 37. Zoller G, Schoner W, Ringert RH: Pre- and postoperative urodynamic findings in children with tethered spinal cord syndrome. Eur Urol 1991; 19:139-141. 38. Yamada S, Iacono RP, Andrade T, et al: Pathophysiology of tethered cord syndrome. Neurosurg Clin North Am 1995; 6:311323. 39. Pang D, Dias MS, Ahab-Barmada M: Split cord malformation: part I: a unified theory of embryogenesis for double spinal cord malformations. Neurosurgery 1992; 31:451-480. 40. Pang D: Split cord malformation: part II: clinical syndrome. Neurosurgery 1992; 31:481-500. 41. Guidera KJ, Raney E, Ogden JA, et al: Caudal regression: a review of seven cases, including the mermaid syndrome. J Pediatr Orthop 1991; 11:743-747. 42. Van Buskirk CS, Ritterbusch JF: Natural history of distal spinal agenesis. J Pediatr Orthop B 1997; 6:146-152. 43. O’Neill OR, Piatt JH Jr, Mitchell P, et al: Agenesis and dysgenesis of the sacrum: neurosurgical implications. Pediatr Neurosurg 1995; 22:20-28.

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39

PRIMARY MYELOPATHIES (DEGENERATIVE, INFECTIVE, METABOLIC) ●

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Mark Paine

A number of conditions may selectively involve the spinal cord; some of these conditions also involve other neural tissues, to a lesser extent. The spinal cord neurons are relatively extensive, and as a result, they may be particularly susceptible to defects, which impair intraneuronal transport mechanisms. This chapter covers primary disorders of the spinal cord, excluding spinal cord trauma, spinal cord compression, and developmental spinal disorders; those topics are covered in Chapters 38, 40, and 99. For discussion, it is convenient to divide the primary myelopathies into acute (including subacute) and chronic clinical manifestations.

ACUTE MYELOPATHIES Acute myelopathy, or acute transverse myelopathy, is a disorder of acute or subacute spinal cord dysfunction resulting from a variety of causes, as listed in Table 39–1. In a clinical study, de Seze and colleagues (2001) found the commonest cause to be multiple sclerosis (43%); other causes included systemic disease (16.5%), spinal cord infarction (14%), infectious or parainfectious conditions (6%), and radiation myelopathy (4%). No underlying cause was found in the remaining 16.5%, despite an average of 29 months’ follow-up. The criteria for the clinical diagnosis of acute transverse myelopathy include (1) acute/subacute onset of sensory and motor symptoms, including symptoms of sphincter dysfunction; (2) spinal segmental level of sensory disturbance with a well-defined upper limit; (3) occurrence of symptoms over no more than 3 weeks and sustained for a period of at least 48 hours; (4) no clinical or radiological evidence of spinal cord compression; and (5) no known history of neurological disease or neurological symptoms. New cases of acute transverse myelopathy occur at a rate of 1 to 4 per million people per year. There is no gender predisposition, in contrast to the predominant female predisposition in multiple sclerosis. Fifty percent of patients develop almost complete paraparesis, most have bladder dysfunction, and 80% to 94% have sensory disturbance. The recovery of the neurological deficit is somewhat variable: One third of patients recover with little or no deficit, one third have moderate disability, and one third have severe disability. Acute transverse myelopathy may be an initial presenting feature of multiple sclerosis. Typically, such patients who ultimately go on to develop multiple sclerosis have an asymmetri-

cal partial transverse myelitis: that is, predominant sensory disturbance with relative motor sparing. Magnetic resonance imaging (MRI) of the spine characteristically shows lesions extending over less than two spinal segments. MRI of the brain may show characteristic demyelinating lesions (in up to 50% of cases manifesting as a clinically isolated syndrome). The cerebrospinal fluid may reveal unmatched oligoclonal bands (in up to 50% of cases manifesting as a clinically isolated syndrome). The diagnostic evaluation of a patient with suspected acute transverse myelopathy initially involves neuroimaging of the spine (usually MRI with gadolinium) to rule out a compressive myelopathy. After a compressive spinal lesion is ruled out, a lumbar puncture helps distinguish an inflammatory myelopathy from a noninflammatory myelopathy. The cerebrospinal fluid analysis includes a cell count determination and differential, protein and glucose level measurements, oligoclonal band analysis, and cytologic studies. If an inflammatory myelopathy is suspected, brain MRI and evoked potentials may indicate whether there is a multifocal inflammatory process, suggestive of multiple sclerosis, acute disseminated encephalomyelitis or neuromyelitis optica (also known as Devic’s syndrome). In the case of neuromyelitis optica, patients may be tested for a specific neuromyelitis optica–immunoglobulin G autoantibody, as recently described by Lennon and associates. A possible infectious/parainfectious cause may manifest with certain clinical features: fever, rash, meningismus, concurrent systemic infection, immunocompromised state, recurrent genital infection, radicular burning pain with vesicles (suggestive of herpes zoster), and lymphadenopathy. In such cases, further investigation includes serum and cerebrospinal fluid viral and bacterial cultures, cerebrospinal fluid viral and bacterial polymerase chain reaction studies, and acute and convalescent serum antibody studies for the infectious agents listed in Table 39–1. Alternatively, certain clinical features such as arthritis, erythema nodosum, xerostomia, Raynaud’s phenomenon, rash, and ulcers may be suggestive of an underlying systemic disease, such as systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis, mixed connective tissue disease, Behçet’s disease, or antiphospholipid antibody syndrome. If a systemic autoimmune disease is suspected, serum should be analyzed for antinuclear antibodies, double-stranded DNA antibodies, Ro and La antibodies, cardiolipin antibodies, lupus anticoagulant,

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T A B L E 3 9 – 1.

Causes of Acute Transverse Myelopathy

T A B L E 3 9 – 2.

Demyelination

Multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica Systemic lupus erythematosus, sarcoid, Sjögren’s syndrome, Behçet’s syndrome, antiphospholipid syndrome, mixed connective tissue disease Herpes simplex viruses 1 and 2, herpes zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, enterovirus, human immunodeficiency virus, human T cell lymphotrophic virus type 1, mycoplasma, Lyme disease, syphilis Arterial, venous, watershed, arteriovenous malformation, fibrocartilaginous embolism Radiation myelopathy, epidural lipomatosis

Spinal multiple sclerosis Primary lateral sclerosis Hereditary spastic paraplegia Spinal muscular atrophy Subacute combined degeneration Radiation myelopathy Paraneoplastic myelopathy Hepatic myelopathy Adrenomyeloneuropathy Infections (human T cell lymphotrophic virus type 1, parasites, toxoplasmosis) Systemic disease (e.g., systemic lupus erythematosus, Sjögren’s syndrome)

Systemic disorders

Infectious/ parainfectious

Vascular Miscellaneous Idiopathic

angiotensin-converting enzyme level, β2-glycoprotein level, and complement levels. Schirmer’s test, lip/salivary gland biopsy, and chest computed tomographic scan should also be considered.

CHRONIC MYELOPATHIES The commonest causes of chronic myelopathy seen in neurological practice include spinal multiple sclerosis, cervical spondylitic radiculomyelopathy, and sporadic motor neuron disease. These topics are covered in more detail elsewhere in the book. Patients with chronic myelopathy typically present with gradually progressive spastic paraparesis and varying spastic paresis of the upper limbs. The extent of sensory loss varies according to the nature of the underlying neuropathology. Sphincter dysfunction is also commonly seen. Causes of chronic myelopathy are listed in Table 39–2.

Causes of Chronic Myelopathy

logical features such as amyotrophy, dementia, epilepsy, optic atrophy, retinopathy, extrapyramidal disease, ataxia, mental retardation, deafness, ichthyosis, and peripheral neuropathy. Patients present at any age, typically with gait disturbance. A patient may present with toe walking, with a tendency to trip because the feet catch on uneven ground, or with premature wear on footwear. In childhood cases, walking may be delayed. Spasticity predominates over weakness, particularly in the lower limbs. The upper limbs are rarely affected. Brisk tendon reflexes with extensor plantar responses are found. Sensory loss, if present, involves mild impairment of vibration sense. Similarly, sphincter involvement is usually mild and results in urinary urgency, frequency, and hesitancy. Some affected patients may be so severely disabled by spasticity that they require a walking aid or wheelchair, despite having normal performance on muscle testing. Some affected family members may be minimally affected or even asymptomatic. The prognosis is highly variable; however, early-onset cases (manifesting before age 35 years) may have a very slowly progressive course with ambulation remaining, whereas later onset cases (after age 35 years) may progress rapidly, rendering patients nonambulatory. The diagnosis is usually made by exclusion of alternative causes, although gene testing is available for some cases.

Hereditary Spastic Paraplegia Hereditary spastic paraplegia is a rare, genetically determined degenerative disorder affecting predominantly corticospinal neurons. The condition is outlined in more detail in Chapter 69. Hereditary spastic paraplegia was first described by Adolf von Strümpell and M. Lorrain during the late 19th century. Although the phenotypic variants are well described elsewhere, knowledge of the genetic basis of this condition has undergone vast changes since the mid-1990s. At the time of this writing, more than 20 genetic loci (labeled SPG1 to SPG23) and nine defined gene products have been discovered. These gene products include spastin (which accounts for 40% of dominantly inherited hereditary spastic paraplegia cases), atlastin, NIPA1, kinesin heavy chain, heat shock protein 60, seipin, paraplegin, spartin, L1 cell adhesion molecule, and proteolipid protein. The precise functions of these gene proteins are not well understood; however, knowledge in this area is rapidly expanding. Hereditary spastic paraplegia displays marked phenotypic and genotypic variabilities. The inheritance may be autosomal dominant, autosomal recessive, or X-linked. The disorder has traditionally been divided clinically into pure and complicated forms; the latter has been associated with additional neuro-

Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a hereditary degenerative disorder involving the anterior horn cells, spinal interneurons, and, in some cases, the bulbar nuclei. The childhood-onset, autosomal recessive, proximal form is the commonest variation of the disorder. The incidence ranges from 1 per 6000 to 1 per 10,000. It is a common genetic cause of death and disability in childhood. The disorder has traditionally been classified into types I, II, and III by age at onset and by severity. Type I, also known as Werdnig-Hoffman disease, is characterized by early age at onset (before 6 months of age) and severe muscle weakness, muscle wasting, and hypotonia. Death from respiratory failure often occurs before the age of 2 years. Type III, also known as Kugelberg-Welander disease, begins after the age of 18 months and is of milder severity. Affected patients usually survive into adulthood, and many can walk or stand without assistance. Type II is an intermediate form. Additional clinical features of SMA include hyporeflexia, tongue fasciculations, and hand tremor. Sensory loss and sphincter disturbance are absent. The electrophysiological investigations reveal changes in denervation on electromyography and normal sensory/motor

chapter 39 primary myelopathies (degenerative, infective, metabolic) conduction velocities. Muscle biopsy also reveals denervative changes with hypertrophic fibers. Genetic linkage analysis has linked SMA types I, II, and III to defects on chromosome 5q11.2-13.3. A mutation in the survival motor neurone gene (SMN1) was discovered as the causative factor. A copy gene, SMN2, acts as a modifier gene, possibly rescuing the phenotype. The SMN1 gene codes for a 38-kD protein, which plays a multifunctional role in ribonucleoprotein metabolism and premessenger RNA splicing. There appears to be a dose effect of the SMN protein, which determines the clinical subtype and therefore the severity of the condition. A number of less common variants of SMAs also occur. A rare subtype of SMA type I, SMARD1, constitutes 1% of cases of infantile SMA. This variant is characterized by severe diaphragmatic weakness with eventration of abdominal contents, which results in respiratory distress. The muscle weakness is usually predominantly distal rather than proximal, as opposed to the more commonly occurring SMA type I. Another subtype is dominant distal SMA, also known as “spinal CMT 2D.” In this variant, there is a predominance for upper limb weakness; the condition is linked to chromosome 7p and has been found to be caused by a mutation in the glycyl transfer RNA synthetase gene. A further variant is X-linked severe SMA with arthrogryposis and bone fractures.

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gerated deep tendon reflexes (11%). Brisk deep tendon reflexes with extensor plantar responses and lower limb spasticity were found in just 6%. The evaluation of a patient with suspected cobalamin deficiency should begin with a serum cobalamin level measurement, and if the level is in the low normal range and the clinical index of suspicion is high, then serum methylmalonic acid and homocystine levels should be measured. If the serum cobalamin level is reduced, measurement of intrinsic factor antibodies and parietal cell antibodies may be useful in diagnosing autoimmune pernicious anemia. Schilling’s test may then be helpful in determining the cause of cobalamin deficiency. Spinal MRI may show characteristic T2 signal changes in the posterior and lateral columns, and somatosensory evoked potentials may demonstrate impairment of central conduction defects. Treatment of cobalamin deficiency requires 1000 μg of intramuscular cobalamin daily for 5 days, followed by monthly doses of similar amount. Exposure to nitrous oxide, either through its use as an anesthetic or through recreational use, may trigger an acute or subacute myelopathy by interfering with cobalamin metabolism. The treatment is the same as for subacute combined degeneration as described previously.

Copper Deficiency Myelopathy Cobalamin Deficiency Myelopathy or Subacute Combined Degeneration Neurological disorders associated with pernicious anemia were first identified in the late 19th century. Although the myelopathy associated with cobalamin deficiency is the predominant neurological manifestation, other recognized features include dementia, neuropathy, and, in rare cases, optic neuropathy. A more comprehensive discussion of the cobalamin deficiency is presented in Chapter 109; however, the myelopathy is briefly described here. Classically, a patient presenting with numbness and weakness in the legs is found to have macrocytic anemia. The examination reveals a smooth tongue, prematurely graying hair, and yellow skin. The diagnosis is then confirmed by demonstration of a low serum cobalamin level. Frequently, however, affected patients present with atypical clinical or laboratory features, such as neurological manifestations without anemia, macrocytosis, or depressed serum cobalamin level. In the last situation, elevated levels of cobalamin metabolites (methylmalonic acid and homocystine) may provide a clue to the diagnosis. Healton and colleagues reported the first large series of patients with neurological manifestations from cobalamin deficiency since the introduction of modern diagnostic techniques and therapeutic measures. Of 369 patients with cobalamin deficiency, 189 (51%) had neurological symptoms and 114 (31%) had neurological symptoms as their presenting symptom. Of those with neurological manifestations, paresthesias occurred in 70% and were disabling in 10%. Twenty-one percent had neurological symptoms but with normal findings on neurological examination. On examination, impaired lower limb vibration sense (88%) and diminished proprioception in the toes and ankles (59%) were the predominant findings. Other findings included impaired touch/pain sensation (30%), gait ataxia (23%), limb weakness (13%), positive Romberg test results (11%), absent or reduced deep tendon reflexes (33%), and exag-

A progressive myelopathy/myeloneuropathy associated with copper deficiency has been recognized. The condition may have been hitherto underrecognized. Kumar and associates (2004) reported a series of such cases with a clinical syndrome resembling subacute combined degeneration. The patients typically presented with a spastic ataxic gait and marked posterior column sensory deficits. MRI may demonstrate posterior column signal changes, and somatosensory evoked potentials may show evidence of central proprioceptive pathway conduction defects. Reduced ceruloplasmin levels were the initial clue to the diagnosis. The cause of reduced levels of serum copper was not known in most cases. Copper supplementation restores the serum copper levels and may prevent further neurological deterioration. Some cases of copper deficiency were associated with elevated zinc levels. As with subacute combined degeneration from cobalamin deficiency, copper deficiency–related myelopathy occurred in the absence of hematological manifestations.

Paraneoplastic Myelopathy Progressive myelopathy has rarely been reported in the context of systemic cancer. Mancall and Rosales reported cases of subacute necrotizing myelopathy associated with visceral carcinoma. Subacute ascending flaccid areflexic paraplegia with sphincter paresis and sensory involvement was the characteristic presentation. The cerebrospinal fluid analysis shows pleocytosis and elevated protein. MRI of the spine shows spinal cord enlargement and T2 signal abnormalities. There is no specific cancer described with the syndrome, and there are no recognized testable autoantibodies that can serve as a marker for a paraneoplastic process.

Hepatic Myelopathy A rare progressive myelopathy may occur in the setting of chronic liver disease and may be part of the clinical spectrum,

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which includes acquired hepatocerebral degeneration. Patients typically have spastic paraparesis with minimal sensory involvement. Pathologically, there is symmetrical demyelination of the lateral pyramidal tracts with a degree of axonal loss. Differential effects of the exposure to toxic metabolic substances that bypass the liver may explain the resultant neurological manifestations (i.e., hepatic myelopathy versus acquired hepatocerebral degeneration).

Adrenomyeloneuropathy Adrenomyeloneuropathy is regarded as a milder variant of adrenoleukodystrophy. Adrenoleukodystrophy is discussed in greater detail in Chapter 80. It is an X-linked disorder caused by a mutation in the Xq28 gene, which codes for a peroxisomal membrane transporter protein (ALDP). The precise role of ALDP is unknown; however, the ALDP mutation leads to the accumulation of very-long-chain fatty acids, particularly tetracosanoic acid (C24:0) and hexacosanoic acid (C26:0) in neural tissue, adrenal glands, and testes. A typical patient with adrenomyeloneuropathy presents with a slowly progressive spastic paraparesis during the third to fourth decades of life. Early sphincter involvement and defects in posterior column sensory function are characteristic. Signs of adrenal and testicular insufficiency may precede, occur synchronously with, or follow the onset of the neurological manifestations. Nevertheless, 15% of affected male patients and 99% of affected female patients (symptomatic carriers) do not develop adrenal insufficiency. Of all patients with adrenomyeloneuropathy, 40% to 50% have cerebral white matter lesions on MRI (“cerebral” adrenomyeloneuropathy). Those without such cerebral white matter lesions (i.e., “pure” adrenomyeloneuropathy) have a better prognosis, whereas 25% of patients with “cerebral” adrenomyeloneuropathy develop a catastrophic course like that of childhood cerebral adrenoleukodystrophy. Pathological studies of adrenomyeloneuropathy suggest a noninflammatory distal axonopathy involving the spinal cord tracts and, to a lesser extent, peripheral nerves. The diagnosis is based on the demonstration of increased levels of serum very-long-chain fatty acids and mutation analysis. In other inborn errors of metabolism (e.g., globoid leukodystrophy and metachromatic leukodystrophy), myelopathy may be part of the clinical manifestation; however, such conditions produce not isolated myelopathy but rather a multisystem neurological disorder.

K E Y ●

P O I N T S

Acute transverse myelopathy can result from a variety of inflammatory processes, including idiopathic transverse myelitis, multiple sclerosis, and neuromyelitis optica; a variety of infectious/parainfectious disorders; and systemic autoimmune disorders such as systemic lupus erythematosus.

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The syndrome of acute transverse myelopathy may also result from noninflammatory processes such as spinal cord infarction and radiation myelopathy.

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Myelopathy resembling subacute combined degeneration can be caused by cobalamin deficiency and also copper deficiency.

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Advances in molecular genetics are rapidly expanding knowledge of the hereditary degenerative myelopathies such as hereditary spastic paraplegia and spinal muscular atrophy.

Suggested Reading De Seze J, Stojkovic T, Breteau G, et al: Acute myelopathies: clinical, laboratory and outcome profiles in 79 cases. Brain 2001; 124:1509-1521. Green R, Kinsella L: Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995; 45:1435-1440. Kumar N, Gross JB, Ahlskog JE: Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004; 63:33-39. Miller AE (ed): Spinal cord disorders [June issue]. Continuum: Lifelong Learning in Neurology 2005; 11(3). Transverse Myelitis Consortium Working Group: Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59:499-505.

References Anderson K, Talbot K: Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol 2003; 16:595-599. Elliott JL: Beginning to understand hereditary spastic paraplegia atlastin. Arch Neurol 2004; 61:1842-1843. Fink JK: The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 2003; 60:1045-1049. Fink JK, Rainier S: Hereditary spastic paraplegia: spastin phenotype and function. Arch Neurol 2004; 61:830-833. Healton EB, Savage DG, Brust JCM, et al: Neurologic aspects of cobalamin deficiency. Medicine 1991; 70:229-244. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364:2106-2112. Lewis M, Howdle PD: The neurology of liver failure. Q J Med 2003; 96:623-633. McDermott CJ, White K, Bushby K, et al: Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 2000; 69:150-160. Mancall EL, Rosales RK: Necrotizing myelopathy associated with visceral carcinoma. Brain 1964; 87:639-656. Moser H, Dubey P, Fatemi A: Progress in X-linked adrenoleukodystrophy. Curr Opin Neurol 2004; 17:263-269. Nicole S, Diaz CC, Frugier T, et al: Spinal muscular atrophy: recent advances and future prospects. Muscle Nerve 2002; 26:4-13. Powers JM, DeCierco DP, Ito M, et al: Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000; 59:89-102. Rudnicki SA, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve and muscle. Muscle Nerve 2000; 23:1800-1818.

CHAPTER

40

SPINAL DISEASE: NEOPLASTIC, DEGENERATIVE, AND INFECTIVE SPINAL CORD DISEASES AND SPINAL CORD COMPRESSION ●

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Shalini A. Amukotuwa and Mark J. Cook

The long, cylindrically shaped spinal cord sits within the bony vertebral canal, tightly enveloped by the meninges. It extends from the foramen magnum to the first lumbar vertebra, where it terminates in the conus medullaris. Below this, the lumbosacral nerve roots form the cauda equina. Anatomically, the spinal cord has a distinctive structural arrangement, illustrated in Figure 40–1A. Functionally, the spinal cord plays a key role in sensorimotor conduction. Because of its special features and relatively primitive reflexes, diseases of the spinal cord give rise to a number of distinctive, sometimes overlapping clinical syndromes (Tables 40–1 and 40–2; see Fig. 40–1B). Segmental (myotomal) lower motor neuron weakness, with depressed or absent deep tendon reflexes, muscle atrophy, and flaccidity/decreased tone, may be present at the level of the lesion, as a result of involvement of anterior horn motor neurons or anterior (motor) nerve roots; this helps clinicians localize the lesion (Table 40–3). Segmental (dermatomal) sensory loss may also be present (Fig. 40–2). Radicular symptoms and signs (see Table 40–2) result from irritation and compression of spinal nerve roots by extramedullary spinal cord lesions, usually before the involvement of long tracts (radiculomyelopathy). Radicular features are unusual with intramedullary lesions; when they do occur, they are most often present in the context of demyelinating disease. Sensorimotor long tract signs usually arise as a result of compression, rather than invasion or destruction, of spinal white matter fasciculi and occur early with intramedullary lesions. Either sensory or motor function may be affected first; the distribution and extent of long tract symptoms and signs are dependent on the site and size of the lesion. A sensory level, below which perception of pain and temperature is altered or lost, is pathognomonic of a spinal cord lesion and should prompt imaging of the spinal cord. Often the signs are subtle in the early stages, and the description of a sensory level should alert the clinician. The highest level of sensory deficit indicates the lower possible level of the lesion, and the pathology may be present anywhere above this level; the sensory level may in fact be well below the actual lesion, and this must be kept in mind

when imaging is ordered. Lamination of sensory fibers (see Fig. 40–1A) can give rise to suspended sensory deficits (i.e., isolated sensory deficit) at the level of the lesion or several segments caudally. Sacral sensation may be spared with deeper intramedullary lesions caused by spinothalamic tract lamination. Progressive spinal cord lesions, such as intramedullary neoplasms, may engender sequential deficits. Back or neck pain is a common complaint with spinal cord disease and may help the clinician localize the level of a structural lesion, such as an epidural abscess or compressive metastatic epidural deposit. Intrinsic spinal lesions tend to produce poorly localized pain. Exacerbation of pain with increased intraspinal pressure (coughing or straining), movement, or recumbency is suggestive of an extramedullary extradural lesion. Focal tenderness on palpation of the spinous process, as well as restriction of movement, may be associated with such lesions. The time course of symptoms is of value in determining the cause of spinal cord dysfunction. An acute onset suggests a mechanical or vascular lesion, whereas inflammatory and infective processes typically follow a subacute course, sometimes with fluctuation over days or weeks. Compressive lesions may follow an acute, subacute, or more protracted course, depending on the underlying process. Degenerative myelopathies classically are insidiously progressive.

IMAGING Magnetic resonance imaging (MRI) has enabled characterization of spinal cord diseases, including their location and internal structure, with the use of different magnetic resonance scanning sequences. The basic spinal MRI study includes T1and T2-weighted sequences in the sagittal plane and contrast material (gadolinium)–enhanced T1-weighted images in the sagittal and axial planes. Myelography involves the introduction of radiopaque dye to the spinal fluid, through lumbar or sometimes cervical roots, but is limited in resolution and the length of cord that can be imaged in one episode. Obstruction to the

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Dorsal nerve root

Spine and Spinal Diseases

Spinous process

Central canal Dorsal columns C T

Neural exit foramen

Dorsal root ganglion

L S Corticospinal tract

Le Tr A Ventral nerve root

Vertebral body Temperature

LT C

Pain

Lateral spinothalamic tract

Touch

A

i

ii

iii

B ■

Figure 40–1. Anatomy of the spinal cord. A, Schematic diagram of the cross-section of the spinal cord, demonstrating sensory and motor long tracts, and gray matter. Myelinated fibers, forming the long tracts, are located peripherally, subjacent to the pia mater, and are laminated (C, cervical; T, thoracic; L, lumbar; S, sacral; A, arm; Le, leg; Tr, trunk). The gray matter is composed of cell bodies of motor neurons innervating skeletal muscles (anterior horns) and sensory neurons involved in conduction of pain and thermal sensation (dorsal horns). The central canal is surrounded by fibers conveying pain and thermal sensation, which cross the midline before joining fibers from more caudal levels to form the anterolateral (spinothalamic) tract. The primary sensory neurons, which innervate peripheral sensory receptors, have their cell bodies within the dorsal root ganglia, which lie within the neural exit foramina. B, Some patterns of spinal cord disease, with accompanying spinal cord syndrome: i, Complete transverse cord syndrome; ii, Brown-Séquard syndrome; iii, syringomyelic/central cord syndrome. (Adapted from Thompson PD, Blumbergs PC: Myelopathies. In Asbury AK, McKhann GM, McDonald WI, et al, eds: Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles, 3rd ed, vol 1. Cambridge, UK: Cambridge University Press, 2002, p 717.)

cerebrospinal column and distortion and enlargement of the cord may all be directly visualized. Combining myelography with computed tomographic scanning of the spine is useful, allowing a greater extent of the cord to be accurately imaged in the one sitting. Plane films of the spine may reveal bony lesions and other local pathological processes, but their utility is quite limited.

SPINAL CORD INFECTIONS Potentially any structure of the spinal cord and its surrounding meninges and vertebral column may be involved in infectious processes. The causative agents include bacteria, viruses, parasites, and fungi (Table 40–4).

chapter 40 spinal disease T A B L E 4 0 – 1. Red Flag Features Indicative of Cord Disease Gait disturbance Lhermitte’s phenomenon: “electric” paresthesias radiating down the back and arms, induced by neck movement (characteristically flexion), indicative of a dorsal column spinal cord lesion Localized back pain (tumor, abscess) and spinal tenderness Segmental/radicular symptoms or sensory/motor deficit Sensory or motor level Paraplegia or quadriplegia: often a late event, by which time neurological damage is usually irreversible Sphincter dysfunction (urinary retention and constipation), usually late in extramedullary lesions and early in intramedullary lesions; may be an early feature, preceding paralysis, in conus medullaris and cauda equina lesions Sexual dysfunction: Erectile dysfunction (male) Impaired perineal and vaginal sensation (female), especially if unilateral

T A B L E 4 0 – 2.

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Infectious and Parainfectious Myelopathies Myelitis is a process intrinsic to the spinal cord; this definition excludes expansive lesions.1 Transverse myelitis is characterized by a focal inflammatory process within the spinal cord, leading to varying degrees of neural injury and dysfunction of neural pathways passing through the inflamed segment.2 This in turn leads to the abrupt onset of varying degrees of weakness, sensory alteration, and autonomic dysfunction. The diagnostic criteria for transverse myelitis include the following:1,3 1. A disturbance of motor capacity and continence; in acute transverse myelitis, the deficit reaches a maximum no later than 4 weeks after initial onset. 2. Bilateral segmental sensory loss. 3. No medullary compression. 4. Consistent MRI and neurophysiological findings.

Spinal Cord Syndromes

Syndrome

Features

Complete transverse spinal cord syndrome (see Fig. 40–1Bi)

Paralysis and anesthesia below level of lesion Often a rim of hyperesthesia at upper level of sensory deficit Paraparesis or paraplegia: lesion at or rostral to lower cervical cord Quadriparesis or quadriplegia: lesion of the upper cervical cord Caused by unilateral spinal cord lesion; may be partial or complete Ipsilateral upper motor neuron (pyramidal) weakness and dorsal column sensory deficit Contralateral spinothalamic (pain and temperature) sensory deficit (vertical stripes in Fig. 40–1Bii) Light touch is usually preserved Caused by involvement of white matter fasciculi Corticospinal tract involvement: upper motor neuron limb weakness (arm and leg weakness caused by cervical cord lesion; leg weakness caused by a lesion rostral to the upper lumbar spine): Hypertonia and clonus (spasticity) Hyperreflexia Extensor planar responses (lesion above the L5 segment, which innervates extensor digitorum longus) Long sensory tracts: paresthesias and sensory loss Dorsal column: paresthesias, numbness, impaired vibration sense, and loss of proprioceptive function (resulting in sensory ataxia); decreased fine motor control of hands Spinothalamic tract: cutaneous dysesthesias, abnormal thermal sensations, loss of pain and temperature sensation, hyperesthesias and hyperpathia; deficits occur contralaterally (i.e., a dissociated loss), as pain and temperature fibers decussate shortly after entering the spinal cord Dorsal (sensory) nerve root involvement: Radicular pain (lancinating pain, radiating distally along the affected dermatome Dermatomal burning dysesthesias or hyperesthesias Sensation loss or diminution in dermatome(s) supplied by compressed root Diminished or absent segmental tendon and cutaneous reflexes (see Fig. 40–2) Ventral (motor) nerve root involvement: Segmental myotomal weakness Wasting Flaccidity/hypotonia Diminished or absent reflexes (see Table 40–3) Seen in syringomyelia and certain other intramedullary lesions Brachial amyotrophy (upper limb weakness, with wasting, and depressed or absent deep tendon reflexes) Segmental suspended dissociated sensory loss, caused by interruption of decussating pain and temperature fibers around central spinal canal Caused by selective involvement of the motor neurons; segmental weakness, atrophy, fasciculations, and absent or diminished reflexes Usually associated with vascular lesions of the anterior spinal artery, resulting in ischemia and neurological deficits within its area of supply (see Fig. 40–2); bilateral upper motor neuron weakness and spinothalamic sensory deficit below the lesion; dorsal column function is spared Pain usually an early feature; asymmetrical lower motor neuron (areflexic, flaccid, atrophic) paralysis of lower limbs; sphincter dysfunction (urinary or fecal incontinence, diminished anal tone) and radicular sensory loss; may difficult to differentiate clinically from lesions of the lumbosacral plexus Early and prominent sphincter dysfunction; back pain; sensory disturbance in sacral dermatomes (perineal: S3-S5; leg: L5-S2); loss of anal tone and reflex; impotence; leg weakness inconsistent, usually mild

Brown-Séquard (hemicord) syndrome (see Fig. 40–1Bii) Sensorimotor spinal tract syndrome

Radicular syndrome

Syringomyelic or central cord syndrome (see Fig. 40–1Biii) Anterior horn syndrome Anterior spinal cord syndrome Cauda equina syndrome Conus medullaris lesions

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T A B L E 4 0 – 3. Segmental Innervation of Muscles and Tendon and Cutaneous Reflexes Segment/ Nerve Root C3, C4 C4, C5 C5 C5, C6 C6 C7 C8 T1 T7-10 T10-12 L1 L2 L3, L4 L4 L5 L5, S1 S1 S1, S2 S4, S5

Muscle

Tendon or Cutaneous Reflex

Trapezius Rhomboids Deltoid Supraspinatus, infraspinatus, biceps Brachioradialis Triceps, extensor digitorum Flexor digitorum superficialis and profundus Intrinsic muscles of hand Upper rectus abdominis Lower rectus abdominis Iliopsoas Adductor magnus Quadriceps femoris Tibialis anterior Extensor hallucis longus Hamstrings Extensor digitorum brevis Soleus, gastrocnemius

— — — Biceps reflex Brachioradialis reflex Triceps reflex Finger-jerk reflex — Upper abdominal reflex Lower abdominal reflex Cremasteric reflex Adductor and cremasteric reflexes Knee-jerk (patellar) reflex — Plantar reflex Ankle-jerk reflex — — Anal reflex

■

C2 C2 C3 C4

C3 C4 T1 T2 T3 T4 T5 T6 T7 T8

C5

C6

C7

C8

L1 L2

C6

T9 T10

T11 T12

C7

T1 T2 T3 T4 T5 T10 T11 T12 L4

C8 T6 T7 T8 T9 L1 L2 L3

L5 S1

S2

L3 S2 L4

L5

S1

C5

L5 L4

Figure 40–2. Distribution of dermatomes on the anterior surface of the body. (From Merck and Company: Merck Manual of Diagnosis and Therapy, Section 14: Neurologic Disorders; redrawn from Keegan JJ, Garrett FD: The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 102:409-437, 1948.)

chapter 40 spinal disease T A B L E 4 0 – 4. Infections of the Spinal Cord Anterior (Anterior Horn Cell) Myelitis Viral Enteroviruses (e.g., poliovirus, enterovirus 71, Coxsackie A7 virus, echovirus) Tickborne encephalitides Flaviviruses (e.g., Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile virus) Herpes viruses (e.g., CMV, EBV, VZV) Transverse Myelitis Viral Herpes viruses (e.g., HSV, VZV, EBV, CMV) HTLV-1 Rabies B virus Enteroviruses (Coxsackie A and B viruses, echoviruses) Other Mycoplasma pneumoniae Dorsolateral Column Myelitis Vacuolar myelopathy of AIDS Tabes dorsalis (syphilitic myelopathy, caused by tertiary Treponema pallidum infection) Necrotizing Ascending Myelopathy VZV myelitis in immunocompromised state AIDS-related opportunistic infections Pyogenic Infections Subacute bacterial meningomyelitis Intraspinal abscess Spinal epidural abscess Vertebral osteomyelitis Tuberculous disease: vertebral osteomyelitis (Pott’s disease), tuberculous meningomyelitis, tuberculoma (caseating granuloma) of spinal cord or epidural space Fungal and Parasitic Infections Epidural abscess, granuloma (noncaseating) Meningomyelitis AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; EBV, EpsteinBarr virus; HSV, herpes simplex virus; HTLV-1, human T cell leukemia/lymphoma virus type 1; VZV, varicella-zoster virus.

Transverse myelitis forms a part of a spectrum of neuroinflammatory conditions and may occur as part of a multifocal central nervous system (CNS) disease, such as multiple sclerosis; as part of a multisystem disease, such as systemic lupus erythematosus; or as an idiopathic, isolated entity.2 Of all cases of idiopathic transverse myelitis, 30% to 60% were preceded by a respiratory, gastrointestinal, or systemic infectious illness.2-5 The underlying pathogenesis of transverse myelitis is varied, depending on the specific underlying disease process. For instance, connective tissue disease–associated transverse myelitis may be secondary to a CNS vasculitis or thrombotic infarction of the cord.6 Most patients have cerebrospinal fluid (CSF) pleocytosis and foci of blood-brain barrier breakdown within the spinal cord.2 Two large etiological groups of inflammatory transverse myelitis are identifiable: the inflammatory demyelinating autoimmune myelopathies, such as multiple sclerosis, and the usually monophasic infectious encephalomyelitides.1 More than 40 such infectious encephalomyelitides have been identified, of which approximately 10 have been established as “pure infectious” myelitides by CSF virus isolation or polymerase chain reaction (PCR) techniques, which indicate that neuro-

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logical injury resulted directly from microbial infection.1,2,8 The remainder are believed to be parainfectious, caused namely by a microbial infection, which in turn incites an immune response against neural tissue. In the latter, the infection may be remote from the immunological response.2 The latency between myelitis and preceding infection does not significantly differ between infectious and postinfectious myelitis. An interval of 9 ± 6 days has been reported for parainfectious cases, 5 days in mumps-related myelitis, 12 days in zoster-related myelitis, and 10 days in Mycoplasma-related myelitis.3,9-11 Although diagnosis of infectious and parainfectious transverse myelitis requires identification of the infectious agent within the CNS, some autoimmune mechanisms, such as molecular mimicry and superantigen-mediated disease, require only peripheral immune activation.2 In molecular mimicry, the putative mechanism of neural injury is antibody-mediated damage, secondary to cross-reaction of antibodies against an infectious agent with molecularly similar antigens in host neural tissue.2 Transverse myelitis is associated pathologically on tissue sampling (biopsy or autopsy) with inflammation.2 Both gray and white matter compartments are affected, although in postinfectious myelitis, white matter changes, demyelination, and axonal injury are prominent. Focal infiltration by lymphocytes and monocytes into segments of the spinal cord and perivascular spaces and activation of astroglial and microglial cells are observed.2 In some biopsies performed during the acute phase of myelitis, infiltration of CD4+ and CD8+ lymphocytes is prominent. Subsequently, during the subacute phase, monocyte and macrophage infiltration may become more prominent. In cases in which transverse myelitis is associated with autoimmune disease such as systemic lupus erythematosus, focal areas of ischemia or infarction secondary to vasculitis may be present, without prominent inflammation, a finding not usually seen in most cases of infectious transverse myelitis.12 PCR techniques, performed on serum and CSF, have facilitated the rapid, sensitive, and noninvasive diagnosis of many infectious forms, particularly viral, of myelitis.1,13,14 Diagnosis is often based on the detection of viral DNA in CSF by PCR.13 Further supportive evidence for a particular viral agent as the cause of myelitis, of value when viral PCR results are negative, is the presence of specific immunoglobulins M (IgM) and G (IgG) antibodies in the CSF, suggestive of intrathecal synthesis.1,13 This is especially the case when the serum:CSF ratio of these antibodies is depressed in relation to total IgG and albumin levels. Infectious and parainfectious transverse myelitis are the focus of discussion in this chapter. The list of antecedent infections includes herpesviruses and Listeria monocytogenes, although in most of these cases, causality has not been established. Infectious and parainfectious transverse myelitis can be further subdivided, on the basis of the components of the neural axis involved, into meningomyelitis, transverse myelitis without meningitis, encephalomyelitis, and anterior horn syndrome with meningitis, among other entities.1 Meningitis is defined here as the clinical syndrome of fever and neck stiffness.1,2

Clinical Features The clinical picture of acute transverse myelitis is one of rapid evolution of neurological deficit; however, the distribution of

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dysfunction, including the modalities affected, depends on the extent and distribution of inflammation within the spinal cord.2 On examination, there is often a clearly defined level of sensory dysfunction.2 When the maximum level of neurological deficit is reached, approximately 50% of affected patients are paraplegic, and 80% to 94% of patients experience sensory disturbances, including numbness, paresthesias, and bandlike dysesthesias.2-5,15,16 Manifestations of autonomic dysfunction include urinary urgency, urinary or fecal incontinence, difficulty or inability opening bladder or bowels, and sexual dysfunction.1

Imaging Acute inflammation is evident on spinal MRI.1,2 This includes swelling of the spinal cord, in inflamed segments, as well as increased signal intensity on T2-weighted imaging. In cases in which nerve roots are involved in the inflammatory process (radiculomyelitis), enhancement of the affected nerve roots with administration of intravenous gadolinium contrast material may be seen.2,13 However, there are several reports in the literature of clinical cases of myelitis in which there is no demonstrable abnormality of the spinal cord on imaging.1,2,13

Differentiating between Infectious/Parainfectious Transverse Myelitis and Multiple Sclerosis In multiple sclerosis, it is unusual to have complete transverse myelitis; there was only one such case of 308 in the Göteborg series.18 The weakness and numbness tend to be less severe in multiple sclerosis.19 Pathologically, CSF oligoclonal bands present in multiple sclerosis are absent in infectious transverse myelitis.1,19 Differences in MRI of the spine are also reported.1,18-20 In multiple sclerosis, the areas of T2 hyperintensity tend to be multifocal, smaller, and limited to one segment of the cord in transverse segments; in infectious and parainfectious transverse myelitis, in contrast, T2 hyperintensities are confluent and elongated, often extending over several spinal segments. Furthermore, plaques of demyelination are usually seen on cerebral MRI in multiple sclerosis but not in infectious transverse myelitis.

Specific Entities Echovirus meningomyelitis There have been case reports of echovirus (types 11 and 18) isolated from either pharyngeal exudate or CSF of children with clinical meningomyelitis, with transient T2 hyperintensity of the spinal cord.21,22

Coxsackie virus–related myelitis and meningomyelitis There exist several case reports of patients with clinical and MRI evidence of transverse myelitis with or without meningitis, from whom Coxsackie virus (B4, B3, B5, A5, and A9) had been isolated or in whom a high titer of specific antibody to this virus had been demonstrated in the CSF or serum.1,23,24 For instance, in one case report of a 6-year-old with rapidly progressive paraplegia, with associated bladder and bowel dysfunction, a rising titer of serum anti-Coxsackie virus B5 antibody was demonstrated.25 The virus was also isolated from the stool. MRI in this

case demonstrated diffuse swelling of the spinal cord on T1weighted imaging.

Mumps-related meningomyelitis The commonest neurological manifestation of mumps virus infection is meningitis; encephalitis occurs in fewer than 0.1% of cases.9 However, there are case reports of myelitis associated with mumps viremia. For instance, a 10-year-old boy developed flaccid paraparesis and neck stiffness in the setting of parotitis and orchitis that are clinically indicative of mumps infection.26 MRI demonstrated T2 hyperintensity from C2 to T12 spinal cord segments, in keeping with myelitis. Mumps infection was confirmed by the presence of IgM class antibodies against mumps in the serum. In another report, a young woman was diagnosed with mumps-associated transverse myelitis on the basis of clinical findings, MRI demonstration of a swollen spinal cord with uniform high-signal change on T2 weighting, and acute mumps viremia.27 No reports of mumps virus isolation from the CSF, in the setting of transverse myelitis, have been found.

Herpes simplex virus–related myelitis Although a well-known cause of viral encephalitis, herpes simplex virus (HSV) is a rare cause of myelitis.13,28-30 This entity was first described by Klatersky and associates and has since been reported in both immunocompromised and immunocompetent patients.13,30 Subtle spinal cord involvement by HSV infection may be underrecognized. HSV type 2 infection and, less frequently, HSV type 1 infection cause genital infection, with vesicles and ulceration.9,32 After primary genital infection, the virus persists latently within the sensory neurons of the dorsal root ganglia and produces recurrent cutaneous disease with intermittent reactivation and retrograde spread along the sensory nerve.9,13,32 On occasion, HSV reactivation may be followed by radiculomyelitis, variably affecting the cauda equina, conus medullaris, and thoracic cord.32 The pathogenesis of HSVassociated myelitis is not well understood, although intraaxonal spread of virus from the sensory ganglion into the spinal cord through the dorsal roots is thought to be the likely mechanism.28 Most cases of HSV-related myelitis described in the literature have been associated with type 2 infection, probably reflective of the recurrence of latent infection mainly with the more commonly HSV type 2 venereal infections.13 In six of a series of nine patients with HSV-related myelitis reported by Nakajima and colleagues, disease onset was marked by bilateral lower limb sensorimotor disturbance and urinary symptoms, with ascending progression of the myelopathy to thoracic or cervical level within the course of a few weeks.13 Most cases of HSV-related myelitis described in the literature followed a similar clinical pattern of an acute, monophasic, usually fatal ascending necrotizing myelitis, with death resulting from respiratory paralysis or meningoencephalitis.13 However, other clinical patterns, including a self-limited, resolving transverse myelitis, a relapsing-remitting form, and chronic myelitis, have been described since the development of improved diagnostic techniques such as PCR which have enabled noninvasive diagnosis.13,28-30,33 In three of the nine patients studied by Nakajima and colleagues, transverse myelitis started in the cervicothoracic cord, with a nonascending pattern and milder sequelae than in the cases of ascending

chapter 40 spinal disease myelitis. There have also been other case reports of transverse myelitis of the cervical and thoracic cord, caused by HSV, that resolved.34 In these cases, demyelination without necrosis was postulated to be the underlying pathological process responsible for myelitis.13 In early reports, HSV-related myelitis was described as being frequently associated, in close temporal relation, with cutaneous herpetic eruptions, which provided a clue as to the diagnosis.13,30 However, it has since then been suggested that this association is seen in very few cases of HSV-related myelitis, and therefore this feature is not useful for early diagnosis. HSV per se is rarely isolated from the CSF.13 Subtle clinical involvement of the spinal cord in patients with genital HSV infections are probably much more common than appreciated, however, and symptoms related to cord involvement are often a prominent feature of the prodromal phase of the illness. The diagnosis of HSV meningoencephalitis is usually based on the detection of HSV DNA in CSF by PCR, with reported sensitivity and specificity of 98% and 94%, respectively.35 In most cases reported since 2000, PCR has been used in the diagnosis of HSV-related myelitis, although numbers have been too small to obtain data on specificity and sensitivity.28 Further evidence of herpetic infection as the cause of myelitis is the presence of anti-HSV IgM and IgG antibodies in the CSF, suggestive of intrathecal synthesis.28 Although demonstration of seroconversion against HSV concurrent with the episode of myelitis enables diagnosis, it should be kept in mind that anti-HSV antibody titers are not always elevated during the early stage of disease.13 CSF pleocytosis, although usually present, is also not a constant feature.29 MRI findings include enlargement of the conus medullaris; intramedullary T2 hyperintensity, particularly of the posterior funiculi; and gadolinium enhancement of the affected dorsal nerve roots, with no enhancement of the ventral roots.13,28 This is in keeping with the expected pattern of involvement of spinal cord structures, if infection is indeed caused by retrograde spread of virus into the cord from dorsal root ganglia. In one case, both T1 and T2 hyperintensities were observed, suggestive of hemorrhagic necrosis of the affected parts of the cord.13 Follow-up imaging may demonstrate atrophy of the cord in the previously inflamed regions.33 Treatment of HSV-related encephalitis with acyclovir is established; however, there are case reports of the value of this antiviral agent only in the treatment of HSV-related myelitis.28 Corticosteroids, in conjunction with antiviral therapy, may prevent ascending necrotizing myelopathy and improve survival.28 With regard to long-term prognosis, in the series by Nakajima and colleagues, three patients recovered, whereas the remaining six had severe persistent neurological deficits, such as paraplegia, despite antiviral therapy.13

Zoster-related transverse myelitis Varicella-zoster virus (VZV) infection may be associated with a wide spectrum of neurological complications, myelitis being the most poorly characterized of these.36 Several reports describe a postinfectious VZV-related myelitis, which is usually an acute, relatively benign transverse myelopathy, associated with a self-limiting paraparesis and sometimes sensory symptoms and sphincter disturbance.37 Chronic and remittingrelapsing temporal profiles of myelopathy have been described in association with VZV.36

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Less commonly, a progressive ascending myelopathy, usually fatal in outcome, is seen in immunocompromised individuals and is thought to be caused by direct VZV invasion of the spinal cord.10,38 Ten cases of necrotizing vasculitis associated with VZV meningoencephalomyelitis have been reported in the literature, all with underlying immunodeficiency, secondary to either malignancy or human immunodeficiency virus (HIV) infection, and all cases fatal within 4 to 32 days.38 The patients typically developed radicular or central back pain within 2 weeks of zoster infection, in association with bilateral motor and sensory signs. The diagnosis of VZV-related myelitis is historically based on the onset of myelopathy within days to weeks of a typical rash.37 The symptoms may be most pronounced ipsilateral to and at the level of the rash. However, there are reports of VZVrelated myelitis, confirmed by positive VZV PCR or culture from the CSF, with no history of cutaneous rash.37,39 VZV per se is rarely isolated from blood or CSF, although the latter usually shows an often profound pleocytosis.37 PCR techniques have enabled the detection of VZV DNA in the CSF of patients suspected of having VZV-related myelopathy, even months later, which enables confirmation of the diagnosis and suggests a role of virus persistence in the pathogenesis of disease.37,38 VZV as the etiological agent in myelopathy is also supported by the presence of antibody (IgG and IgM) to VZV in the CSF, indicative of presence of viral antigen in the nervous system and intrathecal antibody synthesis.37,40 The underlying pathological process in VZV-related myelitis is thought to be a small- or large-vessel vasculopathy, depending on the immune status of the patient.38 Small-vessel disease is seen almost exclusively in immunocompromised patients and includes a necrotizing vasculitis of leptomeningeal vessels, especially around the spinal cord and brainstem.38 VZV has been detected in large and small vessels of the nervous system by PCR, in situ hybridization for VZV antigen, and immunohistochemistry in these cases.38,41,42 Pathological examination may demonstrate intranuclear viral inclusions.38 VZV-related vasculopathy may occur as late as 5 to 6 months after the zoster rash.39 In these patients, the detection of antibody to VZV in CSF, even in the absence of amplifiable VZV DNA, is diagnostic.39,40 There are other reports of zoster-related myelitis in which PCR results for VZV were negative in the presence of anti-VZV antibodies in the CSF or became positive only after several days of clinical symptoms.38,40 It is presumed that the reason why patients with VZV-related vasculopathy may not contain VZV DNA is that active viral replication is confined to CNS arteries.39 Hence CSF PCR for VZV DNA is not as sensitive a test as CSF PCR for HSV.40 MRI demonstrates hyperintensity and swelling, consistent with edema, on T2-weighted sequences.36,38 On T1-weighted images, with gadolinium contrast material, leptomeningeal enhancement over the cerebellum and brainstem is seen in cases of ascending myelitis.38 The treatment of VZV-related myelitis is aggressive antiviral therapy, usually with intravenous acyclovir; however, response is variable.36 VZV strains that are resistant to acyclovir, as well as to related newer compounds such as famciclovir and valacyclovir, have been reported, in both immunodeficient and immunocompetent patients.38,43,44 Resistance results from deficiency or absence of viral thymidine kinase, the enzyme on which these drugs are dependent for intracellular activation via phosphorylation.38,44 These thymidine kinase–deficient VZV

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mutant strains are, however, susceptible to foscarnet and acyclic nucleoside phosphonates, which are active independently of thymidine kinase.44 Because diagnostic tests for VZVmediated myelitis are potentially insensitive, management of patients suspected of having this condition should include broadening of antiviral therapy to overcome possible resistance if there is clinical progression or inadequate response to therapy.38

Cytomegalovirus-related myelitis In the setting of cellular immunodeficiency, such as the acquired immunodeficiency syndrome (AIDS), cytomegalovirus infection of the cord can produce a necrotizing transverse myelitis, typically when CD4 counts are less than 50.45 It is exceedingly rare in immunocompetent persons, although five such cases of cytomegalovirus-associated transverse myelitis were reported by Giobbia and coworkers.46 In all these cases, CSF PCR for cytomegalovirus yielded negative results. The diagnosis was instead obtained on the basis of serological data: namely, cytomegalovirus antigenemia (positivity for cytomegalovirus pp65 antigen) and high serum titers of specific cytomegalovirus IgM and IgG antibodies, positive blood PCR results for cytomegalovirus, and blood or urine cultures. Of note, however, PCR performed on CSF of patients with AIDS demonstrated this test to predict histopathologically confirmed cytomegalovirus-associated CNS disease, including myelitis.47 It is unclear as to whether neuronal injury is immune mediated or caused by a cytotoxic effect of viral infection.

Epstein-Barr virus–related myelitis Epstein-Barr virus, like VZV, can infect multiples sites of the neuraxis and can therefore produce protean clinical manifestations.48 Both CNS and peripheral nervous system disease can occur, with reports of meningitis, encephalitis, transverse myelitis, neuritis, and overlapping syndromes.48-50 The incidence of Epstein-Barr virus–related neurological disease is not known; however, it has been estimated to occur in 1% to 5% of individuals with infectious mononucleosis.48 The mechanism by which Epstein-Barr virus produces neurological disease is unknown; however, the development of neurological disease over weeks is suggestive of either a subacute to chronic viral infection or a postinfectious, immune-mediated process.48 CSF typically shows pleocytosis, with elevated protein levels.48 The diagnosis is made by the isolation of Epstein-Barr virus DNA from CSF, as well as from peripheral blood monocytes, and the exclusion of other herpesvirus infections through PCR techniques.48,51 Serological evidence is supportive.48 Findings on MRI are variable and may demonstrate increased T2 signal intensity; however, normal findings are also reported in the presence of neurological deficits.48 Unfortunately, no definitive treatment for Epstein-Barr virus nervous system infections exists. Although corticosteroids and immunoglobulins have been used, their effect on disease progression is unknown.48 Antiviral agents have not been shown to be clinically useful. Significant neurological deficits may persist after resolution of the acute phase of myelitis.48,51

Mycoplasma-related myelitis It is estimated that CNS manifestations, most commonly encephalitis, occur in 1 per 1000 patients with Mycoplasma pneumoniae infections.52 Myelitis, albeit atypical, and radiculi-

tis have been reported in association with meningitis. In 19 cases of Mycoplasma-associated transverse myelitis, patients often developed a flaccid paraparesis, with bladder paresis.11 A definite sensory level was described in only a few cases. There is usually slight CSF pleocytosis, and M. pneumoniae was isolated in at least seven reported cases. In one case, in a patient who had no antecedent respiratory infection, M. pneumoniae was cultivated from a nasopharyngeal aspirate and detected in the CSF by PCR.11,53 Treatment is with doxycycline for 14 days, although the effects of therapy are debated.1 The overall prognosis is generally good, with complete recovery in most cases, although there is one case report of persistent paraplegia after Mycoplasma-associated transverse myelitis.54

Other Rare Infectious Causes of Myelitis Cases of transverse myelitis associated with Burkholderia pseudomallei (melioidosis) have been described.55 Borrelia recurrentis may also produce myelitis, usually radiculomyelitis rather than isolated myelitis.56 Even so, only 5% of 330 cases of neuroborreliosis were classified as acute meningomyelitis or meningomyeloradiculitis. Transverse myelitis may occur in tuberculous meningitis, usually with severe leptomeningitis.1

Other Myelopathies Subacute combined degeneration of the cord, classically described in association with vitamin B12 deficiency, affects the posterior and lateral columns of the spinal cord.57 A similar syndrome of posterior column degeneration is also seen in tertiary syphilis (Treponema pallidum infection), and is referred to as tabes dorsalis.57 This manifests clinically with a spastic weakness and ataxia of the lower limbs. Chronic meningeal inflammation may be present and may involve the ventral nerve roots. Other clinical spinal syndromes described in association with syphilitic infection are syphilitic meningomyelitis (a chronic meningitis resulting in subpial myelinated fiber loss, with predominantly bilateral corticospinal tract involvement) and spinal meningovascular syphilis, which may result in an anterior spinal artery syndrome.57 The myelopathy associated with the late stages of AIDS also affects the posterior and lateral columns, as demonstrated in histological studies.1,57 Clinical features of spinal cord disease are often obscured by other neurological complications of AIDS, such as neuropathy and encephalopathy, which result from HIV per se or from opportunistic infections. Vacuolation of myelin and relative sparing of the axons occur, and lipidladen macrophages are typically abundant.57,58 This vacuolar myopathy was seen in 48% of autopsy examinations of the cord of 90 patients with AIDS, although the frequency of encephalitis was higher in this population.58 There was no correlation between the proviral HIV type I load and the degree of myelopathy.58 Likewise, there was no correlation between opportunistic infections, particularly cytomegalovirus, and the presence and severity of myelopathy. In a separate series of 21 patients with AIDS-associated myelopathy, MRI demonstrated spinal cord atrophy in 15 cases and diffuse intrinsic signal abnormality in six cases.59 Tropical spastic paraparesis is a syndrome of slowly progressive central paraparesis of proximal lower limb dominance, caused by infection with the human T cell leukemia/lymphoma

chapter 40 spinal disease virus type 1 (HTLV-1). Sensory signs are characteristically minimal and usually only in the lower limbs; paresthesias and ataxia, with diminished proprioceptive function and vibration sense, have been described.57,60 Sphincter dysfunction usually occurs early. An associated polyneuropathy has been reported. Levels of CSF antibodies to HTLV-1 are elevated.57 On pathological examination, the corticospinal tracts and posterior columns are affected by an inflammatory myelitis, with focal spongiform demyelination and necrosis.57,60 Foci of gray matter destruction are also seen.

Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis occurs typically after childhood viral exanthemata, upper respiratory tract infection, or vaccination, with a short latency.1 Although the majority of postinfectious cases follow viral infections, such as measles, mumps, and Epstein-Barr virus infection, acute disseminated encephalomyelitis can occur after bacterial or parasitic infections.1,2 Most cases are disseminated, as the name implies, with alteration of sensorium; however, in some cases, spinal disease dominates the clinical picture.1

Anterior Horn Cell Syndromes The hallmark of damage to lower motor neurons is flaccid paralysis. Viral infection and the resultant inflammation cause direct damage to the motor neurons residing in the anterior horns of the spinal cord, producing an anterior myelitis.61 Viral invasion of anterior horn cells usually occurs as part of an acute viral meningitic illness, with fevers, headache, and meningism.61 This is followed by the rapid onset of asymmetrical weakness without any sensory deficits.61 Bulbar and respiratory musculature may be affected, and ventilatory support may be needed. Examination of CSF demonstrates moderate pleocytosis.61 Neurophysiological testing demonstrates low compound muscle action potential, normal sensory nerve action potentials, and sharp waves and fibrillations on electromyography.61 Flaccid weakness also occurs with damage to peripheral nerves, such as acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy, and should be considered in the differential diagnosis. In contrast to anterior myelitis, the weakness is typically symmetrical and ascends gradually in the neuropathies, and CSF studies demonstrate elevated protein levels but no pleocytosis. Electrophysiological studies enable distinction of polyneuropathy from anterior myelitis, with delayed distal latencies and reduced conduction velocities in both sensory and motor fibers in the former.

Poliomyelitis Acute poliomyelitis is now rarely encountered in the industrialized world, because of the World Health Organization’s global eradication program. Nonetheless, pockets of endemic disease persist in sub-Saharan Africa and the Indian subcontinent, and it continues to occur sporadically elsewhere.62 There is also a small incidence of live vaccine–related poliomyelitis.62 Poliomyelitis is caused by an enterovirus whose main route of infection is via the gastrointestinal tract.62 In approximately 5% of infections, after nonspecific flulike symptoms, nervous system infection occurs and is initially manifested as meningi-

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tis, with high fevers, neck stiffness, and headache.62 The onset of spinal poliomyelitis is heralded by myalgias, with the subsequent development of asymmetrical, lower limb–predominant flaccid weakness or paralysis, reaching a maximum within 48 hours of onset.62 Diagnosis is based on virus isolation of nasopharyngeal secretions and/or the stool. CSF examination demonstrates elevated protein levels and pleocytosis. Serological diagnosis, with demonstration of antipoliovirus IgG and IgM antibodies, can establish the diagnosis in the absence of viral isolate. PCR techniques now enable rapid diagnosis, identification of serotype, and differentiation of wild-type from vaccine-related disease.63 MRI may demonstrate high signal intensity on T2-weighted imaging in the region of the anterior horn cells.64 There is, unfortunately, no curative treatment.62 Management is supportive, aimed at symptom control with analgesia and prevention of complications. The aim of strict bed rest is to prevent progression of paralysis. Passive exercise during the acute phase, followed by more intensive physiotherapy, can prevent or minimize contractures.65

Poliomyelitis-like Syndromes Acute flaccid paralysis secondary to anterior horn cell disease may be associated with other enteroviruses (e.g., enterovirus 71, Coxsackie virus A7, echoviruses), tickborne encephalitides, flaviviruses (e.g., Japanese encephalitis, Murray Valley encephalitis virus, and West Nile virus), herpesviruses (cytomegalovirus, Epstein-Barr virus, VZV), and HIV-related opportunistic infections.57,61-68 West Nile virus, a flavivirus, usually causes a mild febrile illness.61 Neurological disease is reported in 1 per 150 infected persons and usually consists of meningitis and encephalitis; however, there are numerous reports of patients with poliomyelitis-like acute flaccid paralysis, occurring during the acute febrile illness.61,68 Diagnosis is based on identification of anti–West Nile virus antibodies in serum or CSF.61 Confirming an anterior horn cell process, high signal intensity in the anterior horns on T2-weighted MRI has been demonstrated.69 Histopathological examination of autopsy specimens has demonstrated anterior myelitis, with perivascular lymphocytic infiltrate, monocytic infiltration, and gliosis.70 Enterovirus 71, which causes outbreaks of hand-foot-andmouth disease, a common exanthema of childhood characterized by fevers, palmar and plantar rash, and oromucosal ulceration, may be associated with neurological complications, including an acute flaccid paralysis.66

Spinal Epidural Abscess Spinal epidural abscess is an uncommon condition, occurring with an estimated incidence of 0.2 to 2.8 cases per 10,000 per year.71-74 The incidence peaks in the sixth and seventh decades of life.71 Although this condition is potentially fatal, with devastating neurological sequelae if left untreated, early recognition and prompt institution of appropriate therapy can avert complications. Risk factors for spinal epidural abscess include immunocompromised states and are identified in Table 40–5.72 In 20% of cases, there is no identifiable risk factor.71,76 The most common causative agent is Staphylococcus aureus, accounting for 57% to 75% of reported cases.72,73

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Risk Factors for Spinal Epidural Abscess

Hematogenous Seeding Intravenous drug abuse Blunt spinal trauma Immunocompromised states Diabetes mellitus Alcohol abuse Chronic renal failure Malignancy AIDS Direct Inoculation Spinal surgery Open spinal trauma Epidural catheterization AIDS, acquired immunodeficiency syndrome.

Mycobacterium tuberculosis is the next most frequent cause, accounting for 25% of spinal epidural abscess in one series.77 Tuberculous osteomyelitis of the vertebra (Pott’s disease) can give rise to epidural extension, with abscess formation.57 Tuberculous meningitis may also occur. Gram-positive cocci other than S. aureus were cultured in 10% of patients, gramnegative organisms in 18%, and anaerobes in 2% in one series.75 Fungal infections of the spinal cord are rare, and usually occur in immunocompromised persons.57,76 Blastomyces, Coccidioides, and Aspergillus organisms may invade the epidural space via the intervertebral foramina or as a result of direct extension from a focus of vertebral osteomyelitis.57 Both Coccidioides and Blastomyces organisms may hematogenously seed the spinal cord or surrounding meninges. Cryptococcus infection, which can cause meningoencephalitis, is a rare cause of spinal infection.57 In the majority of cases, spinal epidural abscess is thought to arise from hematogenous spread of organisms from remote mucocutaneous sources, such as the site of pharyngitis or dental sepsis.72 These abscesses are usually located posteriorly in the epidural space, the thoracic spine, or the lumbar spine. Contiguous spread of infection into the epidural space from a source adjacent to the spine, such as that of diskitis or vertebral osteomyelitis, is also well described and usually results in an anterior epidural abscess.72,76 Direct extension from retropharyngeal or retroperitoneal abscesses via the vertebral foramina may occur.72 Blunt trauma precedes spinal epidural abscess in 15% to 35% of cases.78 The postulated mechanism in such cases is hematogenous seeding of the nutrient-rich environment of a vertebral hematoma. The mechanism leading to neurological dysfunction in spinal epidural abscess is incompletely understood. Neurological deficits are disproportionate to the degree of direct compression of neural structures by the extradural mass within the rigid bony spinal canal.71 Epidural edema and inflammation with involvement of the epidural venous plexus, resulting in venous ischemia and infarction of the spinal cord, are postulated to potentiate the effects of compression.74,75

Clinical Features Clinical manifestation is usually nonspecific, and symptoms can evolve over a few hours to several months.71 The most common presenting symptoms are fever, malaise, and back

pain.71 The presence of overt neurological symptoms, including radicular pain, weakness, and sphincter dysfunction, is suggestive of disease progression. Systemic sepsis may occur. In patients with chronic infection, constitutional symptoms of fever, anorexia, and weight loss may dominate the clinical picture. There may be focal tenderness of the spine, and neurological deficits may be evident.71 Laboratory investigation usually reveals leukocytosis, with elevated levels of inflammatory markers (C-reactive protein and, if the process is more chronic, erythrocyte sedimentation rate). Blood cultures are positive in more than 60% of cases.75 The imaging modality of choice for diagnosis is MRI with gadolinium contrast material, because it enables the abscess to be distinguished from adjacent compressed thecal sac and differential diagnoses such as herniated intervertebral disk (Fig. 40–3).71 During the early phlegmonous stage of infection, homogenous enhancement is seen. Once the necrotic center liquefies, with surrounding inflammatory tissue, peripheral enhancement is seen with gadolinium. Open biopsy or computed tomography–guided aspiration provides tissue for culture, to isolate the causative organism and facilitate directed therapy.71,72

Treatment The treatment of choice in most patients is surgical evacuation and decompression, followed by intravenous broad-spectrum bactericidal antibiotic therapy for at least 4 to 6 weeks.72 Less invasive endoscopic and percutaneous drainage procedures have been described.79 In patients who present with minimal neurological dysfunction or who are poor surgical candidates, conservative treatment in the form of long-term antibiotic therapy may be undertaken.72 Serial MRI and close neurological monitoring are imperative in these cases; indications for surgical intervention are neurological progression and increasing size of the abscess. Neither conservative management nor surgical treatment has been shown to be superior; evidence indicates that both modalities have good outcomes if treatment is initiated promptly.81,82 Prognosis is dependent on the clinical, particularly neurological, condition of the patient at presentation. Poorer outcomes have been reported when treatment has been delayed.72 Good outcomes are reported when the duration of neurological deficit is less than 72 hours, when the degree of thecal sac compression is less than 50%, and in patients younger than 60 years.82 The rate of mortality from epidural abscess is approximately 14%.72

Intramedullary Spinal Cord Abscess This rare entity, first described by Hans Chiari in 1900, is indistinguishable on the basis of symptoms from epidural abscess, producing fever, pain, and motor and sensory deficits with progression.57 It may occur in the setting of systemic sepsis, either septicemia or infective endocarditis, with hematogenous seeding of the spinal cord. Contiguous spread from a local source of sepsis, via the intervertebral foramina, is also possible. CSF examination demonstrates pleocytosis, with elevated protein levels. MRI is the imaging modality of choice.57 Causative agents reported in the literature include Listeria monocytogenes and M. pneumoniae. Solitary tuberculoma of the spinal cord is extremely rare.57

chapter 40 spinal disease

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Vertebral Osteomyelitis

A

Accounting for approximately 2% to 7% of all cases of osteomyelitis, spinal osteomyelitis occurs more often in elderly persons.83 As in epidural abscess, the most common causative agent, reported to account for more than 50% of cases, is S. aureus.83,84 Hematogenous seeding in association with conditions producing bacteremia, such as infective endocarditis, and, less frequently, with direct inoculation of bacteria result in pyogenic infection.83 Infection is characteristically confined to the vertebral body and intervertebral disk; however, in as many as 20% of cases, the posterior osseous elements are involved.83,84 Clinical features are usually insidious. Back and neck pain is the commonest manifestation, occurring in 90% of affected patients, and neurological deficits secondary to nerve root or spinal cord impingement are reported in 20%.83,84 Complications include spinal deformity secondary to vertebral destruction and epidural abscess formation, both of which may lead to compression of spinal cord and nerve roots.83 Paraspinal or retrospinal abscess formation may occur in association with spinal osteomyelitis. Laboratory investigations are of limited value. MRI is the preferred diagnostic imaging modality, with an accuracy of approximately 90%, enabling visualization of spinal cord, nerve roots, extradural space, and bony elements.83 Single photon emission computed tomography with gallium 67, a functional imaging modality, has also been shown to be of value in diagnosis and may be a valuable adjunct in patients in whom the diagnosis remains uncertain.83 Early surgical decompression, with internal fixation to provide spinal stability, is the contemporary approach to vertebral osteomyelitis with neurological deficit and focal spinal deformity.85 Nonsurgical management—namely, broad-spectrum intravenous bactericidal antibiotic therapy—is indicated in patients with minimal or no neurological deficits and localized kyphotic deformities, although it may fail, necessitating surgical intervention.85

Spinal Meningitis and Meningomyelitis

B ■

Figure 40–3. Spinal epidural abscess. An epidural mass is seen on sagittal (A) and axial (B) views, with peripheral enhancement on gadolinium T1-weighted spin-echo imaging (B, sagittal view).

Parasitic Spinal Cord Disease Parasitic infections of the spinal cord are rare; however, schistosomiasis (Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni) is a cause of myelitis encountered in eastern Asia, Africa, and South America.57 The ova of the schistosomes evoke a granulomatous myelomeningoradiculitis, with destruction of both gray and white matter. Less commonly, an acute transverse myelitis and spinal cord compression caused by a localized granuloma may be present.57

Infections of the spinal meninges may involve primarily the pia mater and arachnoid mater, to produce a leptomeningitis, or the dura mater, causing a pachymeningitis.57 These processes may be either acute or chronic. When the spinal cord is also involved, the process is referred to as meningomyelitis. Viral agents reported to cause myelomeningitis and meningitis include Coxsackie viruses, enteroviruses, and herpesviruses.57 Bacteria, including M. tuberculosis and T. pallidum (syphilis), may cause meningomyelitis, as may some fungal and parasitic infections. Involvement of pial blood vessels can lead to thrombosis, with infarction of the spinal cord (myelomalacia).57 Progressive pial constrictive fibrosis (spinal arachnoiditis) can result from chronic meningeal inflammation, resulting in compression of neural structures and their vascular supply.57 Damage to spinal nerve roots, particularly in the dorsal roots in the lumbosacral region, may occur with protracted meningitis, as seen in syphilitic myelomeningitis (tabes dorsalis).57 Clinical features include those of meningeal irritation (fever, neck or back pain) and symptoms and signs attributable to the particular pattern of involvement of spinal structures. Examination of CSF demonstrates pleocytosis, with elevated

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Classification of Syringomyelia

Type I: Syringomyelia with obstruction of the foramen magnum and dilatation of the central canal A: With Chiari type I malformation B: With other obstructive lesions of the foramen magnum Type II: Syringomyelia without foramen magnum obstruction Type III: Secondary syringomyelia A: Spinal cord tumors B: Traumatic myelopathy C: Spinal arachnoiditis and pachymeningitis Type IV: Pure hydromyelia with or without hydrocephalus

protein levels.57 Gram and other specialized stains may reveal causative agents in cases of pyogenic meningitis, and microbial culture is an imperative diagnostic investigation. MRI with gadolinium contrast material demonstrates leptomeningeal enhancement.57

DEGENERATIVE DISEASES OF THE SPINAL CORD

tracts. Indeed, the frequent association of syrinx with craniocervical junction malformations, which could potentially block the flow of CSF, supports this theory. In a more recent report, it was postulated that the primary event in the formation of syrinx in many cases is reduced volume of the posterior cranial fossa, such as that caused by basilar invagination, with resultant Chiari malformation caused by caudal displacement of structures. Long-standing pulsatile pressure of the herniated structures on the spinal cord leads to syrinx formation as a tertiary event. It was suggested that this was a mechanism serving to protect vital neural structures at the level of the craniovertebral junction at the cost of spinal cord. One report questioned prevailing hydrodynamic theories, on the basis of the facts that syrinx pressure exceeds CSF pressure and the composition of syrinx fluid is not identical to that of CSF.89 An alternative theory is abnormal spinal cord structure, with a tendency to cavitate.57,87 The syrinx initially occupies the central gray matter of the cervical spinal cord, interrupting the crossing spinothalamic tract fibers in the anterior commissure over several cord segments. Progressive symmetrical or asymmetrical enlargement leads to interruption of the posterior and anterior horns of the spinal cord and, finally, the white matter funiculi (lateral and posterior).57

Syringomyelia Primary syringomyelia is a chronic, progressive degenerative disease of the spinal cord, characterized by brachial amyotrophy and dissociated segmental sensory deficit. Cavitation of the central spinal cord is seen, usually in the cervical region, although extension of the process rostrally into the medulla and pons of the brainstem (syringobulbia) or caudally into the thoracic and even the lumbar spine may be seen.57 Syringomyelia may also occur in association with intramedullary spinal cord tumors, mostly gliomas, in 25% to 57% of cases in some series.86 Traumatic myelopathy, radiation myelopathy, myelomalacia (spinal cord infarction), hematomyelia, and spinal arachnoiditis are other associated conditions.57 Bony abnormalities of the vertebral column (e.g., thoracic scoliosis and fusion of vertebrae [Klippel-Feil anomaly]) and the base of the skull (e.g., platybasia or basilar invagination) are frequently associated conditions.57,87 Caudal displacement of the posterior fossa structures—namely, the brainstem and cerebellum—producing a Chiari type I malformation is seen in approximately 90% of cases of syringomyelia.57 A suggested scheme of classification is found in Table 40–6.88

Pathogenesis A number of hypotheses regarding the mechanism of formation of syrinx have been put forward. Many of these suggest that disturbances in CSF hydrodynamics result in interruption of CSF flow between the spinal and intracranial subarachnoid compartments.57,87,89 An early theory was that syringomyelia arose from the prevention of normal flow of CSF by congenital failure of opening of the outlets of the fourth ventricle (foramina of Luschka and Magendie).90 A pulse wave of CSF pressure, generated by systolic pulsation of the choroid plexuses, is transmitted into the spinal cord via the central canal, resulting in dilatation of the central canal, with a diverticulum that ramifies from the central canal and dissects along gray matter and white matter

Clinical Features Types I and II syringomyelia are sporadic and usually begin in middle age; in some cases, an abnormality may be evident at birth. Symptoms develop insidiously, although there are reports of sudden and dramatic worsening after violent strain or a paroxysm of coughing.57 Intermittent progression is the usual course, with patients being bedridden within 5 to 10 years; however, the course is extremely variable, and some patients remain stable for many years.57 The clinical picture varies according to subtype of syringomyelia, particularly the presence or absence of a Chiari malformation. The cross-sectional and longitudinal extent of syrinx determines the clinical profile at any given time in the evolution of the disease. Pain, which is usually unilateral or asymmetrical, is experienced by approximately 50% of patients with types I and II syringomyelia.57 The key clinical feature is dissociated segmental sensory loss—namely, loss of pain and temperature sensation as a result of interruption of spinothalamic pathways—with preservation of dorsal column sensory functions. Tactile sense may, however, be impaired in the region of most dense anesthesia. The distribution of sensory loss is over the neck, shoulders, and arms (cape), often extending to the face, back of the head, and trunk. It is usually bilateral; however, asymmetry, even unilateral sensory loss, may occur. Segmental weakness and atrophy of the upper limbs, which may be asymmetrical, with loss of deep tendon reflexes, are also characteristic. However, there are exceptions in which motor function is preserved. Eventually, spastic lower limb weakness and ataxia develop, with impairment of lower limb proprioception and vibration sense, as a result of corticospinal and posterior column involvement in the inferior medulla and cervical spinal cord, respectively. In some instances, especially when there is a coexistent Chiari malformation, an upper motor neuron pattern of weakness may also be seen in the upper limbs. The presence of a Chiari malformation or a foramen

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T A B L E 4 0 – 7. Static Factors Contributing to Cervical Spondylotic Myelopathy Congenital stenosis of the spinal canal (anteroposterior diameter <13 mm) Intervertebral disk herniation Vertebral body osteophyte formation Degenerative osteophytic lipping of the uncovertebral and facet joints Hypertrophy of the ligaments: ligamentum flavum and posterior longitudinal ligament

Cervical Spondylotic Myelopathy Cervical spondylotic myelopathy (CSM) results from narrowing of the spinal canal, secondary to degenerative or congenital vertebral and disk disease. It is the commonest spinal cord disease in patients older than 55 years.93-95 Clinical manifestations are diverse, and it is often asymptomatic.

Pathophysiology

■

Figure 40–4. Syringomyelia. Enlargement of the central canal of the cervical spinal cord is demonstrated.

magnum lesion is also indicated by nystagmus, cerebellar ataxia, and occipitonuchal pain with maneuvers that increase intracranial pressure.57 Ipsilateral Horner’s syndrome results with involvement of the intermediolateral cell column at C8, T1, and T2 levels.57 MRI is the investigation of choice, demonstrating syrinx and associated abnormalities, including Chiari malformation and foramen magnum lesions (Fig. 40–4).57

Treatment Several surgical procedures have been reported for the treatment of syringomyelia, with the approach tailored to the individual clinical and imaging characteristics.91 There have been no controlled, prospective, or multi-institutional studies on which to base management decisions, reflective of the complexity of treatment selection. The two major approaches to types I and II are syringosubarachnoid shunting and decompression of the foramen magnum and upper cervical spinal canal.91 Decompression has been reported to ameliorate lower limb signs and symptoms; however, upper limb sensorimotor deficits persist.92 Conversely, shunting has produced unpredictable results, although there is some evidence that it may be superior to decompression as a first-line treatment for syringomyelia with Chiari I malformation.57

The primary pathophysiological abnormality is reduced sagittal diameter of the spinal canal, and a dimension of less than 13 mm is thought to be critical in the later development in relation to superimposed degenerative change.93 The mechanical factors involved in the process of CSM fall into two groups: static factors (Table 40–7) and dynamic changes in the spinal column and spinal cord during flexion and extension of the cervical spine under normal physiological loads.93,96 Direct compression of neural structures, as a result of these mechanical factors, is compounded by ischemia of the spinal cord, secondary to compression of the arterial supply (either larger vessels, such as the anterior spinal artery, or the pial plexuses and small penetrating arteries) or draining veins of the spinal cord and nerve roots by degenerative elements.93 Indeed, the highest frequency of myelopathy occurs at the C5-C7 level, which has the most tenuous vascular supply.93

Clinical Features Symptoms and signs are varied, and there are no pathognomonic clinical features. Onset tends to be insidious. Neck, subscapular, or shoulder pain may occur. Loss of hand dexterity may be a marked early feature. Gait disturbance, the commonest presenting symptom of CSM, is a manifestation of long tract dysfunction, with upper motor neuron weakness resulting from corticospinal tract involvement and compounded by proprioceptive (dorsal column) dysfunction.93 Bowel and bladder dysfunction is also common, reported to occur in 15% to 50% of affected patients.93-98 Segmental lower motor neuron deficits are seen at the compressed level of the spinal cord, most commonly at the C5-C6 level. The differential diagnosis includes such important entities as multiple sclerosis, motor neuron disease, spinal cord tumors, and syringomyelia. Like CSM, multiple sclerosis tends to cause both sensory and motor deficits, and the former may be dissociated; however, cranial nerve signs may also occur, in contrast to CSM. In both CSM and motor neuron disease, a combination of upper and lower motor neuron signs may be present; however, no sensory abnormalities occur in the latter.

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Spine and Spinal Diseases However, there are a number of arguments in favor of surgery over medical management. Up to 70% of patients treated medically show no improvement or deteriorate neurologically, as measured by the degree of motor disability and the ability to perform activities of daily living.93 Furthermore, patients with CSM are at increased risk of spinal cord injury from relatively mild traumatic events, because the spinal cord has limited room to move.93 Finally, it has been shown that early surgical intervention can improve prognosis, particularly if symptoms are of less than 1 year’s duration.95,100,101 The two traditional surgical approaches to CSM are a dorsal approach—namely, cervical laminectomy—and a ventral approach, either diskectomy or corpectomy at one or more levels, with interbody fusion.93 After corpectomy, cervical plating is typically necessary to provide stability until fusion occurs.93 No significant difference in outcome of one approach over the other has been demonstrated.93,98,101,102 The choice is therefore guided by the surgeon’s preference, the relative location of the stenosis (dorsal versus ventral), and the alignment of the spinal cord (kyphosis versus lordosis), as well as by individual patient factors.93 Cervical total disk replacement is an evolving modality for the treatment of disk degeneration and herniation in the cervical spine.103

Spondylotic Lumbar Stenosis

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Figure 40–5. Cervical spondylotic myelopathy. T2-weighted spinecho image, demonstrating grossly narrowed cervical spinal canal, with mild hyperintensity of the spinal cord at the level of compression, caused by myelomalacia.

Diagnosis MRI is the imaging modality of choice for evaluating cervical degenerative disease, enabling evaluation of the spinal cord, vertebral bodies, disks, osteophytes, and ligaments.93 In addition to indentation, T2 hyperintensity of the spinal cord may be seen at the level of compression, caused by edema, inflammatory changes, ischemia, myelomalacia, or gliosis (Fig. 40–5).93 The responsible lesion may be difficult to distinguish from clinically silent cord compression on MRI, particularly in elderly patients. In order to avert the high rate of morbidity associated with extensive spinal surgery, the use of electrophysiological measurement of spinal cord evoked potentials may be a valuable adjunctive tool for localizing the spinal level at which clinically significant compression occurs in cervical myelopathy.99 Most often, however, careful clinical judgment is necessary to distinguish clinically relevant CSM from the sometimes striking incidental changes seen in older patients. Some clinicians believe that flexion-extension views of the spine are a useful discriminatory test.

Treatment Traditionally, first-line management is conservative, because of the significant morbidity associated with spinal surgery.93

Osteoarthritic or spondylitic changes in the lumbar region, compounded by an unusually small spinal canal, may lead to compression of the cauda equina, with the nerve roots compressed between the posterior surface of the vertebral body and the ligamentum flavum posterolaterally.57 Symptoms of gradually ascending numbness and leg pain, associated with weakness, occur in the upright position or with ambulation (especially downhill) and are relieved by sitting down or lying down with hips and knees flexed.57 The intermittent nature of these symptoms and their relation to ambulation (hence the term neurogenic claudication) may lead to misdiagnosis of lower limb vascular insufficiency. Back pain occurs in varying severity, and sphincter disturbance is rare. Diagnosis is based on MRI demonstration of narrowing of the lumbar spinal canal, and treatment is decompressive surgery.57

Degenerative Lumbar Intervertebral Disk Disease Herniation of lumbar intervertebral disks is a major cause of morbidity, resulting in severe, chronic, or recurrent low back pain. The incidence peaks in the third to fourth decades of life.57 The disk between the L5 and S1 vertebrae is most commonly involved, with the more cranial intervertebral disks affected with diminishing frequency.57,104 Thoracic disks are rarely affected, accounting for only 0.5% of all surgically confirmed disk prolapses.57 Protrusion of the nucleus pulposus posteriorly (through the annulus) occurs with a flexion injury, with a maneuver that increases intraspinal pressure (e.g., sneezing), or even with a trivial movement, in the setting of degenerative changes within the nucleus pulposus, annulus fibrosus, and posterior longitudinal ligaments. In severe cases, the nucleus pulposus may protrude entirely through the annulus. More often, a fragment extrudes or protrudes through tears in the annulus, usually to a side, to impinge on a nerve root. A large fragment may compress the root or roots against the articular process or lamina,

chapter 40 spinal disease T A B L E 4 0 – 8. Features of Herniated Lumbar Intervertebral Disk Pain, exacerbated by sitting and standing up from a seated position: Mechanical: back and deep to the buttock (inferolateral to the sacroiliac joint) Radicular: lancinating pain, radiating into the thigh, calf and foot (sciatica); may be elicited by palpation along the course of the sciatic nerve Paresthesias Stiff, deformed spine Back tenderness, particularly on palpation over the L5 and S1 spinous processes Radicular neurological deficit: Motor: hyporeflexia or areflexia; myotomal weakness; hypotonia Sensory: dermatomal hyperesthesia or hypoesthesia Position of greatest comfort: dorsal decubitus position (supine, with legs flexed at knees and hips; shoulders elevated on pillows in order to obliterate the lumbar lordosis Posture: antalgic Affected leg slightly flexed at knee and hip (VA); sciatic scoliosis and tilted trunk, caused by reflex contraction of the paraspinal muscles to minimize irritation of nerve root(s) by protruded disk material Gait: antalgic: brief, cautious weight-bearing on the painful leg Positive Lasègue’s maneuver (hip flexion with extended knee): stretch of nerve roots elicits sciatica Restricted straight-leg raising Fajersztajn’s sign: raising of the contralateral leg elicits ipsilateral pain, of lesser severity

giving rise to radicular symptoms. Because this extruded material is often not resorbed, chronic irritation of neural structures may result. Herniation of the disk into the adjacent vertebral body gives rise to a Schmorl nodule, which may be associated with back pain but no signs or symptoms of nerve root compression.

Clinical Features The full complement of features of the syndrome of prolapsed lumbar intervertebral disk is detailed in Table 40–8.57,104 Disk

T A B L E 4 0 – 9.

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degeneration without herniation may lead to low back pain. The pain of disk herniation can be severe, necessitating bed rest and avoidance of any movement. Signs of nerve root involvement may be elicited on the affected side. The clinical features associated with compression of particular nerve roots are detailed in Table 40–9. Frequently, more than one nerve root is compressed by a single herniated disk, giving rise to multilevel signs and symptoms.57 Large central protrusions can produce bilateral features, as well as cauda equina syndrome; however, this is rare.

Diagnosis MRI of the lumbosacral spine is the “gold standard” investigation for diagnosis, demonstrating the protruded disk and annular tears and excluding differential diagnoses such as extradural tumor (Fig. 40–6).104,105 Oblique views, in addition to the traditional protocol of axial and sagittal views, enable visualization of the neural exit foramina, facilitating detection of foraminal nerve root impingement.106 MRI also allows other sites of degenerative disease, including clinically silent lesions, to be identified. Electromyography and nerve conduction studies are valuable adjuncts, particularly when the clinical significance of a lesion is unclear and other differential diagnoses such as a peripheral neuropathy are being entertained. Prolonged F wave latencies and denervation potentials in the paraspinal muscles and in other muscles in a myotomal distribution indicate a radicular rather than a peripheral nerve lesion.57

Treatment Most patients with herniated lumbar intervertebral disk may be treated conservatively, with analgesia and bed rest for the first 48 hours, followed by gradual mobilization and physiotherapy.107 Indications for surgical management include the presence of cauda equina compression, progressive or profound neurological deficit, and disabling pain after 4 to 6 weeks of conservative management.107 Spinal fusion is the traditional surgical approach.107

Clinical Features Associated with Compression of Particular Nerve Roots Disk Protruded

Feature

L5-S1

L4-L5

L2-L3, L3-L4

Nerve root affected Distribution of pain (see Fig. 40–1)

S1 Midgluteal region, posterior thigh, posterior calf (to the heel), lateral plantar surface of foot, and fourth and fifth toes Distal part of leg and outer toes

L5 Hip, posterolateral thigh, lateral calf (to external malleolus), dorsal surface of the foot, and first to third toes In distribution of pain, usually distally Great toe extension (extensor hallucis longus) and foot dorsiflexion; hip abduction (positive Trendelenburg’s test)

L3; L4 Anterolateral thigh and knee Anterolateral thigh and anteromedial leg (L4)

Distribution of paresthesias and sensory deficit Motor deficit

Ankle jerk Knee jerk Location of tenderness

Flexion of foot and toes, toe abduction and knee flexion (hamstrings)

Usually absent or diminished; often the only objective sign Unaffected Midgluteal region (over sacroiliac joint), posterior thigh, and calf

Usually normal; may be diminished or absent Unaffected Lateral gluteal region and near femoral head

Anterolateral thigh and knee and anteromedial leg Knee extension (quadriceps: L2, L3, L4) and hip flexion (iliopsoas: L1, L2, L3); foot dorsiflexion (tibialis anterior: L4) Unaffected Diminished/absent —

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B

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Figure 40–6. Intervertebral disk prolapse. A, Sagittal view of a large central L4-S5 intervertebral disk prolapse, obliterating the spinal canal, and compressing the cauda equina. B, Axial view of a central L5-S1 disk prolapse.

A

TUMORS OF THE SPINAL CORD Most of these tumors are potentially surgically resectable; therefore, early detection, before the occurrence of irreversible neurological damage, is imperative. Tumors of the spinal cord can be divided into primary neoplasms, arising from the cord itself or the surrounding meninges, and secondary neoplasms, which have metastasized to the spine from elsewhere in the body. Further subdivision, into intramedullary and extramedullary lesions, is based on the anatomical distribution within the spinal canal (Table 40–10). Primary spinal tumors are usually intradural, in contrast to the majority of secondary tumors, which are extradurally based.

Epidemiology Spinal cord tumors are rarer than brain tumors, and in contrast to the latter, the majority are benign.57 A Mayo Clinic series of 8784 primary tumors of the CNS revealed that 15% arose from the spinal cord.57 Most seen in the general hospital population are extramedullary; approximately 40% are intradural-extramedullary, 55% are extradural-extramedullary, and only 5% are intramedullary.57

Clinical Features The clinical sequelae of most spinal cord tumors result from local compressive effects rather than direct invasion. The onset of

T A B L E 4 0 – 10. Spinal Cord Tumors Intramedullary Spinal Cord Tumors (20%) Arising within the substance of the spinal cord itself Primary Gliomatous: ependymoma; astrocytoma; subependymoma; ganglioglioma Nongliomatous: hemangioblastoma, paraganglioma, lymphoma and primitive neuroectodermal tumors (PNET), lipomas, dermoids, epidermoids, hemangiomas, and germ cell tumors Secondary (metastatic) (See Table 40–2) Extramedullary Spinal Cord Tumors (80%) Arising outside the spinal cord; extradural: arising within the epidural tissues or the vertebral bodies; intradural: arising within the spinal roots or the leptomeninges Primary Meningioma, neurofibroma, schwannoma, sarcomas, teratomas, vascular tumors, chordomas, and epidermoid tumors Secondary Metastatic carcinoma, lymphoma, and multiple myeloma/plasmocytoma

symptoms is usually gradual, progressing over weeks to months, and asymmetrical.57 Patients often complain of pain in the spine; about one half experience tenderness of spinous processes over the tumor. The pain is characteristically central or dermatomal and is exacerbated by maneuvers increasing intraspinal pressure, such as sneezing, coughing, and recumbency.

chapter 40 spinal disease There are three major, sometimes overlapping clinical neurological syndromes that spinal cord tumors can engender, addressed in the overview:57 (1) a sensorimotor spinal tract syndrome, (2) a painful radicular-spinal cord syndrome, and (3) a syringomyelic syndrome. Spinal cord compression, manifested by clinical features of segmental and long tract involvement, is covered in greater detail later in this chapter. It is often preceded by radicular symptoms, which are common. Tumors in the region of the foramen magnum may produce quadriparesis, with pain in the occipitonuchal region, neck stiffness, weakness, and atrophy of hand and dorsal neck muscles, as well as varying sensory signs.57 In rare cases, extramedullary tumors of the thoracolumbar spine may be associated with dementia and communicating hydrocephalus, ameliorated by shunting and tumor excision.57 When features of spinal disease are present, imaging is imperative, to achieve a diagnosis. Important differential diagnoses to consider include spondylitic degenerative disease, epidural abscess, tuberculous infection, meningomyelitic processes, and adhesive arachnoiditis. In the case of intramedullary lesions, vascular malformations must be considered.

Imaging MRI has enabled characterization of spinal cord tumors, including their location within the spinal canal and internal structure, through the use of different magnetic resonance scanning sequences.108 The basic spinal magnetic resonance study includes T1- and T2-weighted sequences in the sagittal plane, and contrast material (gadolinium)–enhanced T1-weighted images in the sagittal and axial planes.108,109 In comparison with intracranial neoplasms, most spinal cord tumors, even lowgrade forms, are enhanced after the administration of intravenous contrast material, which enables differentiation of solid from cystic components of the tumor. Identification of the extent of the solid enhancing component of tumors is vital, because current neurosurgical practice dictates that laminotomy and laminectomy be limited to this area, in order to minimize the surgical morbidity associated with spinal surgery.

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momas or astrocytomas, although rarer types such subependymomas do occur in the spinal cord.108 Metastases are far less common in the intramedullary than the extramedullary compartment.57,108 There is usually a long antecedent history before the diagnosis.108 Pain is the most common symptom, with mixed sensorimotor tract symptoms and signs.108 Involvement of the central gray matter leads to a syringomyelic central cord syndrome.57 Sacral sparing has been reported to help distinguish between intramedullary and extramedullary tumors; however, no clinical feature is unique to intramedullary tumors.108 Therefore, distinction between the clinical profiles of intramedullary and extramedullary lesions is seldom dependable, and imaging is vital for diagnosis. The key findings in intramedullary spinal cord tumors on MRI are as follows:108,110,111 1. Expansion of the spinal cord. 2. At least some enhancement with gadolinium contrast material in most cases. 3. Cysts, either tumoral or nontumoral, in many cases. Polar cysts, located at the rostral or caudal extent of solid lesions, represent reactive dilatation of the central canal (syringomyelia). They are seen in approximately 60% of intramedullary spinal tumors and are not enhanced with contrast material.108 Conversely, tumoral cysts occur within the tumor itself and usually demonstrate peripheral enhancement. They occur more commonly in astrocytomas than in ependymomas.108 There is an increased incidence of intramedullary spinal cord tumors in patients with neurofibromatosis.112 Ependymomas are associated with type 2 disease, whereas astrocytomas are seen more frequently in type 1 disease. Interestingly, cytogenetic analysis has revealed the mutations of type 2 neurofibromatosis in some cases of sporadic spinal cord ependymoma.

Glial Neoplasms Ependymoma

Management Treatment is dictated by type of lesion and clinical picture. Intradural extramedullary lesions and benign extradural tumors necessitate surgical intervention, because of the risk of progression to spinal cord compression. Extradural tumors are managed according to their histological type, with radiotherapy, hormonal therapy, surgery, and chemotherapy, as well as corticosteroids, in various combinations.

Intramedullary Spinal Cord Neoplasms Intramedullary spinal cord neoplasms are rare, accounting for 4% to 10% of all CNS tumors and 20% of all intraspinal tumors in the adult population.108 They arise within the substance of the spinal cord itself, distorting, invading and destroying white matter tracts and the central gray matter structures. Primary intramedullary tumors have the same cellular origins as primary tumors of the brain.108 Ninety percent to 95% are gliomas, the majority of these being either ependy-

Ependymoma is the most common intramedullary spinal neoplasm in adults, reported to account for 60% of all glial cord tumors.113 The mean age at presentation is 38.8 years, and there is a male preponderance.108,113-115 They are believed to arise from the ependymal cells that line the central canal and are usually slow-growing tumors, which displace rather than infiltrate adjacent neural tissue; the mean duration of symptoms before diagnosis is 36.5 months.108,113-114 They tend to produce symmetrical expansion of the cord, as a result of their central location. Syringomyelia occurs in 9% to 50% of cases.108 Polar cysts are common. The cervical region is most often affected (44% of cases), with 23.5% of cases occurring at the cervicothoracic junction, and 26% occur in the thoracic cord alone.108 Metastasis to the retroperitoneum, lungs, and lymph nodes, may occur.115 Six histological subtypes are recognized: cellular (the most common type), papillary, clear cell, tanycytic, myxopapillary, and melanotic (the rarest).116 Almost all ependymomas are, however, low grade (World Health Organization classification grade I or grade II).108 Myxopapillary ependymomas,

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constituting 13% of all spinal ependymomas, tend to occur in the conus medullaris and filum terminale, in contrast to other subtypes, and consequently are the most common neoplasm in this region of the cord.108 Most affected patients have relatively mild symptoms and are ambulatory at presentation.108 Back or neck pain is reported in 67%.114,117,118 There are often no objective neurological signs. Sensory deficits predominate and are reported in 52%, probably caused by compression or interruption of spinothalamic tracts.108 Motor weakness is reported in 46% but may predominate in very large ependymomas, and sphincter dysfunction occurs in 15%.113,114,117,118 In rare cases, ependymomas may cause subarachnoid hemorrhage.119 On computed tomographic imaging, ependymomas appear either isoattenuated or slightly hyperattenuated in relation to the adjacent normal spinal cord tissue, but they are enhanced intensely after the administration of iodinated intravenous contrast material.113 On T1-weighted MRI (Fig. 40–7), most are isointense or hypointense in relation to normal spinal cord, but they are hyperintense on T2-weighted sequences.120,121 Approximately 20% to 33% of these tumors demonstrated a rim of hypointensity at the poles, the “cap sign,” on T2-weighted images, corresponding to hemosiderin deposition as a result of hemorrhage.117,120,121 Edema surrounding the tumor mass is seen in 60% of cases.117 At least some enhancement is seen with gadolinium in 84% of cases, with 89% of those displaying welldefined margins on contrast material–enhanced images.120,121 The treatment of choice is laminectomy and microsurgical resection.113,117,118 Adjuvant radiotherapy is reserved for cases of recurrent disease.113,117 In the immediate postoperative period, patients often deteriorate neurologically; this is secondary to edema and possibly transient interference with spinal cord blood flow. Preoperative neurological status is the key predictor of ultimate outcome.114 Milder neurological deficits at presentation, smaller lesions, and shorter symptom duration are factors associated with better postoperative outcome. The 5year survival rate is 82%, regardless of neurological status at presentation.108,113

Astrocytoma Astrocytomas constitute approximately one third of all spinal cord gliomas and are the most common intramedullary tumor in children. As with ependymoma, there is a male preponderance (58% of cases); however, the mean age at presentation is younger (29 years) (Table 40–11).117 The thoracic cord is most

commonly involved (67% of cases), followed by the cervical cord (49%).122 Holocord (involvement of the entire spinal cord) occurs in up to 60% of children with this condition.117 Astrocytomas are characteristically ill-defined, fusiform intramedullary enlargements.117 Small, eccentric tumor cysts are common, and syringes may be present. Histologically, astrocytomas are highly cellular and have no surrounding capsule, as a result of which malignant cells infiltrate along the network of normal astrocytes, oligodendrocytes, and axons.115 The degree of pleomorphism correlates with the biological behavior of these tumors. The World Health Organization’s system of classification subdivides astrocytomas into four grades.107,115 Grade I tumors are the most benign, accounting for 75% of spinal cord astrocytomas. Grade II lesions are the classic low-grade astrocytomas, whereas grade III lesions, known as anaplastic astrocytomas, are less differentiated. Grade IV astrocytomas, known as glioblastoma multiforme and displaying the most aggressive biological behavior, are rare in the spinal cord, constituting only 0.2% to 1.5% of spinal cord astrocytomas. The most common manifestations are pain and sensory deficit, occurring in approximately 53% of cases.117 In contrast to ependymomas, in which dysesthesias dominate the sensory symptoms as a result of spinothalamic tract involvement, astrocytomas tend to manifest with paresthesias.118 Motor dysfunction is less common (41.4%), and sphincter dysfunction is infrequent.117 On examination, objective neurological deficits are often absent in lower grade (grades I and II) astrocytomas, which results in diagnostic delay.117 In young children, symptoms occur sooner, with a median duration of 5 months before diagnosis; however, the lesions tend to be low grade, with slow growth and low recurrence rates.123 MRI features of astrocytomas include poor margination and isointensity or hypointensity in relation to normal spinal cord on T1-weighted sequences, with contrast material enhancement.108,123 On T2-weighted imaging, these lesions are hyperintense. In contrast to ependymomas, astrocytomas tend to occur eccentrically (57%) in the cord, reflective of their parenchymal origin, and the “cap sign” is not seen.124 Leptomeningeal spread is reported for 60% of intramedullary glioblastoma multiforme tumors.125 The prognosis for adult patients with astrocytoma is worse than that for ependymoma; mortality rates are much higher than in patients with comparable ependymomas, even in cases of gross total resection.126 This is probably reflective of the infiltrative nature of astrocytomas, with extension of the

T A B L E 4 0 – 11. Features of Ependymoma and Astrocytoma Feature

Ependymoma

Astrocytoma

Characteristic population (mean age at presentation) Location within spinal cord Gross morphology Presence of hemorrhage Contrast enhancement Conus medullaris/filum terminale involvement

Adult (38.8 years)

Pediatric (29 years)

Central Circumscribed Common Intense, focal, homogenous Yes

Eccentric Poorly defined Uncommon Patchy, irregular No

Adapted from Koeller KK, Rosenblum S, Morrison AL: Neoplasms of the spinal cord and filum terminale: radiologic-pathologic correlation. Radiographics 2000; 20:1721-1749.

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Figure 40–7. Magnetic resonance images of ependymoma. A, On T1-weighted spin-echo image, an intrinsic, expansile lesion of the thoracic spinal cord, isointense in relation to normal spinal cord, is seen. B, The lesion is hyperintense on T2-weighted spin-echo imaging, with a rim of hypointensity at the poles (“cap sign”). C, Enhancement is seen after gadolinium administration on T1weighted spin-echo imaging.

C

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neoplastic cells well beyond the gross margin of the tumor, which therefore necessitates more extensive resection of spinal cord, with increased risk of postsurgical neurological deficits.126 The treatment of these tumors is therefore somewhat controversial.108 Some neurosurgeons advocate gross total resection, whereas others prefer initial intraoperative biopsy and frozen section examination, proceeding to debulking in highgrade lesions.117,126 As malignant cells invariably remain despite apparent total macroscopic debulking, gross total resection may not be carried out, with the aim of averting significant neurological morbidity.126 Radiotherapy may be administered, with the aim of eradicating residual disease. Annual surveillance MRI is recommended after treatment.126

Nonglial Neoplasms Hemangioblastoma Constituting 1.0% to 7.2% of all spinal cord neoplasms, these tumors usually occur in patients younger than 40 years and may be extramedullary in 25%.108,117,127 They grow slowly and usually involve either the thoracic (50%) or cervical (40%) cord.108 Most cord hemangioblastomas are solitary; however, multiple lesions are seen in the von Hippel–Lindau syndrome, which is reported to occur in one third of patients with hemangioblastoma.128,129 Spinal hemangioblastomas are highly vascular, circumscribed lesions, which characteristically display prominent dilated, tortuous surface vessels.117,127 Histopathologically, the tumors are composed of sheets of large, pale stromal cells with hyperchromatic nuclei, interspersed with blood vessels of varying sizes.108 Foci of hemorrhage are usually prominent.108 Clinical manifestations, usually slowly progressive, include sensory symptoms (39%), usually impaired proprioception; motor dysfunction (31%); and pain (31%).108 Subarachnoid hemorrhage and hematomyelia are rare complications.128 Spinal angiography demonstrates a highly vascular mass, with a dense, prolonged blush and prominent draining veins.108 On T1-weighted MRI, hemangioblastomas display varying signal intensity, usually isointensity (50%) or hyperintensity (25%) in relation to normal cord, with intense and homogenous contrast material enhancement.117,124 High signal intensity, with flow voids, is seen on T2-weighted images; however, there are reports of hemangioblastomas that are not visible on this sequence.108,117 Three-dimensional magnetic resonance angiography can provide valuable noninvasive preoperative information regarding the architecture of feeding vessels.130

T A B L E 4 0 – 12. Intramedullary Spinal Cord Metastases Primary Tumor Lung carcinoma Breast Melanoma Renal cell carcinoma Colorectal carcinoma Unknown primary tumor

40%-85% 11% 5% 4% 3% 5%

cases), sphincter dysfunction (60%), and paresthesias (50%) are other common manifestations.108,132 MRI typically reveals mild cord expansion over several segments, with a central area of low signal intensity on T1weighted imaging and high signal intensity, reflecting edema and tumor infiltration, on T2-weighted sequences.133 Intense, homogenous enhancement is seen with administration of contrast material.108 Peritumoral edema is often florid, and cysts are rare, in contrast to primary intramedullary neoplasms.108 Radiotherapy and corticosteroids are the mainstays of therapy in the setting of widely metastatic disease, although microsurgical resection of discrete lesions has been advocated, to improve the quality of remaining life.131,132 Prognosis is almost universally poor, with two thirds of these patients dying within 6 months of diagnosis.131

Lymphoma CNS lymphoma is a rare condition, accounting for only 1% of all lymphomas.134-136 Most cases of spinal cord lymphoma involve the vertebra and the epidural compartment, although isolated intramedullary lymphoma occurs in 3.3% of cases of CNS lymphoma, and is usually a solitary lesion. The mean age at presentation is 47. The cervical cord is most often affected.108,134-136 Clinical features include weakness, progressive gait dysfunction, and sensory disturbance.135 Spinal cord lymphoma is usually of B cell phenotype, as demonstrated on immunohistochemistry study, although primary spinal cord T cell lymphomas have been reported, and this may be related to previous human T cell lymphoma virus–related myelopathy.134,135 On MRI, spinal cord lymphomas demonstrate high T2-weighted signal intensity, with intense enhancement after administration of contrast material. Management consists of radiotherapy to the lymphomatous mass, with systemic and intrathecal chemotherapy.134,135

Metastases

Extramedullary Spinal Cord Neoplasms

Intramedullary spinal metastases are rare, reported to be found in 0.9% to 2.1% of patients with cancer at autopsy.131 The most common primary cancer to metastasize to the spinal cord is lung carcinoma, followed by breast carcinoma (11%) (Table 40–12).132 The cervical cord is most commonly affected (45%) and then the thoracic cord (35%); the lumbar spinal cord is infrequently involved (8%).132 Most metastases are solitary.132 Symptoms progress rapidly, in contrast to the gradual onset of symptoms characterizing primary intramedullary neoplasms.108 Weakness is almost universal, and pain (70% of

Extramedullary tumors arise outside the spinal cord and are subdivided on the basis of their relationship to the dura mater: extradural if they arise within the epidural tissues or the vertebral bodies and intradural if they arise within the spinal roots or the leptomeninges. Intradural tumor growth, accounting for approximately 10% of CNS tumors, usually takes the form of a leptomeningeal carcinomatosis or lymphomatosis.57,137,138 The commonest extramedullary tumors are meningiomas and neurilemmomas (neurofibroma and schwannoma), together constituting 55% of all spinal neoplasms, and these

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B Figure 40–8. Magnetic resonance images of meningioma. An intradural extramedullary mass lesion is seen at the T4 level, lying anterior to the cord, an appearance characteristic of meningioma. It is isointense in relation to the spinal cord on T1-weighted spin-echo imaging (A), with intense enhancement after administration of gadolinium (B).

are more often intradural than extradural.57 Metastatic tumors and lymphoma usually occur in the extramedullary extradural compartment and are far commoner than intramedullary disease.57 In fact, extradural myeloma, lymphoma, and carcinoma together form the largest group of spinal tumors. They either seed the extradural space hematogenously or extend directly from vertebral deposits or extraspinal sites via the intervertebral foramina.137

Meningioma Meningiomas represent 16% to 25% of all spinal tumors and 25% to 46% of primary spinal cord tumors.139-141 They are usually encapsulated and extradural and tend to develop on the lateral or posterolateral surface of the spinal cord, which renders them readily surgically resectable.142 However, an “en plaque” form, which usually occurs intradurally, characterized by growth in a sheetlike or collar-like manner around the spinal cord with infiltration of the pia mater, was reported to occur in 3.1% of cases.143 These rare variants also have a tendency to infiltrate the arachnoid plane and the spinal cord parenchyma and are difficult to resect.142 Meningiomas tend to be slow growing, although the clinical history is shorter with the en plaque variant, and produce symptoms through compression of neural structures.139-141

MRI is the imaging modality of choice for the demonstration of meningiomas, with either isointensity or hypointensity on T1-weighted imaging and hyperintensity on T2-weighted sequences, and intense enhancement with intravenous administration of gadolinium (Fig. 40–8).143 The extent of extradural extension and compression of neural structures can be delineated on MRI. Computed tomography is useful for detecting the presence of calcification, an adverse factor in surgical outcome.141 Surgical resection is the mainstay of therapy, with radiotherapy used as an adjuvant treatment or as alternative therapy in patients who are poor surgical candidates.141

Schwannoma Schwannomas are benign, solitary, slow-growing neoplasms, composed of differentiated neoplastic Schwann cells derived from nerve sheaths.138,144,145 They account for approximately 20% of all primary spinal neoplasms.138,144 They usually occur in the intradural extramedullary compartment, and approximately 40% of intradural extramedullary tumors are either schwannomas or neurofibromas.57,138 Spinal cord schwannomas arise predominantly in association with dorsal sensory nerve roots.144 Treatment is surgical excision, usually via a posterior or posterolateral approach, with good outcomes reported.145

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SPINAL CORD COMPRESSION Any of the tumors just mentioned, particularly the extramedullary, may produce spinal cord compression; however, the most common neoplastic cause is metastatic extradural disease, which is the focus of this discussion. Metastatic epidural spinal cord compression (MESCC) is defined as compression of the dural sac and its contents (spinal cord and/or cauda equina) by an extradural tumor mass, with lower motor neuron features at this level and upper motor neuron features below this level of the spinal cord.57,146 Radiological evidence for this is indentation of the theca at the level of clinical features.146 Subclinical MESCC is defined as the presence of radiographic features in the absence of clinical features. It is imperative that symptoms and signs of MESCC be detected early to prevent profound neurological deficits by instituting therapy early. Delay in recognition and inappropriate referral for treatment can result in deterioration and irreversible motor deficit. Education of patients (and clinicians) about the symptoms of MESCC is therefore important, especially for patients known to have vertebral disease or asymptomatic MESCC.146

Epidemiology A population-based study of 3400 patients from 1990 to 1995 demonstrated that MESCC is relatively common; 2.5% who died from their disease had had at least one admission with this complication in the 5 years preceding death.147 The incidence of MESCC varies widely with the type of primary tumor; 7% of patients with myeloma experienced MESCC, in contrast to 0.2% of patients with pancreatic cancer.147 In one retrospective analysis, breast, lung, and prostate cancers, which have a particular predilection for bony metastasis, accounted for 21%, 24%, and 20%, respectively, of episodes of MESCC; 15% of patients experienced multiple episodes.148 A multivariate analysis of patient, imaging, and neurological factors in 258 patients revealed six major predictive risk factors for MESCC (Table 40–13).146,149 Patients with none of these six risk factors had a 4% risk of developing MESCC, in contrast to a 87% risk of MESCC in those with all six risk factors. The estimated lifetime risk of MESCC was 19.3% for asymptomatic patients with all risk factors identified in Table 40–13, whose primary malignancies were prostate cancer, breast cancer, and renal carcinoma and myeloma. Conversely,

T A B L E 4 0 – 13. Factors Predictive of Risk of Metastatic Epidural Spinal Cord Compression

From Talcott JA, Stomper PC, Drislane FW, et al: Assessing suspected spinal cord compression: a multidisciplinary outcomes analysis of 342 episodes. Support Care Cancer 1999; 7:31-38.

the estimated lifetime incidence of MESCC for neurologically asymptomatic patients with leukemia, ovarian, gastric, and pancreatic primary cancers was 0.048%. The natural history of untreated MESCC is usually of progressive and relentless pain, paralysis, sensory deficit, and sphincter dysfunction.146 Approximately 70% of patients are reported to suffer loss of neurological function between the onset of symptoms and the start of treatment.150 The majority of delays were attributable to lack of symptom recognition by the patient and diagnostic delay at the primary care level. In a study of 98 patients, Rades and colleagues found that those with slower development of motor deficits before treatment (>14 days) had the best functional outcome, in comparison with patients with more rapid development (<14 days) of motor deficits.151

Clinical Features Again, a high degree of suspicion for cord compression in patients who present with vague sensorimotor or sphincteric dysfunction is crucial in this clinical emergency. Any suggestion of a sensory or motor level in a neurological syndrome, with or without signs, particularly in patients known to be at risk for cord compression cannot be ignored, and the most significant delays in treatment occur at the primary care level through failure to recognize the syndrome and its importance. Minimizing disability through early therapy is the key to successful treatment. Approximately 90% of patients with MESCC have pain (local back pain or radicular pain), and up to 50% are paretic (nonambulatory and paraparetic) or paraplegic.152-154 Other frequent symptoms of MESCC are weakness, sensory alteration, and bladder dysfunction154 (see Table 40–2 for features of spinal cord compression).

Investigations Studies evaluating the utility of MRI in identifying MESCC support the use of whole-spine MRI for patients with known malignancy and suspected MESCC.146,155 Findings on MRI are of an epidural mass with indentation of the thecal sac (Fig. 40–9).

Role of Systemic Corticosteroids The role of corticosteroids in the management of MESCC is somewhat controversial, and there is a paucity of evidence supporting clinical practice.146 High-dose maintenance dexamethasone has been shown to significantly improve ambulation in comparison with no corticosteroids—however, with an increased incidence of adverse effects, including psychosis and gastric ulcers that necessitate surgery.156 In a small randomized controlled trial (n = 37), high-dose (100-mg) bolus dexamethasone was compared with moderate-dose (10-mg) bolus dexamethasone, before maintenance dexamethasone (16 mg daily for the duration of radiotherapy). Eight percent of patients administered the moderate dose and 20% of those administered high-dose dexamethasone demonstrated improved neurological status, although this difference was not statistically significant.157

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B Figure 40–9. Metastatic epidural spinal cord compression: T1-weighted spin-echo magnetic resonance images. A, Severe pathological compression fracture of T5, in association with a large extradural mass with significant cord compression. B, Multiple metastatic deposits seen through the cervical, thoracic, and lumbar vertebrae. Complete collapse of the C4 vertebra, with an associated epidural mass, causes moderate cord compression at this level. A metastatic deposit at T6 also has an epidural component, which contacts the anterior thoracic cord.

Treatment Radiotherapy Radiotherapy is the mainstay of treatment of MESCC for both radiosensitive and radioresistant tumors, and many studies have addressed its role. The evidence suggests that patients who have no bony compression stand to benefit most, whereas those with bony compression may require surgical decompression in addition.146 Patients with bony compression, particularly those with mild to moderate motor deficit, were less likely to recover or retain the ability to ambulate after radiotherapy than were patients without bony compression.146 Results of an analysis of ambulatory outcomes in patients with MESCC with and without bony compression or spinal instability suggested that the presence of bony compression is a negative predictive factor for the ability to ambulate after radiotherapy.146 For instance, in one retrospective review of 46 patients treated with radiotherapy for MESCC, 66% (23 of 35) of patients with no bony compression were ambulant after radiotherapy, whereas only 27% (3 of 11) of those with bony compression were able to walk.158

In one of the most publicized trials in the area of management of MESCC, Patchell and colleagues compared maximum decompressive surgical resection in addition to radiotherapy (30 Gy in 10 fractions) with radiotherapy alone, in a randomized, nonblinded multicenter trial.159 The primary endpoints were the ability to walk and ambulatory time after treatment. Patients who underwent combined-modality treatment had better outcomes than did those treated with radiotherapy alone, in terms of more time ambulatory (median ambulation 126 versus 35 days, respectively, P = 0.006) and better analgesic control, in addition to a trend toward improved survival (P = 0.08). Only 3 (19%) of patients undergoing radiotherapy alone regained ambulation, in contrast to 9 (58%) of 16 patients treated with the combined-modality approach (P < 0.03). Criticisms of Patchell and colleagues’ study include its relatively small size and its restrictive inclusion criteria, particularly a single focus of MESCC, which may be unrealistic in the cancer population affected by MESCC and may limit the applicability of this study. The prescription of radiotherapy used to treat MESCC varies both within and between centers, as reflected in the various study protocols published. Dosages studied include 30 Gy in 10

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fractions, 37.5 Gy in 15 fractions, 40 Gy in 20 fractions, 28 Gy in 7 fractions and split doses of 15 Gy in 3 fractions followed by 15 Gy in 5 fractions.146 No one regimen has been demonstrated to be superior to the others for any cohort of patients.146 Patients who develop recompression in-field may be candidates for repeated irradiation, particularly if the latency between the completion of the last course of radiotherapy and recurrence of MESCC is more than 6 weeks. Repeated irradiation may lead to radiation myelopathy in a relatively short interval; however, one retrospective review reported no occurrence of radiation myelopathy when the cumulative dose to the cord was less than 100 Gy.160

Surgery Before the availability of radiotherapy for MESCC, surgical decompression, via laminectomy, was the mainstay of therapy.146 However, since the introduction of radiotherapy, and in the context of several large trials demonstrating no benefit from surgery alone or in combination with radiotherapy, there is little consensus regarding the operative indications in patients with MESCC. It is generally accepted by those who manage MESCC that spinal instability is an indication for surgical intervention.146,159 Patchell and colleagues found that MESCC patients undergoing surgery in addition to radiotherapy were more likely to retain or regain their ambulatory status than were patients receiving radiotherapy alone (P = 0.006).159 Surgery is, however, associated with significant morbidity in this population of cancer patients, even in the preradiotherapy setting, and may be an essentially palliative procedure.146 Postoperative complication rates of up to 54% have been reported in the literature, as have mortality rates of 0% to 13%, which must be taken into consideration in the decision between surgery and radiotherapy.146 A posterior surgical approach, with laminectomy, is traditionally adopted. However, the compressive mass in most cases of MESCC originates anteriorly, from the vertebral body.161,162 Laminectomy per se does not remove this compressive mass, which may be difficult to access posteriorly.146,162 Furthermore, this approach may contribute to mechanical instability of the spinal column, by removing the intact posterior osseous elements, thereby potentiating spinal cord compression.162 With anterior and lateral surgical approaches, several uncontrolled studies have demonstrated good outcomes, with improved neurological status and analgesia, even in patients with severe motor deficits.163 However, there is an absence of randomized trials supporting these alternative approaches.

Nonneoplastic Spinal Cord Compression Various nonneoplastic causes of spinal cord compression have been described. Causes addressed elsewhere in this chapter include benign spinal tumors, spinal epidural abscess, degenerative disk disease, and spondylotic disease. The last is easily the most common cause of cord compression but is often asymptomatic. Paget’s disease causes enlargement of the vertebral bodies, laminae, and pedicles, producing narrowing of the spinal canal, which may lead to a clinical picture of spinal cord compression.57 Other causes include traumatic or osteopenic vertebral fracture, tuberculous granulomata and hemangiomas, and intraspinal (either extradural or intradural) lipoma.57 Rare causes of spinal cord compression include solitary osteochondromas of vertebral bodies, vertebral extramedullary hematopoiesis, and arachnoid diverticula.57 Spinal cord sarcoidosis is another rare cause of spinal cord compression.165 Neurological manifestations occur in 5% of patients with sarcoidosis, but spinal cord lesions occur in fewer than 10% of these. Intramedullary, intradural extramedullary, and extradural disease can occur, with the midcervical and thoracic cord being most often affected. MRI demonstrates isointensity on T1-weighted imaging and typically hyperintensity on T2-weighted imaging.165

K E Y ●

Diseases of the spinal cord are numerous, with widely varying causes, and for many, there is no curative or disease-modifying treatment.

●

They are often catastrophic, resulting in progressive and disabling neurological dysfunction, and may be fatal, as a result of respiratory paralysis or complications of neurological disability.

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Effective therapy, to delay progression or even reverse neurological deficits, is available for some spinal cord diseases, including certain infections and neoplasms, prolapsed intervertebral disk, and cervical spondylopathy.

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The likelihood of reversal of damage to spinal cord structures diminishes with the duration of the insult and increasing severity of deficit; paralysis usually occurs late, by which stage the damage is often irreversible.

●

Recognition of potentially treatable conditions enables timely intervention and preservation of neurological function.

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Despite the importance of early recognition, diagnostic delay is common, often because of late presentation or a low index of suspicion by clinicians, who fail to attribute signs and symptoms to a spinal cord disease process.

●

Knowledge of signs and symptoms suggestive of spinal cord disease is therefore vital (see Table 40–1).

●

Often there is a disparity between the extent of spinal cord pathology and clinical features.

●

Magnetic resonance imaging is the “gold standard” imaging investigation for diagnosis of spinal cord diseases.

Prognosis The strongest prognostic factor for overall survival and ability to ambulate after treatment is pretreatment neurological status, particularly motor function.146 In one series of patients with MESCC without bony compression, 100% of ambulatory patients retained ambulation after radiotherapy, whereas patients who were ambulatory with assistance, were paraparetic, or were paraplegic had ambulatory rates of 94%, 60%, and 11%, respectively.164 Patients with paralysis either at presentation or after treatment have a much shorter life expectancy than do ambulatory patients.146,153,164

P O I N T S

chapter 40 spinal disease Suggested Reading Andersen O: Myelitis. Current Opin Neurol 2000; 13:311-316. Kaplin AI, Krishnan C, Deshpande DM, et al: Diagnosis and management of acute myelopathies. Neurologist 2005; 11:2-18. McCormick WE, Steinmetz MP, Benzel EC: Cervical spondylotic myelopathy: make the difficult diagnosis, then refer for surgery. Cleve Clinic J Med 2003; 70;899-904. Nakajima H, Furutama D, Fimura F, et al: Herpes simplex myelitis: clinical manifestations and diagnosis by the polymerase chain reaction. Eur Neurol 1998; 38:163-168. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366:643-648.

References 1. Andersen O: Myelitis. Current Opin Neurol 2000; 13:311-316. 2. Kaplin AI, Krishnan C, Deshpande DM, et al: Diagnosis and management of acute myelopathies. Neurologist 2005; 11:218. 3. Jeffery D, Mandler R, Dacis L: Transverse myelitis: retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol 1993; 50:532-535. 4. Berman M, Feldman S, Alter M, et al: Acute transverse myelitis: incidence and aetiologic considerations. Neurology 1981; 31:966-971. 5. Christensen PB, Wermuth L, Hinge HH, et al: Clinical course and long-term prognosis of acute transverse myelopathy. Acta Neurol Scand 1990; 81:431-435. 6. Adrianakos AA, Duffy J, Suzuki, et al: Transverse myelitis in systemic lupus erythematosus: report of three cases and review of the literature. Ann Intern Med 1975; 83:616-624. 7. Nakano I, Mannen T, Mizutani T, et al: Peripheral white matter lesions of the spinal cord with changes in small arachnoid arteries in systemic lupus erythematosus. Clin Neuropathol 1989; 8:102-108. 8. Griffin D: Encephalitis, myelitis and neuritis. In Mandell G, Bennett J, Dolin R, eds: Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone, 2000, pp 1009-1016. 9. Gnann J: Mumps virus diseases. In McKendall R, Stroop W, eds: Handbook of Neurology. New York: Dekker, 1994, pp 563573. 10. Devinsky O, Cho E, Petito C, et al: Herpes zoster myelitis. Brain 1991; 114:1181-1196. 11. Albucher J, Lauque D, Geyer I, et al: Transverse myelitis caused by Mycoplasma pneumoniae infection. Rev Neurol (Paris) 1995; 151:350-353. 12. de Macedo DD, de Mattos JP, Borges TM: [Transverse myelopathy and systemic lupus erythematosus: report of a case and review of the literature]. Arq Neuropsiquiatr 1979; 37:76-84. 13. Nakajima H, Furutama D, Fimura F, et al: Herpes simplex myelitis: clinical manifestations and diagnosis by the polymerase chain reaction. Eur Neurol 1998; 38:163-168. 14. Aurelius E, Johansson B, Skoldenberg B, et al: Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991; 337:189192. 15. Misra UK, Kalita J, Kumar S: A clinical, MRI and neurophysiological study of acute transverse myelitis. J Neurol Sci 1996; 138:150-156. 16. Lipton HL, Teasdall RD: Acute transverse myelopathy in adults: a follow up study. Arch Neurol 1973; 28:252-257.

535

17. Sakakibara R, Hattori T, Yasuda K, et al: Micturition disturbance in acute transverse myelitis. Spinal Cord 1996; 34:481485. 18. Runmarker B, Andersen O: Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow up. Brain 1993; 116:117-134. 19. Scott T, Bhagavatula K, Snyder R, et al: Transverse myelitis: comparison with spinal cord presentations of multiple sclerosis. Neurology 1998; 50:429-433. 20. Bakshi R, Kinkel RR, Mechtler LL, et al: Magnetic resonance imaging findings in 22 cases of myelitis: comparison between patients with and without multiple sclerosis. Eur J Neurol 1998; 5:35-48. 21. Kibe T, Fujimoto S, Ishikawa T, et al: Serial MRI findings of benign poliomyelitis. Brain Dev 1996; 18:147-149. 22. Takahashi S, Miyamoto A, Oki J, et al: Acute transverse myelitis caused by ECHO virus type 18 infection. Eur J Paediatr 1995; 154:378-380. 23. Ku B, Lee K: Acute transverse myelitis caused by Coxsackie virus B4 infection: a case report. J Korean Med Sci 1998; 13:449-453. 24. Graber D, Fossoud C, Grouteau E, et al: Acute transverse myelitis and Coxsackie A9 virus infection. Paediatr Infect Dis J 1994; 13:77. 25. Minami K, Tsuda Y, Maeda H, et al: Acute transverse myelitis caused by Coxsackie virus B5 infection. J Paediatr Child Health 2004; 40:66-68. 26. Bansal R, Kalita J, Misra U, et al: Myelitis: a rare presentation of mumps. Paediatr Neurosurg 1998; 28:204-206. 27. Bajaj NP, Rose P, Clifford-Jones R, et al: Acute transverse myelitis and Guillain-Barré syndrome overlap with serological evidence for mumps viraemia. Acta Neurol Scand 2001; 104:239-242. 28. Gobbi C, Tosi C, Stadler C, et al: Recurrent myelitis associated with herpes simplex virus type 2. Eur Neurol 2001; 46:215-219. 29. Petereit HF, Bamborschke S, Lanfermann H: Acute transverse myelitis caused by herpes simplex virus. Eur Neurol 1996; 36:52-53. 30. Klatersky J, Cappel R, Snoeck JM, et al: Ascending myelitis in association with herpes simplex virus. N Engl J Med 1972; 287:182-184. 32. Kueker W, Schaade L, Ritter K, et al: MRI follow up of herpes simplex virus (type 1) radiculomyelitis. Neurology 1995; 52:1102-1103. 33. Shyu WC, Lin JC, Chang BC, et al: Recurrent ascending myelitis: an unusual presentation of herpes simplex virus type 1 infection. Ann Neurol 1993; 34:625-627. 34. Hirai T, Korogi Y, Hamatake S, et al: Case report: varicellazoster virus myelitis—serial MR findings. Br J Radiol 1996; 69:1187-1190. 35. Lakeman FD, Whitley RJ: Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995; 171:857-863. 36. Gilden DH, Beinlich B, Rubinstein EM, et al: Varicella-zoster virus: an expanding spectrum. Neurology 1994; 44:18181823. 37. Gilden DH, Mahalingam R, Dueland AN, et al: Herpes zoster: pathogenesis and latency. In Melinck J, ed: Progress in Medical Virology, vol 39. Basel, Switzerland: S. Karger, 1992, pp 19-75. 38. McKelvie PA, Collins S, Thyagarajan D, et al: Meningoencephalomyelitis with vasculitis due to varicella zoster virus: a case report and review of the literature. Pathology 2002; 34:88-93.

536

Section

VIII

Spine and Spinal Diseases

39. Morita Y, Osaki Y, Doi Y, et al: Chronic active VZV infection manifesting as zoster sine herpete, zoster paresis and myelopathy. J Neurol Sci 2003; 212:7-9. 40. Gilden DH, Bennett JL, Kleinschmidt-deMasters BK, et al: The value of cerebrospinal fluid antiviral antibody in the diagnosis of neurological disease produced by varicella zoster virus. J Neurol Sci 1998; 159:140-144. 41. Chretien F, Gray F, Lescs MC, et al: Acute varicella-zoster virus ventriculitis and meningomyeloradiculitis in acquired immunodeficiency syndrome. Acta Neuropathol (Berlin) 1993; 86:659-665. 42. Gray F, Belec L, Lescs MC, et al: Varicella-zoster virus infection of the central nervous system in the acquired immune deficiency syndrome. Brain 1994; 117:987-999. 43. Fillet AM, Dumont B, Caumes E, et al: Acyclovir-resistant varicella-zoster virus: phenotypic and genetic characteristics. J Med Virol 1998; 55:250-254. 44. Snoek R, Andrei G, De Clercq E: Current pharmacological approaches to the therapy of varicella zoster infections: a guide to treatment. Drugs 1999; 57:187-206. 45. Corti M, Soto I, Villafane NF, et al: [Acute necrotising myelitis in an AIDS patient]. Medicina 2003; 63:143-146. 46. Giobbia M, Carniato A, Scotton PG, et al: Cytomegalovirusassociated transverse myelitis in a non-immunocompromised patient. Infection 1999; 27:228-230. 47. Burke D, Leonard D, Imperiale T, et al: The utility of clinical and radiographic features in the diagnosis of cytomegalovirus central nervous system disease in AIDS patients. Mol Diag 1999; 4:37-43. 48. Majid A, Galetta SL, Sweeney CJ, et al: Epstein-Barr virus myeloradiculitis and encephalomyeloradiculitis. Brain 2002; 125:159-165. 49. Rubin DI, Daube JR: Subacute sensory neuropathy associated with Epstein-Barr virus. Muscle Nerve 1999; 22:1607-1610. 50. Feinberg WM, Zonis J, Minnich LL: Epstein-Barr virus–associated myelopathy in an adult. Arch Neurol 1984; 41:454-455. 51. Merelli E, Bedin R, Sola P, et al: Encephalomyeloradiculopathy associated with Epstein-Barr virus: primary infection or reactivation? Acta Neurol Scand 1997; 96:416-420. 52. Koskiniemi M: CNS manifestations associated with Mycoplasma pneumoniae infections: summary of cases at the University of Helsinki and review. Clin Infect Dis 1993; 17:S52-S57. 53. Abele-Horn M, Franck W, Busch U, et al: Transverse myelitis associated with Mycoplasma pneumoniae infection. Clin Infect Dis 1997; 26:909-912. 54. Heller L, Keren O, Mendelson L, et al: Transverse myelitis associated with Mycoplasma pneumoniae: case report. Paraplegia 1990; 28:522-525. 55. Haran MJ, Jenney AW, Keenan RJ, et al: Paraplegia secondary to Burkholderia pseudomallei myelitis: a case report. Arch Phys Med Rehab 2001; 82:1630-1632. 56. Oschmann P, Dordorf W, Hornig C, et al: Stages and syndromes of neuroborreliosis. J Neurol 1998; 245:262272. 57. Adams RD, Victor M: Diseases of the spinal cord. In Adams RD, Victor M, eds: Principles of Neurology, 5th ed. New York: McGraw-Hill, 1993, pp 1078-1116. 58. Shepherd E, Brettle R, Liberski P, et al: Spinal cord pathology and viral burden in homosexuals and drug users with AIDS. Neuropathol Appl Neurobiol 1999; 25:2-10. 59. Chong J, Di Rocco A, Tagliati M, et al: MR findings in AIDSassociated myelopathy. Am J Neuroradiol 1999; 20:14121416. 60. Manns A, Hisada M, La Grenado L: Human T-lymphotropic virus type 1 infection. Lancet 1999; 353:1951-1958. 61. Solomon T, Willison H: Infectious causes of acute flaccid paralysis. Curr Opin Infect Dis 2003; 16:375-381.

62. Howard RS: Poliomyelitis and the postpolio syndrome. BMJ 2005; 330:1314-1318. 63. Kilpatrick DR, Nottay B, Yang CF, et al: Group specific identification of poliovirus by PCR using primers containing mixed-base or deoxyinosine residues at positions of codon degeneracy. J Clin Microbiol 1996; 34:2990-2996. 64. Rao DG, Bateman DE: Hyperintensities of the anterior horn cells on MRI due to poliomyelitis. J Neurol Neurosurg Psychiatry 1997; 63:720. 65. Jubelt B, Agre JC: Characteristics and management of postpolio syndrome. JAMA 2000; 284:412-414. 66. Chen CY, Chang YC, Huang C, et al: Acute flaccid paralysis in infants and young children with enterovirus 71 infection: MR imaging findings and clinical correlates. Am J Neuroradiol 2001; 22:200-205. 67. Leis AA, Stokic DS, Polk JL, et al: A poliomyelitis-like syndrome from West Nile virus infection. N Engl J Med 2002; 347:1279-1280. 68. Mostashari F, Bunning ML, Kitsutani PT, et al: Epidemic West Nile encephalitis, New York 1999: results of a householdbased seroepidemiological survey. Lancet 2001; 358:261-264. 69. Li J, Loeb JA, Shy ME, et al: Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection. Ann Neurol 2003; 53:703-710. 70. Leis AA, Fratkin J, Stokic DS, et al: West Nile poliomyelitis. Lancet Infect Dis 2003; 3:9-10. 71. Chao D, Nanda A: Spinal epidural abscess: a diagnostic challenge. Am Fam Physician 2002; 65:1341-1346. 72. Mackenzie AR, Laing RBS, Smith CC, et al: Spinal epidural abscess: the importance of early diagnosis and treatment. J Neurol Neurosurg Psychiatry 1998; 65:209-212. 73. Baker AS, Ojemann RG, Swartz MN, et al: Spinal epidural abscess. N Engl J Med 1975; 293:463-468. 74. Hlavin ML, Kaminski KJ, Ross JS, et al: Spinal epidural abscess: a 10 year perspective. Neurosurgery 1990; 27:177184. 75. Danner RL, Hartman BJ: Update of spinal epidural abscess: 35 cases and review of the literature. Rev Infect Dis 1987; 9:265-274. 76. Vilke GM, Honingford EA: Cervical spine epidural abscess in a patient with no predisposing risk factors. Ann Emerg Med 1996; 27:777-780. 77. Kaufman DM, Kaplan JG, Litman N: Infectious agents in spinal epidural abscess. Neurology 1980; 30:844-850. 78. Verner EF, Musher DM: Spinal epidural abscess. Med Clin North Am 1985; 69:375-384. 79. Hori K, Kano T, Fukushige T, et al: Successful treatment of epidural abscess with percutaneously introduced 4French catheter for drainage. Anesth Analg 1997; 84:13841386. 80. Wang JS, Fellows DG, Vakharia S, et al: Epidural abscess: early magnetic resonance imaging detection and conservative therapy. Anesth Analg 1996; 82:1069-1071. 81. Manfredi PL, Herskovitz S, Folli F, et al: Spinal epidural abscess: treatment options. Eur Neurol 1998; 40:58-60. 82. Khanna RK, Malik GM, Rock JP, et al: Spinal epidural abscess: evaluation of factors influencing outcome. Neurosurgery 1996; 39:958-964. 83. Love C, Patel M, Lonner BS, et al: Diagnosing spinal osteomyelitis: a comparison of bone and Ga-67 scintigraphy and magnetic resonance imaging. Clin Nucl Med 2000; 25:963-977. 84. Sapico FL, Montgomerie JZ: Pyogenic vertebral osteomyelitis: report of nine cases and review of the literature. Rev Infect Dis 1979; 1:754. 85. Rezai AR, Woo HH, Errico TJ, et al: Contemporary management of spinal osteomyelitis. Neurosurgery 1999; 44:10181025.

chapter 40 spinal disease 86. Keung YK, Cobos E, Whitehead RP, et al: Secondary syringomyelia due to intramedullary spinal cord metastasis: case report and review of the literature. Am J Clin Oncol 1997; 20:577-579. 87. Goel A: Is syringomyelia pathology or a natural protective mechanism? J Postgrad Med 2001; 47:87-88. 88. Barnett HJM, Foster JB, Hodgson P: Syringomyelia. Philadelphia: WB Saunders, 1973. 89. Levine DN: The pathogenesis of syringomyelia associated with lesions at the foramen magnum: a critical review of existing theories and proposal of a new hypothesis. J Neurol Sci 2004; 220:3-21. 90. Gardner WJ: Hydrodynamic mechanism of syringomyelia: its relationship to myelocele. J Neurol Neurosurg Psychiatry 1965; 28:247. 91. Hida K, Iwasaki Y, Koyanagi I, et al: Surgical indication and results of foramen magnum decompression versus syringosubarachnoid shunting for syringomyelia associated with Chiari I malformation. Neurosurgery 1995; 37:673-678. 92. Logue V, Edwards MR: Syringomyelia and its surgical treatment: an analysis of 75 cases. J Neurol Neurosurg Psychiatry 1981; 44:273. 93. McCormick WE, Steinmetz MP, Benzel EC: Cervical spondylotic myelopathy: make the difficult diagnosis, then refer for surgery. Cleve Clin J Med 2003; 70:899-904. 94. Small JM, Dillin WH, Watkins RG: Clinical syndromes in cervical myelopathy. In Herkowitz H, Garfin SR, Balderston RA, et al, eds: The Spine, 4th ed. Philadelphia: WB Saunders, 1999, pp 465-474. 95. Montgomery DM, Brower RS: Cervical spondylotic myelopathy: clinical syndrome and natural history. Orthop Clin North Am 1992; 23:487-493. 96. White AA, Panjabi MM: Biomechanical considerations in the surgical management of cervical spondylitic myelopathy. Spine 1988; 13:856-860. 97. Lundsford LD, Bissonette D, Dorub D: Anterior surgery for cervical disc disease, part 2. J Neurosurg 1980; 53:12-19. 98. Hukuda S, Mochizuki T, Ogata M, et al: Operations for cervical spondylotic myelopathy: a comparison of the results of anterior and posterior procedures. J Bone Joint Surg Br 1985; 67:609-615. 99. Tanaka N, Fujimoto Y, Yasunaga Y, et al: Functional diagnosis using multimodal spinal cord evoked potentials in cervical myelopathy. J Orthopaed Sci 2005; 10:3-7. 100. Phillips DG: Surgical treatment of myelopathy with cervical spondylosis. J Neurol Neurosurg Psychiatry 1973; 36:879884. 101. Ebersold MJ, Pare MC, Quast LM: Surgical treatment for cervical spondylotic myelopathy. J Neurosurg 1995; 82:745-751. 102. Iwasaki M, Ebara S, Miyamoto S, et al: Expansive laminoplasty for cervical radiculomyelopathy due to soft disc herniation. Spine 1996; 21:32-38. 103. Durbukhula MM, Ghiselli G: Cervical total disc replacement part I: rationale, biomechanics and implant types. Orthop Clin North Am 2005; 36:349-354. 104. Boden SD, Wiesel SW: Lumbar spine imaging: role in clinical decision making. J Am Acad Orthop Surg 1996; 4:238-248. 105. Haughton VM: MR imaging of the spine. Radiology 1988; 166:297-301. 106. Humphreys SC, An HS, Eck JC, et al: Oblique MRI as a useful adjunct in evaluation of cervical foraminal impingement. Loyola Univ Orthop J 1997; 6:4-7. 107. Humphreys SC, Eck JC: Clinical evaluation and treatment options for herniated lumbar disc. Am Fam Physician 1999; 59:575-582, 587-588. 108. Koeller KK, Rosenblum S, Morrison AL: Neoplasms of the spinal cord and filum terminale: radiologic-pathologic correlation. Radiographics 2000; 20:1721-1749.

537

109. Sze G, Stimac GK, Bartlett C, et al: Multicenter study of gadopentetate dimeglumine as an MR contrast agent: evaluation in patients with spinal tumors. Am J Neuroradiol 1990; 11:967-974. 110. Takemoto K, Matsumura Y, Hashimoto H, et al: MR imaging of intraspinal tumors: capability in histological differentiation and compartmentalisation of extramedullary tumors. Neuroradiology 1988; 30:303-309. 111. Lee M, Epstein FJ, Rezai AR, et al: Non-neoplastic intramedullary spinal cord lesions mimicking tumors. Neurosurgery 1998; 43:788-795. 112. Lee M, Rezai AR, Freed D, et al: Intramedullary spinal cord tumors in neurofibromatosis. Neurosurgery 196; 38:32-37. 113. Ferrante L, Mastronardi L, Celli P, et al: Intramedullary spinal cord ependymomas: a study of 45 cases with long term follow up. Acta Neurochir 1992; 119:74-79. 114. Hoshimaru M, Koyama T, Hashimoto N, et al: Results of microsurgical treatment for intramedullary spinal cord ependymomas: analysis of 36 cases. Neurosurgery 1999; 44:264-269. 115. Wolff M, Santiago H, Duby MM: Delayed distant metastasis from a subcutaneous sacrococcygeal ependymoma: case report with tissue culture, ultrasound observation and review of the literature. Cancer 1972; 30:1046-1067. 116. Burger PC, Scheithauer BW: Tumors of neuroglia and choroid plexus epithelium. In Burger PC, Scheithauer BW, eds: Tumors of the Central Nervous System. Washington, DC: Armed Forces Institute of Pathology, 1994, pp 25-161. 117. Brotchi J, Fischer G: Treatment. In Fisher G, Brotchi J, eds: Intramedullary Spinal Cord Tumors. Stuttgart, Germany: Thieme, 1996, pp 60-84. 118. Epstein FJ, Fermer JP, Freed D: Adult intramedullary spinal cord ependymomas: the result of surgery in 38 patients. J Neurosurg 1993; 79:204-209. 119. Djindjian M, Djindjian R, Houdart R, et al: Subarachnoid haemorrhage due to intraspinal tumors. Surg Neurol 1978; 9:223-229. 120. Fine MJ, Kricheff II, Freed D, et al: Spinal cord ependymomas: MR imaging features. Radiology 1995; 197:655-658. 121. Kahan H, Sklar EML, Post MJD, et al: MR characteristics of histopathologic subtypes of spinal ependymoma. Am J Neuroradiol 1996; 17:143-150. 122. Epstein F, Epstein N: Surgical treatment of spinal cord astrocytomas of childhood. J Neurosurg 1982; 57:685-689. 123. Constatini S, Houten J, Miller D, et al: Intramedullary spinal cord tumors in children under the age of 3 years. J Neurosurg 1996; 85:1036-1043. 124. Froment JC, Baleriaux D, Turjman F, et al. In Fisher G, Brotchi J, eds: Intramedullary Spinal Cord Tumors. Stuttgart, Germany: Thieme, 1996. 125. Ciapetta P, Salvati M, Capoccia G, et al: Spinal glioblastomas: report of seven cases and review of the literature. Neurosurgery 1991; 28:302-306. 126. Cooper P: Outcome after operative treatment of intramedullary spinal cord tumors in adults: intermediate and long term results in 51 patients. Neurosurgery 1989; 25:855859. 127. Murota T, Symon L: Surgical management of hemangioblastoma of the spinal cord: report of 18 cases. Neurosurgery 1989; 25:699-708. 128. Neumann HPH, Eggert HR, Weigel K, et al: Hemangioblastomas of the central nervous system: a 10 year study with special reference to von Hippel–Lindau syndrome. J Neurosurg 1989; 70:24-30. 129. Browne TR, Adams RD, Robertson GH: Hemangioblastoma of the spinal cord. Arch Neurol 1976; 33:435-441. 130. Mascalchi M, Quilici N, Ferrito G, et al: Identification of the feeding arteries of spinal vascular lesions via phase-contrast

538

131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141.

142. 143. 144.

145.

146.

147. 148. 149.

Section

VIII

Spine and Spinal Diseases

MR angiography with three-dimensional acquisition and phase display. Am J Neuroradiol 1997; 18:351-358. Costigan DA, Winkelman MD: Intramedullary spinal cord metastasis: a clinicopathological study of 13 cases. J Neurosurg 1985; 62:227-233. Findlay JM, Bernstein M, Vanderlinden RG, et al: Microsurgical resection of solitary intramedullary spinal cord metastases. Neurosurgery 1987; 21:911-915. Post MJD, Quencer RM, Green BA, et al: Intramedullary spinal cord metastasis, mainly of nonneurogenic origin. Am J Neuroradiol 1987; 8:339-346. Koeller KK, Smirniotopoulos JG, Jones RV: Primary central nervous system lymphoma: radiologic-pathologic correlation. Radiographics 1997; 17:1497-1526. Schild SE, Wharen RE Jr, Menke DM, et al: Primary lymphoma of the spinal cord. Mayo Clin Proc 1995; 70:256-260. Bluemke DA, Wang H: Primary spinal cord lymphoma: MR appearance. J Comput Assist Tomogr 1990; 14:812-814. McCormick PC, Stein BM: Spinal cord tumors in adults. In Youmans JR, ed: Neurological Surgery. Philadelphia: WB Saunders, 1996, pp 3102-3122. McCormick PC, Post KD, Stein BM: Intradural extramedullary tumors in adults. Neurosurg Clin North Am 1990; 1:591-608. Gezen F, Kahraman S, Çanakci Z, et al: Review of 36 cases of spinal cord meningioma. Spine 2000; 25:727-731. Levy WJ, Bay J, Dohn D: Spinal cord meningioma. J Neurosurg 1982; 57:804-812. Roux FX, Nataf F, Pinaudeau M, et al: Intraspinal meningiomas: review of 54 cases with discussion of poor prognosis factors and modern therapeutic management. Surg Neurol 1996; 46:458-464. Nicholas DS, Weller RO: The fine anatomy of the human spinal meninges: light and scanning electron microscopy study. J Neurosurg 1988; 69:276-282. Caroli E, Acqui M, Roperto R, et al: Spinal en plaque meningiomas: a contemporary experience. Neurosurgery 2004; 55:1275-1279. O’Toole JE, McCormick PC: Midline ventral intradural schwannoma of the cervical spinal cord resected via anterior corpectomy and reconstruction: technical case report and review of the literature. Neurosurgery 2003; 52:1482-1486. Conti P, Pansini G, Mouchaty H, et al: Spinal neurinomas: retrospective analysis and long-term outcome of 179 consecutive operated cases and review of the literature. Surg Neurol 2004; 61:34-43. Loblaw DA, Perry J, Chambers A, et al: Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The Cancer Care Ontario Practice Guidelines Initiative’s Neuro-Oncology Disease Site Group. J Clin Oncol 2005; 23:2028-2037. Loblaw DA, Laperriere NJ, Mackillop WJ: A population-based study of malignant spinal cord compression in Ontario cancer patients. Clin Oncol (R Coll Radiol) 2003; 15:211-217. Loblaw DA, Smith K, Lockwood G, et al: The Princess Margaret Hospital experience of malignant spinal cord compression. Proc Am Soc Clin Oncol 2003; 22:19. Talcott JA, Stomper PC, Drislane FW, et al: Assessing suspected spinal cord compression: a multidisciplinary out-

150. 151.

152. 153. 154.

155.

156.

157.

158. 159.

160. 161.

162. 163. 164.

165.

comes analysis of 342 episodes. Support Care Cancer 1999; 7:31-38. Husband DJ: Malignant spinal cord compression: prospective study of delays in referral and treatment. BMJ 1998; 317:1821. Rades D, Heidenreich F, Karstens JH: Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2002; 53:975979. Perrin RG: Metastatic tumors of the axial spine. Curr Opin Oncol 1992; 4:525-532. Sundaresan N, Galicich JH: Treatment of spinal metastases by vertebral body resection. Cancer Invest 1984; 2:383397. Helweg-Larsen S, Sorensen PS: Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer 1994; 30A:396-398. Cook AM, Lau TN, Tomlinson MJ, et al: Magnetic resonance imaging of the whole spine in suspected malignant spinal cord compression: impact on management. Clin Oncol (R Coll Radiol) 1998; 10:39-43. Sorensen S, Helweg-Larsen S, Mouridsen H, et al: Effect of high dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur J Cancer 194; 30A:22-27. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al: Initial bolus of conventional versus high dose dexamethasone in metastatic spinal cord compression. Neurology 1989; 39:1255-1257. Pigott KH, Baddeley H, Maher EJ: Pattern of disease in spinal cord compression on MRI scan and implications for treatment. Clin Oncol (R Coll Radiol) 1994; 6:7-10. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366:643-648. Wong CS, van Dyk J, Milosevic M, et al: Radiation myelopathy following single courses of radiotherapy and retreatment. Int J Radiat Oncol Biol Phys 1994; 30:575-581. Young RF, Post EM, King GA: Treatment of spinal epidural metastases: randomised prospective comparison of laminectomy and radiotherapy. J Neurosurg 1980; 53:741748. van den Bent MJ: Surgical resection improves outcome in metastatic epidural spinal cord compression [Comment]. Lancet 2005; 366:609-610. Sundaresan N, Rothman A, Manhart K, et al: Surgery for solitary metastases of the spine: rationale and results of treatment. Spine 2002; 27:1802-1806. Maranzano E, Latini P, Beneventi S, et al: Radiotherapy without steroids in selected metastatic spinal cord compression patients: a phase II trial. Am J Clin Oncol 1996; 19:179183. Hamasaki T, Noda M, Kamei N, et al: Intradural extramedullary mass formation in spinal cord sarcoidosis: case report and literature review. Spine 2003; 28:E420E423.

CHAPTER

41

ANATOMY

AND PHYSIOLOGY OF CEREBRAL AND SPINAL CORD CIRCULATION ●

●

●

●

Omar Touzani and Eric T. MacKenzie

Of all the mammalian organs, the central nervous system is the most privileged and protected. Claude Bernard developed the now near-axiomatic concept of the maintenance of the “milieu interieur.” It is essential to recognize that the stability of the internal environment of the brain is primordial and that the homeostasis of other organs is subordinated to the vital stability of the neuronal environment in the central nervous system. Before entering into the anatomical and the physiological details that are specific to the brain, it is worth reflecting on the major general systems that protect the body—above all, the central nervous system. Baroreceptors, strategically placed at the origin of each internal carotid artery, are the sensors to maintain mean arterial pressure—the driving force necessary for a constant perfusion pressure of the central nervous system. Chemoreceptors are essentially located in the carotid bodies but also in the brainstem. Accordingly, PaO2, PaCO2, and pH are controlled and crucially, as is the tissue pH of the brain, as protons do not cross the blood-brain barrier. Hypothalamic regulatory systems include the osmoreceptors, the thermoreceptors, and the general mechanisms controlling metabolic pathways. Integrated control of the cardiovascular system is localized in the brainstem. Finally, the central nervous system processes signals from the external senses that allow the body to react appropriately to the surrounding environment: olfaction, vision, taste, hearing, and touch. However, all these systems are insufficient to optimally ensure functionality of the brain. As further lines of defense, the brain possesses several secondary, even tertiary, systems to optimize the survival of this organ. Simplistically, these defenses can be divided into two major categories: anatomical and physiological. Each is dealt with in subsequent sections.

ANATOMY OF THE CEREBRAL CIRCULATION The brain’s function and survival are highly dependent on the constant and finely regulated provision and regional distribution of oxygen and energy-producing substrates. In order to fulfill its needs, this complex neuronal system uses a high proportion of total body blood flow. Indeed, this organ, that represents only about 2% of total body weight, receives approximately 15% of total resting cardiac output, and consumes about 20% of the body’s resting metabolism. The brain’s

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energy requirements render it highly susceptible to damage following ischemia. The cerebral vascular supply is constructed to protect the cerebral hemispheres and brainstem from the consequences of a major decrease in blood flow.

Arterial Supply The arterial supply to the human brain consists of four major afferent arterial trunks: two internal carotid and two vertebral arteries. The internal together with the external carotid arteries derive from the common carotid artery. In humans, the carotid arteries are quantitatively more important; each contributes approximately 40% to the total perfusion of the brain. The internal carotid arteries enter the cranial cavity through the os petrosum. The vertebral arteries enter the cranial cavity through the foramen magnum, where, after traversing the anterolateral aspect of the medulla oblongata, they fuse to form the basilar artery at the level of the pontomedullary junction (Fig. 41–1). This artery unites with the two internal carotids to form, at the base of the brain, an equalizing distributor named the circle of Willis (see Fig. 41–1). Having fused with the basilar artery, each internal carotid artery divides into four major branches: the anterior cerebral, the middle cerebral, the anterior choroidal, and the posterior communicating arteries. The latter anastomose with the posterior cerebral arteries, which originate from the basilar artery to complete the circle of Willis (see Fig. 41–1). These major cerebral arteries divide into progressively smaller arteries, which, in turn, enter the brain parenchyma at a right angle to the surface of the brain to supply blood to specific regions. The anterior cerebral arteries irrigate the frontal pole and the medial aspects of both frontal and parietal lobes, the corpus callosum, the anterior limb of the internal capsule, and the most rostral part of the caudate nucleus and the putamen. The middle cerebral arteries supply most of the lateral aspects of the cerebral hemispheres, as well as portions of the caudate nucleus and the putamen. The anterior choroidal arteries supply several structures such as the choroid plexus of the lateral ventricle, the optic tract, the hippocampus, the tail of the caudate nucleus, and the amygdala. The posterior communicating arteries supply the genu of the corpus callosum, part of the posterior limb of the internal capsule, the rostral thalamus, and the wall of the third ventricle. The posterior cerebral arteries supply the inferior and medial aspects

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Anterior communicating artery

Anterior cerebral artery

Internal carotid artery Anterior choroidal artery

Middle cerebral artery Lenticulostriate artery Posterior communicating artery

Posterior cerebral artery Superior cerebellar artery Pontine arteries Basilar artery Internal auditory artery Anterior inferior cerebellar artery

Posterior inferior cerebellar artery Vertebral artery

Anterior spinal artery

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Figure 41–1. Basal view of major cerebral arteries and the circle of Willis. (From Sokoloff L: Anatomy of the Cerebral Circulation. In Welch KMA, Caplan LR, Reis DJ, et al, eds: Primer on Cerebrovascular Diseases. Academic Press, 1997.)

of the temporal and the occipital lobes, parts of the hippocampus, and the thalamus (Fig. 41–2). Before giving rise to the posterior cerebral arteries, the basilar artery sends several branches to supply the cerebellum and the brainstem (see Fig. 41–1).

Collateral Blood Supply of the Brain Several types of anastomoses are found in the cerebral circulation.1 The following are the most important.

Circle of Willis As mentioned, the circle of Willis is an anastomosis between the anterior and the posterior circulation via the anterior and the posterior communicating arteries (see Fig. 41–1). Considerable intraspecies and interspecies variability exists in the anatomy of the circle of Willis. In humans, a symmetrical circle is found in only 50% of brains.2 In addition, in most species other than primates, the anterior cerebral communicating artery is absent and the anterior cerebral arteries fuse earlier to form the pericallosal artery.3 This anastomotic ring protects from the disastrous consequences of occlusion of a single supply vessel to the brain. However, under physiological con-

ditions, the blood from the internal carotid and the basilar arteries does not mix because the blood pressure in each arterial trunk is almost identical.

External Carotid-Internal Carotid Anastomoses In humans, this anastomotic pathway is relatively negligible. The ophthalmic artery is the most significant conduit that is capable of bridging the external and internal circulations. However, in many species such as the dog, cat, and sheep, rich and complex connections exist between the internal and external carotid arteries via a structure termed the rete mirabile.3

Leptomeningeal Anastomoses The leptomeningeal anastomoses, organized in the subarachnoid space between the arterial boundary zones, represent connections between distal branches of major cerebral arteries (i.e., between the anterior cerebral and middle cerebral arteries and between the middle cerebral and the posterior cerebral arteries) (Fig. 41–3). These arterial boundary zones, also termed “watershed zones,” are especially susceptible to damage following any generalized decrease in blood flow as in the case of severe systemic hypotension.

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Figure 41–2. Cerebral areas irrigated by the anterior cerebral arteries (orange), the middle cerebral artery (yellow) and the posterior cerebral arteries (green). Left: a left lateral view, middle: a right medial view, and right: a basal view with dissection of the left temporal lobe and cerebellar hemisphere. (From Edvinsson L, McCulloch J, MacKenzie ET: General and comparative anatomy of the cerebral circulation. In Edvinsson L, MacKenzie ET, McCulloch J, et al, eds: Cerebral Blood Flow and Metabolism. New York: Raven Press, 1993.)

Venous Drainage

Blood Supply to the Spinal Cord

The venous circulation of the central nervous system is particular in that (1) the veins do not run parallel to arteries as in many other organs and (2) the major fraction of blood that drains the brain is collected in the dural sinuses, which represent the final intracranial collecting blood vessels.4 Briefly, there are three groups of valveless vessels that allow for drainage. These are the superficial cortical veins located on the surface of the cortex, the deep or central veins, and the venous sinuses within the dura (Fig. 41–4). The superficial veins convey blood from the cortex and the adjacent white matter and empty into the dural venous sinuses. The deep cerebral veins drain blood in a centripetal direction from the deep white matter, the basal ganglia, and the diencephalon toward the lateral ventricles. Large subependymal veins empty into the internal cerebral and basal veins, which unite and contribute to the formation of the great cerebral vein also known as the “vein of Galen.” The cerebral venous system is also exceptional in that these vessels are endowed with arachnoid villae, which allow cerebrospinal fluid and various metabolites to drain into the systemic circulation.

The basic pattern of blood supply to the spinal cord consists of three longitudinal trunks, as follows: 1. The ventral spinal artery that lies in the ventral fissure of the spinal cord, and gives rise to the vertical arteries that pass through the center of the cord and supply most of the gray matter 2. Two dorsolateral spinal arteries that run along the dorsolateral aspect of the cord A network of irregular anastomosing arteries connects the ventral spinal and dorsolateral arteries. The dorsolateral arteries and their anastomosing branches give rise to radial arteries that supply both gray and white matter in the spinal cord. Each body segment has paired spinal arteries that give rise to a dorsal root artery and a ventral root artery, which follow the nerve connections on each side of the cord. These arteries feed into a spinal arterial ring that surrounds the cord at the level of each intervertebral foramen. The venous architecture of the spinal cord is considerably more variable than the corresponding arterial distribution, and the blood vessels are more tortuous. There

ACA MCA PCA Watershed zone

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Figure 41–3. The cerebral arterial boundary zones in man. (From Edvinsson L, McCulloch J, MacKenzie ET: General and comparative anatomy of the cerebral circulation. In Edvinsson L, MacKenzie ET, McCulloch J, et al, eds: Cerebral Blood Flow and Metabolism. New York: Raven Press, 1993.)

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Superior sagittal sinus Inferior sagittal sinus

Great anastomotic vein of Trolard

Great vein of Galen

Internal cerebral vein Basal vein

Straight sinus Intercavernous sinus Torcular Herophili Right sinus

Cavernous sinus Basilar plexus Pterygoid plexus

Occipital sinus Anastomotic vein of Labbé External jugular vein

Inferior petrosal sinus Superior petrosal sinus

Internal jugular vein Common facial vein ■

Figure 41–4. The brain venous system. (From Sokoloff L: Anatomy of the cerebral circulation. In Welch KMA, Caplan LR, Reis DJ, et al, eds: Primer on Cerebrovascular Diseases. New York: Academic Press, 1997.)

tends to be a prominent midline vein that in general follows the course of the posterior median sulcus. Otherwise, the veins follow the same pattern as the intrinsic, radial, and segmental arteries (for details, see Shamji et al5).

Microcirculation The main arteries enter the subarachnoid space and divide many times before penetrating the substance of the brain to form smaller arterioles and capillaries. The smallest pial arteries enter the brain parenchyma at a right angle to the surface of the brain. These pial arteries are formed by endothelial and smooth muscle cell layers as well as an outer layer of cells, termed the adventitia, which contains collagen, fibroblasts, and perivascular nerves. The penetrating arterioles are surrounded by an invagination of the pia matter, creating a perivascular space (Virchow-Robin space) that is contiguous with the subarachnoid space. As the arterioles penetrate deeper into the brain, this space disappears and the vascular basement membrane comes into direct contact with the astrocytic end-feet (intracerebral arterioles and capillaries). Capillaries are formed by one layer of endothelial cells and show a marked heterogeneous distribution that is correlated with synaptic density and local energy metabolism.6,7 In most regions of the brain, endothelial cells are unique in that they lack fenestrations and are interconnected by specific intercellular junctions, known as tight junctions. These morphological features, in conjunction with metabolic activity that is essentially limited to cerebral endothelial cells, constitute the blood-brain barrier that excludes large molecules, neurotransmitters, and toxins by both forming a physical barrier and lacking the typical transport mechanisms that operate in blood vessels most in other regions of the body. It should be emphasized, however, that the endothelial cell is more than the anatomical interface between

cerebrovascular muscle and the blood; it plays an important functional role in the regulation of cerebral blood flow.8 Indeed, the cerebrovascular endothelium is able to produce a variety of vasodilatatory and constrictory agents. Intraparenchymal blood vessels are almost completely ensheathed by astrocyte processes. Recent reports indicate that astrocytes are involved in local regulation of blood supply in response to neuronal activation.9,10 In the central nervous system, pericytes are found and are closely apposed to the abluminal surface of the capillaries of which they cover, on average, 25%. The function of pericytes is not well known, but some studies suggest that they may influence the diameter of capillaries because they display contractile properties.11 One distinguishing feature of the cerebrovascular bed is the presence of a rich and complex innervation.12 Large intracranial and pial vessels are densely innervated by perivascular nerves that originate from autonomic and sensory ganglia (extrinsic innervation) and contain many agents that can potentially modify vascular tone. Intracerebral arterioles and capillaries are contacted by neural processes that originate from local interneurons or from central pathways (intrinsic innervation). These processes also contain many vasoactive substances. These neurally produced transmitters and modulators are likely to participate in the control of the microvascular tone and, thereby, local cerebral blood flow.

Physiology of the Cerebral Circulation Pressure-Flow Relationships If the cerebral vascular bed was a system of nondistensible pipes, cerebral blood flow (F) would be, according to Ohm’s law, a simple function derived from the perfusion pressure (the difference between arterial inflow and downstream pressure ΔP)

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divided by the resistance to flow along these pipes (F = ΔP/R). Resistance to flow is determined by the caliber of the vascular segment, its length, and the nature of the fluid that flows along it. By analogy to Poiseuille’s equation that applies to a rigid system of tubing perfused by a newtonian fluid: F=

p r 4 ⋅ ΔP 8hL

where F is flow, r is vascular radius, ΔP is the pressure gradient between inflow and outflow, η is viscosity, and L is length. Although this equation cannot be totally applicable to the cerebrovascular bed, because it is not a rigid system, its effective length is not known, and blood is a non-newtonian fluid, Poiseuille’s law can reasonably describe the fundamental relationships between cerebral blood flow, perfusion pressure, and resistance. Of great interest, this equation emphasizes that cerebral blood flow is related to the fourth power of vessel radius; thus even minor changes in arterial diameter have a significant impact on cerebral blood flow. Cerebral perfusion pressure is the difference between intraarterial pressure where the vessels enter the subarachnoid space and pressure in the thin-walled veins in the subarachnoid space. Venous pressure changes in parallel to intracranial pressure and is normally 2 to 5 mm Hg higher than intracranial pressure. Under physiological conditions, the intracranial pressure is determined by the volume of three compartments: brain parenchyma, quantity of cerebrospinal fluid, and intravascular blood pool. Because of the rigidity of the cranium, increases in the size of one component of the intracranial contents must be accompanied by removal of an equivalent amount of another otherwise intracranial pressure will increase.13

Cerebral Autoregulation Autoregulation of blood flow is a regulatory mechanism that allows blood flow in a vascular bed to remain relatively constant during variations of arterial pressure. This is particularly well developed in the brain and plays an important protective role against the danger of hypoxia at low perfusion pressure and the risk of brain edema at higher arterial pressure. Indeed, in normotensive humans, cerebral blood flow remains relatively but not absolutely constant over a range of perfusion pressures (approximately 60 to 160 mm Hg) (Fig. 41–5). These two values determine the lower and the upper limits of autoregulation, respectively. The relative constancy of cerebral blood flow during autoregulation is due to the variations of cerebrovascular resistance (Fig. 41–6). Once the limits of autoregulation are reached, cerebral blood flow increases or decreases passively with concomitant increases or decreases in perfusion pressure (see Fig. 41–5). Nonetheless, it should be emphasized that the lower limit of autoregulation does not correspond to maximal vasodilatation because cerebral resistance arteries continue to dilate to some degree below that limit.14 When perfusion pressure decreases below the lower limit of autoregulation, cerebral blood flow decreases in parallel. However, the brain oxygen metabolism remains essentially unaffected because of an increase in oxygen extraction fraction from blood. In this stage, qualified as oligemia, no clinical symptoms of functional disruption are observed. However, further decreases in cerebral perfusion pressure further compromise cerebral blood flow, and so when the oxygen extraction fraction reaches the limit of 100% it becomes insufficient to satisfy the metabolic demands

200

200

100

Diameter

100

100 Flow

50

Autoregulatory plateau

0 0 ■

100

50 100 150 Arterial pessure (mm Hg)

50 0 200

Cerebral blood flow (% control)

Section

Arterial diameter (% control)

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Figure 41–5. Schematic representation of the autoregulation of cerebral blood flow. (From Chillon JM, Baumbach GL: Autoregulation of cerebral blood flow. In Welch KMA, Caplan LR, Reis DJ, et al, eds: Primer on Cerebrovascular Diseases. New York: Academic Press, 1997.)

of the cerebral tissues. This stage, defined as ischemia, results in functional disturbance and, depending on its duration, neuronal death may occur.15,16 When mean arterial pressure increases above the upper limit of autoregulation, resistance arteries in the brain cannot sustain vasoconstriction. An early sign is the appearance of the ‘‘sausage string’’ phenomenon characterized by an alternating pattern of dilated arterial segments with focal regions of constriction. The dilated segments represent regions of passive dilatation, and the constricted segments, regions of sustained autoregulation. Further increases in cerebral perfusion pressure result in general arteriolar dilatation and cerebral blood flow increases passively. This is accompanied by damage to the cerebrovascular endothelium and disruption of the blood-brain barrier, which leads to extravasation of plasma proteins through the vessel wall and subsequent edema.14 The limits of autoregulation are not fixed but vary with physiological stimuli and in disease states. Activation of the sympathetic nerves results in upward shift of both the lower and upper limits of autoregulation—a potentially protective response because acute elevations in arterial pressure are usually accompanied by sympathetic activation. The autoregulatory plateau is shifted to higher values in patients with chronic hypertension. This protective response can have deleterious effects if there is significant hypotension, when symptoms of ischemia may occur at a relatively higher arterial pressure.14 The mechanisms underlying cerebral blood flow autoregulation are not definitively understood. Three classic hypotheses involve neurogenic, myogenic, and metabolic factors. According to the myogenic hypothesis, smooth muscle in the resistance arteries directly contracts or relaxes in response to increases or decreases in perfusion pressure respectively. The rapidity of the autoregulatory response supports a myogenic hypothesis.17 Autoregulation is preserved in animals that have undergone sympathetic and parasympathetic denervation, suggesting that this factor is not of primary importance. Autonomic nerves, however, may play a role by modulating autoregulation. Indeed, it has been shown that sympathetic stimulation or parasympathetic denervation results in a shift of the lower autoregulatory limit toward higher levels of blood pressure.14,18 The metabolic hypothesis states that reductions in cerebral blood flow stimulate the release of vasoactive sub-

chapter 41 anatomy and physiology of cerebral and spinal cord circulation ■

Astrocyte Presynaptic neuron

Glutamate

Glu

Ca2+

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Figure 41–6. Schematic representation of potential mechanisms of neuronal activitymediated cerebrovascular dilatation. AA, arachidonic acid; COX, cyclooxygenase; EETs, epoxyeicosatrienoic acids; Glu, glutamate; mGluR, metabotropic glutamate receptor; NOS, nitric oxide synthase; PGs, prostaglandins; P450, cytochrome P450 epoxygenase. (Modified from Anderson CM, Nedergaard M: Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 2003; 26:340-344.)

AA Glu

Glu

mGluR

P450 COX

K+

EETs PGs Ca2+ K+

Postsynaptic neuron

NOS COX

NO PGs K+,H+ Lactate Adenosine

stances from the brain, which in turn stimulates the dilatation of cerebral resistance arteries. Several candidates for this role have been proposed—including carbon dioxide, hydrogen ions, oxygen, adenosine, potassium, and calcium—but no definitive role has been demonstrated for any of these.19

Neurogenic Regulation of the Cerebral Circulation As mentioned, cerebral vessels are endowed with a dense and complex innervation that originates from the autonomic nerves (sympathetic, parasympathetic, and sensory nerves) as well as from intracerebral neurons. This innervation involves a variety of transmitters of different chemical natures, which have potent vascular actions (Table 41–1). The role and influence of the perivascular nerves on cerebral blood flow regulation have been the subject of considerable controversy. The description of their actions is beyond the scope of this chapter; the reader can refer to published reviews.20 Here, we briefly illustrate the concepts by taking the cholinergic system as an example. Morphological and functional evidence exists to support a role of cholinergic neurons in the regulation of local cerebral blood flow. Major cerebral arteries and small pial vessels are innervated by parasympathetic cholinergic nerves that originate mainly from the sphenopalatine and the otic ganglia. However, vessels located within the cerebral cortex mainly receive projections from cholinergic neurons located in the basal forebrain.21 Electrical or chemical stimulation of these

Arteriole

intrinsic cholinergic neurons has been shown to induce a marked vasodilatation and subsequently a cerebral blood flow increase in the cerebral cortex. These vascular effects are reduced by the administration of atropine, an antagonist of muscarinic receptors, and potentiated by the administration of physostigmine, an inhibitor of acetylcholine esterase—findings that support the involvement of acetylcholine in neurovascular regulation.22 Moreover, Vaucher and colleagues23 demonstrated T A B L E 41–1. Vasoactive Transmitters Implicated in Neurovascular Regulation Transmitters Norepinephrine Acetylcholine Serotonin Dopamine Nitric oxide Vasoactive intestinal peptide Neuropeptide Y Pituitary adenylate cyclase–activating polypeptide Substance P Calcitonin gene–related peptide Neurokinin A

Effect of Stimulation on Cerebral Blood Flow − + +/− + + + − + + + +

+, −, and +/− indicate increase, decrease, and both increase and decrease in cerebral blood flow, respectively.

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that the vasodilatation induced by stimulation of cholinergic neurons of the basal forebrain was not accompanied by any change in brain metabolism. Overall, these studies indicate that the changes in perfusion cannot be attributed to increased metabolic activity but rather to a direct action of cholinergic neurons on cerebral blood vessels. Another argument to support the involvement of the cholinergic system in the regulation of intraparenchymal vessels is that lesions of the basal forebrain result in considerable reduction of cerebral blood flow in the cerebral cortex.24 Nonetheless, the significance of the cholinergic system in the regulation of local blood flow in response to cerebral activation is not fully investigated.22 Apart from the direct innervation of cerebral vessels, a neurogenic control of blood flow can also be produced by stimulation of neurotransmitter receptors. As an example, activation of glutamate receptors induces vasodilatation and increase of cerebral blood flow. These effects are mediated by vasoactive factors whose synthesis is triggered by the changes in intracellular Ca2+ associated with the activation of glutamatergic receptors. The increase in Ca2+ activates Ca2+-dependent enzymes that produce potent vasodilators such as nitric oxide and certain arachidonic acid products (see Fig. 41–6).25 A glutamate-induced Ca2+ increase activates the neuronal isoform of nitric oxide synthase (nNOS), which produces nitric oxide. The vasodilatation produced by the topical application of N-methyl-D-aspartate or glutamate is reduced by nNOS inhibitors. Moreover, the cortical cerebral blood flow increase induced by sensory stimulation is generally associated with nitric oxide release and is attenuated by nNOS inhibitors.25 These findings indicate an important role for nitric oxide in the mechanisms of vasodilatation seen during functional activation. An increase in intracellular Ca2+ evoked by glutamate also activates phospholipase A2, leading to production of arachidonic acid. Arachidonic acid is then metabolized by the cyclooxygenase (COX) pathway, producing vasodilatatory prostaglandins. Functionally, the cerebral blood flow increase evoked by somatosensory stimulation is attenuated by COX-2 inhibitors or in COX-2–null mice, whereas COX-1 does not participate in this response.26 The COX-2 metabolites responsible for vasodilatation are likely to involve vasodilatatory prostaglandins. Other arachidonic acid products involved in functional hyperemia include metabolites of the P450 pathway, such as epoxyeicosatrienoic acids.10,27 There is a growing body of evidence to show that neurovascular regulation of cerebral vessels implicates not only neurons but also glial cells.10,25 Zonta and associates28 showed, through the use of brain slices, that neuronal activation induces glutamate release, which activates metabotropic glutamate receptors located on cortical astrocytes, leading to increases in Ca2+ concentrations in perivascular end-feet, which in turn cause arteriolar dilatation by release of vasoactive cyclooxygenase products (see Fig. 41–6). Similar results were obtained in studies performed in mice using in vivo imaging, further supporting the pivotal role of astrocytes in cerebral blood flow regulation in response to neuronal synaptic activity.29

Metabolic Regulation of the Cerebral Circulation According to the metabolic hypothesis of regulation of blood flow, neurons release products of neuronal activity that diffuse

to the vasculature and result in vasodilatation. This concept of coupling was introduced in a seminal paper by Roy and Sherrington in 1890,30 in which they proposed that “the chemical products of cerebral metabolism . . . can cause variations of the caliber of the cerebral vessels.” Several factors have been implicated in this type of regulation, including vasoactive ions (K+ and H+), CO2, lactate, and adenosine (see Fig. 41–6). It could well be that the co-release of two or several factors is necessary to meaningfully effect changes in cerebrovascular tone.

Potassium Potassium ions are released by the extracellular ionic currents induced by action potentials and synaptic transmission. It is well known that increases in extracellular K+ up to 10 mM cause dilatation of arterioles both in vitro and in vivo.31,32 This effect is mediated by the opening of K+ channels on the membrane of arterial smooth muscle cells, leading to their hyperpolarization and subsequent relaxation.8

Carbon Dioxide The effect of carbon dioxide on the cerebral vasculature is one of the most pronounced and reproduced phenomena observed in the cerebral circulation. Hypercapnia causes cerebral vasodilatation with a cerebral blood flow increase and hypocapnia causes cerebral vasoconstriction with a cerebral blood flow decrease. In humans, 5% CO2 inhalation raises cerebral blood flow by approximately 50%, and 7% CO2, by 100%.33 It is not the CO2 tension per se that is responsible for the flow changes but the accompanying shift in perivascular pH. Increases of arteriolar CO2 tension in the cerebrospinal fluid do not affect pial arteriolar caliber unless acidification of the milieu occurs.34 Other mediators, such as prostaglandins and nitric oxide, have been shown to modify cerebral blood flow responses to increased CO2 tension.35,36

Adenosine Several published studies indicate that adenosine, a purinergic nucleoside, is one of the major regulators of the cerebral circulation.37 In general, administration of exogenous adenosine potently relaxes cerebral arterioles and arteries with a subsequent increase in cerebral blood flow.37 Adenosine concentrations are rapidly elevated in response to a number of stimuli known to increase cerebral blood flow, such as hypoxia, hypotension, seizures, and neuronal activation. Theophylline, an antagonist of adenosine receptors, blocks the hyperemia observed during cerebral activation, findings that implicate adenosine, which can be produced during adenosine triphosphate catabolism, in the coupling between brain metabolism and blood flow.38

Endothelial Regulation One of the major mechanisms involved in the regulation of cerebrovascular tone implicates endothelial factors. Indeed, more than simply a physical barrier, endothelial cells play a critical role in the regulation of brain perfusion through the production and release of potent relaxing and contracting factors that regulate the tone of underlying vascular muscle in

chapter 41 anatomy and physiology of cerebral and spinal cord circulation Endothelial cells

PGI2 NO PGE2 EDHF

Relaxation

PGF2α ET-1 TXA2

Constriction

Vascular smooth muscle cells ■

Figure 41–7. Endothelium-derived factors that affect vascular smooth muscle tone. NO, nitric oxide, EDHF, endothelium-derived hyperpolarizing factor, PGI2, prostaglandin I2, PGE2, prostaglandin E2, ET-1, endothelin-1, TXA2, thromboxane A2, PGF2α, prostaglandin F2α.

response to chemical and mechanical stimuli. These factors include nitric oxide, endothelium-derived hyperpolarizing factors, certain eicosanoids, and endothelin-18,39 (see Fig. 41–7). In this section, we discuss briefly the involvement of nitric oxide and eicosanoids.

Nitric Oxide Nitric oxide, a molecular messenger synthesized by NOS, is involved in a wide variety of biological processes. There are three isoforms of NOS: nNOS, inducible (iNOS), and endothelial (eNOS). In endothelial cells, eNOS is constitutively expressed and requires an elevation of intracellular calcium concentration for activation. The multitude of nitric oxide sources and the lack of specific inhibitors of eNOS have rendered difficult the definition of the relative involvement of neuronal and endothelial nitric oxide in the regulation of vascular tone. Under basal conditions, tonic release of nitric oxide is a significant regulator of resting cerebral blood flow. Accordingly, NOS inhibition constricts cerebral arteries both in vitro and in vivo and decreases cerebral blood flow.8,39 Nitric oxide generated by eNOS diffuses from the endothelium to the smooth muscle where it binds to and stimulates soluble guanylate cyclase resulting in relaxation of smooth muscle. Reductions of cerebral blood flow in response to N-nitro-L-arginine, a nonselective NOS inhibitor, are absent in mice that are deficient in expression of the gene for eNOS, suggesting that endothelium is the primary source of nitric oxide that influences basal tone.40 Nitric oxide has also been shown to play an essential role in cerebral vasodilatation induced by shear stress, acetylcholine, bradykinin, and other humoral agents.8

Eicosanoids Eicosanoids are a diverse group of substances derived from arachidonic acid, which is metabolized via three general path-

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ways that involve cyclooxygenases (COX), lipooxygenases, and cytochrome P450 monooxygenases.41 These various eicosanoids can either promote vasodilatation or vasoconstriction. The eicosanoids are synthesized in a variety of cellular types, including neurons, astrocytes, and endothelial cells. As discussed, certain eicosanoids, released by astrocytes, have been implicated in the hyperemia associated with neuronal activation. Among the various eicosanoids, those produced by the COX pathway, namely prostaglandins and thromboxanes, are the most extensively studied. Prostaglandin I2, prostaglandin E2, and prostaglandin D2 are vasodilators, whereas prostaglandin F2α and thromboxane A2 mediate vasoconstriction.41 In contrast to the complex effects of the prostaglandins on the cerebral circulation, the cyclooxygenase inhibitor, indomethacin, consistently decreases cerebral blood flow in basal conditions and in response to certain stimuli such as hypercapnia.35,42 Prostaglandin I2 and stable prostaglandin I2 analogs produce relaxation of cerebral arteries in vitro and cerebral arterioles in vivo8 (see Fig. 41–7). After synthesis, PGI2 diffuses to the smooth muscle, where it activates adenylate cyclase through G protein–coupled receptors, increasing cyclic adenosine monophosphate and protein kinase A activity. The activation of protein kinase A causes K+ channels to open and produces smooth muscle hyperpolarization.43,44 Under normal conditions, prostaglandin I2 is the primary prostaglandin produced by the endothelium and is thought to play an important role in regulation of blood flow in response to intraluminal pressure, shear stress, and humoral agents.41 However, the relative contributions of prostaglandin I2 and the other prostaglandins to cerebrovascular tone are not well known and may vary as a function of age, species, vessel size, and external stimulation. These prostaglandins also show complex interactions with other endothelium-derived factors such as nitric oxide. Overall, it is clear that the cerebral circulation is subject to complex and fine regulation. This regulation should and cannot be conveniently subdivided according to the effects of independent factors such as metabolic and neurogenic regulation. Regulation is rather multifactorial and results from several factors of different nature produced by various cellular types in the brain.

K E Y

P O I N T S

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The brain is a complex and heterogeneous organ that is critically dependent on its blood supply. Compared with the peripheral circulations, the cerebral circulation has unique anatomical and functional features.

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Autoregulation in the cerebral circulation is a crucial mechanism that protects the brain against the dangers of hypoxia at low arterial pressure and against the risks of brain edema at high perfusion pressure.

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The regulation of the cerebral circulation in response to functional activation or to other stimuli is likely to be mediated by a myriad of vasoactive factors that derive from neurons, glia, and cerebral blood vessels, acting as an integrated unit.

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Suggested Reading Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002. Faraci FM, Heistad DD: Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 1998; 78:53-97. Iadecola C: Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004; 5:347-360.

References 1. Liebeskind DS: Collateral circulation. Stroke 2003; 34:22792284. 2. Alpers BG, Berry RG, Paddison RM: Anatomical studies in the circle of Willis in normal brains. Arch Neurol Psychiatry 1959; 81:409-418. 3. Edvinsson L, MacKenzie ET: General and comparative anatomy of the cerebral circulation. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002, pp 3-29. 4. Capra NF, Kapp JP: Anatomic and physiologic aspects of the venous system. In Wood JH, ed: Cerebral Blood Flow: Physiologic and Clinical Aspects. New York: McGraw-Hill Book Company, 1987, pp 37-58. 5. Shamji MF, Maziak DE, Shamji FM, et al: Circulation of the spinal cord: an important consideration for thoracic surgeons. Ann Thorac Surg. 2003; 176:315-321. 6. Dunning HS, Wolff HG: The relative vascularity of various parts of the central and peripheral nervous system of the cat and its relation to function. J Comp Neurol 1937; 67:433-450. 7. Sokoloff L, Reivich M, Kennedy C, et al: The (14C)-deoxyglucose method for measurement of local cerebral glucose utilisation: theory, procedure, and normal values in the conscious and anesthetised albino rat. J Neurochem 1977; 28:897-916. 8. Faraci FM, Heistad DD: Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 1998; 78:53-97. 9. Anderson CM, Nedergaard M: Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 2003; 26:340-344. 10. Koehler RC, Gebremedhin D, Harder DR: Role of astrocytes in cerebrovascular regulation. J Appl Physiol. 2006; 100:307-317. 11. Shepro D, Morel NM: Pericyte physiology. FASEB J. 1993; 7:1031-1038. 12. Edvinsson L, Hamel E: Perivascular nerves in brain vessels. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002, pp 43-70. 13. Miller JD, Bell BA: Cerebral blood flow variations with perfusion pressure and metabolism. In Wood JH, ed: Cerebral Blood Flow: Physiologic and Clinical Aspects. New York: McGraw-Hill Book Company, 1987, pp 119-130. 14. Paulson OB, Strandgaard S, Edvinsson L: Cerebral autoregulation. Cerebrovasc Brain Metab Rev. 1990; 2:161-192. 15. Powers WJ: Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol 1991; 29:231-240. 16. Baron JC: Positron tomography in cerebral ischemia. A review. Neuroradiology 1985; 27:509-516. 17. Kontos HA, Wei EP, Navari RM, et al: Responses of cerebral arteries and arterioles to acute hypotension and Hypertension. Am J Physiol 1978; 234:H371-H383. 18. Morita Y, Hardebo JE, Bouskela E: Influence of cerebrovascular parasympathetic nerves on resting cerebral blood flow, spontaneous vasomotion, autoregulation, hypercapnic vasodilation and sympathetic vasoconstriction. J Auton Nerv Syst 1994; 49:S9-S14.

19. Chillon JM, Baumbach GL: Autoregulation: arterial and intracranial pressure. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 395-412. 20. Goadsby PJ, Edvinsson L: Neurovascular control of the cerebral circulation. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 172-190. 21. Dauphin F, MacKenzie ET: Cholinergic and vasoactive intestinal polypeptidergic innervation of the cerebral arteries. Pharmacol Ther 1995; 67:385-417. 22. Hamel E, Lacombe P: Acetylcholine. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 222-247. 23. Vaucher E, Borredon J, Bonvento G, et al: Autoradiographic evidence for flow-metabolism uncoupling during stimulation of the nucleus basalis of Meynert in the conscious rat. J Cereb Blood Flow Metab 1997; 17:686-694. 24. Waite JJ, Holschneider DP, Scremin OU: Selective immunotoxin-induced cholinergic deafferentation alters blood flow distribution in the cerebral cortex. Brain Res 1999; 818:1-11. 25. Iadecola C: Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004; 5:347-360. 26. Niwa K, Araki E, Morham SG, et al: Cyclooxygenase 2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 2000; 20:763-770. 27. Peng X, Carhuapoma JR, Bhardwaj A, et al: Suppression of cortical functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors. Am J Physiol 2002; 283:H2029H2037. 28. Zonta M, Angulo MC, Gobbo S, et al: Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 2003; 6:43-50. 29. Takano T, Tian GF, Peng W, et al: Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 2006; 9:260-267. 30. Roy CS, Sherrington C: On the regulation of the blood supply of the brain. J Physiol 1890; 11:85-108. 31. Kuschinsky W, Wahl M, Bosse O, et al: Perivascular potassium and pH as determinants of local pial arterial diameter in cats. A microapplication study. Circ Res 1972; 31:240-247. 32. Nguyen TS, Winn HR, Janigro D: ATP-sensitive potassium channels may participate in the coupling of neuronal activity and cerebrovascular tone. Am J Physiol 2000; 278:H878H885. 33. Kety SS, Schmidt CF: The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 1948; 27:484-492. 34. Kontos HA, Raper AJ, Patterson JL: Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels. Stroke 1977; 8:358-360. 35. Pickard JD, Mackenzie ET: Inhibition of prostaglandin synthesis and the response of baboon cerebral circulation to carbon dioxide. Nat New Biol 1973; 245:187-188. 36. Iadecola C: Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci U S A 1992; 89:3913-3916. 37. O’Regan M: Adenosine and the regulation of cerebral blood flow. Neurol Res 2005; 27:175-181. 38. Ko KR, Ngai AC, Winn HR: Role of adenosine in regulation of regional cerebral blood flow in sensory cortex. Am J Physiol 1990; 259:H1703-H1708. 39. Andresen J, Shafi NI, Bryan RM: Endothelial influences on cerebrovascular tone. J Appl Physiol 2006; 100:318-327. 40. Ma J, Meng W, Ayata C, et al: L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice. Am J Physiol 1996; 71:H1717-H1719.

chapter 41 anatomy and physiology of cerebral and spinal cord circulation 41. Busija DW: Prostaglandins and other eicosanoids. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002, pp 325-338. 42. Schumann P, Touzani O, Young AR, et al: Effects of indomethacin on cerebral blood flow and oxygen metabolism: a positron emission tomographic investigation in the anaesthetized baboon. Neurosci Lett 1996; 220:137-141.

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43. Parkington HC, Coleman HA, Tare M: Prostacyclin and endothelium-dependent hyperpolarization. Pharmacol Res 2004; 49:509-514. 44. Corriu C, Feletou M, Canet E, et al: Endothelium-derived factors and hyperpolarization of the carotid artery of the guinea-pig. Br J Pharmacol 1996; 119:959-964.

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42

ISCHEMIC STROKE: MECHANISMS, EVALUATION, AND TREATMENT ●

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Bernardo Liberato and John W. Krakauer

Stroke is a major public health problem. An estimated 500,000 new and 200,000 recurrent strokes occur in the United States annually, and the number of stroke survivors is estimated to be about 4.8 million. Stroke is the leading cause of disability and the third leading cause of death in the United States (after coronary heart disease and cancer) and accounts for a health care cost burden estimated at $53 billion spent in the year 2004.1 Of all cases of stroke, 80% are ischemic and 20% are hemorrhagic (parenchymal and subarachnoid hemorrhages). This chapter focuses exclusively on ischemic stroke, discussing underlying causes, syndromes, acute treatment, and strategies for secondary prevention.

DEFINITION Ischemic stroke is defined as an acute neurological deficit caused by damage to an area in the central nervous system (CNS) as a result of decreased blood flow. The majority of ischemic strokes are arterial in origin, caused by occlusion of a feeding artery by a thromboembolic process. Reduction in tissue perfusion below a certain threshold renders neurons ischemic and dysfunctional, and then, if flow is not restored, the tissue becomes irreversibly damaged (infarction).

TRANSIENT ISCHEMIC ATTACK Transient ischemic attacks (TIAs) have traditionally been distinguished from ischemic stroke on the basis of symptom duration, with the assumption, largely justified, that otherwise the two entities share risk factors and causes and that evaluation findings and secondary prophylaxis are similar for the two. TIA has traditionally been defined as a focal neurological deficit of abrupt onset, referable to a vascular territory, that lasts less than 24 hours. However, the 24-hour definition is arbitrary and is not based on any plausible biological mechanism. In fact, most TIAs resolve in less than an hour. In addition, studies have demonstrated that a significant proportion of clinically defined TIAs are not necessarily transient at the tissue level; there is evidence of tissue infarction on magnetic resonance imaging (MRI) performed early in the course of the syndrome.2,3 Indeed, in view of the advances in neuroimaging and epidemiological studies, a panel of experts has proposed that TIA be defined as a brief episode of neurological dysfunction caused by retinal

or brain ischemia with symptoms lasting less than 1 hour and without evidence of acute infarction on neuroimaging (diffusion-weighted imaging [DWI] or computed tomography [CT] scan).4 When the symptoms and signs do not fit criteria for a TIA—that is, they persist for more than 1 hour and/or there is evidence on neuroimaging of tissue infarction—the syndrome is classified as an ischemic stroke. The modified duration for TIA is of practical benefit, in view of the new time window–dependent strategies for acute stroke management, when a decision for acute intervention should not be contingent on resolution of a patient’s signs and symptoms within 24 hours. However, the neuroimaging component of the proposed new definition is problematic because it sidesteps what is arguably most important about clinically defined TIAs: their reversibility. If symptoms resolve in under an hour but a lesion is identified with DWI, then what is the difference between this entity and ischemic stroke whose symptoms do not resolve? In addition, a definition of TIA based on the absence of a DWI lesion has the odd consequence of eliminating duration as an important distinguishing feature, inasmuch as studies have shown that a substantial proportion of patients with symptoms lasting less than an hour have DWI lesions. Indeed, one DWI study revealed that symptom duration could not distinguish TIA from ischemic stroke.5 Study findings support the contention that it is symptom duration or, more specifically, the rate of symptom reversal from time of onset, that is the essential characteristic of TIA; data indicate that risk of recurrent stroke is substantially higher in patients with rapid recovery than in those with fixed deficits and subsequent slow recovery.6-8 The largest study of risk of recurrent stroke after TIA showed that 50% of all ischemic strokes after TIA occur within 48 hours of the TIA.9 Thus, the presence or absence of lesions on DWI should not be required for a definition of TIA, only that the deficit substantially reverses, not necessarily fully, in less than an hour. This is not to say that DWI does not provide useful information about TIA mechanisms. For example, it has been shown that patients with deficits that reverse in less than 24 hours but who have DWI lesions have the highest risk of in-hospital recurrent stroke. This subgroup may have made up a substantial proportion of the patients in the large study mentioned previously. The critical implication of the spate of studies on TIA is that TIA reflects a more unstable condition than does stroke and merits immediate attention. A TIA is to the brain what

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unstable angina or non–Q-wave myocardial infarction is to the heart, a condition of fluctuating tissue perfusion that is unstable and threatens tissue viability. TIA should be viewed as a medical emergency that necessitates immediate diagnostic workup and treatment. The clinical seriousness of TIA makes accurate diagnosis very important, but because the symptoms have nearly always resolved by the time the patient is seen by a physician, careful history taking is essential. This can be a challenge because a large number of nonischemic conditions, such as migraine, seizures, and multiple sclerosis, cause transient neurological symptoms. TIAs themselves vary in their mode of presentation, variation attributable primarily to the underlying cause. Different TIA presentations are therefore discussed as follows as they relate to each stroke subtype.

ISCHEMIC STROKE Ischemic strokes usually cause sudden loss of one or more functions as a result of acute damage to specific CNS structures supplied by a particular vessel. However, symptoms can also give patients the sense that something unpleasant, such as vertigo or hiccoughing, has been acquired rather than lost. The presentation can be more or less fulminant and depends on the specific structures involved and the amount of tissue damage. All strokes are ultimately caused by tissue perfusion failure. The brain goes through a series of autoregulatory protective responses as cerebral perfusion pressure (CPP) drops, as a result of either systemic hypotension or a local arterial stenosis, or both. As CPP falls, arterioles dilate to maintain cerebral blood flow (CBF), which results in an increase in cerebral blood volume. When no further vasodilation is possible, CBF becomes passively dependent on CPP, but over a certain range of low CPP, neuronal metabolism (the cerebral metabolic rate of oxygen) can be maintained by increasing the blood oxygen extraction fraction (OEF). OEF is usually about 30% to 40% but can increase to near 100%. Experimental studies in nonhuman animals and observations in patients indicate that there are two critical CBF thresholds. Below the first, 16 to 18 mL/100 g/minute, there is loss of neuronal electrical function (electrical failure). Below the second, 10 to 12 mL/100 g/minute, there is loss of cellular ion homeostasis (membrane failure). The concept of the ischemic penumbra is of central importance to therapeutic approaches to stroke and follows directly from the observation that there are separate CBF thresholds for electrical and membrane failure. The ischemic penumbra is a shell of electrically unexcitable but still viable neuronal tissue surrounding a core of ischemic irreversibly damaged tissue. The ischemic penumbra is in a state of misery perfusion where CBF is reduced, OEF is increased, and cerebral metabolic rate of oxygen is relatively preserved. The therapeutic importance is that a state of misery perfusion cannot be sustained indefinitely, and if CBF is not restored, the tissue proceeds to infarction. In order to salvage penumbral tissue, CBF must be restored in the critical time window between electrical and membrane failure. There is good evidence, obtained mainly with positron emission tomographic (PET) studies,10 that ischemic penumbra exists in human and nonhuman primates and that it remains viable for longer and more variable periods of time than was suggested by initial small mammal experiments. Advances in MRI have made significant inroads in identifying

the ischemic penumbra in patients after stroke and making it a target for therapeutic intervention (see “Stroke Evaluation” section). TIA might represent a form of penumbral phenomenon without an infarct core, and new data on the instability of TIA reflect the high risk of proceeding to infarction in this penumbral tissue.

STROKE CLASSIFICATION BY MECHANISM (STROKE SUBTYPES) Despite the final common pathway for tissue ischemia and infarction, it is important to classify ischemic strokes according to their etiological subtype. This is achieved on the basis of clinical features and results of ancillary tests. Accurate subclassification ensures consistency in terminology for larger registries and clinical trials, and conversely, correct translation to the practice setting of knowledge obtained from clinical trials. Assigning a stroke a subtype designation implies an inference about mechanism and natural history, both crucial for treatment and prognosis. Causes of ischemic strokes are generally subdivided into large-artery atherosclerosis (LAA), penetrating small-artery disease, cardiac embolism, cryptogenic stroke, and strokes of other determined cause such as hypercoagulability, migraine, and cervical artery dissection. These subdivisions are not mutually exclusive in terms of stroke mechanism. For example, atherosclerosis with superimposed thrombus in a large vessel may lead to occlusion of an exiting perforator. Thus, although the underlying cause is LAA, the mechanism of stroke is small-vessel occlusion. Similarly, the mechanisms of stroke in the category of strokes of other determined cause overlap substantially with those of the other four categories, but they nevertheless have unique etiological features that merit individual consideration.

Large-Artery Atherosclerosis This subtype is characterized by evidence for atherosclerosis (anterior or posterior circulation) in the large-vessel vascular distribution of a brain infarction, in the absence of a cardiac source of embolism. The most common location for atherosclerotic changes is at the bifurcation or proximal takeoff of the large vessels, where the shear stress on the wall, from turbulent flow usually related to long-standing hypertension, is maximal. The arterial narrowing can be either extracranial (in the carotid or vertebral arterial system) or intracranial (in the many tributaries of the circle of Willis and their branches). The pattern of parenchymal involvement can be small or large, cortical or subcortical, and is determined largely by the status of pial-pial collaterals and the circle of Willis. There are two other infarction patterns associated with proximal large vessel disease: border zone and watershed. Border zone infarction corresponds to involvement of areas at the junction of the distal fields of two nonanastomosing arterial systems. Watershed infarctions occur at a zone of pial-pial artery anastomoses between two large vessels: for example, the middle cerebral artery (MCA)–posterior cerebral artery (PCA) watershed. There are internal border zones (misleadingly also referred to as internal watersheds) in the centrum semiovale and paraventricular corona radiata, regions at the junction of subcortical and

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment medullary penetrators off the MCA, and in the subinsular zone, a region between small insular penetrating arteries and the lateral lenticulostriate vessels.11 Thus, for example, critical internal carotid artery (ICA) stenosis or occlusion can cause watershed infarction at (1) the boundary of the anterior cerebral artery (ACA) and MCA, manifesting as a thin wedge extending from the anterior horn of the lateral ventricle to the frontal cortex or a string of infarction at the medial convexity surface; (2) the MCA/ACA/PCA boundary, often more difficult to distinguish from MCA branch occlusion, but again appearing as a cortical wedge extending from the occipital horn of the lateral ventricle to parieto-occipital cortex; and (3) a confluent or discontinuous long lesion in the centrum semiovale running parallel to the lateral ventricle. Interpretation of patterns of infarction from large vessel disease is based on assumptions about underlying mechanisms: (1) large-vessel stenosis or occlusion by in situ disease or artery-to-artery embolism and (2) flow-failure distally from a more proximal occlusion or hypotension. However, these mechanisms are likely to coexist. A high-grade ICA or MCA stenosis may be both emboligenic and cause a low-flow state. The low-flow state reduces the chances of clearing small embolic particles from distal arterial beds, leading to a border zone or watershed pattern of infarction.12 In addition to producing cortical , subcortical, and watershed patterns of infarction, LAA can occlude the os of a single penetrating small vessel, causing a lacunar infarct (see later discussion). Thus, the variety of infarct patterns possible with LAA makes diagnosis based on clinical examination or infarct pattern alone difficult. A bruit on examination and the presence of other atherosclerotic risk factors or markers such as hypertension, elevated cholesterol, diabetes, smoking history, peripheral arterial disease, and coronary artery disease, are marginally helpful at best. Indeed, it is debatable whether there is any significant difference in modifiable risk factor profile and predisposition to LAA versus small-vessel disease.13 Information regarding race/ethnicity can be helpful, inasmuch as white persons have a higher incidence of extracranial atherosclerosis, whereas Asian, black, and Hispanic persons have a higher incidence of intracranial atherosclerosis. Interestingly, unlike completed infarction, LAA-associated TIAs do have distinctive features that help make the diagnosis. Intermittent flow-failure through a critical stenosis, often brought on when the patient stands up suddenly or by overly aggressive antihypertensive therapy, can cause focal neurological deficits that reverse when the patient lies down. More rarely, patients manifest a “limb-shaking” TIA, consisting of brief periods of shaking of an extremity brought on by standing or sitting up, easily confused with a focal motor seizure. Another strong clue to LAA is an unstable course in the first 24 hours after stroke onset, manifested by deterioration after improvement.14 Determination of LAA as the underlying cause of a stroke through ancillary testing (see “Stroke Evaluation” section) is important because there is a high rate of early stroke recurrence in this subgroup of patients,15 both for extracranial and intracranial atherosclerosis. This is also true for the long term because patients with symptomatic ICA stenosis with greater than 70% diameter reduction have a stroke recurrence risk of 26% in 2 years.16 The recurrence rate for patients with symptomatic MCA stenosis is about 10% a year.17,18 Because of this relatively high risk of early recurrence and the established benefit of early

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endarterectomy in long-term stroke prevention for ICA stenosis, identification of this subtype of stroke is critical.19

Small-Vessel Atherosclerosis (Lacunar Strokes) The definition of lacunar infarction has become quite confused. We believe that it should be a combined clinical and radiological diagnosis that is based on a presentation with one of a handful of typical syndromes (see “Lacunar Syndromes” section) and imaging evidence for a small infarct (2 to 20 mm in diameter) in the deep cerebral white matter, basal ganglia, thalamus, or pons. Evidence suggests that in situ single perforator disease is the cause in the majority of cases. Exclusion of LAA and a cardiac source of embolism is important, because lacunar infarction is estimated to originate from emboli or LAA in about 10% to 15% of cases.20 This may be true particularly for patients who have a lacunar syndrome with evidence of multiple subacute lesions on neuroimaging.21 The lacunar hypothesis remains controversial, and some commentators have gone as far as to recommend abolishing the category and substituting it with “small stroke,” assuming the same risk factors and causes as large strokes. This understandable exasperation stems from the tendency to use the term lacune for any small subcortical stroke, with the associated erroneous assumption that all subcortical strokes are caused by in situ small vessel disease. Thus, it should be emphasized that the term should be reserved for the clinicoradiological definition given at the beginning of this section. Subcortical strokes can also arise from occlusion of medullary penetrators that supply the centrum semiovale, from internal border zone infarctions, and from multiple perforator involvement resulting from embolic or intrinsic large-vessel disease (e.g., striatocapsular infarction from MCA stem disease). However, despite these concerns, evidence favors preserving the lacunar infarction stroke category from a pathophysiological standpoint. First, the presence of lacunar infarcts is correlated with leukoaraiosis and with subcortical microhemorrhages.22 These correlations suggest that lacunar infarcts are manifestations of a more diffuse abnormality of small cerebral arterioles.23 Second, the proportion of embolic sources identified in patients with lacunar infarction is lower than that of hemispherical ischemic strokes. Third, after a lacunar infarction, a recurrent stroke is more likely to be lacunar than nonlacunar.23a This would not be expected if lacunar infarcts shared the same mechanism with larger cortical strokes. In addition, the early stroke recurrence rate is lower than those for LAA and cardioembolic stroke. Fourth, in a primate model, only 6% of even the smallest particles injected in the carotid artery ended up in the lenticulostriate vessels.23b The pathology underlying lacunar infarction is still debated, mainly because lacunar infarcts are seldom fatal and cases are thus rarely subjected to autopsy. Nevertheless, it is assumed that lacunar infarction results from occlusion of a small penetrator by atheroma blocking its origin, by embolus, or by an intrinsic process, lipohyalinosis (narrowing the lumen at points along its length). Lenticulostriate pathology after lacunar infarction has been visualized with MRI.24 These images show a linear structure with signal features consistent with perforator occlusion by thrombus or leakage of vessel contents into the surrounding parenchyma. These findings support the idea of a pathological process unique to deep perforating

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arteries, which can cause lacunar infarction. Occlusion of the vessel itself might cause infarction, or blood vessel contents might be toxic to surrounding parenchyma. A spectrum of perforator disease with luminal thrombus and leakage of contents into the blood vessel wall and then into the perivascular tissue might explain the previously mentioned correlation among lacunar infarcts, leukoaraiosis, and deep microhemorrhages. In addition, a leakage mechanism might also explain an interesting feature of TIAs associated with lacunar infarction: the “capsular warning syndrome.” This consists of a stuttering cluster of stereotypical events over a period of about 72 hours. These events are brief bursts of typical lacunar phenomena that can come and go over minutes. Many of these patients progress to a fixed deficit; it is possible that the capsular warning syndrome evolves because a single penetrator undergoes occlusion or leakage damages surrounding tissue directly.23

Cardioembolic Strokes Embolism of cardiac origin accounts for about 20% to 40% of ischemic strokes. Atrial fibrillation is the best established cause of cardioembolic stroke, and its identification is extremely important, in view of the relatively high recurrence rates (about 10% a year) and the effective prophylaxis (approximately 60% absolute risk reduction) achieved with chronic oral anticoagulation. Other known emboligenic sources, treated with anticoagulation, are valvular disease (especially prosthetic valves), documented intraventricular thrombus present in severe cardiomyopathies, and recent myocardial infarction. In one study, transesophageal echocardiography (TEE) was used to assess 151 consecutive patients, 1 week after ischemic stroke or TIA.24a Intracardiac thrombus was identified in 26% of the patients (70% in the left atrial appendage). Multivariate analysis showed an association with large stroke, symptomatic coronary artery disease, and evidence for ischemia on electrocardiogram. Interatrial septal abnormalities, such as patent foramen ovale (PFO) and atrial septal aneurysm (ASA), result from failure of the septum to close at birth and occur in about 25% of the general population.24b Interatrial septal abnormalities are thought to be an important cause of embolic stroke in patients younger than 55. A PFO is an intact interatrial connection through the two overlapping septa that form the interatrial septum. An ASA is a hypermobile piece of the atrial septum that can protrude through the PFO into the left atrium during the cardiac cycle. PFOs can serve as a conduit for embolism originating from the venous circulation (lower extremity or pelvic venous thromboses) to the arterial circulation through rightto-left shunting of blood during the cardiac cycle and especially during Valsalva maneuvers. ASAs seem to enhance the stroke risk of a PFO, possibly by directing flow through the PFO or acting as a nidus for thrombus formation itself. A metaanalysis revealed a 24-fold increased risk of stroke in patients younger than 55 who had both a PFO and an ASA, in comparison with a fivefold risk in patients with only a PFO.25 The high frequency of interatrial septal abnormalities in the general population in comparison with the relatively low incidence of stroke in persons younger than 55 suggests that a second factor needs to combine with PFO in order for stroke to occur. Studies have shown increased frequency of two inherited hypercoagulable disorders, the factor V Leiden and the prothrombin 20210 mutations, in young patients with stroke and PFO.25a,25b Thus, perhaps a combination of PFO and an underlying hypercoagu-

lable state, either acquired or inherited, is required in order for a PFO-related stroke to occur. In contrast to patients younger than 55, it does not seem that interatrial septal abnormalities are a substantial stroke risk in older patients, possibly because left-sided atrial pressures increase with aging. In all patients with stroke and PFO, it is important to emphasize the need for a thorough search for the other potential causes of stroke before attributing it to the PFO. Prospective studies have shown that aortic arch atheroma is found more often in patients with stroke and that the presence of aortic arch atheroma, detected by TEE, is associated with increased risk of future stroke. A meta-analysis of these prospective studies gave an odds ratio for recurrent stroke of 3.76, similar in magnitude to those for atrial fibrillation and high-grade carotid stenosis.26 Aortic arch atheroma, occurring with increasing age and in people with vascular risk factors,27 may be just a marker for atherosclerosis. However, a number of observations suggest that aortic arch atheroma causes embolic stroke. First, aortic arch atheroma is often present in patients with stroke but without concomitant carotid disease. Second, stroke risk is highest for atheroma with mobile components. Third, stroke is more common in the presence of aortic arch atheroma than with atheroma in the thoracic aorta.28 Fourth, left hemisphere events are more common than right hemisphere events, and most atheroma is found in the middle to distal arch, after takeoff of the innominate artery.29 Less common sources of embolism from the heart are infectious and noninfectious (marantic) endocarditis, fibroelastoma, air, and atrial myxoma. In addition, there are a number of cardiac abnormalities whose embolic potential remains uncertain but is likely to be low. These include mitral valve prolapse, valvular strands, and mitral annulus calcification. A number of clinical features and radiographic features suggest cardioembolic stroke: (1) sudden onset with rapid progression to maximal focal neurological deficit (<5 minutes); (2) simultaneous or sequential strokes in multiple arterial territories, such as a left homonymous hemianopia and a right hemiparesis; (3) Wernicke’s aphasia (inferior division of the left MCA) and visual field cuts (distal PCA); (4) a large deficit that then rapidly regresses, probably as a result of recanalization of a large proximal vessel; (5) appearance on imaging, especially DWI, of bihemispherical, both anterior and posterior territory, or bilateral or multilevel posterior circulation infarcts (the typical pattern of stroke on MRI is a wedge-shaped lesion with its base at the cortex and the apex located subcortically); (6) hemorrhagic transformation of an ischemic infarct as a result of recanalization and irrigation of infarcted tissue or, less likely, dissection at the site of thrombus impact; and (7) the presence of single or multiple small subcortical infarcts in the absence of cortical infarcts, which makes the diagnosis of embolic stroke less likely.30

Cryptogenic Strokes Despite extensive diagnostic workup, about 40% of all ischemic strokes are secondary to other unknown processes other than atherosclerosis or cardiac embolism. This frequency may be even higher in young patients without the common atherosclerotic risk factors. The patient with cryptogenic stroke lacks a documented cardioembolic source despite investigation with transthoracic echocardiography (TTE) or TEE; does not show evidence of

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment extracranial or intracranial large-artery pathology on ultrasonographic or angiographic studies; and does not have the expected risk factor profile, clinical syndrome, and imaging characteristics for a diagnosis of a lacunar stroke. The neuroimaging features can be variable and may include cortical or subcortical pattern or even the presence of infarcts in multiple arterial territories not explained by a readily identifiable embolic source. It is likely that in the near future, as diagnostic accuracy improves, the overall frequency of diagnosis of cryptogenic strokes will decrease.

Stroke of Other Determined Cause Other determined causes can be found in about 5% of patients with stroke after extensive diagnostic investigation. Causes include arterial dissection (spontaneous or traumatic), migraine, moyamoya disease, inherited or acquired hypercoagulable states, inflammatory vasculopathy (primary or secondary CNS angiitis), hyperviscosity, and vasospasm (secondary to aneurysmal subarachnoid hemorrhage, vasoconstrictive drugs, or pregnancy). Some of these are discussed in more detail as follows. Dissection is a tear in the intima or the media that allows luminal blood to be redirected into a false lumen within the blood vessel wall, with formation of an intramural hematoma, which may limit flow (Fig. 42–1) or cause aneurysmal dilatation. Arterial dissection of the extracranial portions of the carotid and vertebral arteries accounts for only about 2% of all ischemic strokes but for up to 25% of ischemic strokes in patients younger than 55. Cervical artery dissection can occur after clear-cut neck trauma (motor vehicle accidents, attempted

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Figure 42–1. Lateral angiographic view after right common carotid artery injection, showing occlusion of the right internal carotid artery above its origin in a young woman with fibromuscular dysphasia. This appearance is consistent with an internal carotid artery dissection.

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strangulation, fall with neck injury), after relatively trivial mobilization of the neck (hair washing, chiropractic manipulation),31 or spontaneously, without any obvious precipitant. The latter two scenarios probably reflect an underlying structural weakness of the arterial wall, inasmuch as dermal connective tissue abnormalities have been detected in up to a third of these cases. Approximately 5% of spontaneous dissections can be attributed to inherited disorders of collagen structure, the most common of which is Ehlers-Danlos syndrome type IV. Others include Marfan’s syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I. In addition, about 5% of patients have a family history of dissection. Approximately 15% of patients have angiographic evidence of fibromuscular dysplasia. Infection, migraine, and elevated homocysteine have also been associated with dissection, but these risk factors have mainly been assessed with casecontrol studies, which are subject to information and selection bias, as well as confounding.32 The extracranial carotid and vertebral arteries are particularly prone to dissection because they are mobile and thus susceptible to injury from bony structures such as the cervical vertebrae or the styloid process. In addition, exposure of the media to blood leads to thrombus formation, which can embolize distally. Carotid dissection usually occurs 1 to 2 cm above the bifurcation and classically manifests with a subset or with all of the following: unilateral facial, retroorbital, or neck pain; partial Horner’s syndrome (facial anhidrosis is not present because facial sweat glands are innervated by sympathetic nerves traveling on the external carotid artery); and cerebral or retinal ischemia at a delay of hours to days. The lower cranial nerves, most often the hypoglossal, can also be affected. Vertebral dissection usually occurs either at the level of the first and second cervical vertebrae or proximally, just before entry into the intervertebral foramen, and classically manifests with posterior neck pain radiating to the occiput and delayed ischemia in the posterior circulation; with posterior inferior cerebellar artery (PICA) territory infarction being most common. There is fairly good evidence of a relationship between migraine and stroke, but proving causality is much more difficult: Does a stroke precipitate a migraine attack in predisposed patients, or does migraine lead to infarction? The truth, as always, is likely to be that both can occur. The best evidence for migraine as a direct cause of stroke is migrainous infarction, defined as a stroke that occurs during a migraine attack, and the deficit is a persistent version of the patient’s typical aura. For example, homonymous hemianopia is a frequent aura in patients with migraine, and the occipital cortex is the most frequent site pf migrainous infarction. Even in this scenario, which is rare, the diagnosis of migrainous infarction should be made only if no other cause of the stroke can be determined. Migrainous infarction tends to occur after prolonged migraine attacks, which suggest that efforts should be made to abort such attacks. In addition to migrainous infarction, migraine with aura is a risk factor in women younger than 45 for stroke occurring outside a period of migraine attack, a risk that is substantially increased by smoking and/or oral contraceptive use. Moyamoya disease occurs in younger patients and is characterized by a progressive intracranial occlusive noninflammatory vasculopathy of the distal ICA and its bifurcation into the middle and anterior cerebral arteries. Its hallmark is the development of deep intracranial collateral vessels, usually in the

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C e r e b r o va s c u l a r D i s e a s e T A B L E 42–1. Classic Lacunar Syndromes with Vascular Territories and Anatomical Structures Most Commonly Affected Lacunar Syndromes (Structures Affected)

Vessel Distribution

Pure Sensory Syndrome Thalamus

Thalamic perforators

Pure Motor Hemiparesis Basis pontis Posterior limb of internal capsule Cerebral peduncle

Pontine penetrators (basilar branch) Lenticulostriate vessels (MCA branches) Basilar or PCA penetrators

Dysarthria–Clumsy Hand Syndrome Anterior limb or genu of Lenticulostriate vessels (MCA internal capsule branches) Basis pontis Pontine penetrators (basilar branch)

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Figure 42–2. Lateral angiographic view after internal carotid artery injection, demonstrating occlusion of the proximal middle cerebral artery with dilated lenticulostriate collateral vessels. This appearance is consistent with the moyamoya pattern.

lenticulostriate vessels, giving its peculiar characteristic defined by Japanese investigators as “puff-of-smoke” (Fig. 42–2). Its cause is unclear but does not seem to be an inflammatory process, as in the primary CNS vasculitides. A similar pattern can occur with other conditions such as prior pituitary tumor irradiation, Down syndrome, neurofibromatosis, and sickle cell disease. In these situations, the pattern appears secondary to the underlying condition and is described as moyamoya syndrome rather than moyamoya disease. It should be suspected in young patients with deep hemispherical hemorrhage but without the associated risk factors for intracerebral hemorrhage (ICH) and in young patients with cryptogenic ischemic stroke, especially if one of the commonly associated conditions listed previously is present.

CLINICAL SYNDROMES Lacunar Syndromes There are five classical lacunar syndromes (Table 42–1): pure motor hemiparesis, pure sensory syndrome, sensorimotor syndrome, dysarthria–clumsy hand syndrome, and ataxic hemiparesis. It should be emphasized however, that many additional, albeit rarer, lacunar syndromes almost certainly exist and that nonlacunar subcortical and cortical strokes can cause the classical syndromes.32a For example, an embolus to the rolandic branch of the MCA could affect the primary sensorimotor cortex and cause sensorimotor syndrome. Another example is occlusion of a paramedian pontine penetrator by basilar artery atheroma, causing pure motor hemiparesis. However, studies have shown an excellent positive predictive value of the lacunar syndromes for the presence of lacunar infarction on brain imaging.

Ataxic Hemiparesis Contralateral basis pontis Contralateral thalamus Posterior limb of internal capsule

Pontine penetrators Thalamic penetrators Lenticulostriate branches

Sensorimotor Syndrome Posterior limb of internal capsule and thalamus

Lenticulostriate branches

MCA, middle cerebral artery; PCA, posterior cerebral artery.

The typical clinical presentations of a lacunar stroke reflect the most commonly involved structures: putamen, caudate, thalamus, basis pontis, internal capsule, and corona radiata.

Pure Motor Hemiparesis This is the most common manifestation of a lacunar stroke. In this syndrome, there is motor involvement of the face, arm, and leg, sometimes with more involvement of one than the other, but with absence of sensory, visual, language, or other cortical symptoms. There are often varying degrees of dysarthria and dysphagia, as a result of involvement of corticobulbar tracts. Structures commonly involved in this syndrome reflect the descending course of the corticospinal tract: the corona radiata, the posterior limb of the internal capsule (Fig. 42–3), and the basis pontis. Less often, a midbrain peduncular or medullary pyramidal infarct (with sparing of the face) can also cause this syndrome. The diagnosis of brainstem pure motor hemiparesis requires the absence of all the following: vertigo, deafness, tinnitus, diplopia, nystagmus, and ataxia. Traditionally, it has been taught that isolated monoparesis, usually brachial, is rarely caused by lacunar infarct but instead indicates a cortical or centrum semiovale lesion, regions where the motor homunculus is more spatially separated. However, with the advent of MRI, this has been shown not to be the case. Isolated monoparesis is compatible with small-vessel disease: for example, in the corona radiata and pons.33

Pure Sensory Syndrome Although this is considered the sensory analogue of pure motor hemiparesis, it occurs far less frequently than pure motor hemiparesis. It is usually caused by infarction of the ventro-

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hand, and leg weakness. The usual stroke locations are the anterior limb or genu of the internal capsule and the basis pontis.

Ataxic Hemiparesis The classic syndrome, caused by basis pontis infarction, was described as limb ataxia ipsilateral to distal leg paresis with minimal or no facial or arm weakness. This diagnosis can be difficult to establish, because limb dysmetria must be out of proportion to the hemiparesis. Other typical locations of infarction are the corona radiata, the anterior or posterior limb of the internal capsule, and the thalamus. The cerebellum has been implicated in some cases. Larger cortical strokes involving the ACA territory may manifest in a similar way, but the more pronounced leg involvement and the many behavioral abnormalities occurring with ACA-distribution strokes may help differentiate the two (see Table 42–1).

Cortical Syndromes ■

Figure 42–3. Diffusion-weighted MR image revealing a lacunar infarction in the posterior limb of the internal capsule on the right.

posteromedial and ventroposterolateral nuclei of the thalamus as a result of involvement of the inferolateral artery off the P2 segment of the PCA, but it can also result from corona radiata infarction through interruption of thalamocortical projections. Both spinothalamic and lemniscal modalities are usually affected, but selective sensory impairment can also occur. Perfect splitting of the midline on sensory testing can be observed, and involvement of midline structures such as tongue and genitalia may also be present. The hemisensory deficits may be complete or incomplete with a cheiro-oral predominance. Some patients may develop a chronic pain syndrome, especially with right thalamic lesions, with pronounced dysesthesias and paresthesias on the side contralateral to the thalamic involvement (Dejerine-Roussy syndrome). This syndrome usually appears in the subacute or chronic period and can be difficult to manage.

Sensorimotor Syndrome This condition is a combination of sensory and motor deficits. Although single penetrator disease can probably cause this syndrome, there have been only a few autopsy studies, and the specificity of this syndrome for a lacunar mechanism is probably lower than for the other four syndromes. Nevertheless, most authors postulate predominant involvement of the thalamus with impingement on the adjacent posterior limb of the internal capsule. An alternative explanation, however, is that both the sensory loss and hemiparesis result from thalamic involvement alone, inasmuch as the inferolateral artery also supplies the ventrolateral nucleus, which projects to motor cortex.34 It is likely that MRI will help to better define the anatomical basis of this syndrome.

Dysarthria–Clumsy Hand Syndrome In this uncommon syndrome, there is a predominance of dysarthria and upper limb ataxia over the other clinical features. Less pronounced findings are mild to moderate facial,

The most commonly encountered clinical syndromes (Table 42–2) are briefly reviewed according to vessel distribution and associated stroke causes.

Anterior Circulation Middle Cerebral Arteries The MCAs account for about 80% of the blood flow to the cerebral hemispheres and are the arteries most commonly involved in hemispherical strokes. Also, because of the key structures supplied by them, they give rise to some of the most florid and dramatic ischemic stroke syndromes found in clinical practice. The mechanisms by which the MCAs can be affected are multiple but most commonly involve either an embolism from a more proximal source such as the heart, aorta, or the large cervical vessels (i.e., cardioembolic and large-artery strokes, progressive intracranial disease from atherosclerosis) or other less common conditions such as sickle cell disease, postirradiation changes, moyamoya syndrome, primary CNS angiitis, and focal intracranial dissection. The location in which embolic material can lodge is variable and includes the proximal MCA stem (usually associated with a more severe syndrome due to involvement of lenticulostriate arteries), its bifurcation (in which case the deep lenticulostriate branches are spared), or at one of the more distal branches beyond the bifurcation (the superior or inferior division and their smaller distal branches). The site of vessel occlusion and the extent of the collateral supply in a given individual determine the amount of tissue damage and therefore the clinical presentation. Individuals with limited collateral supply (from distal branches of the large vessels in the circle of Willis or from extracranial to intracranial anastomoses) are the more severely affected and have the worst prognosis. These patients usually have very large hemispherical strokes affecting the cortical and subcortical territories and are prone to massive hemispherical swelling and subsequent herniation (the “malignant MCA syndrome”).

Middle Cerebral Artery Stem Occlusion The proximal syndrome is usually dramatic and reflects damage to the basal ganglia and internal capsule, supplied by the medial

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T A B L E 42–2. Clinical Stroke Syndromes with Corresponding CNS Structures and Arterial Territory Affected Artery Involved Carotid Artery Territory Anterior choroidal artery

Anterior cerebral artery

Middle cerebral artery Stem: lenticulostriate vessels (M1)

CNS Structures Involved

Clinical Syndromes

Etiologies

Posterior limb of internal capsule, medial pallidum, head of caudate, lateral geniculate body, optic radiation, medial temporal lobe Medial upper frontal and parietal lobes, paramedian hemispheres, anterior corpus callosum, anterior limb of internal capsule, anterior putamen, caudate nucleus

Contralateral hemiparesis/hemisensory deficits (face/arm/leg), homonymous hemianopia with sparing of horizontal segment Contralateral weakness (distal leg and shoulder), abulia, mutism, left-hand apraxia (anterior disconnection syndrome), transcortical motor aphasia Frontal release signs, urinary incontinence

Focal atherosclerosis Emboli (cardiac, arterial) Aneurysm surgery (ICA)

Cortical and subcortical frontoparietal hemisphere Corona radiata, striatum, external and internal capsule (posterior limb), lateral temporal lobe

Contralateral hemisensory/motor syndrome (face/arm/leg), global aphasia with dominant hemisphere involvement, visuospatial neglect when non-dominant hemisphere involvement Contralateral gaze paresis, contralateral homonymous hemianopia Obtundation or agitated delirium Contralateral hemisensory/motor syndrome (face and arm more than leg), motor (Broca’s) aphasia with dominant hemisphere involvement, variable visuospatial neglect with nondominant hemisphere involvement Contralateral gaze paresis Hemispatial neglect, hemianopia/ quadrantanopia, sensory (Wernicke’s) aphasia, agitated delirium

Artery-to-artery emboli Cardiac emboli In-situ thrombosis Focal stenosis Intracranial dissection Vasospasm (SAH, drugs)) Moyamoya syndrome

Superior division (M2)

Lateral frontal hemisphere, corona radiata Sparing of structures supplied by lenticulostriate branches (internal capsule, basal ganglia)

Inferior division (M2)

Lateral temporal lobe, lower parietal lobe, angular gyrus

Vertebral Artery Territory Posterior inferior cerebellar artery

Basilar Artery Territory Anterior inferior cerebellar artery

Artery-to-artery embolism Cardiac embolism In situ thrombosis (rare) Vasospasm (SAH, drugs) CNS angiitis

Artery-to-artery emboli Cardiac emboli CNS angiitis Vasospasm (SAH, drugs)

Artery-to-artery emboli Cardiac emboli CNS angiitis Vasospasm (SAH, drugs)

Inferior and posterior aspects of the cerebellar hemispheres, inferior vermis inferior cerebellar peduncle, inferior/ lateral medulla (descending sympathetic tract and spinothalamic tract) Lateral medulla involved more commonly as a result of involvement of intracranial vertebral artery

Ipsilateral Horner’s syndrome when lateral medulla involved Vertigo, nystagmus, ataxia, dysphagia, dysarthria, gaze paresis, lethargy, and coma

Cardiac/arterial emboli Vertebral artery dissection

Anterior and inferior surfaces of cerebellum (flocculus, superior cerebellar lobule), middle cerebellar peduncle, lower lateral pontine tegmentum (trigeminal nuclei and spinothalamic tract)

Vertigo, vomiting, nystagmus Ipsilateral facial anesthesia and weakness Ipsilateral Horner’s syndrome Ipsilateral deafness Contralateral decrease in temperature and pain sensation in limbs Ipsilateral ataxia Lacunar syndromes such as pure motor hemiparesis, ataxia-hemiparesis, dysarthria–clumsy hand syndrome Variable syndrome depending on level involved and cranial nerve affected Vertigo, nystagmus, ipsilateral Horner’s syndrome, contralateral cranial nerve IV palsy, ipsilateral ataxia, ipsilateral tremor/dyskinesia, contralateral decreased sensation to pain/temperature in the trunk

Atherosclerosis Arterial emboli Cardiac emboli

Paramedian and circumferential basilar penetrators

Paramedian/lateral pons and midbrain, including the nuclei of cranial nerves III to VIII

Superior cerebellar artery

Vermis, superior half of cerebellar hemisphere, dentate nucleus, superior cerebellar peduncle, upper pontine tegmentum (descending sympathetic tract and spinothalamic tract)

Lipohyalinosis/ microatheroma

Cardiac emboli Artery-to-artery emboli Atherosclerosis

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T A B L E 42–2. Clinical Stroke Syndromes with Corresponding CNS Structures and Arterial Territory Affected—cont’d Artery Involved

CNS Structures Involved

Clinical Syndromes

Etiologies

Posterior Cerebral Artery

Mediobasal temporal lobes, occipital lobes Midbrain, thalamus, medial and lateral geniculate bodies (through deep perforating branches)

Contralateral homonymous hemianopsia (macular sparing if purely cortical stroke) If bilateral, Balint’s or cortical blindness with/without Anton’s syndrome (denial of blindness) Dysnomic aphasia with alexia without agraphia (when dominant side involved) Memory disturbance, color dysnomia Agitated delirium Hemisensory deficits with thalamic stroke

Cardiac emboli Artery-to-artery emboli Intracranial atherosclerosis Vasospasm (SAH, drugs) Transtentorial herniation CNS angiitis

CNS, central nervous system; ICA, internal carotid artery; SAH, subarachnoid hemorrhage.

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Figure 42–4. Diffusion-weighted MR image showing a large right hemispherical infarction from a right middle cerebral artery stem occlusion.

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Figure 42–5. Angiogram after left internal carotid artery injection. Left middle cerebral artery shows a blockage distal to the origin of the lenticulostriate vessels, predominantly affecting the middle cerebral artery superior division.

and lateral lenticulostriate branches that arise from the dorsal surface of the MCA stem, as well as large areas of cortical infarction in the territories of the superior and inferior divisions of the MCA (Fig. 42–4). The typical patient presents with contralateral hemiplegia with equal involvement of the arm and leg, variable degrees of primary sensory abnormality, dysphagia, and hemianopia. There is forced eye deviation toward the side of the affected hemisphere, sometimes with accompanying ipsilateral head deviation. With dominant hemispherical involvement, there is usually global aphasia, buccofacial apraxia, and ideomotor apraxia. In the first few days there may be frank mutism. With nondominant hemispherical involvement, there is usually contralateral hemineglect, contralateral anosognosia, and delirium. Less frequently, syndromes more often associated with bilateral hemispherical damage, such as prosopagnosia and the reduplicative paramnesias, can be present with unilateral nondominant hemisphere damage.

Individuals with an MCA stem occlusion are the most likely to develop massive hemispherical swelling with midline shift, and subfalcine and transtentorial herniation. The prognosis for these patients is guarded, and in complete MCA-distribution strokes, the mortality rate can be as high as 80% despite neurointensive care efforts.

Middle Cerebral Artery Upper Division Occlusion Isolated involvement is uncommon because the superior trunk is short, but when it occurs, it is usually caused by ICA or MCA atherosclerosis (Fig. 42–5). This division supplies most of the frontal convexity and anterior parietal lobe, and the syndrome resembles stem occlusion with a contralateral hemiparesis, forced eye and head deviation toward the side of the lesion, and

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variable degrees of aphasia and hemineglect. In contrast to stem occlusion, motor deficits are characterized by a gradient of weakness with the contralateral side of the face and arm (brachiofacial pattern) more severely affected than the leg, reflecting the involvement of the corresponding cortical structures rather than the internal capsule. A visual field defect is usually absent. With dominant hemispherical involvement, there is language disturbance characterized in the acute phase by global aphasia, which tends to reduce to predominantly Broca’s aphasia and speech apraxia. This highlights the fact that in the acute stroke setting, vascular aphasias are often global and nonclassic in their presentation.35 With nondominant involvement, there may be some degree of visuospatial neglect but usually not as pronounced as with a larger territorial infarct. Acute agitated delirium is usually not present, because this requires infarction of the right middle temporal gyrus and inferior parietal lobule, supplied by the inferior division of the MCA (see later discussion). Because of the smaller volume of tissue infarction, upper-division MCA-distribution strokes do not cause the same high rate of mortality observed with holo-MCA strokes but carry a significant degree of long-term disability that necessitates intensive rehabilitation.

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Figure 42–6. Diffusion-weighted MR image showing a right parasagittal infarction in the distribution of the right anterior cerebral artery.

Middle Cerebral Artery Lower Division Occlusion This condition is usually caused by cardiac embolism. In this syndrome, hemiparesis and forced eye-head deviation are usually absent, because there is sparing of perirolandic structures. Hemianopia can be present from involvement of the optic radiations, but the most obvious abnormalities are in the domains of language and behavior. With involvement of the dominant hemisphere, a predominantly fluent (sensory or Wernicke’s) or a conduction-type aphasia (inability to repeat spoken language) can be present in isolation, although an initial global aphasia can also be present. When the nondominant hemisphere is affected, behavioral abnormalities predominate with confusion/delirium and mild degrees of visuospatial inattention. Sensory aprosody may also occur in the acute state. The prognosis after such a stroke is relatively good, and the potential for rehabilitation can be greater than for other types of MCA-distribution strokes, because of the smaller territory involved and the absence of significant motor or sensory deficits. There are syndromes associated with occlusion of each of the 12 vessels that branch off the two main MCA trunks. Space precludes description of MCA branch syndromes, but suffice to say that subcomponents of the trunk syndromes are observed and more subtle behavioral abnormalities may be apparent, because they are not obscured by more global abnormalities present with stem and trunk occlusions.

Anterior Cerebral Arteries In comparison with strokes in the MCA distribution, ACAdistribution strokes are uncommon and are most often secondary to embolism from a proximal source such as the carotid artery or the heart. Less frequent causes of an ACA-distribution stroke include vasospasm from a ruptured saccular aneurysm (anterior communicating artery), in which case the strokes may be bilateral, and inflammatory vasculopathy involving the intracranial vessels. The most common manifestations of an

infarct in the distal territory of the ACA are a function of the territories supplied: anterior and medial frontal lobes, including the motor-sensory cortex for the contralateral foot and leg; the supplementary motor area; and the central bladder representation, and also of lesion side36 (Fig. 42–6). Left-sided infarction causes transient akinetic mutism (abulia), transcortical motor aphasia, contralateral leg and shoulder weakness with sparing of the distal upper extremity and face, and contralateral deficits in higher order sensory functions such as stereognosis (ability to discriminate two simultaneous stimuli) and joint-position sense discrimination. Right-sided infarction causes acute confusional state, motor hemineglect, transient akinetic mutism, contralateral hemiparesis, and sensory deficits in the pattern described for leftsided infarction. Predominant leg weakness is not unique to ACA infarction; it is also present with MCA-territory cortical infarction. It can also be present with capsular and pontine infarcts. In general, lesions that affect the medial premotor cortex, the supplementary motor area, and the rear portion of the medial part of the precentral gyrus, or their projections, can cause leg-predominant hemiparesis.37 Bilateral ACA infarction causes persistent akinetic mutism, sphincter dysfunction (urinary more than defecatory incontinence) and paraplegia or tetraplegia. Bilateral ACA strokes can occur when both ACAs originate from the same carotid system, when only one ACA supplies both medial hemispheres (azygous ACA), in vasospasm from subarachnoid hemorrhage, or in the setting of an extrinsic lesion compressing both the ACAs (intraparenchymal hemorrhage, head trauma, subfalcine herniation). In addition to abulia and predominant leg weakness, callosal disconnection syndromes can help distinguish ACA from MCA infarcts. The three main syndromes are left unilateral ideomotor apraxia, agraphia, and tactile anomia. All three syndromes affect the left hand in right-handed patients. Left unilateral

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment ideomotor apraxia, also called the anterior disconnection syndrome, is the inability to perform overlearned skilled movements in response to verbal command. Patients with left-hand agraphia have severely impaired handwriting with their left hands but not their right. Patients with unilateral tactile anomia are unable to name objects placed in their left hands. All three syndromes are probably caused by interruption of transcallosal information to or from the language areas in the left hemisphere. They usually result from infarcts in different regions of the corpus callosum caused by interruption of pericallosal branches of the ACA. However, these syndromes, although of phenomenological interest, are overemphasized, in view of their low frequency of occurrence. They are relatively rare probably because the anterior corpus callosum is supplied by both ACAs. The two to four recurrent arteries of Heubner arise near the junction of the anterior communicating artery and the ACA and supply the inferior part of the head of the caudate nucleus, the adjacent anterior limb of the internal capsule, and the subfrontal white matter. Caudate infarcts cause prominent behavioral abnormalities, including abulia, agitation, aphasia, and hemineglect. Extension of the infarct into the anterior limb of the internal capsule and anterior putamen can lead to dysarthria, movement disorders, and mild hemiparesis. However, the only study to associate symptomatic caudate infarcts with their culprit vascular territory showed that only one infarct was in the territory of Heubner’s arteries; the rest were in the territory of lenticulostriate vessels off the MCA.

Anterior Choroidal Artery The anterior choroidal artery (AChA) is the most distal branch of the ICA, originates just after the origin of the posterior communicating artery, and courses posterolaterally to supply the anterior medial temporal lobe, the optic tract, the geniculate body, the medial globus pallidus, the medial third of the cerebral peduncle, portions of the ventral and pulvinar thalamus, and the posterior limb of the internal capsule. There is controversy over whether the AChA or the lateral lenticulostriate vessels supply the posterior paraventricular region of the corona radiata. The regions most often infarcted are the posterior limb of the internal capsule, the medial globus pallidus, and the lateral geniculate body. As a result, the most common clinical syndrome includes a contralateral hemiparesis and contralateral visual field defect. The visual field defect can consist of a complete homonymous hemianopsia or may manifest with a distinctive feature—sparing of the meridian, called sectoranopsia—a fact explained by the arrangement of the afferent visual fibers as they course through the geniculate ganglia. There can also be variable degrees of hemisensory loss (proprioception is usually spared) from capsular and ventrolateral thalamic involvement. Traditionally, the absence of a higher cognitive deficit in a patient with a hemiparesis and homolateral visual field deficit has been considered suggestive of involvement of the AChA, as opposed to the MCA. However, apraxia, hemineglect, and aphasia have been described with AChA territory infarction. The likely cause of AChA infarction is small-artery focal atherosclerosis secondary to long-standing hypertension and diabetes when the infarct is restricted to the posterior limb of the internal capsule and medial globus pallidus, but

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more extensive infarcts are probably caused by cardiac or ICA disease.

Internal Carotid Artery When a stroke involves a combination of the syndromes described previously, it can be devastating and probably represents the involvement of the ICA before it branches off into the above divisions. The occlusive process can be extracranial or intracranial and has varied causes. The most common process leading to focal occlusive disease of the ICA is advanced atherosclerosis with progressive narrowing and significant reduction in distal blood flow. As described earlier in this chapter, a focus of atherosclerosis also represents a source of thrombus with potential for distal embolization. Less common processes include extracranial spontaneous or traumatic ICA dissection and postirradiation ICA stenosis. An acute cardiac embolism that lodges at the top of the ICA intracranially, blocking the origins of the ipsilateral MCA and ACA, can also be present and is usually associated with a more sudden dramatic manifestation. The clinical syndrome observed with an acute ICA-distribution stroke is usually a combination of the syndromes described previously with involvement of both MCA and ACA territories. Sometimes, however, the ACA territory is spared in patients with adequate collateral circulation through an intact circle of Willis, where blood is diverted from the other hemisphere through a functional anterior communicating artery. The manifestation is often stepwise, reflecting slow failure of distal collateral vessels as the ICA occlusive process progresses. When the occlusion is total and hemodynamic reserve is no longer sufficient, the patient has a sudden decline and is prone to rapid deterioration from extensive ongoing ischemia and hemispherical swelling. Many times, it is difficult to differentiate an ICA-territory infarction, especially when the onset is abrupt, from embolic MCA strokes. The hallmark of a proximal ICA disease is a history of a preceding TIA, either retinal (transient monocular blindness or amaurosis fugax) or hemispherical. Its presence is strongly suggestive of ICA disease proximal to the origin of the ophthalmic artery and should prompt rapid investigation of the extracranial carotid system. ICA dissection is another possible cause (see Table 42–2).

Posterior Circulation Twenty percent of ischemic events involve areas supplied by the posterior circulation, but they are often incorrectly diagnosed. For example, isolated lightheadedness, syncope, and vertigo are frequently blamed on a posterior circulation process even though it is almost never the cause of these symptoms. Conversely, a patient with multiple stroke risk factors may present with vertigo and gait ataxia resulting from brainstem ischemia, but vestibular neuronitis may be diagnosed. The term vertebrobasilar insufficiency, although popular, is vague with regard to mechanism and should be avoided. Overall, in patients with posterior circulation TIA and minor stroke, the risk of subsequent stroke or death is similar to that in patients presenting with carotid disease, although their risk is probably slightly higher than that of carotid patients in the acute phase. Posterior circulation TIAs carry a higher risk of recurrence than do anterior circulation TIAs.

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Vertebrobasilar Territory Strokes Extracranial Vertebral Arteries The extracranial vertebral arteries (ECVAs) are frequently affected by atherosclerosis and this condition is a relatively common cause of posterior circulation strokes. The most common sites for atherosclerosis are at or near their origin from the subclavian arteries, analogous to atherosclerosis at the ICA origin, and at their entry point into the skull. The ECVAs are also susceptible to traumatic or spontaneous dissection (see “Stroke of Other Determined Causes” section). Progressive narrowing at the vertebral artery origin can eventually lead to total occlusion or serve as a nidus for thrombosis and distal embolization. Occlusion of one vertebral artery is usually well tolerated when the contralateral artery is patent and of sufficient caliber. In addition, the ECVA, unlike the ICA, gives off muscular branches and therefore can be reconstituted distally in the setting of origin stenosis. Thus, TIAs and strokes caused by ECVA stenosis result from embolism rather than from flow failure. The most common recipient sites for emboli from the ECVAs are the ipsilateral intracranial vertebral artery (ICVAs) and the top of the basilar artery.

Intracranial Vertebral Arteries The most common site for ICVA atherosclerosis is the distal segment of the artery near the vertebrobasilar junction, after takeoff of the PICA and lateral medullary penetrators. The most common stroke syndrome associated with focal ICVA disease is the lateral medullary syndrome (Wallenberg’s syndrome), and it usually represents involvement of vertebral artery branches directly supplying the lateral medulla. In contrast, involvement of PICA itself usually causes cerebellar rather than medullary infarction and results from cardiac or ECVA embolism. Lateral medullary syndrome manifests with a subset of the following symptoms and signs: vertigo, dysphagia, hoarseness, ipsilateral facial and contralateral trunk and limb thermoanalgesia, ipsilateral oculosympathetic dysfunction, ipsilateral limb ataxia, gait ataxia, nausea, and vomiting. The specific constellation of symptoms depends on the rostrocaudal and horizontal extent of the medullary lesion. Occlusion of the medial PICA branch causes infarction of the dorsal medulla and the inferior cerebellar vermis. Involvement of the lateral PICA branch causes infarction of the posteroinferior cerebellar hemisphere, with truncal ataxia and ipsilateral limb ataxia. Brainstem signs such as vertigo and dysarthria are usually not present. Full PICA territory infarction causes vomiting, gait and ipsilateral limb ataxia, and truncal lateral pulsion. Multidirectional nystagmus may also be present. A full PICA infarction can lead to considerable edema, usually within 24 to 48 hours, with “pseudotumoral” mass effect. This can be rapidly fatal as a result of progressive pontine and medullary compression. Surgical decompression is necessary. Clues to brainstem compression include headache, vomiting, drowsiness, ipsilateral gaze preference, and ipsilateral hemiparesis.

Basilar Artery Branches The basilar artery originates from the confluence of the two vertebral arteries at the pontomedullary junction and represents the main vascular supply to the brainstem and rostral cerebellum. Atherosclerosis is by far the most important pathology of the basilar artery, strokes are usually preceded by TIAs, and

the paramedian pontine base is the most common site of infarction. The main branches off the basilar artery arise in pairs: the anterior inferior cerebellar artery, the superior cerebellar artery, and the PCA. Throughout its course, the basilar artery gives rise to multiple penetrating and circumferential branches that supply the brainstem; it is responsible for the whole blood supply of the pons and much of the distal brainstem. Anterior Inferior Cerebellar Arteries. Infarction in this territory, usually resulting from in situ atherosclerosis unless there is bilateral involvement, is dominated by brainstem (the caudolateral pontine syndrome) rather than cerebellar symptoms. The mid-pons and middle cerebellar peduncle are the areas most often involved. The typical manifestation is ipsilateral peripheral facial weakness, Horner’s syndrome, deafness, limb ataxia, and contralateral hemiparesis with limb and trunk hypesthesia. In very rare cases, and only in patients with diabetes, isolated involvement of the internal auditory artery can manifest with isolated vertigo and/or hearing loss. This is mentioned to emphasize the fact that, apart from this exception, isolated vertigo is almost never caused by ischemic vertebrobasilar disease. Superior Cerebellar Arteries. Traditionally, it was thought that isolated superior cerebellar artery territory infarcts were rare but instead occurred in combination with midbrain, thalamic, and PCA territory infarcts, as a result of embolism to the top of the basilar artery. However, modern MRI suggests that the occurrence of isolated superior cerebellar artery infarcts has been underestimated.38 These infarcts can be small or territorial, both most commonly caused by embolism. The superior cerebellar artery supplies most of the cerebellar cortex, the cerebellar nuclei, and the superior cerebellar peduncle. Superior cerebellar artery infarcts result in a combination of the following signs and symptoms: vertigo and dizziness, nystagmus, limb ataxia, gait ataxia, and mild hemiparesis. Clinical brainstem signs are usually absent. Basilar Artery and Its Penetrators. The posterior wall of the basilar artery gives rise to small paramedian and short circumferential arteries that supply the paramedian and lateral pontine regions. These arteries can be affected by either microatheroma at their origins or lipohyalinosis along their length. These are believed to be distinct pathological processes. Stroke from basilar artery disease is very variable and can range from a mild lacunar stroke, resulting from a small penetrator disease, to a large, devastating syndrome with extensive destruction of the brainstem from complete or almost complete basilar occlusion (Fig. 42–7). Pontine syndromes reflect the particular structures affected, with a basic division between strokes that predominantly affect the anterior pons and those that affect predominantly the pontine tegmentum. Anterior pontine infarctions can manifest as classic lacunar syndromes with pure motor hemiparesis or ataxic hemiparesis/dysarthria– clumsy hand syndrome, as a result of damage to the corticospinal tract and crossing corticopontocerebellar fibers. Strokes that predominantly affect the pontine tegmentum manifest with a constellation of brainstem signs as a result of involvement of the medial lemniscus, the medial longitudinal fasciculus, the cerebellar peduncles, the abducens nucleus, and the vestibular nuclei.

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Locked-in Syndrome. One of the most devastating conditions in clinical neurology is observed after basilar artery occlusion with extensive infarction of the ventral pons (basis pontis) and is commonly referred to as locked-in syndrome. Because of infarction of key motor structures in the basis pontis (pontine nuclei, corticospinal tract, and corticobulbar tract), the patients present with tetraparesis evolving to tetraplegia, pronounced dysphagia, and anarthria. Extraocular movements are affected, most notably with bilateral gaze paresis, often with preserved vertical gaze. Vertical gaze, as well as normal alert-

Figure 42–7 A, Extensive infarction of brainstem, occipital lobes, temporal lobes, and bilateral thalamus, resulting from acute basilar occlusion. B, Angiographic lateral view in the same patient, demonstrating midbasilar and distal basilar occlusion with distal reconstitution through superficial cerebellar collateral vessels.

ness, is intact because of preservation of the rostral structures in the midbrain and pontine tegmentum, respectively. Blinking may be spared, and in these cases patients can communicate only with vertical eye movements or blinking of the eyes. With a more extensive damage and rostral midbrain involvement, blinking can also be affected, and patients may have bilateral ptosis, a situation difficult to differentiate from a comatose state. The locked-in syndrome usually results from extensive in situ thrombosis of the basilar artery and carries a poor prognosis.

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Top-of-the-Basilar Syndrome. When an embolic particle arises either from the heart or from the proximal vertebral arteries, it travels all the way downstream until it lodges in a vessel with a diameter equal to or less than that of the particle size. Because of the relatively large diameter of the basilar artery, this usually occurs at the distal segment, where it gives rise to both superior cerebellar arteries and PCAs and leads to a constellation of signs and symptoms commonly referred to as the “top-of-thebasilar” syndrome. Infarction of the rostral midbrain (tectum, posterior commissure, red nucleus) leads to oculomotor abnormalities such as vertical gaze palsies, convergence retractive nystagmus, bilateral hyperconvergence (“pseudo-sixth” nerve palsy), and eyelid retraction. The involvement of the more caudal midbrain results in damage to the cranial nerve III nucleus and fascicle and is responsible for cranial nerve III palsy with bilateral ptosis, midposition and poorly reactive pupils, and internuclear ophthalmoparesis. Midbrain involvement also includes damage to the ascending reticular activating system with consequent somnolence or stupor. In rare cases, patients may present with vivid, well-formed visual hallucinations after strokes in the distal basilar territory, a phenomenon called peduncular hallucinosis. There exist few pathological studies of the usual location and nature of the lesions causing such a syndrome, but it is thought to occur from rostral midbrain or thalamic involvement. Other structures that can be affected by an embolus to the distal basilar artery include the occipital lobes, medial temporal lobes, and thalami (Fig. 42–8). Their involvement can be either unilateral or bilateral and gives rise to multiple signs or symptoms referable to the involvement of the PCA territory (see next section).39 Posterior Cerebral Arteries. The PCAs are the terminal branches arising from the basilar artery. In about 30% of patients, one PCA arises from the ipsilateral ICA; this is a socalled fetal PCA. Infarcts in the PCA territory are mainly caused by emboli, which is perhaps not surprising because the PCAs are the end territory of the posterior circulation. The first, P1, segment of the PCA courses posteriorly around the midbrain and gives off small branches to the midbrain and medial thalamus before it becomes the P2 segment, which supplies the ventral and lateral thalamus, the occipital lobe, and the medial temporal lobe. The three most prominent symptoms and signs after PCA territory infarction are headache, positive and negative visual field defects, and hemisensory disturbances. The most common visual field abnormality is a hemianopia from infarction of the optic radiations or calcarine cortex. If the field cut is transient, release hallucinations can occur at its edges as it clears. Involvement of the lateral thalamus and surrounding afferent white matter tracts is responsible for hemisensory disturbances, which can range from hemibody tingling to frank hemianesthesia in all sensory modalities. Sometimes the sensory complaints are accompanied by clumsiness and ataxia, also probably attributable to thalamic involvement, whereas dense hemiparesis results from infarction of the cerebral peduncle. In addition to the common symptoms and signs described previously, there are unique neuropsychological deficits in up to 60% of patients with visual field defects. These neuropsychological deficits are hemisphere specific or hemisphere predominant. Some of the neuropsychological deficits are more florid when there is bilateral PCA infarction. Infarction in the

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Figure 42–8. Computed tomographic scan demonstrating bilateral thalamic strokes secondary to embolization to the top of the basilar artery (“top-of-basilar” syndrome) from a cardiac source.

territory of the left PCA that extends to the splenium of the corpus callosum or to its neighboring parieto-occipital white matter leads to alexia without agraphia. Visual perception is normal in the preserved left hemifield, but the information cannot reach language areas of the left hemisphere. In addition, there is color anomia because color percepts are purely visual and therefore no other sensory modality can be evoked to provide a clue to the left language region. In addition to alexia without agraphia and color anomia, some patients have visual object agnosia. Alexia with agraphia, along with some anomia, occurs with infarcts in the left temporo-occipital junction. Infarction of the left medial temporal lobe can lead to anterograde and retrograde amnesia, which can last months. Presumably, the contralateral hippocampus can take over with time. It follows that permanent anterograde amnesia can result from bilateral PCA infarcts. Prosopagnosia can occur with right inferior occipitotemporal lesions. Other behavioral syndromes associated with right PCA infarction are less specific and probably reflect right parietal syndromes, inasmuch as the PCA sometimes supplies parts of the right posterior parietal lobe. Balint’s syndrome can arise after unilateral or bilateral infarction of the superior parietal lobule at the parietooccipital junction, supplied by the MCA-PCA watershed. The syndrome, also known as optic ataxia, is characterized by defective directional control of visually guided reaching movements, but motor execution is normal when other sensory modalities are used. On-line control is more impaired than feedforward planning, and errors in reaching are variable with no appreciable constant errors. Anton’s syndrome is denial of blindness

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment despite clear physiological evidence for it after bilateral occipital infarction. This syndrome can be accompanied by agitation/delirium, possibly from the decreased visual input or concomitant involvement of the temporal lobes.

STROKE EVALUATION Parenchymal Imaging Critical in the evaluation of a presumed ischemic stroke, especially in the hyperacute period, is assessment of the extent and location of affected brain parenchyma, as well as ruling out stroke mimics such as ICH, subdural hematoma, subarachnoid hemorrhage, and brain tumor. CT scanning of the head should be the first step in such an evaluation, because of its widespread availability and short scanning time. CT scan is still considered the “gold standard” for detecting hyperacute hemorrhage, although one prospective study showed 100% sensitivity for hyperacute ICH with T2* MRI. Besides obvious intraparenchymal hemorrhage, abnormalities on CT scan related to hyperacute stroke, include blurring of the gray-white matter interface, effacement of the sulcal margins, loss of the normal sharp definition between the basal ganglia and surrounding white matter, and effacement of the insular cortex. These abnormalities confirm ischemia as the most likely cause of the acute syndrome and help predict not only the area at risk and ultimate infarct size but also which patients are likely to develop significant brain edema and require more aggressive monitoring in the intensive care unit. The extent of these early changes also has a direct relationship with the risk of symptomatic intracranial hemorrhage from systemic thrombolysis and is predictive of a poor outcome.40,41 In the subacute period, infarcted tissue becomes more evident as one or more clear-cut areas of hypodensity. In the early subacute period, the focus of the evaluation of the CT scan then shifts from the initial diagnostic purpose to the prediction and monitoring of changes compatible with hemorrhagic conversion and cerebral edema with consequent brain herniation. In the late subacute to chronic periods, the CT scan demonstrates progressive gliosis with loss of tissue volume (i.e., encephalomalacia). MRI, increasingly available for the evaluation of ischemic stroke in the acute setting, is more sensitive than CT scanning for detecting acute ischemia and is the only reliable method for detecting ultra-early ischemic changes (<1 hour after stroke onset). Different magnetic resonance sequences are available, each emphasizing different tissue components and different degrees of tissue definition and contrast. The sequences of most utility in the evaluation of patients with stroke are T1-weighted imaging, T2-weighted imaging, fluid-attenuated inversion recovery, DWI, proton density imaging, and gradient-echo imaging, the last being the most sensitive for detection of hemorrhage in all stages of evolution. In the hyperacute evaluation, DWI identifies early ischemic lesions and distinguishes them from old infarcts. Ischemia is characterized by a hyperintense signal, which represents the restricted intracellular diffusion of hydrogen ions, which normally diffuse freely in interstitial fluid but are shifted intracellularly because of cytotoxic edema in the affected area. In humans, DWI is able to detect ischemia as early as 40 minutes after stroke onset and in one study, based on con-

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firmation at autopsy, had a sensitivity of 88% and a specificity of 96.6%. Abnormalities observed on DWI can be short lived, resolving within 2 weeks of the ischemic insult; this feature is not seen with the other magnetic resonance sequences.42,43 However, hyperintense lesions on DWI do not distinguish reversible from irreversible ischemia, can be observed with other conditions (brain abscess, seizure, acute multiple sclerosis plaque, hypoglycemia, and brain tumors), and may result from T2 decay (T2 shine-through) rather than a diffusion abnormality. T2 shine-through can be ruled out with computation of a directionally averaged diffusion coefficient (ADC). On an ADC map, only ischemia appears dark, indicative of a low ADC. The utility of ADC values to reliably distinguish differing degrees of ischemia—a critical issue, inasmuch as the entire rationale for acute treatment of stroke is to rescue areas of reversible ischemia—is under active investigation but seems questionable. Currently, rather than reliance on differential ADC values, the favored approach with MRI is to identify areas of reduced perfusion beyond the boundaries of the DWI abnormality (see next section).

Vascular Imaging In addition to identification of areas of reversible and irreversible parenchymal injury, it is also necessary to establish whether there is a persistent stenosis or occlusion in an intracranial or extracranial artery that continues to put viable brain tissue at risk and to ascertain the extent of compensation by collateral arteries. Noninvasive tests should be performed first and include duplex Doppler imaging of the extracranial and intracranial circulation, magnetic resonance angiography (MRA), and computed tomographic angiography (CTA). These tests have been extensively studied and have proved valuable and reliable when used by experienced operators. However, these noninvasive methods do not have perfect sensitivity and specificity, and often a combination of two or more of them is necessary to obtain optimal anatomical information.

Duplex Doppler and Transcranial Doppler Imaging The Doppler effect is noted through detection of flow velocity of a moving object, determined by the time between insonation and reflection of ultrasound waves through a given medium. In the case of duplex Doppler study, anatomical imaging is determined through the B-mode gray scale whereas Doppler shift values are determined through the reflection of the ultrasound waves by the moving red blood cells in the extracranial and intracranial vessels. When the intracranial vasculature is studied, both technologies can be used, but the use of Doppler studies, without the anatomical definition provided by the Bmode gray scale, is the most widely available. Duplex study of the extracranial circulation is most useful in the determination of the degree of stenosis of the ICA (Fig. 42–9). This determination is crucial because of the difference in the approach to patients with a recent ischemic stroke related to an ipsilateral ICA stenosis (see later discussion). Analysis of the ECVAs also provides valuable information in patients with posterior circulation strokes. When duplex Doppler imaging is compared with the “gold standard” for anatomical definition (digital subtraction angiog-

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raphy), the sensitivity and specificity for hemodynamically significant (>70% diameter narrowing) extracranial ICA stenosis varies between 85% to 90% and 75% to 80%, respectively.44 On the basis of these numbers, the best approach is to combine duplex Doppler study with another noninvasive imaging modality, such as MRA, because both tests, when concordant, have been shown to accurately predict significant extracranial ICA stenosis in more than 90% of the cases.45,46 Nonconcordance most often occurs because ultrasonography and MRA can differ in the degree of stenosis they reveal, with a tendency for MRA to overcall degree of stenosis. Another concern is whether noninvasive techniques can reliably differentiate high-grade stenosis from occlusion, a critical factor in surgical decision making. For example, Doppler imaging might demonstrate total ICA occlusion, whereas, in fact, a string sign is present; conversely, an ascending pharyngeal artery or muscular branch may be mistaken for residual flow through an occluded ICA. In such a situation, conventional angiography, CTA, or gadoliniumenhanced MRA should be considered. Transcranial Doppler (TCD) imaging is used to determine the blood flow velocities of the large and medium-sized intracranial arteries, and indirectly, estimate flow. The approaches used when TCD imaging is performed can be the

transtemporal approach (ACA, MCA, and PCA), the transforaminal approach (vertebrobasilar system), and the transorbital approach (ophthalmic vessels and carotid siphons). Flow velocities can help identify a focal stenosis, proximal occlusion with decreased distal flow, or complete occlusion of one of the three cerebral arteries. TCD imaging is particularly helpful in cases of stenosis of the intracranial arteries, such as those in atherosclerotic or inflammatory vasculopathies, and is a test of proven utility in helping determine the need for exchange transfusion in patients with sickle cell disease. TCD imaging is a valuable tool in the assessment of the intracranial consequences of cervical carotid or vertebral stenosis. Specifically, TCD imaging can detect blunted waveforms and recruitment of collateral pathways (e.g., cross-filling from the anterior communicating artery) (Fig. 42–10). TCD imaging can also provide information on adequacy of collateral flow through the use of vasodilatory challenges such as carbon dioxide inhalation (see later discussion). Also, TCD imaging can be used to monitor the MCAs for evidence of intermittent embolization from a proximal arterial or cardiac (PFO, atrial fibrillation) source (Fig. 42–11).

Computed Tomographic Angiography This technique combines injection of intravenous contrast as a bolus, with high-speed continuous CT scanning of a volume of interest, followed by three-dimensional reconstruction of the extracranial and intracranial vasculature from the original cross-sectional images. CTA is of great potential benefit for evaluation of patients for acute thrombolytic treatment, because these patients must obtain a CT scan anyway to rule out hemorrhage, and CT scanning is still much more available than MRI in the emergency setting. If occlusion and high-grade stenosis of intracranial vessels off the circle of Willis are not identified, perhaps because of spontaneous recanalization, then mobilization of an interventional radiology team may not be justified. CTA has some important limitations, however. First, CTA cannot always reliably distinguish between moderate and highgrade stenosis. This is especially true when mural calcification is present. Second, patients undergoing CTA must ingest an intravenous contrast agent, which can be toxic to the kidneys in patients with preexisting renal insufficiency, dehydration, and poorly controlled diabetes.

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Figure 42–9. Duplex Doppler image of the extracranial carotid system, demonstrating high-degree stenosis at the origin of the internal carotid artery (ICA). CCA, common carotid artery.

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Figure 42–10. Transcranial Doppler image after bilateral middle cerebral artery insonation, demonstrating blunted waveform on the right in comparison with the left. This appearance is compatible with a proximal internal carotid artery high-grade stenosis.

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment cm/s 120

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Figure 42–11. Transcranial Doppler image after agitated saline injection, demonstrating multiple microembolic signals (MES) compatible with a right-toleft cardiac shunting from a patent foramen ovale (PFO). PI, pulsatility index.

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technique is to maximize signal coming from the vessel while minimizing background signal. The most popular sequences are two- and three-dimensional time-of-flight (TOF) MRA. TOF MRA is based on flow-related enhancement of blood signal, which allows blood to be differentiated from stationary tissues. The data may be acquired as single slices (two-dimensional) or as a thick slab that is subsequently reconstructed into thin sections (three-dimensional). In the case of three-dimensional imaging, blood flow must be more rapid in order to traverse the whole slab before saturation occurs with attendant loss of signal. Thus, three-dimensional TOF is usually better for vessels in which flow velocity is high (i.e., cervical arteries and the circle of Willis), whereas two-dimensional TOF is better for assessing cerebral veins and sinuses. Phase-contrast MRA is another technique that is time-consuming and has not had much application in the workup of ischemic stroke so far. One scenario in which phase-contrast MRA can be helpful is when an arterial lumen is stenosed by subacute thrombus, which is bright on T1 images. Thus, a TOF MRA might misread a bright vessel as patent when it is in fact occupied by subacute thrombus. This high signal is subtracted out in phase-contrast imaging. TOF MRA is helpful as a screening test for significant (>70% diameter reduction) ICA stenosis because it has comparable sensitivity to digital subtraction angiography. However, TOF images can be contaminated by artifacts in the presence of slow flow or turbulence. This is a problem mainly when slow flow caused by ICA stenosis leads to signal dropout, which is mistaken for very high-grade stenosis or complete ICA occlusion. Therefore, when no ICA stenosis is identified on MRA, no further testing is necessary, but when significant stenosis is detected, imaging with another noninvasive modality should be obtained (duplex Doppler imaging or CTA).46 In the case when MRA suggests complete occlusion, CTA, gadolinium-enhanced three-dimensional MRA, or conventional angiography should be used as confirmatory tests, despite the high sensitivity and specificity of MRA in complete ICA occlusion reported in some studies.47 MRA also has utility in detecting intracranial athero-

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stenotic disease but, again, tends to overestimate the degree of stenosis and should be followed by digital subtraction angiography for better spatial definition and determination of whether the lesion is amenable to interventional radiological approaches. Other pathologies detectable by MRA are extracranial dissection, Takayasu’s arteritis, and moyamoya syndrome. MRA is usually followed by digital subtraction angiography when intervention is planned.

Assessing Cerebral Tissue Perfusion As outlined in “Ischemic Stroke”, stroke ultimately results when the metabolic demands of brain tissue outstrip perfusion. Both chronic and acute arterial occlusive disease can lead to a state of reduced tissue perfusion, which can lie along a spectrum from autoregulated to oligemia to ischemic penumbra (misery perfusion). There are a number of scenarios in which determination of a patient’s condition along the perfusion spectrum guides clinical management. Two examples are as follows: (1) A patient with an acute stroke is found to have an M1 occlusion. Identification of penumbral areas beyond the infarct core can help make the decision whether to instigate intra-arterial thrombolytic therapy or mechanical extraction to open the occlusion. (2) A patient is discovered to have a chronic asymptomatic high-grade ICA stenosis or a symptomatic ICA occlusion. In either case, the decision to intervene surgically can be informed by identifying tissue in a state of misery perfusion. A variety of imaging methods are available to address questions about perfusion. PET scans can quantitate CBF, cerebral blood volume, cerebral metabolic rate of oxygen and OEF, but are expensive, not widely available, and require injection of a radioactive tracer. Single photon emission computed tomography (SPECT) can only estimate relative CBF and also requires injection of a radionuclide agent. Neither PET scanning nor SPECT is practical for making decisions in the acute stroke setting, but they nonetheless have a role in decisions about revascularization procedures in patients with chronic occlusive

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disease. For example, PET scanning is being used in an ongoing study of extracranial-intracranial bypass surgery in patients with stroke and carotid occlusion (Carotid Occlusion Surgery Study, described later). Xenon CT scanning is another reliable test for quantifying CBF and can be performed at the time of the initial head CT scanning, but the technique has lost ground despite its reliability because of the need for xenon, its intolerance to head motion, and the development of perfusion MRI and CT scanning. Magnetic resonance perfusion-weighted imaging (PWI) involves acquisition of sequential images during intravascular transit of an endogenous contrast agent (arterial spin-labeled protons) or an exogenous contrast agent (gadolinium) in order to analyze areas of hypoperfusion. At the current time, because of several technical considerations, only gadolinium PWI has application in the setting of acute stroke. The raw images obtained during intravascular transit of gadolinium are used to generate images that depict regional variation in several perfusion-related parameters; these include relative cerebral blood volume, relative CBF, and mean transit time. The utility of these measures for guiding therapeutic decisions in the management of acute stroke is under active investigation, but because the goal of acute stroke treatment is to identify viable tissue at risk of imminent infarction, the use of techniques that measure physiological variables rather than minutes and hours, can be expected only to grow (see “Intravenous Thrombolysis Beyond the 3-hour Period”). Identification of misery perfusion resulting from chronic arterial occlusive disease can be accomplished by vasodilatory challenge. The main concept behind these techniques is that the first autoregulatory response to occur in reaction to reduced CPP is arteriolar vasodilation. This means that any additional vasodilatory challenge will elicit a reduced response because the vessels are already partially or completely dilated. The most often used techniques are TCD imaging after CO2 inhalation and SPECT before and after acetazolamide injection. The first test relies on the potent vasodilatory capacity of CO2 and the changes in blood flow velocity observed in normal subjects after the inhalation of 5% CO2. Shortly after the inhalation of this gas, flow velocity increases in normal subjects (about 4% for every 1-mm Hg increase in arterial CO2 tension), defining the normal autoregulatory curve. In patients with an exhausted capacity for vasodilation (present with proximal stenosis or occlusion of the ICA or MCA), such response does not occur, and they are said to have an exhausted compensatory state. Similar information is obtained with SPECT after acetazolamide injection. Because of its potent vasodilatory effects (probably secondary to reduction of the pH in the cerebrospinal fluid), acetazolamide helps determine which areas have a limited ability to vasodilate because they are hypoperfused and already maximally dilated.

Other Laboratory Tests The initial laboratory evaluation of an ischemic stroke patient serves three main purposes: 1. Detection of antecedent pathology that might have directly contributed to the acute stroke: for example, diabetes, hyperlipidemia, hypercoagulability, and hemoglobinopathy. 2. Detection of antecedent pathology with a less well understood but possibly significant role in ischemic stroke, such

as anemia and elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, interleukins). 3. Determination of the minimal laboratory inclusion/ exclusion criteria for acute use of thrombolytics, if otherwise eligible. Tests that should be routinely obtained in patients with ischemic stroke include complete blood cell count; basic metabolic profile with evaluation of renal and hepatic function; and measurement of glucose levels, including glycosylated hemoglobin; lipid profile; coagulation profile (prothrombin time and partial thromboplastin time); and platelet count. In an individual with clear risk factors, it might not be necessary to obtain further studies, unless dictated by other medical conditions. In patients without a clear-cut risk factor profile, and especially in young patients with a cryptogenic stroke, a more comprehensive diagnostic workup should be obtained. This should include evaluation for prothrombotic states with determination of factor V Leiden, prothrombin gene mutation, anticardiolipin antibodies, lupus anticoagulant, hemoglobin electrophoresis (depending on the ethnic background), C-reactive protein as a marker of proinflammatory state, and autoimmune serological profiles, if immune-mediated diseases are a consideration. A search for genetic markers predisposing to early accelerated atherosclerosis such as lipoprotein (a) can also be considered, especially for patients with a positive family history. Other tests addressing hypercoagulable states, such as determinations of proteins C and S and antithrombin III levels produce results less likely to be associated with arterial thrombosis and have a low yield.

Workup for a Cardioembolic Source Ischemic stroke is a vascular disease and is frequently caused by cardiac embolism. Thus, investigation of the cardiovascular system is an integral part of the diagnostic workup. Electrocardiography is helpful in determining the baseline rhythm, as well as identifying markers of cardiovascular risk factors such as ventricular or atrial enlargement and evidence of a prior myocardial infarction. When the initial electrocardiogram yields little information, 24-hour Holter monitoring should be considered, especially when the presentation, neurological examination findings, and pattern of infarction are suggestive of embolus. TTE should also be performed in patients after stroke to rule out mechanical abnormalities of the cardiac chambers or valves predisposing to thrombus formation. TTE is especially important in patients with prior large myocardial infarction, to rule out ventricular aneurysm with superimposed thrombus. When TTE does not reveal a potential embolic source, TEE should be considered. With the exception of the patient with an otherwise obvious source of distal embolism such as tight ipsilateral ICA stenosis or known atrial fibrillation, all other patients should undergo evaluation with TEE to definitely rule out a cardiac embolic source. TEE has considerably higher sensitivity and specificity than TTE for valvular abnormalities, including vegetations; left atrial and atrial appendage thrombus; atrial myxoma and other cardiac tumors; presence of spontaneous echo contrast in the atrium; and PFO with associated ASA. TTE, because of the close proximity of the left ventricle to the thoracic wall, has a higher yield than does TEE for left ventricular thrombus.

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment ACUTE TREATMENT Pre–Emergency Room Management The earlier that therapeutic intervention is initiated after stroke onset, the better the outcome is likely to be (“time is brain”). Thus, initial recognition and prompt presentation to the hospital are crucial. Management of an acute stroke starts with recognition by the patient or by family members that certain signs and symptoms might represent a stroke and, more important, that help should be sought immediately. Multiple prospective and retrospective studies have demonstrated a consistent delay before patients seek medical attention after stroke onset; thus, they miss the optimal time for intravenous thrombolytic therapy. One reason for the delay, failure to recognize the signs and symptoms of a stroke, has been implicated in many studies.

Emergency Room Evaluation Although symptom recognition and stroke awareness are important limiting factors for timely stroke evaluation, studies have also shown that triage is often inadequate and have identified significant in-hospital delays for physician evaluation and for obtaining and interpreting initial CT scans.48,49 Dedicated acute stroke teams and an algorithm for emergency evaluation of acute stroke in the emergency department are necessary to overcome these obstacles. Evaluation by emergency room physicians has been validated by multiple studies and should improve as more community hospitals assume an active role in treating acute stroke.50,51 In many smaller hospitals, where a consulting neurologist might not be immediately available, the emergency room physician ultimately evaluates and treats those patients in the crucial first few hours after ictus. The initial management of a patient with acute stroke is no different from that in other medical emergencies, with assessment of the status of the airway, of ventilation/oxygenation, and of the circulation. Specific areas that require particular attention in the first few hours of stroke are addressed in the following sections.

Adequate Oxygenation Despite promising results with animal models52,53 and anecdotal reports of clinical efficacy, there is currently no definitive evidence to support the use of supplemental oxygen therapy, despite its widespread use in victims of acute stroke.54 When hypoxemia is present, it should be treated aggressively because it is extremely detrimental to penumbral brain tissue. All efforts in the emergency room should be geared toward avoiding further neuronal loss through transformation of the ischemic penumbra into infarct.

Blood Pressure Management Many patients with acute stroke have an elevated blood pressure in the first few hours to days after the ictus. The levels may be above 200 mm Hg for systolic blood pressure but usually normalize without treatment within a few days. In view of the current notion of a viable ischemic penumbra and loss of local vessel tone in the area surrounding an acute infarction (where

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cerebral vascular resistance is less responsive to changes in CPP), it is imperative that no attempt is made to reduce the blood pressure in the acute peristroke period. Moreover, in chronically hypertensive individuals, the upper and lower limits of the autoregulatory curve are shifted upward, and therefore blood pressure reduction to within the normal range may extend infarction into penumbral regions. Two important exceptions are made: (1) for patients eligible for intravenous tissue-type plasminogen (tPA), because current guidelines require that systolic blood pressure be less than 185 mm Hg and diastolic pressure less than 110 mm Hg, and (2) patients with evidence of ongoing or imminent end-organ damage, such as pulmonary edema, acute myocardial infarction, acute aortic dissection, or acute renal insufficiency.55 In such patients, careful gradual blood pressure lowering can be attempted with parenteral medications such as β blockers (labetalol) or calcium channel blockers (nicardipine). When possible, these agents are preferred over direct venodilators such as nitroprusside or nitroglycerin. Research has focused on the dependence of peri-infarct brain perfusion on systemic blood pressure and its relevance for short- and long-term recovery. Investigators using SPECT found a negative relationship between blood pressure reduction and improvement in CBF,56 but the sample size was too small to extrapolate the results to the general stroke population. In two prospective studies, investigators found deleterious effects of acute blood pressure lowering on outcomes at 21 days57 and at 3 months, respectively.58 In the debate on how to better manage blood pressure in the peristroke period, a new concept has arisen: pharmacologically induced hypertension in patients in whom acute, reversible flow failure is suspected on clinical grounds or from perfusion MRI/CT scan. The approach seems most plausible for patients with acute large-vessel stenosis or occlusion, in whom penumbral tissue would benefit from increased perfusion and further recruitment of collateral channels. However, except for small pilot studies,59 no universally accepted protocol is in place, and this strategy cannot be recommended outside of a clinical trial.

Glycemic Control The notion that hyperglycemia is detrimental to ischemic brain tissue is not new.60 Only since 2000, however, have the concepts of neuronal damage and infarct expansion been demonstrated for hyperglyamia in humans by neuroimaging61 and functional outcomes studies.62 In the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) trial, hyperglycemia was identified as an independent predictor of worse outcomes as well as a risk factor for ICH complicating treatment with thrombolytics.63 Hyperglycemia also seems to reduce the effect of thrombolysis, probably by making the ischemic penumbra less amenable to the benefits of reperfusion.64 The effects of hyperglycemia are likely to predispose to acute clinical worsening65 and possibly play a significant role in long-term recovery and mortality.66 Although there is nearly consensus on the detrimental effects of hyperglycemia in the acute stroke period, more studies are needed to determine its optimal management. The only large multicenter trial to date to address the safety of aggressive glycemic control was the United Kingdom Glucose Insulin Trial (GISTUK). The investigators concluded that continuous infusion of glucose/potassium/insulin solutions is feasible and safe in the peristroke period.67 A smaller group of patients has been

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reported in whom tight glycemic control was maintained with a continuous insulin infusion, but symptomatic, readily reversible hypoglycemia occurred in 20% of the patients.68 It is currently not known whether aggressive control of blood glucose translates into short- or long-term benefits or whether there is increased risk of hypoglycemic episodes. Despite the lack of current guidelines and formal recommendations, it seems reasonable that the patients with acute stroke, particularly those eligible for thrombolytic treatment, should undergo aggressive correction of hyperglycemia.

T A B L E 42–3. Modified Rankin Scale Grade

Description

0 1

No symptoms No significant disability despite symptoms: able to carry out all usual duties and activities Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance Moderate disability: requiring some help but able to walk without assistance Moderate-severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability: bedridden, incontinent, requiring constant nursing care Dead

2 3 4

Temperature Control

5

Although hypothermia seems plausible as a neuroprotective strategy, studies are still scarce, and no clear recommendations can be made at this point. Animal studies have reliably demonstrated adverse outcomes associated with hyperthermia in the peristroke period, but only as recently as 2000 have objective data in humans shown an effect of elevated temperature on clinical outcomes.69 Two large studies demonstrated the benefit of induced hypothermia in hypoxic-ischemic brain damage after cardiac arrest, but there are no comparable studies on the effects of hypothermia on focal ischemic lesions.70,71 It is reasonable to recommend control of peristroke pyrexia with the usual measures available in current clinical practice, acetaminophen and cooling blankets, until more data become available.

6

Recanalization Strategies Intravenous Thrombolysis With the demonstration of efficacy of intravenous thrombolytics in acute myocardial infarction, it was only a matter of time until a similar approach was investigated in the setting of acute ischemic stroke. On the basis of successful animal studies, the first large trials to employ intravenous thrombolytics were conducted with streptokinase administered within 6 hours of stroke onset.72,73 Both studies revealed excess mortality in the groups treated with streptokinase, especially when streptokinase was combined with aspirin in the acute setting. In 1996, the Australian Streptokinase Study (ASK) investigated the efficacy of streptokinase within 3 hours and between 3 and 6 hours of stroke onset. The results showed worse outcomes for those receiving streptokinase within 3 and 6 hours of stroke onset and a significant decrease in mortality in patients treated within 3 hours in comparison with those treated between 3 and 6 hours. This, however, was not translated into a significant clinical benefit for thrombolysis at 3 months in comparison with placebo.74 In view of these results, streptokinase was abandoned, and attention shifted to rt-PA, a more selective, fibrindependent plasmin generator. Results from multiple animal studies, which showed efficacy of rt-PA for recanalization and with lower rates of ICH than streptokinase, paved the way for clinical trials in humans. The first large, randomized, multicenter clinical trial to evaluate the use of rt-PA in acute ischemic stroke was the European Cooperative Acute Stroke Study (ECASS). Patients were enrolled within 6 hours of their ischemic stroke and were randomly assigned to received rt-PA (alteplase) at 1.1 mg/kg or placebo. The primary outcomes analyzed were the Barthel index (a measure of functional impairment in the activities of daily

living) and the modified Rankin scale (a measure of neurological disability) at 3 months (Table 42–3). Even though the overall rate of ICH was not different between the two groups, the rate of large ICH was significantly higher in the treated group. No definite benefit was observed for the tPA group, but a post hoc analysis revealed a statistically insignificant treatment effect in patients treated within 3 hours, which suggested that this time window should be further explored.75 In 1995, the NINDS rt-PA Stroke Study group published the results of their trial.76 It was a randomized, placebo-controlled, multicenter trial that enrolled patients within 3 hours of the onset of an acute ischemic stroke who were then randomly assigned to receive either intravenous rt-PA (0.9 mg/kg) or placebo. There were strict exclusion criteria to ensure adequate patient selection and to improve the odds of a favorable result (Table 42–4). The dose of rt-PA chosen was lower than that for ECASS, and the blood pressure exclusion criteria were stricter (systolic blood pressure <185 mm Hg and diastolic blood pressure <110 mm Hg) (Table 42–5). Endpoints were defined in two parts: Part 1 required an improvement in the first 24 hours of more than 4 points in the National Institutes of Health Stroke Score (NIHSS) scale. Part 2 required improvement at 3 months on the Barthel Index (score = 95 to 100), the modified Rankin Scale (score = 1), and the Glasgow Outcome Scale (score = 1). The results of part 1 did not show a significant difference between the two groups. In part 2, benefit from tPA was observed in all outcome measures: Patients treated with tPA were 30% to 50% more likely to have no or minimal disability at 3 months than were those treated with placebo.76 The benefit was maintained regardless of stroke subtype and was still present 6 months and 1 year after stroke.77 The rate of symptomatic ICH was 6.4% in the tPA-treated individuals, in comparison with 0.6% in the placebo arm, but the mortality rates at 3 months and 1 year were not different between the two groups. Predictors of better outcome were treatment within 90 minutes78 (Fig. 42–12) and decrease in NIHSS score at 24 hours.79 Independent risk factors for symptomatic ICH were the severity of the stroke (measured by the NIHSS score), brain edema, or mass effect at baseline CT scan.80 Later studies showed that elevated blood glucose level at the time of treatment was also independently associated with higher risk of ICH.63 In 1996, on the basis of these favorable results, the U.S. Food and Drug Administration (FDA) approved the use of intra-

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment T A B L E 42–4. Inclusion and Exclusion Criteria for rt-PA Administration According to the National Institute of Neurological Disorders and Stroke Study

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T A B L E 42–5. National Institute of Neurological Disorders and Stroke rt-PA Study Protocol for Intravenous Thrombolysis in Acute Ischemic Stroke

Inclusion Criteria for rt-PA Administration Measurable neurological deficit of <3 hours of onset Brain CT without evidence of hemorrhage Exclusion Criteria for rt-PA Administration Rapidly improving or mild symptoms Symptoms suggestive of subarachnoid hemorrhage Head trauma or prior stroke in previous 3 months Myocardial infarction in the previous 3 months Gastrointestinal or urinary tract hemorrhage in previous 21 days Major surgery in the previous 14 days Arterial puncture at a noncompressible site in the previous 7 days History of previous intracranial hemorrhage Persistently elevated blood pressure (systolic >185 mm Hg and/or diastolic >110 mm Hg) Evidence of active bleeding or acute trauma (fracture) on examination If oral anticoagulant being taken and INR > 1.5 Heparin in previous 48 hours and prolonged aPTT Platelet count <100,000 mm3 Blood glucose concentration <50 mg/dL or > 400 mg/dL Seizure at the onset with postictal residual neurological impairments Adapted from Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587. aPTT, activated partial thromboplastin time; CT, computed tomography; INR, international normalized ratio; rt-PA, recombinant tissue plasmin activator.

venous tPA for acute ischemic stroke within 3 hours of onset in patients who met inclusion/exclusion criteria. After a post hoc analysis of ECASS demonstrated benefit in patients treated within 3 hours of stroke onset, a second trial (ECASS II) was conducted. The changes in the original protocol included a lower dose of tPA (0.9 mg/kg) and the exclusion of patients with CT evidence of large infarction (more than one third of the MCA territory involved, diffuse swelling). Other exclusion criteria were similar to those in the NINDS trial. The final analysis showed no significant difference between the treatment and the placebo recipients when the favorable outcome of a modified Rankin Scale score of 0 or 1 was considered (minimal or no disability). However, a post hoc analysis dichotomizing patients as either functionally dependent (modified Rankin Scale score > 2) or independent (modified Rankin Scale score = 2) found a significant 8.3% absolute difference in favor of the treatment recipients.41 As observed in the NINDS trial, the rate of symptomatic ICH was higher in the treatment recipients (8.8%) than in the placebo recipients (3.4%), but the 3-month mortality rates were similar. The FDA approval of intravenous tPA for acute stroke, along with subsequent favorable reanalyses and meta-analyses of existing intravenous tPA trials, has led to a broad consensus that it is an effective treatment for acute stroke. However, there have been many criticisms of the NINDS trial, and there remain many questions that will be answered only by further trials, not by reanalyzing old data. It is notable that the American Heart Association/American Stroke Association guidelines for intravenous tPA did not change from 2003 to 2005; which reflects the absence of new information. Some of the major concerns with the extant tPA trials and meta-analyses, along with questions that remain, are as follows:

From Adams, HP, Adams RJ, Brott T, et al: Guidelines for the early management of patients with ischemic stroke. Stroke 2003; 34:1056-1083. CT, computed tomography; rt-PA, recombinant tissue plasmin activator.

(1) The efficacy of intravenous tPA is small and available to only a very limited group of patients. (2) The NINDS trial is the only one to show benefit based on prespecified outcome measures. The other trials required post hoc analysis to show a benefit. (3) There was a statistically significant difference between the treatment groups in the NINDS study. Of note, in the 91- to 180-minute time window within which most patients receive intravenous tPA, there were over four times more patients in the mildest stroke severity category who received intravenous tPA than patients who received placebo. (4) Information on stroke etiology was inadequate, and therefore it is still not known which stroke subtypes are best treated with intravenous tPA. For example, it is unclear whether lacunar infarcts in the absence of large vessel disease are really ameliorated with intravenous tPA. (5) The effects of age, prior aspirin use, white matter disease, and stroke subtype on hemorrhage risk are unknown. (6) It is not known whether there are systematic differences in recanalization rates for ICA, MCA stem, basilar, and branch occlusions. (7) Recent data suggest that patients with rapidly improving or mild symptoms should still receive tPA. (8) Patients with very high NIHSS scores show only minimal benefit from tPA.

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Figure 42–12. Graph of model estimating odds ratio for favorable outcome at 3 months in patients treated with recombinant tissue plasminogen activator (rt-PA) in comparison with those treated with placebo by time from stroke onset to treatment. Odds ratio > 1 indicates greater odds that rt-PA treated patients will have a favorable outcome at 3 months in comparison with the placebo-treated patients. (From Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000; 55:1649-1655).

Intravenous Thrombolysis Beyond the 3-Hour Period The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was designed in an attempt to expand the narrow window for intravenous tPA use.81 The study tested the safety and effectiveness of intravenous tPA (0.9 mg/kg) within 5 hours of stroke onset. The primary endpoint was excellent neurological recovery (NIHSS score = 1) at day 90. The tPA dose and the other inclusion and exclusion criteria were similar to those of the NINDS trial. The result was negative; tPA treated patients had higher rates of symptomatic ICH and mortality at 90 days. The delayed time window drove the negative result, as only 15% of patients were treated within 3 hours of onset. A meta-analysis of pooled data from the NINDS, ATLANTIS, and ECASS trials has been performed. A total of 2775 patients treated with either placebo or intravenous thrombolysis within 360 minutes of stroke onset were analyzed. The odds ratios of a favorable outcome at 3 months were 2.81 for the patients treated within 90 minutes and 1.55 for those treated within 91 to180 minutes. There was no significant difference in mortality between patients treated within 270 minutes, but the mortality rate among patients given thrombolytics more than 270 minutes after stroke onset was in excess of 45%. Hemorrhage rate did not appear to be related to the time for thrombolysis but was related to age and the use of thrombolytics as opposed to placebo.82 Of note, this meta-analysis, like a Cochrane review,82a also suggested some benefit in patients treated between 180 and 270 minutes after stroke onset (odds ratio, 1.4). Nevertheless, intravenous thrombolysis is currently not recommended more than 3 hours after stroke onset. It is clear that 3 hours is not a magic number, and more physiological measures are sorely needed to optimally select patients for recanalization therapy. There are almost certainly patients in whom recanalization and completion of infarction have occurred within 3 hours and who would therefore not benefit from intravenous tPA and only be placed at unnecessary risk

for hemorrhage. Conversely, there may be other patients, with persistent occlusion and large areas of misery perfusion, who could still benefit from recanalization more than 3 hours after stroke onset. The critical measures are likely to be the demonstration of both large-artery occlusion and the presence of a substantial volume of penumbral tissue beyond the infarct core. A way forward is to use the combination of DWI, PWI, and MRA to provide a rapid assessment of the ischemic infarct core (DWI), the presence of arterial occlusion (MRA), and tissue at risk, defined as an area of reduced perfusion that extends beyond the boundaries of the diffusion abnormality. This is known as PWI-DWI mismatch. The concept of PWI-DWI mismatch has recently been modified for two reasons. First, as noted in the “Ischemic stroke” section, there is a spectrum of reversible ischemia from benign oligemia to impending necrosis. Second, DWI abnormalities are not always indicative of irreversible ischemia. Thus, the new definition of the penumbra (tissue at risk) excludes a rim of benign oligemia and includes some of the DWI core with high ADC values.83 A recent magnetic resonance study of the evolution of DWIand PWI-observed lesion volumes, from acute to subacute time points, showed a contraction of the PWI-observed lesion by 85% and an expansion of the DWI-observed lesion by 136%.84 The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) pilot study showed improved recanalization, reduced DWI expansion, and penumbral salvage in patients who received intravenous tPA within 6 hours.61 The magnetic resonance surrogate measures were correlated with clinical outcome measures. These theoretical considerations, observational studies, and pilot studies have led to five ongoing studies (EPITHET; Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution [DEFUSE]; Desmoteplase in Acute Ischemic Stroke Trial [DIAS]; MR and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE]; and ReoPro Retavase Reperfusion of Stroke Safety Study [ROSIE]) evaluating tPA or mechanical thrombolysis on the basis of penumbral dynamics. Preliminary data are favorable,85 but it is necessary to wait until the trials are completed because many intuitively appealing ideas for stroke treatment have been shown to be untenable after completion of properly randomized trials.

Thrombolysis in the Community With the approval of intravenous tPA for acute stroke treatment, multiple groups tried to ascertain whether the benefits observed in the NINDS trial were reproducible at the community care level. In 2000, Katzan and colleagues published the experience at 29 hospitals in the Cleveland area and determined the rate of use of thrombolytics, related complications, and protocol violations.86 Their results showed that only 1.8% of all patients admitted with a diagnosis of ischemic stroke received intravenous tPA. Moreover, of the treated patients, 15.7% had symptomatic ICH, and the NINDS protocol was violated in 50% of the cases. The analysis also showed higher in-hospital mortality rates in the tPA-treated patients than in the placebotreated patients.86 Protocol violations were also high in another community-based study87; not surprisingly, there was a higher rate of symptomatic ICH than in the original NINDS trial. With increased awareness of its indications and the importance to adhere strictly to the published protocol, tPA use was reanalyzed in the Cleveland area 2 years after the first study. A higher percentage (2.7%) of patients received treatment; they

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment represented 18.8% of all eligible patients. Protocol violations occurred for 19% of patients, and symptomatic ICH occurred in 6.4%,88 a significant improvement from the original study. Familiarity with the use of thrombolytics and better adherence to published guidelines were likely reasons for the observed improvement. However, the overall tPA usage rates were not impressive, and this raises the possibility that specialized centers, analogous to designated trauma centers, might be a better option. In 2001 Grotta and associates published the Houston experience with tPA for acute stroke. In a period of 4 years, 15% of all patients presenting with an acute ischemic stroke were treated with intravenous tPA; almost a third of those were treated within 2 hours after onset. The rate of symptomatic ICH was 4.5%, and protocol violations occurred for 13% of all treated patients. This study proved that a well-organized team approach and adherence to currently accepted protocols are key to successful implementation of intravenous thrombolysis.89 In 2002, a group from Canada evaluated their experience with over 1000 patients treated with intravenous tPA over a period of 30 months. Their results were similar to the NINDS trial, in which 30% of the treated patients had no or minimal deficits at 90 days. The ICH rate was 4.6%, and protocol violations were observed in 15% of cases.90 Other studies have yielded similar results.

Intra-Arterial Thrombolysis For more than a decade, small case series were published on the feasibility and angiographic efficacy of intra-arterial delivery of thrombolytics. There has since been great improvement in angiographic catheter technology, as well as an increase in the experience of interventionalists. In many academic settings, intra-arterial thrombolysis is commonly employed in patients for whom the 3-hour window for intravenous thrombolysis is past or in those with an absolute contraindication to systemic thrombolysis. The potential advantages are the higher rates of recanalization achieved by delivering the drug locally at the site of the occlusive thrombus/embolus and fewer systemic side effects. It is unclear whether any particular agent is more effective, but those that are more fibrin selective might have a theoretical advantage (tPA, recombinant tPA, recombinant prourokinase) over less selective agents, such as urokinase. Despite the inherent plausibility of an intra-arterial approach, only one placebo-controlled, double-blind multicenter trial has been completed. The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT) was published in two parts. In PROACT I, recombinant prourokinase, a highly fibrin-selective agent, was administered intra-arterially, and its effects were compared with those of placebo in patients with an angiographically documented MCA (M1 or M2) occlusion within 6 hours of stroke onset. Inclusion criteria included a NIHSS score of at least 4, as well as the other NINDS tPA trial inclusion/exclusion criteria, including those for blood pressure. Heparin was administered concomitantly for 4 hours in both groups, and mechanical clot disruption was not allowed in either group. Forty patients were enrolled, and the rate of angiographically proven recanalization was 57.7% for the treatment recipients and 14.3% for the placebo recipients. Among patients who received higher doses of intravenous heparin together with the intra-arterial recombinant prourokinase, recanalization and symptomatic ICH rates were higher

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(81.8% and 27%, respectively). The recanalization rate was lower in the patients given lower dose heparin (40%), but the rate of symptomatic ICH was also significantly lower (6%). Overall, the rate of ICH was 15.4% among patients receiving thrombolytics and 14.3% among those receiving placebo. The trend toward effectiveness in this phase 2 trial prompted the second part of the trial (PROACT II), which tested clinical efficacy. The inclusion criteria in PROACT II were similar to those of PROACT I except, as in to ECASS, patients with CT hypodensity representing involvement of more than a third of the MCA territory were excluded. The baseline severity of strokes was higher than in the NINDS tPA trial (mean NIHSS scores = 17 versus 14) and the median time from onset to treatment was 5.3 hours. The primary outcome was the proportion of patients with a modified Rankin Scale score of 2 or less (independent) at 90 days. The study found a 15% absolute benefit in the patients who received treatment (intra-arterial recombinant prourokinase followed by intravenous heparin for 4 hours) in comparison with those who received placebo (only intravenous heparin for 4 hours). This translates into a number-needed-totreat of seven. Symptomatic ICH occurred in 10% of recombinant prourokinase recipients and 2% of the control group, and recanalization rates at 2 hours were 66% for the treatment recipients and 18% for the control group. No difference in mortality rates was observed between the two groups.91,92 Data from the PROACT suggest that patients outside the currently accepted treatment window for intravenous tPA could benefit from an aggressive interventional approach. However, the results of PROACT II did not suffice for FDA approval. Nevertheless, this approach is likely to be particularly useful for those patients with either ICA or MCA occlusion (Fig. 42–13A and B), in whom the rate of recanalization with systemic thrombolysis appears to be much lower than that with locally delivered thrombolytics. The existence of a sizable subgroup of patients who cannot receive systemic thrombolysis (because of recent surgery, recent nonhead trauma, previous stroke) is a strong incentive for development of intra-arterial therapies. Areas under active investigation include the use of mechanical extraction devices that remove an obstructing clot without many of the attendant risks of a thrombolytic agent. Several such devices are currently under investigation. The use of PWI-DWI mismatch, as previously discussed, is certain to be used in the future to select patients most likely to benefit from intraarterial therapy. Vertebrobasilar thrombosis has extremely high overall morbidity and mortality rates (approximately 70% to 80%), whereas successful recanalization is associated with a survival rate of 55% to 75%. Thus, basilar thrombosis is another situation in which intra-arterial thrombolysis may prove more efficacious than systemic thrombolysis. Despite the absence of a large randomized study to prove its safety and efficacy, the potential longer window (up to 24 or even 72 hours in selected cases) for therapy, based on multiple case series, makes acute basilar thrombosis a compelling scenario for use of intra-arterial thrombolysis or mechanical clot extraction.

Combined Intravenous and Intra-Arterial Thrombolysis The rate of complete recanalization of ICA or MCA occlusion after intravenous tPA appears to be low, ranging from 10% to 30%. Moreover, in many instances, recanalization is followed

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A ■

B

Figure 42–13. A, Complete occlusion of the left middle cerebral artery stem. B, Recanalization of the middle cerebral artery stem and its branches after intra-arterial tissue plasminogen activator was administered to a patient with onset of a stroke 2 hours earlier, who was not a candidate for intravenous thrombolysis.

by reocclusion and neurological worsening. The Emergency Management of Stroke (EMS) pilot study aimed at establishing the safety and feasibility of lower dose intravenous thrombolysis (0.6 mg/kg) within 3 hours, followed by intra-arterial tPA for presumed MCA or ICA occlusion (NIHSS score > 5). The rationale behind this approach is to combine speed of delivery of intravenous tPA with the higher recanalization rate and extended time window of intra-arterial tPA. The study results showed that the combination of intravenous and intra-arterial thrombolysis led to higher recanalization rates and more bleeding complications, without appreciable effect on overall outcome.93 A follow-up study, the Interventional Management of Stroke (IMS) trial, enrolled 44 patients to the intravenous/ intra-arterial tPA treatment group. The rate of symptomatic ICH was 6.3%. In comparison with the historical data from the NINDS intravenous tPA trial, in which 36% of patients with a NIHSS score higher than 10 achieved a good outcome, 56% of such patients in the IMS study had a good outcome, which is suggestive of added benefit from intra-arterial therapy in patients with probable large-vessel occlusion.94 Currently, however, such an approach is experimental and is not recommended outside a clinical trial setting.

SECONDARY PREVENTION Antiplatelet Therapy Aspirin Aspirin use is a time-honored strategy for secondary prevention of ischemic stroke in both the acute and chronic settings. Mul-

tiple clinical trials have been conducted, the most important being the French, British, European, and Canadian trials. They revealed a benefit ranging from 20% to 30% relative risk reduction for stroke and vascular death. The Antithrombotic Trialists Collaboration addressed the role of aspirin among patients at high risk for vascular events, including those with a prior ischemic stroke. The benefit of aspirin was modest, with a 22% relative risk reduction for vascular events (stroke, myocardial infarction, vascular death) in patients with a prior TIA/stroke. The absolute benefit of aspirin, across all doses, was a modest 2.5% (Fig. 42–14).95 Whereas most studies agree on the benefit of aspirin, its optimal dose has been a matter of some controversy. The Dutch trial showed equal benefit for very low and moderate doses of salicylates (30 mg/day versus 283 mg/day),95a a finding similar to that in the British trial,95b in which very different dosing schedules were used (300 mg/day versus 1200 mg/day). In view of the potential side effects, mainly from gastrointestinal bleeding and ulceration, it is reasonable to prescribe low-dose aspirin (81 mg/day) for long-term secondary stroke prevention, although efficacy at this low dose of aspirin for long-term stroke prevention has not been determined. The International Stroke Trial (IST) evaluated patients within 48 hours of an acute stroke and established the benefit of 300 mg/day of aspirin in reducing recurrent strokes at 14 days and death or dependency at 6 months.96 The Chinese Acute Stroke Trial (CAST) evaluated the use of 160 mg/day of aspirin within 48 hours of suspected ischemic stroke (13% of patients had no confirmatory CT scan before randomization).97 Analysis of the results showed a 12% relative risk reduction of death or recurrent stroke within 4 weeks for the aspirin recipients. Together, the IST and CAST trials showed an improved outcome for patients receiving

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment Benefit per 1000 patients (SE): Adjusted % of patients (+1 SE)

P value:

6(2)

25(5)

7(4)

15(5)

0.0009

<0.0001

0.04

0.002

Antiplatelet therapy Control 1248/ 11527 (10.8%)

10 957/ 11493 (8.3%)

5

0 Outcome:

1475/ 11527 1303/ (12.8%) 11493 (11.3%) 1003/ 915/ 11527 11493 (8.7%) (8.0%)

251/ 191/ 11338 11310 (23%) (1.7%)

Non-fatal myocardial infarction

Non-fatal stroke recurrence

Vascular death

aspirin within 48 hours of a stroke, with 13 fewer dead or dependent patients in the months after the event.96,97 Aspirin is often discontinued for elective surgery or bleeding complications. There have been concerns for some time that discontinuation of aspirin, and other antiplatelet agents, might lead to a transient prothrombotic “rebound” effect that increases the risk of ischemic stroke. This concern is supported by a case-control study whose results suggest that aspirin discontinuation can increaset the risk of ischemic stroke, especially in patients with multiple cardiovascular risk factors.97a

Clopidogrel Clopidogrel inhibits adenosine diphosphate–induced platelet aggregation. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study investigated its use for the prevention of ischemic strokes. Patients with nondisabling ischemic strokes, patients with recent myocardial infarction, and patients with symptomatic peripheral arterial disease were randomly assigned to receive aspirin (325 mg/day) or clopidogrel (75 mg/day). The primary outcome was an aggregate of myocardial infarction, ischemic stroke, and vascular death. Overall, events occurred in 5.3% of patients receiving clopidogrel and 5.8% in those receiving aspirin; this represented a relative risk reduction of 8.7% in favor of clopidogrel. This benefit was achieved mainly from a relative risk reduction of 23.8% in the patients with peripheral arterial disease and was not observed in the patients with a prior ischemic stroke, in whom a nonsignificant relative risk reduction of 7.3% in favor of clopidogrel was observed. The rate of gastrointestinal hemorrhage was lower in the clopidogrel recipients (1.99%) than in those taking aspirin (2.66%), but the rates of ICH were similar. These results suggest that in patients with a prior ischemic stroke, clopidogrel is no more effective than aspirin. Its use is justified in patients with aspirin intolerance and in patients with symptomatic peripheral arterial disease. The history of a prior gastrointestinal bleeding episode during aspirin therapy would, in theory, also justify using clopidogrel. Thrombotic thrombocytopenic purpura is a concern with clopidogrel, but CAPRIE did not show a higher risk of fatal thrombocytopenia than with the use of aspirin.

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Figure 42–14. Absolute effects of antiplatelet therapy on various outcomes in patients with previous stroke or transient ischemic attack (21 trials). In the “any death” columns, nonvascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths). (From Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomized trials of antiplatelet therapy for the prevention of death, MI, and stroke in high risk patients. BMJ 2002; 324:71-86.)

Any death

Combination Antiplatelet Therapy Clopidogrel and Aspirin The rationale behind combination antiplatelet therapy is that the agents have different mechanisms of antiplatelet activity. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study evaluated the role of the combination of clopidogrel and aspirin in comparison with aspirin alone in patients with non–ST-elevation acute coronary syndrome. The combination therapy led to a 20% relative risk reduction in the composite outcome of myocardial infarction, ischemic stroke, and vascular death in comparison with aspirin alone. Even though the rates of ICH were small and not different between the two groups, the CURE trial results could not be extrapolated to secondary stroke prevention because most of the patients were stroke free at the time of enrollment. To specifically answer the question whether the clopidogrelaspirin combination is more effective in reducing the risk of stroke recurrence than aspirin alone, the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic or Ischemic Stroke (MATCH) trial was conducted. The 7599 patients already taking clopidogrel (75 mg/day) who had had a recent TIA or stroke (and at least one other risk factor) were randomly assigned to receive aspirin or placebo. The duration of treatment and follow-up was 18 months. The primary endpoint was a composite of ischemic stroke, myocardial infarction, vascular death, or hospitalization for acute ischemic event (including TIA, angina, or peripheral arterial disease). The primary endpoint was reached by 15.7% of patients receiving clopidogrel/aspirin and by 16.7% of those receiving aspirin alone. This relative risk reduction of 6.4% was offset by the significantly higher rates of life-threatening bleeding episodes in the patients receiving combination therapy (2.6% versus 1.3%). The degree to which the MATCH results apply to secondary stroke prevention in general is questionable for a number of reasons. First, 70% of the patients enrolled had diabetes. The study was designed to enroll patients with multiple stroke risk factors to increase the background stroke recurrence rate, which was high in both groups. It is possible that this population has such severe small-vessel disease that

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inhibiting platelets was not sufficient to prevent lacunar infarction. Indeed, 54% of the recurrent strokes were lacunar. The question, extrapolated from CURE, of whether patients with TIA or stroke from LAA might benefit from aspirin and clopidogrel, was not really addressed by MATCH. For example, in the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial, dual antiplatelet therapy with clopidogrel and aspirin was superior to aspirin alone for reduction of embolic signals in the MCA in patients with symptomatic carotid stenosis. This was admittedly a small study with a surrogate marker, but the results do tend to support the idea that LAA might be more amenable to combination therapy than is small-vessel disease. Nevertheless, in view of the elevated risk of hemorrhage and the nonsignificant increase in protection, combination therapy of clopidogrel and aspirin cannot currently be recommended for secondary stroke prevention, with the possible exception of patients with extracranial or intracranial stents.

Dipyridamole and Aspirin The European Stroke Prevention Study II (ESPS-II) was a double-blind, randomized investigation of the different efficacy of placebo in comparison with aspirin (25 mg twice daily), extended-release dipyridamole (200 mg twice daily), and the combination of aspirin and extended-release dipyridamole. The outcomes of stroke and/or death were measured over a followup period of 2 years. The results showed a stroke rate of 15.8% in the placebo recipients, 13.2% in the extended-release dipyridamole recipients, 12.9% in the aspirin recipients, and 9.9% in the combination recipients. The combination therapy yielded a 23% relative risk reduction in comparison with either aspirin or dipyridamole alone and a 37% relative risk reduction in comparison with placebo.98 Moderate to severe bleeding events were almost twice as common in the aspirin recipients; mortality rates were not statistically different among the four groups. The combination is therefore a valid first-line option for secondary prevention after a noncardioembolic stroke and is being increasingly used in clinical practice. The main limitation of this therapy is the frequent headaches observed at the initiation of therapy (present in as many as 40% of patients). However, a slow dose-escalation schedule and use of over-thecounter pain medications usually lead to resolution of headaches within 2 weeks. Overall, the aspirin trials—CAPRIE, ESPS-2, Warfarin Aspirin Recurrent Stroke Study (WARSS), and MATCH—have not shown a relative risk reduction beyond 25%, and the number needed to treat to prevent one recurrent stroke is approximately 25 for all agents studied thus far. In contrast, trials that focused on a single underlying stroke mechanism, such as atrial fibrillation or high-grade carotid stenosis, have demonstrated more dramatic relative risk reductions, of about 60% to 70%. This discrepancy raises doubts about the utility of large secondary prevention trials, which lump together all stroke etiological subtypes. Instead, there should be more detailed characterization of each enrolled patient’s stroke subtype and trials powered to differentiate between these stroke subtypes. Alternatively, trials should be conducted on a single stroke subtype only. Until this is done, it can be envisaged that antiplatelet trials will continue to yield unimpressive results because some stroke causes will respond favorably to the agent in question but the mean effect will be diluted by other causes

that respond poorly or not at all. A final point is that a shift in focus from inhibition of platelet aggregation to inhibition of platelet adhesion might provide greater benefit and reduced hemorrhagic risk.

Anticoagulants Heparin and Heparinoids The debate over the use of anticoagulants in the acute stroke setting continues relentlessly. Proponents of anticoagulation favor its use on the basis of biologically plausible arguments: 1. Anticoagulation in the acute setting stops clot propagation and embolization and optimizes the action of the intrinsic fibrinolytic system to maintain collateral flow to penumbral tissue. 2. Anticoagulation in the acute setting stabilizes a ruptured atherosclerotic plaque by decreasing in situ thrombosis, thereby reducing the chances of fluctuating or “crescendo” TIAs or “stroke in evolution.” 3. The anti-inflammatory effects of intravenous heparin, suggested by animal studies, decrease the amount of local cytokine production, leukocyte migration, and tissue destruction. 4. Anticoagulation in the acute stage prevents deep venous thrombosis and pulmonary embolism, especially after a hemiplegic stroke. However, despite these arguments, the use of unfractionated or low-molecular-weight heparin (LMWH) in the acute stroke setting is not supported by current evidence. In 1997, the IST evaluated the use of subcutaneous unfractionated heparin in the acute stroke setting. Chosen outcomes measures were death at 14 days and death and dependency at 6 months. The investigators used a factorial design in which patients were given subcutaneous unfractionated heparin (5000 IU or 12,500 IU twice a day), placebo in addition to aspirin (300 mg/day), or placebo. Treatment was started within 48 hours of an acute stroke and continued for 14 days. Among heparin-treated patients, there were nonsignificantly fewer deaths within 14 days than among patients who received no heparin (9.0% versus 9.3%, respectively), corresponding to 3 fewer deaths for every 1000 patients treated. Also, there was no difference between the groups in dead or dependent patients at 6 months. Patients receiving heparin had significantly fewer recurrent ischemic strokes within 14 days (2.9% versus 3.8%), a finding offset by a similar increase in hemorrhagic strokes (1.2% versus 0.4%). Heparin use was also associated with a greater risk of any extracranial hemorrhage and hemorrhages necessitating transfusion; the higher risks were present with higher heparin doses. The nonsignificant decrease in deaths at 14 days was similar to that observed with the use of aspirin alone. Indeed, the reduction at 6 months in death or nonfatal recurrent stroke was greater in the aspirin group than in the heparin group, predominantly because of lower rates of ICH in the aspirin-treated group. The conclusion drawn from this study was that heparin is of no obvious benefit in the prevention of either stroke recurrence, death, or disability, and therefore there is no support for the use of high-dose subcutaneous heparin (exceeding 5000 IU twice daily) in the acute stroke setting.96 The major limitations of the IST study were the open-label nature of the study,

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment absence of initial CT scan in up to one third of all patients, lack of anticoagulation parameter control in the heparin-treated patients, and lack of weight adjustment of the heparin dose. In the late 1980s, Duke and colleagues investigated the role of intravenous unfractionated heparin or placebo up to 24 hours after an acute, stable, noncardioembolic ischemic stroke. Rates of stroke progression, death, and recovery were similar in the two groups.99 Many smaller studies and case series have been published since, with most results suggesting no benefit from acute use of intravenous unfractionated heparin. The use of LMWH in acute ischemic stroke has also been investigated in small studies, the majority of which revealed no significant benefit of subcutaneous LMWH in the prevention of recurrence or death after an acute ischemic stroke. Most notable, the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) evaluated the efficacy of two different doses of subcutaneous LMWH (tinzaparin), in comparison with aspirin, for 10 days after an acute ischemic stroke. The results revealed no differences in outcome of clinical deterioration and stroke recurrence in 15 days or in modified Rankin Scale score at 6 months between the two groups, in all subtypes of ischemic stroke, including cardioembolic stroke. There was a higher rate of symptomatic intracranial hemorrhage in the tinzaparin-treated patients and a higher rate of venous thromboembolism in the aspirin-treated patients.100 The Trial of ORG 10172 in Acute Stroke Treatment (TOAST) enrolled approximately 1300 patients to receive either placebo or intravenous danaparoid (LMWH) for 7 days after an acute ischemic stroke.101 The primary endpoint was a favorable outcome (based on scores on the Glasgow Outcome Scale and the Barthel index) at 3 months. The level of anticoagulation was corrected according to anti–factor Xa levels. The outcomes of neurological worsening and recurrent ischemic stroke at 7 days and the 3-month outcomes were similar in the two groups. When the subgroups were evaluated according to stroke subtype, the early recurrence rates for patients with cardioembolic stroke were similar in the two treatment groups. However, in contrast to the TAIST trial, the only patients who showed a trend toward benefit from intravenous danaparoid were those with LAA. When embolic stroke subtypes are considered, the results of the Heparin in Acute Embolic Stroke (HAEST) trial provide some insight.102 It was a double-blind, randomized investigation of the effectiveness of LMWH (dalteparin) given subcutaneously in comparison with aspirin (160 mg/day) in patients with an acute stroke presumably secondary to atrial fibrillation. The patients were assigned to receive either dalteparin or aspirin within 30 hours of the ischemic stroke and were treated for 10 days. The primary outcome of recurrent stroke within 14 days occurred in 7.5% of the aspirin-treated patients and 8.5% of the dalteparin-treated patients, with a trend toward more ICH in the dalteparin-treated group. This study emphasizes that the recurrence after a cardioembolic stroke is lower than previously thought and that emergency anticoagulation may be more harmful than helpful. In summary, the role for acute heparin use after an ischemic stroke, including those with a cardioembolic mechanism, is not supported by current evidence.103 In some cases, however, scenarios may arise that were not systematically investigated by existing trials. In such scenarios, the underlying pathophysiology (arterial dissection, “stuttering” TIAs, acutely symptomatic critical arterial stenosis, large left ventricular thrombus) might

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nonetheless justify anticoagulation. In these circumstances, a careful weighing of the (at best theoretical) benefit of acute anticoagulation against its risks should be the rule.

Oral Anticoagulation Cardioembolic Strokes Atrial fibrillation, valvular heart disease, prosthetic valves, and reduced cardiac contractility predispose to ischemic stroke by blood stasis, thrombus formation, and distal embolization. Stroke registries have shown cardioembolic strokes to represent about 25% of all ischemic stroke subtypes. The annual risk of stroke in chronic atrial fibrillation ranges from 5% to 12% a year, with the highest statistics in patients with other risk factors, concomitant valvular disease, and a prior stroke. The importance of atrial fibrillation is evident when its prevalence in the population is considered: 5% of persons at the age of 65 and 10% of persons aged 80 or older have chronic atrial fibrillation. Atrial fibrillation does not put all patients at the same risk level. The presence of other risk factors such as age older than 65, prior stroke or TIA, hypertension, and impaired left ventricular function increase the risk considerably in comparison with absence of those risk factors (“lone” atrial fibrillation). Women older than 75 and diabetic patients also have an increased risk of stroke. In view of the modest benefit of aspirin in both primary and secondary stroke prevention in patients with atrial fibrillation, various studies investigated warfarin as a more effective prophylactic agent. Multiple randomized clinical trials established the effectiveness of warfarin for both primary and secondary stroke prevention in patients with chronic atrial fibrillation.104 When all results are considered, warfarin has shown relative risk reductions of 59% in primary prevention and 68% in secondary prevention, with overall acceptable bleeding risk ranging from 0.3% to 2.0% per year. These results are put into perspective when the absolute risk reductions for warfarin (3% per year for primary prevention and 8% per year for secondary prevention) are compared with those of aspirin (1.5% and 2.5%, respectively). The recommended intensity of anticoagulation in nonvalvular atrial fibrillation is an international normalized ratio (INR) between 2.0 and 3.0, given the increased risk of bleeding with higher levels.105 On the basis of the trial results, the choice to administer anticoagulants to patients with atrial fibrillation (either chronic or paroxysmal) should be based on stratification of their stroke risk. All patients with a prior cardioembolic stroke or TIA should undergo long-term anticoagulation unless a strong contraindication is present. For primary prevention, the patients who would benefit the most from long-term anticoagulation are the ones with the risk factors mentioned previously. For patients without risk factors (lone atrial fibrillation) and/or younger than 65, aspirin is justifiable, in view of the low incidence of ischemic stroke (1% per year). Alternative oral anticoagulants are under investigation for stroke prevention in patients with atrial fibrillation. The Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF III) trial was a study of ximelagatran, a non–vitamin K-dependent direct thrombin inhibitor.106 It was an open-label study that randomly assigned patients with atrial fibrillation and one or more other stroke risk factors to receive

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either dose-adjusted warfarin (target INR of 2.0 to 3.0) or fixed-dose ximelagatran (36 mg twice daily). Results showed that patients receiving ximelagatran had fewer ischemic strokes or systemic emboli than did those receiving warfarin (1.6% versus 2.3% per year, respectively), with a relative risk reduction of 29%. Rates of disabling or fatal stroke, mortality, and major bleeding were similar in both groups, but combined minor and major hemorrhage rates were lower with ximelagatran than with warfarin (29.8% versus 25.8% per year). The major side effect from ximelagatran in this study was elevation in serum alanine aminotransferase level. The major advantages of this direct thrombin inhibitor over warfarin are the fixed dose with more predictive effects without the need for constant monitoring and the lack of significant food or drug interactions. Liver toxicity is the main limitation, and the use of ximelagatran is not currently approved in the United States. There is less evidence for the use of chronic anticoagulation in other cardiac conditions such as valvular heart disease and severely reduced left ventricular function. Dilated cardiomyopathy predisposes to thrombus formation in as many as 50% of affected patients and is therefore a significant risk factor for cardioembolic stroke (3% to 4% per year). Currently, two large trials (Warfarin vs. Aspirin in Reduced Ejection Fraction [WARCEF] and Warfarin and Antiplatelet Trial in Chronic Heart Failure [WATCH]) are evaluating the benefits of chronic anticoagulation over the use of aspirin in the rates of stroke and death in patients with severely reduced ejection fraction (<35%).107 Previous myocardial infarction confers a risk of stroke of 1% to 2% per year, with higher rates in the first 3 months after the event and particularly with anterior wall myocardial infarction. The modest risk reduction offered by conventional dosages of warfarin balanced against the increased risk of hemorrhagic complications does not allow the recommendation of long-term anticoagulation in unselected patients after a myocardial infarction. In patients with an anterior wall myocardial infarction, in whom the risk of mural thrombus formation can be as high as 40%, and in patients with documented ventricular thrombus, in whom the annual risk of systemic embolization may be as high as 20%, anticoagulation with warfarin is indicated. Despite the lack of randomized studies, current practice is for patients to receive anticoagulants for 6 months after an anterior wall myocardial infarction with documented intraventricular thrombus. Resolution of the thrombus should be assessed by serial echocardiographic studies and the length of therapy adjusted accordingly. In cases of an anterior wall myocardial infarction but no documented thrombus, a shorter period of anticoagulation is reasonable. Prosthetic valves also carry a high risk of systemic embolization and therefore are a significant risk factor for cardioembolic stroke. Mechanical valves carry a greater risk and warrant lifelong anticoagulation with warfarin with a target INR of 2.5 to 3.5. The combination of aspirin and warfarin provides more protection than does warfarin alone but at the expense of more bleeding complications. Bioprosthetic valves carry a smaller risk and do not necessitate long-term anticoagulation. In those instances, warfarin is often used in the first 3 months when the risk of embolization is greatest. Long-term anticoagulation is recommended for patients with bioprosthetic valves and other risk factors for atrial stasis such as mitral valve prosthesis, atrial fibrillation, and documented left atrial thrombus.

Noncardioembolic Stroke Traditionally, neurologists used long-term anticoagulation in patients with noncardioembolic stroke in whom secondary prevention with aspirin was deemed ineffective (“aspirin failure”). The poor prognosis associated with strokes secondary to intracranial atherosclerosis despite the use of antiplatelet agents has also been a common justification for long-term anticoagulation. Two studies have shed light onto these two issues. The WARSS was the first large trial to investigate whether warfarin was superior to aspirin for the secondary prevention of noncardioembolic ischemic stroke. It was a multicenter, double-blind, randomized trial that enrolled more than 2200 patients to receive either aspirin (325 mg/day) or warfarin for a target INR of 1.4 to 2.8. At the 2-year follow up, the primary endpoint of recurrent stroke or death was observed in 16% of patients receiving aspirin and 17.8% of those receiving warfarin; these percentages represented a statistically insignificant difference. The beneficial effects of warfarin seemed to be mostly in the INR range of 1.5 without significant additive benefits above that range. The endpoint was achieved in a similar proportion of patients in both groups regardless of the underlying stroke etiology, with a comparable rate of bleeding complications in the two groups (2.22%/year for warfarin and 1.49%/year for aspirin). The WARSS investigators concluded that aspirin and warfarin are equivalent in efficacy in the secondary prevention of noncardioembolic strokes, with a comparable relatively low risk of bleeding complications.108 The risk of recurrent stroke in large-vessel intracranial atherosclerosis can be as high as 10% per year. The retrospective portion of the Warfarin Aspirin for Symptomatic Intracranial Disease (WASID) trial evaluated the efficacy of anticoagulation in comparison with antiplatelet therapy for the secondary prevention of strokes attributable to posterior circulation intracranial atherosclerosis.109 The results of the retrospective analysis, showing recurrence rates of 10.4% per year in the aspirin recipients and 3.6%/year in the warfarin recipients, led to a prospective trial. The prospective part of the WASID study was a double-blind randomized trial that enrolled patients with symptomatic, angiographically proven, high-degree (>50% diameter reduction) intracranial stenosis. Patients were assigned to receive either warfarin (INR goal of 2.0 to 3.0) or aspirin (1300 mg/day). Determination of recurrent stroke or vascular death at 3-year follow-up was planned, but the study was prematurely interrupted after a mean follow-up of only 1.8 years because interim analysis showed higher rates of major hemorrhagic complications in the warfarin-treated group (8.3% for warfarin versus 3.2% for aspirin). The rates for all strokes or vascular death were similar in both groups (21.8% for warfarin versus 22.1% for aspirin). These results argue against the widespread practice of chronic anticoagulation for patients with symptomatic intracranial atherosclerosis.18 However, they also attest to the inadequacy of either medication. Further evidence for the nonsuperiority of warfarin over aspirin was provided by a Cochrane review.110 A meta-analysis of five trials (>4000 patients) that compared anticoagulation with antiplatelet therapy for the secondary prevention of noncardioembolic strokes showed similar rates of recurrent stroke at all levels of anticoagulation (INR ranges 1.4 to 2.8, 2.1 to 3.6, and 3.0 to 4.5) in comparison with antiplatelet therapy. Major bleeding rates were significantly higher in patients receiving high-intensity anticoagulation but similar in the patients

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment receiving low- and medium-intensity anticoagulation in comparison with antiplatelet therapy.

Strokes Associated with Antiphospholipid Antibodies The best therapy, antiplatelet or anticoagulation, for patients with stroke who also have positive results on tests for antiphospholipid antibody is still a matter of debate. A WARSS substudy, the Antiphospholipid Antibodies and Stroke Study (APASS), sought to answer this question. Of the 1770 patients from WARSS who had blood tests for antiphospholipid antibodies, 41% were found to have positive results. These patients showed no differences in the rates of death or thrombotic events in comparison with those who had negative results for antibodies. Of more importance, there was no difference in outcome of recurrent stroke or death when the treatment with either aspirin or warfarin was considered.111 However, the WARSS population had an average age of more than 50, and the study was not powered to answer questions of antibody titer or subtype. It remains possible that patients younger than 45 with high titers of immunoglobulin G antiphospholipid antibody, who evidence suggests are at risk for arterial stroke as well as venous thrombosis, might benefit from anticoagulation.

Stroke Associated with a Patent Foramen Ovale In patients with a cryptogenic stroke and a documented PFO, the best strategy for secondary prevention has been a matter of intense debate. The results of a prospective study evaluating young patients (<55 years old) with cryptogenic stroke and a PFO found the risk of recurrent stroke to be 15% over 4 years, with aspirin, when the PFO was associated with an ASA. This recurrence rate was dramatically higher than for isolated PFO112 and suggested that aspirin is inadequate. The Patent foramen ovale In Cryptogenic Stroke Study (PICSS), another substudy of WARSS, is the only randomized, double-blind study to investigate the best medical management of PFO.113 Six hundred and thirty patients from WARSS underwent a transesophageal examination; a PFO was found in 39% of patients with cryptogenic strokes and in 29.9% of patients with other known causes. Besides reinforcement of the notion of a PFO being a risk factor for a first-ever stroke, other aspects of the PICSS results are worth noting: 1. For the entire study population, there was no significant difference in the primary outcome between the groups with and without a PFO and in the groups with a cryptogenic or other known stroke mechanism. 2. The size of the PFO and the presence of an associated ASA were not determinants of recurrent stroke. 3. After 2 years of follow-up, the rates of recurrent stroke or death were similar in the patients treated with warfarin and those treated with aspirin (16.5% and 13.2%). These results do not support long-term anticoagulation for unselected patients with a cryptogenic stroke and a PFO, without a known underlying venous thrombosis or a hypercoagulable state. Unfortunately, the average age of the patients in WARSS was 59, and so the applicability of these results to the population younger than 45 without conventional risk factors is highly questionable. The role for endovascular or surgical

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closure of such a defect is currently being investigated by a clinical trial and cannot be routinely recommended at this point; however, closure might be appropriate in a young patient with stroke who is found to have a large PFO and associated ASA.

Blood Pressure Control for Secondary Stroke Prevention Many studies have shown the benefit of blood pressure control in primary stroke prevention, but only a few studies have assessed the effect of blood pressure control on secondary stroke prevention. The Heart Outcomes Prevention Evaluation (HOPE) study was a double-blind, randomized trial that investigated the role of angiotensin-converting enzyme (ACE) inhibitor (ramipril) as a protective strategy for patients with evidence of coronary artery disease, peripheral vascular disease, or prior stroke. Diabetes and at least one vascular risk factor were required for inclusion in the study. The study had a 2 × 2 factorial design in which 9297 patients were randomly assigned to receive ramipril (10 mg/day), vitamin E (400 IU/day), or placebo. Patients were monitored for over 5 years. Primary endpoints were myocardial infarction, stroke, and vascular death. Approximately 11% of patients in both ramipril and placebo groups had a history of prior stroke, and approximately 80% had a history of coronary artery disease. There was a statistically significant reduction in all primary outcomes in the ramipril recipients, in comparison with the placebo recipients (14% versus 17.8%). Stroke was the primary outcome in 3.4% of patients receiving ramipril and 4.9% of those receiving placebo. Fatal strokes occurred in 0.4% and 1.0%, and ischemic strokes in 2.2% and 3.4%, of patients receiving ramipril and the placebo groups, respectively.114 Only a small part of the benefit was attributable to reduction in blood pressure, inasmuch as only a minority of patients were hypertensive at baseline. A benefit for ramipril was observed regardless of the degree of blood pressure reduction.115 These results, although more applicable to primary stroke prevention in patients at high risk, make a strong case for long-term ACE inhibitor therapy as part of secondary stroke prevention, perhaps independent of baseline blood pressure. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was conducted to investigate the effects of a blood-pressure regimen with the ACE inhibitor perindopril on hypertensive and nonhypertensive patients with prior stroke or TIA. The study enrolled 6105 patients with a history of a prior stroke or TIA in the preceding 5 years, and they were randomly assigned to receive placebo or active treatment consisting of perindopril (4 mg/day) with or without the addition of the thiazide diuretic indapamide (2 to 2.5 mg/day), at the discretion of the treating physician (58% received combination therapy and 42% received perindopril alone). More individuals with baseline hypertension were identified in PROGRESS than in the HOPE trial. The primary outcome was fatal or nonfatal stroke. After 4 years of follow-up, 10% of patients receiving perindopril and 14% of patients receiving placebo had had a stroke, with an annual rate of stroke of 2.7% and 3.8%, respectively. This reduction occurred with both ischemic and hemorrhagic strokes, and fewer patients receiving perindopril had had fatal or disabling strokes. The association of perindopril with indapamide conferred a 43% relative risk reduction in comparison

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with placebo, whereas the use of perindopril alone had no discernible effect in stroke risk reduction. This medication combination was also associated with a more significant blood pressure reduction than the one produced with perindopril alone (12/5 mm Hg versus 5/3 mm Hg), and the benefit was observed in patients with or without hypertension at baseline.116 Whether the results observed were secondary to blood pressure control or to a direct effect of both the ACE agent and the diuretic remains unknown. The PROGRESS and HOPE studies suggest that ACE inhibitors, together with antithrombotics, should be considered first-line agents for secondary stroke prevention.

Cholesterol-Reducing Strategies Most prospective studies of cholesterol-lowering strategies have focused on ischemic heart disease. Only a few trials have focused on statin agents and secondary stroke prevention. The Heart Protection Study (HPS) was a randomized trial in which simvastatin (40 mg/day) was compared with placebo for prevention of vascular events (myocardial infarction, stroke, vascular death) in patients at high risk between 40 and 80 years old. High risk was defined as having prior occlusive arterial disease, diabetes, and elevated cholesterol. More than 3000 of the total 20,000 patients had a history of ischemic stroke or TIA. Over 5 years, the mean total cholesterol was reduced by 20%, and the odds for all ischemic strokes were reduced by 25% and for fatal strokes by 19%. All major vascular events were decreased by 30% in the simvastatin recipients. Of importance, ICH was observed with equal frequency in the two groups.117 In other smaller trials (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm [ASCOT-LLA]; Cholesterol and Recurrent Events [CARE]; Long-term Intervention with Pravastatin in Ischaemic Disease [LIPID]; and Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT]), researchers also examined the effect of various statins on prevention of vascular events, including strokes. Most showed a 15% to 25% reduction in the incidence in TIA or stroke. However, although these results show that statins are effective as a primary prevention strategy for TIA/stroke in patients at high risk, their effects on secondary prevention cannot be fully appreciated, because most patients enrolled in such studies were stroke free. Another unexpected result from these studies is the possibility that statins might be as effective in patients with normal cholesterol levels as they are in patients at high risk with elevated total cholesterol, elevated low-density lipoprotein, and low high-density lipoprotein levels. Current recommendations are that all patients with prior stroke and elevated cholesterol levels should take a statin. For patients with a prior TIA/stroke and other vascular risk factors, the use of statins also seems indicated. More data are necessary to determine whether a statin is indicated for patients with TIA/stroke but without elevated cholesterol or other vascular risk factors. In addition to antiplatelet, blood pressure, and cholesterollowering medications, lifestyle modification, through smoking cessation, dietary changes, increased physical activity, and moderate alcohol consumption, should also be encouraged. Tight control of glucose levels in diabetic patients

is also an important component of secondary stroke prevention.

Control of Other Potential Risk Factors Elevated Homocysteine Level Elevated blood homocysteine levels have been observed in patients with coronary artery disease, as well as in patients with a prior TIA/stroke. Whether these represent a marker of advanced atherosclerosis or have a causal role in the pathogenesis of vascular disease remains to be determined. Blood homocysteine levels are inversely related to the dietary intake of folic acid, vitamin B6, and vitamin B12. However, whether dietary supplementation with these vitamins to lower homocysteine levels decreases cardiovascular risk is uncertain. In the Vitamin Intervention for Stroke Prevention (VISP) trial, in which more than 10,000 patients with a prior TIA/stroke were given vitamin supplementation (folate, vitamin B6, and vitamin B12) or placebo, results showed that vitamin supplementation did not reduce the risk of recurrent stroke over 2 years.118 The Vitamins To Prevent Stroke (VITATOPS) study was also an evaluation of the effect of vitamin supplementation on a large population of patients with prior TIA/stroke. Preliminary results revealed no significant reduction in markers of vascular inflammation (C-reactive protein) or hypercoagulability (prothrombin fragments, D-dimer), despite reduction in total homocysteine levels.119,120 The benefits, if any, on stroke recurrence will be known only after completion of the study. Routine use of folic acid, cobalamin, and pyridoxine supplementation is not currently recommended for secondary stroke prevention.

Hormone Replacement Therapy The use of hormone replacement therapy, with either estrogen or a combination of estrogen and progesterone, has increased dramatically since the mid-1990s. The main indication is prevention of postmenopausal osteoporosis. Accumulating evidence, however, points to an increased risk of cardiovascular disease. In the Women’s Estrogen for Stroke Trial (WEST), estrogen replacement was compared with placebo in more than 600 menopausal women with a history of a prior TIA/stroke. After a mean follow-up period of 2.8 years, estrogen was not shown to provide any protection against minor strokes (odds ratio = 1.0) but was shown to be associated with increased risk of fatal strokes in comparison with placebo (odds ratio = 2.8). Even though the numbers of minor strokes were comparable in both groups, strokes in the estrogen recipients were associated with slightly worse neurological and functional deficits.121 Those results were reinforced by the Women’s Health Initiative (WHI) study. The main goal of the WHI study was to investigate primary prevention of cardiovascular disease in postmenopausal women and hormone replacement therapy. Nevertheless, it demonstrated an odds ratio for ischemic stroke of 1.5, independent of all other stroke risk factors.122 On the basis of these results, hormone replacement therapy is not recommended as primary prevention for stroke and certainly should not be used in women with a history of prior TIA/stroke. In postmenopausal women without cardiovascular risk factors, its use may be considered if truly indicated.

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment Surgical and Interventional Strategies for Secondary Stroke Prevention Carotid Endarterectomy In the early 1980s, resection of the stenotic portion of the ICA, or carotid endarterectomy (CEA), was a common surgical procedure. The conviction that CEA was an optimal form of secondary stroke prevention arose from recognition of the fact that large-artery atherosclerotic strokes are associated with a high rate of early recurrence. However, in the middle to late 1980s, the uncertainty about the efficacy of CEA in comparison with optimal medical therapy and the failure of the extracranialintracranial bypass trial led to a decrease in enthusiasm for the CEA. However, in 1991, the North American Symptomatic Carotid Endarterectomy (NASCET) trial published its results.123 There was an absolute risk reduction in the incidence of recurrent stroke of 17% for CEA in comparison with medical treatment in symptomatic patients with ICA stenosis of more than 70% diameter reduction. In absolute numbers, strokes recurred within 2 years in 26% of the medically treated patients and 9% of the surgically treated patients; this was a 66% relative risk reduction for CEA. The risks of major or fatal ipsilateral stroke in the surgically and medically treated patients were 2.5% and 13.1%, respectively.16 When all centers were considered, the overall surgical morbidity and mortality rate was 5.8%. In their latest results, the NASCET investigators found that in patients with a moderate degree of ICA stenosis (50% to 69% diameter reduction), the benefit was more modest, with a 5-year rate of stroke in the surgically and medically treated patients of 15.7% and 22.2%, respectively.124 The Veterans Affairs Cooperative Study yielded similar results, with an absolute risk reduction of 11.7% for surgery versus medical therapy at 1 year of follow-up. Patients had ICA stenosis that ranged from 50% to 99% diameter reduction, and, as in the NASCET trial, the results showed greater benefit for patients with higher degrees of stenosis. The perioperative morbidity and mortality rate was approximately 5%.125 The European Carotid Surgery Trial (ECST) was conducted around the same time as the two other CEA trials. There were some important differences between ECST and NASCET, which led to slightly different results. The main methodological differences were in the angiographic measurement of the degree of stenosis (the ECST method overestimated degree of stenosis in comparison with the NASCET method) and in the definition of the stroke outcome (ECST defined stroke as a deficit persistent for >7 days, and NASCET defined stroke as a neurological deficit persisting for >24 hours). The final ECST results for 3-year risk of stroke or death showed a 26.5% risk in medically treated patients with a symptomatic ICA stenosis of more than 80% diameter reduction, and a 14.9% risk for patients undergoing CEA; the absolute benefit for surgery was 11.6%. The risk of major stroke or death complicating surgery was 7%.126-128 Reanalysis of the ECST results, with degree of stenosis recalculated with the NASCET method, revealed an absolute risk reduction of 21.2% for 5-year risk of stroke or death after CEA in comparison with medical treatment in patients with ICA stenosis of 70% to 99% diameter reduction.128 Various post hoc analyses have been performed to further stratify recurrent stroke and surgical risk in patients with symptomatic high-degree ICA stenosis in order to better select

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patients who will maximally benefit from CEA. In medically treated patients, certain features other than the degree of stenosis are associated with a higher risk of stroke. These include absence of adequate collateral circulation on angiogram, ulcerated plaque or intraluminal thrombus, contralateral occlusion, male gender, hemispherical as opposed to retinal symptoms, and stroke as opposed to TIA as the presenting syndrome. Similarly, for patients treated with CEA, certain features are predictive of higher risk of perioperative stroke. These include female gender, age older than 75, contralateral occlusion, intraluminal thrombus, ulcerated plaque, peripheral vascular disease, and neurological instability. Traditionally, CEA was delayed for 4 to 6 weeks after an acute stroke to reduce the risk of ICH, perhaps caused by reperfusion at higher pressure than the hemisphere was used to. However, an analysis of pooled NASCET and ECST data showed maximal benefit from CEA if it was performed within 2 weeks of nondisabling stroke. Similar information on timing of CEA after TIA is not available, but in view of data that show a greater risk of stroke after TIA than after stroke, it is likely that these patients should also undergo CEA within a week or two, as long as they are stable. The smallest benefit of CEA was observed in patients undergoing operation after 12 weeks. To qualify for these trials, patients had to have had an ipsilateral event within 6 months of random assignment. At 2 years, the annual stroke risk never exceeded 3%. Another reanalysis showed a small benefit for CEA with stenosis of 50% to 69% diameter reduction and no benefit for 30% to 49% diameter reduction. Symptomatic complete ICA occlusion is a special case that is not amenable to CEA. No benefit was observed for extracranial-intracranial bypass surgery in unselected patients in a trial in 1985,129 which failed to show a benefit from the surgical procedure as a result of high complication rates. However, the elevated risks of recurrent stroke in this patient population (as high as 14% per year in some studies), justifies another trial with better selection of candidates based on preoperative evaluation of hemodynamic reserve, because it is thought that recurrent stroke in these patients is caused by flow failure rather than embolus. The Carotid Occlusion Surgery Study is currently under way and aims to determine whether extracranial-intracranial bypass is superior to medical therapy in patients with recently symptomatic unilateral ICA occlusion and with evidence on PET scan for misery perfusion with increased OEF. Although these results are not available, risk factor modification, antiplatelet medications, and aggressive cholesterol control are the recommended treatment modalities for these patients.

Angioplasty and Stenting Angioplasty and stenting are currently considered preferable to surgery in cases of ICA stenosis secondary to prior radiation therapy in the neck, previous CEA with recurrent stenosis, contralateral ICA occlusion, and surgically inaccessible high bifurcation of the common carotid artery.130 In addition, angioplasty and stenting might be preferable in patients with multiple comorbid conditions who might not be ideal surgical candidates. The efficacy of angioplasty and stenting in comparison with CEA remains to be determined by ongoing trials (Carotid Revascularization Endarterectomy versus Stent Trial [CREST]; Stent-protected Percutaneous Angioplasty of the Carotid vs. Endarterectomy [SPACE]; International Carotid Stenting Study

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of the Carotid and Vertebral Artery Transluminal Angioplasty Study [CAVATAS-2]). The first large study to compare the safety and efficacy of CEA and angioplasty was the Carotid and Vertebral artery Transluminal and Angioplasty Study (CAVATAS). About 500 patients were randomly assigned to undergo either CEA or angioplasty (with or without stent implantation) and were monitored for 1 year. Major perioperative morbidity, mortality, and stroke rates were similar in the two groups at 30 days, and stroke rates were similar at 1 year, although the rate of restenosis was greater for the patients who underwent angioplasty. Of importance, angioplasty was followed by stent implantation, a procedure thought necessary to maintain vessel patency, in only 26% of the patients undergoing endovascular treatment. In addition, no distal protection device to minimize embolization was used in this trial.131 CAVATAS-2 is currently under way and should answer some questions with regard to equivalency to CEA, when both stent deployment and distal protection devices are used during the endovascular procedure. The recent Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial was designed to determine the noninferiority of angioplasty with stent implantation with ICA stenosis in comparison with CEA. The SAPPHIRE study showed a 7.9% absolute benefit in the outcome of stroke/myocardial infarction/death at 30 days and ipsilateral stroke or death at 1 year in favor of angioplasty with stent implantation over CEA in patients considered to be at high risk (with associated medical comorbid conditions). For the patients undergoing angioplasty and stent implantation, the perioperative morbidity and mortality rate was about half of that observed after CEA. However, a major problem with this study is that almost 70% of the patients were asymptomatic. It is already known from the CEA trials for high-grade asymptomatic carotid stenosis (see Chapter 46) that patients with medical comorbid conditions should not undergo operation because they need to be alive at 5 years to show the modest benefit. Thus, it is not clear why asymptomatic patients with associated medical comorbid conditions should undergo angioplasty and stent implantation at all. What are needed are studies of angioplasty with stent implantation versus CEA as a secondary prevention strategy in patients without comorbid conditions and those at high risk. The ongoing CREST should answer the former question. Angioplasty and stent implantation for symptomatic intracranial stenoses remain investigational and controversial. The seriousness of intracranial atherosclerosis was made plain by the WASID study (discussed previously), which showed, over a 1.8-year follow-up period, that ischemic stroke recurrence rate for intracranial stenoses of more than 50% diameter reduction ranged from 17% to 20%, almost half being fatal or disabling strokes. In view of this poor prognosis and the lack of better secondary prevention strategies, small studies have been performed to investigate safety, feasibility, and efficacy of interventional procedures in patients with symptomatic intracranial atherosclerosis. A review of a single center’s experience with intracranial stent implantation over a 6-year period revealed a very high overall periprocedural complication rate of 28% for patients in whom the procedure was deemed a last resort.132 Unfortunately, the idea of last resort assumes good natural history data for medically treated symptomatic intracranial stenoses; however, such data are not available. There have been two studies of elective stent implantation with symptomatic M1 stenosis. The rationale for pursuing this treatment is that

symptomatic M1 stenosis carries an annual stroke recurrence rate of about 8%. One study enrolled 14 patients, and the other enrolled 40. The former had morbidity and mortality rates of 33.3% and 8.3%, respectively; the latter, 10% and 2.5%. In the larger study, M1 lesions were classified on the basis of their location, morphology, and access. All three factors were relevant to periprocedural complication rates and efficacy at 10month median follow-up. The Stenting for Symptomatic Atherosclerotic Lesions in the Vertebral and Intracranial Arteries (SSYLVIA) trial, the only prospective multicenter trial of intracranial angioplasty and stent implantation to date, investigated the feasibility of intracranial stent implantation for patients with symptomatic intracranial LAA. In 95% of the patients, a stent was successfully deployed with a 30-day stroke rate of 6.6%. All strokes were observed in the posterior circulation, but no deaths occurred. At 6 months, one third of the patients after intracranial stent implantation experienced restenosis involving more than 50% diameter reduction, about 40% of these stenoses being symptomatic. SSYLVIA had important limitations. First, patients who entered this trial were not “medication failures”; that is, they had not necessarily received currently accepted maximal medical therapy (antiplatelets, statins, and aggressive risk factor modification). Second, it was not a randomized study; therefore, it could not answer the questions of whether intracranial angioplasty is superior to currently accepted medical therapy. These few studies indicate that angioplasty and stent implantation for symptomatic intracranial stenoses carry relatively high morbidity and mortality rates. However, the disease itself seems to have a poor natural history, according to existing data. Prospective randomized trials with a maximal medical therapy condition are needed.

K E Y

P O I N T S

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Stroke is the third leading cause of death and the leading cause of long-term disability in the United States. Annually, about 700,000 strokes occur in the United States and 150,000 in the United Kingdom.

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Eighty percent of strokes are ischemic, and 20% are hemorrhagic.

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The majority of ischemic strokes can be classified, with regard to etiology, into one of the following groups: large artery, lacunar, embolic, cryptogenic, or stroke of other determined cause.

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Identification of a patient’s stroke syndrome provides insight into underlying mechanism, prognosis, and plan for rehabilitation.

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Large clinical trials often “lump” many stroke types together, but advances in diagnostic technology provides the capability to distinguish strokes into mechanistic subtypes. It can be predicted that future therapeutic trials will be directed at specific stroke subtypes in order to target specific pathophysiological mechanisms.

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Stroke mortality has declined in the last few years, probably as a result of better medical care and dedicated stroke and neurointensive care units.

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment ●

Intravenous recombinant tissue plasminogen activator is approved for all ischemic stroke subtypes within 3 hours of onset if the inclusion and exclusion criteria are met. Advances in imaging of the ischemic penumbra may enable identification of patients who would benefit from intravenous tissue-type plasminogen activator outside the 3-hour window. Intra-arterial thrombolysis or mechanical extraction is an alternative treatment after the 3-hour window period.

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Multiple clinical trials have established the efficacy of antiplatelet agents for secondary stroke prevention. Oral anticoagulation is the treatment of choice for primary and secondary stroke prevention in patients with atrial fibrillation.

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Evidence does not support the use of heparin (either low-molecular-weight or unfractionated) in acute stroke treatment.

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Carotid endarterectomy is well established as the treatment of choice for symptomatic patients with high-degree internal carotid artery stenosis. A lesser benefit is observed for asymptomatic patients, but more strict selection criteria should be used. Angioplasty and stent implantation in the carotid artery are available as alternative treatments for patients with high operative risk because of comorbid medical conditions or for surgically inaccessible lesions.

Suggested Reading Algra A, De Schryver ELLM, van Gijn J, et al: Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischemic attack or minor stroke of presumed arterial origin. Cochrane Database Syst Rev 2006; 3:CD001342. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325:445-453. Hacke W, Donnan G, Fieschi C, et al: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363:768-774. Hart RG, Palacio S, Pearce LA: Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke 2002; 33:2722-2727. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587.

References 1. American Heart Association: Heart Diseases and Stroke Statistics—2005 Update. Dallas: American Heart Association, 2005, pp 16-20. 2. Saver JL, Kidwell C: Neuroimaging in TIAs. Neurology 2004; 62(8, Suppl 6):S22-S25. 3. Rovira A, Rovira-Gols A, Pedraza S, et al: Diffusion-weighted MR imaging in the acute phase of transient ischemic attacks. AJNR Am J Neuroradiol 2002; 23:77-83. 4. Albers GW, Caplan LR, Easton JD, et al: TIA working group (2002). Transient ischemic attack—proposal for a new definition. N Engl J Med 2002; 347:1713-1716.

583

5. Ay H, Koroshetz W, Benner T, et al: Transient ischemic attack with infarction: a unique syndrome? Ann Neurol 2005; 57:679-686. 6. Hill MD, Yiannakoulias N, Jeerakathil T, et al: The high risk of stroke immediately after transient ischemic attack. Neurology 2004; 62:2015-2020. 7. Lovett JK, Dennis MS, Sandercock PAG, et al: Very early risk of stroke after a first transient ischemic attack. Stroke 2003; 34:e138-e142. 8. Lisabeth LD, Ireland JK, Risser JMH, et al: Stroke risk after transient ischemic attack in a population-based setting. Stroke 2004; 35:1842-1846. 9. Johnston SC, Gress DR, Browner WS, et al: Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284:2901-2906. 10. Baron JC: Mapping the ischaemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis 1999; 9:193-201. 11. Wong EW, Pullicino PM, Benedict R: Deep cerebral infarcts extending to the subinsular region. Stroke 2001; 32:22722277. 12. Wong KS, Gao S, Chan YL, et al: Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002; 52:74-81. 13. Jackson C, Sudlow C: Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke 2005; 36:891-901. 14. Alexandrov AV, Felberg RA, Demchuck AM, et al: Deterioration following spontaneous improvement: sonographic findings in patients with acutely resolving symptoms of cerebral ischemia. Stroke. 2000; 31:915-919. 15. Eliasziw M, Kennedy J, Hill MD, et al: Early stroke risk after a transient ischemic attack in patients with internal carotid artery disease. CMAJ 2004; 170:1105-1109. 16. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445-453. 17. Arenillas JF, Molina CA, Montaner J, et al: Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: a long-term follow-up transcranial Doppler ultrasound study. Stroke 2001; 32:2898-2904. 18. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al: Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305-1316. 19. Gasecki AP, Ferguson GG, Eliasziw M, et al: Endarterectomy for severe carotid artery stenosis after a nondisabling stroke: results from the North American Symptomatic Carotid Endarterectomy Trial. J Vasc Surg 1994; 20:288-295. 20. Gan R, Sacco RL, Kargman DE, et al: Testing the validity of the lacunar hypothesis: the Northern Manhattan Stroke Study experience. Neurology 1997; 48:1204-1211. 21. Ay H, Oliveira-Filho J, Buonanno FS, et al: Diffusion weighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke 1999; 30:2644-2650. 22. Kato H, Izumiyama M, Izumiyama K, et al: Silent cerebral microbleeds on T2*-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002; 33:1536-1540. 23. Wardlaw JM: What causes lacunar stroke? J Neurol Neurosurg Psychiatry 2005; 76:617-619. 23a. Cerebrovasc Dis 2004; 17(Suppl 5):52. 23b. Macdonald RL, Kowalczuk A, Johns L: Emboli enter penetrating arteries of monkey brain in relation to their size. Stroke 1995; 26:1247-1250. 24. Wardlaw JM, Dennis MS, Warlaw CP: Imaging appearance of the symptomatic perforating artery in patients with lacunar

584

Section

IX

C e r e b r o va s c u l a r D i s e a s e

infarction: occlusion or other vascular pathology? Ann Neurol 2001; 50:208-215. 24a. Sen S, Laowatana S, Lima J, Oppenheimer SM: Risk factors for intracardiac thrombus in patients with recent ischemic cerebrovascular events. J Neurol Neurosurg Psychiatry 2004; 75:1421-1425. 24b. Hagen PT, Scholz DG, Edwards WD: Incidence and size of patient foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59:17-20. 25. Overell JR, Bone I, Lees KR: Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172-1179. 25a. Karttunen V, Hiltunen L, Rasi V, et al: Factor V Leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patient foramen ovale. Blood Coagul Fibrinolysis 2003; 14:261-268. 25b. Pezzini A, Del Zotto E, Magoni M: Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke 2003; 34:28-33. 26. Mcleod MR, Amarenco P, Davis SM, et al: Atheroma of the aortic arch: an important and poorly recognised factor in the aetiology of stroke. Lancet Neurol 2004; 3:408-414. 27. Agmon Y, Khanderia BK, Meissner I, et al: Relation of coronary artery disease and cerebrovascular disease with atherosclerosis of the thoracic aorta in the general population. Am J Cardiol 2002; 89:262-267. 28. Amarenco P, Cohen A, Tzourio C, et al: Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474-1479. 29. Tunick PA, Perez JL, Kronzon I: Protruding atheromas in the thoracic aorta and systemic embolization. Ann Intern Med 1991; 115:423-427. 30. Chowdhury D, Wardlaw JM, Dennis MS: Are multiple acute small subcortical infarctions caused by embolic mechanisms? J Neurol Neurosurg Psychiatry 2004; 75:1416-1420. 31. Dziewas R, Konrad C, Drager B, et al: Cervical artery dissection—clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003; 250:1179-1184. 32. Rubinstein SM, Peerdeman SM, van Tulder MW, et al: A systematic review of the risk factors for cervical artery dissection. Stroke 2005; 36:1575-1580. 32a. Arboix A, Lopez-Grau M, Casasnovas C, et al: Clinical study of 39 patients with atypical lacunar syndrome. J Neurol Neurosurg Psychiatry 2006; 77:381-384. 33. Paciaroni M, Caso V, Milia P: Isolated monoparesis following stroke. J Neurol Neurosurg Psychiatry 2005; 76:805-807. 34. Schmahmann JD: Vascular syndromes of the thalamus. Stroke 2003; 34:2264-2278. 35. Godefroy O, Dubois C, Debachy B, et al: Vascular aphasias: main characteristics of patients hospitalized in acute stroke units. Stroke 2002; 33:702-705. 36. Kumral E, Bayulkem G, Evyapan D, et al: Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings. Eur J Neurol 2002; 9:615-624. 37. Schneider R, Gautier JC: Leg weakness due to stroke. Site of lesions, weakness patterns and causes. Brain 1994; 117(Pt 2):347-354. 38. Kumral E, Kisabay A, Atac C: Lesion patterns and etiology of ischemia in superior cerebellar artery territory infarcts. Cerebrovasc Dis 2005; 19:283-290. 39. Caplan LR: “Top of the basilar” syndrome. Neurology 1980; 30:72-79. 40. Barber PA, Demchuk AM, Zhang J, et al: Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670-1674.

41. Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352:1245-1251. 42. Davis S, Fisher M, Warach S (eds): Magnetic Resonance Imaging in Stroke. Cambridge, UK: Cambridge University Press, 2003. 43. Li F, Silva MD, Sotak CH, et al: Temporal evolution of ischemic injury evaluated with diffusion-, perfusion-, and T2weighted MRI. Neurology 2000; 54:689. 44. Buskens E, Nederkoorn P, Tineke BW, et al: Imaging of carotid arteries in symptomatic patients: cost-effectiveness of diagnostic strategies. Radiology 2004; 233:101-112. 45. Long A, Lepoutre A, Corbillon E, et al: Critical review of nonor minimally invasive methods (duplex ultrasonography, MRand CT-angiography) for evaluating stenosis of the proximal internal carotid artery. Eur J Vasc Endovasc Surg 2002; 24:4352. 46. Johnston DCC, Goldstein LB: Clinical carotid endarterectomy decision making: noninvasive vascular imaging versus angiography. Neurology 2001; 56:1009-1015. 47. El-Saden SM, Grant EG, Hathout GM, et al: Imaging of the internal carotid artery: the dilemma of total versus near total occlusion. Radiology 2001; 221:301-308. 48. Wester P, Radberg J, Lundgren B, et al: Factors associated with delayed admission to hospital and in-hospital delays in acute stroke and TIA: a prospective, multicenter study. Stroke 1999; 30: 40-48. 49. Morris DL, Rosamond W, Madden K, et al: Prehospital and emergency department delays after acute stroke. The Genentech Stroke Presentation Survey. Stroke 2000; 31:2585-2590. 50. Kothari RU, Brott T, Broderick JP, et al: Emergency physicians: accuracy in the diagnosis of stroke. Stroke 1995; 26:2238-2241. 51. Ferro JM, Pinto AN, Falcao I, et al: Diagnosis of stroke by the nonneurologist. A validation study. Stroke 1998; 29:11061109. 52. Flynn EP, Auer RN: Eubaric hyperoxemia and experimental cerebral infarction. Ann Neurol 2002; 52:566-572. 53. Singhal AB, Dijkhuizen RM, Rosen B, et al: Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke. Neurology 2002; 58:945-952. 54. Pancioli AM, Bullard MJ, Grulee ME, et al: Supplemental oxygen use in ischemic stroke patients: does utilization correspond to need for oxygen therapy? Arch Intern Med 2002; 162:49-52. 55. Goldstein L: Blood pressure management in patients with acute ischemic stroke. Hypertension 2004; 43:137-141. 56. Lisk DR, Grotta JC, Lamki LM, et al: Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Arch Neurol 1993; 50:855-862. 57. Wahlgren NG, MacMahon DG, DeKeyser J, et al: Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis 1994; 4:204-210. 58. Oliveira-Filho J, Silva SCS, Trabuco CC, et al: Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology 2003; 61:1047-1051. 59. Rordorf G, Koroshetz WJ, Ezzeddine MA, et al: A pilot study of drug-induced hypertension for treatment of acute stroke. Neurology 2001; 56:1210-1213. 60. Pulsinelli WA, Waldman S, Rawlinson D, et al: Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 1982:1239-1246. 61. Parsons MW, Barber A, Desmond PM, et al: Acute hyperglycemia adversely affects stroke outcome: a magnetic reso-

chapter 42 ischemic stroke: mechanisms, evaluation, and treatment

62. 63. 64.

65. 66. 67. 68. 69. 70. 71. 72.

73. 74.

75.

76. 77.

78. 79.

80. 81.

nance imaging and spectroscopy study. Ann Neurol 2002; 52:20-28. Baird TA, Parsons MW, Phanh T, et al: Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 2003; 34:2208-2214. Bruno A, Levine SR, Frankel MR, at al: Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002; 59:669-674. Alvarez-Sabin J, Molina C, Ribo M, et al: Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke 2004; 35:2493-2499. Leigh R, Zaidat OO, Suri MF, et al: Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. Stroke 2004; 35:1903-1907. Williams LS, Rotich J, Qi R, et al: Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology 2002; 59:67-71. Gray CS, Hildreth AJ, Alberti GKMM, et al: Poststroke hyperglycemia. Natural history and immediate management. Stroke 2004; 35:122-126. Bruno A, Saha C, Williams LS, et al: IV Insulin during acute cerebral infarction in diabetic patients. Neurology 2004; 62:1441-1442. Hajat CH, Hajat S, Sharma P: Effects of poststroke pyrexia on stroke outcome: a meta-analysis of studies in patients. Stroke 2000; 31:410-414. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557-563. The Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556. Multicentre Acute Stroke Trial—Italy (MAST-I) Group: Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346:1509-1514. The Multicenter Acute Stroke Trial—Europe Study Group (MAST-E): Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335:145-150. Donnan GA, Davis SM, Chambers BR, et al: Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276:961-966. Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274:1017-1025. The NINDS rt-PA Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587. Kwiatkowski TG, Libman RB, Frankel M, et al: Effects of tissue plasminogen activator for acute ischemic stroke at one year. NINDS Recombinant Tissue Plasminogen Activator Stroke Study. N Engl J Med 1999; 10:1781-1787. Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome. The NINDS rt-PA Stroke Study. Neurology 2000; 55:1649-1655. Broderick JP, Lu M, Kothari R, et al: Finding the most powerful measures of effectiveness of tissue plasminogen activator in the NINDS t-PA Stroke Trial. Stroke 2000; 31:2335-2341. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. NINDS rt-PA Stroke Study Group. Stroke 1997; 28:2109-2118. Clark WM, Wissman S, Albers GW, et al: Recombinant tissuetype plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS study: a randomized controlled trial. JAMA 1999; 282:2019-2026.

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82. The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363:768-774. 82a. Wardlaw JM, Zoppo G, Yamaguchi T, Berge E: Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003; (3):CD000213. 83. Kidwell CS, Alger JR, Saver JL: Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 2003; 34:27292735. 84. Barber PA, Parsons MW, Desmond PM, et al: The use of PWI and DWI measures in the design of “proof-of-concept” stroke trials. J Neuroimaging 2004; 14:123-132. 85. Kidwell C, Starkman S, Jahan R, et al: Pretreatment MRI penumbral pattern predicts good clinical outcome following mechanical embolectomy [Abstract]. Stroke 2004; 35:294. 86. Katzan IL, Furlan AJ, Lloyd LE, et al: Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000; 283:1151-1158. 87. Lopez-Yunez AM, Bruno A, Williams L, et al: Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke 2001; 32:12-16. 88. Katzan IL, Hammer MD, Furlan AJ, et al: Quality improvement and tissue-type plasminogen activator for acute ischemic stroke. A Cleveland update. Stroke 2003; 34:799-800. 89. Grotta J, Burgin WS, El-Mitwalli A, et al: Intravenous tissuetype plasminogen activator therapy for ischemic stroke. Arch Neurol 2001; 58:2009-2013. 90. Hill MD, Buchan AM: Canadian Activase for Stroke Effectiveness Study (CASES). Can J Neurol Sci 2001; 28:232-238. 91. Del Zoppo GJ, Higashida RT, Furlan AJ, et al: PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998; 29:4-11. 92. Furlan AJ, Higashida RT Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke—The PROACT II study: a randomized controlled trial. JAMA 1999; 282:2003-2011. 93. Lewandowski CA, Frankel M, Tomsick TA, et al: Combined intravenous and intra-arterial t-PA versus intra-arterial therapy for acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999; 30:2598-2605. 94. Tomsick T, Broderick JP, Pancioli AP, at al: Combined IV-IA tPA treatment in major acute ischemic stroke [Abstract]. Stroke 2002; 33:359. 95. Antithrombotic Trialists’ Collaboration: Collaborative metaanalysis of randomized trials of antiplatelet therapy for the prevention of death, MI, and stroke in high risk patients. BMJ 2002; 324:71-86. 95a. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N Engl J Med 1991; 325:1261-1266. 95b. Farrell B, Godwin J, Richards S, Warlow C: The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54:1044-1054. 96. International Stroke Trial Collaborative Group: The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349:1569-1581. 97. Chinese Acute Stroke Trial collaborative group: CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349:16411649. 97a. Maulaz AB, Bezerra DC, Michel P, Bogousslavsky J: Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2006; 62:1217-1220.

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98. Diener HC, Cunha L, Forbes C, et al: European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1-13. 99. Duke RJ, Bloch RF, Fong HC, et al: Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med 1986; 105:825-828. 100. Bath PM, Lindenstrom E, Boysen G, et al: Tinzaparin in Acute Ischemic Stroke (TAIST): a randomised aspirin-controlled trial. Lancet 2001; 358:702-710. 101. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) investigators. JAMA 1998; 279:1265-1272. 102. Berge E, Abdelnoor M, Nakstad PH, et al: Low molecularweight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355:1205-1210. 103. Hart RG, Palacio S, Pearce LA: Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke 2002; 33:2722-2727. 104. Hart RG, Benavente O, McBride R, et al: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131:492-501. 105. SPIRIT study: a randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann Neurol 1997; 42:857-865. 106. Olsson SB, Executive Steering Committee on behalf of the SPORTIF III Investigators: Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362:1691-1698. 107. Pullicino PM, Halperin JL, Thompson JL: Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000; 54:288-294. 108. Mohr JP, Thompson JL, Lazar RM, et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345:1444-1451. 109. Chimowitz MI, Kokkinos J, Strong J, et al: The WarfarinAspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488-1493. 110. Algra A, De Schryver ELLM, van Gijn J, et al: Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischemic attack or minor stroke of presumed arterial origin. Cochrane Database Syst Rev 2006; 3:CD001342. 111. Levine SR, Tilley BC, Thompson JL, et al: Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 2004; 291:576-584. 112. Mas JL, Arquizan C, Lamy C, et al: Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysms or both. N Engl J Med 2001; 345:1740-1746. 113. Homma S, Sacco RL, Di Tullio MR, et al: Effect of medical treatment in stroke patients with patent foramen ovale. Circulation 2002; 105:2625-2631. 114. Bosch J, Yusuf S, Pogue J, et al: Use of ramipril in preventing stroke: double blind randomized trial. BMJ 2002; 324:699-704. 115. Yusuf S, Sleight P, Pogue J, et al: Effects of angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:145153. 116. PROGRESS Collaborative group: Randomised trial of a perindopril-based blood pressure-lowering regimen among

117.

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123.

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126.

127. 128.

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6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033-1041. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002; 360:7-22. Toole JF, Malinow MR, Chambless LE, et al: Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004; 291:565-575. Dusitanond P, Eikelboom JW, Hankey GJ, et al: Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial. Stroke 2005; 36:144-146. VITATOPS Trial Study Group: The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteinelowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis 2002; 13:120-126. Viscoli CM, Brass LM, Kernan WN, et al: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345:1243-1249. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al: Effect of estrogen plus progestin on stroke in postmenopausal women. The Women’s Health Initiative: a randomized trial. JAMA 2003; 289:2673-2684. North American Symptomatic Carotid Endarterectomy Trialist’s Collaborative Group: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415-1425. Mayberg MR, Wilson SE, Yatsu F, et al: Veterans Affairs Cooperative Studies Program 309 Trialist Group. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991; 266:3289-3294 European Carotid Surgery Triallists Collaborative Group: MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or mild (0-29%) carotid stenosis. Lancet 1991; 337:1235-1243. European Carotid Surgery Trialists’ Collaborative Group: Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Surgery Trial (ECST). Lancet 1998; 351:1379-1387. Rothwell PM, Gutnikov SA, Warlow CP: Reanalysis of the final results of the European Carotid Surgery Trial. Stroke 2003; 34:514-523. Rothwell PM, Eliasziw M, Gutnikov SA, et al: Sex difference in the effect of time from symptoms to surgery on benefit from carotid endarterectomy for transient ischemic attack and nondisabling stroke. Stroke 2004; 35:2855-2861. Brott TG, Brown RD, Meyer FB, et al: Carotid revascularization for prevention of stroke: carotid endarterectomy and carotid artery stenting. Mayo Clin Proc 2004; 79:1197-1208. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001; 357:1729-1737. Yadav JS, Wholey MH, Kuntz RE, et al: Protected carotidartery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004; 351:1493-1501. SSYLVIA Study Investigators: Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004; 35:1388-1392.

CHAPTER

43

INTRACRANIAL HEMORRHAGE: ANEURYSMAL, IDIOPATHIC, AND HYPERTENSIVE ●

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Jon Sen, Rasheed Afinowi, Neil Kitchen, and Antonio Belli

Bleeding in the cranial space, or intracranial hemorrhage (ICH), often results in disastrous consequences for patients. ICH can be classified in terms of location, being either intraparenchymal or within spaces such as the subarachnoid, ventricular, subdural, or extradural space. Bleeding may be spontaneous or traumatic; sometimes no cause is found. It should be remembered that intracranial vascular abnormalities can also manifest without bleeding; early signs may be caused by compression of surrounding anatomical structures. The effect of ICH on the general population can be fully grasped when viewed within the broader category of stroke, currently the leading cause of neurological deficit in the world and the third leading cause of death in the United States, accounting for 15% of all U.S. deaths annually.1 ICH accounts for 10% to 17% of all strokes, and the rate of mortality from ICH is considerably higher than that from nonhemorrhagic or ischemic stroke; some studies quote a mortality rate as high as 90%.2 This chapter focuses on ICH with particular regard to cerebral aneurysm and hypertensive and idiopathic hemorrhage.

ANEURYSMAL INTRACRANIAL HEMORRHAGE More than 50% of cases of nontraumatic ICH are secondary to rupture of an intracranial aneurysm. Approximately 20% of patients with subarachnoid hemorrhage (SAH) present with an associated intracerebral hematoma. Outcome is related to extent of neuronal loss at the time of the hemorrhage (primary brain injury) and in the subsequent days (secondary brain injury). Further neuronal death secondary to cerebral ischemia is the final common pathway of secondary brain damage; this is preventable, and prevention forms the basis of management. Occlusion of the aneurysm is an integral part of this management strategy, because of the high risk of catastrophic rebleeding.

Epidemiology Cerebral aneurysm has been recognized as a cause of human illness since the end of the 19th century, but the actual incidence is difficult to estimate. In autopsy studies, the prevalence ranges from 0.2% to 7.9%. Other studies indicate a prevalence

of 5%.3 The ratio of ruptured aneurysm to unruptured (incidental) aneurysm is 5:3 to 5:6 (rough estimate is 1:1; i.e., 50% of these aneurysms rupture).4 Only 2% of aneurysms manifest during childhood.5

Etiology The exact pathophysiology of the development of aneurysms is controversial, but abnormal vascular anatomy and flow dynamics are important factors. In contrast to extracranial blood vessels, there is less elastic in the tunica media and adventitia of cerebral blood vessels, the media has less muscle, the adventitia is thinner, and the internal elastic lamina is more prominent.6,7 Outpouching is more likely to occur because of this, but it is also noteworthy that aneurysms are usually found at vessel bifurcations at sites of greatest flow. This, together with the fact that large cerebral blood vessels lie within the subarachnoid space with little supporting connective tissue,8,8a may predispose these vessels to the development of saccular aneurysms. Aneurysm formation is more common in women and in smokers. Beyond the third decade in particular, SAH is usually caused by rupture of a cerebral aneurysm. Other than size of aneurysm alone, the “aspect ratio” (aneurysm depth to aneurysm neck) has also been shown to be a potentially useful predictor of rupture (Figs. 43–1 and 43–2).9 The etiology of aneurysms may be any of the following: ■ Congenital predisposition (e.g., defect in the muscular layer

of the arterial wall) ■ “Atherosclerotic” or hypertensive, the presumed etiology of

■ ■ ■ ■ ■

most saccular aneurysms; probably interacts with congenital predisposition Embolic: as in atrial myxoma Infectious (“mycotic aneurysms”) Traumatic Associated with other conditions Location related

Saccular, or berry, aneurysms are usually located at bifurcations of the major cerebral arteries. Aneurysms located more peripherally do occur, but these tend to be associated with infection (mycotic aneurysms) or trauma. Fusiform aneurysms are more common in the vertebrobasilar system.

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(Lactate, Pyruvate)

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Of all saccular aneurysms, 85% to 95% are located in the carotid system, with the following three most common locations: (1) the anterior communicating artery (ACom) for 30% (aneurysms in the ACom and anterior cerebral artery are more common in male patients); (2) the posterior communicating artery for 25%; and (3) the middle cerebral artery for 20%. Of the remaining saccular aneurysms, 5% to 15% are located in posterior circulation (vertebrobasilar); 10%, at the basilar tip (most common), followed by the basilar artery–superior cerebellar artery junction, basilar artery–vertebral artery junction, and anterior inferior cerebellar artery; and 5%, on the vertebral artery (vertebral artery–posterior inferior cerebellar artery

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junction most common). Twenty percent to 30% of patients with aneurysm have multiple aneurysms.10

Manifestation of Aneurysms Major rupture is the most frequent manifestation leading to SAH. Clinical features may vary from sudden headache to a moribund comatose state. Neurological deficits, if present, depend on location and size of the hematoma. Signs of meningism with photophobia, neck stiffness, and vomiting are often seen. Progressive neurological deficit or decreasing con-

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Figure 43–1. Plot 1 with markers. Microdialysis markers of 64-year-old woman who presented with a World Federation of Neurosurgical Societies grade 5 subarachnoid hemorrhage. The patient recovered to the point of full consciousness, but she had to be sedated and paralyzed for the management of a chest infection. Time is on the x axis (one tick = 24 hours). The vertical red line on the left marks the beginning of a gradual deterioration of the brain metabolic state, illustrated by a surge in lactate/ pyruvate (L/P) ratio and glycerol level above normal values, in the absence of any other clinical signs. A few hours later, the patient became hypertensive, and her pupils became fixed and dilated (vertical red line on the right). A computed tomographic scan confirmed the development of a large infarct in the right middle cerebral territory, ipsilateral to the microdialysis probe.

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Figure 43–2. Plot 2 with markers. Microdialysis markers of 53-year-old woman who presented with a World Federation of Neurosurgical Societies grade 5 subarachnoid hemorrhage. The patient died several days later without regaining consciousness. Values of lactate/pyruvate (L/P) ratio, glycerol (μmol/L), glutamate (μmol/L) and transcranial Doppler (TCD) imaging velocities (cm/second) of the ipsilateral middle cerebral artery are plotted against time (one tick = 24 hours). Values above the dotted horizontal lines are considered abnormal. The plot shows persistent high levels of microdialysis markers, indicating a prolonged metabolic crisis of the brain. Many TCD imaging values are above the dotted line, which suggests the presence of cerebral vasospasm, and appear to parallel glutamate levels closely.

chapter 43 intracranial hemorrhage scious level may occur as a result of mass effect from a growing hematoma or the development of hydrocephalus. Ruptured cerebral aneurysm may be accompanied by the following: ■ Intracerebral hemorrhage, which occurs in 20% to 40% of

affected patients (more common with aneurysms distal to the circle of Willis; e.g., middle cerebral artery aneurysms). ■ Intraventricular hemorrhage, which occurs in 13% to 28%.11 ■ Subdural hemorrhage, which occurs in 2% to 5%. Intraventricular hemorrhage occurs with 13% to 28% of ruptured aneurysms in clinical series (higher in autopsy series)11 and may lead to obstructive hydrocephalus. The presence of intraventricular hemorrhage is an indicator of poor prognosis11 (64% rate of mortality); ventricular size on admission is the most important prognostic factor (large ventricles being worse). Patterns that may occur include the following: ■ ACom aneurysm, which tends to produce intraventricular

hemorrhage by rupture through the lamina terminalis into the lateral or anterior third ventricles. ■ Distal basilar or carotid terminus aneurysms, which may rupture through the floor of the third ventricle. ■ Distal posterior inferior cerebellar artery aneurysms, which may rupture directly into the fourth ventricle through the foramen of Luschka.12

Other Possible Presentations Mass effect can give rise to possible “warning signs”: for example, giant aneurysms can include brainstem compression, which produces hemiparesis and cranial neuropathies; cranial neuropathy (average latency from symptom to SAH was 110 days) can include non–pupil-sparing third nerve palsy produced by expanding posterior communicating artery aneurysm; rarer cranial neuropathies produce visual loss as a result of compressive optic neuropathy12 (ophthalmic artery aneurysms) and chiasmal syndromes (ophthalmic, ACom, or basilar apex aneurysms). Facial pain syndromes in the ophthalmic or maxillary nerve distribution that may mimic trigeminal neuralgia can occur with intracavernous or supraclinoid aneurysms.13,14 Also, intrasellar aneurysm may produce disturbances in the endocrine system.15 Warning or sentinel hemorrhage (minor bleeding) may occur; this condition has the shortest latency (10 days) between symptom onset and SAH.16 Headache without hemorrhage may occur; this may be acute, severe, and “thunderclap” in nature, sometimes described as the “worst headache of my life.” It may be caused by aneurysmal expansion, thrombosis, or intramural bleeding17 (all without rupture). Alternatively, it can be chronic, having usually been present for more than 2 weeks, is unilateral (often retro-orbital or periorbital) in about one half of cases, and is possibly caused by dural irritation. In the other one half of cases, it is diffuse or bilateral, possibly caused by mass effect that produces raised intracranial pressure. Asymptomatic aneurysm may be discovered incidentally on angiography, computed tomographic (CT) scan, or magnetic resonance imaging obtained for other reasons. Conditions associated with aneurysms include the following: ■ Autosomal dominant polycystic kidney disease ■ Fibromuscular dysplasia

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■ Arteriovenous malformations ■ Connective tissue disorders: Ehlers-Danlos syndrome type ■ ■ ■ ■

IV, Marfan’s syndrome Osler-Weber-Rendu syndrome Family history of intracranial aneurysms Bacterial endocarditis Coarctation of the aorta

Diagnosis and Investigations Diagnosis of aneurysmal SAH is crucial, and there are two main components to this: identification of blood on CT scan and demonstration of blood breakdown products on spectroscopy. Computed tomography is 98% sensitive for detection of SAH in the first 12 hours after the ictus, but this rate declines to approximately 70% by day 3. Thus, without other diagnostic facilities, CT scanning alone may miss SAH. Lumbar puncture performed 12 hours after the onset of symptoms is therefore vital for diagnosis if CT scan results are negative or equivocal. The presence of bilirubin in the cerebrospinal fluid confirms SAH. Cerebral angiography is the “gold standard” for demonstrating the cerebral vasculature and is mandatory in SAH. An adequate study should reveal the causative aneurysm. Computed tomographic angiography is being increasingly used to diagnose and provide information for treatment of intracranial aneurysms. Conventional angiography is usually carried out by a neuroradiologist through a femoral artery puncture with local anesthetic, whereas computed tomographic angiography can be performed with injection of contrast medium into a forearm vein. This can be done in the computed tomography suite immediately after the diagnostic CT scan.

Treatment Exclusion of the Aneurysm Aneurysmal rebleeding carries high rates of morbidity and mortality. Risk is highest in the first 24 to 48 hours after hemorrhage, but there is a continuing risk of about 50% over the first month. Removal of the aneurysm from the circulation is therefore crucial, although this forms only a part of the whole management plan. Traditionally, aneurysmal occlusion was achievable only with craniotomy and dissection of the aneurysm in the basal cisterns and surgical clipping of the aneurysm neck. However, endovascular occlusion with platinum coils is being increasingly used as an alternative to craniotomy. This trend has been influenced by the results of the International Subarachnoid Aneurysm Trial (ISAT), which concluded that coiling is a safer treatment option than surgery (Molyneux et al, 2002).18 This remains a controversial area, however, and long-term studies investigating the risk of rebleeding (i.e., efficacy) after coiling are particularly required.

Cerebral Vasospasm Cerebral vasospasm is constriction of the cerebral arterial vasculature that leads to delayed cerebral ischemia. The

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pathophysiology is poorly understood. Traditionally, rebleeding was the major concern after rupture of a cerebral aneurysm. However, the general shift to early occlusive therapy has minimized the effect of rebleeding. Indeed, except for the initial hemorrhage, cerebral vasospasm is now recognized as the most significant cause of death and disability, killing 7% of patients and leading to severe disability in another 7%.19 It is present in 20% to 30% of cases of aneurysmal SAH and is seen in 30% to 70% of angiograms at day 7 after SAH with and without clinical deficit. Vasospasm typically occurs at days 3 to 5 but has been reported up until day 21. Common manifestations include reduced Glasgow Coma Scale (GCS) score, confusion, and focal deficit. Risk is related to amount of blood seen on CT scan (Fisher grade), location (more risk in ACom than in middle cerebral artery), and the World Federation of Neurological Surgeons grade (a useful scale that combines GCS score with the presence or absence of neurological deficit). Management of vasospasm combines triple-H therapy (hypervolemia, hypertension, and hemodilution) with the calcium channel antagonist nimodipine20 and transcranial Doppler ultrasonography. Hypertension is achieved with inotropes and is facilitated by early occlusion of the aneurysm. Several studies have shown the benefit of volume expansion in reversing deficits,21 but triple-H therapy has yet to be tested in a randomized controlled trial. In total, 11 trials of calcium channel antagonists have been reported, and the evidence suggests that they reduce the risk of vasospasm, although the results depended mainly on one trial with nimodipine.22 The exact mechanism of action of nimodipine remains unknown, but it is now standard therapy for vasospasm prophylaxis. Detection and monitoring of vasospasm are also possible with measurement of transcranial Doppler velocities, but this technique is unreliable: It is not “on-line,” and interoperator variability is large. Developments such as the application of microdialysis to the injured human brain may improve monitoring and detection of cerebral vasospasm.23 There is good evidence that an increase in ratio of lactate to pyruvate precedes onset of vasospasm by several hours.24 Other studies point to the possibility that outcome after SAH is genetically predetermined.25

Outcome The outcome depends on the severity of the primary brain injury and the extent to which secondary injury has been offset. Removal of an aneurysm from the cerebral circulation by surgical clipping or coiling is crucial but is only part of the overall medical management, which includes hydration, judicious control of blood pressure with inotropes if necessary, and administration of nimodipine to reduce the risk of delayed cerebral ischemia and further neurological deterioration as a consequence. More research is needed to elucidate the natural history of aneurysms and to clarify many issues regarding their treatment.

HYPERTENSIVE INTRACRANIAL HEMORRHAGE Hypertension is a major cause of spontaneous (i.e., nontraumatic) ICH. Hypertensive hemorrhage most often occurs into the brain parenchyma (cerebral hemispheres, cerebellum, and

brainstem) and may also involve, by extension, the ventricular system, subarachnoid spaces, or subdural spaces.

Epidemiology Stroke is the third most common cause of mortality and the leading cause of chronic neurological morbidity worldwide.26–30 Spontaneous intracerebral hemorrhage accounts for approximately 10% to 15% of all cases of stroke, with an estimated annual incidence of 37,000 cases in the United States; hypertension causes 40% to 60% of spontaneous intracerebral hemorrhages.28,36 ICH is associated with a much higher rate of mortality than are ischemic forms of stroke.27,28,56,57

Etiology Hypertensive hemorrhages may result from both chronically and acutely raised blood pressures, causes of which are listed as follows: ■ ■ ■ ■

Chronic hypertension (most common cause)29,40,48,49 Primary (essential) hypertension Secondary systemic hypertension Acute rise in blood pressure32 after (sympathomimetic) rise in blood pressure induced by drugs (amphetamines, cocaine, pseudoephedrine, and heroin); cold exposure; trigeminal stimulation; and acute increase in cerebral blood flow with resulting intracranial arterial hypertension after carotid endarterectomy or cardiac surgery

Pathology Chronic hypertension is believed to alter vascular wall structure, resulting in degenerative weakening and consequent rupture, but the exact pathological process involved remains controversial.31a,33 Jean-Martin Charcot and Charles-Joseph Bouchard first described miliary aneurysms, which were thought to be responsible for hypertensive hemorrhages, inasmuch as they are commonly found on the perforating arteries of the basal ganglia and pons (common sites of hypertensive hemorrhages) and were believed to be more common in hypertensive patients. Fischer demonstrated these to be false aneurysms representing small (0.2- to 1.0-mm) healed foci of arteriolar bleeds. He attributed hypertensive hemorrhages to lipohyalinosis (found closer to sites of rupture than Charcot-Bouchard miliary aneurysms), as well as to plasmatic destruction and atherosclerosis of the vessel wall.38,39 It has also been hypothesized that the walls of arteries supplying regions that commonly bleed are thinner than vessels of similar size and are, in addition, subject to higher pressures as they originate from larger vessels.42

Distribution of Hypertensive Hemorrhage In most hypertensive hemorrhages, bleeding is primarily into the brain parenchyma. This may be associated with extensions into the ventricular system, the subarachnoid space, and, in rare cases, the subdural space. Subarachnoid and intraventricular hemorrhages, occurring in the absence of parenchymal bleeding, usually result from other pathology, such as

chapter 43 intracranial hemorrhage T A B L E 4 3 – 1. Distribution (Frequency) of Hypertensive Parenchymal Hemorrhage Location Supratentorial Infratentorial Putamen Thalamus Subcortical white matter Cerebellum Pons

Frequency 80% 20% 55% 10% 15% 10% 10%

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and subarachnoid or intraventricular extension. Magnetic resonance imaging and angiography are less useful in the acute phase but may be useful in the differential diagnosis.36,37 It is necessary to rule out other causes of hemorrhage before a diagnosis of hypertensive hemorrhage can be made.

Treatment Medical treatment is the mainstay in the initial management of hypertensive ICH.26 Treatment is aimed at several objectives: ■ Intensive monitoring and care in specialist units, including

serial neuroimaging in the early stages. ■ Control of raised intracranial pressure: hyperventilation,

aneurysms.52 Table 43–1 shows the distribution (frequency) of hypertensive parenchymal hemorrhage.59

Pathophysiology After a parenchymal hemorrhage, a circular hematoma forms and directly destroys and may compress and displace adjacent brain tissue, which results in neurological deficit. Surrounding the hematoma is a salvageable ischemic area of brain, the penumbra, loss of which results in secondary damage.31 Bleeding is usually brief but may continue for some hours, resulting in large or irregular-shaped hematomas and may occur in patients with a bleeding diathesis.41,51,53,58 A hematoma may track along white matter tracts or dissect brain parenchyma with extension into the ventricular system or subarachnoid space. Parenchyma immediately surrounding a hematoma undergoes necrosis and is invaded by inflammatory cells with resolution of liquefied clot, leaving a smaller hemosiderinstained cavity surrounded by an area of gliosis.43

Clinical Features Clinical features depend on the location and size of hemorrhage, and manifestation may be asymptomatic. The more common features are summarized as follows:44 ■ Putaminal hemorrhage: hemiplegia, dysphasia, and con-

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jugate gaze paresis with deviation toward the side with hematoma. Thalamic hemorrhage: hemiplegia, hemisensory loss, dysphasia, abnormalities of vertical gaze, and pupillary changes. Cerebellar hemorrhage: severe headache (occipital), nausea and vomiting, and ataxia; motor deficit is not usual. Pontine hemorrhage: coma, pinpoint pupils, decerebrate posture, and locked-in state. Cortical hemorrhage: headache, seizures, and focal neurological deficits. Intraventricular extension: decreased consciousness, autonomic dysfunction, obstructive hydrocephalus, and high mortality rate. Subarachnoid extension: headache, nausea, meningism, photophobia, and decreased consciousness.

Diagnosis Definitive diagnosis of ICH requires neuroimaging. CT scan shows the location, size, and mass effect (parenchymal and ventricular shift or compression) of hemorrhages, hydrocephalus,

head elevation, diuretics (mannitol, frusemide), ventricular drainage. ■ Treatment of hypertension.35,55 ■ Treatment of systemic disorders and complications: coagulation; fever; hypoxia; seizures; gastrointestinal, endocrine, pulmonary, and cardiovascular disease; infections; and electrolyte abnormalities. Surgical treatment is generally reserved for cases in which medical treatment fails to control intracranial pressure or to relieve compression and herniation, and it is more often performed for infratentorial hemorrhages, because of the high risk of herniation. Ventriculostomy involves placement of catheters in the cerebral ventricles and enables monitoring of intracranial pressure and drainage of cerebrospinal fluid when decompression is needed. Hematomas may necessitate evacuation through stereotactic aspiration or open surgery.34

Prognosis Prognosis after hemorrhage depends on several factors, of which size and location of the hemorrhage and GCS score play primary roles:28,45,50,54 ■ Size (poor prognosis if supratentorial hematoma >50 mL). ■ Location (worse prognosis if brainstem or diencephalon is

affected). ■ GCS score <8 (60% rate of mortality). ■ Intraventricular extension (poor prognosis if volume >20

mL). ■ Age. ■ Presence of complications: neurological (cerebral edema,

obstructive hydrocephalus, herniation) and systemic (pulmonary, cardiovascular, gastrointestinal, and endocrine disorders; electrolyte abnormalities; and infections).

IDIOPATHIC INTRACRANIAL HEMORRHAGE The cause of ICH is not always apparent on initial investigation and is often multifactorial in nature (e.g., hypertension may coexist with other disorders and may be a reflex response to raised intracranial pressure). It is important, however, to establish the cause of all hemorrhages in order to target management strategies appropriately. The various causes of ICH are listed as follows:46,47,49 ■ Hypertension: chronic and acute ■ Vascular: aneurysms, arteriovenous malformations and

fistulas, amyloid angiopathy, cavernous and venous

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angiomas, telangiectasias, arterial dissection, caroticocavernous fistula Coagulation: clotting factor deficiency, leukemia, thrombocytopenia Tumors Alcohol Drugs: sympathomimetic drugs (cocaine, amphetamine, pseudoephedrine), anticoagulants, antiplatelet drugs, thrombolysis Vasculitis Postoperative: intracranial, carotid, and cardiac operations Delayed post-traumatic hemorrhage (spät-apoplexie) Infectious: mycotic aneurysms, septic arteritis Hemorrhagic transformation of arterial infarct Intracranial venous thrombosis Migraine Moyamoya syndrome Pregnancy Neonatal Pituitary apoplexy Sickle cell disease Unknown cause

Difficulty in establishing a definite cause of hemorrhage should prompt extensive and thorough reassessment of the history, which may contribute to clarification of the diagnosis. Initial CT scan does not always reveal the underlying pathology, and it may be useful to consider reviewing or repeating the scan and other investigations or to investigate the patient with magnetic resonance imaging or angiography. Despite intensive investigation, some vascular lesions remain occult.26

Spontaneous Intracranial Hemorrhage: Early Surgery or Initial Conservative Management? The role of surgery in spontaneous supratentorial ICH has been a point of controversy for many years. However, a prospective randomized trial was performed to compare early surgery with initial conservative treatment for such patients59 and appears to have shed some light on the appropriate course of management. The authors used a parallel-group trial design. Early surgery combined hematoma evacuation (within 24 hours of random assignment) with medical treatment. Initial conservative treatment entailed medical treatment, although later evacuation was allowed if necessary. In this study, 1033 patients from 83 centers in 27 countries were randomly assigned to undergo early surgery (503) or receive initial conservative treatment (530). At 6 months, 51 patients could not be monitored for follow-up, and 17 were alive with unknown status. Of 468 patients who underwent early surgery, 122 (26%) had a favorable outcome, in comparison with 118 (24%) of 496 who received initial conservative treatment (odds ratio = 0.89 [95% confidence interval = 0.66 to 1.19], P = 0.414); the absolute benefit was 2.3% (−3.2 to 7.7), and the relative benefit was 10% (−13 to 33). The authors concluded that patients with spontaneous supratentorial intracerebral hemorrhage in neurosurgical units show no overall benefit from early surgery in comparison with initial conservative treatment.

K E Y

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Intracranial hemorrhage (ICH) is bleeding in the cranial space and may be classified as spontaneous (nontraumatic) or traumatic or, alternatively, in terms of hemorrhage location. It accounts for 10% to 17% of all types of stroke and has a very high mortality rate.

●

More than 50% of cases of ICH are secondary to rupture of an intracranial aneurysm. Surgical or neuroradiological occlusion of the aneurysm is central to management. Apart from the initial hemorrhage, further neuronal death secondary to cerebral vasospasm is the main cause of death and disability in affected patients, and medical management of this is crucial in outcome.

●

Hypertension is a major cause of spontaneous (nontraumatic) ICH. Hypertensive hemorrhages may result from both chronically and acutely raised blood pressures. Computed tomographic scan is the primary method of demonstrating the hemorrhage, but it is necessary to exclude all other causes of hemorrhage before a diagnosis of hypertensive ICH is made.

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The cause of idiopathic ICH may not be apparent on initial assessment and investigation and is often multifactorial in nature. The potential underlying cause may remain occult despite extensive attempts at diagnosis.

Suggested Reading Edlow JA, Caplan LR: Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000; 342:29-36. Kase CS, Mohr JP, Caplan LR: Intracerebral hemorrhage. In Barnett HJM, Mohr JP, Stein BM, et al, eds: Stroke: Pathophysiology, Diagnosis, and Management, 2nd ed. New York: Churchill Livingstone, 1992. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002; 360:1267-1274. van Gijn J, Rinkel GJ: Subarachnoid hemorrhage: diagnosis, causes, and management. Brain 2001; 124:249-278. Woo D, Haverbusch M, Sekar P, et al: Effect of untreated hypertension on hemorrhagic stroke. Stroke 2004; 35:1703-1708.

References 1. Kuller LH: Incidence, rates of stroke in the 80s. Stroke 1989; 20:841-843. 2. Wolf PA, Kannel WB, McGee DL, et al: Epidemiology of strokes in North America. In Barnett HJM, Mohr JP, Stein BM, et al, eds: Stroke: Pathophysiology, Diagnosis, and Management. New York: Churchill Livingstone, 1986, pp 19-29. 3. Wiebers DO, Whisnant JP, Sundt TM, et al: The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987; 66:23-29. 4. Fox JL: Intracranial Aneurysms. New York: Springer-Verlag, 1983. 5. Almeida GM, Pindaro J, Plese P, et al: Intracranial arterial aneurysms in infancy and childhood. Childs Brain 1977; 3:193199.

chapter 43 intracranial hemorrhage 6. Fang H: A comparison of blood vessels of the brain and peripheral blood vessels. In Wright IS, Millikan CH, eds: Cerebral Vascular Diseases. New York: Grune & Stratton, 1958, pp 1722. 7. Wilkinson IMS: The vertebral artery: extracranial and intracranial structure. Arch Neurol 1972; 27:392-396. 8. Youmans JR, ed: Neurological Surgery, 3rd ed. Philadelphia: WB Saunders, 1990. 8a. Nader-Sepahi A, Casimiro M, Sen J, et al: Is aspect ratio a reliable predictor of aneurysmal rupture? Neurosurgery 2004; 54:1343-1348. 9. Nehls DG, Flom RA, Carter LP, et al: Multiple intracranial aneurysms: determining the site of rupture. J Neurosurg 1985; 63:342-348. 10. Mohr G, Ferguson G, Khan M, et al: Intraventricular hemorrhage from ruptured aneurysm: retrospective analysis of 91 cases. J Neurosurg 1983; 58:482-487. 11. Yeh HS, Tomsick TA, Tew JM: Intraventricular hemorrhage due to aneurysms of the distal posterior inferior cerebellar artery. J Neurosurg 1985; 62:772-775. 12. Raps EC, Galetta SL, Solomon RA, et al: The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol 1993; 50:265-268. 13. Sano H, Jain VK, Kato Y, et al: Bilateral giant intracavernous aneurysms: technique of unilateral operation. Surg Neurol 1988; 29:35-38. 14. White JC, Ballantine HT: Intrasellar aneurysms simulating hypophyseal tumors. J Neurosurg 1961; 18:34-50. 15. Okawara S H: Warning signs prior to rupture of an intracranial aneurysm. J Neurosurg 1973; 38:575-580. 16. Verweij RD, Wijdicks EFM, van Gijn J: Warning headache in aneurysmal subarachnoid hemorrhage: a case-control study. Arch Neurol 1988; 45:1019-1020. 17. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002; 360:1267-1274. 18. Kassel NF, Torner JC, Haley EC Jr: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1. Overall management results. J Neurosurg 1990; 73:18. 19. Sen J, Belli A, Albon H, et al: Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol 2003; 2:614-21. 20. Kassel NF, Peerless SJ, Durward QJ: Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery 1982; 11:337-343. 21. Rinkel GJE, Feigin VL, Algra A, et al: Calcium antagonists for aneurysmal subarachnoid haemorrhage (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software. 22. Sen J, Belli A, Petzold A, et al: Extracellular fluid S100B in the CNS: a future surrogate marker of acute brain injury. Acta Neurochir, in press. 23. Unterberg AW, Sakowitz OW, Sarrafzadeh AS, et al: Role of bedside microdialysis in the diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 2001; 94:740-749. 24. Morgan L, Montgomery H, Grieve J, et al: Association of interleukin 6–174G/C and –572G/C promoter polymorphisms with cerebral aneurysms. Interv Neuroradiol 2003; 9:168. 25. Batjer HH, Kopitnik TA Jr, Friberg L: Spontaneous intracerebral and intracerebellar haemorrhage: differential diagnosis. In Youmans JR, ed: Neurological Surgery, 4th ed, vol 2. Philadelphia: WB Saunders, 1996, pp 1449-1464. 26. Bozzola FG, Gorelick PB, Jensen JM: Epidemiology of intracranial hemorrhage. Neuroimaging Clin North Am 1992; 2:1.

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27. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: a powerful and easy to use predictor of 30-day mortality. Stroke 1993; 24:987-993. 28. Broderick JP, Brott T, Tomsick T, et al: Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993; 78:188-191. 29. Brown RD, Whisnant JP, Sicks JD, et al: Stroke incidence, prevalence and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996; 27:373-380. 30. Camarata PJ, Heros RC, Latchaw RD: “Brain attack:” the rationale for treating stroke as a medical emergency. Neurosurgery 1994; 34:144-158. 31. Caplan L: Intracerebral hemorrhage revisited. Neurology 1988; 38:624-627. 31a.Challa VR, Moody DM, Bell MA: The Charcot-Bouchard aneurysm controversy: impact of a new histologic technique. J Neuropathol Exp Neurol 1992; 51:264-271. 32. Crowell RM, Ojemann RG, Ogilvy CS: Brain hemorrhage. In Ojemann RG, Ogilvy CS, Crowell RM, et al, eds. Surgical Management of Neurovascular Disease, 3rd ed. Baltimore: Williams & Wilkins, 1995, pp 561-580. 33. Dandapani BK, Suzuki S, Kelley RE, et al: Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995; 26:21-24. 34. Drury ID, Whisnant JP, Garraway WM: Primary intracerebral hemorrhage: impact of CT on incidence. Neurology 1984; 34:653. 35. Findlay JM: Current management of aneurysmal subarachnoid haemorrhage. Guidelines from the Canadian Neurological Society. Can J Neurol Sci 1997; 24:161-170. 36. Fischer CM: Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 1971; 30:536-550. 37. Fischer CM: Cerebral miliary aneurysms in hypertension. Am J Pathol 1972; 66:313-330. 38. Frankowski RF: Epidemiology of stroke and intracerebral hemorrhage. In Kaufman HH, ed: Intracerebral Hematomas. New York: Raven Press, 1992. 39. Fujii Y, Tanaka R, Takeuchi S, et al: Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 1994; 80:51-57. 40. Garcia JH, Ho K-L: Pathology of hypotensive arteriopathy. Neurosurg Clin North Am 1992; 3:497. 41. Garcia JH, Ho K-L, Caccamo DV: Intracerebral hemorrhage: pathology of selected topics. In Kase CS, Caplan LR, eds: Intracerebral Hemorrhage. Boston: Butterworth-Heineman, 1994. 42. Hamilton MG, Zabramski JM: Intracerebral hematomas. In Carter LP, Spetzler RF, Hamilton MG, eds: Neurovascular Surgery. New York: McGraw-Hill, 1995, pp 477-496. 43. Juvela S: Risk factors for impaired outcome after spontaneous intracerebral hemorrhage. Arch Neurol 1995; 52: 1193-1200. 44. Juvela S, Hillbom M, Palomaki H: Risk factors for spontaneous intracerebral hemorrhage. Stroke 1995; 26:1558-1564. 45. Kase C: Intracerebral hemorrhage: non-hypertensive causes. Stroke 1986; 17:4590-4595. 46. Kase CS, Mohr JP, Caplan LR: Intracerebral hemorrhage. In Barnett HJM, Mohr JP, Stein BM, et al, eds: Stroke: Pathophysiology, Diagnosis, and Management, 2nd ed. New York: Churchill Livingstone, 1992. 47. Kaufman HH: Spontaneous intracerebral hematomas. In Grossman RG, Hamilton WJ, eds: Principles of Neurosurgery. New York: Raven Press, 1991, pp 65-78. 48. Lampl Y, Gilad R, Eshel Y, et al: Neurological and functional outcomes in patients with supratentorial hemorrhages: a prospective study. Stroke 1995; 26:2249-2253. 49. Lee K, Bae H, Yun I: Recurrent intracerebral hemorrhage due to hypertension. Neurosurgery 1990; 26:586-590.

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50. Mayberg MR, Batjer HH, Dacey R, et al: Guidelines for the management of aneurysmal subarachnoid haemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1994; 25:2315-2328. 51. Mayer SA, Sacco RL, Shi T, et al: Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology 1994; 44:1379-1384. 52. Mori S, Sadoshima S, Ibayashi S, et al: Impact of thalamic hematoma on 6-month mortality and motor and cognitive functional outcome. Stroke 1995; 26:620-626. 53. Powers WJ: Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993; 43:461-467. 54. Sacco RL, Wolf PA, Bharucha NE, et al: Subarachnoid and intracerebral hemorrhage: Natural history, prognosis, and precursive factors in the Framingham study. Neurology 1984; 34:847.

55. Schuetz H, Dommer T, Boedeker R-H, et al: Changing pattern of brain hemorrhage during 12 years of computed axial tomography. Stroke 1992; 23:653. 56. Wijdicks EFM, Fulgham JR: Acute fatal deterioration in putaminal hemorrhage. Stroke 1995; 26:1953-1955. 57. Wiener H, Cooper P: The management of spontaneous intracerebral hemorrhage. Contemp Neurosurg 1992; 14(21):1-8. 58. Wityk RJ, Caplan LR: Hypertensive intracerebral hemorrhage: epidemiology and clinical pathology. Neurosurg Clin North Am 1992; 3:521. 59. Mendelow AD, Gregson BA, Fernandes HM, et al: Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365:387397.

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44

ARTERIOVENOUS MALFORMATIONS THE BRAIN AND SPINAL CORD ●

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Soke Miang Chng, Hortensia Alvarez, Georges Rodesch, and Pierre Lasjaunias

An arteriovenous malformation (AVM) consists of one or more arteriovenous shunts, which corresponds to an abnormal capillary bed with a shortened arteriovenous transit time. Two broad categories of arteriovenous shunts can be recognized: AVMs and arteriovenous fistulae (AVFs). AVMs are characterized by a network of abnormal channels (nidi) between the arterial feeders and the draining veins. AVFs, in contrast, consist of a direct communication or opening between a feeding artery and a draining vein. AVMs and AVFs are the two basic forms of arteriovenous shunts that can be found throughout the central nervous system. AVMs of both the brain and the spinal cord are not common diseases. Spinal cord AVMs (SCAVMs) in particular are still underdiagnosed entities that can give rise to acute-subacute spinal cord symptoms or progressive myelopathy. Clinical signs and symptoms vary, depending on the location and angioarchitecture of the lesion. A complete clinical evaluation combined with imaging information are necessary for making the correct therapeutic decision. The primary diagnostic modality is currently magnetic resonance imaging (MRI), which is excellent in topographically localizing lesions. Digital subtraction angiography (DSA) gives important complementary information regarding the angioarchitecture and hemodynamics of lesions, which is crucial in treatment planning. The aim of treatment should be a significant improvement over the natural history of the disease, in comparison with the risks of therapy. In the past, most AVMs were diagnosed during clinically recognized episodes. The access to imaging facilities has allowed their preclinical diagnosis. Follow-up of this incidentally discovered population of patients with AVMs suggests that the clinical course is more benign than previously believed. The classic postulate that AVMs are congenital malformations, hence implying their presence at birth, has not been supported by antenatal or pediatric imaging. On the contrary, it is likely that lesions found in young adults, although probably resulting from an early in utero “event,” are not present at birth. Pediatric cases or even neonatal series represent only a small portion of the cases and pertain to specific disease groups (hereditary hemorrhagic telangiectasia [HHT], vein of Galen malformations, pial AVFs).1 The purpose of this chapter is to give an overview of the classifications, angioarchitectures, clinical manifestations, and

natural history of these diseases, with a brief review of the diagnostic and therapeutic approaches.

BRAIN ARTERIOVENOUS MALFORMATION Incidence The prevalence of brain AVMs (BAVMs) in a given population is difficult to estimate. It is believed that between 0.14% and 0.8% of the population may present with a BAVM in a given year.2,3 The variation in statistics results from studies of disparate populations, ranging from the residents in a small community4 to subjects of autopsy series.3 As previously alluded to, these numbers represent data collected before the era of noninvasive high-quality imaging modalities.

Classification and Angioarchitecture There are two broad categories of arteriovenous shunts: malformations (AVMs) and fistulae (AVFs). AVMs may be small (micro-AVMs) with one or more “normal”-sized arteries, one or more draining veins, and a nidus smaller than 1 cm in diameter. Macro-AVMs, in contrast, have arteries and veins that are larger than normal; the size of the nidus is larger than 1 cm in diameter. Compartments can be observed within lesions either during angiography or at surgery. Each compartment may have a single or multiple arterial feeders. There may be single or multiple draining veins (Fig. 44–1). Similarly, AVFs may be of the micro or macro type. AVFs are more frequent in children and are rare in adults (Fig. 44–2). The architecture of an AVM is specific to the lesion. However, the chronicity of the shunt and the shear stresses on the remaining vasculature create nonmalformative secondary changes called high-flow angiopathy. These may by themselves create additional symptoms; under certain circumstances, they may also regress if the AVM is treated even partially.

Topography The topography of a BAVM is best assessed by combining both MRI and angiographic information. Lesions in most locations

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recruit predictable arterial feeders and specific draining veins (Table 44–1). The primary defect is at the capillary level. In contrast to aneurysms (arterial defective) or cavernomas (venous defective), in which associated arterial and venous anomalies are seen, respectively, the arterial tree from where the AVM feeders originate and the venous system that drains the AVM have a classic anatomical disposition. Several general types of lesions can be differentiated on the basis of location. Of note, however, is that both macro- and micro-AVFs are encountered mostly on the surface of the brain. All so-called BAVMs are subpial in location with regard to the meningeal spaces. Vein of Galen aneurysmal malformation and

Figure 44–1. Arteriovenous malformation (AVM) in the brain. The patient, a 57-year-old woman, presented with chronic headache for several years. There was no associated seizure or neurological deficit. A and B, Magnetic resonance imaging (axial T2-weighted images) showed a nidus-type AVM located in the left precentral sulcus, displacing the precentral gyrus anteriorly. This AVM drained via a superficial cortical vein. C, Angiography (left carotid injection, arterial phase) showed the corresponding precentral cortical vein draining into the superior sagittal sinus.

adult choroidal AVMs are separate groups located outside the subpial space.

Lesions at the cortex Arteriovenous lesions exclusively involving the cortex are exclusively fed by cortical arteries and drain into superficial veins. These lesions represent sulcal AVMs, as described by Valavanis and Yasargil.5 Cortical-subcortical lesions recruit cortical arteries and drain into superficial veins but may also drain into the deep venous system if the transcerebral venous system is patent.

chapter 44 arteriovenous malformations of the brain and spinal cord

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D Figure 44–2. Brain arteriovenous fistula (AVF). The patient, a 4-year-old girl, presented at the age of 3 years with language delay. There was no family history to suggest hereditary hemorrhagic telangiectasia. A and B, Magnetic resonance imaging (coronal T2weighted and axial fluid-attenuated inversion recovery images) revealed a single-hole AVF located in the left sylvian fissure, associated with a large venous pouch. C and D, Angiography (left carotid injection in the frontal and lateral projections) showed a single, ectatic arterial feeder arising from the left middle cerebral artery, opening directly into the venous pouch. Venous drainage was via an embryonic tentorial sinus into the left sigmoid sinus, with reflux into the opposite transverse and sigmoid sinuses. Embolization of this fistula was subsequently performed.

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T A B L E 4 4 – 1. Topography of Intracranial Arteriovenous Lesions and Vascular Territories

From Berenstein A, Lasjaunias P, Ter Brugge KG: Surgical Neurorangiography, vol 2.2: Clinical and Endovascular Treatment Aspects in Adults, 2nd ed., Berlin: SpringerVerlag, 2004. +, involved; −, not involved. *Can be recruited via transcerebral veins. † Insular and cerebellar.

These represent the gyral type of AVMs described by Valavanis and Yasargil.5 In both cortical and cortical-subcortical lesions, some regions of the cortex drain to deeply located veins that should not be considered as truly part of the “deep venous system.” Such vessels include the medial veins of the temporal lobe and the basal vein of Rosenthal, the veins of the cerebellar vermis, and the precentral cerebellar veins. Corticoventricular arteriovenous lesions correspond to the classic pyramid-shaped malformation, reaching the ventricular wall at their apex. Feeding arteries are both perforating and cortical. Draining veins are also deeply and superficially located. Corticocallosal lesions belong to the corticoventricular group, inasmuch as they have the same venous characteristics, but they do not recruit “basal perforating” arteries. They drain into the subependymal veins and, later, into the deep venous system. The arterial supply to the corpus callosum is linked to the cortical arterial network (even though it may simulate perforating arterial channels in the supraoptic region) and to choroidal arteries at the splenium.

bral veins. These extra-axial lesions, too, can be distinguished from intra-axial ones with angiographic criteria.

Deep-seated lesions

Calcifications

Deep-seated lesions can be located supratentorially or infratentorially in the depth of the telencephalon, diencephalon, brainstem, or cerebellum. The nidus involves the deep nuclei and the long fiber tracts with their arterial and venous connections. They recruit exclusively perforating arteries and drain into the deep venous system. They may use transcerebral veins if patent, either as a direct venous outlet or as a collateral pathway. Transcortical arteries from the insular branches of the middle cerebral artery and the hemispherical collateral vessels of the cerebellar arteries can be involved in lenticulostriate and in dentate nuclear lesions, respectively. MRI and DSA are able to distinguish these deep-seated lesions from corticosubcortical lesions, particularly because the dominant supply of the intracerebrally located deep lesions arises from the perforators.

Calcifications in BAVMs are usually related to venous ischemia. In children, calcifications may occur at a distance from the shunt, in watershed venous zones, in the white matter, or in the deep nuclei.

Angioarchitecture Analysis of the angioarchitecture of BAVMs should include the study of the various components of the lesion (arteries, nidus, and veins) and how these components affect the rest of the circulation. The clinician should be able to distinguish the primary abnormality (the BAVM) from the secondary changes (high flow angiopathy) that occur in response to an increased diastolic fraction resulting from arteriovenous shunting. These include arterial stenosis, aneurysms, angiectasia, venous stenosis and ectasia, and angiogenesis. The high-flow hemodynamics and/or decreased tissue perfusion associated with chronic arteriovenous shunting stimulate these angiogenetic developments. Thrombosis of a draining vein, development of transdural supply, or intranidal ectasias may also be observed after previous hemorrhage within the AVM. These changes may be temporary or permanent.

Multiple Brain Arteriovenous Malformations Multiple BAVMs are rare. In this heterogeneous group of multifocal BAVMs, three types of patients can be distinguished: (1) those with HHT, also known as Rendu-Osler-Weber disease; (2) those with cerebrofacial arteriovenous metameric syndrome (CAMSs); and (3) those with unclassified multiple lesions. This distinction refers to the timing of the insult that created the malformations, later to be revealed morphologically or clinically (e.g., germinal, somatic-segmental).

Choroid plexus lesions Choroid plexus AVMs are important to recognize because of their extra-axial location. These lesions are fed by choroidal and subependymal arteries arising from the circle of Willis. There is no cortical arterial supply in this type of lesion. Drainage is via ventricular veins, with occasional recruitment of transcere-

Hereditary hemorrhagic telangiectasia HHT is an autosomal dominant disorder characterized by a multisystemic vascular dysplasia and recurrent hemorrhage.6 Two gene mutations have been identified: on chromosome 9 (affecting production of endoglin; this form is known as type

chapter 44 arteriovenous malformations of the brain and spinal cord 1)7 and on chromosome 12 (affecting production of activin receptor–like kinase; this form is known as type 2). An uncharacterized third mutation is also suspected. These mutations lead to the formation of abnormal vessels and abnormal connections between vessels. It has to be emphasized that the target of dysfunction in HHT is not in arteries but in venules. In the general population of patients with BAVMs, up to 2.2% of cases may be associated with HHT.8 With multiple BAVMs, however, up to 25% of cases are associated with HHT.9 Ten percent to 20% of HHT patients have cerebral involvement.10 In these patients, the cerebral vascular malformations manifest in three main phenotypes: large AVFs, small AVMs with a nidal diameter between 1 and 3 cm, and micro-AVMs with a nidal diameter smaller than 1 cm. These AVMs are often multiple and are almost exclusively located near the cortex.8,11 Although characteristic telangiectasia occur in the skin, oral mucosa, and the lips of patients with HHT, telangiectasia is not known to develop in the brain. High-flow type AVFs with venous ectasias are seen in children younger than 5 to 6 years of age; nidus-type lesions both large and small are seen in older children and in adults.1,12-14 Twenty-five percent of single AVFs in children and 50% of multifocal AVFs occur in patients with HHT. Cerebral DSA may demonstrate multiple areas of arteriovenous shunting, always cortical in location, either supratentorial or infratentorial. In addition, high-quality cerebral DSA can demonstrate tiny lesions, particularly micro-AVMs, which may appear occult on MRI, because these lesions usually have normal-sized feeding arteries and draining veins.10 However, patients with HHT who present with systemic complaints are more likely to develop acute neurological symptoms from embolic phenomena related to underlying pulmonary AVFs (recurrent brain abscesses, embolic stroke) than to the presence of a BAVM per se.

Cerebrofacial arteriovenous metameric syndromes CAMSs,15 also called Wyburn-Mason or Bonnet-DechaumeBlanc syndrome, are associated with ipsilateral AVMs of the brain, retina, and facial regions. Their segmental expression reflects their common origin from tissues involved in cerebrofacial vasculogenesis and angiogenesis. The metameric pattern of involvement is suggestive of a disorder of the neural crest or adjacent cephalic mesoderm15 at early segmental stages of differentiation.

Unclassified multiple brain arteriovenous malformations Several case reports have described so-called multifocal BAVMs. They seem to be twice more frequent in children than in adults. They can be randomly spread on the cortex; mirror-image deepseated nidi have been reported. One half of multifocal AVFs in children belong to this group.1,14

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normal brain parenchyma, and the veins are either normal sized or only slightly enlarged. The “nidus” is typically diffuse, involving a hemisphere. There are no dominant arterial feeders. The early venous filling that is observed results from a faster capillary transit time rather than true arteriovenous shunting. Late proximal cerebral arterial occlusion may occur, resulting in ischemic phenomena and diffuse transdural angiogenesis. The most common clinical manifestation is seizures. Headaches and progressive neurological deficit are less common, and hemorrhage is exceptional. Treatment is directed at the management of seizures with medical therapy. Embolization is employed in exceptional cases: when there is evidence of focal angioarchitectural weakness within the lesion, for which partial targeted embolization to reduce any constraints to functional parts of the brain may be beneficial. The effects of medication on headaches and seizure are often beneficial. The role of surgery is limited to the correction of hemispherical ischemia by bur holes, as in moyamoya disease, when spontaneous transdural angiogenesis is absent or insufficient. Hemorrhagic angiopathy is another entity that typically manifests with an episode of hemorrhage. Encountered in some rare cases of intracerebral hematomas in children most often after the age of 5 years, it corresponds to a network of intracerebral subcortical arterioles with normal structure and sequential venous drainage. Recurrent hemorrhage is frequent and therefore therapy is indicated. These lesions are extremely sensitive to radiation. Partial embolization of focal areas of weakness in the angioarchitecture can also be performed to reduce future hemorrhagic risk.

Developmental venous anomalies with ectasias Developmental venous anomalies (DVAs) are anatomical variations that can involve one or both hemispheres and can also be located infratentorially. They involve extremes in variations in the venous drainage of white matter. Superficial DVAs represent the superficial medullary veins that drain the deeper medullary regions into the cortical veins. The deep group of DVAs drains the subcortical territories of the superficial medullary veins into the deep venous collectors. The venous channels are morphologically normal and drain normal functioning brain, although transit time through their venules is sometimes rapid and almost as rapid as that in slow-flow BAVMs. The frequent incidental appearance of DVAs on crosssectional imaging and angiography attest to their benign nature. Any associated clinical symptom is caused primarily by associated malformations (cavernomas or arteriovenous shunts). Their lack of flexibility as a result of being an anatomical variant of the venous drainage to the brain in the region may also produce ischemic episodes of varying severity. However, because DVAs drain normal areas of the brain, they should never be eradicated. Rarely does a true AVM drain into a DVA. In this instance, a true arteriovenous shunt is demonstrated within an otherwise normal network of vessels. Treatment of such patients requires extreme care to preserve normal venous channels.

Proliferative and hemorrhagic angiopathies Proliferative and hemorrhagic angiopathies are entities often confused with BAVMs. They are rare, proliferative, vascular lesions seen usually in children and young women. The appearance of proliferative angiopathy is typically that of a nidus-like cortical network of vessels intermingled with

Pathophysiology, Clinical Manifestation, and Natural History The clinical manifestation of BAVM may be related to the shunt itself or to secondary changes (visible on high-flow angiopathy)

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that occur in response to chronic shunting. It also depends on the age of the patient. Manifesting clinical features include chronic headaches, seizures, cerebral hemorrhage, and neurological deficits.

Neonates, Infants, and Children Neonates with BAVMs may present with high-output cardiac failure related to the presence of high-flow shunts in the AVM. In young children, alterations in cerebrospinal fluid circulation and absorption in the immature brain caused by increased venous pressure may lead to water retention, macrocrania, and hydrocephalus, and venous congestion may rapidly lead to focal ischemia, convulsions, and hemorrhage. Meltingbrain syndrome can occur in neonates and young infants. This involves a rapid destruction of the brain, usually the white matter, with ventricular enlargement. This phenomenon, which is never encountered in adults, corresponds to a regional decrease in the cerebral blood flow caused by retrograde venous hypertension and subsequent venous congestion leading to hydrovenous dysfunction. It is usually bilateral and symmetrical, associated with severe neurological manifestations and no signs of increased intracranial pressure, although they are usually present before the syndrome manifests.

Hemorrhage Hemorrhage in a patient with a BAVM represents a significant change in the compliance of the vascular system. Bleeding can result from rupture of the AVM nidus, arterial aneurysm rupture, or venous rupture, which may occur close to or remote from the AVM. It has been shown that arterial aneurysms are not significantly associated with hemorrhagic manifestation,5 of BAVMs. The presence of aneurysms within an AVM nidus is, however, noted to significantly worsen the natural history of future hemorrhages.16 Deep venous drainage and deep location of a BAVM are associated with a higher risk of hemorrhagic manifestation.17

Seizure and Neurological Deficit Seizure is the second most frequent manifesting symptom in all BAVM patients and occurs in up to 53% of cases. The AVM locations most frequently associated with seizure production are the motor-sensory strip and the temporal areas, representing close to 70% of cases of BAVM with seizures. For most of the less functional brain areas, seizure manifestations may be overlooked unless secondarily generalized. Neurological deficit not associated with hemorrhage, in contrast, is an infrequent symptom, occurring in only 8% of patients over a 10-year period.18 Neurological deficits and seizures may be caused by an AVM by several possible mechanisms: (1) ischemia, (2) hemorrhage, (3) direct or indirect mechanical compression, and (4) postseizure neurological deficit. Arterial ischemia may theoretically result from two types of mechanism: a “steal” phenomenon or occlusive changes. The concept of “steal” is based on the angiographic nonvisualization of vessels in a normal area of the brain that should have been visualized at the time of injection. However, careful angiographic evaluation always demonstrates the “missing” branches through leptomeningeal anastomoses from adjacent territories,

thus expressing the adaptability of the brain’s circulation. Arterial stenosis and occlusion proximal to an AVM may range in appearance from a single vessel narrowing to a moyamoya pattern. Such changes are usually slowly progressive, allowing for stepwise compensation, including leptomeningeal angiectasia, which accounts for their clinically silent development. These changes may eventually lead to progressive symptoms such as headaches, neurological deficits, and seizures. Multivariate analysis has shown that patients with such occlusive changes and angiogenesis may have lesser hemorrhagic risk than do patients without such changes.19 The concept of venous ischemia is accepted by most authors involved in the management of cerebral arteriovenous lesions but is rarely acknowledged for its significance. It is important to remember that 60% to 80% of the cerebral blood volume is located in the venules of the cerebral venous system. They have all the necessary characteristics for active exchange with the surrounding tissue, a testament to their role in nutrient exchange. Flow in venules in the white matter is bidirectional, allowing them to fulfill their nutrient role even in a retrograde manner. This function is disrupted with increasing pressure in the veins. The progressive nature of deficits in relation to some BAVMs and their fluctuation reflect the attempts of the collateral circulation to overcome increased pressure in the venous outlet of a shunt. Decreased tissue perfusion secondary to venous ischemia may produce virtually any type of neurological symptom (e.g., motor or sensory deficits, neuropsychological alteration, seizures). Most of the symptoms result in effects remote from the nidus. Posterior fossa AVMs may thus manifest with supratentorial manifestations. The greater the distance between the shunt site and its venous drainage into a dural sinus, the higher are its chances of interfering with the normal brain circulation. The onset of seizures in a previously healthy individual may also reflect an acute change in hemodynamics, which may be caused by rerouting of drainage from the malformation through a vein that previously drained normal areas of the brain. The increase in pressure produces secondary neurological dysfunction of the affected areas of the brain, and seizures may result. New-onset seizures and headaches can also occur when venous thrombosis develops in association with a BAVM.

Headache Headache is the first symptom in approximately 60% of patients with BAVM. These headaches can be divided into (1) those that accompany an episode of intracranial hemorrhage or venous thrombosis and (2) those that are more subacute or chronic in nature. The acute headaches associated with hemorrhage or acute venous thrombosis typically manifest abruptly and are usually severe in nature, associated with photophobia, nausea, vomiting, convulsion, and loss of consciousness. Constant headaches or episodes of throbbing (“migrainelike”) headaches can occur in the same patient. The headaches are often localized to the same side as the AVM. In most cases, the exact cause of the headache remains unclear, although in some patients, there may be a relationship between the angioarchitectural features and the headaches. Dural and posterior cerebral artery supplies to a BAVM are known to be potentially responsible for headaches that tend to disappear after emboliza-

chapter 44 arteriovenous malformations of the brain and spinal cord tion therapy, in our experience. Conversely, embolization of middle and anterior cerebral artery supply to a parietal lobe BAVM may worsen headaches if the posterior cerebral artery supply is increased after such embolization. It does not seem that transdural supply to an AVM causes headache; such a feature is suggestive of ischemia of the underlying cortex.

Diagnosis, Management, and Treatment The current modes of therapy for BAVMs include endovascular embolization with glue (N-butyl cyanoacrylate), surgery, stereotactic radiation therapy, and or combined therapy. The type of treatment may vary from center to center and is dependent on physicians’ strengths and capabilities. The discovery of a BAVM in a patient does not represent an automatic indication for treatment. There is growing evidence in both the surgical and endovascular literature that every BAVM is unique and that different BAVMs do not carry a similar risk for future symptoms.20 The risk associated with treatment should be lesser than that of the natural history of a particular lesion. The age of the patient is also important, and the therapeutic strategy should be based on the post-therapeutic clinical benefit expected over time and the therapeutic risks associated with therapy. The treatment of BAVMs requires complete information with regard to the clinical circumstances and the imaging characteristics, including the angioarchitecture of the AVM and the brain. The angioarchitecture of the AVM influences both the approach to a lesion and the expected chances of reaching the therapeutic goal.

Imaging Modalities The topographic location of a malformation is best assessed by MRI or computed tomography. MRI delineates accurately the location of the lesion and is more sensitive than computed tomography in demonstrating secondary effects on the brain parenchyma, particularly the changes in white matter edema secondary to chronic venous congestion and hemosiderin from previous hemorrhage. DSA, however, enables the anatomical identification of the arterial feeders, the angioarchitecture of the nidus, the draining veins, and the hemodynamic aspects of the shunt. The presence of other associated vascular lesions and significant arterial and venous variations, as well as the vascular anatomy and physiology of the normal cerebral vasculature, may also be visualized. This complete information is necessary in deciding and planning a treatment strategy. New data from advanced MRI techniques such as diffusionweighted imaging, perfusion imaging, and functional MRI with neuronal activation have also been useful in studying abnormal brain areas near or remote from the AVM nidus. These techniques are able to show hemodynamic and neuronal adaptive phenomena in the areas involved by the AVM and in the surrounding areas of the brain. For example, reduced cerebral perfusion in the areas around the AVM related to venous congestion may be demonstrated. Functional MRI with mapping of cortical function in relation to the AVM can also be performed. This information may help the clinician correlate clinical symptoms with their anatomical and functional substrate and influence any decisions about invasive therapy.21

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Indications for Intervention The information obtained by the angiographic investigation plays a key role in the decision about the need for treatment. This is based on the demonstration of evidence of weakness in the angioarchitecture, which may point to a potential instability. The presence of a pseudoaneurysm or an associated arterial aneurysm (on the feeding pedicle or in the nidus), venous thrombosis, outflow restriction, venous hyperpressure, venous pouches, or venous dilatations is a factor favoring active intervention. But when the risk of total elimination of the malformation (by either embolization or microsurgery or by a combination of therapies) is prohibitive, then a different management strategy, such as partial targeted embolization to eliminate the points of weakness to reduce further risk of hemorrhage, must be considered, rather than an attempt to achieve a complete cure of the lesion. An important part of the management of incidentally discovered BAVMs is to provide the patient with information regarding the natural history as it may apply to the particular situation, as well as the treatment options and associated risks that are available in the local treatment environment. If no angioarchitectural weaknesses are demonstrated, a medical follow-up treatment strategy can be proposed with the patient reassured that he or she is expected to lead a normal, productive life without restrictions. However, the evolution of BAVMs is not linear, and biological events may produce unexpected changes, which may remain subclinical for a long time. Followup is therefore crucial in all patients, including those for whom a decision not to treat was chosen. Follow-up is usually clinical with imaging (MRI), but if clinical or imaging changes are noted, then repeat angiography may be indicated.

Specific Factors Affecting Therapeutic Decisions Hemorrhage The treatment strategy after presentation with hemorrhage is dependent on how well the hemorrhage is tolerated. When surgical intervention is necessary to remove an intracerebral hematoma, excision of the malformation at the same time is sometimes possible. Most hemorrhages are well tolerated,22 and no immediate AVM treatment is usually necessary. There is seldom a need for urgent treatment after BAVM hemorrhage, and a treatment strategy can be planned accordingly. Careful analysis of the angioarchitecture is important in order to look for suspicious angiographic features that are probably responsible for the hemorrhage (prenidal or intranidal aneurysm, pseudoaneurysm). These represent an indication for early treatment targeted toward obliteration of such weak points (partial targeted embolization). Large size of a BAVM is associated with increased risk of future hemorrhage.23 Partial targeted embolization with reduction of nidal size and specific angioarchitectural features has been shown to reduce future risk of hemorrhage.24

Seizures Seizures occur at presentation in 10% to 53% of patients with BAVMs, the majority being partial or partial complex seizures. Subsequent seizure control with antiepileptic medication is achieved in most patients; therefore, seizure control by itself

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rarely becomes an indication for intervention. Refractory status epilepticus is an exception that may represent an indication for endovascular treatment, and such management has been successful in bringing seizure management under control. Worsening or new onset of seizures after treatment is rare.

Age The younger the patient is at the time of presentation, the more likely it is that active treatment should be considered. Presentation at an early age represents an early imbalance between the lesion and host. Newborns with congestive heart failure are the most dramatic examples of such an imbalance. Hydrocephalus in infants may also be secondary to cerebrospinal fluid absorption abnormalities and may result in irreversible developmental delay if endovascular treatment is not undertaken. The melting brain syndrome may also develop rapidly in some young infants if treatment is delayed.25 Patients older than 60 years at presentation are at a higher risk of bleeding,18 up to 89% by 9 years, in comparison with a 15% risk in the same period for patients aged 20 to 29. In addition, in older patients, bleeding carries very high rates of morbidity and mortality, because the older brain has less plasticity to recover. This may influence the management strategy for partial targeted therapy to restore once again the equilibrium between host and AVM.

Modes of Therapy The role of surgery, endovascular glue embolization, stereotactic radiosurgery, and/or combined therapy in the treatment of BAVMs varies from center to center, depending on the expertise available. The location of a malformation, the size, and deep venous drainage are the most important factors in determining the risks of surgical resection of an AVM,26 whereas these features are of only minor concern in the endovascular approach. Technically, morbidity associated with embolization is related to the capacity to reach the lesion endovascularly and to remain strictly within the nidus during glue embolization. Therefore, deep lesions such as brainstem, thalamic, or basal ganglia lesions, although obviously more risky to treat, can be obliterated by careful embolization, whereas surgery in such locations would carry much higher risks. Stereotactic radiosurgery with the gamma beam, linear accelerator, or proton beam is another accepted mode of BAVM therapy. Radiosurgery leads to progressive occlusion of BAVMs by inducing vessel wall thickening, thrombosis, and, finally, occlusion of the vessel lumen. This occurs over a period of typically 2 years. During this period of 2 years, however, it does not provide immediate protection from future hemorrhage. The efficacy of radiosurgery also depends on lesion size and volume,27-29 the success rate being lower for large lesions, which require a much higher radiation dose. Radiosurgery is therefore generally an option for nidus-type lesions that are smaller than 3 cm and are not easily accessible via endovascular or surgical means. Combination treatments may facilitate the complete cure of an AVM that might not have been possible with a single modality alone. Presurgical embolization has a well-accepted role in facilitating surgical removal of AVMs. Often, the role of endovascular embolization in such cases is to eliminate a deep arterial feeder, to occlude an intranidal fistula, or to reduce overall size and flow through the nidus before surgery.

Embolization before radiosurgery may also be performed with the aim of achieving reductions in lesion size and volume, and embolization may be targeted toward specific angioarchitectural features such as intranidal aneurysms, false sacs, or intranidal fistulae. When using combination therapy, the clinician must always bear in mind the increased therapeutic risk to the patient (combined risk of the different treatment modalities), and weigh this against the overall benefits of the combined therapy.

SPINAL CORD ARTERIOVENOUS MALFORMATIONS Incidence Vascular malformations of the spine and spinal cord are considered uncommon lesions. Their incidence, expressed as a percentage of the total number of the various types of spinal space-occupying lesions, ranges from 3%30 to 16%.31 The discrepancy is explained by the introduction of better diagnostic modalities. Nevertheless, the true incidence of spine and spinal cord vascular malformations may be underestimated. Although cerebral vascular malformations are more common than spinal ones, the comparative incidence in relation to brain versus spinal tumors is very similar, ranging from 2% to 4%.32,33 This suggests that the frequency of SCAVMs in comparison with BAVMs is correlated with the mass or volume ratio between spinal cord and brain tissue. The prevalence of incidental or asymptomatic spinal vascular malformations is difficult to ascertain, inasmuch as the spinal cord is usually not inspected on routine autopsy.

Classification and Angioarchitecture SCAVMs are arteriovenous shunts located intradurally and supplied by radicular arteries (radiculomedullary and radiculopial), the anterior spinal artery, the pial network, their perforators, or any combination of these. The lesion may be located along the surface of the cord (extramedullary), within the cord substance (intramedullary), or both. This group also includes AVMs that are located along the intradural portion of the spinal nerves and on the filum terminale. They are likely to be both subarachnoid and subpial because the pial veins of the cord are subarachnoid. These lesions are distinct from AVMs that are extradural or paraspinal in location and from spinal dural AVFs, which are located within or on the outer surface of dura along the spinal canal. As in the brain, SCAVMs may be divided into nidal (AVMs) or fistulous types (AVFs). Nidus-type lesions are characterized by a network of abnormal channels (nidi) between the arterial feeders and the draining veins (Fig. 44–3). Fistula-type lesions, in contrast, consist of a direct communication or opening between a feeding artery and a draining vein (Fig. 44–4). Large nidus-type lesions are usually embedded within the spinal cord, whereas small lesions are often more superficial, near the surface of the cord. Fistula-type lesions, which may also be distinguished as large (macro-AVFs) and small (micro-AVFs), are always found on the surface of the spinal cord (extramedullary). SCAVMs may be classified into three main groups (Table 44–2), described as follows.34

chapter 44 arteriovenous malformations of the brain and spinal cord ■

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Figure 44–3. Arteriovenous malformation (AVM) in the spinal cord. The patient, an 18-yearold man, presented with sudden onset of paraplegia associated with urinary symptoms. A and B, Magnetic resonance imaging (MRI) (sagittal T2- and T1-weighted images) showed a hematoma within the spinal cord at the second thoracic level, associated with cord edema extending from the upper thoracic to the cervical level. Dilated vessels were noted along the dorsal surface of the spinal cord. continued

A

B

Genetic Hereditary Lesions This first group of SCAVMs is caused by a genetic hereditary disorder, in which vascular germinal cells are affected by disease. The main syndrome in which genetic links can be recognized is HHT (see section on BAVMs). SCAVMs associated with HHT are almost always single macro-AVFs, particularly in the pediatric population. Indeed, macro-AVFs may be the first expression of the disease in children; the discovery of a spinal cord macro-AVF

T A B L E 4 4 – 2.

should therefore raise the possibility of this underlying genetic hereditary disease.13,35 These lesions are usually single at the cord but can be associated to intracranial ones.36

Genetic Nonhereditary Lesions This second group of SCAVMs is not related to a hereditary disorder; it includes multifocal lesions potentially sharing metameric links (see also section on BAVMs).37

Classification of Spinal Cord Arteriovenous Malformations

Rodesch G, Hurth M, Alvarez H, et al: Classification of spinal cord arteriovenous shunts: proposal for a reappraisal—the Bicêtre experience with 155 consecutive patients treated between 1981 and 1999. Neurosurgery 2002; 51:374-380. *Multifocal lesions sharing metameric links. AVF, arteriovenous fistula; AVM, arteriovenous malformation.

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Figure 44–3, cont’d. C and D, Angiography (left third thoracic intercostal artery injection) showed an AVM nidus associated with a false aneurysm sac, which corresponded to the hematoma seen on MRI. Dilated veins could be seen draining superiorly, with smaller veins draining inferiorly, contributing to venous congestion and cord edema. Embolization of this AVM was performed with glue (N-butyl cyanoacrylate), which succeeded in removing the false aneurysm during the first session.

C

D

Each segment in the spine involves the spinal cord (corresponding myelomere); nerve root; bone; and paraspinal, subcutaneous, and skin tissues. A patient may therefore present with multiple shunts, which involve several different myelomeres (segments) of the spinal cord (multimyelomeric SCAVMs) both on the cord and on intradural nerve roots. The association of a SCAVM with a nerve root AVM in the same patient is metameric if the spinal cord segment (myelomere) involved corresponds to that of the nerve involved. This spinal arteriovenous metameric syndrome, also known as Cobb’s syndrome, can be numbered from 1 to 31, depending on its location at the vertebral and metameric levels. Klippel-Trénaunay and Parkes-Weber syndromes are characterized by cutaneous capillary hemangiomas or port wine stains, varicosities and lymphedema, and bone and soft tissue hypertrophy of the affected extremity, usually the lower limb. Parkes-Weber syndrome is also associated with the presence of AVMs in the involved extremity. Associated SCAVMs are known to occur in these syndromes.34,38 In such cases, the SCAVMs are usually multiple, and a metameric disposition is suspected but cannot be definitely demonstrated. Other multifocal spinal cord lesions have been described without metameric linkage.

Single Lesions This third group of SCAVMs consists of all classic single lesions, either nidal or fistulous. This group may reflect an incomplete expression of one of the previously described situations and includes lesions of the spinal cord, nerve root, and filum terminale.

Clinical Presentation In SCAVM series that include adults and children, the mean age of presentation is in the mid-20s.39-41 However, in close to 20% of cases, the lesion is diagnosed in children younger than 16 years of age.42 In a more recent series,43 30% were children. Common clinical manifestations include acute neurological symptoms usually caused by hemorrhagic events, chronic progressive neurological deficit associated with venous congestion, and acute nonhemorrhagic symptoms.

Spinal Hemorrhage The most striking symptom in the clinical presentation of SCAVMs is the high incidence of hemorrhage, which may be

chapter 44 arteriovenous malformations of the brain and spinal cord ■

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Figure 44–4. Spinal cord arteriovenous fistula (AVF). The patient, an 11-month-old boy, had presented at the age of 3 months with progressive paraparesis, associated with increasing spasticity of the lower limbs and sphincteric problems. A, Magnetic resonance imaging (MRI) showed a large vascular pouch within the spinal canal. B, Angiography showed a macroAVF. The vascular pouch seen on MRI was due to an ectatic venous pouch. The presence of a macro-AVF was suggestive of hereditary hemorrhagic telangiectasia, but no family history could be found. This fistula was successfully embolized with glue (Nbutyl cyanoacrylate) in two sessions.

A

B

either subarachnoid or within the spinal cord itself (hematomyelia) and occurs in 50% of all SCAVM patients. Hemorrhage, particularly hematomyelia, is associated with the onset of new, significant, and often devastating neurological deficits or with aggravating preexisting deficits. Hemorrhage is seen more frequently in cervical lesions than in thoracic and lumbar lesions.39-41 Hemorrhage is also more common in children.43 Hemorrhage may be caused by rupture of associated aneurysms, rerupture of a false aneurysm, rupture of spinal cord veins, or rupture of the AVM nidus. Hemorrhagic transformation of venous infarction is not observed in the cord. The typical syndrome of spinal hemorrhage is severe pain, which frequently starts in the interscapular region and/or at the site of the rupture and then rapidly spreads to the rest of the back, to the nuchal area, and to the legs. When hemorrhage is profuse or, in cervical lesions, when blood extends into the intracranial cavity, there may be headaches and disturbance of consciousness. In severe cases, papilledema, cranial nerve palsies, and convulsions may be observed. The signs and symptoms can be so severe and rapid in their onset that they may be mistaken for intracranial subarachnoid hemorrhage. In other cases, limb weakness, sensory loss, and disorders of micturition or defecation may follow bleeding within the cord itself (hematomyelia) or may result from compression of the cord by

a blood clot. In rare instances, in cases of severe upper cord dysfunction, respiratory paralysis can occur.

Nonhemorrhagic Symptoms Acute, nonhemorrhagic neurological deficit may result from acute intralesional venous thrombosis. This may occur as a venous response to chronic hemodynamic changes in the SCAVM. More often, patients present with chronic progressive neurological symptoms caused by venous congestion within the spinal cord. Of note is that the venous proportion of the vascular system is of greater hemodynamic significance in the spinal cord than in the cerebral circulation. This can be explained by the contragravity venous drainage of the spinal cord (which is mostly below the level of the heart), in comparison with that of the brain. Chronic progressive symptoms may manifest in a continuous or stepwise manner. Early symptoms include nerve root or back pain. Weakness eventually develops in over 90% of affected patients. Other common symptoms include sensory changes and impotence. Bowel and bladder dysfunction is present in almost all patients. The presence of a bruit is a relatively uncommon finding. If present, however, a bruit is strongly suggestive of a high-flow lesion.

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Muscle atrophy and sensory disturbances that may result in multiple injuries can be observed in patients with SCAVMs. Spinal deformities such as kyphosis and scoliosis are also seen. In addition, complications common to other types of spinal cord dysfunction, such as urinary tract infections, respiratory infections, and decubitus ulcerations, may also be present and must be taken into consideration in determining the morbidity and final outcome of these patients.

Diagnosis and Clinical Assessment The first step in the assessment of patients with suspected vascular disorders of the spinal cord is a complete clinical history and physical examination. The neurological status needs to be accurately determined and often must be repeated in time to objectively establish stability or worsening of neurological status. This is followed by a complete pretherapeutic evaluation, including noninvasive imaging techniques and spinal angiography.

Noninvasive Imaging Techniques MRI has become the modality of choice in the preliminary assessment of patients referred for investigation of vascular pathology of the spinal cord. Computed tomography and myelography no longer have a significant role in the initial screening of suspected SCAVM, except for cases in which MRI is contraindicated. MRI is both sensitive in lesion detection and able to demonstrate the extent of an AVM, including the demonstration of any extraspinal extension in cases of metameric syndromes. MRI is also useful in delineating intramedullary pathologic processes such as spinal cord hematoma, intravascular thrombosis, and subarachnoid hemorrhage and the secondary changes of cord edema, intramedullary cavities, or cord atrophy secondary to chronic venous hypertension. Changes at a distance from the malformation may be present and may explain otherwise confusing neurological symptoms. MRI remains limited in its ability to accurately locate the site of arteriovenous communication and the evaluation of the angioarchitecture of an AVM. Pitfalls of this technique in the assessment of patients with vascular lesions of the spinal cord are related primarily to cerebrospinal fluid pulsation artifacts that may produce images highly suggestive of spinal cord vascular lesions.44 This is of particular importance in pediatric patients, in whom such artifacts may lead to unnecessary angiographic exploration. If, however, the study findings are negative or inconclusive and if the diagnosis is compatible with venous congestion from a small arteriovenous shunt draining into the ventral spinal cord vein, spinal DSA should be performed.45 For treatment planning, spinal DSA still remains the study of choice.

Spinal Angiography DSA remains a “gold standard” in the diagnosis and treatment planning of vascular lesions of the spine and spinal cord. Spinal DSA is usually performed with the patient under general anesthesia and with controlled respiration.

Spinal DSA is performed according to different protocols at different institutions and may be guided by MRI. However, as in any other vascular study, a territorial approach must be undertaken. As in all other anatomical areas, the angiographic examination must outline the normal vasculature around the vascular pathology to ensure that the full extent of the lesion is visualized and that the effect of the lesion on the remainder of the spinal cord is understood and in order to properly plan and monitor treatment. Specific attention should be paid to the angioarchitecture of the lesion and remaining vascular supply to the cord. Features such as radicular aneurysms, intranidal aneurysms, and venous congestion should be noted.

Treatment and Management The final outcomes of patients with vascular lesions of the spinal cord are directly related to the prompt diagnosis and treatment of the abnormality.

Endovascular Embolization and Surgery The main modes of therapy are surgery and endovascular embolization. In current practice, the first line of treatment for SCAVMs is usually endovascular embolization with glue (Nbutyl cyanoacrylate). In rare instances in which endovascular embolization is not possible or may carry high risk, surgery may be considered. Radiosurgery currently has no role in the treatment of SCAVMs. The indications for treatment include all symptomatic lesions that can be cured. Factors that modify the objectives in a particular patient include (1) the age of the patient; (2) the clinical manifestation (e.g., hemorrhage, more than one hemorrhage); (3) the angioarchitecture of the lesion (the presence of, e.g., an aneurysm, venous ectasia); and (4) impaired arterial flow or venous drainage of the spinal cord (stagnation in the anterior spinal artery circulation; nonvisualization of the medullary veins, indicating impaired venous drainage). In the young symptomatic patient, treatment should be pursued aggressively. As in BAVMs, even when complete cure may not be possible at an acceptable level of risk, partial targeted treatment can be proposed with the aim of arresting or improving the clinical situation or favorably modifying the natural history of disease. The purpose of a partial targeted approach is to obliterate weak points in the angioarchitecture (e.g., arterial aneurysm and nidus aneurysm) and to reduce nidal size and flow to decongest the venous drainage. These procedures relieve the venous drainage of the normal spinal cord, often with beneficial effect. In the acute stage after a spinal hemorrhage, the neurological deficit may be severe, including total loss of function. Although rebleeding is a risk, most patients improve significantly over the next several weeks or months. Emergency and aggressive intervention is generally unnecessary and may interfere with the process of natural recovery. Spinal angiography may be performed early to rule out a pseudoaneurysm or another potentially risky angioarchitectural feature that may justify early targeted embolization, usually if more than one hemorrhage has occurred. In patients with a fixed deficit or severe clinical signs of cord transection, treatment is of unlikely functional benefit. Nonetheless, treatment is indicated, especially in cases of

chapter 44 arteriovenous malformations of the brain and spinal cord repeated hemorrhage and in high cord lesions, to reduce the risk of repeated life-threatening spinal hemorrhage. In some patients with severe pain related to compressive symptoms, palliative embolization may also be beneficial.

neonatal series represent only a small proportion of AVMs and pertain to specific disease groups. ●

Magnetic resonance imaging and digital subtraction angiography are currently the modalities of choice in the diagnosis and evaluation of these lesions.

●

The aim of treatment is an improvement over the expected natural history of the disease rather than a morphological endpoint. The treatment strategy is specific to each patient and based on the clinical circumstances, the age of the patient, and the angioarchitecture of the lesion.

Medical Therapy Medical treatment for the various complications of spinal vascular lesions is an important part of patient management and should be provided. Physical therapy, nursing, pain control management, and psychotherapy all play important roles in the management of patients with SCAVMs. A properly trained team is essential for obtaining the best overall results.

607

CONCLUSION

Suggested Reading

Both BAVMs and SCAVMs are relatively uncommon diseases. The exact incidence of these diseases is, however, difficult to estimate. Differences in the disease prevalence reported in the literature are probably related to differing referral patterns and population differences, as well as the diagnostic modalities available. Patients may present with a wide range of clinical symptoms, which vary according to lesion location, the angioarchitecture of the malformation, and the age of the patient. When either a BAVM or SCAVM is suspected in a patient, a complete clinical and neurological assessment is crucial. This is essential both in the pretreatment evaluation and for subsequent follow-up of the patient’s progress after therapy. Current imaging modalities in the evaluation of these vascular lesions involve mainly MRI and DSA, the latter being necessary for the accurate delineation of lesion angioarchitecture and hence in treatment planning. Of the therapeutic modalities discussed, endovascular embolization is becoming an increasingly important tool in the treatment of both BAVMs and SCAVMs. Whereas a complete cure is often obtained in single-hole fistulae or small AVMs, it may not be possible in many complex lesions without risk of increased morbidity. In such cases, a partial targeted approach may be taken instead, to treat high-risk areas within such lesions. The aim of treatment is, above all, to improve the natural history of the disease, in comparison with the risk of therapy, and to achieve amelioration of clinical symptoms when possible.

Berenstein A, Lasjaunias P, Ter Brugge KG: Surgical Neurorangiography, vol 2.2: Clinical and Endovascular Treatment Aspects in Adults, 2nd ed. Berlin: Springer-Verlag, 2004, pp 609-735, 760-847. Hofmeister C, Stapf C, Hartmann A, et al: Epidemiological, clinical and morphological characteristics of 1289 patients with cerebral arteriovenous malformation. Stroke 2000; 31:13071310. Lasjaunias P: Vascular Diseases in Neonates, Infants and Children: Interventional Neuroradiology Management. Berlin: SpringerVerlag, 1997, pp 203-319. Mansmann U, Meisel J, Brock M, et al: Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery 2000; 46:272-281. Meisel HJ, Mansmann U, Alvarez H, et al: Cerebral arteriovenous malformation and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery 2000; 46:793802. Rodesch G, Hurth M, Alvarez H, et al: Angioarchitecture of spinal cord arteriovenous shunts at presentation. Clinical correlations in adults and children: the Bicêtre experience on 155 consecutive patients seen between 1981-1999. Acta Neurochir 2004; 146:217-227. Stefani MA, Porter PJ, Ter Brugge KG, et al: Angioarchitectural factors present in brain arteriovenous malformations associated with hemorrhagic presentation. Stroke 2002; 33:920-924. Valavanis A, Yasargil MG: The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg 1998; 24:131-214.

References

K E Y ●

P O I N T S

Arteriovenous malformations (AVMs) in the brain and spinal cord are uncommon. The concept that AVMs are congenital (morphologically detectable at birth) is not supported by antenatal or pediatric imaging and clinical experience. On the contrary, it is likely that lesions found in young adults, although likely to result from an early in utero “event,” are not present at birth but appear later as a result of various (unknown) exogenous or endogenous “revealing” triggers. This empirical observation contributes to the evolution of the malformation concept from a morphological (detectable) to a biological (quiescent) one. Pediatric cases or even

1. Weon YC, Yoshida Y, Sachet M, et al: Supratentorial cerebral arteriovenous fistulas (AVFs) in children: review of 41 cases with 63 non choroidal single-hole AVFs. Acta Neurochir 2005; 147:17-31. 2. Garretson HD: Intraranial arteriovenous malformations. In Wilkins RH, Rengachary SS, eds: Neurosurgery. New York: McGraw-Hill, 1985, pp 1448-1457. 3. Jellinger K: Vascular malformations of the central nervous system: a morphological overview. Neurosurg Rev 1986; 9:177216. 4. Mohr JP: Neurological manifestations and factors related to therapeutic decisions. In Wilson CB, Stein BM, eds: Intracranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984, pp 12-23. 5. Valavanis A, Yasargil MG: The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg 1998; 24:131-214.

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6. Guttmacher AE, Marchuk DA, White RIJ: Hereditary hemorrhagic telangiectasia. N Engl J Med 1995; 333:918-924. 7. McAllister KA, Grogg KM, Johnson DW: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary hemorrhagic telangiectasia type 1. Nat Genet 1994; 8:345-351. 8. Mahadevan J, Ozanne A, Yoshida Y, et al: Hereditary haemorrhagic telangiectasia cerebrospinal localization in adults and children: review of 39 cases. Interv Neuroradiol 2004; 10:2735. 9. Willinsky RA, Lasjaunias P, Ter Brugge KG, et al: Multiple cerebral arteriovenous malformations: review of our experience from 203 patients with cerebral vascular lesions. Neuroradiology 1990; 32:207-210. 10. Fullbright RK, Chaloupka JC, Putman CM, et al: MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 1998; 19:477-484. 11. Matsubara S, Mandzia JL, Ter Brugge KG, et al: Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol 2000; 21:1016-1020. 12. Krings T, Ozanne A, Chng SM, et al: Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age: review of 50 consecutive patients aged 1 day–60 years. Neuroradiology 2005; 47:711-720. 13. Garcia-Monaco R, Taylor W, Rodesch G, et al: Pial arteriovenous fistula in children as presenting manifestation of RenduOsler-Weber disease. Neuroradiology 1995; 37:60-64. 14. Yoshida Y, Weon YC, Sachet M, et al: Posterior cranial fossa single-hole arteriovenous fistulae in children: 14 consecutive cases. Neuroradiology 2004; 46:474-481. 15. Bhattacharya J, Luo CB, Suh DC, et al: Wyburn-Mason or Bonnet-Dechaume-Blanc as cerebrofacial arteriovenous metameric syndromes (CAMS): a new concept and a new classification. Interv Neuroradiol 2001; 7:5-17. 16. Meisel HJ, Mansmann U, Alvarez H, et al: Cerebral arteriovenous malformation and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery 2000; 46:793802. 17. Stefani MA, Porter PJ, Ter Brugge KG, et al: Angioarchitectural factors present in brain arteriovenous malformations associated with hemorrhagic presentation. Stroke 2002; 33:920-924. 18. Crawford PM, West CR, Chadwick DW, et al: Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986; 49:1-10. 19. Mansmann U, Meisel J, Brock M, et al: Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery 2000; 46:272-281. 20. Hofmeister C, Stapf C, Hartmann A, et al: Epidemiological, clinical and morphological characteristics of 1289 patients with cerebral arteriovenous malformation. Stroke 2000; 31:1307-1310. 21. Ducreux D, Desal H, Bittoun J, et al: Diffusion, perfusion and activation functional MRI studies of brain arteriovenous malformations. J Neuroradiol 2004; 31:25-34. 22. Berenstein A, Lasjaunias P, Ter Brugge KG: Goals and objectives in the management of brain arteriovenous malformations. In Surgical Neurorangiography, vol 2.2: Clinical and Endovascular Treatment Aspects in Adults, 2nd ed. Berlin: Springer-Verlag, 2004, p 703. 23. Stefani MA, Porter PJ, Ter Brugge KG, et al: Large and deep brain arteriovenous malformations are associated with risk of future hemorrhage. Stroke 2002; 33:1220-1224. 24. Meisel HJ, Mansmann U, Alvarez H, et al: Effect of partial targeted NBCA embolization in brain AVM. Acta Neurochir 2002; 144:879-888.

25. Lasjaunias P: Vascular Diseases in Neonates, Infants and Children: Interventional Neuroradiology Management. Berlin: Springer-Verlag, 1997, p 41. 26. Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 1986; 65:476-483. 27. Karlsson B, Lindquist C, Steiner L: Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations. Neurosurgery 1997; 40:425-431. 28. Pollock B, Flickinger J, Lunsford D, et al: Factors associated with successful arteriovenous malformation radiosurgery. Neurosurgery 1998; 42:1239-1247. 29. Schlienger M, Atlan D, Lefkopoulos D, et al: Linac radiosurgery for cerebral arteriovenous malformations: results in 169 patients. Int J Radiation Oncol Biol Phys 2000; 46:1135-1142. 30. Wyburn-Mason R: The Vascular Abnormalities and Tumours of the Spinal Cord and Its Membranes. London: H. Kimpton, 1943. 31. Pia HW, Vogelsang H: Diagnose und Therapie spinaler Angiome [Diagnosis and therapy of spinal angioma]. Dtsch Z Nervenheilkd 1965; 187:74-96. 32. Olivecrona H: The cerebellar angioreticulomas. J Neurosurg 1957; 9:317-330. 33. Krenchel NJ: Intracranial Racemose Angiomas: a Clinical Study. Copenhagen: Universitetsforlaget i Aarhus, 1961. 34. Rodesch G, Hurth M, Alvarez H, et al: Classification of spinal cord arteriovenous shunts: proposal for a reappraisal—the Bicêtre experience with 155 consecutive patients treated between 1981 and 1999. Neurosurgery 2002; 51:374-380. 35. Mandzia JL, Ter Brugge K, Faughnan ME, et al: Spinal cord arteriovenous malformations in two patients with hereditary hemorrhagic telangiectasia. Childs Nerv Syst 1999; 15:80-83. 36. Mazighi M, Porter P, Alvarez H, et al: Associated cerebral and spinal AVM in infant and adult: report of two cases treated by endovascular approach. Intervent Neuroradiol 2000; 6:321326. 37. Matsumaru Y, Pongpech S, Laothamas J, et al: Multifocal and metameric spinal cord arteriovenous malformations: review of 19 cases. Interv Neuroradiol 1999; 5:27-34. 38. Nimii Y, Ito U, Tone O, et al: Multiple spinal perimedullary arteriovenous fistulae associated with the Parkes-Weber syndrome. Interv Neuroradiol 1998; 4:151-157. 39. Djindjian M, Djindjian R, Hurth M, et al: Spinal cord arteriovenous malformations and the Klippel-Trénaunay-Weber syndrome. Surg Neurol 1977; 8:229-237. 40. Rosenblum B, Oldfield EH, Doppman JL, et al: Spinal arteriovenous malformations: a comparison of dural arteriovenous fistulae and intradural AVM’s in 81 patients. J Neurosurg 1987; 67:795-802. 41. Berenstein A, Lasjaunias P: Surgical Neuroangiography, vol 4. Berlin: Springer-Verlag, 1992, pp 197-251. 42. Yasargil MG, Symon L, Teddy PG: Arteriovenous malformations of the spinal cord. In Symon L, ed: Advances and Technical Standards in Neurosurgery, vol 11. Vienna: SpringerVerlag, 1984, pp 61-102. 43. Rodesch G, Hurth M, Alvarez H, et al: Angio-architecture of spinal cord arteriovenous shunts at presentation: clinical correlations in adults and children. The Bicêtre experience on 155 consecutive patients seen between 1981-1999. Acta Neurochir 2004; 146:217-227. 44. Levy LM, di Chiro G, Brooks RA, et al: Spinal cord artifacts from truncation errors during MR imaging. Radiology 1988; 166:479-483. 45. Lasjaunias P, Berenstein A, Terbrugge KG: Spine and spinal cord arteries and veins. In Surgical Neuroangiography, vol 1: Clinical Vascular Anatomy and Variations, 2nd ed. Berlin: Springer-Verlag, 2001, pp 73-164.

CHAPTER

45

PROTHROMBOTIC STATES AND RELATED CONDITIONS ●

●

●

●

Paul Bentley and Pankaj Sharma

THE HEMOSTATIC SYSTEM

PATHOLOGY OF EXCESSIVE HEMOSTASIS

The human circulatory system does not act simply as an array of inert, lifeless pipes that convey blood between organs; it is an organ itself with functions beyond those of the various compounds and cells that pass through its conduits. One of these functions is the maintenance of its own structural integrity, essential for transmitting blood pressure, ensuring continuity of flow, and minimizing spread of infection. There has evolved a complex hemostatic system that enables on-line monitoring of a large area of endothelial space (approximately 600 m2, or the equivalent of three tennis courts), with rapid, local restoration of breaches as they occur. This system is composed of multifarious actions and interactions among solid-phase vessel wall, cellular platelets, and humoral coagulation factors; Figure 45–1 is a basic schema of the events that follow vessel injury. It is preferable to talk about this system as a whole rather than as a separate “coagulation system” because of the strong interdependence among these three components. An important attribute of hemostasis is the requirement of both “on knobs” and “off knobs,” delicately adjusted, to prevent a response to vessel wall injury from overshooting and resulting in a sealing of both the defect (which is desired) and the vessel lumen itself (which would cause local hypoperfusion). Endogenous anticoagulant systems are shown in Figure 45–2. As with most metabolic systems, the physiological state is optimized by both prohemostatic and antihemostatic reactions occurring simultaneously (i.e., a dynamic system); the net outcome depends on local vessel integrity. This chapter is concerned with states that predispose to excessive hemostasis (vessel closure) and their neurological effects. By far the commonest mechanism by which vessels close off pathologically is the formation of thrombus, and so such states are commonly referred to as prothrombotic states. A thrombus is a concretion of activated platelets and fibrin, the latter product being the insoluble end product of the coagulation cascade. However, vessel closure may also occur through embolism, progressive thickening of the arterial wall, vasospasm, or cell sludging. Within the neurological system, the most likely outcome of vessel closure is ischemic stroke, but other diseases, such as peripheral nerve ischemia, optic neuropathy, spinal cord infarction, dementia, and parkinsonism, may also be the consequence of ischemic injury to nervous tissue.

In the same way that the physiology of hemostasis is shared among the trio of vessel wall, platelets, and clotting factors, the pathophysiology of excessive hemostasis can be summarized by its own triad. This so-called Virchow’s triad represents three sets of factors, each of which may give rise to vessel closure, thrombosis being a final common pathway in most cases (Fig. 45–3). A modern-day listing of Virchow’s triad has changed little since its original formulation in 1860: 1. Vessel wall defect (especially with endothelial disruption). 2. Stasis of blood (including turbulence). 3. Hypercoagulability (or excessive platelet activation). Figure 45–4 lists the various causes within each of these categories, including states predisposing to thrombosis or vessel closure by other means (e.g., vasospasm). These causes can be remembered by the mnemonic “ADVISE OR HEPARINISE.” In reality, it is likely that a synergistic interaction of two or three factors contribute to thrombosis. In the arterial circulation, although normal cerebral vessels can withstand a pressure of approximately 1500 mm Hg, the commonest scenario is as follows: An atherosclerotic plaque ruptures or hemorrhages (through a vessel wall defect), thereby inducing local activation of coagulation factors and platelets (hypercoagulability), as well as turbulence with pockets of slow or reversed flow (stasis). In the venous circulation, the initiating event is usually a combination of stasis (e.g., immobility), and a hypercoagulable state (e.g., stress response secondary to recent surgery). In general, vessel wall defects are far more predominant and likely to result in thrombosis in arteries or arterioles, whereas stasis is found in the parts of the circulation in which rate of blood transit is at its lowest: namely, veins. Hypercoagulable states are associated with both arterial and venous thromboses but more commonly result in the latter, possibly because of the prior requirement of local stasis in order for an activated coagulation cascade to result in a significant accumulation of fibrin. A thrombosis consists of a solid aggregation of platelets and erythrocytes within a fibrin mesh adherent to the vessel wall. Microscopic observation reveals that thrombi within arteries have a higher platelet composition (in relation to fibrin) than do those in veins. Because fibrin tends to adhere to red blood

609

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Endothelial disruption

Stenosis vasospasm

Intrinsic pathway XIIa XI

Platelet release reaction ␣-granules: release vWF, fibrinogen, V ␦-granules: release ADP, serotonin, calcium Tubular system: thromboxane A2

vWF, VIIIa

VII XIa

IX

VIIa

+ Tissue factor IXa

X

Xa

II

←

XII

Extrinsic pathway

←

Platelet adhesion Via glycoprotein-Ib—von Willebrand factor adherence to subendothelial microfibrils

Exposure of: i) Collagen ii) Tissue factor

Removal of inhibitors: i) Prostaglandin I2 ii) Heparin, AT-III, tPA

←

Turbulence – pockets of stasis

Release of: i) von Willebrand factor ii) Fibronectin

←

IX

←

Section

←

610

Va

Fibrinogen ←

XIII Common pathway

IIa (Thrombin) ←

Platelet metamorphosis i) Exposes GP IIb-IIIa to fibrinogen ii) Exposes other glycoproteins for platelet– monocyte interactions

Fibrin

XIIIa Cross-linked fibrin

Platelet-fibrin thrombus ■

Figure 45–1. Hemostatic system showing interdependence among vessel wall, platelets, and coagulation cascade. ADP, adenosine diphosphate; AT-III, antithrombin III; GP, glycoprotein; t-PA, tissue-type plasminogen activator; vWF, von Willebrand factor.

cells, arterial thrombi appear relatively white, whereas venous thromboses, with a higher fibrin content, appear red.

NEUROLOGICAL CONSEQUENCES OF EXCESSIVE HEMOSTASIS Stroke represents the neurological consequence of a disordered hemostatic system; causes may be logically divided into excessive hemostasis, which results in ischemia, or inadequate hemostasis, which results in hemorrhage. Ischemic strokes, accounting for about 80% of all strokes, result predominantly from arterial occlusion but occasionally result from venous blockage. Most arterial strokes, whether ischemic or hemorrhagic, occur because of lesions affecting the vessel wall component of the hemostatic system. Atherosclerosis results in stenosis of large-vessel arteries, which itself predisposes to development of superimposed thrombosis and resultant vessel occlusion. Diseases of the myocardium result in impaired contractility, which may secondarily cause blood stasis, cardiac thrombus, and eventually embolism into arteries of the brain,

spinal cord, or eye (as well as into arteries of other organs). Arterial aneurysms are predisposed to rupture, which overwhelms the hemostatic system’s ability for self repair. Not all strokes are caused by dysfunctional hemostasis: one such example is severe hypotension, such as that caused by cardiac arrhythmia, which results in temporary arrest of blood flow in watershed areas of the brain. Venous occlusion typically occurs in the venous sinuses located posteriorly within the cranium or in the superior cerebral, ophthalmic, or spinal veins and causes focal ischemia and infarction in the tissue drained by the occluded vein. Because arterial blood continues to enter the infarcted region, capillaries enlarge and eventually rupture, which accounts for the frequent presentation of venous thrombosis as multiple intracerebral hemorrhages. An alternative manifestation is raised intracranial pressure (causing coma or papilledema, for instance) that may be explained by the fact that the cerebral venous sinuses act as the outflow for cerebrospinal fluid drainage. Thromboembolism represents the commonest cause of ischemic stroke; other pathological processes may also result

chapter 45 prothrombotic states and related conditions

Anticoagulants derived from endothelium (local) or liver (circulating)

Prostaglandin I2 (prostacyclin)

Heparin Anti-thrombin-III

Tissue factor pathway inhibitor

XIa

IX

VIIa

IXa

X

Plasminogen

Xa

Plasmin

Va IIa

Fibrinogen

←

Protein S

←

Platelet metamorphosis

Tissue plasminogen activator (tPA)

+ Tissue factor

←

XI

←

vWF, VIIIa

VII

XIIa ←

Activated protein C

←

XII

Platelet release reaction

tPA Inhibitor

Extrinsic pathway

Intrinsic pathway

Platelet adhesion

←

Nitric oxide

Vasodilatation

611

II

Protein C

Common pathway

Fibrin

Fibrin degradation products Activation

Platelet–fibrin thrombus ■

Inhibition

Figure 45–2. Hemostatic system showing endogenous anticoagulation, fibrinolytic, and antiplatelet systems. vWF, von Willebrand factor.

in vessel closure to produce regional ischemia within the nervous system. Examples of such pathological processes are vasospasm (that in the brain results in migrainous auras), arteriosclerotic lipohyalinosis (commonly caused by hypertension and resulting in isolated “lacunar” strokes or, when diffuse, a subcortical dementia), and vasculitis. Figure 45–5 depicts the varied neurological effects of ischemia secondary to thromboembolism or other processes resulting in vessel closure.

VESSEL WALL DEFECTS Atherosclerosis Atherosclerosis describes the pathological appearance of the vessel wall in most cases of strokes and myocardial infarctions. Microscopically, it is characterized by the accumulation of lipid and inflammatory cells within the arterial intima. However, these lesions build up over decades and have relatively inconsequential hemodynamic effects until they encroach on a significant proportion of the vessel lumen. Even when significant stenosis has developed, it is usually insufficient to result in endorgan damage unless a fall in blood pressure across the diseased

blood vessel occurs. Hence, the additional factor that appears necessary in the pathogenesis of most clinical syndromes of infarction is the formation of thrombus on a preexisting atherosclerotic plaque. This development probably occurs rapidly, over hours, and is triggered by conformational or biochemical changes within the atherosclerotic lesion and/or by the appearance of prothrombotic substances within the blood. Because any atherosclerotic lesion has the potential of suddenly transforming itself into a substrate for thrombosis, conditions that predispose to atherosclerosis should be regarded as contributing (albeit indirectly) to a prothrombotic state. Postmortem appearances of arteries from people who died from nonischemic causes have shown that atherosclerotic lesions are virtually universal after middle age, especially in residents of industrialized nations. In fact, the strong geographical dependence of atherosclerosis risk corresponds to recognized environmental factors that may initiate atherogenesis (Fig. 45–6). The most important predisposing state is a high circulating triglyceride (lipid) load, especially during the postprandial period—which for many residents of the industrialized world represents most of the waking day. Because triglyceride-rich particles (very-low-density lipoprotein) continuously exchange their triglycerides with cholesterol found within high-density lipoprotein particles, the

612

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ARTERIAL THROMBOSIS

Stenosis

Endothelial disruption

VENOUS THROMBOSIS

VENOUS ± ARTERIAL THROMBOSIS

Stasis

Hypercoagulability tPAI Heparin Anti-thrombin-III

tPA

Platelet adhesion

Platelet metamorphosis

IX

XIa

VIIa

+ Tissue factor IXa

X

←

Activated protein C

XI

←

vWF, VIIIa

VII

XIIa ←

XII

Platelet release reaction

←

tPA Inhibitor

←

tPA

Plasminogen

Plasmin

Xa

Va

Protein C

■

Fibrinogen

IIa ←

II

←

CARDIAC (mural) THROMBOSIS

Protein S

Fibrin

FDPs

Figure 45–3. Virchow’s triad superimposed on the hemostatic system: Each main factor may cause vessel closure (principally thrombosis), although the relative contribution each factor provides depends on the part of the circulatory system at which the occluding lesion occurs. FDP, fibrin degradation products; t-PA, tissue-type plasminogen activator; t-PAI, t-PA inhibitor; vWF, von Willebrand factor.

level of high-density lipoprotein–cholesterol is inversely correlated with, and an accurate predictor of, atherosclerosis risk. The level of low-density lipoprotein (LDL)–cholesterol is less predictive of atherosclerosis, although a subset of LDLcholesterol particles formed under high triglyceride conditions, called small, dense LDL-cholesterol, are highly atherogenic (after oxidation or glycation). Although diet is the leading global factor in accounting for the distribution of atherosclerosis-related diseases, there are multiple other associations. Some of these factors act through secondary effects on lipid metabolism. Diabetes mellitus results in both a high circulating triglyceride level and glycation of small, dense LDL-cholesterol, both predisposing to premature atherosclerosis. Of interest, most genetic types of hypertriacylglyceridemia are not associated with atherosclerosis, whereas familial hypercholesterolemia (usually caused by a LDLcholesterol receptor mutation) is strongly associated with premature atherosclerosis; homozygous patients suffer

ischemic heart disease or strokes in their 20s. There are other genetic factors for atherosclerosis that may or may not result from interactions with lipid metabolism (Table 45–1). Both lipoprotein(a) and homocysteine levels are risk factors for atherosclerosis that also have strong genetic influences; these factors also have prothrombotic effects as a result of interactions with the coagulation cascade (see later discussion). Certain factors, such as hypertension, smoking, and epinephrine (present with, e.g., “easily stressed” personalities) act as synergistic factors with lipid metabolism for atherogenesis. Exercise and fish oils rich in omega-3 fatty acids (e.g., eicosapentaenoic acid) engender a more favorable lipid profile and correspondingly reduce atherosclerosis. Although the influences of lipid and glucose metabolism on atheroma formation are well established, the contributions played by the immune system on both atherogenesis and plaque destabilization are becoming increasingly appreciated. Inflammation is triggered at the first sign of vessel wall injury and

chapter 45 prothrombotic states and related conditions ARTERIAL THROMBOSIS or CLOSURE

CAUSES Atherosclerosis Arteriosclerosis—hypertension Dissection Dysplasia, fibromuscular Vasculitis - Autoimmune, sarcoid, infection Injury - Iatrogenic: radiation, catheter Spasm: migraine Extra: embolism, compression

Vessel wall defect

VENOUS ± ARTERIAL THROMBOSIS or CLOSURE

VENOUS THROMBOSIS or CLOSURE Stasis

CAUSES Operation, especially: Orthopedic or Obstetric (i.e., peripartum) Obesity Overland flights (i.e., long-haul) Reduced circulating volume (i.e., hypovolemia) Right-sided heart failure CARDIAC (mural) THROMBOSIS CAUSES Atrial fibrillation Aneurysm - Congenital - Myocardial infarction Cardiomyopathy

■

613

Hypercoagulability Platelets

Coagulation cascade —fibrinolysis

CAUSES Hereditary: factor V Leiden, prothrombin mutations Endocrine: estrogen (OCP, HRT), testosterone, diabetes hyperosmolar nonketotic coma Polycythemia and other hematological, including platelets: Paraproteinemia, paroxysmal nocturnal hemoglobinuria, sickle cell anemia Platelets: sticky platelet syndrome; thrombocythemia Autoimmune: antiphospholipid syndrome, Behçet’s syndrome Renal: nephrotic syndrome, volume depletion Infection: systemic: TB, chlamydia, any cause of raised CRP local: otitis media or mastoiditis Neoplasia: adenocarcinoma, acute myeloid leukemia, head-neck carcinoma Injury: fracture, sympathetic stress response Smoking (also causes atherosclerosis) Exogenous: chemotherapy, COX-2 inhibitors

Figure 45–4. Pathological causes of Virchow’s triad. COX-2, cyclooxygenase 2; CRP, C-reactive protein; HRT, hormone replacement therapy; OCP, oral contraceptive pill; TB, tuberculosis.

results in upregulation of cell-adhesion molecules, release of chemotaxins and reactive oxygen species, and facilitation of lipid influx and storage. Eventually, the fibrinous cap and endothelial lining of an atherosclerotic plaque becomes degraded by proteolytic enzymes derived from the inflammatory infiltrate, and at this point, rapid thrombus development is triggered. The effects of local inflammation within the vessel wall can often be observed through levels of circulating inflammatory markers. Hence, levels of C-reactive protein, an acute-phase reactant, and of CD3 provide indexes of the risk of ischemic heart disease or stroke. In addition to mirroring the inflammatory turnover within atherosclerotic lesions, these proteins act together to accelerate atheroma formation. Of interest, statins have been found to have anti-inflammatory effects, including reduction of C-reactive protein levels, and these effects have been associated with reduction of stroke or myocardial infarction risk, independent of the effect that these drugs have through lowering cholesterol.

Arteriosclerosis Arteriosclerosis is the progressive replacement of smooth muscle cells with proteinaceous material (predominantly collagen) within the media of small arteries and arterioles (40 to 400 μm in diameter). The microscopic appearance is of concentric layers of a hyaline substance in the same location where smooth muscle normally occurs. The most strongly associated risk factors are hypertension and diabetes. As the process continues, the lumen constricts, which results in progressive tissue hypoperfusion. The latter is exacerbated during periods of hypotension, because the loss of smooth muscle prevents vasodilation. In certain cases, especially with accelerated hypertension, the same vessels develop a more disorganized process, which results in patchy fibrinoid accumulation, necrosis, and foam cell formation. When this accumulation is rapid, the end result may be acute small-vessel or lacunar infarction. From a therapeutic point of view, this knowledge is important, because

A

C ■

B

D Figure 45–5. Diverse neurological consequences of vessel closure, usually caused by thromboembolism. A, Middle cerebral artery infarction with secondary edema. B, Superior sagittal sinus venous thrombosis with bilateral cerebral infarctions and secondary hemorrhage. C, Bilateral subcortical ischemia (Binswanger’s leukoencephalopathy), resulting from chronic hypertension and causing dementia and gait apraxia. D, Thoracic spinal cord infarction, resulting from embolism from a cardiac source and causing paraparesis, anesthesia of lower limbs, and double incontinence. Continued

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chapter 45 prothrombotic states and related conditions

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T A B L E 4 5 – 1. Genetic Causes of Thrombophilia Genetic Causes of Hypercoagulability Prothrombin G20210A mutation Factor V Leiden mutation (activated protein C resistance) Protein C deficiency Protein S deficiency Tissue plasminogen activator inhibitor–1 overactivity Plasminogen deficiency Hyperhomocysteinemia: MTHFR: C667T mutation Lipoprotein(a) elevation Hyperfibrinogenemia Dysfibrinogenemia (β-chain variants) Genetic Causes of Atherosclerosis Familial hyperlipidemias Familial hypercholesterolemia: LDL receptor mutation Familial combined hyperlipidemia Familial dysbetalipoproteinemia (hypertriacylglyceridemia) Hyperhomocysteinemia: MTHFR: C667T mutation Lipoprotein(a) elevation Hyperfibrinogenemia Dysfibrinogenemia (β-chain variants)

E LDL, low-density lipoprotein; MTHFR, methylene tetrahydrofolate reductase.

Vasculitis

F ■

Figure 45–5, cont’d. E, Inferior branch retinal artery occlusion secondary to embolism, causing monocular altitudinal (superior) loss of visual acuity. F, Left abducens nerve palsy resulting from small-vessel infarction of the sixth cranial nerve in a diabetic patient. (B, From http://www.aic.cuhk.edu.hk/web8/ 0294_Cerebral_venous_haemorrhagic_infarction.jpg. Copyright © Chanles Gomersall. C, From http://www.kup.at/kup/ images/thumbs/336.jpg. E, From The Robert Bendheim Digital Atlas of Ophthalmology, The New York Eye and Ear Infirmary, http://www.nyee.edu/page_deliv.html?page_no=50. F, From http://medicine.ucsd.edu/clinicalmed/eyes-cn6-palsy3.jpg.)

it explains why anticoagulation and thrombolysis have no effect on stroke from this cause.

Dissection Large arteries may be injured by an externally applied stretch or twist to cause, first, an endothelial breach and, subsequently, an elongating, longitudinal split between intima and media that is driven by the shearing forces within the arterial lumen. As blood enters the wall defect, the intimal aspect is forced into the lumen to create stenosis, with resultant turbulence and stasis. Together with the original endothelial breach, these conditions are ripe for thrombus formation within the true lumen. The initiating event for such dissections may be an apparently trivial movement, such as lifting or looking up, but the history is one classically of the patient’s suffering at the hands of overenthusiastic hairdressers or osteopaths.

Inflammation centered on the vessel wall results in progressive luminal narrowing as a result of cellular infiltration and deposition of proteins, including fibrin. At the same time, inflammatory cell and cytokine interactions with platelets and coagulation factors favor a prothrombotic state. There are multiple causes of this lesion type, ranging from primary endogenous “vasculitides” to exogenous factors such as infections (e.g., herpes zoster or tuberculosis), toxins, and radiotherapy. An important example with neurological consequences is giant cell arteritis, a large-artery vasculitis in elderly people that results in headache, ischemic optic neuropathy, and stroke. In younger patients, the large or medium-sized vessel vasculitides Takayasu’s arteritis, polyarteritis nodosa, or ChurgStrauss syndrome should be considered, especially in patients with recurrent ischemic events, renal dysfunction, rash, or constitutional symptoms such as fever, myalgia, and testicular pain.

Spasm The commonest neurological result of vasospasm—indeed one of the commonest neurological conditions—is migraine. More specifically, intracranial arterial spasm results in focal cerebral or brainstem ischemia that correlates with the migrainous “aura” phase in which affected patients complain of a focal sensory disturbance, typically a visual scotoma or flickering jagged lines. A rare but well-recognized complication of the migrainous aura is progression of the ischemia to infarction, typically in a small-vessel territory.

STASIS Wherever the circulation becomes sluggish, activated clotting factors may accumulate to reach a concentration that surpasses

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C e r e b r o va s c u l a r D i s e a s e INFLAMMATION—TISSUE-BOUND 1. Differentiation of monocytes into macrophages 2. Absorption of remnant particles and oxidized-LDL cholesterol into macrophages via “scavenger receptor” CD36 to form “foam cells”

Pressure effect, hemorrhage into plaque

Sub-endothelial space ENDOTHELIAL ACTIVATION 1. Expression of cell-adhesion molecules (CAMs) and selectins 2. Formation of reactive oxygen species (ROS) 3. Downregulation of nitric oxide synthase (NOS) Lumen

PLAQUE DESTABILIZATION Lipid influx

INITIATION 1. Dyslipidemia: LDL-cholesterol, especially small, dense (becomes oxidized or glycated) VLDL—cholesterol Free fatty acids—obesity Remnant particles Lipoprotein(a), homocysteine 2. Shear stress—hypertension 3. Glucose—diabetes mellitus 4. Smoking 5. Sympathetic tone—type A personality ■

Adhesion + Transmigration of monocytes + T lymphocytes

INFLAMMATION—CIRCULATING

THROMBUS FORMATION Degradation of fibrin cap by • Neutrophil-derived elastase or gelatinase • Matrix metalloproteinases • TNF-␣ • ROS

Recruitment of monocytes, neutrophils, and lymphocytes via chemokines IL-6 (induces CRP in liver), IL-8, MCP-1 LDL: low-density lipoprotein VLDL: very-low-density lipoprotein ROS: reactive oxygen species IL: interleukin MCP: monocyte chemoattractant protein TNF: tumor necrosis factor CRP: C-reactive protein

Figure 45–6. Pathogenesis of atherosclerosis and subsequent plaque destabilization with thrombus formation.

a critical threshold, potentiating formation of an expanding fibrin core and, ultimately, thrombus. The most common predisposing circumstance is prolonged immobility, when thrombosis tends to form in the deep leg veins and usually when an additional hypercoagulability risk factor, such as infection or genetic status, prevails. The usual clinical consequences of this are local pressure effects in the leg and, more devastatingly, pulmonary embolism. However, in patients with a right-to-left cardiopulmonary shunt, a dislodged venous thrombus may course into the arterial circulation to cause, among other outcomes, cerebral embolism. This “paradoxical embolism” occurs most commonly in patients with either congenital cyanotic heart disease or a pulmonary arteriovenous malformation (e.g., as part of hereditary hemorrhagic telangiectasia), but in rare cases, it occurs in patients with a patent foramen ovale (present in up to 25% of the population) during, for example, inadvertent performance of the Valsalva maneuver. Stasis of venous circulation may also cause neurological disease through the formation of intracranial venous

thrombosis, most often within the superior sagittal or transverse sinuses. Factors that tend to encourage intracranial venous stasis are hypovolemia (e.g., from prolonged vomiting), raised central venous pressure (e.g., from heart failure), obesity, and pregnancy. Intracranial venous thrombosis may also be triggered by vessel wall defects that secondarily result in turbulence and stasis effects, such as tumor compression or indwelling catheter within the jugular vein or superior vena cava, causing back-propagation of thrombosis; bacterial or fungal infection of a bony sinus or orbit; or traction of sinuses after lumbar puncture (rarely associated with thrombosis). Neoplastic and infective processes are also associated with hypercoagulability (see later discussion). Stasis may also be caused by hyperviscosity as a result of increase in circulating cell numbers, reduced cell deformability, or increased plasma proteins. Because some of these conditions also encourage coagulation, they are discussed as follows.

chapter 45 prothrombotic states and related conditions HYPERCOAGULABILITY Hereditary Many of the recognized genetic causes of hypercoagulability (and ischemic stroke) can be appreciated by reference to the endogenous coagulation and anticoagulation pathways (see Fig. 45–3 and Table 45–1). Hence, one of the most common abnormalities, factor V Leiden mutation, can be explained as an insensitivity of factor V to deactivation by protein C, which leads to deregulation of the production of thrombin. Mutations of endogenous anticoagulant/coagulant proteins are associated most strongly with venous thrombosis, although certain mutations (mainly factor V Leiden and prothrombin mutations and protein S deficiency) are also associated with arterial thrombosis, including stroke. The odds ratio associated with these conditions is approximately 10 for development of venous thrombosis and less than 3 for development of an arterial thrombosis. Whether a particular mutation results in an ischemic event depends on whether other prothrombotic or vascular risk factors coexist. Factor V Leiden and prothrombin mutations occur in approximately 10% and 5% of the population, respectively. Most affected people are heterozygous for the mutations although the relative risk for thrombosis is much greater in people with homozygous mutations. Deficiencies of protein C, protein S, and antithrombin III occur in fewer than 1% of the population for each. Most of these mutations are autosomal dominant, except for plasminogen deficiency, which is autosomal recessive. Screening of children or young adults who present with arterial stroke has revealed that fewer than 25% have a recognized inherited prothrombotic state. Measurements of

baseline coagulation and anticoagulation factor activity are often depressed for several weeks after an ischemic event (because of peripheral factor consumption), which necessitates delay in measurements of functional components of the thrombophilia screen. Genetic mutation analyses are, however, time independent. Also, measurements from functional assays of certain coagulation components (e.g., protein C) increase with age, which necessitates use of appropriate normal ranges. Protein S deficiency may also be acquired (e.g., because of infection or antiphospholipid syndrome). When a known prothrombotic mutation is identified, genetic counseling can be offered and family members tested. Although anticoagulation or antiplatelet drugs are not recommended for asymptomatic carriers or homozygotes, such information may influence future care in the event of illness. Both hyperhomocysteinemia and elevated lipoprotein(a) levels are strong risk factors for ischemic stroke in either arterial or venous circulations, which indicates that these conditions incur risks of both atherosclerosis and hypercoagulability. The main determinant of the population’s distribution of homocysteine levels lies with the methylene-tetrahydrofolate reductase (MTHFR) genotype: high levels are predicted by the TT genotype and low levels by the CC wild-type (abbreviations refer to a single nucleic acid polymorphism within the gene). A high homocysteine level may be exacerbated by deficiencies of folate or vitamin B12, both of which are required for the metabolism of homocysteine (Fig. 45–7). Homocysteine interacts with all three components of the hemostatic system: increasing platelet adhesiveness, activating coagulation factors, and resulting in endothelial disruption; it is also involved in the conversion of LDL-cholesterol into proatherogenic forms. Hyperhomocysteinemia may be treated with supplemental folic acid and vitamins B12 and B6, although there is insufficient

Dietary folate

dUMP (deoxy-Uridine MonoPhosphate)

S-Adenosyl Homocysteine

MTHF (5,10-MethyleneTetraHydra Folate)

Demyelination

Thrombosis

Homocysteine

Atherogenesis MTHF reductase Vitamin B12

Vitamin B6 dTMP (deoxy-Thymidine MonoPhosphate)

Nucleotide synthesis ■

Tetrahydrafolate

617

Methionine

S-Adenosyl Methionine

Cysteine

Deficiency causes demyelination

Figure 45–7. Relationships of homocysteine, folate, vitamin B12, and vitamin B6 metabolism, showing pathological effects of impaired homocysteine breakdown. Vitamin B12 and vitamin B6 act as co-factors, rather than being intermediary products.

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evidence at present to support this form of treatment routinely for prophylaxis against arterial events. Lipoprotein(a) is a cholesterol-rich lipoprotein that also has close homology with plasminogen, the latter fact helping explain its influence on coagulation.

Endocrine Estrogen exerts a prothrombotic influence and is associated with deep venous thrombosis. A diagnosis of cerebral venous sinuses thrombosis should therefore be considered in all women who present with headache, epilepsy, or confusion who are taking oral contraceptive pills, are taking hormone replacement therapy (HRT), or are peripartum. The risk of venous thrombosis with the oral contraceptive pill, approximately threefold greater than in control subjects, is increased by concomitant thrombophilic factors, including a family history of deep vein thrombosis, obesity, or when taken as a combined preparation containing a third-generation progestagen (e.g., desogestrel or gestodene). The oral contraceptive pill is also associated with arterial stroke, especially in migraine sufferers who have experienced aura (i.e., focal cerebral ischemia), smokers, or hypertensive patients. Estrogens also have a modulatory effect on atherogenesis, although the manner of this relationship differs between physiological and pharmacologically induced states. The risk of atherosclerosis, myocardial infarction, and ischemic stroke is decreased in women in relation to men of the same age, but only up to menopause (even when this occurs prematurely). However, the supplementation of estrogen in women after menopause in the form of HRT has been found either to confer no protection or even to increase the risk of atherosclerosisrelated disease, including stroke. The reason for this may relate to the rise in C-reactive protein found with conjugated equine estrogen (the commonly administered form of HRT). Another endocrinological association with thrombosis is excessive levels of either testosterone or erythropoietin, both of which can result in excessive circulating cell counts (polycythemia) and predispose to thrombosis. Both of these hormones may be taken illicitly by athletes, testosterone in the form of anabolic steroids. The antiandrogen cyproterone acetate, often used in women to counter virilization, is also associated with venous thrombosis, even more strongly than oral contraceptive pills. Further examples of endocrinological association with thrombosis are diabetes mellitus (which accelerates atherogenesis and may be associated with a hypovolemic and prothrombotic state, especially during hyperosmolar nonketotic acidosis) and acromegaly (which accelerates atherosclerosis).

Polycythemia and Other Hematological Disorders An increase in the number of any circulating cell lineage predisposes to thrombosis both because of hyperviscosity (which encourages stasis) and because of the facilitation that cell surfaces provide to an activated coagulation cascade (via interactions with phospholipids and glycoproteins). Increases in platelet counts, most notably with essential thrombocythemia or splenectomy, are especially likely to predispose to arterial and venous thromboses. Hyperviscosity, particularly in the form of paraproteinemia (especially immunoglobulin M type)

and cryoglobulinemia, may also be caused by increased plasma proteins, and each should be tested for separately. These substances also serve to interfere with coagulation proteins and so such patients are at risk for both cerebral hemorrhages and infarcts. Sickle cell anemia is strongly associated with arterial and venous thromboses as a result of hyperviscosity, despite a reduced circulating erythrocyte count. The fundamental defect arises when hemoglobin S polymerizes within the erythrocyte into long rods under hypoxic or acidotic conditions. Such polymerization constrains the erythrocyte membrane, which adopts its rigid shape that fails to deform as the red blood cell travels through the microcirculation. In consequence, ischemic strokes tend to occur in deep small arteries, especially in the watershed regions of the cerebral convexities, the brainstem, spinal cord, and retina. Large-artery occlusive disease (e.g., in the distal carotid artery or circle of Willis) also occurs, possibly because of initial occlusion of the vasa vasorum, their own blood supply, which leads to intimal and smooth muscle proliferation within the large vessel walls with consequent luminal stenosis.

Autoimmune Disorders Arterial and venous thromboses, as well as thrombotic endocarditis, are complications of multisystemic autoimmune conditions such as systemic lupus erythematosus and Behçet’s disease. One cause of vessel closure, including arterial stroke, in these conditions is vasculitis (see “Vessel Wall Defects” section). However, thrombosis itself may be triggered by an activated immune system or by autoantibodies directed against platelets or components of the coagulation cascade. One of the most well-recognized thrombophilic autoimmune conditions is the antiphospholipid syndrome, which may occur on its own or in association with systemic lupus erythematosus. Patients with this condition have an approximately 10-fold greater risk of arterial or venous thromboses, including recurrent strokes, than do healthy individuals. Recurrent miscarriages and certain rashes (e.g., livedo reticularis) also characterize this syndrome. Autoantibodies found in such patients undoubtedly play a pathogenic role in that their targets include β2-glycoprotein I, a component of the platelet-coagulation interaction, and prothrombin. These antibodies have in common the property of targeting plasma proteins bound to anionic surfaces, the latter of which are most commonly phospholipids (e.g., cardiolipin) on outer cell surfaces. Paradoxically, these antibodies are also termed lupus anticoagulants because the original method of detecting their presence was through their in vitro effect of prolonging phospholipiddependent clotting times, such as the activated partial thromboplastin time. A further paradox, in view of the thrombophilic nature of the disease, is that patients often exhibit an immunemediated thrombocytopenia.

Renal Disorders Nephrotic syndrome predisposes to venous thrombosis because of preferential renal loss of anticoagulants, such as antithrombin III, and by encouraging hypovolemia. In the long term, it is associated with hypercholesterolemia and

chapter 45 prothrombotic states and related conditions accelerated atherosclerosis as a result of filtering of apolipoproteins.

Inflammation Generalized inflammation, such as that secondary to infection or neoplasia, can result in a prothrombotic state and predispose to ischemic stroke. One mechanism for this is through activation of the complement system that leads to increased binding of protein S to C4b, resulting in apparent protein S deficiency. Certain causes of intracranial venous thrombosis are an inflammatory state; for example, bacterial mastoiditis or paranasal sinusitis results in thrombosis within contiguous transverse or cavernous venous sinuses, respectively. The association of diffuse head injury with cerebral venous thrombosis may also arise from inflammatory factors. Systemic infection may also result in widespread thromboses; for example, virus-associated purpura fulminans is caused by acquired protein C, protein S, and antithrombin III deficiencies, and enterohemorrhagic Escherichia coli food poisoning results in thrombotic thrombocytopenic purpura. Treatment entails infusion of both fresh-frozen plasma and anticoagulant factor concentrates in the former condition, and plasma exchange in the latter condition.

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depending on the circumstance: heavy acute or chronic consumption increases, whereas mild chronic consumption decreases stroke risk. Both cocaine and amphetamines predispose to arterial ischemic stroke through sympathomimeticdriven vasoconstriction and hypertension, vasculitis, and, in the case of cocaine, depletion of protein C and antithrombin III. It has been found that the newest class of nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors such as rofecoxib, is linked to an increase in arterial ischemic events including strokes. This has been attributed to the cyclooxygenase-2 enzyme’s being essential for formation of the prostaglandin prostacyclin (which inhibits thrombogenesis), whereas the platelet-derived prostanoid thromboxane (which activates platelets) is dependent on the cyclooxygenase-1 form of the enzyme. The main pharmacological association of cerebral venous thrombosis is estrogen-containing contraceptive pills (see previous discussion), but another recognized thrombophilic drug is asparaginase, used in treating childhood leukemias.

K E Y

P O I N T S

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Impaired blood flow underlies some of the commonest neurological conditions, such as ischemic stroke, migraine with aura, and multi-infarct dementia.

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Causes of impaired blood flow can be categorized into insufficient cardiac output, which causes global hypoperfusion, or vessel stenosis and occlusion, which cause regional ischemia or infarction.

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The pathogenesis of vessel stenosis and occlusion involves the three components of hemostasis: vessel wall, platelets, and coagulation cascade.

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The commonest mechanism of vascular occlusion is the formation of thrombus, a solid-phase composite of activated platelets and fibrin, in which fibrin represents the end product of the coagulation cascade.

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Causes of thrombus formation can be divided according to “Virchow’s triad”—endothelial injury, blood stasis or turbulence, and hypercoagulability—although most instances of thrombus are caused by two or three of these categories, acting synergistically.

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The commonest cause of endothelial injury is atherosclerosis—irregular, focal deposits of lipid and inflammation—which predisposes to acute syndromes of arterial occlusion, such as ischemic stroke and myocardial infarction.

Exogenous

●

Many drugs of abuse are associated with stroke, although the pathogenesis of each is often multifactorial. Tobacco smoke promotes atherosclerosis, damages endothelium (both directly through nicotine and indirectly through its hypertensive effect), increases platelet reactivity and fibrinogen levels, inhibits prostacyclin formation, and eventually predisposes to a hypoxic and polycythemic state. Both arterial and venous thromboses are linked to smoking. Ethanol has both prothrombotic and antithrombotic consequences, the net outcome

Blood stasis typically occurs in the large-capacitance venous system. Venous thrombi most commonly occur in deep leg veins but may occur in the cerebral venous sinuses to cause cerebral infarction, hemorrhage, or raised intracranial pressure alone.

●

A large range of hypercoagulability states exists. Common causes include prothrombin and factor V Leiden mutations, oral contraceptive pills, smoking, infection (either locally within the brain or septicemia), and adenocarcinoma.

Neoplasia The classic association of a generalized thrombophilic state with neoplasia is that seen with mucinous adenocarcinoma of the lung, stomach, or pancreas. Although both arterial and venous thromboses are encouraged, the commonest cause of symptomatic cerebral infarcts in such patients is nonbacterial thrombotic endocarditis (caused by valvular accumulations of fibrin and platelets). The cause of this phenomenon lies in the release of procoagulant substances from the tumor, including sialic acid residues, phospholipid, and tissue factor, as well as interleukin-6, which acts as a stimulant for thrombocytosis. A related paraneoplastic syndrome is disseminated intravascular coagulation, in which excessive consumption of clotting factors and platelets results in widespread small-vessel cerebral, venous sinus, and endocarditic thrombi, as well as predisposing to intracranial hemorrhage. This occurs with adenocarcinomas, as well as myeloid leukemia. Strokes may also occur with tumors (lung and rectum carcinoma) as a result of thrombotic thrombocytopenic purpura, vasculitis (lung and lymphoproliferative disease), or development of antiphospholipid antibodies.

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Suggested Reading Bogousslavsky J, Caplan LR: Uncommon Causes of Stroke. Cambridge, UK: Cambridge University Press, 2001. International Congress on Thrombosis. 18th Congress, Ljubljana, June 2004: Reports [special issue]. Pathophysiol Haemost Thromb 2003/2004; 33:233-506.

Kullo IJ, Ballantyne CM: Conditional risk factors for atherosclerosis. Mayo Clin Proc 2005; 80:219-230. Meschia JF, Brott TG, Brown RD Jr: Genetics of cerebrovascular disorders. Mayo Clin Proc 2005; 80:122-132. Stam J: Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005; 352:1791-1798.

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CEREBRAL VENOUS THROMBOSIS ●

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Gian Luigi Lenzi, Alessio Mercurio, and Marta Altieri

Cerebral vein and sinus thrombosis (CVST) is a rare event in comparison with arterial stroke, accounting for less than 1% of all strokes. CVST occurs in all age groups, peaking in incidence among neonates and young adults. Clinical diagnosis is difficult, because of the wide spectrum of clinical symptoms of CVST. The achievements of neuroimaging since the 1970s have been fundamental for diagnosing and treating CVST and for a better understanding of its pathogenesis. Early diagnosis of CVST is crucial, because therapy, based mainly on anticoagulation, reduces the risk of fatal outcome and severe disability.1,2

ANATOMY OF THE INTRACRANIAL VENOUS SYSTEM Cortical Cerebral Veins These veins drain blood from the superficial part of the brain (cortex and the adjacent white matter) and are composed of three systems: 1. The dorsomedial system drains into the superior sagittal sinus (SSS) and the inferior sagittal sinus (ISS), receiving blood from the convexity and the midline of the brain. 2. The posteroinferior system drains into the lateral sinus, receiving blood from the temporo-occipital areas. 3. The anterior system drains into the cavernous or the pterygoid venous plexus through sylvian veins, receiving blood from the frontal pole, the inferior part of the frontal lobe, and the anterior part of the temporal lobe. These systems show variations among the population: Any of the three major components may be missing or hypoplastic. In these cases, the other components are hypertrophic. Cortical veins are connected to the dural sinuses by the so-called bridging veins.

Deep Cerebral Veins These veins drain the deepest parts of the white matter, the basal ganglia, and the diencephalon. The septal and thalamostriate veins, called the subependymal veins, are the most important and drain into the internal cerebral vein.

1. The septal veins receive blood from the genu of the corpus callosum, from the septum pellucidum, and from the anterior part of the caudate nucleus, and they drain into the thalamostriate veins. 2. The thalamostriate veins receive blood from the basal ganglia and from the internal and external capsules; they pass through the roof of the third ventricle, cross in the interventricular foramen of Monro, and end in the internal cerebral veins. 3. The posterior choroidal veins drain blood from the pineal gland and from the choroid plexus of the lateral ventricles and end in the thalamostriate veins. 4. The internal cerebral veins run parallel beneath the choroidal vein of the third ventricle to join their counterpart and form the vein of Galen. 5. The vein of Galen, unique and median, runs from the posterior part of the diencephalon up to the straight sinus, between the cerebellum and the splenium of the corpus callosum; early in its course, it receives the paired basal veins of Rosenthal. 6. The basal veins of Rosenthal drain the bottom parts of the basal ganglia; the bottom parts of the temporal, frontal, and occipital lobes; and the medial parts of the insula and the temporal lobe. These veins originate in correspondence to the anterior perforated substance near the confluence of two vessels—the anterior limbic vein and the deep middle cerebral vein (or insular vein)—and then they “tie” into a bow around the mesencephalon before ending in the vein of Galen. Sometimes they receive the posterior limbic veins, the hippocampal veins, and the middle superior cerebellar veins. 7. The anterior limbic veins drain the cingulate circumvolution. In correspondence with the genu and the rostrum of the corpus callosum, they bend to reach the basis of the brain, in order to join the deep middle cerebral vein on the same side and to form the homolateral basal vein of Rosenthal.

Posterior Fossa Veins The venous drainage of the posterior fossa is highly variable. Four main systems can be outlined: 1. The posterosuperior system drains the dorsal cerebellum, vermis, and the upper portion of the brainstem into the vein

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of Galen. The most important vessels of this group are the superior cerebellar hemispheric veins and the superior vermian veins. 2. The anteromedial system is formed by the anterior pontomesencephalic vein, which drains into the basal vein of Rosenthal on both sides. 3. The anterolateral system is formed by the petrosal veins, which drain the ventral cerebellum and the upper part of the brainstem, and by the choroidal vein of the fourth ventricle, which drains the lower part of the brainstem. 4. The posteroinferior system is formed by the inferior cerebellar hemispheric veins, which are tributaries of the transverse sinus, and by the bilateral posterior spinal vein, which ends in the inferior retrotonsillar vein; this vein and the superior retrotonsillar vein form the inferior vermian vein. This vessel is finally a tributary of the ISS.

2.

3.

4.

Dural Sinuses The dural sinuses are situated between the leaves of the falx and the tentorium and are triangular in section. They drain blood from the cortex, the meninges, and the scalp (through the calvarian veins) and deliver it to the internal jugular veins. They are connected with the extracranial veins in the scalp by the emissary veins. This may explain dural involvement after cutaneous contusions or infections (Fig. 46–1). 1. The SSS begins at the foramen cecum, before the crista galli, and runs along the curve of the inner table of the skull to reach the torcular Herophili, where it converges with the straight sinus. Their combined flows drain into the transverse sinus. The SSS receives blood from frontal, parietal, and occipital superior regions of the cortex. The SSS, and other sinuses, contains the arachnoid villi and granulations in which the absorption of cerebrospinal fluid takes place. There is a direct dependency of cerebrospinal fluid pressure on the intracranial venous pressure, which explains the frequent increase in intracranial pressure in CVST. The dura mater adjacent to the sinus contains important venous plexuses, which represent a potential alternative drainage route when a sinus is occluded; this explains the “empty-

Caudate Dural nucleus vein Foramen of Monro Choroid vein

Ant. pillars of fornix Median plexus

Optic nerve Internal carotid artery Oculomotor nerve Diaphragma sellae Attached margin Free margin of tentorium of tentorium Superior sagittal sinus Venous lacuna

Verous lacuna

Great cerebral vein ■

6.

Velum Choroid plexus

Velar veins

A

5.

delta” sign, which is visible on computed tomographic (CT) scan in occlusion of the SSS. The straight sinus is formed by the junction of the tentorium, falx cerebri, and falx cerebelli and receives blood from the vein of Galen and from the ISS. It ends in the torcular Herophili or in the left transverse sinus. The ISS runs parallel to the SSS in correspondence to the free margin of the cerebral falx, receiving blood from the middle regions of the brain that drains into the SSS through the venous vessels of the cerebral falx. The lateral sinus connects the torcular Herophili with the internal jugular veins on both sides and is formed by two components: the transverse sinus, which lies in the peripheral margin of the tentorium cerebelli, and the sigmoid sinus. The transverse sinuses are frequently of unequal size; the left one, which receives blood from the SSS, is usually larger. Atresia or agenesis of the transverse sinus is related to alternative filling of the sigmoid sinus by the vein of Labbé. The sigmoid sinus starts at the end of the transverse sinus and reaches the jugular vein; agenesis and atresia of this sinus are very uncommon. The cavernous sinuses are situated on the sphenoid bone, laterally to the sella turcica. Their walls contain the cranial nerves III, IV, V2, and V3 of both sides, whereas the cranial nerve V1, the intracavernous tract of the internal carotid artery, and the pericarotid sympathetic plexus are contained in their lumen. They drain the ophthalmic veins, the anterior and middle cranial fossa, and the sphenoparietal sinus (the medial extension of the superficial sylvian vein). Blood drains posterolaterally along petrosal sinuses to the lateral sinus and the jugular vein through the inferior petrosal sinus. The two cavernous sinuses are connected by the intracavernous sinus, which lies on the clivus behind the sella turcica: this strict anatomical connection explains their frequent simultaneous involvement (Fig. 46–2). The petrosal sinuses are four in number, two for each side (superior and inferior). The first one is the anterior continuation of the transverse sinus and corresponds to the oblique insertion of the tentorium on the rocca petrosa, ending in the cavernous sinuses. The second begins at the

B

C

Figure 46–1. A, Anatomy of the deep venous circulation of the brain. B, Anatomy of the superior sagittal sinus. C, Anatomy of the lateral sinus (divided into its components: transverse sinus and sigmoid sinus) and the straight sinus.

chapter 46 cerebral venous thrombosis Internal carotid artery Cavernous sinus Oculomotor nerve Trochlear nerve Ophthalmic nerve Abducent nerve

Maxillary nerve

■

Figure 46–2. Anatomy of the cavernous sinus.

inferior part of the intercavernous sinus to end, together with the sigmoid sinus, in the jugular vein. 7. The occipital sinus is located at the insertion of the falx cerebelli on the occipital bone, and it drains blood from the dorsal regions of the cerebellum vermis.

Venous Anastomoses The intracranial venous system has no valves and therefore allows reversals of the blood flow direction, following pressure gradients. The most important vessels of this system are (1) the great anastomotic vein of Trolard that runs from the sylvian fissure to the SSS, thus forming an anastomosis between the SSS and the petrosal sinuses, and (2) the little anastomotic vein of Labbé, which connects the superficial sylvian vein with the transverse sinus or connects the SSS with the transverse sinus (depending on interindividual variability). There are also other, less important links, such as those between the little cortical veins and the adjacent sinuses or those between the basal vein of Rosenthal and the cortical veins. Transcerebral veins are virtual vessels that, when necessary, connect superficial and deep veins, crossing the cerebral parenchyma. The dural sinuses also communicate with the meningeal, diploic, and calvarian veins through the emissary veins.1-5

EPIDEMIOLOGY CVST may manifest with such a wide spectrum of clinical signs and symptoms that it goes unrecognized in quite a few patients. It follows that epidemiological studies are difficult to perform. On the basis of retrospective trials, CVST accounts for about 0.1% to 9% (mean, about 1%) of all deaths for stroke, with great geographic and ethnic variabilities.1,2,6-8 In industrialized countries, the incidence of CVST is estimated between 1.5 and 2.5 cases per 100,000 per year.6 Although these numbers, based on CT scan or magnetic resonance imaging (MRI) findings, are remarkably higher than those observed before the neuroimaging era, they still account for only patients who present with the more severe consequences of CVST: namely, hemorrhagic or ischemic venous strokes. As the frequency of venous stroke ranges from 30% to 80% of all cases, the prevalence of patients

623

who develop symptoms related to intracranial hypertension might be considerably higher.6,9-12 In a multicenter prospective observational study, 624 patients with CVST were enrolled. Female gender was prevalent (74.5%); the mean age was 39 years. Patients were predominantly white (79.2% versus 9.3% Hispanic, 5% black, 3.4% Asian, and 3.1% other races). Ischemic venous infarction was present in 46.5% patients, and hemorrhagic lesions were detected in 39.3% patients. Ischemic and hemorrhagic infarcts coexisted in some patients; the cumulative rate of parenchymal lesions at neuroimaging was 62.9%. The SSS was the most frequently involved (62%), followed by the left lateral sinus (44.7%), the right transverse sinus (41.2%), the straight sinus (18%), the choroidal vein (17.1%), and the jugular veins (11.9%). The deep venous system was involved in 10.9% of patients, and the cavernous sinuses in 1.3%. A posterior fossa vein thrombosis was reported in only 0.3%.13 In one study, researchers have investigated the distribution of risk factors and clinical features of CVST among white and African-Brazilian patients. The female/male ratio was higher among the African-Brazilian patients than among the white patients (4.75 versus 1.36), whereas the mean ages were similar. African-Brazilian patients had higher rates of focal deficits (60.8% versus 46.1%) and decreased consciousness (47.8% versus 27%); however, these differences were not significant.7 A high incidence of CVST in young women, especially during pregnancy and the puerperium, has been reported in several studies.6,11,12 As a matter of fact, estimates of CVST associated with pregnancy and the puerperium range from 2 to 60 per 100,000 deliveries in western Europe and North America and from 200 to 500 per 100,000 in India.1,2 The use of oral contraceptives appears to be a risk factor for CVST.1,2,6,10-13

PATHOPHYSIOLOGY The causal factors leading to CVST are essentially four: (1) prothrombotic state; (2) venous stasis; (3) direct involvement of the venous wall; and (4) abnormal blood viscosity.14 Symptoms of sinovenous occlusion may arise directly from the primary or underlying process, venous obstruction, vascular inflammation, or secondary complications. Venous obstruction causes a rise of venous and parenchymal pressure in its competence territory, which leads to venous distension and edema. Many of the clinical consequences of CVST arise from brain swelling and increased intracranial pressure caused both by venous engorgement and by decreased cerebrospinal fluid absorption secondary to venous hypertension. Furthermore, in the majority of cases, thrombosis involves multiple dural sinuses or both sinuses and veins.1,2,13,15 Experimental studies have contributed to a better definition of the pathological features of CVST. A subacute occlusion of SSS provokes clinical manifestations only when the occlusion spreads to cortical or bridging veins.16-20 SSS occlusion is usually associated with brain swelling, an increase in intracranial pressure, and diffuse cellular damage.16-21 On the other hand, occlusion of bridging and cortical veins produces a localized well-shaped venous infarction, with both ischemic and hemorrhagic features, surrounded by brain swelling and edema.19-23 In cats, the ligature of SSS provokes a stroke only when located after the confluence between this sinus and the rolandic vein, because the anterior third of the sinus is well

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compensated by collateral vessels. What is remarkable is that ischemic/hemorrhagic lesions are absent at 2 hours but present at 24 hours; this demonstrates that the acute occlusion of a dural sinus, at least in experimental conditions, is related not to an acute infarction but only to a subacute one.19 This observation could also apply to humans, inasmuch as the majority of patients with dural sinus involvement exhibit a subacute onset of the CVST signs and symptoms. Also remarkable is that neither the site nor the extent of a sinus occlusion is indicative of the final site and size of the corresponding ischemic lesion. On the contrary: The thrombosis of a cortical vein produces a definite area of infarction in the gray and superficial white matter. As a consequence, patients with cortical and deep vein thrombosis show the worst clinical outcome,22 because the deep vein thrombosis produces a widespread lesion that involves the thalamus, the deep white matter, and the upper parts of the brainstem.1,2,24

DIAGNOSIS AND CLINICAL FEATURES CVSTs manifest with a wide spectrum of signs and symptoms; therefore, the differential diagnosis should account for a number of possible conditions. The variability of clinical features of CVST is high in relation to the site and extent of thrombosis, the rate of propagation of the occlusion, the age of the patient, and the underlying pathology. Spinal cord venous involvement in these thrombotic processes is also possible, but it is very rare and related mostly to the propagation of an infectious thrombophlebitis of the pelvic veins. Headache is the most frequent presenting symptom and the most common complaint (75% of cases).1,2,12,25 The headache is usually diffuse and progressive, with no typical clinical characteristics or temporal profile. In the 2004 International Classification of Headache Syndromes, headache associated with CVST is classified as follows: (1) any new headache, with or without neurological signs, that fulfills the second and third criteria; (2) headache with neuroimaging evidence of CVST; (3) headache (and neurological signs, if present) that develops in close temporal relation to CVST.26 Despite its polymorphism, the most frequent clinical features of CVST can be grouped into three syndromes, according to their physiopathology: (1) intracranial hypertension syndrome (IHS); (2) stroke-related syndrome; and (3) encephalopathic syndrome.

Intracranial Hypertension Syndrome Headache is the most common clinical symptom of IHS, reported in 75% to 95% of patients.6 It represents the inaugural symptom in 70% to 75% of cases and is often the unique clinical manifestation of IHS.6-27 The headache may be any grade of severity, diffuse or localized, and persistent or intermittent. The onset is usually subacute (2 to 30 days) but can also be acute (>2 days) or chronic (>30 days).1,2 Attacks may mimic migraine or may be interpreted as a subarachnoid hemorrhage manifesting as a thunderclap-type headache, with instantaneous onset and coming on very quickly.27 Papilledema is observed in about 50% of affected patients.11 Only 20% to 40% of patients have the complete syndrome of isolated IHS with headache, nausea, vomiting, papilledema, transient visual obscurations, and eventually cranial nerve VI

palsy. The involvement of other cranial nerves is very rare.6 IHS resulting from CVST should be differentiated by the idiopathic intracranial hypertension or pseudotumor cerebri, with a complete neuroradiological workup. IHS is more frequently caused by the occlusion of the dural sinuses, particularly the SSS.1,2,27

Stroke-Related Syndrome This syndrome is typically related to the occurrence of a venous infarction that can be both ischemic and hemorrhagic. In the majority of cases, the pattern is represented by multiple small intraparenchymal hemorrhages, surrounded either by normal parenchyma or by ischemic areas. Its clinical features are illdefined and differ from those of an arterial stroke, which is more sharply outlined and wedge-shaped. The abundance of collateral vessels and anastomosis of the venous circulation, in comparison with the arterial circulation, is responsible for the lack of topographic localization of the lesions. Focal neurological signs (sensory and motor deficits, speech disturbances, hemianopia) are present in 40% to 60% of all cases.6 Headache, vomiting, and ataxia with acute onset are the most frequent symptoms in patients with cerebellar vein thrombosis, which is always associated with a concomitant effect on the lateral sagittal sinus and SSS.6

Encephalopathic Syndrome This condition is the least frequent manifestation of CVST but also the most severe. It is typically related to the involvement of the deep venous system, with diffuse damage of the white matter, basal ganglia, thalamus, and mesencephalon. Parenchymal damage may be related to necrosis, hemorrhages, and brain swelling.1,2,28 The clinical syndrome is characterized by generalized seizures, psychiatric disturbances, confusion, and variable levels of consciousness, disorders of which range from stupor to coma.1,2,6,10,11,25 Major cognitive impairments are reported in only 15% to 19% of cases.6 Focal or generalized seizures are present in more than 40% of patients with CVST2 and may occur in every related clinical syndrome. During the puerperium, the incidence is even higher (76%).6,12 Among the focal forms, the jacksonian type is the most common and is characteristically associated with Todd’s postconvulsive paresis, which is rare in idiopathic epilepsy.6,12,29 Nonetheless, only a few cases progress to epilepsy.29 Cavernous sinus thrombosis provokes a peculiar neurological syndrome characterized by any combination of unilateral chemosis, proptosis, and eyelid edema (caused by inadequate ocular venous drainage from the ophthalmic vein), with diplopia resulting from the involvement of the oculomotor nerves. Myosis and ptosis may also be present as a result of involvement of the third cranial nerve, as may mydriasis, caused by the involvement of the pericarotic sympathetic plexus. Retro-orbital and/or frontotemporal pain and anesthesia in the territories of the first and second branches of the trigeminus may also be present, constituting the so-called painful ophthalmoplegia. In the case of slow occlusion of the sinus, the only clinical manifestation may be limited to the sixth nerve palsy accompanied with pain. The thrombosis may extend to the contralateral sinuses. The differential diagnosis should take into consideration other causes of painful oph-

chapter 46 cerebral venous thrombosis thalmoplegia such as the Tolosa-Hunt syndrome, which is an idiopathic granulomatous inflammation of the dural wall of the cavernous sinuses; giant cells arteritis; sarcoidosis; local or general neoplasm; pseudotumor orbitae; and infectious thrombophlebitis caused by the propagation of a septic process from the face or neck into the cavernous sinuses.30

DIAGNOSTIC METHODS Venous angiography was the first instrumental technique used to diagnose CVST. Today, its clinical use is limited to dubious cases because of its excellent sensitivity. Angiography shows venous thrombosis as an interruption of flow that may be differentiated by sinus aplasia by the presence of a tortuous collateral circulation, consisting of “corkscrew vessels.”1,2 These vessels cannot be visualized by any other technique, and thus angiography remains the most important diagnostic tool in these cases.31 CT scan is usually the first investigation performed in the emergency department6; thus, it plays an important role in differential diagnosis, allowing the clinician to rule out disorders that may mimic CVST, such as tumors, encephalitis, brain abscesses, and subarachnoid hemorrhage.32 However, CT scans may be normal in 25% to 30% of patients.6 On CT scan, CVST may show direct and indirect signs. Direct signs are as follows: 1. The empty delta sign is the most frequent direct sign of CVST, being detected in 25% to 30% of patients with CSVT.6 Visible only after injection of contrast material, it appears as a hypodense area, because of the presence of a clot in the torcular Herophili, surrounded by a hyperdense triangular (delta-shaped) image, because of the enhancement of collateral vessels developed in the context of the dural wall.1,2,6,10,11,33 False-positive findings may result from early division, septa, or duplications of SSS.6,10 2. The cord sign is a focus of increased density, resulting from the presence of fresh thrombus, on the vessel parallel to the scanning plane. Its specificity is low. 3. The triangle sign is a fresh thrombus localized in the posterior part of SSS and may be visualized as a hyperdense triangle in the coronal slices without contrast. A hyperdensity may also be visible in other sinuses when they are involved in the thrombotic process. Indirect signs, more frequent than the direct ones, are not specific but may be suggestive of a CVST: 1. Local or generalized brain swelling, as indicated by the presence of small ventricle and sulci and diffuse relative low density of the white matter. 2. Intense contrast enhancement of the falx cerebri or the tentorium cerebelli, as a result of dural venous collaterals or stasis. 3. Hypodense parenchymal lesions corresponding to venous infarction or hyperdense lesions related to hemorrhagic areas. Hemorrhagic infarcts range from a large hematoma (very rare) to petechial areas within a hypodensity.1,2,6,11 Unlike the arterial hemorrhage, a venous one is frequently caused by diapedesis and not the breaking of a vessel. A bilateral altered density of thalami is highly suggestive of cerebral deep venous system thrombosis, and it is associated with a poor prognosis.

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4. Subarachnoid hemorrhage is a rare event, but it is possible in CVST, particularly when it achieves a gyral extension. In a subarachnoid hemorrhage secondary to CVST, vascular alterations are absent.34 Subdural hemorrhage related to CVST is possible, but it is a rare event. Since 2000, new CT techniques have improved the diagnostic sensitivity in detecting CVST. In particular, helical CT venography has improved the sensitivity of computed tomography to 95%,35 demonstrating an even higher sensitivity than digital subtraction angiography of the venous phase used to visualize thrombosis in cavernous sinuses and ISS. Multislice CT angiography is frequently available in the emergency department, and it is useful to differentiate arterial from venous infarction.36 Nowadays, MRI is the “gold standard” for diagnosing CVST. The signal characteristics of venous thrombi evolve in several stages. In the first days, the thrombus is isointense on T1-weighted sequences and hypointense on T2-weighted sequences. If the posterior part of the SSS is involved, a dural wall hyperintensity, similar to the CT delta sign, is visible after gadolinium injection. Afterward, the clot becomes hyperintense, first in T1-weighted sequences and later also in T2weighted sequences, with a characteristic progression of the hyperintensity from the periphery to the center. This phenomenon results from the transformation of hemoglobin into methemoglobin.6,11,24 After the first month, the hyperintensity disappears, first in T1- and then in T2-weighted sequences; therefore, the persistent occlusion can be visible, as an isointense signal, only in flow-sensitive gadolinium-enhanced sequences.1,2,6,11,24 Venous infarction on MRI appears as multiple areas of hyperintensity mixed with isointense or hypointense areas.6,24 Magnetic resonance venous angiography is an excellent tool for diagnosing the sharp interruption of a dural sinus; however, its capability to diagnose thrombosis of specific cortical veins is still weak, because of the individual variability and complexity of the cerebral venous system. Resolution and sensitivity are increased with the phase-contrast technique in regard to the time-of-flight technique.6 Magnetic resonance venous angiography is also useful for studying the hypoplasia of intracranial sinuses, an important source of pitfalls in the diagnosis of CVST.37 A promising technique is the gadolinium-enhanced auto-triggered elliptical centric-ordered magnetic resonance venography, which produces three-dimensional and digitally amplified images and is more sensitive than the classic gadolinium-enhanced magnetic resonance venography.38 Diffusion-weighted imaging (DWI) has demonstrated high sensitivity in detecting ischemic strokes in their initial phase. In CVST, DWI may be used to diagnose a venous infarction in the earlier hours, when it is more likely to be ameliorated with adequate medical intervention.6,24 It demonstrates the coexistence in the venous infarction of cytotoxic and vasogenic edema24,39,40 (Fig. 46–3). Another possible application of DWI may be to detect early recanalization, as demonstrated by Bousser and coworkers. Twenty-eight patients with recent CVST were studied with DWI in the acute phase, in order to identify hyperintense signals in the sinuses that corresponded to the thrombus. DWI hyperintense signals in the sinuses were detected in 12 of the 28 patients (43%) corresponding to 20 occluded veins or sinus. Two or three months after the beginning of anticoagulant administration, this phenomenon

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Figure 46–3. Fluid-attenuated inversion recovery (A), T2-weighted (B), and diffusion-weighted (C) magnetic resonance imaging sequences of a thalamocapsular venous infarction in a patient with transverse sinus thrombosis.

significantly decreased (35% versus 88%; P = 0.05) probably because of the different molecular structure of the clot.41 Since 2000, some advances have been made in testing possible applications of transcranial Doppler (TCD) imaging in CVST. In patients with CVST, higher values of peak systolic, end-diastolic, and mean blood flow velocities have been reported in the deep venous system than in controls.42,43 However, although blood flow alterations in patients with CVST are more frequent than in controls, the sensitivity of TCD imaging is lower than that of MRI.43,44 Interestingly, patients with CVST showed a decrease in velocity values after starting heparin therapy, with a rebound of velocity values immediately after heparin suspension. Higher velocities in the acute phase were significantly associated with disturbances of consciousness. No relation was found between increased flow velocities and disease onset, severity of motor deficits, and presence of bleeding. In addition, the initial blood flow velocity was not predictive of stroke outcome.44 In another study, 26 patients with CVST, all treated with intravenous heparin and then with warfarin for 12 months, were monitored for a mean of 316 days, in order to evaluate whether hemodynamic factors, related to alternative flow patterns, could predict stroke outcome. All patients underwent TCD sonography at admission. The majority of patients (69%) showed pathological blood flow velocities at admission. Four alternative drainage patterns were found: 1. In the cavernous sinus drainage type, there was increased flow into this sinus and its major contributors (sphenoparietal sinus and the superior petrosal sinus). Headache was the only symptom affected patients complained of, and the outcome was good. It was related to sigmoid sinus thrombosis. 2. In the deep cerebral venous drainage type, there was increased flow in the galenic system. It was related to SSS occlusion, and affected patients had a good prognosis. 3. In the reverse flow in the basal vein of Rosenthal drainage type, inversion of flow in this vein resulted from the occlu-

sion of the straight sinus. Headache was the only symptom, and the outcome was good. 4. In the transverse sinus drainage type, inversion of flow in the proximal part of the sinus occurred when the distal was occluded; an increased flow in the contralateral transverse sinus was found in proximal occlusions. This TCD pattern was related to the encephalopathic syndrome, and affected patients had the worst outcome.45 The Doppler technique is also useful in patients with CVST in detecting microembolic signals in the internal jugular vein, which are higher than in controls.46 Echocontrast techniques have been applied in order to increase TCD resolution.47

RISK FACTORS Several conditions have been found to be associated with CVST, but only few of them produce an effective increase of the relative risk. The most common risk factors for CVST are listed in Table 46–1. Idiopathic cases account for 25% to 30% of cases of CVST.1,2,10,11,25 Etiological factors may be divided into two main categories: septic CVST, which accounts for 5% to 15% of the cases, and aseptic CVST, which is predominant in industrialized countries. There are local and general causes for CVST. Local causes are related to head and neck infections (10.3%), tumors (2.2%), head injuries (1.1%), and neurosurgery (0.6%)13,48 (Fig. 46–4). Lumbar puncture, particularly with an intrarachidian injection of drugs (1.9%), may also produce CVST.49,50 In women, the most frequent general causes are pregnancy, puerperium, use of oral anticoagulants, and hormone replacement therapy. All these conditions are associated with high estrogen levels13,51-53 (Fig. 46–5). In the absence of thrombophilias, recurrence of CVST during another pregnancy is very rare.54 On the other hand, recurrences are very frequent in cases of puerperal CVST, which carry the greatest day-by-day risk of development of a vein thrombosis.6 Thus, anticoagulation is recommended in all

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Figure 46–4. A, Magnetic resonance image of a brain abscess of the right temporal lobe, caused by a septic otomastoiditis in a young adult without human immunodeficiency virus. B, Magnetic resonance venous angiogram in the same patient, showing septic thrombosis in the right superior sagittal sinus, straight sinus, and petrosal sinus.

A T A B L E 4 6 – 1. Septic thrombosis Head injuries Hematological disorders Thrombophilic disorders Metabolic disorders Neoplasia Inflammatory states Phakomatoses Hormonal Vascular disorders Medications Others

B Risk Factors for Cerebral Vein and Sinus Thrombosis Bacterial (including syphilis), fungal (Mucor, Aspergillus, Rhizopus), viral (HIV, herpes zoster) and parasitic (Trichinella) infections Penetrating and nonpenetrating head injuries, surgery, intravascular foreign bodies, iopamidol myelography Polycythemia vera, altitude-induced polycythemia, sickle cell anemia, cryofibrinogenemia, paroxysmal nocturnal hemoglobinuria, thrombocytosis, multiple myeloma, severe anemia Antithrombin III deficiency, protein C and/or protein S deficiency, activated protein C resistance, G20210A prothrombin mutation, antiphospholipid antibody syndrome, disseminated intravascular coagulation, MTHFR mutation, hyperhomocysteinemia, factor V Leiden, transfusion reaction, nephrotic syndrome Homocystinuria, carbon monoxide, diabetes, thyroid disorders, hypertriglyceridemia Metastatic (usually hematogenous malignancies), nonmetastatic complications, meningioma Behçet’s syndrome, inflammatory bowel disease (ulcerative colitis, Crohn’s disease), Wegener’s granulomatosis, Cogan’s syndrome, Köhlmeier-Degos disease, polyarteritis nodosa, systemic lupus erythematosus, sarcoidosis, thromboangiitis obliterans, rheumatoid arthritis Sturge-Weber syndrome Pregnancy and puerperium, thyrotoxicosis Arteriovenous malformations, arterial occlusions, jugular catheter occlusion, dural fistula Androgens, oral contraceptives, progestogens, L-asparaginase, pentosan, hormone replacement therapy, cocaine Dehydration, fever, cardiac decompensation, skull abnormalities (achondroplasia, craniometaphyseal dysplasia), lumbar puncture, epidural anesthesia, CSF hypotension

CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; MTHFR, methylene-tetrahydrofolate reductase.

patients with previous puerperal thrombosis.55 Thrombophilias, both hereditary and acquired, are reported in 20% to 50% of patients with CVST.13 In a series of 121 patients with CVST, prothrombin G20210A was present in 21.5% of patients, factor V Leyden in 12.4%, protein C deficiency in 5.2%, protein S deficiency in 3.1%, and antithrombin III deficiency in 2.5%.56 The presence of prothrombin G20210A and factor V Leyden increased the odds of developing CVST even in the heterozygous form by acting as cofactors with other conditions.56 Less common genetic thrombophilias such as hyperfibrinogenemia, alteration in the plasmin cascade,57 and hyperhomocysteinemia are associated with an increased risk of developing CVST.56,58 Hyperhomocysteinemia may provoke CVST, inducing endothelial toxicity, which is higher for the cerebral vascular system,59,60 and interferes with the clotting cascade.60,61 In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT),

the rate of with hyperhomocysteinemia in the whole population was 4.5%, reaching 27% in the series specifically dedicated to estimate the incidence and the risk of CVST associated with thrombophilic disorders.13 Acquired thrombophilic disorders accounted for 6.5% of patients: 5.9% were referable to antiphospholipid antibody syndrome and 0.6% to nephrotic syndrome.13 Another important category of risk factors for CVST is represented by systemic inflammatory disorders, especially if associated with vasculitis. In the ISCVT, systemic lupus erythematosus was found in 1% of patients, Behçet’s disease in 1%, rheumatoid arthritis in 0.2%, thromboangiitis obliterans in 0.2%, inflammatory bowel disease (ulcerative colitis and Crohn’s disease) in 1.6%, and sarcoidosis in 0.2%13 (Fig. 46–6). Systemic infections are reported in 4.3% of patients; cultures and sensitivities are necessary to determine treatment.

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Figure 46–5. A, Magnetic resonance image of frontal hematoma related to complete thrombosis of the left transverse sinus and superior sagittal sinus and partial thrombosis of the right transverse sinus occurred during the puerperal period. B, Magnetic resonance venogram of the same patient.

A

B tant cause of thrombosis in neonates and young children. These patients are also very frequently at risk for anemia with CVST.62,63 Aseptic cerebral venous thrombosis is also reported in association with tuberculosis.64

TREATMENT Treatment of CVST should address the thrombotic process (causal treatment), the consequences of CVST (symptomatic treatment), and the underlying causes.

Treatment of the Thrombotic Process

■

Figure 46–6. Complete left transverse sinus and partial right transverse sinus thrombosis in a female patient affected by Sjögren’s syndrome.

More diffuse in the past and related to very poor hygienic conditions and the absence of antibiotics, they remain an important cause of CVST and deep vein thrombosis in less industrialized countries. Systemic infections may be an impor-

Among the causal treatments, anticoagulants are the more widely used. They are expected not to eliminate an already formed thrombus but to prevent extension of thrombosis to other venous channels. Nonetheless, the use of anticoagulants in patients with CVST is still debated.65-69 The main argument against anticoagulation is the risk of a major hemorrhage in the venous infarct, which is often already a hemorrhagic infarct. Several retrospective trials have shown a potential benefit of anticoagulation in patients with CVST.65,68 To date, however, findings from only two randomized placebocontrolled trials of anticoagulation in CVST are available. The first case-control study involved dose-adjusted intravenous heparin and was prematurely discontinued because of a statistically significant difference in favor of treated patients over controls.67 This was the first study demonstrating that the benefits of intravenous heparin also apply to patients with intracranial hypertension. Furthermore, no additional intracranial hypertension was detected during heparin treatment. In the European double-blind, controlled multicenter trial, weightadjusted subcutaneous nadroparin for 3 weeks, followed by oral anticoagulation for 3 months, was compared with placebo in 60 patients with CVST. After 3 weeks, a poor outcome (defined as a Barthel Index <15) was observed in 20% of patients receiving nadroparin, in comparison with 24% of the controls. At 12

chapter 46 cerebral venous thrombosis weeks, a poor outcome was observed in 10% of patients receiving nadroparin, in contrast to 21% of the controls. A complete recovery was observed in 12% of patients receiving nadroparin and 28% of the controls. None of these differences was statistically significant.70 A meta-analysis of the two reported trials showed an absolute risk reduction of 14% in mortality and 15% in mortality and dependency combined in patients undergoing anticoagulation.69 These results, although not statistically significant, are encouraging and strongly endorse, in our opinion, the use of anticoagulants in CVST irrespective of the presence of intracranial hypertension.69,71,72 Anticoagulant treatment should be continued orally for a period of at least 3 to 6 months. In case of puerperium, it should be prolonged for 12 months.73 If prothrombotic risk factors are present, long-term treatment is mandatory.6,73 Of importance is that during pregnancy, particularly in the first 3 months, vitamin K antagonists such as warfarin should be avoided, because they are linked with an increased rate of malformations.73 The first therapeutic choice in this case is therefore lowmolecular-weight heparin.6 The use of thrombolytic agents in CVST has been evaluated.65,74-88 Thrombolytic therapy aims at rapid recanalization of the occluded vessel, including, in our case, the cortical veins.71,72 The efficacy and safety of this treatment are debated.74-88 Two different thrombolytic agents have been used in CVST. Urokinase was compared with intravenous heparin in SSS thrombosis. It was fairly well tolerated and more effective than heparin.74-77,83,85,88 The intrathrombus combination of recombinant tissue-type plasminogen activator (rtPA) and intravenous heparin was compared with intravenous heparin alone in patients with sinuses thrombosis. Both treatments were effective and safe, although the outcome was worse in patients with major hemorrhages treated with rtPA.79,82 A retrospective meta-analysis (72 studies, 169 patients enrolled) demonstrated that thrombolytic treatment is associated with a better outcome and is sufficiently safe.83 Nevertheless, to date there is no proof that thrombolytic therapy is better than anticoagulation in patients with CVST. Therefore, it should be used as second choice of therapy in patients whose condition worsens in spite of correct anticoagulation.76,84,89 The use of antiaggregates in patients with acute CVST has been poorly investigated. Experimental studies revealed a better neurological outcome and a higher rate of recanalization with rtPA in combination with the glycoprotein IIb/IIIa direct inhibitor abciximab, in comparison with the association of rtPA with enoxaparine.90 So far, clinical studies investigating the use of glycoprotein IIb/IIIa direct inhibitors in CVST have never been performed. There is little information concerning the use of mechanical treatments, such as rheolytic catheter thrombectomy or angioplasty in CVST, and further evidence of their efficacy is needed.91-99 A great limitation of these techniques is represented by the inaccessibility to some intracranial vessels, particularly cortical, bridging, and deep veins, because of their size in comparison with the caliber of the catheter.91-93 Open surgical thrombectomy, combined with local infusion of rtPA, showed a good outcome when used in patients with severe dural sinus thrombosis and deterioration despite anticoagulation. All patients returned to normal activities after surgical treatment.100,101

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Symptomatic Treatment The prophylactic use of anticonvulsants in patients with CVST is still controversial because of their negative effects on brain metabolism and on the level of consciousness. The general attitude, and our advice, is to use these drugs only in patients with seizures.1,2,6,25,29 Focal neurological deficits, cerebral edema, and infarction (especially hemorrhagic) observed on neuroimaging seem to be significant predictors of seizure in patients with CVST.29 A prophylactic treatment with anticonvulsants might be justified in these patients. Treatment of increased intracranial pressure caused by brain swelling is based on the use of mannitol, seldom in association with other diuretics such as acetazolamide or furosemide. Steroids are not indicated, because of their antifibrinolytic activity (although there are no clinical trials demonstrating a worse outcome in CVST patients treated with steroids).1,2,6,11,25 Tris(hydroxymethyl)aminomethane, which decreases intracranial pressure by alkalotic vasoconstriction, could be used in ventilated patients.6 Treatment of septic CVST must be based on the antibiogram, but while the clinician waits for these findings, an empirical treatment may be started with a third-generation cephalosporin (such as ceftriaxone or cefotaxime) or with a penicillinaseresistant penicillin. Metronidazole is the first choice when an anaerobic infection is suspected; in the nosocomial infections, meropenem, ceftazidime, and vancomycin may be used.

PROGNOSIS CVST was long thought to be a rare disease with a poor prognosis.1,2,9-11 Since the mid-1970s, neuroimaging has produced a better understanding of this disease, and the use of anticoagulant therapy has increased the number of good outcomes. In the ISCVT study, after a 16-month median follow-up period, 13.4% of the patients had a modified Rankin scale score of more than 2, and 8.3% had died. Multivariate predictors of death or dependence were central nervous system infections (HR = 3.3%), cancer (HR = 2.9), deep venous system involvement (HR = 2.9), coma (HR = 2.7), age older than 37 years (HR = 2), mental status disorders (HR = 2), hemorrhage visible on CT scan (HR = 1.9), and male gender (HR = 1.6). Only 2.2% of the patients had a recurrent sinus thrombosis, and 4.3% had other thrombotic events.13 The rate of recurrences in patients with CVST ranges from 0% to 11.7%,102 and it is most common in the first year after the previous thrombosis.6,102 The mortality rate ranges between 6% and 33%, and it is higher in septic CVST.11 In one study, researchers investigated the variables influencing the delay between the onset of symptoms and hospital admission for patients with CVST. Twenty-two percent of patients were admitted within 24 hours and 75% within 13 days. In multiple logistic regression analysis, admission within 24 hours was associated positively with mental status disorders (delirium/ abulia) and negatively with headache. Intracranial hypertension was associated with an admission delay of more than 4 days, and papilledema, with a delay of more than 13 days. Mean delay between onset and hospital admission was 4 days. Not surprisingly, anticoagulation was started earlier in patients with a more precocious diagnosis, but the proportion of patients treated was not influenced by the delay of admission. Headache was the most common presenting symptom; therefore, CVST

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should be considered in patients with a new-onset headache or an important change in the clinical features of a preexisting one.11,27 A number of researchers investigated the relationship between delay of anticoagulant treatments and CVST prognosis.103-105 So far, there is no evidence that delay in admission (and diagnosis) might influence CVST prognosis. Female gender, pregnancy, and puerperium, all related to high estrogens levels, seem to be predictive of a good outcome.6,106 Early recanalization, which is a common phenomenon on neuroimaging, has no influence on outcome.107

CONCLUSION The thrombotic process in CVST leads to a wide spectrum of clinical symptoms varying from isolated headache to focal neurological signs or even coma. Neuroimaging techniques allow a quick diagnosis, limiting the number of cases that remain uncertain to few. Anticoagulation is the first-line therapy for CVST, but some patients may require no therapy at all, whereas others may benefit from more aggressive treatment, such as thrombolysis.

K E Y

P O I N T S

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CVST accounts for fewer than 1% of all strokes and for about 0.1% to 9% (mean, about 1%) of all deaths from cerebrovascular diseases. There is great geography- and ethnicity-associated variability.

●

The causal factors leading to CVST have been classically grouped into (1) prothrombotic state, (2) venous stasis, (3) direct involvement of the venous wall, and (4) abnormal blood viscosity.

●

The clinical features of CVST can be grouped into three syndromes: (1) intracranial hypertension syndrome; (2) strokerelated syndrome; and (3) encephalopathic syndrome.

●

Early diagnosis of CVST is crucial, because anticoagulation reduces the risk of fatal outcome and severe disability.

Suggested Reading Canhao P, Batista P, Falcao F: Lumbar puncture and dural sinus thrombosis: a causal or casual association? Cerebrovasc Dis 2005; 19:53-56. Camargo EC, Massaro AR, Bacheschi LA, et al: Ethnic differences in cerebral venous thrombosis. Cerebrovasc Dis 2005; 19:147151. Ferro JM, Lopes MG, Rosas MJ, et al: Delay in hospital admission of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2005;19:152-156. Rottger C, Madlener K, Heil M, et al: Is heparin treatment the optimal management for cerebral venous thrombosis? Effect of abciximab, recombinant tissue plasminogen activator, and enoxaparin in experimentally induced superior sagittal sinus thrombosis. Stroke 2005; 36:841-846. Stolz E, Rahimi A, Gerriets T, et al: Cerebral venous thrombosis: an all or nothing disease? Prognostic factors and long-term outcome. Clin Neurol Neurosurg 2005; 107:99-107.

References 1. Ginsberg MD, Bogousslavsky J: Cerebrovascular Diseases, vol 2. Malden, MA: Blackwell Science, 1998. 2. Bogousslavsky J, Caplan L: Stroke Syndromes. Cambridge, UK: Cambridge University Press, 2001. 3. Williams PL, Warwick R: Gray’s Anatomy, 37th ed, vol 2. Essex, UK: Longman Group, 1989. 4. Mazzocchi G, Nussdorfer G: Anatomia Funzionale del Sistema Nervoso. Padua, Italy: Libreria Cortina, 1993. 5. Netter FH: Atlante di Anatomia Umana [Italian ed]. Origgio, Italy: Ciba-Geigy, 1990. 6. Masuhr F, Mehraein S, Einhaupl K: Cerebral venous and sinus thrombosis. J Neurol 2004; 251:11-23. 7. Camargo EC, Massaro AR, Bacheschi LA, et al: Ethnic differences in cerebral venous thrombosis. Cerebrovasc Dis 2005; 19:147-151. 8. Liu HS, Kho BC, Chan JC, et al: Venous thromboembolism in the Chinese population: experience in a regional hospital in Hong Kong. Hong Kong Med J 2002; 8:400-405. 9. Stolz E, Rahimi A, Gerriets T, et al: Cerebral venous thrombosis: an all or nothing disease? Prognostic factors and longterm outcome. Clin Neurol Neurosurg 2005; 107:99-107. 10. Bousser MG, Ross Russel R: Cerebral Venous Thrombosis, vol 1. London: WB Saunders, 1997. 11. Crassard I, Bousser MG: Cerebral venous thrombosis. J Neuroophthalmol 2004; 24:156-163. 12. Ameri A, Bousser MG: Cerebral venous thrombosis. Neurol Clin 1992; 10:87-111. 13. Ferro JM, Canhao P, Stam J, et al: Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004; 35:664-670. 14. Lowe GD: Virchow’s triad revisited: abnormal flow. Pathophysiol Haemost Thromb 2003/2004; 33(5-6):455-457. 15. Gettelfinger DM, Kokmen E: Superior sagittal sinus thrombosis. Arch Neurol 1977; 34:2-6. 16. Gotoh M, Ohmoto T, Kuyama H: Experimental study of venous circulatory disturbance by dural sinus occlusion. Acta Neurochir 1993; 124:120-126. 17. Tychmanowicz K, Czernicki Z, Czosnyka M, et al: Early pathomorphological changes and intracranial volume-pressure: relations following the experimental sagittal sinus occlusion. Acta Neurochir Suppl 1990; 51:233-235. 18. Tuzgen S, Canbaz B, Kaya AH, et al: Experimental study of rapid versus slow sagittal sinus occlusion in dogs. Neurol India 2003; 51:482-486. 19. Schaller B, Graf R, Wienhard K, et al: A new animal model of cerebral venous infarction: ligation of the posterior part of the superior sagittal sinus in the cat. Swiss Med Wkly 2003; 133(29-30):412-418. 20. Cervos-Navarro J, Kannuki S, Matsumoto K: Neuropathological changes following occlusion of the superior sagittal sinus and cerebral veins in the cat. Neuropathol Appl Neurobiol 1994; 20:122-129. 21. Vosko MR, Rother J, Friedl B, et al: Microvascular damage following experimental sinus-vein thrombosis in rats. Acta Neuropathol 2003; 106:501-505. 22. Fries G, Wallenfang T, Hennen J, et al: Occlusion of the pig superior sagittal sinus, bridging and cortical veins: multistep evolution of sinus-vein thrombosis. J Neurosurg 1992; 77:127-133. 23. Bergui M, Bradac GB, Daniele D: Brain lesions due to cerebral venous thrombosis do not correlate with sinus involvement. Neuroradiology 1999; 41:419-424. 24. Haage P, Krings T, Schmitz-Rode T: Nontraumatic vascular emergencies: imaging and intervention in acute venous occlusion. Eur Radiol 2002; 12:2627-2643.

chapter 46 cerebral venous thrombosis 25. Loeb C, Favale E: Neurologia di Fazio-Loeb, 3rd ed. Rome: Casa Editrice Universo, 2003. 26. Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24(Suppl 1):1160. 27. Iurlaro S, Beghi E, Massetto N, et al: Does headache represent a clinical marker in early diagnosis of cerebral venous thrombosis? A prospective multicentric study. Neurol Sci 2004; 25(Suppl 3):S298-S299. 28. Madan A, Sluzewski M, van Rooij WJ, et al: Thrombosis of the deep cerebral veins: CT and MRI findings with pathologic correlation. Neuroradiology 1997; 39:777-780. 29. Ferro JM, Correia M, Rosas MJ, et al: Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2003; 15:78-83. 30. Lenzi GL, Fieschi C: Superior orbital fissure syndrome: review of 130 cases. Eur Neurol 1977; 16:23-30. 31. Wetzel SG, Kirsch E, Stock KW, et al: Cerebral veins: comparative study of CT venography with intraarterial digital subtraction angiography. Am J Neuroradiol 1999; 20:249255. 32. Giraud P, Thobois S, Hermier M, et al: Intravenous hypertrophic Pacchioni granulations: differentiation from venous dural thrombosis. J Neurol Neurosurg Psychiatry 2001; 70:700-701. 33. Deus-Silva L, Voetsch B, Nucci A, et al: An unusual “empty delta sign.” J Neurol Neurosurg Psychiatry 2004; 75:1287. 34. Chang R, Friedman DP: Isolated cortical venous thrombosis presenting as subarachnoid hemorrhage: a report of three cases. Am J Neuroradiol 2004; 25:1676-1679. 35. Casey SO, Alberico RA, Patel M, et al: Cerebral CT venography. Radiology 1996; 198:163-170. 36. Klingebiel R, Busch M, Bohner G, et al: Multi-slice CT angiography in the evaluation of patients with acute cerebrovascular disease: a promising new diagnostic tool. J Neurol 2002; 249:43-49. 37. Alper F, Kantarci M, Dane S, et al: Importance of anatomical asymmetries of transverse sinuses: an MR venographic study. Cerebrovasc Dis 2004; 18:236-239. 38. Farb RI, Scott JN, Willinsky RA, et al: Intracranial venous system: gadolinium-enhanced three-dimensional MR venography with auto-triggered elliptic centric-ordered sequence—initial experience. Radiology 2003; 226:203209. 39. Lovblad KO, Bassetti C, Schneider J, et al: Diffusion-weighted MRI suggests the coexistence of cytotoxic and vasogenic oedema in a case of deep cerebral venous thrombosis. Neuroradiology 2000; 42:728-731. 40. Keller E, Flacke S, Urbach H, et al: Diffusion- and perfusionweighted magnetic resonance imaging in deep cerebral venous thrombosis. Stroke 1999; 30:1144-1146. 41. Favrole P, Guichard JP, Crassard I, et al: Diffusion-weighted imaging of intravascular clots in cerebral venous thrombosis. Stroke 2004; 35:99-103. 42. Schreiber SJ, Stolz E, Valdueza JM: Transcranial ultrasonography of cerebral veins and sinuses. Eur J Ultrasound 2002; 16:59-72. 43. Canhao P, Batista P, Ferro JM: Venous transcranial Doppler in acute dural sinus thrombosis. J Neurol 1998; 245:276279. 44. Valdueza JM, Hoffmann O, Weih M, et al: Monitoring of venous hemodynamics in patients with cerebral venous thrombosis by transcranial Doppler ultrasound. Arch Neurol 1999; 56:229-234. 45. Stolz E, Gerriets T, Bodeker RH, et al: Intracranial venous hemodynamics is a factor related to a favorable outcome in cerebral venous thrombosis. Stroke 2002; 33:1645-1650.

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46. Valdueza JM, Harms L, Doepp F, et al: Venous microembolic signals detected in patients with cerebral sinus thrombosis. Stroke 1997; 28:1607-1609. 47. Ries S, Steinke W, Neff KW, et al: Echocontrast-enhanced transcranial color-coded sonography for the diagnosis of transverse sinus venous thrombosis. Stroke 1997; 28:696700. 48. Knudson MM, Ikossi DG: Venous thromboembolism after trauma. Curr Opin Crit Care 2004; 10:539-548. 49. Canhao P, Batista P, Falcao F: Lumbar puncture and dural sinus thrombosis—a causal or casual association? Cerebrovasc Dis 2005; 19:53-56. 50. Aidi S, Chaunu MP, Biousse V, et al: Changing pattern of headache pointing to cerebral venous thrombosis after lumbar puncture and intravenous high-dose corticosteroids. Headache 1999; 39:559-564. 51. de Bruijn SF, Stam J, Koopman MM, et al: Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in (correction of who are) carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. BMJ 1998; 316:589592. 52. Buccino G, Scoditti U, Pini M, et al: Low-oestrogen oral contraceptives as a major risk factor for cerebral venous and sinus thrombosis: evidence from a clinical series. Ital J Neurol Sci 1999; 20:231-235. 53. Vander T, Medvedovsky M, Shelef I, et al: Postmenopausal HRT is not independent risk factor for dural sinus thrombosis. Eur J Neurol 2004; 11:569-571. 54. Derex L, Philippeau F, Nighoghossian N, et al: Postpartum cerebral venous thrombosis, congenital protein C deficiency, and activated protein C resistance due to heterozygous factor V Leiden mutation. J Neurol Neurosurg Psychiatry 1998; 65:801-802. 55. Cantu C, Barinagarrementeria F: Cerebral venous thrombosis associated with pregnancy and puerperium: review of 67 cases. Stroke 1993; 24:1880-1884. 56. Martinelli I, Battaglioli T, Pedotti P, et al: Hyperhomocysteinemia in cerebral vein thrombosis. Blood 2003; 102:13631366. 57. Baumeister FA, Auberger K, Schneider K: Thrombosis of the deep cerebral veins with excessive bilateral infarction in a premature infant with the thrombogenic 4G/4G genotype of the plasminogen activator inhibitor-1. Eur J Pediatr 2000; 159:239-242. 58. Cattaneo M: Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81:165-176. 59. Gupta M, Gupta S, Saxena R, et al: Familial hyperhomocysteinemia: multiple venous thrombosis in four generations of a family. Ann Hematol 2003; 82:178-180. 60. Harpel PC, Zhang X, Borth W: Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr 1996; 126(4, Suppl):S1285-S1289. 61. Ventura P, Cobelli M, Marietta M, et al: Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis. Cerebrovasc Dis 2004; 17:153-159. 62. Farstad H, Gaustad P, Kristiansen P, et al: Cerebral venous thrombosis and Escherichia coli infection in neonates. Acta Paediatr 2003; 92:254-257. 63. Benedict SL, Bonkowsky JL, Thompson JA, et al: Cerebral sinovenous thrombosis in children: another reason to treat iron deficiency anemia. J Child Neurol 2004; 19:526531. 64. Kakkar N, Banerjee AK, Vasishta RK, et al: Aseptic cerebral venous thrombosis associated with abdominal tuberculosis. Neurol India 2003; 51:128-129.

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65. Brucker AB, Vollert-Rogenhofer H, Wagner M, et al: Heparin treatment in acute cerebral sinus venous thrombosis: a retrospective clinical and MR analysis of 42 cases. Cerebrovasc Dis 1998; 8:331-337. 66. Benamer HT, Bone I: Cerebral venous thrombosis: anticoagulants or thrombolytic therapy? J Neurol Neurosurg Psychiatry 2000; 69:427-430. 67. Einhaupl KM, Villringer A, Meister W, et al: Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597-600. 68. Stam J, de Bruijn S, deVeber G: Anticoagulation for cerebral sinus thrombosis. Stroke 2003; 34:1054-1055. 69. Stam J, de Bruijn SF, DeVeber G: Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev 2002; (4):CD002005. 70. de Bruijn SF, Stam J: Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484-488. 71. Lewis MB, Bousser MG: Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke 1999; 30:1729. 72. Bousser MG: Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke 1999; 30:481-483. 73. Bates SM, Greer IA, Hirsh J, et al: Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3, Suppl):627S-644S. 74. Aoki N, Uchinuno H, Tanikawa T, et al: Superior sagittal sinus thrombosis treated with combined local thrombolytic and systemic anticoagulation therapy. Acta Neurochir 1997; 139:332-335. 75. D’Alise MD, Fichtel F, Horowitz M: Sagittal sinus thrombosis following minor head injury treated with continuous urokinase infusion. Surg Neurol 1998; 49:430-435. 76. Ciccone A, Canhao P, Falcao F, et al: Thrombolysis for cerebral vein and dural sinus thrombosis. Stroke 2004; 35:2428. 77. Di Rocco C, Iannelli A, Leone G, et al: Heparin-urokinase treatment in aseptic dural sinus thrombosis. Arch Neurol 1981; 38:431-435. 78. Eskridge JM, Wessbecher FW: Thrombolysis for superior sagittal sinus thrombosis. J Vasc Interv Radiol 1991; 2:89-93. 79. Frey JL, Muro GJ, McDougall CG, et al: Cerebral venous thrombosis: combined intrathrombus rtPA and intravenous heparin. Stroke 1999; 30:489-494. 80. Gebara BM, Goetting MG, Wang AM: Dural sinus thrombosis complicating subclavian vein catheterization: treatment with local thrombolysis. Pediatrics 1995; 95:138-140. 81. Horowitz M, Purdy P, Unwin H, et al: Treatment of dural sinus thrombosis using selective catheterization and urokinase. Ann Neurol 1995; 38:58-67. 82. Kim SY, Suh JH: Direct endovascular thrombolytic therapy for dural sinus thrombosis: infusion of alteplase. Am J Neuroradiol 1997; 18:639-645. 83. Canhao P, Falcao F, Ferro JM: Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis 2003; 15:159-166. 84. Ciccone A, Canhao P, Falcao F, et al: Thrombolysis for cerebral vein and dural sinus thrombosis. Cochrane Database Syst Rev 2004; (1):CD003693. 85. Gerszten PC, Welch WC, Spearman MP, et al: Isolated deep cerebral venous thrombosis treated by direct endovascular thrombolysis. Surg Neurol 1997; 48:261-266. 86. Spearman MP, Jungreis CA, Wehner JJ, et al: Endovascular thrombolysis in deep cerebral venous thrombosis. Am J Neuroradiol 1997; 18:502-506. 87. Ferro JM, Lopes GC, Rosas MJ, et al: Do randomised clinical trials influence practice? The example of cerebral vein and dural sinus thrombosis. J Neurol 2002; 249:1595-1596.

88. Wasay M, Bakshi R, Kojan S, et al: Nonrandomized comparison of local urokinase thrombolysis versus systemic heparin anticoagulation for superior sagittal sinus thrombosis. Stroke 2001; 32:2310-2317. 89. Barnwell SL, Nesbit GM, Clark WM: Local thrombolytic therapy for cerebrovascular disease: current Oregon Health Sciences University experience (July 1991 through April 1995). J Vasc Interv Radiol 1995; 6(6, Pt 2 Su):78S-82S. 90. Rottger C, Madlener K, Heil M, et al: Is heparin treatment the optimal management for cerebral venous thrombosis? Effect of abciximab, recombinant tissue plasminogen activator, and enoxaparin in experimentally induced superior sagittal sinus thrombosis. Stroke 2005; 36:841-846. 91. Curtin KR, Shaibani A, Resnick SA, et al: Rheolytic catheter thrombectomy, balloon angioplasty, and direct recombinant tissue plasminogen activator thrombolysis of dural sinus thrombosis with preexisting hemorrhagic infarctions. AJNR Am J Neuroradiol 2004; 25:1807-1811. 92. Opatowsky MJ, Morris PP, Regan JD, et al: Rapid thrombectomy of superior sagittal sinus and transverse sinus thrombosis with a rheolytic catheter device. Am J Neuroradiol 1999; 20:414-417. 93. Dowd CF, Malek AM, Phatouros CC, et al: Application of a rheolytic thrombectomy device in the treatment of dural sinus thrombosis: a new technique. Am J Neuroradiol 1999; 20:568570. 94. Baker MD, Opatowsky MJ, Wilson JA, et al: Rheolytic catheter and thrombolysis of dural venous sinus thrombosis: a case series. Neurosurgery 2001; 48:487-493. 95. Scarrow AM, Williams RL, Jungreis CA, et al: Removal of a thrombus from the sigmoid and transverse sinuses with a rheolytic thrombectomy catheter. Am J Neuroradiol 1999; 20:1467-1469. 96. Chaloupka JC, Mangla S, Huddle DC: Use of mechanical thrombolysis via microballoon percutaneous transluminal angioplasty for the treatment of acute dural sinus thrombosis: case presentation and technical report. Neurosurgery 1999; 45:650-656. 97. Chow K, Gobin YP, Saver J, et al: Endovascular treatment of dural sinus thrombosis with rheolytic thrombectomy and intra-arterial thrombolysis. Stroke 2000; 31:14201425. 98. Gomez CR, Misra VK, Terry JB, et al: Emergency endovascular treatment of cerebral sinus thrombosis with a rheolytic catheter device. J Neuroimaging 2000; 10:177-180. 99. Baker MD, Opatowsky MJ, Wilson JA, et al: Rheolytic catheter and thrombolysis of dural venous sinus thrombosis: a case series. Neurosurgery 2001; 48:487-493; discussion, 493494. 100. Ekseth K, Bostrom S, Vegfors M: Reversibility of severe sagittal sinus thrombosis with open surgical thrombectomy combined with local infusion of tissue plasminogen activator: technical case report. Neurosurgery 1998; 43:960965. 101. Chahlavi A, Steinmetz MP, Masaryk TJ, et al: A transcranial approach for direct mechanical thrombectomy of dural sinus thrombosis: report of two cases. J Neurosurg 2004; 101:347351. 102. Preter M, Tzourio C, Ameri A, et al: Long-term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke 1996; 27:243-246. 103. Ferro JM, Lopes MG, Rosas MJ, et al: Long-term prognosis of cerebral vein and dural sinus thrombosis: results of the VENOPORT study. Cerebrovasc Dis 2002; 13:272278. 104. Ferro JM, Lopes MG, Rosas MJ, et al: Delay in hospital admission of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2005; 19:152-156.

chapter 46 cerebral venous thrombosis 105. Breteau G, Mounier-Vehier F, Godefroy O, et al: Cerebral venous thrombosis 3-year clinical outcome in 55 consecutive patients. J Neurol 2003; 250:29-35. 106. Brill-Edwards P, Ginsberg JS, Gent M, et al: Safety of withholding heparin in pregnant women with a history of venous

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thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med 2000; 343:1439-1444. 107. Stolz E, Trittmacher S, Rahimi A, et al: Influence of recanalization on outcome in dural sinus thrombosis: a prospective study. Stroke 2004; 35:544-547.

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47

VASCULAR DEMENTIA ●

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Gustavo C. Román

Cerebrovascular disease constitutes a well-defined cause of dementia first recognized by Sir Thomas Willis in 1672 under the name postapoplectic dementia. Vascular dementia is considered the second major cause of dementia in elderly persons, after Alzheimer’s disease, representing 15% to 20% of all cases of dementia worldwide.1,2 Furthermore, it has been recognized that cerebrovascular disease may serve as a catalyst for converting low-grade Alzheimer’s disease to clinical dementia. The diagnosis of vascular dementia is relatively straightforward, particularly in cases with abrupt loss of cognitive functions after stroke or in individuals with a genetic history of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).3 The diagnosis may be less obvious in very old patients, in whom cerebrovascular disease and degenerative pathology (neurofibrillary tangles, amyloid deposits, Lewy bodies) may coexist. However, even in these cases of so-called mixed dementia, the contribution of the vascular pathology seems to outweigh the age-associated degenerative pathology. Moreover, vascular dementia is usually unrecognized in patients in whom cerebral hypoperfusion complicates cardiac failure and circulatory diseases. Judicious treatment of vascular risk factors at population level may lessen the predicted epidemic increase of dementia among elderly persons.

Diagnostic Criteria In most controlled trials in vascular dementia, investigators have used the clinical criteria proposed by Román and colleagues4 on behalf of the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN criteria). Most cases of acute poststroke vascular dementia fulfill criteria for probable vascular dementia, modified as follows:5 1. There is acute onset of dementia, demonstrated by executive dysfunction causing loss of functional independence. 2. Relevant cerebrovascular lesions are demonstrated by neuroimaging. 3. A temporal relation between stroke and cognitive loss is evident. This last criterion usually cannot be fulfilled in subacute forms of vascular dementia.

Vascular Cognitive Disorder Numerous diseases and syndromes can produce a vascular cognitive disorder.5 Table 47–1 provides a comprehensive list of potential causes of vascular cognitive disorder.

DEFINITIONS Vascular Cognitive Impairment Vascular Dementia Vascular dementia is an etiological category of dementia characterized by severe cognitive impairment resulting from ischemic or hemorrhagic stroke or from hypoperfusion affecting brain regions important for memory, cognition, and behavior. Vascular dementia is most frequently caused by the following lesions: 1. Hypoperfusive lesions such as global or selective ischemia, border-zone infarcts, and incomplete white matter ischemia. 2. Ischemic lesions involving large or small vessels: strategic single strokes, multi-infarct dementia (MID), small-vessel disease, lacunes, and venous occlusions.

This term designates a wide range of severity of cognitive alterations of vascular nature. However, the term is preferably restricted to cases of vascular cognitive impairment without dementia (vascular mild cognitive impairment).5

EPIDEMIOLOGY In some of the most heavily populated regions of the world— including China, Japan, India, and Mexico—a vascular etiology is the most frequent cause of dementia. As the population in most of the world ages, likely increases in stroke and heart disease associated with old age will render vascular dementia the most frequent cause of dementia worldwide.

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Hemorrhage

Embolic causes

Hematologic disorders

Toxic causes

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Potential Etiologies of the Vascular Cognitive Disorder Amyloidosis angiopathy Arterial dissection Atherosclerosis of large or mid-sized arteries Cardiopulmonary arrest Diabetes mellitus Dural arteriovenous malformation Fibromuscular dysplasia Giant cerebral aneurysm with compression Hyperlipidemia Hypertensive arteriolosclerosis Moyamoya disease Recurrent hypotension with syncope Vasospasm/migraine Amyloid angiopathy Aneurysms Arteriovenous malformations Cavernous angioma Charcot-Bouchard aneurysm CNS hemosiderosis with recurrent bleeding Hematologic bleeding diathesis Hemorrhagic transformation of infarction Hypertension Neoplasm (glioblastoma or metastatic) Pharmacologic (e.g., anticoagulants) Posthemorrhagic normal-pressure hydrocephalus Telangiectasis Vasculitis Venous angioma Venous thrombosis Atherosclerotic stenosis with embolization Atrial fibrillation Atrial myxoma Cardiac surgery, including CAGB Cardiomyopathy Congenital heart disease Libman-Sacks endocarditis Marantic endocarditis Mitral valve prolapse syndrome Myocardial infarction with mural thrombus Nitrogen bubble emboli Prosthetic valves Rheumatic endocarditis and valvulopathies Septal defect with paradoxical emboli Septic, air, or fat emboli Subacute bacterial endocarditis Antiphospholipid/anticardiolipin antibodies Antithrombin III deficiency Arylsulfatase A pseudodeficiency Cryoglobulinemia Disseminated intravascular coagulation Dysfibrinogenemias Dysproteinemias Factor V Leyden mutation Factors V, VII, XII, and XIII deficiencies Hemoglobinopathies (e.g., sickle cell disease) Heparin cofactor II deficiency Hyperviscosity syndromes Idiopathic thrombocytosis Leukemias Nephrotic syndrome Polycythemia vera Pregnancy and oral contraceptives Protein C or S deficiency Thrombotic thrombocytopenic purpura Waldenström’s macroglobulinemia Amphetamines Arsenic Carbon monoxide Cocaine or crack Ergot alkaloids Oral contraceptives Radiation-induced vasculopathy

Noninfectious inflammatory or autoimmune causes

Infectious causes of stroke

Genetic causes

Allergic or hypersensitivity angiitis Anticardiolipin or antiphospholipid antibodies Behçet’s syndrome Burgher’s disease Cogan’s syndrome Dermatomyositis-polymyositis Disseminated neocortical and subcortical encephalopathies Drug-induced vasculitis Endocardial fibroelastosis Henoch-Schönlein purpura (radiation, tumor) Kawasaki syndrome Köhlmeier-Degos disease Lupus anticoagulant Polyarteritis nodosa Primary CNS vasculitis Relapsing polychondritis Rheumatoid arthritis with arteritis Sarcoidosis Scleroderma Sjögren’s syndrome Systemic lupus erythematosus Takayasu’s arteritis Temporal (giant cell) arteritis Thromboangiitis obliterans Thrombotic microangiopathy Ulcerative colitis Vogt-Koyanagi-Harada syndrome Wegener’s granulomatosis AIDS Bacterial meningitis with arteritis Cat-scratch disease Cysticercosis Herpes zoster ophthalmicus Lyme disease Meningovascular infectious arteritis Parasites and ova Rickettsial arteritis Syphilis Tuberculosis Viral arteritis Yeast and fungal arteritis 11β-hydroxylase deficiency 11β-ketoreductase deficiency 17α-hydroxylase deficiency Antithrombin III deficiency β-Thalassemia major Bannayan-Zonana syndrome Bloom’s syndrome CADASIL Chronic familial cerebral vasculopathy Cockayne’s syndrome Dysfibrinogenemia Ehlers-Danlos syndrome, especially type IV Fabry’s disease Factors VII to XIII deficiencies Familial atrial myxoma Familial cavernous angioma Familial hemiplegic migraine Familial hypercholesterolemia Familial hypoalphalipoproteinemia Familial intracranial aneurysm Familial oculoleptomeningeal amyloidosis Familial porencephaly Familial triglyceridemia Fibromuscular dysplasia Hemoglobin SC Heparin cofactor II deficiency Hereditary arteriovenous malformations Hereditary cardiac conduction disorder Hereditary cardiomyopathies Hereditary cerebral amyloidosis

chapter 47 vascular dementia T A B L E 4 7 – 1. Genetic causes (cont’d)

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Potential Etiologies of the Vascular Cognitive Disorder—cont’d Hereditary platelet defect (Wiskott-Aldrich syndrome) Hereditary polycythemia Homocystinuria Hyperlipoproteinemia (types III and IV) Klippel-Trénaunay-Weber syndrome Leigh’s disease Marfan syndrome MELAS syndrome Menkes’ syndrome Methylmalonic, propionic, and isovaleric acidemia; glutamic aciduria type I Mitral valve prolapse Moyamoya disease Neurofibromatosis Plasminogen deficiency Progeria

Miscellaneous causes

Prekallikrein deficiency Protein C or protein S deficiency Pseudoxanthoma elasticum Rendu-Osler-Weber syndrome Rhabdomyomas Sickle-cell disease Sturge-Weber syndrome Sulfite oxidase deficiency Tangier disease Tuberous sclerosis Von Hippel–Lindau syndrome Metastatic deposits Neoplastic anagioendotheliosis Sneddon’s syndrome Spatz-Lindenberg disease Susac’s disease

Modified From Mendez MF, Cummings JL: Dementia: A Clinical Approach, 3rd ed. Philadelphia: Butterworth-Heinemann (Elsevier Science), 2003. AIDS, acquired immunodeficiency syndrome; CABG, coronary artery bypass graft; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central nervous system; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms (syndrome).

Prevalence Jorm and Jolley6 performed a meta-analysis of 47 international studies on the prevalence of vascular dementia and found the following consistent trends: 1. Age-specific rates: Vascular dementia increases exponentially with age. Prevalence rates double after age 70 with every 5.3year increase in age (in comparison with 4.5-year increases for Alzheimer’s disease), ranging from 1.5% at ages 70 to 75 years to 14% to 16.3% at ages 80 years and older. 2. Gender distribution: Vascular dementia is more common in men, especially before age 75. 3. Geographic (racial) variation: Vascular dementia is more prevalent in Asian, black, and Hispanic populations than in white populations. Hypertensive small-vessel disease is particularly common in the former groups.

Incidence Incidence data for vascular dementia are quite limited. Dubois and Herbert2 used age-standardized incidence ratios to analyze data from 10 incidence studies of vascular dementia. These ratios ranged from 0.42 to 2.68, confirming the geographic and racial variations of vascular dementia.

CLINICAL FEATURES Despite the apparent complexity of vascular dementia, the clinical diagnosis may be simplified into two major groups, acute and subacute, according to the temporal profile of presentation (Table 47–2).

Acute Forms of Vascular Dementia In acute forms, patients exhibit new-onset dementia after a vascular event (cerebral hemorrhage, ischemic “strategic” stroke). For instance, occlusion of the left posterior parietal branch of

the middle cerebral artery that damages the supramarginal gyrus usually produces cortical sensory loss, Wernicke’s aphasia, and Gerstmann’s syndrome with right-left disorientation, finger agnosia, acalculia, and agraphia.

Multi-infarct Dementia MID results from multiple cortical strokes; about one third (range, 25% to 41%) of all ischemic stroke survivors aged 65 years and older may develop vascular dementia.7,8 This represents about 125,000 new cases per year of poststroke vascular dementia in the United States. Table 47–3 lists the most important risk factors for poststroke vascular dementia.

Strategic Strokes Single ischemic strokes in three possible vascular territories— the posterior cerebral artery, anterior cerebral artery, and thalamus-basal ganglia—may produce vascular dementia.

Posterior cerebral artery infarctions involving the ventralmedial temporal lobe, occipital structures, and thalamus About 25% of affected patients develop amnesia from damage of the hippocampus-mammillothalamic-cingulum circuit. Leftsided lesions cause verbal amnesia, whereas right-sided lesions alter visuospatial (location) memory; bilateral damage causes global amnesia. Visual signs (homonymous hemianopsia, color agnosia, visual agnosia) occur in 80% or more of patients with posterior cerebral artery strokes. Left-sided lesions may produce transcortical sensory aphasia, or alexia without agraphia. Spatial disorientation occurs with right-sided lesions and Anton’s syndrome (cortical blindness with anosognosia) with bilateral occipital lesions. Bilateral parieto-occipital infarctions above the calcarine fissure may result in Balint’s syndrome (inability to direct the eyes to a certain point in the visual field) with simultagnosia, optic ataxia, and ocular apraxia.

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Clinical Forms of Vascular Dementia According to Temporal Pattern of Presentation

Acute Forms 1. Posterior forms caused by lesions in the territory of the PCA, inferomedial temporal lobes, hippocampus, thalamus Clinical features Amnesia, visual disturbances (homonymous hemianopsia, color agnosia, visual agnosia) Left-sided lesions: transcortical sensory aphasia, alexia without agraphia Right-sided lesions: spatial disorientation Bilateral occipital lesions: Anton’s syndrome Bilateral parieto-occipital lesions: Balint’s syndrome 2. Lesions in the ACA territory and medial frontal lobe Lesions Ruptured AComA aneurysm or proximal ACA Clinical features Severe anterograde amnesia for verbal or visuospatial material Severe apathy Lack of initiative and spontaneity Executive dysfunction 3. Thalamus and basal ganglia a. Thalamic dementia Lesions Anterior (polar) thalamic territories (polar thalamic artery, from PComA) DMn or mammillothalamic tract Clinical features Impairments of attention, motivation, initiative, executive functions, and memory Verbal and motor slowness and apathy Vertical gaze paresis, medial rectus paresis, and absent convergence; dysarthria and mild hemiparesis b. Inferior genu stroke Lesions Lacune in inferior genu of internal capsule Inferior capsular genu stroke, producing diaschisis of frontal lobes and cerebellum Clinical features Sudden change in cognition Fluctuating attention Confusion Abulia Striking psychomotor retardation Inattention Executive dysfunction Mild to absent focal findings such as hemiparesis or dysarthria 4. Multi-infarct dementia Lesions may involve posterior association areas such as the gyrus angularis, PCA territories, watershed or border-zone areas (superior frontal and parietal regions), bilateral ACA territories, anterior choroidal artery, basal forebrain, and frontal white matter lesions Subacute Forms 1. Subcortical ischemic vascular dementia (SIVD) Lesions Small-vessel disease with presence of white matter ischemic lesions and lacunae in basal ganglia and white matter Clinical features Subacute onset, chronic course, fluctuations, and progressive worsening Subcortical-type dementia, frontal lobe deficits, depressive mood, psychomotor slowing, parkinsonian features, pseudobulbar palsy, urinary urgency Main forms of SIVD: Binswanger’s disease, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and some types of cerebral amyloid angiopathy ACA, anterior cerebral artery; AComA, anterior communicating artery; DMn, dorsomedial nucleus of the thalamus; PCA, posterior cerebral artery; PComA, posterior communicating artery.

Anterior cerebral artery territory and medial frontal lobe lesions Ischemic injury of cholinergic nuclei in the basal forebrain may occur with subarachnoid hemorrhage from ruptured aneurysms of the anterior communicating artery or proximal anterior cerebral artery, usually after surgical repair. Such hemorrhage leads to severe anterograde amnesia, apathy, and executive dysfunction.

Lesions of the thalamus and basal ganglia Thalamic dementia occurs after paramedian thalamic ischemic strokes. The lesions involve the anterior thalamus, which is irrigated by the polar thalamic artery, a branch of the posterior communicating artery, or the medial and central thalamus, involving the dorsomedial nucleus and the mammillothalamic

tract. Damage of the mammillothalamic tract is critical in thalamic amnesia. Patients are initially unresponsive but improve over days to weeks, revealing impairments in attention, motivation, initiative, executive functions, and memory; verbal and motor slowness; and apathy. Gaze abnormalities include vertical gaze, medial rectus paresis, and absence of convergence. Dysarthria and mild hemiparesis occur with larger lesions. Left-sided thalamic lesions cause memory deficits more often than do right-sided ones. Global amnesia occurs with bilateral lesions or with simultaneous damage to the mammillothalamic tract and inferior thalamic peduncle. Severe attentional and motivational deficits play roles in the amnesia. Inferior genu stroke is a lacunar infarction of the inferior genu of the internal capsule, manifested by sudden change in cognitive function, often in association with fluctuating attention, confusion, abulia, striking psychomotor retardation, inat-

chapter 47 vascular dementia T A B L E 4 7 – 3. Vascular Dementia Age Education Personal factors Genetic factors Stroke type Stroke location Stroke volume

Stroke complications Stroke manifestations

Main Risk Factors for Poststroke Older age Lower educational level Lower income, current smokers Family history of dementia Recurrent strokes Left-sided lesions, “strategic strokes” Lesions larger than 50-100 mL of tissue destruction, large perilesional incomplete ischemic areas involving white matter, larger periventricular white matter ischemic lesions Hypoxic and ischemic complications of acute stroke (i.e., seizures, cardiac arrhythmias, aspiration pneumonia, hypotension) Dysphagia, gait limitations, urinary impairment

tention, executive dysfunction, and other features of frontal lobe dysfunction but with mild focal findings such as hemiparesis or dysarthria. These deficits are caused by ipsilateral blood flow reduction to the inferomedial frontal cortex, ipsilateral temporal lobe, and contralateral cerebellar hemisphere by a mechanism of diaschisis. Severed pathways that contain cholinergic fibers from the nucleus basalis of Meyner may have an effect in reducing blood flow.

Basal ganglia lacunes Neuropsychological deficits occur in up to 34% of patients with lacunes in the territory of deep middle cerebral artery perforators.

Caudate nucleus lesions Rare cases of vascular dementia have been reported after infarction of the caudate nucleus.

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ponding thalamocortical connections. Many strokes in this common type of vascular dementia are clinically silent; that is, they do not appear with the usual sensorimotor manifestations associated with stroke but with changes in personality, mood, behavior, or cognition. Therefore, brain imaging (computed tomography/magnetic resonance imaging) is crucial for correct diagnosis. The main forms of SIVD are Binswanger’s disease, CADASIL, lacunar dementia (lacunar state, or état lacunaire) with multiple lacunes and extensive perifocal incomplete infarctions or with abundant microinfarctions, and some types of cerebral amyloid angiopathy.

Binswanger’s Disease The hallmark of this condition is an ischemic periventricular leukoencephalopathy that typically spares the arcuate subcortical U fibers. These periventricular, distal-territory, white matter lesions in the elderly brain are caused by chronic ischemia with incomplete infarction. Small-vessel disease and multiple lacunes often coexist in Binswanger’s disease. Clinical manifestations include a subcortical dementia with cognitive and motor executive dysfunction, loss of verbal fluency, perseveration, impersistence, inattention, difficulties with set shifting, and abnormal performance on Luria’s kinetic melody tests. Memory loss is characterized by poor retrieval and intact recognition. Apathy, depression, and behavioral problems are common. Mild residual hemiparesis, discrete focal findings, and short-stepped gait (marche à petits pas), dysarthria, and pseudobulbar palsy are common. Extrapyramidal features, such as inexpressive facies, slowness of movement, axial rigidity, loss of postural reflexes, frequent falls, increased urinary frequency, and nocturia are also common findings. Brain T2-weighted magnetic resonance imaging findings include extensive hyperintense lesions in the periventricular regions with frontal and parietal preponderance.

CADASIL Subacute Forms of Vascular Dementia Subcortical ischemic vascular dementia (SIVD) refers to forms of vascular dementia characterized by subacute onset, caused by small-vessel disease that produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter as a result of critical stenosis of medullary arterioles and hypoperfusion (Binswanger’s disease).7 The term subcortical refers both to the location of lesions that involve predominantly basal ganglia, cerebral white matter, and brainstem and to their manifestations with preponderant executive dysfunction (subcortical dementia as opposed to cortical dementia). The main mechanism of dementia causation in SIVD is ischemic brain injury; this label includes both complete infarction (mainly lacunar strokes and microinfarcts) as well as incomplete infarction of deep cerebral white matter. The temporal profile is typically subacute, with a chronic course marked by fluctuations and slowly progressive worsening. This subcortical type of dementia is manifested by motor and cognitive executive function slowing, forgetfulness, dysarthria, mood changes, pseudobulbar palsy, urinary symptoms, parkinsonian features, and short-stepped gait. Manifestations probably result from ischemic interruption of parallel circuits from prefrontal cortex to basal ganglia and corres-

This genetic form of vascular dementia was first identified in France in 1991.3 CADASIL is a systemic autosomal dominant arteriopathy caused by mutations of the Notch3 gene in chromosome 19.8 The vascular lesion shows fragmentation of the internal elastica and eosinophilic deposits in media. Electron microscopy reveals typical granular osmiophilic material in the basement membranes of vascular smooth muscle cells of arterioles (100 to 400 μm in diameter) and in capillaries, primarily in the brain but also in other organs. The diagnosis may be established by genetic studies and by skin biopsy with confirmation by immunostaining with a Notch3 monoclonal antibody. Neuropathology examination demonstrates lacunar strokes associated with extensive, confluent areas of frontal ischemic leukoencephalopathy. Clinically, CADASIL is a subcortical vascular dementia identical to Binswanger’s disease. Onset is early for stroke (mean age, 46 years) with recurrent transient ischemic attacks or lacunar strokes, in the absence of vascular risk factors, culminating in vascular dementia and death, usually about 20 years after onset. Migraine with aura and depression are common. The dementia is subcortical, frontal, and accompanied by gait disturbances, urinary incontinence, and pseudobulbar palsy. Magnetic resonance imaging shows

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striking white matter changes with a typical predilection for the temporal lobes, along with lacunar strokes, in both symptomatic and asymptomatic members of families affected by CADASIL.

Hypertension

Risk factor

Arteriolosclerosis

Resultant cerebrovascular disease

PATHOLOGY AND PATHOPHYSIOLOGY The main mechanism of production of vascular dementia is ischemic brain injury, occurring as the result of either vascular occlusion or hypoperfusion. From the neuropathological viewpoint, ischemia includes both complete and incomplete infarctions.

Occlusion

Hypoperfusion

Cause of ischemia

Complete infarct

Incomplete infarct

Type of brain injury

Lacune

White matter signal hyperintensities

Lesion on MRI

Complete Infarctions These are typical embolic or atherothrombotic large-vessel ischemic infarcts involving well-defined arterial territories, cortical or cortical-subcortical in location, usually with perifocal incomplete white matter infarction. Small-vessel occlusion causes lacunes and microinfarcts.

Lacunar Infarcts Lacunes (Latin lacuna, plural lacunae: a minute cavity, hole, or pit) are small cavitating ischemic infarcts, less than 15 mm in diameter, typically located in the basal ganglia, internal capsule, thalamus, pons, corona radiata, and centrum semiovale. White matter lacunes may overlap with nonconfluent areas of ischemic white matter changes.

Microinfarcts These are minute areas of ischemic infarction, not visible to the naked eye and not visualized with current imaging techniques, ranging from a few microns to about one tenth the size of lacunes. They are usually noncavitated and found in cortical and subcortical structures.

Incomplete Infarctions These lesions are caused by hypoperfusion9 and typically affect watershed territories such as the CA1 sector of the hippocampus; the cortex posterior to the interparietal sulcus or the central white matter between deep territories at the boundaries between the anterior cerebral artery and middle cerebral artery in cases of extracranial internal carotid artery occlusion; and the periventricular white matter fed by long-penetrating endarterioles, as in Binswanger’s disease. White matter lesions include diffuse myelin pallor that spares the U fibers, astrocytic gliosis, loss of oligodendrocytes progressing to rarefaction, spongiosis (vacuolization), widening of perivascular spaces (état criblé), with myelin and axonal loss but without definite necrosis (incomplete white matter infarction) that culminates in necrosis and cavitations (lacunes). Pure incomplete white matter infarction, similar to that observed in the penumbra of large infarcts, is typically seen in hypoperfusive disease. Figures 47–1 and 47–2 illustrate the two main pathophysiological pathways leading to the aforementioned ischemic lesions:

Lacunar state ■

Binswanger’s disease

Clinical syndrome

Figure 47–1. Two pathophysiological pathways of ischemic brain injury. The pathway on the left is initiated by occlusion of an arterial lumen. This leads to discrete areas of complete infarction (i.e., lacunar infarcts) and functional disruption within a distributed network (e.g., dementia). The pathway on the right is defined by critical stenosis and hypoperfusion involving multiple small arterioles mainly in deep white matter. These two pathways often coexist in the same patient. MRI, magnetic resonance imaging. (From Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002; 1:426-436.)

1. Occlusion of the arteriolar lumen leads to lacunes and the lacunar state (état lacunaire). 2. Critical stenosis and hypoperfusion of multiple penetrating medullary arterioles causes widespread incomplete infarction of deep white matter in Binswanger’s disease. Table 47–4 summarizes important physical principles and pathophysiological mechanisms relevant to the microcirculation in SIVD; these include hemorheological factors, increased resistance to flow, decreased autoregulation, endothelial changes, blood-brain barrier dysfunction, and dilatation of perivascular spaces. Their combined effects result in hypoperfusion and incomplete infarction of deep white matter. Earlier concepts of MID required the loss of more than 50 to 100 mL of brain tissue from ischemia. Stroke location appears to be equally important. In fact, small lesions in strategic areas are capable of causing vascular dementia by interrupting memory and behavioral circuits, such as the prefrontal–basal ganglia–thalamocortical loops that are crucial for executive function and independent living.

DIAGNOSIS In practical terms, the diagnosis of vascular dementia should be suspected in patients with significant vascular risk factors, stroke, or heart disease who exhibit abrupt changes in cognition. Brain imaging demonstrating the presence of relevant lesions of cerebrovascular disease is crucial for the diagnosis of vascular dementia. Most of the diagnostic difficulties in vascular dementia occur with the subacute, slowly progressive forms of vascular dementia that, in the opinion of some clinicians,

chapter 47 vascular dementia

Ischemia

■

Hypoperfusion

Occlusion

Incomplete white matter infarction

Lacunar stroke

Figure 47–2. Factors leading to brain ischemia and hypoperfusion in elderly people. Striking age-dependent morphological changes in brain vessels include tortuosity with formation of skeins in cortical arterioles (A) and elongation, which results in loops and tangles (B), particularly of long penetrating arterioles supplying deep white matter. Increase in blood vessel length raises the blood pressure threshold for perfusion of periventricular white matter at the distal ends of the these vessels. Furthermore, the lumen is stenosed by senile concentric arteriolosclerosis (D), often with calcification of vessels (C, top right). Under normal conditions, autoregulatory mechanisms induce vasodilation in response to decreases in mean arterial perfusion pressure; these mechanisms become inoperative in patients with arteriolosclerosis and calcified vessels (C). The elderly brain is therefore more susceptible to hypotension and pump failure (cardiac arrhythmias and congestive heart failure). Delivery of oxygen to tissues and other metabolic exchanges are impeded by increased thickness of vessel walls (D) and widespread widening of perivascular spaces (état criblé) (C) with enlargement of perivascular spaces of Virchow-Robin, which results from tortuosity of elongated arterioles. (A from Duvernoy HM, Delon S, Vanson JL: Cortical blood vessels of the human brain. Brain Res Bull 1981; 7:519-579. B to D from GC Román: Vascular dementia. In Fisher M, ed: Clinical Atlas of Cerebrovascular Disorders. London: Wolfe/Mosby–Year Book Europe, 1994, pp 13.1-13.23.)

could be confused with Alzheimer’s disease. A closer look at these subcortical forms of vascular dementia reveals significant differences, as listed in Table 47–5.

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chomotor performance in SIVD. Of the neuroprotective or nootropic agents, piracetam, oxiracetam, and nicergoline appear to be modestly effective for the MID form of vascular dementia. Citicoline showed positive short-term effects on memory and behavior in patients with vascular dementia. In the multicenter European Pentoxifylline Multi-Infarct Dementia Study,10 pentoxifylline, a xanthine derivative with hemorheological and immunomodulatory properties, produced significant cognitive improvement in MID, in comparison with placebo. Pentoxifylline is useful in Binswanger’s disease, improving hyperviscosity, sedimentation rate, hyperfibrinogenemia, and increased acute-phase reactants (tumor necrosis factor α). Currently, the most promising therapies for vascular dementia and vascular cognitive impairment include the cholinesterase inhibitors donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), as well as the N-methylD-aspartate (NMDA)–glutamate receptor antagonist memantine. Cholinesterase inhibitors, approved for the treatment of Alzheimer’s disease, appear to be an effective and safe alternative for patients with vascular dementia.11

PREVENTION Age, gender, ethnicity, and genetic makeup are nonmodifiable risk factors for stroke. However, a number of risk factors for vascular dementia (Table 47–6) can be prevented. Primary prevention is directed to the control of vascular risk factors in an effort to prevent stroke, ischemic heart disease, and vascular dementia. Secondary prevention addresses prevention of further ischemic episodes.

Primary Prevention Treatment of hypertension appears to decrease the incidence of dementia. Other treatable risk factors include diabetes mellitus, the metabolic syndrome, raised homocysteine level, and smoking. Homocysteine is lowered with oral folate and parenteral vitamin B12 supplementation. The beneficial cardiovascular effects of a Mediterranean diet rich in fruits and antioxidants have been well documented. Statins (3-hydroxy-3methylglutaryl–coenzyme A [HMG-CoA] reductase inhibitors) may reduce dementia risk, but its use in nondemented, nonhyperlipidemic patients cannot currently be recommended.

Secondary Prevention TREATMENT Recently, a number of treatment trials in patients with vascular dementia were successfully completed. Despite progress, there are no approved drugs for symptomatic treatment of vascular dementia. The antiplatelet agents aspirin, triflusal, and Ginkgo biloba have been used in patients with MID or with Alzheimer’s disease plus cerebrovascular disease, with modest results, mainly by decreasing vascular dementia progression by lowering the risk of recurrent stroke. Vasodilators have no proved effects on vascular dementia, except for niacin, which has lipid-lowering effects. The calcium-channel blockers nimodipine and nicardipine have moderate efficacy in tests of attention and psy-

Optimal management of acute stroke and swift implementation of secondary prevention are mandatory to prevent vascular dementia. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),12 blood pressure lowering in patients with previous stroke or transient ischemic attack reduced the incidence of secondary stroke by 28%, that of major vascular events by 26%, and that of major coronary events by 26%. These reductions were all magnified by approximately 50% in a subgroup of patients in whom the angiotensin-converting enzyme inhibitor perindopril was routinely combined with the diuretic indapamide. This combination alone could reduce the burden of stroke and could avert between 0.5 million and 1 million strokes each year worldwide.

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T A B L E 4 7 – 4. Relevant Hemorheological and Autoregulatory Circulatory Factors in White Matter Hypoperfusion Hemorheological Factors O2 delivery to tissues depends on blood flow and red cell concentration. The rate of blood flow through a tubular vessel is determined by Poiseuille’s law: Blood flow = perfusion pressure · π · radius4/8 · η · length Blood flow declines as the length of the vessel increases and its radius decreases. A salient feature of the equation is the overriding influence of vessel radius (π · radius4). In vessels with small, fixed radius, such as in small-artery disease, the flow of blood is determined mainly by systolic blood pressure and by blood viscosity (η); i.e., by the force or “shear stress” required to overcome the resistance of the tube wall to the fluid at a given flow velocity. Blood is a nonhomogenous and nonnewtonian fluid; i.e., viscosity increases at low velocities in the arteriolar bed and microcirculation. Inside vessels affected by arteriolosclerosis; the resulting hyperviscosity may slow or halt blood flow. In arterioles, there is disproportionate increase of blood viscosity with increases in hematocrit, plasma viscosity, red blood cell deformability, hyperglycemia, and hyperlipidemia. Autoregulatory Changes Because of anatomical features, local cerebral blood flow is lowest in periventricular and deep white matter regions perfused by long, narrow, no-collateral end-arterioles. Perfusion threshold for ischemic injury increases if hypoperfusion persists over longer periods of time. With autoregulation, when cerebral perfusion pressure falls, blood vessels dilate increasing blood volume and initially maintaining regional cerebral blood flow (rCBF). When blood flow starts to decline, oxygen extraction fraction (OEF) increases to maintain cerebral oxygen metabolism (rCMRO2): rCMRO2 = OEF * arterial oxygen content * rCBF When failing perfusion pressure exceeds compensatory mechanisms, oxygen metabolism is compromised. Neuronal-glial function is lost, followed by irreversible necrosis. In infarcted tissue, both CMRO2 and OEF values are minimal. Thus, increased OEF is a transitional phenomenon, signaling a critical period of incipient ischemia. From Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002;1:426-436.

T A B L E 4 7 – 5. Important Feature Differences between Subcortical Vascular Dementia and Alzheimer’s Disease Clinical Feature

Alzheimer’s Disease

Vascular Dementia

Memory loss Language disorder Gait Falls Executive dysfunction Mood and personality Urinary problems Onset Progression

Early, severe amnesia Early aphasia Normal Rare Late Intact Late incontinence Slow Rapid

Forgetfulness, poor recall Loss of verbal fluency, dysarthria Abnormal, marche à petits pas Frequent Early and severe Changes: apathy, depression, crying spells Urgency, nocturia Abrupt Slow, stepwise, fluctuating

T A B L E 4 7 – 6.

Risk Factors for Vascular Dementia

Advanced age Long-term, untreated arterial hypertension Isolated systolic hypertension in elderly patients Diabetes mellitus Cigarette smoking Hyperlipidemia Hyperhomocysteinemia Hyperfibrinogenemia Congestive heart failure Atrial fibrillation Carotid disease Other cardiac arrhythmias Complicated stroke Recurrent stroke Orthostatic hypotension Obstructive sleep apnea Major surgery in elderly patients Coronary artery bypass graft (CABG) surgery

chapter 47 vascular dementia In brief, control of blood pressure in the general population could significantly decrease the social and economic burdens of dementia in years to come.

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Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002; 1:426-436.

References

K E Y

P O I N T S

●

With aging of the world population, cardiovascular disease and stroke will increase steadily. For this reason, the incidence of dementia resulting from cerebrovascular disease will also rise. Vascular dementia is predicted to become the most common cause of cognitive decline in elderly persons.

●

Vascular dementia may result not only from large-vessel strokes (multi-infarct dementia) but also from ischemic lesions caused by small-vessel pathology, including lacunar strokes and incomplete white matter ischemia (subcortical ischemic vascular dementia), as well as from hypoperfusion caused by heart disease or circulatory disturbances.

●

Prevention of vascular dementia is achievable both by decreasing the risk of stroke (primary prevention) and by lowering the possibility of recurrent stroke (secondary prevention).

Suggested Reading Bowler JV, Hachinski V, eds: Vascular Cognitive Impairment: preventable Dementia. Oxford, UK: Oxford University Press, 2003. Erkinjuntti T, Román G, Gauthier S, et al: Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35:1010-1017. Paul RH, Cohen R, Ott BR, et al, eds: Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management. Totowa, NJ: Humana Press, 2005. Román GC, ed: Advances in vascular dementia [whole issue]. Semin Cerebrovasc Dis Stroke 2004; 4(2).

1. Lobo A, Launer LJ, Fratiglioni L, et al: Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000; 54(Suppl 5):S4-S9. 2. Dubois MF, Herbert R: The incidence of vascular dementia in Canada: a comparison with Europe and East Asia. Neuroepidemiology 2001; 20:179-187. 3. Bousser MG, Tournier-Lasserve E: Summary of the Proceedings of the First International Workshop on CADASIL. Paris, May 19-21, 1993. Stroke 1994; 25:704-707. 4. Román GC, Tatemichi TK, Erkinjuntti T, et al: Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology 1993; 43: 250-260. 5. Román GC, Sachdev P, Royall DR, et al: Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004; 226:8187. 6. Jorm AF, Jolley D: The incidence of dementia: a meta-analysis. Neurology 1998; 51:728-733. 7. Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002; 1:426436. 8. Tournier-Lasserve E, Joutel A, Melki J, et al: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993; 3:256-259. 9. Román GC: Brain hypoperfusion: a critical factor in vascular dementia. Neurol Res 2004; 26:454-458. 10. European Pentoxifylline Multi-Infarct Dementia Study. Eur Neurol 1996; 36:315-321. 11. Erkinjuntti T, Román G, Gauthier S, et al: Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35:1010-1017. 12. Tzourio C, Anderson C, Chapman N, et al: Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163:1069-1075.

CHAPTER

REHABILITATION ●

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STROKE

●

Richard Greenwood and Nick Ward

Stroke, or vascular brain injury, has an incidence of between about 1.1 and 2.6 per 1000 adults1 and a prevalence of 5 to 8 per 1000.2 It is a leading cause of chronic disability worldwide; in the United Kingdom, it is the commonest single cause of severe disability in people living at home.3,4 About 75% of affected patients are older than 65 years, and 10% are younger than 55. Each year in England and Wales, stroke occurs in about 10,000 people younger than 55 and 1000 people younger than 30. Six to 12 months after stroke, only 60% of patients with hemiplegic stroke have achieved independence in personal care, and those with sensory or visual field loss are more disabled; 30% to 40% of survivors are depressed, 10% to 15% severely so; 50% need help with either housework, meal preparation, or shopping; and a similar percentage lack a meaningful social, recreational, or occupational activity during the day.5-8 In addition to the personal consequences, the economic consequences of stroke are also enormous; direct health care costs account for approximately 4% of total health care costs, or about £3 billion in the United Kingdom (about $5.3 billion in U.S. dollars) per annum at 2005 prices9; these costs will increase as the population ages. Neuroprotective interventions to reverse the immediate consequences of stroke are not widely applicable.10 In these circumstances, when reversal of pathology is incomplete, the majority of stroke survivors need the multidimensional process termed rehabilitation to enhance their functional activity and societal participation and to reduce the effect of limitations in these areas, so that life quality is improved and life is “worth living.”11 Rehabilitation goals are achieved through the prevention of secondary complications; through facilitation of neural protection, restoration, and substitution; and through functional compensation, which involves both behavioral adaptation and substitution, as well as modification of personal, environmental, and social contextual factors (Table 48–1). This process must also be accompanied by often difficult and less frequently admitted adjustment to loss and change, a need that is easily forgotten in the gym or during a functional imaging study. This chapter explores the delivery and effectiveness of these interventions during rehabilitation after stroke. The high incidence and prevalence of stroke have provided an opportunity to test the effectiveness of many components of the rehabilitation process. Trials have shown convincingly that organized care produces better outcomes than disorganized care; this result has far-reaching implications for health care

systems in general, let alone those focusing on stroke. Many of the areas addressed in this chapter are included in evidenceand expert opinion–based guidelines produced in the United Kingdom by the Royal College of Physicians12 and the Scottish Intercollegiate Guidelines Network,13 in Australia by the National Stroke Foundation,14 and in the United States by the Department of Veterans Affairs and the Department of Defense.15

COMPLEX ORGANIZATIONAL INTERVENTIONS Rehabilitation after single-incident brain injury, including stroke, should be delivered through polymodal inpatient and community-based service delivery systems that differ by structure and process. A classification of these different service options, as a “rehabilitation typology,” remains to be agreed upon, at least cross-culturally, and would facilitate comparisons of different studies.16 The use of each component is determined by a variety of clinical and social factors, including length of time since injury, level of dependency, characteristics of the residual impairment, age of the patient, and resources available.17 Recommendations that different types of care after stroke are incorporated into systems of clinical care (e.g., Schwamm et al18) also emphasize the use of acute and rehabilitation interventions in parallel rather than in series (Fig. 48–1), so that strategies optimizing neural protection acutely are combined with key factors identified in postacute care. The benefits of organized complex polymodal interventions so far reported are likely to reflect mainly the effects of preventing the complications described later in this chapter and shown in Table 48–2, functional interventions that focus on teaching new skills, and the use of aids and appliances and environmental modifications to help patients adapt to their impairments, rather than the effects of neural reorganization. Until about 1995, 20% to 50% of patients after stroke were managed acutely at home in some European countries,19 despite recommendations to the contrary.20 The benefits of stroke unit care and the gradual introduction of thrombolysis and neuroprotective agents are, alone, likely to reduce this percentage dramatically. Furthermore, patients randomly assigned to receive acute care at home after moderately severe stroke (sufficient to cause persistent neurological deficit affecting continence, mobility, and self-care, and necessitating multidisciplinary treatment), rather than to receive care in an acute and

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rehabilitation stroke unit or a general ward with stroke team support, were significantly more likely at 1 year to be dead or institutionalized (24% versus 14%; P = 0.03) and less likely to be alive without severe disability (85% versus 71%; P = 0.002) than were patients admitted to the stroke unit.21 In their meta-analysis of 23 trials, the Stroke Unit Trialists’ Collaboration22 compared care in stroke units, nine of which were “comprehensive” and included both acute and rehabilitation components, with care given by alternative services, usually in a general medical or geriatric ward with or without a visiting stroke team. The meta-analysis showed that patients who receive unit-based inpatient care do not stay longer in hospital and are more likely to be alive, independent, and living

at home 1 year after the stroke, regardless of gender, age, and stroke severity (Fig. 48–2). Thus, in comparison with alternative services, stroke unit care produced reductions in the odds of death at 1 year (odds ratio, 0.86; 95% confidence interval,

Injury

Rehabilitation A Acute treatments NOT

T A B L E 48–1. Mechanisms of Recovery after Stroke Prevention of Complications Neural Protection, Restoration, and Substitution via Resolution of edema, mass effects, toxic-metabolic dysfunction, and diaschisis Neural regrowth and replacement Reorganization of use-dependent neuronal networks Functional Compensation via Behavioral adaptation and substitution Modification of personal, environmental, and social contextual factors

Acute treatments

B

Rehabilitation

Injury ■

Figure 48–1. Acute treatments focus on neural and systemic protection, whereas rehabilitation involves goal-directed restorative and compensatory training strategies. Both form the basis of practice in postacute stroke rehabilitation units. Optimal outcomes over time (→) are most likely to result from their use in parallel (A), not in series (B).

T A B L E 48–2. Complications after Stroke during Inpatient Rehabilitation and Their Management Cause and Effect

Stroke Unit Frequency % (95% Confidence Interval)

Management

Comorbid Conditions Hypertension/hypotension Cardiac events Fever GI bleed Drug side effects Musculoskeletal pain

15/8199 13199 20199 3196/4199 9198 14198/38197

Antihypertensive/treat cause Specific medical treatments Antipyretics ? Prophylaxis; avoid NSAIDs Drug withdrawal Physical therapies

Physical Dependency Pressure sores Sores and skin breaks Contractures PEs and DVTs Falls Shoulder pain

4198 21 (16-25)195/18196

Pressure care, 24-hr handling and positioning

3 (0-3)195/5198 25 (21-30)195/20256/11198 9 (6-12)195/24256

Thromboprophylaxis Risk assessment Handling and positioning

Neurological Damage Malnutrition and dehydration Chest infections Urinary tract infections Confusion and agitation Epilepsy Sleep-disordered breathing Fatigue

5198 and 10198/10199 22 (18-27)195/4199 23 (18-28)195/15256/31198 36 (30-41)195/4199 3 (1-5)195/2256/2198 62257 40-60223

NG/PEG feeding and dietetics Dysphagia management Toileting program Environmental management ± drugs AEDs if no other trigger CPAP ? Retraining

Vascular Brain Injury Mass effects Hydrocephalus Catastrophic illness Depression Anxiety Family breakdown

Neurosurgical decompression Shunting 16 (12-21)195/ 26256/13198 14 (10-18)195/8198

CBT ± drugs CBT ± drugs Information + training

AED, antiepileptic drug; CBT, cognitive-behavior therapy; CCF, congestive cardiac failure; CPAP, continuous positive airway pressure; DVT, deep vein thrombosis; GI, gastrointestinal; NG/PEG, nasogastric/percutaneous endoscopic gastrostomy; NSAID, nonsteroidal anti-inflammatory drug; PE, pulmonary embolism.

chapter 48 rehabilitation after stroke ■

ORGANIZATIONAL ASPECTS OF REHABILITATION Stroke Unit (SU) or Mixed Rehab (MR) vs General Medical Ward (GMW) ± Peripatetic Team (PT) Care Odds of death or institutional care SU vs GMW (13 trials; 3200 pts)

P = 0.008

SU vs Mixed Rehab (4 trials; 540 pts)

NS

Mixed Rehab vs GMW (5 trials; 580 pts)

P = 0.04

PT vs GMW (2 trials; 240 pts)

NS

SU vs GMW + PT (1 trial; 305 pts)

P = 0.0009

TOTAL

P = 0.0002 0.5 SU/MR better

1

647

Figure 48–2. Care in stroke units or mixed rehabilitation units can be organized and is thus more effective than in general medical wards where it remains disorganized, with or without input from a peripatetic team. NS, nonsignificant. (Adapted from Stroke Unit Trialists’ Collaboration: Organised inpatient [stroke unit] care for stroke. Cochrane Database Syst Rev 2001; [3]:CD000197.)

2 GMW better

0.71 to 0.94; P = 0.005), of death or institutionalized care (odds ratio, 0.80; 95% confidence interval, 0.71 to 0.90; P = 0.0002), and of death or dependency (odds ratio, 0.78; 95% confidence interval, 0.68 to 0.89; P = 0.0003). A subsequent systematic review of results from nine postacute units, which admitted patients more than 1 week after stroke, in comparison with an alternative service, revealed benefits similar to those resulting from combined acute and postacute units,23 and in the United States, compliance with postacute but not acute stroke unit guidelines (Table 48–3) has been shown to be correlated with outcome.16 Secondary analysis has indicated that the reduction in stroke unit deaths probably results from a reduction in the complications of immobility rather than in neurological or cardiovascular complications. The increased number of patients discharged home from stroke units and the reduced requirement for institutional care were attributable largely to an increase in the number of patients returning home physically independent (Rankin score, 0 to 2), rather than dependent (Rankin score, 3 to 5).24 Langhorne and Pollock25 identified aspects of care common to 11 stroke units, 8 of which included acute care, reporting beneficial effects between 1985 and 2000 in the Stroke Unit Trialists’ Collaboration’s systematic review.22 These included comprehensive medical, nursing, and therapy assessments; integration of nursing care within the multidisciplinary team; early mobilization and treatment of hypoxia, hyperglycemia, and suspected infection; avoidance of urinary catheterization; and formalized goal-oriented multidisciplinary team care, with early discharge planning and education and involvement of caretakers. Evans and associates26 found that many of these aspects of care were not delivered by a peripatetic specialist stroke team (PSST). They compared care delivered to 304 patients randomly assigned to an acute and rehabilitation stroke unit (n = 152) or to general wards supported by a PSST (n = 152). Patients in the stroke unit were monitored more frequently, and more of those patients received oxygen, antipyretics, measures to reduce aspiration, and early nutrition than those in general wards. Many aspects of multidisciplinary care occurred more fre-

T A B L E 48–3. Dimensions of Acute Rehabilitation after Stroke 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Multidisciplinary team coordination Baseline assessment Goal setting Treatment plan Monitoring of progress Management of impairments/disabilities Prevention of complications Prevention of recurrent stroke Family involvement Patient and family education Discharge planning

After Duncan PW, Horner RD, Reker DM, et al: Adherence to postacute guidelines is associated with functional recovery in stroke. Stroke 2002; 33:167-178. Compliance with these dimensions of process during postacute rehabilitation after stroke is correlated with outcome.

quently in the stroke unit, in which complications including stroke progression, chest infections, and dehydration were less frequent. Early feeding, stroke unit management, frequency of complications, and measures to prevent aspiration independently affected outcome. In 1984, a PSST’s input to general ward care was shown to nonsignificantly reduce mortality rates and significantly improve functional recovery in men.27 More recently, in a head-to-head comparison at 1 year of patients randomly assigned to receive care from the PSST with those receiving care in a combined acute and rehabilitation stroke unit, more patients in the PSST group were dead or institutionalized (30% versus 14%; P < 0.001) and fewer were alive without severe disability (66% versus 85%; P < 0.001).21 Retrospective data collected by van der Walt and colleagues28 before and 2 years after the introduction of a PSST to a general ward showed significant improvements in prophylaxis for deep vein thrombosis, incontinence management, premorbid function documentation, frequent neurological observations, and early occupational therapy, with fewer severe complications (9% after versus 24% before; P = 0.004), reduced median length

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of stay (12.0 after versus 18.5 days before; P = 0.003), and more patients independent at discharge (32% after versus 9% before; P < 0.001). It is thus possible that practice developed in stroke units can now be delivered more effectively by a PSST, and further comparison of these two methods of service delivery remains legitimate. More recently, high-dependency care has been introduced immediately after stroke, providing continuous rather than manual monitoring for hypoxia, hyperglycemia, hypotension, cardiac arrhythmias, and elevated body temperature during the first 48 to 72 hours after admission.29,30 Currently, its effectiveness is relatively unexplored, but there is a suggestion that it may reduce mortality rates at 3 months and 1 year among patients with severe stroke, without increasing dependency.31,32 Remarkably, the differences between stroke unit and alternative care persist for many years. Indredavik and colleagues33 found that even 10 years after random assignment to an acute and rehabilitation stroke unit or a general ward, fewer patients in the stroke unit had died (75.5% versus 87.3%; P = 0.008), more were at home (19.1% versus 8.2%; P = 0.018), and more were at least partly independent with a Barthel Index score of 60 or higher (20.0% versus 8.2%; P = 0.012) or independent with a Barthel Index score of 95 or higher (12.7% versus 5.4%; P = 0.061). Increased survival times 5 years after random assignment to a stroke rehabilitation unit, versus a general medical or geriatric ward, were also reported by Lincoln and colleagues.34 Early discharge, supported by a multidisciplinary outreach team, of medically stable patients after mild and moderate stroke, with an admission Barthel Index score of more than 9, supplements initial stroke unit gains. A meta-analysis of individual patient data from 11 trials of early supported discharge versus conventional care showed that the patients with early supported discharge had a reduced risk of death or dependency (odds ratio, 0.79; 95% confidence interval, 0.64 to 0.97; P = 0.02), a hospital stay shortened by 8 days (P < 0.0001), and significant improvement in extended activities of daily living (P = 0.05), although not in subjective health status or mood in either patients or caretakers. Patients were moderately disabled at discharge with a median discharge Barthel Index score of 15.35 One study revealed that these gains can include better life quality, assessed by the Nottingham Health Profile, at 1 year,36 and another study revealed that gains in domestic and extended activities of daily living are still evident after 5 years.37 Once in the community, patients are known to be at risk of deteriorating as a result of multiple health problems, including falls, depression, and physical and social inactivity and isolation, in addition to age-related symptoms and comorbidity, and health-related quality of life has been shown to significantly decline in the 6 months after discharge.38 Nursing home care does not substitute for stroke unit care,39 but the place for and the optimal process in other service systems for patients later after stroke (e.g., nurse-led wards, nursing homes, or residential placements) remain to be examined. A meta-analysis of trials of therapy-based outpatient or domiciliary rehabilitation, delivered by either a multidisciplinary team or by a physiotherapist or occupational therapist, with the goal of improving task-oriented behaviors, has shown that deterioration is prevented (odds ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P = 0.009) and dependency in personal care reduced (95% confidence interval, 0.02 to 0.25; P = 0.02).40 The effective components and best location for this type

of service need further exploration, but benefit has been consistent in trials of community-based occupational therapy, which have provided sufficient data for a meta-analysis of eight trials that showed that intervention was associated with improved personal, extended, and leisure-based activities of daily living, depending on the intervention target.41 These findings were confirmed in a more wide-ranging systematic review of occupational therapy for stroke patients by Steultjens and associates,42 who also noted the need for further studies of the effectiveness of splinting. Most studies of physiotherapy in patients in the community after stroke investigate the effect of a particular physiotherapy treatment on upper or lower limb function at the level of impairment and mobility, which may improve, rather than on limitations in activity and independence, which, if examined, may not improve. Domiciliary physiotherapy within 6 months after stroke has been shown to reduce probability of readmission after an average of only 2.9 (range, 1 to 8) visits43 and to reduce dependency at less cost than for day hospital attendance.44,45 In patients more than 1 year after stroke, only four to five physiotherapy sessions produced a clinically small but significant improvement in mobility.46 Informal caretakers should be recognized as an important resource: They enable patients to remain in the community,47 their support is likely to facilitate patient outcomes,48 and depression is more severe in caretakers who feel poorly supported.49 Formal support for caretakers is difficult to obtain in the United Kingdom. Trials of psychosocial interventions to support caretakers of patients with stroke, involving information packages, specialist nurses, a mental health worker, or family support workers, have failed to show functional or psychological benefit in patients and only modest psychosocial benefit for caretakers.50-57 In contrast, there is evidence that caretaker adjustment is increased by education and counseling or by training in social problem-solving skills.58 Kalra and colleagues59,60 demonstrated that training informal caretakers in basic nursing skills and facilitation of personal care techniques reduced costs and caregiver burden and improved psychosocial outcomes for the caretaker and the patient, although there was still no change in patients’ rates of mortality, institutionalization, and disability.

MANAGEMENT OF NEUROLOGICAL IMPAIRMENTS Evidence of dysphagia, with consequent risk of dehydration, further malnutrition, and chest infections resulting from aspiration, has been reported to occur clinically in about 50% of all patients with stroke admitted to a hospital, with videofluoroscopic evidence of a swallowing abnormality in up to 65% of patients and of aspiration in about 20%.61,62 Videofluoroscopic and flexible endoscopic evaluation of swallowing increase the reliability with which aspiration can be identified63,64 when clinicians select which patients need tube feeding. However, whether other aspects of dysphagia management, including dietary modification and compensatory swallowing techniques, reduce the need for tube feeding or the risk of aspiration pneumonia remains unclear despite assertion to the contrary.65 The Feed or Ordinary Diet (FOOD) trials66 revealed that in 859 patients randomly assigned to receive nasogastric feeding within a week, in contrast to more than a week, after stroke,

chapter 48 rehabilitation after stroke absolute mortality rates were reduced by 5.8% (95% confidence interval, −0.8 to 12.5; P = 0.09) in the group fed early; in 321 patients randomly assigned to undergo percutaneous enteral gastrostomy (PEG) feeding or nasogastric tube feeding a median of 1 week after stroke, PEG feeding was associated with an absolute increase in risk of death of 1.0% (95% confidence interval, −10.0 to 11.9; P = 0.9) and an increased risk of death or other poor outcome of 7.8% (95% confidence interval, 0.0 to 15.5; P = 0.05). Thus, as is recommended current practice in hospitalized adult patients in general,67 nasogastric feeding should be used for dysphagic patients soon after stroke, whereas PEG feeding is reserved for patients who do not tolerate nasogastric feeding and as required in the longer-term care of dysphagic patients. After stroke, early incontinence is predictive of poor outcomes, including death, lengthy hospital stay, institutionalization, and severe disability.68 New urinary incontinence occurs in 40% to 50% of patients during the first week after admission and in 10% to 20% by 6-month follow-up68,69; it appears to remain at this level in the community over the long term.70 The proportions of stroke patients with new fecal incontinence on admission and at 6-month follow-up are lower, at 30% to 40% and 5% to 10%, respectively.68,69 Causes and predictors68,71,72 of fecal and urinary incontinence include age; stroke type and severity; “functional incontinence” resulting from strokerelated cognitive and communication difficulties and mobility problems; autonomic neuropathies, usually diabetic in origin; medications causing bladder and bowel hyporeflexia; preexisting bladder outflow obstruction in men or stress incontinence in women; and perhaps depression and lowered self-esteem that result from the incontinence itself.73,74 Current guidelines (e.g., Royal College of Physicians12) for the management of incontinence after stroke recommend initial definition of its cause and associations through a full clinical assessment. The neurogenic cause after stroke is usually disruption of suprapontine inhibition of bladder contractility resulting in detrusor hyperreflexia, but bladder hyporeflexia may occur after cerebellar stroke.75 Evidence for the effectiveness of methods promoting continence after stroke is currently derived largely from trials in other (nonstroke) patient groups. Management of urinary incontinence76 includes a combination of anticholinergic drug therapy, bladder training by prompted and/or timed voiding77,78 or biofeedback,79 and appropriate management of outflow obstruction and stress incontinence, for which one small study of 26 stroke patients randomly assigned to receive treatment or to control conditions showed no benefit from a 12-week pelvic floor muscle training program.80 Similar general principles apply to the management of fecal incontinence,81 which in inpatients or in discharged patients is associated with needing help to use the toilet82 and thus might be addressed by improving functional independence, whereas constipation but not fecal incontinence after stroke is improved by a single clinical/educational nurse intervention up to 6 months later.83 Impairment of trunk control and sitting balance after acute stroke is common, and recovery is a reliable predictor of functional outcome after stroke. Trunk control, measured by the trunk control test at rehabilitation admission a median of 5 weeks after stroke, accounted for 71% of the variance of the motor component of the Functional Independence Measure at discharge 10 weeks after stroke84; as measured by the Postural Assessment Scale for Stroke Patients within 2 weeks after

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stroke, trunk control was strongly correlated with functional outcome, rated by a combined score of both personal (Barthel Index) and instrumental (Frenchay Activities Index) activities of daily living at 6 months after stroke.85 A positive correlation has also been found between sitting balance and the Barthel Index score86 and between sitting balance and gait at 6 months.87 Mudie and associates88 found that three specific treatment approaches implemented early after stroke improved sitting balance in the short term in comparison with a nonspecific control approach. Whether early targeting of sitting balance for treatment could improve mobility over the long term is an interesting question that remains to be explored. Disordered motor control of the limbs after stroke is usually caused by the positive and negative effects of the upper motor neuron syndrome, in which the central abnormality is usually muscle weakness and co-contraction resulting from a failure of coordinated high-frequency motor neuron firing during movement, rather than high tone resulting from spasticity and contracture found at rest,89 which is seen clinically in only 20% to 30% of hemiparetic patients 3 to 12 months after stroke.90,91 Spasticity at rest, when it is a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, is of diagnostic use but does not contribute significantly to impairment during active voluntary movement and function in either the leg or the arm92,93 and is only one factor contributing to increased muscle tone in the upper motor neuron syndrome, in which co-contraction and biomechanical changes contribute significantly to the resistance to passive movement.94 It has thus been easier to show that pharmacological treatments that reduce the hypertonus of spasticity and co-contraction benefit passive rather than active functional activities, including hand and perineal hygiene, dressing, pain, and limb position,95-100 and even correction of equinovarus at the ankle to improve weight bearing by the affected leg is unlikely to translate into functional improvements in gait101,102 unless it is followed by physical measures to reduce soft tissue shortening and a program of task-related training.103,104 Thus, although treatments for spasticity after stroke achieve passive functional goals by preventing contracture or reduce pain and are of particular value in dependent patients unable to participate in skill learning, the results of treatments for spasticity in general and after stroke have emphasized the fundamental truth of Landau’s statement in 1974105 that “If the major disability of the upper motor neuron syndrome is due to diminished neural input to segmental control of the final common path (negative symptoms), it follows that only some method of provoking [central nervous system] neuronal regeneration or of improving the potency of and control by surviving upper level neurons could provide a direct remedy.” Landau’s next sentence was “No such approach is on the horizon,” and at that time the focus in rehabilitation was on training in compensatory strategies and social and environmental modification. Since the mid-1990s, however, there have been investigations of neurobiological rehabilitation strategies designed to modify the neural processes and behaviors that occur during recovery (Fig. 48–3) (Dobkin, 2004).106 Meta-analyses of physiotherapy after stroke have revealed significant improvements in independence in activities of daily living and reduction in impairments with higher intensities of physiotherapy.107-109 Traditional physiotherapeutic strategies emphasize cutaneous and proprioceptive stimulation, reduction of tone, and therapist-induced central facilitation of

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A

B ■

Figure 48–3. Both patient A and patient B suffered a stroke affecting the right hand. The T1-weighted magnetic resonance imaging scans on the left (“infarct”) demonstrate that patient A suffered a left pontine infarction and patient B suffered a left middle cerebral artery territory infarction. The five scans to the right of each structural scan show patterns of brain activation, measured with functional magnetic resonance imaging, during repetitive gripping with the affected right hand at different time points over the first 3 months after stroke. (The brain is seen from above, with the anterior aspect at the top of the image.) Recovery of function in patient A is associated with early widespread activation within recognized motor related areas, followed by a gradual focusing toward a normal lateralized pattern; the 3-month (far right) scan shows activity confined largely to the left sensorimotor cortex, as in normal subjects. Recovery of function in patient B is also associated with focusing of the early pattern of widespread activation, but in this instance activity focuses toward the right sensorimotor cortex, ipsilateral to the affected hand. Ipsilateral sensorimotor cortex activation is rarely seen in normal subjects. This focusing is due to increasingly efficient neural circuitry, very similar to that seen during learning of a new complex motor task in the undamaged human brain. However, it is possible to focus only onto regions of the brain that can still generate a motor output signal. In the case of patient B, many of the left hemisphere cortical motor regions have been disconnected by the infarct. Thus, there appears to be a reliance on right motor cortex to generate right hand movements. This “secondary” system is necessarily less efficient, and this is reflected in less complete recovery of patient B in comparison with patient A (hand grip of 64% of the unaffected side for patient B at 3 months, in comparison with 89% for patient A). This finding suggests two important consequences: (1) It ought to be possible to use therapies that are designed to drive this process toward the optimally configured motor system and (2) it helps clinicians appreciate that damage to brain structures is likely to be a major constraint to this process and that reorganization can take place only in surviving brain regions; this has implications about how much recovery can be expected.

normal movement, rather than voluntary activation of proximal or distal musculature to relearn functional tasks. This type of task-related motor relearning was first shown to be effective in improving the ability to balance during seated reaching activities late after stroke.110 Although this approach has not yet been consistently shown to improve functional outcomes and resource use early after stroke,111,112 its principles of repetition, task orientation, attention, and reward are similar to those that result in motor learning and cortical neural reorganization in nonhuman primates with and without ischemic cortical damage.113 It is thus a “neurobiological” approach to skill relearning in which repetition of graded and motivating taskrelated learning programs is envisaged to drive the acquisition of motor, linguistic, and cognitive skills and more complex behaviors through activity-dependent neural reorganization, regrowth, and replacement.114 Although these techniques can be shown to produce neuroplastic effects—in humans, usually by functional imaging techniques—these changes should not be confused with the potential clinical usefulness of these techniques, which requires a robust behavioral effect if measurable functional benefit is to occur. The effects of task-related training are seen most obvi-

ously in the function targeted for treatment; change has been demonstrated after stroke in upper and lower limb function and linguistic skills. Factors that optimize skill learning, including implicit rather than explicit feedback115 and a random rather than blocked learning schedule,116 are likely to affect the rate at which a task is learned and the extent of carryover into novel environments. In the arm, training is focused on practicing graded motivating functional tasks, including grasping, reaching, leaning, and manipulating clothing by the affected limb; in the trunk and leg, training is focused on the recovery of bed mobility, sitting and standing balance, transfers, gait stability and velocity, and stair climbing. Kwakkel and colleagues117 showed that leg training of this sort for an average of 30 minutes of therapy 5 days a week for 20 weeks after stroke onset, in contrast to immobilization of the limb in an inflatable cuff for a similar time, increased performance in activities of daily living (measured by the Barthel Index), walking ability, and also hand dexterity, whereas arm training increased arm dexterity alone. What determines when, in whom, and how task-oriented training should be carried out after stroke, in an individual as well as in a population, remains open to investigation. The duration in training can be increased: for example, to an

chapter 48 rehabilitation after stroke impractical 6 hours a day for 10 weekdays late after stroke. Training can be performed solely with a therapist or also automated with a robotic,118,119 most commonly as a treadmill with or without body weight support for gait training120 or in a virtual environment,121 or it can be encouraged, probably at both cortical122 and functional levels, and also in animals,123 by constraint of the unaffected upper limb.124-126 It can also be combined with a variety of impairment-based adjunctive therapies, including muscle-strengthening exercises,127 an orthotic,128 electrical stimulation of the arm or leg,129-131 sensory stimulation,132 mental imagery,133 and musical feedback.134 The available evidence for the effectiveness of these and other physical therapies was systematically reviewed in 2004 by van Peppen and colleagues.135 Which therapy modalities should be used, to what purpose, how they should be combined, at what stage after stroke, at what intensity and for how long, and in which patients are questions that are beginning to be answered clinically with an evidence base, rather than at best theory and at worst belief. The need to be able to do this is emphasized particularly by the evidence beginning to show long-term persistence of task-related training effects136,137 and the useful effects of interventions late after stroke (e.g., Werner and Kessler138 and van der Lee et al139). It is accompanied by a need to explore how the new technologies, which may not always yield benefit (e.g., Richards et al140), can best be put best to work. Similar principles are beginning to drive trials of rehabilitation therapies of the focal, rather than global,141 cognitive disorders observed after stroke. According to results of clinical measures, language impairments affect about 40% of the stroke population at stroke onset142 and about 10% at 6 months after stroke.143 Minimal spontaneous improvement in language functions occur more than 1 year after stroke. An early metaanalysis144 and review145 of trials of speech and language therapies concluded that there was evidence of effectiveness, but restriction of the evidence to randomized controlled trials, in comparison with no therapy, informal support, or another speech and language therapy, failed to yield clear evidence of effectiveness.146 However, Bhogal and colleagues147 found that increased intensity of therapy was associated with improvement, which occurred in four studies that provided an average of 9 hours of therapy per week for 11 weeks, in contrast to four studies with negative results that provided approximately 2 hours per week for 23 weeks. Although the type of therapy required remains unclear (e.g., Doesborgh et al148), Pulvermüller and colleagues149 suggested that the principles of (a) massed practice—for example, 30 to 35 hours of therapy over 10 days rather than the same therapy time over a longer period—and of (b) constraint (in this case of maladaptive methods of communication), and of (c) everyday behavioral relevance are important factors in generating neuroplastic and thus functional changes in language skills. The presence of other cognitive problems in the acute phase are important independent predictors of long-term outcome, in addition to neurological deficits rated by standard measures, particularly unilateral neglect150,151 and executive dysfunction.152 Neglect, as currently measured, is seen in more than 60% of patients assessed within 2 to 3 days of admission for stroke, more commonly after right than left hemisphere stroke.153 Of patients with neglect 2 to 4 weeks after stroke, 80% still exhibit aspects of neglect on testing at 6 months,154 and the poor functional outcome predicted by the presence of early neglect is still seen if neglect has resolved on testing,151 possibly as a result of residual problems with nonlateralized

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attention.155 Neglect, like dysphasia, is heterogeneous; different combinations of lateralized and nonlateralized attentional and motor deficits are identifiable in each patient. A number of techniques have been shown to improve lateralized spatial representation, including caloric stimulation156,157; contralesional neck muscle vibration, in one trial with scanning training158; prism adaptation159; and contralesional limb activation,160 as well as alerting techniques to increase nonlateralized loss of attentional capacity.161 Some of these techniques have also been reported to improve activities of daily living, notably neck muscle vibration with scanning training158 and prism adaptation,162 and contralesional limb activation in one study reduced length of stay by 24 days.150 Whether a treatment battery tailored to the neglect subtypes present in each patient163,164 will prove sufficiently practical and robust to produce significant functional benefits, not yet evident in the literature on systematic review,165 remains to be explored. In the context of stroke, use-dependent neural reorganization after damage is facilitated by other extrinsic and intrinsic inputs that modulate neural excitability and augment long-term synaptic potentiation. Use-dependent network remodeling at cellular and systems levels is also likely to be needed for the successful application of techniques to promote neural regrowth and/or replacement.166,167 Adjunctive facilitators of this process include manipulation of attention168; increase or decrease of somatosensory input, shown to improve swallowing169 and leg170 and arm122 function; neuromodulatory drugs171; electrical172 and magnetic173 stimulation of the brain; and possibly exercise.174 Pharmacological facilitation and inhibition of neurological recovery after stroke are also likely to be of clinical relevance. The use-dependent plasticity that underpins motor training and perceptual learning is dependent on N-methyl-D-aspartate receptor activation and γ-amino butyric acid–mediated (GABAergic) inhibition,175,176 and these are in turn modulated by cholinergic, noradrenergic, serotonergic, and dopaminergic transmitter systems.171 Early experiments by Feeney and coworkers177 in rats showed that motor recovery after suction ablation of the sensorimotor cortex was improved by amphetamine before practice on a beam-walking task; neither practice nor amphetamine alone had any benefit. Subsequently, α2 antagonists, increasing noradrenergic effects, were found to facilitate motor recovery, and α1 antagonists and α2 agonists, which decrease norepinephrine release or block its postsynaptic effects, reinstate deficit in clinically recovered animals or slow their recovery.178,179 There is also evidence that modulation of other neurotransmitter systems has similar effects.180 The beneficial effect of these pharmacological interventions is dose dependent, and the timing of administration is likely to be important, the effect being dependent on close temporal linkage to behavioral experience. In animals, there is a strong correlation between the functional effects of altering levels of various neurotransmitters and their ability to facilitate increases in synaptic efficacy through long term potentiation.180 Attempts have been made to translate these findings into treatments for stroke patients. In the first clinical trial of noradrenergic enhancement coupled with physical therapy, patients who had suffered from hemiplegic stroke were randomly assigned to receive either 10 mg of dextroamphetamine or placebo 45 minutes before physiotherapy.181 Follow-up assessment 24 hours after treatment revealed a 40% improvement from baseline scores with dextroamphetamine in comparison with placebo. Small numbers of patients in this study made interpretation difficult. A subsequent failure to replicate

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these findings by Borucki and associates182 was attributed to a different experimental design, particularly a failure to schedule physiotherapy immediately after amphetamine treatment. More recent studies with dextroamphetamine have had conflicting results,183,184 but positive results have been published for daily doses of levodopa (100 mg) used in conjunction with physiotherapy.185 Studies of the effects of drugs used in conjunction with speech therapy have yielded some success.186 Although larger scale studies are under way, the use of pharmacological agents to facilitate the effects of physical and speech therapy is currently only experimental. Conversely, there is some evidence to suggest that patients receiving drugs that reduce the effects of norepinephrine or dopamine, or increase the effects of GABA, at the time of stroke or shortly afterward have poorer outcomes than do patients who do not receive any of these drugs187; thus, care must be taken in their prescription. Maladaptive or ineffective neural reorganization after stroke may contribute to emotionalism, central poststroke pain (CPSP), and involuntary movement disorders, which include hemiballismus, hemichoreoathetosis, distal resting and/or action tremor, and proximal postural tremor. CPSP, originally described in 1906 as a phenomenon after thalamic stroke by Dejerine and Roussy,188 was found in 16 (8%) of 207 hospitalized stroke patients 6 months after stroke by Andersen and colleagues.48,49 Pain may result from stroke involving spinothalamocortical afferent pathways in the medulla, pons, midbrain, thalamus, subcortical white matter, and cortex. Leijon and colleagues189 found in 27 patients with CPSP that the thalamus was involved in only 9, lesions were in the lower brainstem in 8 and lateral and superior to the thalamus in 6, and onset of the pain was delayed by more than a month in 13 patients. The pain was described as “burning, aching, pricking, and lacerating”; the intensity was increased by external stimuli, either noxious (hyperalgesia) or not noxious (allodynia), the most common being joint movements, cold and light touch, and, in five patients, emotional stimuli. All patients had decreased temperature sensation. Hypersensitivity to cutaneous stimuli was found in 88% of the patients, and sensations of touch and vibration were abnormal in only 52% and 41%, respectively. There were also relatively low incidences of weakness and ataxia, which were present in 48% and 62%, respectively. Treatments in individual patients include all the drugs and physical methods used for neuropathic pain in general; descending modulation of pain pathways by electrical motor cortex stimulation,190 rather than deep brain stimulation,191 and more recently repetitive TMS over the hand area of the motor cortex192 have shown some promise in the treatment of CPSP. Both deep brain stimulation and electrical motor cortex stimulation have been used with some success to treat poststroke movement disorders,191 whereas antidepressants are effective in treating emotionalism.192–194

MANAGEMENT OF SYSTEMIC COMPLICATIONS In a prospective study of 311 consecutive patients recruited within 7 days of stroke onset, Langhorne and colleagues195 recorded complications in 85% of the patients during hospital admission (see Table 48–3); 6, 18, and 30 months after discharge, there was a high frequency of infections, falls, unexplained blackouts, pain, and symptoms of depression and anxiety. Seizures and chest infections tend to occur soon after admission; other common complications, including venous thromboem-

bolism, skin breakdown, urinary tract infections, falls, and depression, are still occurring at 30 days.196 More than 60% of patients have more than one complication during inpatient rehabilitation, and complications are more common with increasing age, stroke severity, premorbid disability, and low serum albumin level.195-197 The occurrence of a complication is more likely to be associated with death,196 and the causes of death most likely to be prevented by stroke unit care are those resulting from immobility, particularly as a result of infection and venous thromboembolism. More recently, emphasis on acute care after stroke has begun to define potentially avoidable complications that cause disordered physiological homeostasis acutely and may affect mortality rates, morbidity, length of stay, and longer-term outcome31,32,198; these include airway patency and disordered breathing (lowering blood oxygenation), cardiac problems, blood pressure control, temperature regulation, and glycemic control.30 The prevention and early treatment of the acute, early, and later systemic complications of stroke are thus an important aspect of organized multidisciplinary care and rehabilitation after stroke. They require at least easy access to acute care and diagnostic facilities,196,197 if not high-dependency care in the acute phase for some patients, with continuous monitoring of cardiac, respiratory, metabolic, and neurological functions during the first 72 hours after stroke. Venous thromboembolism was once common after stroke; symptomatic and asymptomatic deep vein thrombosis and pulmonary embolism were present in up to 70% of, respectively, all patients and those studied post mortem.200 In contrast, nearly 20 years later, Kelly and associates200,201 found that in 102 unselected patients receiving stroke unit care, aspirin, and compressive therapy with stockings, symptomatic deep vein thrombosis and pulmonary embolism occurred in only 3% and 5% of patients, respectively; however, noninvasive magnetic resonance direct thrombus imaging revealed the prevalence of venous thromboembolism, deep vein thrombosis, and pulmonary embolism to be high (40%, 18%, and 12%, respectively, and increasing to 63%, 30%, and 20%) in nonambulatory patients with a Barthel Index score of 9 two days after stroke. In the context of early mobilization and stroke unit care, either aspirin or low-dose unfractionated heparin has been shown to reduce the frequency of symptomatic pulmonary embolism to below 1%.203,204 Because there is no evidence that routine low-dose subcutaneous lowmolecular-weight heparin is superior to aspirin in preventing pulmonary embolism or deep vein thrombosis,205 current guidelines for routine venous thromboprophylaxis (e.g., Royal College of Physicians12) recommend aspirin, early mobilization, and, for patients with leg weakness, graduated compression stockings, which prevented deep vein thrombosis in all hospitalized patients in one study205 but for which there is insufficient evidence at present to show that this is the case after stroke.206 Factors thought to confer higher risk, such as previous deep vein thrombosis or pulmonary embolism, necessitate individualized treatment decisions, and management in other high-risk groups, such as those initially nonambulatory after stroke, probably requires further definition (e.g., Kelly et al201,202). The detraining effects of immobility and reduced activity208 compound the increased difficulty in completing activities of daily living that results from comorbid musculoskeletal and cardiorespiratory dysfunction and from the increased aerobic requirements of walking that are secondary to neurological impairments. Even in normal people, bed rest for 4 to 6 weeks results in a loss in exercise capacity of 0.9% per day209 and a

chapter 48 rehabilitation after stroke decrease in muscle strength of up to 40%.210 After stroke, exercise capacity is reduced to about 60% of normal at 1 month,211 making the performance of activities of daily living effortful and fatiguing. Although activities of daily living exert a training effect, so that exercise capacity improves, it remains reduced at 6 months212 and probably in the long term. Activity intolerance is thus common among stroke survivors, who may work close to their individual maximal exercise capacity while engaged only in domestic chores, in comparison with age- and weightmatched controls.213 Either aerobic training214 or muscle strengthening215,216 or both217 usually improve targeted physiological outcomes and sometimes balance, walking speed, and distance, but not consistently activities of daily living136,218; this finding is sufficient to contribute to recommendations for exercise after stroke from the American Heart Association.219 Detraining is likely to be one of the factors contributing to poststroke fatigue, which occurs in 40% to 70% of patients late after stroke in community studies,220-222 and patient-derived stroke-specific, health-related quality-of-life measures identify lack of energy as one of the four most consequential problems, together with those related to physical, psychosocial, and communication difficulties.223,224 Despite its relevance to quality of life, the natural history, causes, and management of poststroke fatigue remain underinvestigated. It often occurs independently of prestroke fatigue and depression and poststroke depression220,221,225 as “primary” poststroke fatigue, possibly resulting from stroke-disordered attention,226 or in association with physical impairment,221 psychological factors, sleep-disordered breathing and obstructive sleep apnea,227 or incidental systemic comorbid conditions. Management clearly starts with accurate differential diagnosis, but there are no guidelines to direct management of primary poststroke fatigue or evidence that modafinil, which may228 or may not229 be of benefit in multiple sclerosis, is of benefit after stroke. During hospital admission after stroke, patients suffering from undernutrition have a greater risk of pneumonia, other infections, and gastrointestinal bleeding than that in other patients.230 A higher risk of chest infection and poor nutritional status within the first month after stroke is predicted by abnormal swallowing, which is also associated with increased disability, length of hospital stay, and institutional care and is an independent predictor of mortality during the first 6 months after stroke61,62; rates of death from pneumonia over the longer term are also higher if dysphagia persists.231 Although the prevention of chest infections remains problematic, the prevention of undernutrition in hospital has been clarified. Routine oral supplementation versus no supplementation in admitted stroke patients could not be shown to reduce death or poor outcome when the rate of malnutrition on admission was only 8%232; whether it would with the higher rates of malnutrition on admission of about 40% reported before 1995233 has not been investigated. Nasogastric tube feeding within a week of stroke reduces the mortality rate,66 probably by preventing malnutrition, as it does in other groups of vulnerable hospitalized patients,234 rather than by reducing the incidence of chest infections, which nonetheless occurred, for example, in 44% of nasogastrically fed patients reported by Dziewas and colleagues.235 Pain after stroke is most often musculoskeletal in origin, rather than CPSP, and the result of an exacerbation of preexisting osteoarthritis and/or reduced movement and mobility caused by the stroke. Shoulder pain occurs in more than 60% of patients during the 6 months after stroke and its incidence

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may increase after discharge.236 Its occurrence is correlated with prestroke shoulder pain, severe upper limb weakness, neglect, sensory loss, visual field defects, and glenohumeral subluxation, but their role in its pathogenesis remains uncertain, and shoulder subluxation is not clearly a cause. Vasomotor changes in the limb, shoulder-hand syndrome, and reflex sympathetic dystrophy may also be present but should not be confused with the painful shoulder, and other disorders of the shoulder including fractures should be ruled out. Shoulder pain causes considerable morbidity and, once established, is difficult to treat. Prevention, particularly in patients at high risk, should include support of the flaccid arm237 and appropriate handling techniques to avoid traction injury. Treatment is likely to be determined partly by the tone in shoulder muscles238: A flaccid shoulder requires support at all times and possibly benefits from functional electrical stimulation (e.g., Renzenbrink and IJzerman239), whereas a spastic shoulder requires maintenance of range of motion by physical techniques and possibly the addition of botulinum toxin. Local steroid injection should be avoided unless there is clear evidence of an inflammatory component to the pain. There is a high cumulative incidence of psychiatric disorder after stroke. It can be difficult to diagnose in the presence of speech disturbance, anosognosia, and abulia, and it includes major and minor depression, agoraphobia, social withdrawal, apathy and self-neglect, irritability, and pathological emotionalism. However, in 128 community-dwelling patients during the first year after stroke, House and colleagues240 found that little of it persisted, and only two cases of major depression manifested during the whole 12 months. This frequency is lower than that found in other studies: for example, about 25% in a rehabilitation unit within 3 months after stroke241 and 15% in community-dwelling patients 4 months after stroke in the study by Burvill and colleagues242 in Perth, Australia. There remains a suggestion that left-sided anterior strokes affecting frontal-subcortical circuits predispose to depression,243,244 but the majority of studies emphasize that the major risk factors for depression are nonspecific, of the sort seen in older people with other physical illness,245 and they include a history of previous depression, stroke severity, physical dependency, and social inactivity.48,49,246 Over the longer term, any association between stroke and depressive symptoms is attributable largely to physical limitations.247 Although depression soon after stroke probably reduces later functional outcome248 and its presence 1 year later is clearly related to a reduced quality of life,6 two systematic reviews revealed that the evidence of benefit from early prevention or diagnosis and treatment was minimal.249,250

FUTURE DEVELOPMENTS Further research and development in rehabilitation after stroke should continue to focus on maximizing effective service delivery and investigating new organizational systems and restorative techniques and their transfer into routine clinical use. Because of the evidence for the effectiveness of comprehensive acute and rehabilitation stroke unit care and subsequent supported discharge and intervention in the community, and the national recommendations and guidelines that this evidence makes possible, these service delivery systems of care and rehabilitation can be available to a greater proportion of patients admitted after stroke, particularly when linked to an

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explicit multisite audit of the organization and process of stroke care of the sort undertaken at intervals by the Royal College of Physicians of London.251 Linkage of these stroke care systems into networks will be gradually developed to facilitate multicenter clinical research, hasten enlargement of the interventional evidence base,252 and promote the delivery of coordinated rather than fragmented systems of care.18 Parallel networks aiming to facilitate the transfer of proof-of-principle studies in the translational restorative neurosciences, while the pharmaceutical industry continues to focus on new methods of neural protection, are likely to follow. It is now established that the characteristic features of comprehensive stroke unit care include a standardized protocol for acute assessment, intermittent monitoring, medical treatments, and a strategy for the prevention of complications through the work of a multidisciplinary team integrating medical care, nursing, and rehabilitation. Clinical research networks will enable exploration of the effectiveness of further aspects of plant and process that contribute to outcome, including the usefulness of acute continuous physiological monitoring32; other strategies to detect and prevent complications, such as very early mobilization253; and further definition of the aspects of acute and early goal-focused interdisciplinary rehabilitation that optimize functional outcome.17 Since the mid-1990s, the neural reorganization that takes place longitudinally in response to damage and its relation to functional recovery have become better understood.254 This understanding has, for example, provided a biological rationale for the efficacy of task-related training and the need for intensive therapy, and it has led to investigations of how and whether other drivers of neural reorganization can increase function. Although these techniques may reduce impairments in the laboratory and at the proof-of-principle level, the generation of robust functional gains remains elusive, and their introduction and relevance to the clinical domain remain unclear.255 Exploration of how restorative techniques can be applied clinically to generate functionally relevant neural reorganization, regrowth, and repair through novel technologies and drugs, alone or in combination, and in the context of task-related training is a journey of universal interest.

K E Y

P O I N T S

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Organized care reduces mortality and morbidity.

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The effects of unit-based care far exceed the benefit of any drug.

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Further developments in acute care systems are likely to improve outcome.

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Goal-focused interdisciplinary training is a fundamental part of inpatient and community-based rehabilitation.

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Gains are achieved through the prevention of complications and through functional compensation and neural restoration.

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Lesion-induced neural reorganization is functionally relevant.

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Clinical applications for drivers of use-dependent neural reorganization require further investigation.

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Neural replacement and regeneration techniques are likely to be use- and activity-dependent.

Suggested Reading Dobkin BH: Neurobiology of rehabilitation. Ann N Y Acad Sci 2004; 1038:148-170. Greenwood R, Barnes MP, McMillan TM, et al, eds: Handbook of Neurological Rehabilitation. London: Psychology Press, 2003. McCrum R: My Year Off; Rediscovering Life after a Stroke. London: Picador, 1998. Warlow C, Dennis MS, van Gijn J, et al, eds: Stroke. A Practical Guide to Management. London: Blackwell, 2003. World Health Organization: The International Classification of Functioning, Disability and Health—ICF. Geneva: World Health Organization, 2002. http://www.who.int/classification/icf.

References 1. Stewart JA, Dundas R, Howard RS, et al: Ethnic differences in incidence of stroke: prospective study with stroke register. BMJ 1999; 318:967-971. 2. Feigin VL, Lawes CMM, Bennett DA, et al: Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th Century. Lancet Neurol 2003; 2:43-53. 3. Martin J, Meltzer H, Elliot D: OPCS surveys of disability in Great Britain. Report 1. In: The Prevalence of Disability among Adults. London: HMSO, Office of Population Censuses and Surveys, 1988. 4. Wolfe CDA: The impact of stroke. Br Med Bull 2000; 56:275286. 5. Thorngren M, Westling B, Norrving B: Outcome after stroke in patients discharged to independent living. Stroke 1990; 21:236-240. 6. Kauhanen ML, Korpelainen JT, Hiltunen P, et al: Domains and determinants of quality of life after stroke caused by brain infarction. Arch Phys Med Rehabil 2000; 81:1541-1546. 7. Patel A, Duncan P, Lai S, et al: The relation between impairments and functional outcomes poststroke. Arch Phys Med Rehabil 2000; 81:1357-1363. 8. Mayo NE, Wood-Dauphinee S, Côté R, et al: Activity, participation and quality of life 6 months post stroke. Arch Phys Med Rehabil 2002; 83:1035-1042. 9. Dewey HM, Thrift AG, Mihalopoulos C, et al: Lifetime cost of stroke subtypes in Australia: findings from the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke 2003; 34:2502-2507. 10. Wardlaw JM, del Zoppo G, Yamaguchi T, et al: Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003; (3):CD000213. 11. Fuhrer MJ: Subjective well-being: implications for medical rehabilitation outcomes and models of disablement. Am J Phys Med Rehabil 1994; 73:358-64 12. Royal College of Physicians: National Clinical Guidelines for Stroke, 2nd ed. Available at: http://www.rcplondon.ac.uk/pubs/ books/stroke/stroke_guidelines_2ed.pdf (accessed January 30, 2006). 13. Scottish Intercollegiate Guidelines Network (SIGN). Management of Patients with Stroke. Available at: www.sign.ac.uk/ guidelines/published/index.html (accessed January 30, 2006). 14. National Stroke Foundation (Australia). National Clinical Guidelines for acute stroke management, 2003. http://www.strokefoundation.com.au (accessed January 30, 2006). 15. Department of Veterans Affairs and Department of Defense: VA/DoD Clinical Practice Guideline for the Management of Stroke Rehabilitation. Washington, DC: Department of Veterans Affairs and Department of Defense, 2003.

chapter 48 rehabilitation after stroke 16. Duncan PW, Horner RD, Reker DM, et al: Adherence to postacute guidelines is associated with functional recovery in stroke. Stroke 2002; 33:167-178. 17. Meijer R, Ihnenfeldt D, Vermeulen M, et al: The use of a modified Delphi procedure for the determination of 26 prognostic factors in the sub-acute stage of stroke. Int J Rehabil Res 2003; 26:265-270. 18. Schwamm LH, Pancioli A, Acker JE III, et al: Recommendations for the establishment of stroke systems of care: recommendations from the American Stroke Association’s Task Force on the Development of Stroke Systems. Stroke 2005; 36:690-703. 19. Shah E, Harwood R: Acute Management: Admission to Hospital in Stroke: Epidemiology, Evidence and Clinical Practice, 2nd ed. Oxford, UK: Oxford University Press, 1999. 20. Aboderin I, Venables G: Stroke management in Europe. Pan European consensus meeting on stroke management. J Intern Med 1996; 240:173-180. 21. Kalra L, Evans A, Perez I, et al: Alternative strategies for stroke care: a prospective randomised controlled trial. Lancet 2000; 356:894-899. 22. Stroke Unit Trialists’ Collaboration: Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev 2001; (3):CD000197. 23. Langhorne P, Duncan P: Does the organization of postacute stroke care really matter? Stroke 2001; 32:268-274. 24. Stroke Unit Trialists’ Collaboration: How do stroke units improve patient outcomes? A collaborative systematic review of the randomized trials. Stroke 1997; 28:2139-2144. 25. Langhorne P, Pollock A: What are the components of effective stroke unit care? Age Ageing 2002; 31:365-371. 26. Evans A, Perez I, Harraf F, et al: Can differences in management processes explain different outcomes between stroke unit and stroke-team care? Lancet 2001; 358:1586-1592. 27. Wood-Dauphinee S, Shapiro S, Bass E, et al: A randomized trial of team care following stroke. Stroke 1984; 15:864-872. 28. van der Walt A, Gilligan AK, Cadilhac DA, et al: Quality of stroke care within a hospital: effects of a mobile stroke service. Med J Aust 2005; 182:160-163. 29. Brown DL, Haley LH: Post-emergency department management of stroke. Emerg Med Clin North Am 2002; 20:687702. 30. Adams H P, Adams R J, Brott T, et al: Guidelines for the early management of patients with ischemic stroke. Stroke 2003; 34:1056. 31. Sulter G, Elting JW, Langedijk M, et al: Admitting acute ischemic stroke patients to a stroke care monitoring unit versus a conventional stroke unit: a randomized pilot study. Stroke, 2003; 34:101-104. 32. Silva Y, Puigdemont M, Castellanos M, et al: Semi-intensive monitoring in acute stroke and long-term outcome. Cerebrovasc Dis 2005; 19:23-30. 33. Indredavik B, Bakke F, Slordahl SA, et al: Stroke unit treatment. 10-year follow-up. Stroke 1999; 30:1524-1527. 34. Lincoln NB, Husbands S, Trescoli C, et al: Five year follow up of a randomised controlled trial of a stroke rehabilitation unit. BMJ 2000; 320:549 35. Langhorne P, Taylor G, Murray G, et al: Early supported discharge services for stroke patients: a meta-analysis of individual patients’ data. Lancet 2005; 365:501-506. 36. Fjaertoft H, Indredavik B, Johnsen R, et al: Acute stroke unit care combined with early supported discharge. Long-term effects on quality of life. A randomized controlled trial. Clin Rehabil 2004; 18:580-586. 37. Thorsén AM, Holmqvist LW, de-Pedro CJ, et al: A randomized controlled trial of early supported discharge and continued rehabilitation at home after stroke: five-year follow-up of patient outcome. Stroke 2005; 36:297-303.

655

38. Hopman WM, Verner J: Quality of life during and after inpatient stroke rehabilitation. Stroke 2003; 34:801-805. 39. Kramer AM, Steiner JF, Schlenker RE, et al: Outcomes and costs after hip fracture and stroke: a comparison of rehabilitation settings. JAMA 1997; 277:396-404. 40. Outpatient Therapy Trialists: Rehabilitation therapy services for stroke patients living at home: systematic review of randomised trials. Lancet 2004; 363:352-356. 41. Walker MF, Leonardi BJ, Bath P, et al: Individual patient data meta-analysis of randomized controlled trials of community occupational therapy for stroke patients. Stroke 2004; 35:2226-2232. 42. Steultjens EMJ, Dekker J, Bouter LM, et al: Occupational therapy for stroke patients: a systematic review. Stroke 2003; 34:676-687. 43. Anderson C, Mhurcha CN, Rubenach S, et al: Home or hospital for stroke rehabilitation? Results of a randomised controlled trial. 1: health outcomes at 6 months. Stroke 2000; 31:1024-1031. 44. Young JB, Forster A: The Bradford community stroke trial: results at six months. BMJ 1992; 304:1085-1089. 45. Young J, Forster A: Day hospital and home physiotherapy for stroke patients: a comparative cost-effectiveness study. J R Coll Physicians Lond 1993; 27:252-258. 46. Green J, Young J, Forster A, et al: Combined analysis of two randomized trials of community physiotherapy for patients more than one year post stroke. Clin Rehabil 2004; 18:249252. 47. Hancock R, Jarvis C: The Long Term Effects of Being a Carer. London: HMSO, 1994. 48. Andersen G, Vestergaard K, Ingemann-Nielsen M, et al: Risk factors for post-stroke depression. Acta Psychiatr Scand 1995; 92:193-198. 49. Morris PL, Robinson RG, Raphael B, et al: The relationship between the perception of social support in post-stroke depression in hospitalised patients. Psychiatry 1991; 54:306316. 50. Christie D, Weigall D: Social work effectiveness in two-year stroke survivors: a randomised controlled trial. Community Health Stud 1984; 8:26-32. 51. Friedland JF, McColl M: Social support interventions after stroke: results of a randomised trial. Arch Phys Med Rehabil 1992; 73:573-581. 52. Forster A, Young J: Specialist nurse support for patients with stroke in the community: a randomised controlled trial. BMJ 1996; 312:1642-1646. 53. Dennis M, O’Rourke S, Slattery J, et al: Evaluation of a stroke family careworker: results of a randomised controlled trial. BMJ 1997; 314:1071-1076. 54. Mant J, Carter J, Wade DT, et al: Family support for stroke: a randomised controlled trial. Lancet 2000; 356:808813. 55. Lincoln NB, Francis VM, Lilley SA, et al: Evaluation of a stroke family support organiser. A randomised controlled trial. Stroke 2003; 34:116-121. 56. Boter H, for the HESTIA Study Group: Multicenter randomized controlled trial of an outreach nursing support program for recently discharged stroke patients. Stroke 2004; 35:28672872. 57. Glass TA, Berkman LF, Hiltunen EF, et al: The Families In Recovery From Stroke Trial (FIRST): primary study results. Psychosom Med 2004; 66:889-897. 58. Grant JS, Elliott TR, Weaver M, et al: Telephone intervention with family caregivers of stroke survivors after rehabilitation. Stroke 2002; 33:2000-2065. 59. Kalra L, Evans A, Perez I, et al: Training carers of stroke patients: randomised controlled trial. BMJ 2004; 328:10991101.

656

Section

IX

C e r e b r o va s c u l a r D i s e a s e

60. Patel A, Knapp M, Evans A, et al: Training care givers of stroke patients: economic evaluation. BMJ 2004; 328:1102-1104. 61. Smithard D, O’Neill P, Park C, et al: Complications and outcome after acute stroke: does dysphagia matter? Stroke 1996; 27:1200-1204. 62. Mann G, Hankey GJ, Cameron D: Swallowing function after stroke. Prognosis and prognostic factors at 6 months. Stroke 1999; 30:744-748. 63. Splaingard ML, Hutchins B, Sulton LD, et al: Aspiration in rehabilitation patients: videofluoroscopy vs bedside clinical assessment. Arch Phys Med Rehabil 1988; 69:637-640. 64. Leder SB, Espinosa JF: Aspiration risk after acute stroke: comparison of clinical examination and fiberoptic endoscopic evaluation of swallowing. Dysphagia 2002; 17:214-218. 65. Odderson IR, Keaton JC, McKenna BS: Swallow management in patients on an acute stroke pathway: quality is cost effective. Arch Phys Med Rehabil 1995; 76:1130-1133. 66. Dennis MS, Lewis SC, Warlow C: Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial. Lancet 2005; 365:764-772. 67. Stroud M, Duncan H, Nightingale J: Guidelines for enteral feeding in adult hospital patients. Gut 2003; 52(Suppl 7):vii1vii12. 68. Brittain KR, Peet SM, Castleden CM: Stroke and Incontinence. Stroke 1998; 29:524-528. 69. Nakayama H, Jørgensen HS, Pedersen PM, et al: Prevalence and risk factors of incontinence after stroke. The Copenhagen stroke study. Stroke 1997; 28:58-62. 70. Jørgensen L, Engstad T, Jacobsen BK: Self-reported urinary incontinence in noninstitutionalized long-term stroke survivors: A population-based study. Arch Phys Med Rehabil 2005; 86:416-420. 71. Gelber DA, Good DC, Laven LJ, et al: Causes of urinary incontinence after acute hemisphere stroke. Stroke 1993; 24:378382. 72. Barrett JA: Bladder and bowel problems after a stroke. Rev Clin Gerontol 2001; 12:253-267 73. Barer DH: Continence after stroke: useful predictor or goal of therapy? Age Ageing 1989; 18:183-191. 74. Patel M, Coshal C, Lawrence E, et al: Recovery from poststroke urinary incontinence: associated factors and impact on outcome. J Am Geriatr Soc 2001; 49:1229-1233. 75. Burney TL, Senepati M, Desai S, et al: Acute cerebrovascular accident and lower urinary tract dysfunction: a prospective correlation of the site of brain injury with urodynamic findings. J Urol 1996; 156:1748-1750. 76. Marinkovic S, Badlani G: Voiding and sexual dysfunction after cerebrovascular accidents. J Urol 2001; 165:359-370. 77. Eustice S, Roe B, Paterson J: Prompted voiding for the management of urinary incontinence in adults. Cochrane Database Syst Rev 2000; (2):CD002113. 78. Ostaszkiewicz J, Johnston L, Roe B: Timed voiding for the management of urinary incontinence in adults. Cochrane Database Syst Rev 2004; (1):CD002802. 79. Middaugh SJ, Whitehead WE, Burgio KL, et al: Biofeedback in treatment of urinary incontinence in stroke patients. Biofeedback Self Regul 1989; 14:3-19. 80. Tibaek S, Jensen R, Lindskov G, et al: Can quality of life be improved by pelvic floor muscle training in women with urinary incontinence after ischemic stroke? A randomised, controlled and blinded study. Int Urogynecol J Pelvic Floor Dysfunct 2004; 15:117-123. 81. Cooper ZR, Rose S: Fecal incontinence: a clinical approach. Mount Sinai J Med 2000; 67:96-105. 82. Harari D, Coshall C, Rudd AG, et al: New-onset fecal incontinence after stroke: prevalence, natural history, risk factors, and impact. Stroke 2003; 34:144-150.

83. Harari D, Norton C, Lockwood L, et al: Treatment of constipation and fecal incontinence in stroke patients: randomized controlled trial. Stroke 2004; 35:2549-2555. 84. Franchignoni FP, Tesio L, Ricupero C, et al: Trunk control test (TCT) as an early predictor of stroke rehabilitation outcome. Stroke 1997; 28:1382-1385. 85. Hsieh CL, Sheu CF, Hsueh IP, et al: Trunk control as an early predictor of comprehensive activities of daily living function in stroke patients. Stroke 2002; 33:2626-2630. 86. Sandin KJ, Smith BS: The measure of balance in sitting in stroke rehabilitation prognosis. Stroke 1990; 21:82-86. 87. Feigin L, Sharon B, Czaczkes B, et al: Sitting equilibrium 2 weeks after a stroke can predict the walking ability after 6 months. Gerontology 1996; 42:348-353. 88. Mudie MH, Winzeler-Mercay U, Radwan S, et al: Training symmetry of weight distribution after stroke: a randomized controlled pilot study comparing task-related reach, Bobath and feedback training approaches. Clin Rehabil 2002; 16:582592. 89. Dietz V: Spastic movement disorder: what is the impact of research on clinical practice? J Neurol Neurosurg Psychiatry 2003; 74:820-821. 90. O’Dwyer NJ, Ada L, Neilson PD: Spasticity and muscle contracture following stroke. Brain 1996; 119:17371749. 91. Sommerfeld DK, Eek EUB, Svensson AK, et al: Spasticity after stroke: its occurrence and association with motor impairments and activity limitations. Stroke 2004; 35:134139. 92. Ada L, Vattanasilp W, O’Dwyer NJ, et al: Does spasticity contribute to walking dysfunction after stroke? J Neurol Neurosurg Psychiatry 1998; 64:628-663. 93. Burne JA, Carleton VL, O’Dwyer NJ: The spasticity paradox: movement disorder or disorder of resting limbs? J Neurol Neurosurg Psychiatry 2005; 76:47-54. 94. Sheean GL: Pathophysiology of spasticity. In Sheean GL, ed: Spasticity Rehabilitation. London: Churchill Communications Europe, 1998, pp 17-38. 95. Bhakta BB, Cozens JA, Chamberlain MA, et al: Impact of botulinum toxin type A on disability and carer burden due to arm spasticity after stroke: a randomised double blind placebo controlled trial. J Neurol Neurosurg Psychiatry 2000; 69:217221. 96. Meythaler JM, Guin-Renfroe S, Brunner RC, et al: Intrathecal baclofen for spastic hypertonia from stroke. Stroke 2001; 32:2099-2109. 97. Brashear A, Gordon MF, Elovic E, et al: Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002; 347:395-400. 98. Fukuhara T, Kamata I: Selective posterior rhizotomy for painful spasticity in the lower limbs of hemiplegic patients after stroke: report of two cases. Neurosurgery 2004; 54:12681273. 99. Francis HP, Wade DT, Turner-Stokes L, et al: Does reducing spasticity translate into functional benefit? An exploratory meta-analysis. J Neurol Neurosurg Psychiatry 2004; 75:15471551. 100. Gordon MF, Brashear A, Elovic E, et al: Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 2004; 63:1971-1973. 101. Hesse S, Lucke D, Malezic M, et al: Botulinum toxin treatment for lower limb extensor spasticity in chronic hemiparetic patients. J Neurol Neurosurg Psychiatry 1994; 57:1321-1324. 102. Hesse S, Krajnik J, Luecke D, et al: Ankle muscle activity before and after botulinum toxin therapy for lower limb extensor spasticity in chronic hemiparetic patients. Stroke 1996; 27:455-60

chapter 48 rehabilitation after stroke 103. Richardson D, Sheean G, Werring D, et al: Evaluating the role of botulinum toxin in the management of focal hypertonia in adults. J Neurol Neurosurg Psychiatry 2000; 69:499-506. 104. Thompson AJ, Jarrett L, Lockley L, et al: Clinical management of spasticity. J Neurol Neurosurg Psychiatry 2005; 76:459-463. 105. Landau WM: Spasticity: the fable of a neurological demon and the emperor’s new therapy [Editorial]. Arch Neurol 1974; 31:217-219. 106. Dobkin BH: Strategies for stroke rehabilitation. Lancet Neurol 2004; 3:528-536. 107. Langhorne P, Wagenaar RC, Partridge C: Physiotherapy after stroke: more is better? Physiother Res Int 1996; 1:75-88. 108. Kwakkel G, Wagenaar RC, Koelman TW, et al: Effects of intensity of rehabilitation after stroke. Stroke 1997; 28:15501556. 109. Kwakkel G, van Peppen R, Wagenaar RC, et al: Effects of augmented exercise therapy time after stroke. A meta-analysis. Stroke. 2004; 35:2529-2539. 110. Dean CM, Shepherd RB: Task-related training improves performance of seated reaching tasks after stroke. A randomized controlled trial. Stroke 1997; 28:722-728. 111. Langhammer B, Stanghelle JK: Bobath or motor relearning programme? A comparison of two different approaches of physiotherapy in stroke rehabilitation: a randomized controlled study. Clin Rehabil 2000; 14:361-369. 112. van Vliet PM, Lincoln NB, Foxall A: Comparison of Bobath based and movement science based treatment for stroke: a randomised controlled trial. J Neurol Neurosurg Psychiatry 2005; 76:503-508. 113. Nudo RJ, Wise BM, SiFuentes F, et al: Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996; 272:1791-1794. 114. Kempermann G, van Praag H, Gage FH: Activity-dependent regulation of neuronal plasticity and self repair. Prog Brain Res 2000; 127:35-48. 115. Boyd LA, Winstein CJ: Providing explicit information disrupts implicit motor learning after basal ganglia stroke. Learning Memory 2004; 11:388-396. 116. Hanlon RE: Motor learning following unilateral stroke. Arch Phys Med Rehabil 1996; 77:811-815. 117. Kwakkel G, Wagenaar RC, Twisk JWR, et al: Intensity of leg and arm training after primary middle-cerebral-artery stroke: a randomised trial. Lancet 1999; 354:191-196. 118. Hesse S, Schmidt H, Werner C, et al: Upper and lower extremity robotic devices for rehabilitation and for studying motor control. Curr Opin Neurol 2003; 16:705-710. 119. Lum PS, Taub E, Schwandt D, et al: Automated constraintinduced therapy extension (AutoCITE) for movement deficits after stroke. J Rehabil Res Dev 2004; 41:249-258. 120. Moseley AM, Stark A, Cameron ID, et al: Treadmill training and body weight support for walking after stroke. Cochrane Database Syst Rev 2003; (3):CD002840. 121. Deutsch JE, Merians AS, Adamovich S, et al: Development and application of virtual reality technology to improve hand use and gait of individuals post-stroke. Restor Neurol Neurosci 2004; 22:371-386. 122. Floel A, Nagorsen U, Werhahn KJ, et al: Influence of somatosensory input on motor function in patients with chronic stroke. Ann Neurol 2004; 56:206-212. 123. DeBow SB, Davies MLA, Clarke HL, et al: Constraint-induced movement therapy and rehabilitation exercises lessen motor deficits and volume of brain injury after striatal hemorrhagic stroke in rats. Stroke 2003; 34:1021-1026. 124. Miltner WH, Bauder H, Sommer M, et al: Effects of constraint-induced movement therapy on patients with chronic motor deficits after stroke: a replication. Stroke 1999; 30:586592.

657

125. Uswatte G, Taub E: Constraint-induced movement therapy: new approaches to outcome measurement in rehabilitation. In Stuss DT, Winocur G, Robertson IH, eds: Cognitive Neurorehabilitation: A Comprehensive Approach. Cambridge, UK: Cambridge University Press, 1999, pp 215-229. 126. Page SJ, Levine P, Leonard AC: Modified constraint-induced therapy in acute stroke: a randomized controlled pilot study. Neurorehabil Neural Repair 2005; 19:27-32. 127. Patten C, Lexell J, Brown HE: Weakness and strength training in persons with poststroke hemiplegia: rationale, method, and efficacy. J Rehab Res Dev 2004; 41:293-312. 128. de Wit DCM, Buurke JH, Nijlant JMM, et al: The effect of an ankle-foot orthosis on walking ability in chronic stroke patients: a randomized controlled trial. Clin Rehabil 2004; 18:550-557. 129. de Kroon JR, van der Lee JH, IJzerman MJ, et al: Therapeutic electrical stimulation to improve motor control and functional abilities of the upper extremity after stroke: a systematic review. Clin Rehabil 2002; 16:350-360. 130. Ring H, Rosenthal N: Controlled study of neuroprosthetic functional electrical stimulation in sub-acute post-stroke rehabilitation. J Rehabil Med 2005; 37:32-36. 131. Kottink AIR, Oostendorp LJM, Buurke JH, et al: The orthotic effect of functional electrical stimulation on the improvement of walking in stroke patients with a dropped foot: a systematic review. Artif Organs 2004; 28:577-586. 132. Peurala SH, Pitkänen K, Sivenius J, et al: Cutaneous electrical stimulation may enhance sensorimotor recovery in chronic stroke. Clin Rehabil 2002; 16:709-716. 133. Liu KP, Chan CC, Lee TM, et al: Mental imagery for promoting relearning for people after stroke: a randomized controlled trial. Arch Phys Med Rehabil 2004; 85:1403-1408. 134. Schauer M, Mauritz KH: Musical motor feedback (MMF) in walking hemiparetic stroke patients: randomized trials of gait improvement. Clin Rehabil 2003; 7:713-722. 135. Van Peppen RPS, Kwakkel G, Wood-Dauphinee S, et al: The impact of physical therapy on functional outcomes after stroke: what’s the evidence? Clin Rehabil 2004; 18:833862. 136. Kwakkel G, Kollen BJ, Wagenaar RC: Long term effects of intensity of upper and lower limb training after stroke: a randomised trial. J Neurol Neurosurg Psychiatry 2002; 72:473479. 137. Feys H, De Weerdt W, Verbeke G, et al: Early and repetitive stimulation of the arm can substantially improve the longterm outcome after stroke: a 5-year follow-up study of a randomized trial. Stroke 2004; 35:924. 138. Werner RA, Kessler S: Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients. Am J Phys Med Rehabil 1996; 75:114-120. 139. van der Lee JH, Wagenaar RC, Lankhorst GJ, et al: Forced use of the upper extremity in chronic stroke patients. Results from a single-blind randomized clinical trial. Stroke. 1999; 30:2369-2375. 140. Richards CL, Malouin F, Bravo G, et al: The role of technology in task-oriented training in persons with subacute stroke: a randomized controlled trial. Neurorehabil Neural Repair 2004; 18:199-211. 141. Bowler JV: Dementia after stroke [Editorial]. Stroke 2004; 35:1268-1269. 142. Pedersen PM, Jorgensen HS, Nakayama H, et al: Aphasia in acute stroke: incidence, determinants, and recovery. Ann Neurol 1995; 38:659-666. 143. Wade DT, Hewer RL, David RM, et al: Aphasia after stroke: natural history and associated deficits. J Neurol Neurosurg Psychiatry 1986; 49:11-16. 144. Robey R: The efficacy of treatment for aphasic persons: a meta-analysis. Brain Lang 1994; 47:582-608.

658

Section

IX

C e r e b r o va s c u l a r D i s e a s e

145. Holland A, Fromm D, DeRuyter F, et al: Treatment efficacy: aphasia. J Speech Hear Res 1996; 39:S27-S36. 146. Greener J, Enderby P, Whurr R: Speech and language therapy for aphasia following stroke. Cochrane Database Syst Rev 1999; (4):CD000425. 147. Bhogal SK, Teasell R, Speechley M: Intensity of aphasia therapy, impact on recovery. Stroke 2003; 34:987-993. 148. Doesborgh SJC, van de Sandt-Koenderman MWE, Dippel DWJ, et al: Effects of semantic treatment on verbal communication and linguistic processing in aphasia after stroke: a randomized controlled trial. Stroke 2004; 35:141146. 149. Pulvermüller F, Neininger B, Elbert T, et al: Constraintinduced therapy of chronic aphasia after stroke. Stroke 2001; 32:1621-1626. 150. Kalra L, Perez I, Gupta S, et al: The influence of visual neglect on stroke rehabilitation. Stroke 1997; 28:1386-1391. 151. Nys GMS, van Zandvoort MJE, de Kort PLM, et al: The prognostic value of domain-specific cognitive abilities in acute first-ever stroke. Neurology 2005; 64:821-827. 152. Pohjasvaara T, Leskelä M, Vataja R, et al: Post-stroke depression, executive dysfunction and functional outcome. Eur J Neurol 2002; 9:269-275. 153. Stone SP, Wilson B, Wroot A, et al: The assessment of visuospatial neglect after acute stroke. J Neurol Neurosurg Psychiatry 1991; 54:345-350. 154. Appelros P, Nydevik I, Karlsson GM, et al: Recovery from unilateral neglect after right-hemisphere stroke. Disabil Rehabil 2004; 26:471-477. 155. Mark VW: Acute versus chronic functional aspects of unilateral spatial neglect. Front Biosci 2003; 8:172-189. 156. Rubens AB: Caloric stimulation and unilateral visual neglect. Neurology 1985; 35:1019-1024. 157. Rode G, Perenin MT: Temporary remission of representational hemineglect through vestibular stimulation. Neuroreport 1994; 5:869-872. 158. Schindler I, Kerhoff G, Karnath H-O, et al: Neck muscle vibration induces lasting recovery in spatial neglect. J Neurol Neurosurg Psychiatry 2002; 73:412-419. 159. Frassinetti F, Angeli V, Meneghello F, et al: Long-lasting amelioration of visuospatial neglect by prism adaptation. Brain 2002; 125(Pt 3):608-623. 160. Robertson IH, Hogg K, McMillan TM: Rehabilitation of unilateral neglect: improving function by contralesional limb activation. Neuropsychol Rehabil 1998; 8:19-29. 161. Robertson IH, Mattingley JB, Rorden C, et al: Phasic alerting of neglect patients overcomes their spatial deficit in visual awareness. Nature 1998; 395:169-172. 162. Rode G, Pisella L, Rossetti Y, et al: Bottom-up transfer of sensory-motor plasticity to recovery of spatial cognition: visuomotor adaptation and spatial neglect. Prog Brain Res 2003; 142:273-287. 163. Buxbaum LJ, Ferraro MK, Veramonti T, et al: Hemispatial neglect. Subtypes, neuroanatomy, and disability. Neurology 2004; 62:749-756. 164. Parton A, Malhotra P, Husain M: Hemispatial neglect. J Neurol Neurosurg Psychiatry 2004; 75:13-21. 165. Bowen A, Lincoln NB, Dewey M: Cognitive rehabilitation for spatial neglect following stroke. Cochrane Database Syst Rev 2002; (2):CD003586. 166. Mattsson B, Sorensen JC, Zimmer J, et al: Neural grafting to experimental neocortical infarcts improves behavioral outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments. Stroke 1997; 28:1225-1231. 167. Cairns K, Finklestein SP: Growth factors and stem cells as treatments for stroke recovery. Phys Med Rehabil Clin North Am 2003; 14(1 Suppl):S135-S142.

168. Stefan K, Wycislo M, Classen J: Modulation of associative human motor cortical plasticity by attention. J Neurophysiol 2004; 92:66-72. 169. Fraser C, Power M, Hamdy S, et al: Driving plasticity in human adult motor cortex is associated with improved motor function after brain injury. Neuron 2002; 34:831-840. 170. Uy J, Ridding MC, Hillier S, et al: Does induction of plastic change in motor cortex improve leg function after stroke? Neurology 2003; 61:982-984. 171. Gu Q: Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience 2002; 111:815-835. 172. Hummel F, Celnik P, Giraux P, et al: Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 2005; 128:490-499. 173. Huang YZ, Edwards MJ, Rounis E, et al: Theta burst stimulation of the human motor cortex. Neuron 2005; 45: 201-206. 174. Cotman CW, Berchtold NC: Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002; 25:295-301. 175. Dinse HR, Ragert P, Pleger B, et al: Pharmacological modulation of perceptual learning and associated cortical reorganization. Science 2003; 301:91-94. 176. Dinse HR, Ragert P, Pleger B, et al: GABAergic mechanisms gate tactile discrimination learning. Neuroreport 2003; 14:1747-1751. 177. Feeney DM, Gonzalez A, Law WA: Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 1982; 217:855-857. 178. Sutton RL, Feeney DM: α-Noradrenergic agonists and antagonists affect recovery and maintenance of beam walking ability after sensorimotor cortex ablation in the rat. Restor Neurol Neurosci 1992; 4:1-11. 179. Feeney DM, De Smet AM, Rai S: Noradrenergic modulation of hemiplegia: facilitation and maintenance of recovery. Restor Neurol Neurosci 2004; 22:175-190. 180. Goldstein LB: Pharmacology of recovery after stroke. Stroke 1990; 21(11 Suppl):139-142. 181. Crisostomo EA, Duncan PW, Propst M, et al: Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol 1988; 23:9497. 182. Borucki SJ, Landberg J, Redding M: The effect of dextroamphetamine on motor recovery after stroke. Neurology 1992; 42(Suppl 3):329. 183. Walker-Batson D, Smith P, Curtis S, et al: Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Stroke 1995; 26:2254-2259. 184. Sonde L, Nordstrom M, Nilsson CG, et al: A double-blind placebo-controlled study of the effects of amphetamine and physiotherapy after stroke. Cerebrovasc Dis 2001; 12:253257. 185. Scheidtmann K, Fries W, Muller F, et al: Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 2001; 358:787-790. 186. Walker-Batson D, Curtis S, Natarajan R, et al: A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke 2001; 32:2093-2098. 187. Goldstein LB: Common drugs may influence motor recovery after stroke. The Sygen In Acute Stroke Study Investigators. Neurology 1995; 45:865-871. 188. Dejerine J, Roussy G: Le syndrome douloureux thalamique. Rev Neurol 1906; 14:521-532. 189. Leijon G, Boivie J, Johansson I: Central post-stroke pain— neurological symptoms and pain characteristics. Pain 1989; 36:13-25.

chapter 48 rehabilitation after stroke 190. Tsubokawa T, Katayama Y, Yamamoto T, et al: Chronic motor cortex stimulation in patients with thalamic pain. J Neurosurg 1993; 78:393-401. 191. Katayama Y, Yamamoto T, Kobayashi K, et al: Deep brain and motor cortex stimulation for post-stroke movement disorders and post-stroke pain. Acta Neurochir Suppl 2003; 87:121-123. 192. Lefaucheur JP, Drouot X, Menard-Lefaucheur I, et al: Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry 2004; 75:612-616. 193. Andersen G, Vestergaard K, Ingeman-Nielsen M, et al: Incidence of central post-stroke pain. Pain 1995; 61:187193. 194. House AO, Hackett ML, Anderson CS, et al: Pharmaceutical interventions for emotionalism after stroke. Cochrane Database Syst Rev 2004; (1):CD003690. 195. Langhorne P, Stott DJ, Robertson L, et al: Medical complications after stroke: a multicenter study. Stroke 2000; 31:12231229. 196. Davenport RJ, Dennis MS, Wellwood I, et al: Complications after acute stroke. Stroke 1996; 27:415-420. 197. Kalra L, Yu G, Wilson K, et al: Medical complications during stroke rehabilitation. Stroke 1995; 26:990-994. 198. Roth EJ, Lovell L, Harvey RL, et al: Incidence of and risk factors for medical complications during stroke rehabilitation. Stroke 2001; 32:523-529. 199. Cavallini A, Micieli G, Marcheselli S, et al: Role of monitoring in management of acute ischemic stroke patients. Stroke 2003; 34:2599-2603. 200. McCarthy ST, Turner J: Low-dose subcutaneous heparin in the prevention of deep-vein thrombosis and pulmonary emboli following acute stroke. Age Ageing 1986; 15:84-88. 201. Kelly J, Rudd A, Lewis RR, et al: Screening for proximal deep vein thrombosis after acute ischemic stroke: a prospective study using clinical factors and plasma D-dimers. J Thromb Haemost 2004; 2:1321-1326. 202. Kelly J, Rudd A, Lewis RR, et al: Venous thromboembolism after acute ischemic stroke: a prospective study using magnetic resonance direct thrombus imaging. Stroke 2004; 35:2320-2325. 203. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349:1569-1581. 204. Antithrombotic Trialists’ Collaboration: Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71-86. 205. Gubitz G, Sandercock P, Counsell C: Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2004; (2):CD000024. 206. Amaragiri SV, Lees TA: Elastic compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev 2000; (1):CD001484. 207. Mazzone C, Chiodo-Grandi F, Sandercock P, et al: Physical methods for preventing deep vein thrombosis in stroke. Cochrane Database Syst Rev 2004; (4):CD001922. 208. Yamey G, Greenwood R: Physical consequences of neurological disablement. In Greenwood RJ, Barnes MP, McMillan TM, et al, eds: Handbook of Neurological Rehabilitation. Hove, UK: Psychology Press, 2003, pp 191-222. 209. Convertino VA: Cardiovascular consequences of bed rest: effect on maximal oxygen uptake. Med Sci Sports Exerc 1997; 29:191-196. 210. Bloomfield SA: Changes in musculoskeletal structure and function with prolonged bed rest. Med Sci Sports Exerc 1997; 29:197-206.

659

211. Mackay-Lyons MJ, Makrides L: Exercise capacity early after stroke. Arch Phys Med Rehabil 2002; 83:1697-1702. 212. Mackay-Lyons MJ, Makrides L: Longitudinal changes in exercise capacity after stroke. Arch Phys Med Rehabil 2004; 85:1608-1612. 213. Bjurö T, Fugl-Meyer AR, Grimby G, et al: Domestic work in patients with neuromuscular handicap. Scand J Rehabil Med Suppl 1978; 6:193-196. 214. Potempa K, Lopez M, Braun L, et al: Physiological outcomes of aerobic exercise training in hemiparetic stroke patients. Stroke. 1995; 26:101-105. 215. Weiss A, Suzuki T, Bean J, et al: High intensity strength training improves strength and functional performance after stroke. Am J Phys Med Rehabil. 2000; 79:369376. 216. Ouellette MM, LeBrasseur NK, Bean JF, et al: High-intensity resistance training improves muscle strength, self-reported function, and disability in long-term stroke survivors. Stroke 2004; 35:1404-1409. 217. Duncan P, Studenski S, Richards L, et al: Randomized clinical trial of therapeutic exercise in subacute stroke. Stroke 2003; 34:2173-2180. 218. Saunders DH, Greig CA, Young A, et al: Physical fitness training for stroke patients. Cochrane Database Syst Rev 2004; (1):CD003316. 219. Gordon NF, Gulanick M, Fernando CF, et al: Physical activity and exercise recommendations for stroke survivors. Stroke 2004; 35:1230. 220. Ingles JL, Eskes GA, Phillips SJ: Fatigue after stroke. Arch Phys Med Rehabil 1999; 80:173-178. 221. van der Werf SP, van den Broek HL, Anten HW, et al: Experience of severe fatigue long after stroke and its relation to depressive symptoms and disease characteristics. Eur Neurol 2001; 45:28-33. 222. Glader EL, Stegmayr B, Asplund KL: Poststroke fatigue: a 2year follow-up study of stroke patients in Sweden. Stroke 2002; 33:1327-1333. 223. Williams LS, Weinberger M, Harris LE, et al: Development of a stroke-specific quality of life scale. Stroke 1999; 30:13621369. 224. Hilari K, Byng S, Lamping DL, et al: Stroke and aphasia quality of life scale-39 (SAQOL-39): evaluation of acceptability, reliability, and validity. Stroke 2003; 34:1944-1950. 225. Choi KS, Han SW, Kwon SU, et al: Poststroke fatigue: characteristics and related factors. Cerebrovasc Dis 2005; 19:8490. 226. Staub F, Bogousslavsky J: Fatigue after stroke: a major but neglected issue. Cerebrovasc Dis 2001; 12:75-81. 227. Bassetti CL: Sleep and stroke. Semin Neurol 2005; 25:19-32. 228. Rosenberg JH, Shafor R: Fatigue in multiple sclerosis: a rational approach to evaluation and treatment. Curr Neurol Neurosci Rep 2005; 5:140-146. 229. Stankoff B, Waubant E, Confavreux C, et al: Modafinil for fatigue in MS: a randomized placebo-controlled double- blind study. Neurology 2005; 64:1139-1143. 230. The FOOD Trial Collaboration: Poor nutritional status on admission predicts poor outcomes after stroke: observational data from the FOOD trial. Stroke 2003; 34:1450-1456. 231. Iwamoto T, Fukuda S, Kikawada M, et al: Prognostic implications of swallowing ability in elderly patients after initial recovery from stroke. J Gerontol A Biol Sci Med Sci 2005; 60:120-124. 232. Dennis MS, Lewis SC, Warlow C: Routine oral nutritional supplementation for stroke patients in hospital (FOOD): a multicentre randomised controlled trial. Lancet 2005; 365:755-763. 233. McWhirter JP, Pennington CR: Incidence and recognition of malnutrition in hospital. BMJ 1994; 308:945-948.

660

Section

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234. Potter J, Langhorne P, Roberts M: Routine protein energy supplementation in adults: systematic review. BMJ 1999; 317:495-501. 235. Dziewas R, Ritter M, Schilling M, et al: Pneumonia in acute stroke patients fed by nasogastric tube. J Neurol Neurosurg Psychiatry 2004; 75:852-856. 236. Wanklyn P, Forster A, Young J: Hemiplegic shoulder pain (HSP): natural history and investigation of associated features. Disabil Rehabil 1996; 18:497-501. 237. Ada L, Foongchomcheay A, Canning C: Supportive devices for preventing and treating subluxation of the shoulder after stroke. Cochrane Database Syst Rev 2005; (1):CD003863. 238. Turner-Stokes L, Jackson D: Shoulder pain after stroke: a review of the evidence base to inform the development of an integrated care pathway. Clin Rehabil 2002; 16:276-298. 239. Renzenbrink GJ, IJzerman MJ: Percutaneous neuromuscular electrical stimulation (P-NMES) for treating shoulder pain in chronic hemiplegia. Effects on shoulder pain and quality of life. Clin Rehabil 2004; 18:359-365. 240. House A, Dennis M, Mogridge L, et al: Mood disorders in the year after first stroke. Br J Psychiatry 1991; 158:83-92. 241. Wiart L, Petit H, Joseph PA, et al: Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke 2000; 31:1829-1832. 242. Burvill PW, Johnson GA, Jamrozik KD, et al: Prevalence of depression after stroke: the Perth Community Stroke Study. Br J Psychiatry 1995; 166:320-327. 243. Robinson RG, Kubos KL, Starr LB, et al: Mood disorders in stroke patients: importance of location of lesion. Brain. 1984; 107:81-93. 244. Vataja R, Leppävuori A, Pohjasvaara T, et al: Poststroke depression and lesion location revisited. J Neuropsychiatry Clin Neurosci 2004; 16:156-162. 245. Lenze EJ, Rogers JC, Martire LM, et al: The association of latelife depression and anxiety with physical disability: a review

246. 247.

248. 249. 250.

251. 252. 253. 254. 255.

of the literature and prospectus for future research. Am J Geriatr Psychiatry 2001; 9:113-135. Singh A, Black HE, Herrmann N, et al: Functional and neuroanatomic correlations in poststroke depression: the Sunnybrook Stroke Study. Stroke 2000; 31:637-644. Bisschop MI, Kriegsman DMW, Deeg DJH, et al: The longitudinal relation between chronic diseases and depression in older persons in the community: the Longitudinal Aging Study Amsterdam. J Clin Epidemiol 2004; 57:187-194. Parikh RM, Robinson RG, Lipsey JR, et al: The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. Arch Neurol 1990; 47:785-789. Anderson CS, Hackett ML, House AO: Interventions for preventing depression after stroke. Cochrane Database Syst Rev 2004; (1):CD003689. Hackett ML, Anderson CS, House AO: Interventions for treating depression after stroke. Cochrane Database Syst Rev 2004; (3): CD003437. DOI: 10.1001/14651858. CD003437. pub 2. Royal College of Physicians: National Sentinel Stroke Audit Report 2004. London: Royal College of Physicians, 2005. Forster A, Young J: Research networks for stroke rehabilitation: opportunities and barriers. Clin Med 2005; 5:4246. Indredavik B, Bakke F, Slørdahl SA, et al: Treatment in a combined acute and rehabilitation stroke unit: which aspects are most important? Stroke 1999; 30:917-923. Ward NS: Functional reorganization of the cerebral motor system after stroke. Curr Opin Neurol 2004; 17:725730. Academy of Medical Sciences: Restoring neurological function: putting the neurosciences to work in neurorehabilitation, 2004. Available at: http://www.acmedsci.ac.uk/ index.php?pid=48&prid=15 (accessed January 30, 2006).

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Maxime Guye and Patrick Chauvel

Developmental defects are among the most frequent causes of epilepsy, particularly of refractory epilepsy. They constitute a very broad range of pathological processes occurring during brain development. Each step of brain maturation, from neurogenesis to cortical organization, may be affected, which leads to several cortical malformations and/or molecular/cellular defects affecting synapses, neurotransmitter receptors, or ion channels. Advances in research, mainly in the fields of neuroimaging, electrophysiology, and genetics, have yielded a better understanding of the pathophysiology of these developmental epilepsies. This chapter focuses on malformations caused by abnormalities of cortical development (MCDs) responsible for epilepsy. Several aspects are covered: (1) definition and classification, (2) neurogenetics, (3) neuroimaging, and (4) electrophysiological-clinical data and relevance to epilepsy surgery. Each section highlights specific data of relevance to the pathophysiology of developmental defects associated with epilepsy.

DEFINITION AND CLASSIFICATION MCDs have become more easily recognized in vivo since the 1980s because of technical improvements in magnetic resonance imaging (MRI). The term malformations caused by abnormalities of cortical development1 encompasses many forms of developmental defect resulting in architectural alteration of the cerebral cortex with or without abnormal cells (neuron and/or aberrant cells). MCDs are also referred to as disorders of cortical development,2 cortical dysplasias, and cortical dysgenesis. However, malformations caused by abnormalities of cortical development appears to us to be the most useful label. Focal cortical dysplasia (FCD) is a specific form of MCD. Although FCD is the type of MCD that most frequently causes drug-resistant epilepsy, the term should not be used generically to describe cortical malformations. The term neuronal migration disorders has also been improperly confused with MCD; these disorders constitute a group of malformations occurring during only during the neuronal migration period of brain development. MCDs comprise all architectural abnormalities occurring during the different processes involved in cortical formation that can be schematically divided into three overlapping steps

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(which are themselves not temporally separated): (1) cell proliferation, differentiation, and apoptosis; (2) neuronal migration; and (3) cortical organization. This scheme was used by Barkovich and colleagues to provide one of the most used classifications of MCD (Table 49–1).3 Other classifications based on either imaging aspects or etiology have also been proposed.4 However, the principal advantage of the Barkovich classification is that it incorporates several processes that combine to generate the complexity of clinical manifestations of MCDs, including embryological, genetic, anatomical, and neuropathological factors. This comprehensive classification includes all MCDs: not only those responsible for epilepsy but also those associated with encephalopathy with severe developmental delay. Thus, the spectrum of clinical manifestation of MCD is in fact very wide and heterogeneous. This chapter focuses on MCD as a cause of localizationrelated refractory epilepsy, excluding clinical manifestations with severe mental retardation. Therefore, only the following focal forms of MCD are discussed in this chapter: FCDs, cortical hamartomas of tuberous sclerosis, neoplastic MCD (i.e., dysembryoplastic neuroepithelial tumors [DNETs], ganglioglioma, and gangliocytoma), subcortical band heterotopia, periventricular (subependymal) and subcortical heterotopia, polymicrogyria and schizencephaly, and mild MCD (replacing the term microdysgenesis; see later discussion). Drug-resistant partial epilepsies associated with MCD represent a critical issue in pediatric and adult clinical neurology. In such cases, modern surgical approaches to epilepsy may represent a unique and curative solution for patients. A careful comprehensive presurgical assessment is required and must take into account all aspects of the epilepsy, from lesion to seizure phenomena. Recognition of MCD by magnetic resonance techniques has dramatically modified presurgical assessment. However, two critical issues remain: the precise localization of an epileptogenic zone responsible for seizure onset and the relationship between MRI-defined lesions and the epileptogenic zone, which may be complex.5 Moreover, up to 20% of MRI scans appear normal on visual inspection in such patients.6 No specific epidemiological studies on the prevalence of MCD are available in the literature; therefore, the only estimates of the proportion of each MCD subtype come from specialized tertiary centers.7,8 Nevertheless, it appears that FCDs are the principal cause of MCDs responsible for drug-resistant

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T A B L E 49–1. Malformations Caused by Abnormalities of Cortical Development (MCDs): Classification Scheme

T A B L E 49–2. Focal Cortical Dysplasia (FCD): Classification Scheme

Malformations Caused by Abnormal Neuronal and Glial Proliferation, Differentiation, or Apoptosis Decreased proliferation/increased apoptosis: microcephalies Microcephaly (with normal to thin cortex) Microlissencephaly (microcephaly with thick cortex) Microcephaly associated with other MCDs (polymicrogyria and/or focal cortical dysplasia) Increased proliferation/decreased apoptosis (normal neuronal and glial cells): megalencephaly Abnormal proliferation/differentiation (abnormal cell types) Nonneoplastic Cortical hamartomas of tuberous sclerosis* Focal cortical dysplasia* with dysmorphic neurons ± balloon cells (type II* of Palmini’s classification [cf. Table 49–2]) Hemimegalencephaly Neoplastic Dysembryoplastic neuroepithelial tumor (DNET)* Ganglioglioma* Gangliocytoma

Type I: FCD without dysmorphic neurons or balloon cells (invisible on conventional MRI) Type IA: Isolated architectural abnormalities (dyslamination ± other abnormalities of mild MCD) Type IB: Architectural abnormalities, giant or immature but not dysmorphic neurons Type II: FCD with dysmorphic neurons or balloon cells (Taylor-type FCD, potentially visible on MRI) Type IIA: Architectural abnormalities with dysmorphic neurons b but without balloon cells Type IIB: Architectural abnormalities with dysmorphic neurons and balloon cells (T2 hypersignal on MRI)

Malformations Caused by Abnormal Neuronal Migration Lissencephaly/subcortical band heterotopia spectrum* Cobblestone complex Heterotopia* Periventricular (subependymal) Subcortical (other than band heterotopia) Marginal glioneural (also considered part of the group of mild MCD [microdysgenesis]) Malformations Caused by Abnormal Cortical Organization Polymicrogyria and schizencephaly* Bilateral polymicrogyria syndromes Schizencephaly (polymicrogyria with clefts) Polymicrogyria with other brain MCDs Focal cortical dysplasia* without dysmorphic neurons or balloon cells (type I* of Palmini’s classification [cf. Table 49–2]) Mild MCD (microdysgenesis)* Malformations of Cortical Development Not Otherwise Classified Includes malformations secondary to inborn errors of metabolism (i.e., mitochondrial, pyruvate, peroxisomal disorders) and sublobar dysplasia Adapted from Barkovich AJ, Kuzniecky RI, Jackson GD, et al: Classification system for malformations of cortical development: update 2001. Neurology 2001 57:21682178. *Classically associated with epilepsy.

partial epilepsy that is potentially treatable by surgery. Therefore, since the first description of surgical specimens from epileptic patients by Taylor and colleagues in 1971,9 FCD has been of interest to physicians and researchers working with epilepsy surgery. Today, it is well recognized that FCD is not a homogeneous entity but exhibits different histopathological features with variable cytological components and degrees of architectural disruption. This observation implies a range of genetic and molecular mechanisms and variable alterations in cortical connectivity. This variability affects the visibility of FCD on MRI scans. However, from such diversity, it is possible to describe correlations between histopathological and MRI features and, to some extent, clinical electrophysiological features.10,11 Thus, Palmini and colleagues proposed a specific classification of FCDs that is clinically particularly useful (Table 49–2).12,13 In the same report, the result of a panel discussion between epileptologists, neuroradiologists, and neuropathologists

Adapted from Palmini A, Najm I, Avanzini G, et al: Terminology and classification of the cortical dysplasias. Neurology 2004 62(6, Suppl 3):S2-S8. MCD, malformation caused by abnormalities of cortical development; MRI, magnetic resonance imaging.

specializing in the field, Palmini and colleagues12 also brought clarity to the concept of microdysgenesis. This category of MCD is important because it represents another frequent cause of drug-resistant partial epilepsy in which MRI scans are normal.14 The term microdysgenesis has been used to describe microscopic changes that constitute cortical laminar disorganization; abnormal cortical myelinated fibers; neuronal clustering; and heterotopic or excessively numerous neurons in white matter, subcortical areas, or cortical layer I. Today, the term mild MCD is preferred to describe such microscopic histopathological changes. Palmini and colleagues classified mild MCD into type I (with ectopically placed neurons in or adjacent to layer I) and type II (with microscopic neuronal heterotopia outside layer I). It is worth noting that several types of MCD may be observed in the same patient. This fact illustrates the complexity of this broad spectrum of pathological processes that affect cortical mantle formation.

NEUROGENETICS Since the first reports of familial cases of lissencephaly and subcortical heterotopia2 in the early 1990s, the genetic basis of MCD has been increasingly recognized.15,16 Like many developmental neurological disorders, MCD is the result of a combination of genetic defect and gestational environmental insult.17 Thus, although genetic discoveries have brought new insights and a better understanding of the causes of MCD, they have also revealed more complexity as concerns an understanding of pathophysiology. Indeed, the same mutation may lead to different types of MCD, and conversely, the same phenotype may be linked to different mutations.7 Lissencephaly and subcortical band heterotopia are the first MCDs for which a genetic basis was found. However, these MCDs are not commonly associated with epilepsy. They represent a spectrum of abnormalities, and both can be encountered in the same families. Two genes have been discovered: LIS118 on chromosome 17 and DCX19 on chromosome X. LIS1 mutations can lead to isolated lissencephaly or a more severe phenotype (Miller-Dieker syndrome) in the case of heterozygous deletions. DCX mutations can lead to lissencephaly in boys, subcortical band heterotopia in girls, or mixed phenotypes.

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Several familial forms of polymicrogyria have been linked to a number of genes, mainly on chromosome X.20,21 Familial schizencephaly linked to a mutation within the EMX2 gene has also been reported.21 Finally, one report linked a mutation of the TSC1 gene to molecular defects associated with FCD.22

NEUROIMAGING Modern imaging based on magnetic resonance has dramatically modified not only the definition of MCD but also an understanding of the physiology and pathophysiology of MCD.

Hamartomas of the Tuberous Sclerosis Complex Typical cortical hamartomas (Fig. 49–2) potentially responsible for refractory epilepsy are usually called tubers and may mimic some of the features of FCD. However, they do not show regular cortical thickening or transmantle hypersignal spreading to the ventricle. The more typical findings are cortical or subcortical hyperintensity on T2-weighted images. Tubers are generally associated with other characteristic hamartomous lesions such as subependymal nodules and subependymal giant cell astrocytomas. They may also be calcified, and signal appearances may change with age.

Neoplastic MCDs Conventional Magnetic Resonance Imaging High-resolution conventional MRI used according to an optimal protocol defined by the Neuroimaging Commission of the International League against Epilepsy allows the diagnosis of most MCDs. High-resolution MRI with specific sequences is required for presurgical evaluation for patients with drug-resistant epilepsy. The MRI appearances in each type of epilepsy-associated MCD without severe developmental retardation can be summarized as follows.

Focal Cortical Dysplasia Not all the subtypes of FCD (Fig. 49–1) can be identified on MRI. Type I FCD is almost always invisible on MRI and is usually discovered on neuropathological examination after surgery. The most commonly identified lesions on MRI are those associated with type II (Taylor-type) FCD. Several features can be observed: focal cortical thickening, blurring of the junction between gray and white matter, increased signal intensity on T2-weighted, proton density, or fluid-attenuated inversion recovery imaging (FLAIR), classically linked to the balloon cell content of the FCD (type IIB) and extension of this hypersignal from the cortex to the ventricle (also called transmantle dysplasia in the literature). A distinction must be made with the hamartomas of tuberous sclerosis (a potentially very difficult differential diagnosis in the absence of other clinical or radiological symptoms suggestive of tuberous sclerosis), low-grade gliomas, and dysplastic MCDs such as DNETs and gangliogliomas.

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Dysembryoplastic neuroepithelial tumors DNETs (Fig. 49–3) are nonmalignant neoplastic malformations in cortical “locations.” DNETs can share MRI features with FCD (cortical thickening, T2 hyperintensity) but are found more often in the temporal lobes. They are, as in the case of tubers, usually well circumscribed, without blurring of the junction between the gray and white matter, although they may involve the white matter. A typical feature is molding of the overlying skull. Calcification, best seen on computed tomographic scan, and cystic components may be observed. Enhancement with contrast material is rare. DNETs must be differentiated from low-grade gliomas.

Ganglioglioma Gangliogliomas (Fig. 49–4) are difficult to differentiate from DNETs, although greater enhancement with contrast material is generally seen in gangliogliomas. The presence of T2 hyperintensity, cysts, and high-contrast enhancement and the lack of perifocal edema may suggest a low-grade or pilocytic astrocytoma. Superficial enhancement extending to the leptomeninges may likewise suggest the diagnosis of a pleomorphic xanthoastrocytoma.

Subcortical Band Heterotopia Subcortical band heterotopia (Fig. 49–5) manifests radiologically as a band of cortical tissue underlying the cortical surface from which it is separated by a thin strip of white matter. The band comprises normal appearing neurons with a signal similar to that of cortical gray matter. Band thickness may vary, as may

Figure 49–1. Focal cortical dysplasia (FCD). A, FCD visible as a blurring of gray and white matter associated with cortical-subcortical hyperintensity on fluid-attenuated inversion recovery imaging (FLAIR) (arrows). B, FCD demonstrating not only the same features as in A but also the typical transmantle FLAIR or T2 hyperintensity from the cortex to the ventricle (arrow).

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Figure 49–2. Tuberous sclerosis hamartomas. A, Classic isolated cortical tuber. B, More severe case with numerous large tubers associated with subependymal nodules (arrow).

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Figure 49–3. Dysembryoplastic neuroepithelial tumor (DNET). Note the specific overlying skull molding (arrow).

position along the fronto-occipital axis, leading to a spectrum of type and severity of cognitive impairment.

Periventricular Heterotopia Periventricular heterotopia is easily diagnosed as normalappearing gray matter in the form of nodules or short bands in an ectopic, periventricular position; such heterotopia may also be subcortical.

Polymicrogyria Polymicrogyria (Fig. 49–6) is a gyration defect resulting in a cortex composed of microgyri with excessive folding. However,

in thick MRI slices, the appearances of polymicrogyria may be confused with pachygyria, which resembles thick and smooth cortex. Thin slices reveal the excessively folded and thin cortex. This pattern is often bilateral (either symmetrical or asymmetrical) but may be unilateral and diffuse or well localized. Several morphoclinical forms have been described: bilateral perisylvian, frontal, and parieto-occipital.

Schizencephaly Schizencephaly (Fig. 49–7) manifests as a transcerebral cleft, with edges lined by cortical tissue, often associated with polymicrogyria along the cleft borders. Bilateral forms occur, and there is an association with other brain malformations of

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Figure 49–4. Ganglioglioma.

Figure 49–5. Band heterotopia (or “double cortex”). A, Axial image demonstrating a diffuse-band heterotopia (arrow). B, Top image shows a posterior form of band heterotopia (arrow), whereas bottom image shows an anterior form of band heterotopia (arrow).

the septum, optic nerve, corpus callosum, cingulate cortex, or hippocampus.

niques providing functional information are of particular interest and help define changes associated with MCD more comprehensively.

Mild MCD By definition, mild MCDs are not visible on conventional MRI scans.

Functional Imaging and Advanced Magnetic Resonance Imaging Techniques In conclusion, conventional MRI allows the diagnosis of most cases of MCD. However, in about 20%, the MRI scan appears normal (mostly in mild MCD or FCD). Visually identified structural abnormalities may not be the only changes associated with MCD. Advanced magnetic resonance tech-

Functional Imaging Several imaging studies have investigated the potential functions of dysplastic cortex. This issue is of particular interest in relation to the importance of individual MCD-associated pathophysiology for surgical planning. Functional MRI studies with motor, visual, or cognitive tasks have shown that hemimegalencephaly, subcortical band heterotopia, periventricular heterotopia, FCD, and polymicrogyria may all be functionally active.23-25 These findings confirm those of previous positron emission tomographic studies, which demonstrated participation of MCD in functionally reorganized cortex.26 These

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Figure 49–6. Polymicrogyria. Right image shows the apparent thick cortex (arrow) in a 4-mm thickness slice (fluid-attenuated inversion recovery image), whereas left image shows better the excessively folded cortex (arrow) (T1-weighted image).

of diffusivity and anisotropy has revealed structural abnormalities beyond visually defined structural lesions on conventional MRI, which indicates more widespread morphological changes than those visible with conventional scanning.28 Tractography has been used in a preliminary manner to study the architecture of white matter in MCD. It has been used to show normal-appearing connectivity of band heterotopia to underlying cortex—a result that concords with functionality demonstrated by functional MRI.29 Conversely, tractography has also demonstrated diffuse impairment of white matter connectivity patterns.30 Further research is needed to better define reorganization of the brain in terms of neural connectivity. This may lead to a better understanding of the pathophysiology of MCD, especially the anatomical substrate of neural networks implicated in epileptogenic zones, which may themselves be more widespread than conventional MRI visible lesions.

Morphometry

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Figure 49–7. Schizencephaly. The arrow points to the cleft.

findings suggest that careful mapping of cerebral functions before surgery is vital in cases of MCD located in functionally eloquent cortex.27

Diffusion Tensor Imaging and Tractography Diffusion tensor imaging is a magnetic resonance technique in which the three-dimensional measurement of tissue water diffusion is used to infer both the integrity (quantification of diffusivity and anisotropy) and orientation of white matter axonal fibers in vivo (tractography). Parametric quantification

Several analytical techniques can quantify structural changes from T1-weighted images, including the respective amounts of white and gray matter present regionally. Such analyses have demonstrated both increased and decreased amounts of gray matter within and beyond visible lesions, which, again, shows that anatomical defects are more widespread than they appear on conventional structural scanning.31,32

Metabolic Imaging Metabolic imaging by means of magnetic resonance spectroscopic imaging (MRSI) or positron emission tomography has also contributed to a better description of biochemical disturbances associated with MCD. MRSI shows differential patterns of metabolite changes (mainly affecting N-acetylaspartate, choline-containing compounds, and creatinephosphocreatine ratios) according to type of MCD, and may

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be used to differentiate FCD and DNET from low-grade gliomas.33,34 Positron emission tomography with positronlabeled amino acids can differentiate DNET from other benign tumors associated with epilepsy, or differentiate active epileptogenic tubers from nonactive ones in tuberous sclerosis.35,36 MRSI and positron emission tomography (with one of the positron-labeled tracers flumazenil, serotonin, and glucose) are promising, and such techniques may provide a description of metabolic abnormalities linked to epileptiform discharges rather than lesions per se.37-39 In conclusion, conventional MRI allows an in vivo description and classification of MCD, leading in most cases to a diagnosis of MCD type. Such diagnoses may suggest the type of epilepsy to be expected and the potential outcome of surgical treatment. However, advanced imaging techniques frequently show more widespread MCD-associated structural, functional, and connectivity changes, thus illustrating the potentially complex relationship between a visible lesion and the real epileptogenic zone. Accurate study of such relationships depends on electrophysiology.

receptors) and molecular factors (N-methyl-D-aspartate– mediated excitatory mechanisms and GABAA receptor– mediated synchronicity) leading to epileptogenicity.43 With regard to the different forms of MCD, FCD is much more epileptogenic than nodular heterotopia, polymicrogyria, or schizencephaly.2

Human In Vivo Studies In addition to the microscopic changes described in vitro, the electrical and electrical-clinical features of MCD-associated epilepsy have been investigated in vivo. Several techniques have been used: surface extracranial recordings (electroencephalography and magnetoencephalography) and intracranial recordings (electrocorticography), consisting of direct surface cortical recordings on strips or grids, and stereoelectroencephalography (SEEG), consisting of deep recordings with depth electrodes implanted directly into cerebral structures. All these techniques allow recording of interictal paroxysmal events as well as ictal discharges.

Surface recordings

ELECTROPHYSIOLOGICAL-CLINICAL DATA AND RELEVANCE TO EPILEPSY SURGERY Electrophysiology Animal Model Studies Most animal models of MCD have been produced through genetic modification or environmental insults applied in utero to rodent embryos.40,41 Three models of focal cortical malformation are available: (1) a pharmacological model with methylazoxymethanol, (2) an irradiation model, and (3) a cold lesion model. These interventions usually result in heterotopia or microgyria. Thus, the models result in MCD with abnormal connectivity through aberrant circuitry.40 It is still a matter of debate whether heterotopic tissue secondarily triggers seizures that propagate to the cortex. It is more likely that more complex heterotopic-cortical neuronal networks may be involved in the generation of seizures.

Human In Vitro Studies In vitro studies have provided fundamental research data on the pathophysiology of MCD in humans, with new insights particularly into type II FCD (which probably represents the most frequent cause of refractory partial epilepsy considered for surgery). Intrinsic epileptogenicity has now been well demonstrated by studies of FCD surgical specimens.2 Data support the idea that cytomegalic neurons rather than balloon cells are the generators of epileptogenic activity.42 However, on MRI scans, T2 hyperintensity probably results from the presence of balloon cells.13 Thus, there is a potential discrepancy between MRI-visible abnormalities and electrically discharging lesions. Surrounding normal tissue may also demonstrate hyperexcitability. Several potential mechanisms of hyperexcitability have been demonstrated. They are mediated by cellular changes (loss of inhibitory GABAergic interneurones, increase of abnormally oriented pyramidal neurons exhibiting excitatory

In all types of MCD classically associated with epilepsy, Raymond and colleagues found in a study of 100 patients no interictal electroencephalographic (EEG) abnormality in only 15% of cases.8 Generalized EEG features (synchronous and bilateral) were observed in 19%. Most of these patients had bilateral or diffuse MCD consisting of heterotopias, polymicrogyria, or a tuberous sclerosis complex. However, in 63 of 68 patients with focal or unilateral MCD, the EEG features were either focal or lateralized. There are particular features described in FCD. Thus, focal rhythmic interictal discharges on electroencephalography are considered typical of FCD. They correspond to continuous epileptiform discharges recorded with electrocorticography.44 This feature is very significant for localization of the epileptogenic zone. Magnetoencephalography and electroencephalography with source localization of interictal spikes may also help localize the origin of epileptogenic processes. Using both techniques together in cases of polymicrogyria and FCD, several investigators have demonstrated spike source localizations concordant with the location of MRI visible lesions.45 Thus, interictal event localization may help define the epileptogenicity of a given case of MCD. Ictal recordings and especially video-EEG recordings are also very useful in defining sites of ictal onset, especially if surgery is contemplated. Electrical-clinical correlations depict any discrepancies between anatomical and electrical lesion localization (if seen) and the clinical symptoms. When all the diagnostic data are concordant (i.e., well-defined MRI localization of a focal lesion, especially FCD and DNET, and compatible interictal epileptiform events, especially focal rhythmic discharges, with a compatible electrical-clinical ictal picture), intracranial recording may not be required. However, in most cases, intracranial recordings remain necessary for the precise definition of the epileptogenic zone.

Intracranial recordings Numerous researchers have investigated the intracranial electrophysiological features of MCD, using either electrocorticography46-48 or stereoelectroencephalography (SEEG).10,49-52 They

chapter 49 developmental defects and pathophysiology have focused on specific MCDs: FCD,10,46,48,49 DNET,47 nodular heterotopia,52 or band heterotopia.51 Intrinsic epileptogenicity has been well demonstrated in FCD, but seizures may also be initiated in surrounding cortex. As already mentioned, ictal onset involves dysmorphic neurons and never balloon cells; therefore, T2 hyperintensity seen on MRI are not correlated perfectly with the epileptogenic zone. The cortex surrounding a DNET is much more epileptogenic than the tumor itself. In nodular heterotopia, specific interictal patterns are recorded from nodules, but seizures are not initiated solely in them; they are also initiated from overlying cortex or simultaneously in both. Polymicrogyria and band heterotopia are characterized by a broad epileptogenic zone involving complex networks comprising both normal- and abnormal-appearing cortex.51 Thus, in addition to intrinsic epileptogenicity, neuronal plasticity (a kindling effect) may also lead to enlargement of an epileptogenic zone beyond the confines of a lesion. This effect may depend on the type of cortical area involved by a lesion; for instance, MCD of primary cortices appears less prone to propagate to other areas than does MCD in association cortex. Interestingly, epilepsy surgery for frontal lobe MCD is less successful than that for temporal lobe MCD. Presurgical evaluation of MCD must always take into account the fact that the epileptogenic zone may not overlap a visible MRI-defined lesion accurately.

Epilepsy Surgery for MCD Epilepsies associated with MCD are commonly resistant to drugs; therefore, epilepsy surgery is increasingly used worldwide for their treatment. Modern approaches to presurgical evaluation and new surgical techniques can lead to freedom from seizures or at least significant improvement in epilepsy. Because MCDs are benign lesions, the goal of any surgical approach to them is to cure epilepsy.

Surgical Outcomes: Prognostic Factors Numerous studies have investigated the potential benefit of MCD surgery. Surgery can render about 40% of MCD patients seizure free for at least 2 years for all types and locations.5,8 The remaining 60% of patients experience improvement or no change. The outcome is more variable in view of the different types and locations of MCD. Presurgical evaluation, type of resection, and specific prognostic factors may affect the eventual outcome in individual cases.

MCD subtype The pathological type and grade of MCD have an effect on surgical outcome. DNET and FCD surgery lead to the best results, rendering seizure free 40% to 65% of patients with FCD and up to 80% with DNET.11,53,54 FCD subtype I has a better prognosis.11 The heterotopias are usually considered less amenable to surgery. However, working with SEEG, Tassi and colleagues52 reported seven patients with unilateral nodular heterotopia rendered seizure free after surgery. None of their bilaterally heterotopic patients became seizure free, but they experienced a decrease in seizure frequency. Surgery for band heterotopia is classically associated with a poor outcome.55,56 However, it seems that SEEG-guided surgery may lead to freedom from seizures in some cases.50 Poor outcome is also associated with

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polymicrogyria and schizencephaly, but, again, there are reports of freedom from seizures after intracranial recording–guided surgery.5

Complete lesion resection Complete resection of the lesion is considered a major prognostic factor for good postsurgical outcome, especially in FCD and neoplastic dysplasia (DNET and ganglioglioma).46

Complete resection of epileptogenic zone It is now well demonstrated (after lengthy debate) that resection of both lesional and nonlesional epileptogenic areas is necessary for surgery to be successful. This is easy and obvious in cases in which lesion and epileptogenic zone overlap but less so when the epileptogenic zone involves a distributed epileptogenic network that is more widespread than the visible lesion.5,49,52

MCD and epileptogenic zone location Outcome may also depend on the lobe affected; a high rate of freedom from seizures postoperatively is associated particularly with temporal lobe lesions.46 Different locations in the brain imply potential involvement of different types of neural system. This is consistent with the postulate that not only the type of lesion but also the type of cortex (i.e., primary or association) and its connectivity play a part in determining the character of the epileptogenic zone (possibly via kindling mechanisms).

Perspectives for Improving Surgical Outcome: The Concepts of Hidden Lesion and Distributed Epileptogenic Network A critical issue is why surgical failures happen. In other words, what is the exact pathophysiology of MCD-related epilepsy? Each type of MCD should be approached specifically, but there are two classical theories that provide possible explanations. The first theoretical assumption is to consider that the dysplastic tissue seen on MRI represents only an obvious problem and that other histological abnormalities (not only surrounding but also potentially remote from the visible lesion) may initiate seizures despite removal of the obvious lesion. This argument is supported by the finding of remote abnormalities through advanced MRI techniques. The second theory is to consider that epilepsy associated with MCD may be initiated in an epileptogenic network more or less distributed, depending on the type of MCD and the neural system involved. This second explanation could account for the clinical observation that complete, histologically proven lesion resection in some cases fails to ameliorate the epilepsy, whereas in other cases, incomplete lesion resection may lead to freedom from seizures. The second hypothesis implies that presurgical evaluation should rely more on electrophysiological and functional imaging than structural imaging alone. Both theories must be taken into consideration when efforts are made to improve the outcome of epilepsy surgery for MCD. Only a comprehensive approach comprising clinical, electrophysiological, and multimodal imaging assessments will lead to a better understanding of the exact pathophysiology of MCD in individual patients seen in clinical practice (Fig. 49–8).

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Interictal SEEG

Source localization

Figure 49–8. Comprehensive assessment with electrophysiology and imaging, in a case of frontal lobe focal cortical dysplasia not visible on conventional magnetic resonance imaging (MRI). A, Conventional structural MRI corresponding to the slices explored by magnetic resonance spectroscopic imaging. B, One slice of two-dimensional spectroscopic imaging exploring the frontal lobe, demonstrating localized metabolic abnormalities in the anterior part of the left cingulate gyrus (i.e., relative decrease of a neuronal marker, N-acetyl-aspartate). C, High-resolution electroencephalographic recording of interictal paroxysmal events: left, slow spikes recorded from the surface; right, the display of a color-coded map corresponding to the likelihood of source localization of these spikes (through use of the multiple-signal classification [MUSIC] algorithm; note that red represents the highest probability of source location of the recorded spikes). D, Sampling of interictal intracranial recordings with stereoelectroencephalography (SEEG), showing subcontinuous spikes, slow waves, and fast discharges typical of focal cortical dysplasia (FCD) in the medial leads of two selected orthogonally implanted electrodes, located in the left anterior cingulate gyrus. Red plots stand for the position of the most medial leads of the electrodes. Note that the investigations were also guided by ictal semiology analyzed with video-electroencephalography and video-SEEG. Thus, conclusion was that the epileptogenic zone was located in the left anterior part of the cingulate gyrus (Brodmann area 32). Resective surgery demonstrated Taylor-type FCD. The patient remains seizure-free without drugs since surgery (after more than 4 years’ follow-up).

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chapter 49 developmental defects and pathophysiology

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Malformations caused by abnormalities of cortical development (MCDs) are among the better-recognized developmental defects responsible for epilepsy, representing the second commonest cause of drug-resistant epilepsy.

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Research and clinical advances in several fields of imaging, genetics, and electrophysiology have led to a better understanding of the pathophysiology of MCD.

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MCD encompasses a broad range of lesions of different pathophysiology. Thus, some MCDs are associated with refractory epilepsy. Their treatment relies mostly on surgery. The goal of such epilepsy surgery must be to remove the epileptogenic zone, which, however, is not always congruent with an MRI-visible lesion.

Suggested Reading Barkovich AJ, Kuzniecky RI, Jackson GD, et al: Classification system for malformations of cortical development: update 2001. Neurology 2001; 57:2168-2178. Guerrini R, Andermann F, Canapicchi R, et al, eds: Dysplasias of Cerebral Cortex and Epilepsy. New York: Lippincott-Raven, 1996. Palmini A: Disorders of cortical development. Curr Opin Neurol 2000; 13:183-192. Sarnat HB: Cerebral Dysgenesis: Embryology and Clinical Expression. New York: Oxford University Press, 1992. Sisodiya SM: Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004; 3:29-38.

References 1. Barkovich AJ, Kuzniecky RI, Dobyns WB, et al: A classification scheme for malformations of cortical development. Neuropediatrics 1996; 27:59-63. 2. Palmini A: Disorders of cortical development. Curr Opin Neurol 2000; 13:183-192. 3. Barkovich AJ, Kuzniecky RI, Jackson GD, et al: Classification system for malformations of cortical development: update 2001. Neurology 2001; 57:2168-2178. 4. Sarnat HB, Flores-Sarnat L: A new classification of malformations of the nervous system: an integration of morphological and molecular genetic criteria as patterns of genetic expression. Eur J Paediatr Neurol 2001; 5:57-64. 5. Sisodiya SM: Surgery for malformations of cortical development causing epilepsy. Brain 2000; 123(Pt 6):1075-1091. 6. Duncan JS: Imaging and epilepsy. Brain 1997; 120(Pt 2):339377. 7. Sisodiya SM: Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004; 3:29-38. 8. Raymond AA, Fish DR, Sisodiya SM, et al: Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. Brain 1995; 118(Pt 3):629-660. 9. Taylor DC, Falconer MA, Bruton CJ, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971; 34:369-387.

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10. Tassi L, Colombo N, Garbelli R, et al: Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 2002; 125(Pt 8):1719-1732. 11. Fauser S, Schulze-Bonhage A, Honegger J, et al: Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology. Brain 2004; 127(Pt 11):2406-2418. 12. Palmini A, Najm I, Avanzini G, et al: Terminology and classification of the cortical dysplasias. Neurology 2004; 62(6, Suppl 3):S2-S8. 13. Widdess-Walsh P, Kellinghaus C, Jeha L, et al: Electro-clinical and imaging characteristics of focal cortical dysplasia: correlation with pathological subtypes. Epilepsy Res 2005; 67(12):25-33. 14. Eriksson SH, Malmgren K, Nordborg C: Microdysgenesis in epilepsy. Acta Neurol Scand 2005; 111:279-290. 15. Walsh CA: Genetic malformations of the human cerebral cortex. Neuron 1999; 23:19-29. 16. Guerrini R, Carrozzo R: Epilepsy and genetic malformations of the cerebral cortex. Am J Med Genet 2001; 106:160-173. 17. Palmini A, Andermann E, Andermann F: Prenatal events and genetic factors in epileptic patients with neuronal migration disorders. Epilepsia 1994; 35:965-973. 18. Reiner O, Carrozzo R, Shen Y, et al: Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit–like repeats. Nature 1993; 364:717-721. 19. des Portes V, Francis F, Pinard JM, et al: doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet 1998; 7:1063-1070. 20. Villard L, Nguyen K, Cardoso C, et al: A locus for bilateral perisylvian polymicrogyria maps to Xq28. Am J Hum Genet 2002; 70:1003-1008. 21. Granata T, Farina L, Faiella A, et al: Familial schizencephaly associated with EMX2 mutation. Neurology 1997; 48:14031406. 22. Becker AJ, Urbach H, Scheffler B, et al: Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann Neurol 2002; 52:29-37. 23. Spreer J, Martin P, Greenlee MW, et al: Functional MRI in patients with band heterotopia. Neuroimage 2001; 14:357-365. 24. Innocenti GM, Maeder P, Knyazeva MG, et al: Functional activation of microgyric visual cortex in a human. Ann Neurol 2001; 50:672-676. 25. Janszky J, Ebner A, Kruse B, et al: Functional organization of the brain with malformations of cortical development. Ann Neurol 2003; 53:759-767. 26. Richardson MP, Koepp MJ, Brooks DJ, et al: Cerebral activation in malformations of cortical development. Brain 1998; 121(Pt 7):1295-1304. 27. Chang BS, Walsh CA: Mapping form and function in the human brain: the emerging field of functional neuroimaging in cortical malformations. Epilepsy Behav 2003; 4:618-625. 28. Eriksson SH, Rugg-Gunn FJ, Symms MR, et al: Diffusion tensor imaging in patients with epilepsy and malformations of cortical development. Brain 2001; 124(Pt 3):617-626. 29. Eriksson SH, Symms MR, Rugg-Gunn FJ, et al: Exploring white matter tracts in band heterotopia using diffusion tractography. Ann Neurol 2002; 52:327-334. 30. Lim CC, Yin H, Loh NK, et al: Malformations of cortical development: high-resolution MR and diffusion tensor imaging of fiber tracts at 3T. AJNR Am J Neuroradiol 2005; 26:61-64. 31. Sisodiya SM, Free SL, Stevens JM, et al: Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy. Brain 1995; 118(Pt 4):1039-1050. 32. Colliot O, Bernasconi N, Khalili N, et al: Individual voxel-based analysis of gray matter in focal cortical dysplasia. Neuroimage 2006; 29:162-171.

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33. Li LM, Cendes F, Bastos AC, et al: Neuronal metabolic dysfunction in patients with cortical developmental malformations: a proton magnetic resonance spectroscopic imaging study. Neurology 1998; 50:755-759. 34. Vuori K, Kankaanranta L, Hakkinen AM, et al: Low-grade gliomas and focal cortical developmental malformations: differentiation with proton MR spectroscopy. Radiology 2004; 230:703-708. 35. Maehara T, Nariai T, Arai N, et al: Usefulness of [11C]methionine PET in the diagnosis of dysembryoplastic neuroepithelial tumor with temporal lobe epilepsy. Epilepsia 2004; 45:41-45. 36. Kagawa K, Chugani DC, Asano E, et al: Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). J Child Neurol 2005; 20:429-438. 37. Hammers A, Koepp MJ, Brooks DJ, et al: Periventricular white matter flumazenil binding and postoperative outcome in hippocampal sclerosis. Epilepsia 2005; 46:944-948. 38. Merlet I, Ryvlin P, Costes N, et al: Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG. Neuroimage 2004; 22:886-896. 39. Guye M, Ranjeva JP, Le Fur Y, et al: 1H-MRS imaging in intractable frontal lobe epilepsies characterized by depth electrode recording. Neuroimage 2005; 26:1174-1183. 40. Chevassus-Au-Louis N, Congar P, Represa A, et al: Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex. Proc Natl Acad Sci U S A 1998; 95:10263-10268. 41. Chevassus-au-Louis N, Baraban SC, Gaiarsa JL, et al: Cortical malformations and epilepsy: new insights from animal models. Epilepsia 1999; 40:811-821. 42. Cepeda C, Andre VM, Vinters HV, et al: Are cytomegalic neurons and balloon cells generators of epileptic activity in pediatric cortical dysplasia? Epilepsia 2005; 46(Suppl 5):82-88. 43. Avoli M, Louvel J, Mattia D, et al: Epileptiform synchronization in the human dysplastic cortex. Epilept Disord 2003; 5(Suppl 2):S45-S50. 44. Gambardella A, Palmini A, Andermann F, et al: Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol 1996; 98:243-249.

45. Bast T, Oezkan O, Rona S, et al: EEG and MEG source analysis of single and averaged interictal spikes reveals intrinsic epileptogenicity in focal cortical dysplasia. Epilepsia 2004; 45:621-631. 46. Palmini A, Gambardella A, Andermann F, et al: Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995; 37:476-487. 47. Seo DW, Hong SB: Epileptogenic foci on subdural recording in intractable epilepsy patients with temporal dysembryoplastic neuroepithelial tumor. J Korean Med Sci 2003; 18:559565. 48. Boonyapisit K, Najm I, Klem G, et al: Epileptogenicity of focal malformations due to abnormal cortical development: direct electrocorticographic-histopathologic correlations. Epilepsia 2003; 44:69-76. 49. Chassoux F, Devaux B, Landre E, et al: Stereoelectroencephalography in focal cortical dysplasia: a 3D approach to delineating the dysplastic cortex. Brain 2000; 123(Pt 8):17331751. 50. Francione S, Kahane P, Tassi L, et al: Stereo-EEG of interictal and ictal electrical activity of a histologically proved heterotopic gray matter associated with partial epilepsy. Electroencephalogr Clin Neurophysiol 1994; 90:284-290. 51. Mai R, Tassi L, Cossu M, et al: A neuropathological, stereoEEG, and MRI study of subcortical band heterotopia. Neurology 2003; 60:1834-1838. 52. Tassi L, Colombo N, Cossu M, et al: Electroclinical, MRI and neuropathological study of 10 patients with nodular heterotopia, with surgical outcomes. Brain 2005; 128(Pt 2):321-337. 53. Nolan MA, Sakuta R, Chuang N, et al: Dysembryoplastic neuroepithelial tumors in childhood: long-term outcome and prognostic features. Neurology 2004; 62:2270-2276. 54. Bingaman WE: Surgery for focal cortical dysplasia. Neurology 2004; 62(6, Suppl 3):S30-S34. 55. Dubeau F, Palmini A, Fish D, et al: The significance of electrocorticographic findings in focal cortical dysplasia: a review of their clinical, electrophysiological and neurochemical characteristics. Electroencephalogr Clin Neurophysiol Suppl 1998; 48:77-96. 56. Bernasconi A, Martinez V, Rosa-Neto P, et al: Surgical resection for intractable epilepsy in “double cortex” syndrome yields inadequate results. Epilepsia 2001; 42:1124-1129.

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50

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Michel Baulac

The clinical spectrum of epilepsy is vast. In terms of symptomatology, the expression of epileptic seizures is very diverse and depends on the function of the part of the brain that is involved by the abnormal neuronal discharge. The age of the affected individual at disease onset and during its evolution ranges from neonates to elderly persons, leading to multiple clinical scenarios. Certain epileptic disorders that occur early in life may have severe consequences on the developing brain. Another key determinant of epileptic diseases is the etiological background, which may include genetic factors, acquired brain lesions, or progressive brain dysfunction but may also remain unknown. This diversity and sometimes complexity are well reflected by the classifications—classification of epileptic seizures on the one hand and classification of epilepsies and epileptic syndromes on the other. All of these parameters should be analyzed by a clinician in a syndromic approach to the patient’s condition. This type of approach facilitates development of a rational management strategy, with selection of the most appropriate drugs as a function of their spectrum of efficacy, and establishes a reasonably reliable prognosis. The severity of the different epileptic syndromes varies from very benign and transient conditions to devastating diseases.

DEFINITIONS AND EPIDEMIOLOGY Any epidemiological approach requires solid definitions of the events and conditions that are under study. Consensual agreement on even the definition of the terms seizure and epilepsy has proved difficult. ■ An epileptic seizure can be defined as a transient occurrence

of signs and/or symptoms due to abnormal or excessive synchronous brain activity. ■ Epilepsy is a family of disorders of the brain characterized by an enduring predisposition to epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Epileptic seizures are pleomorphic, although usually stereotyped for a given individual. Unlike most neurological disorders, the majority of patients with epileptic seizures do not have permanent physical signs and can be diagnosed only by taking a history or by the chance observation of a seizure. Diagnosis is a discretionary judgment that may vary depending

on the skill and experience of clinicians and the quality of available information from witnesses. Electroencephalographic and other complementary investigations are useful in classifying epilepsy but are of limited help in making the diagnosis. Some patients with seizures may never seek medical attention because they ignore or misinterpret their symptoms, or indeed they may be unaware of them. In practice, both false-positive and false-negative diagnoses are common. The definitions of epilepsy have often included the notion of unprovoked seizures and of recurrence. Epileptic seizures may occur as a result of a variety of acute brain insults or metabolic disorders. Those seizures triggered by clear precipitants are termed “acute symptomatic seizures” but, despite exhibiting clear epileptiform phenomenology, they are not classified as epilepsy. The distinction between provoked and unprovoked seizures, however, is not always clear-cut or reliable for epilepsy diagnosis. Indeed, precipitating factors such as lack of sleep or alcohol may facilitate seizures in well-established epileptic diseases. The notion of recurrence, which theoretically implies at least two seizures, is not a necessary characteristic for epilepsy diagnosis. The occurrence of one seizure may be sufficient when clinical or paraclinical elements suggest that there is an enduring alteration in the brain that increases the likelihood of future seizures. More than recurrence, it is the potential for recurrence of seizures that defines epilepsy. All of these distinctions and evolving concepts increase the difficulty of diagnostic accuracy and case ascertainment necessary for the accurate study of epilepsy epidemiology. The overall annual incidence of epilepsy is generally believed to be around 50 per 100 000 (range, 40 to 70 per 100 000/year) in industrialized countries, but socioeconomically deprived people are at greater risk. First seizures are estimated to be around 70 per 100 000 annually. There is a mild predominance in males. The specific incidence as a function of age shows a bimodal curve, with two peaks, one in childhood, with figures of more than 100 per 100,000 during the first year of life, although there is evidence of a decrease in childhood incidence in recent decades. A second peak is observed in elderly people with an estimate of 150 per 100,000 over the age of 80 years, which is attributed to the many prevalent causes of brain damage at that age, with cardiovascular diseases being the most frequent (Fig. 50–1).

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Figure 50–1. Epidemiology of epilepsy in terms of incidence and lifetime cumulative risk.

Incidence/100,000

120 100 3% 80 Cumulative risk 60 2% 40 20

<1

1–4

5–14 15–24 25–34 35–44 45–54 55–64 65–74 Age (y)

In terms of prevalence, several studies conducted in different regions of the world have suggested that epilepsy affects 5 to 8 per 1000 population. These estimates are based on individuals with active epilepsy, defined as patients with a seizure in the previous 5 years or still receiving antiepileptic drug treatment. When isolated seizures are included, the cumulative risk or incidence, which measures the lifetime risk of having a nonfebrile seizure, is very high, ranging from 2% to 8% between 40 and 80 years of age. From the difference between incidence and prevalence of active epilepsy, it is apparent that most patients with epilepsy cease to have seizures or die. It is also likely that the condition remits in many patients. However, epilepsy is associated with increased mortality, particularly but not exclusively in patients with brain lesions.

CLINICAL APPROACH TO EPILEPTIC DISORDERS The clinical approach should consist of a description of the ictal semiology, using as far as possible a standardized terminology. A description of the ictal event(s) should be carefully obtained from the patient and relatives without reference to etiology, anatomy, or mechanisms. Detailed descriptions of the onset and evolution of focal ictal phenomena are not always necessary to make a diagnosis of partial seizure, but they are useful in patients who are candidates for surgical treatment or for research designed to elucidate the anatomical substrates or pathophysiological mechanisms underlying specific clinical behaviors. Electroencephalographic video monitoring, including direct interaction with the patient during an event, is the investigation that permits the most accurate and detailed analysis of symptoms. The next step is to characterize the epileptic seizure type relative to the list of different types defined by the International Classification of Seizures (Table 50–1). It is essential to identify or rule out seizure types by detailed questioning of patients and relatives. Localization within the brain should be specified when this is appropriate; in the case of reflex or provoked

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T A B L E 50–1. International Classification of Seizures (1981) Partial or Focal Seizures Simple (consciousness not impaired) With motor symptoms With somatosensory or special sensory symptoms With autonomic symptoms With psychic symptoms Complex (with impairment of consciousness) Beginning as simple partial seizure (progressing to complex seizure) Impairment of consciousness at onset Impairment of consciousness only With automatism Partial seizures becoming secondarily generalized Generalized Seizures Absence seizures Typical Atypical Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures Unclassified Seizures

seizures, the specific stimulus should also be specified. Electroencephalographic data are often incorporated at this stage of the diagnostic process, as many seizures are also associated with specific electroclinical characteristics. Age at onset is also a critical piece of information. Certain specific seizure types may by themselves be more or less indicative of diagnostic entities with etiological, therapeutic, and/or prognostic implications. A syndromic diagnosis should then be made whenever possible, again using the common terms proscribed by the International Classification of Epilepsies and Epileptic Syndromes. This syndromic diagnosis relies on the grouping of information: on seizure type or types, pattern of recurrence or frequency, age

chapter 50 clinical spectrum at onset, personal and familial antecedents, natural history, and other neurological and extraneurological manifestations. The electroencephalographic data, both interictal and sometimes ictal, are essential, as is a brain imaging examination. Magnetic resonance imaging is indicated in the majority of situations but can be omitted when certitude is reached about the diagnosis of an idiopathic generalized syndrome. Clinical and paraclinical investigations can also help to identify specific etiologies. The etiology can consist of a specific disease frequently associated with epileptic seizures or syndromes, a genetic defect, or a specific pathological substrate, for instance, for the symptomatic focal epilepsies. Finally, it is essential to evaluate the degree of impairment caused by the epileptic condition and to try to establish a prognosis in parallel to making decisions about the therapeutic measures to be exhibited. These steps are strongly influenced by analysis of seizure type and the syndromic diagnosis.

EPILEPTIC SEIZURES Three great categories have been identified—generalized, partial or focal seizures, and unclassified seizures. Here they are described as individual events, with a well-defined temporal course from onset to termination. Almost every type of seizure can occur continuously or repetitively, thus constituting status epilepticus. In this case, some of the seizure characteristics may become less readily identifiable.

Generalized Seizures In generalized seizures, the paroxysmal discharge involves both hemispheres simultaneously and in a diffuse manner. Clinical manifestations are usually bilateral and symmetrical. The electroencephalographic correlates consist of spikes, polyspikes, spikes and waves, or polyspikes and waves that are typically bilateral, synchronous, and symmetrical in the two hemispheres.

Tonic-Clonic Seizures Also termed grand mal seizures, these are the most frequent generalized seizures. Typically they start with a tonic phase of 10 to 20 seconds, a scream, a sustained contraction of all the skeletal musculature initially in flexion, followed by extension. Apnea and vegetative changes are frequent, and tongue biting, typically affecting the lateral part of the tongue, may occur at this stage. A clonic phase follows with bilateral synchronous jerking activity that slows progressively, before stopping after a duration on the order of 30 seconds. It is followed by a phase of resolution lasting from a few minutes to several tens of minutes. The patient is unconscious, completely hypotonic, and enuresis may occur. Breathing is unencumbered but eventually disturbed by bronchial and salivary hypersecretion. The patient may sleep immediately or return to a normal state of consciousness after a variable phase of confusion. The electroencephalogram consists of fast activity, initially of low voltage and then of increasing amplitude during the tonic phase; polyspikes or polyspike-waves characterize the clonic phase. Muscular artifacts often mask the epileptic electrical activity. Slow waves appear during the postictal period and may persist for several hours or days.

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Clonic Seizures These consist of bilateral clonic jerks with progressively decreasing frequency and unconsciousness, and they occur most often in children, sometimes in the context of a febrile seizure.

Tonic Seizures These are characterized by sustained muscular contraction, alteration of consciousness, apnea, and vegetative changes, which may occur in clusters. They may predominate in the axial musculature, leading to sudden falls and injury. They may also occur at night. They are generally encountered in the context of severe epileptic encephalopathies in association with other seizure types. Electroencephalographic correlates consist of a progressively recruiting discharge of generalized polyspikes.

Absence Seizures Typical absence seizures are characterized by sudden episodes lasting 5 to 30 seconds, during which patients (most often children) lose contact with their surroundings and stop normal activity, before returning instantaneously to normal, without any memory of these events. Associated manifestations such as mild clonic, atonic, or vegetative components, as well as automatisms, are possible. More pronounced myoclonic activity affecting the eyelids or perioral muscles may suggest a syndrome that is now regarded as separate from typical and usually benign absence epilepsy. Typical absences are associated with regular 3-Hz spike-wave electroencephalographic activity and are usually precipitated by hyperventilation. Atypical absences present with a more progressive onset and less abrupt termination and with a longer duration with lesspronounced loss of consciousness. Tonic, atonic, or myoclonic components are more obvious, and head dropping or falls are also possible. They are associated with bilateral spike-wave activity, often irregular and asymmetrical and slower than in typical absences. The electroencephalographic background is often abnormal; other seizure types are also frequent, reflecting the commonly associated underlying seizure-related encephalopathy

Myoclonic Seizures They are described as brief muscular contractions, inducing jerks of the limbs or of the neck, sometimes leading to dropping of objects or even falls. A bilateral and synchronous discharge of polyspike-waves is the typical scalpelectroencephalogram correlate. Careful neurophysiological analysis may be useful in identification of negative myoclonias that are characterized by a brief interruption of muscular tone. The generators involved in negative myoclonic phenomena are presumed to be cortical, but in some instances subcortical areas and even the spinal cord are implicated. The associated jerks are generally considered to be nonepileptic myoclonias.

Atonic Seizures They correspond to a loss of postural tone, leading to a fall or limited to a head drop. Their duration varies from seconds to minutes. The electroencephalogram usually consists of a slow

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and irregular discharge of spike-waves, which are usually seen in the context of childhood epileptic encephalopathies.

Partial Seizures Partial seizures are very polymorphic, they reflect the function of the brain area where they take origin—the focus or the epileptogenic zone and of the pattern of spread of epileptic activity. They are, however, remarkably stereotyped in individual patients. The first clinical symptoms of a seizure have strong localizing value. When they are perceived by the patient, they define the aura. A postictal deficit can be observed, resulting from acute dysfunction of some brain areas that have been involved by the epileptic discharge. A postictal deficit may be motor, a hemianopsia, or an aphasia. Clinically, these are generally of good lateralizing value. Interictal and ictal scalp electroencephalographic abnormalities may correlate more or less with the brain areas invaded by the discharge, but they can be difficult to detect when epileptic neuronal activity remains confined within small or deep brain areas. Intracerebral recordings with stereotaxically implanted electrodes performed in candidates for surgical treatment have contributed considerably to an understanding of anatomical-clinical correlations in partial seizures. The terminology of simple partial seizure is used when the patient remains conscious, whereas complex partial is used when some degree of altered consciousness can be identified. The latter generally implies that larger or bilateral brain areas are involved by the ictal discharge. In the absence of videoelectroencephalographic monitoring and direct interaction with the patient during a seizure, it is not always possible to ascertain the presence or absence of brief, partial alterations of consciousness. Although the dichotomy of simple versus complex may be useful in terms of appreciating seizure severity, its significance otherwise is questionable. Recent classifications give priority to associated features.

Simple Partial Seizures With Motor Symptoms In somatomotor seizures with a jacksonian march, the epileptic discharge moves along the precentral motor strip, although it remains confined to the rolandic cortex. Clinically, a tonic contraction is followed by clonic jerks that initially affect a specific part of a limb or one half of the face, which then propagate to adjacent body parts as a function of the somatotopic representation. Other types of somatomotor seizures combine various patterns of clonic and/or tonic and postural manifestations that affect a more or less extensive part of one half of the body. The contralateral discharge involves simultaneously the primary motor cortex and premotor areas. A rotation of the head and/or of the eyes is frequent. Oculomotor symptoms may also result from an occipital lobe discharge. When head deviation is associated with an elevation in abduction of the ipsilateral arm, speech arrest, or vocalization, the supplementary motor area is often implicated. Paroxysmal speech disorders such as speech arrest, vocalization, and pallilalia can be observed with seizures affecting the third frontal gyrus. Jargon phasia evokes the possible implication of the superior temporal gyrus.

With Somatosensory or Special Sensory Symptoms Somatosensory seizures result from a discharge affecting the postcentral gyrus. Contralateral manifestations involving more or less extensive parts of one half of the body may include sensations of tingling, numbness, paraesthesias, or pain. Visual seizures corresponding to a discharge in the occipital cortex are characterized by elementary hallucinations that can be positive (flashing lights, colored dots, etc.) or negative in the form of scotomas. More complex or elaborate visual hallucinations such as brief scenarios, macropsia, and the like generally result from implication of occipital and temporal regions. Auditory seizures may include sound or voice distortions or hallucinations (noise, music). They result from discharges in the superior temporal gyrus (Heschl’s gyrus). Olfactory hallucinations are usually described as the sudden perception of an unpleasant odor. They result from involvement of the region of the uncus of the temporal lobe but sometimes of the orbitofrontal cortex. Gustatory seizures, sometimes difficult to differentiate from olfactory manifestations, have their origin in the posterior supra-sylvian cortex. Vertiginous symptoms may rarely be an epileptic manifestation, sometimes associated with a floating sensation, implicating the inferior parietal region.

With Autonomic Symptoms Autonomic symptoms (pallor, sweating, flushing, piloerection, pupillary dilation) can be generated by many areas of the brain, both cortical and subcortical. They have little localizing value and are frequently associated with other manifestations of partial seizures. An ascending epigastric sensation, frequently of mesial temporal origin, may also be generated by the insula and mesial frontal regions. Many components of the autonomic system can be involved—digestive, ocular, urinary, respiratory, and cardiovascular. Some symptoms result from disturbance of the thermoregulatory system.

With Psychic Symptoms These are characterized by conscious disturbances of higher cortical functions expressed by perceptive, mnesic, or affective manifestations. The term “dreamy state” covers diverse phenomena or illusions, including feelings of strangeness, unreality, reminiscence of past experiences, and familiarity (déjà vu, déjà vécu). They often result from paroxysmal disorganization of mesial temporal lobe structures, leading to false interpretations of normally encoded notions. Affective symptoms include fear, anxiety, even terror, and, more rarely, euphoria or sensations of pleasure. Phenomena of forced thinking are also encountered, generally implicating the frontal lobes. Gelastic (laughter) seizures, generally occurring without any affective component, are highly suggestive of a hypothalamic origin and hamartomatous pathology.

Complex Partial Seizures These are defined by a disturbance of consciousness, either at onset or after an initial phase of simple partial manifestations (aura). They are often accompanied by automatisms, gestural, oroalimentary (masticatory, swallowing), verbal, or more or

chapter 50 clinical spectrum less elaborated or adapted behavioral sequences. All of these automatisms, taken separately, have very little localizing value. Their sequence or combination of such diverse automatisms with other manifestations, however, may have some localizing value. A masticatory automatism is a good indicator of involvement of the amygdala in the context of temporal lobe seizures. The mesial temporal lobe is frequently at the origin of complex partial seizures that include an aura, often an ascending epigastric sensation with autonomic or psychic symptoms, with fear being frequent. Alteration of consciousness begins with an arrest or staring reaction, followed by oroalimentary automatisms, gestual automatisms, and limb dystonia (most often contralateral to the focus). A postictal dysphasia may be present if the dominant hemisphere is implicated. However, complex partial seizures may take their origin in other regions of the brain. The frontal lobes can generate either absence-like seizures or prominent motor automatisms.

Unclassified Seizures Many seizures remain difficult to classify in the absence of other data (interictal electroencephalography, brain imaging). For instance, nocturnal convulsive events may correspond to primary or secondary generalized tonic-clonic seizures. Many neonatal seizures are difficult to analyze. Spasms, most often infantile, consist of brief muscular contractions in flexion or extension that occur in clusters. Whether they should be considered as generalized seizures or as unclassified seizures is unclear.

Reflex Seizures Seizures can also be characterized by a specific mode of precipitation, independent of their classification into partial or generalized. Many precipitating stimuli eliciting reflex seizures have been described: ■ Visual stimuli, flickering light—color, particular patterns

(black-white contrast) ■ Diverse stimuli: eating, reading, somatosensory, proprio-

ceptive, contact with water, audiogenic, thinking music ■ Startle seizures

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T A B L E 50–2. International Classification of Epilepsies and Epileptic Syndromes 1. Focal syndromes (also partial or localization-related) a. Idiopathic, age-related Benign childhood epilepsy with centrotemporal spikes Childhood epilepsy with occipital paroxysms Reading epilepsy b. Symptomatic Continuous partial epilepsy (Kojewnikow’s syndrome) Lobar epilepsies (some common causes: vascular, infectious, tumors, degenerative, malformation of the cerebral cortex, traumatic) Frontal lobe epilepsies Temporal lobe epilepsies Parietal lobe epilepsies Occipital lobe epilepsies Multilobar epilepsies c. Cryptogenic (in fact, presumed symptomatic) 2. Generalized syndromes a. Idiopathic, age related in chronological order Benign neonatal seizures (familial or not) Benign myoclonic epilepsy in infancy Childhood absence-epilepsy (petit mal) Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with grand mal seizures on awakening b. Cryptogenic or symptomatic Infantile spasms (West’s syndrome) Lennox-Gastaut syndrome Myoclonic-astatic epilepsy Epilepsy with myoclonic absences c. Symptomatic Without specific etiology Early myoclonic encephalopathy Encephalopathy with suppression burst (Ohtahara’s syndrome) With specific etiology* 3. Undetermined as to focal or generalized a. Combination of focal and generalized seizures Neonatal seizures Severe myoclonic epilepsy in infancy (Dravet’s syndrome) Epilepsy with continuous spike waves during slow wave sleep Epilepsy with acquired aphasia (Landau-Kleffner syndrome) b. Without unequivocal generalized or focal features 4. Special syndromes (that do not require a diagnosis of epilepsy) a. Febrile seizures b. Alcohol withdrawal seizures c. Drug or other chemically induced seizures d. Immediate and early post-traumatic seizures e. Single seizures or isolated clusters of seizures

EPILEPSIES AND EPILEPTIC SYNDROMES

*Many metabolic or degenerative etiologies are possible. The progressive myoclonic epilepsies like Lafora and Unverricht-Lundborg diseases are classified here.

A classification system is extremely useful from many points of view—the determination of diagnosis criteria, the elaboration of a strategy for organizing complementary investigations, the rationalization of therapeutic options based on the efficacy profile of the different drugs, the establishment of a prognosis, and the facilitation of clinical research. The international classification (Table 50–2) may give the impression that it is simply a very long list of diseases, without providing the reader with some essential organizing notions like frequency or severity. Some syndromes are very frequent, whereas others correspond to orphan diseases, emphasizing an extraordinarily vast and diversified spectrum. The current international classification is based on two main axes, or dichotomies. The first axis refers to the notion of partial versus generalized syndromes. In generalized epilepsies, all of the seizures are generalized seizures; the electroencephalo-

graphic characteristics are bilaterality, diffuseness, and symmetry. In partial or focal epilepsies, seizures take their origin in a focal or an epileptic zone, regardless of the fact that some seizures may become secondarily generalized. However, the term focal does not mean the epileptogenic region is a small, well-delineated focus of neuronal pathology. Focal seizures and syndromes are often due to diffuse and at times widespread areas of cerebral dysfunction. Furthermore, for several syndromes, it is unclear whether they are focal or generalized. In fact, there is a variety of conditions giving rise to a range of focal through generalized epilepsies that include diffuse hemispheric abnormalities, multifocal abnormalities, and bilaterally symmetrical localized abnormalities. Although concepts of partial and generalized epileptogenicity have value, perhaps more with respect to ictal events than to syndromes, it may not

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be appropriate or even useful to attempt to classify all seizures and syndromes within one or the other of these categories. The second axis opposes the notions of idiopathic versus symptomatic. In idiopathic epilepsies, there is no brain lesion and the main etiological factor is a genetic predisposition that is identified or presumed. Symptomatic epilepsies result from structural changes in the brain, whether fixed abnormalities (scar, malformation of the cortex) or evolving damage (metabolic or degenerative disease). Brain imaging (MRI) or biological markers show the pathological context. Electroencephalographic background activity may also indicate focal regions of brain dysfunction. The term cryptogenic (presumed symptomatic) was introduced to qualify symptomatic epilepsies for which structural changes are presumed to exist but cannot be identified by current investigations. The use of brain MRI has reduced considerably the number of cryptogenic varieties by permitting the identification of hippocampal sclerosis and a variety of other malformations of the cerebral cortex. The classification should be regarded as an evolving one. Progress in genetics and brain imaging is having a major impact on different concepts of epileptogenesis. Indeed, the rapidly moving field of genetics has contributed greatly to a better understanding of some epileptic disorders. But the relationship between genetic variations or mutations and phenotypic expression remains complicated. Because a single, relatively well-defined, idiopathic epilepsy syndrome can be due to more than one genetic abnormality and because members of a family sharing a common genetic abnormality can present with different epilepsy syndromes, it is premature to attempt a classification of epilepsy syndromes solely on the basis of specific genetic etiologies.

Febrile Seizures: A “Special Syndrome” Febrile seizures are the most common human convulsive event with an incidence of 2% to 5% in Europe and North America, higher figures being observed in Asia. They are not viewed as constituting a true epileptic disease but rather as a special syndrome characterized by the provoking factor, fever and a typical age range of 6 months to 6 years. Febrile seizures are brief generalized, clonic, tonic-clonic or atonic seizures, occurring without evidence of intracranial infection, other definable cause, or antecedent unprovoked seizures. They recur in 30% to 40% of cases. They are benign and do not require antiepileptic drug treatment. Although the prognosis is usually very good, individuals who have experienced febrile seizures run a higher risk of developing spontaneous, afebrile seizures with an incidence of 2% to 7%, two to ten times higher than in the general population.

Juvenile Myoclonic Epilepsy: The Most Common Idiopathic Generalized Epilepsy Juvenile myoclonic epilepsy is characterized by myoclonic seizures. It is the most common idiopathic generalized epilepsy of adults, especially in women. Isolated myoclonic jerks of the arms, especially shortly after awakening, are characteristic. Generalized tonic-clonic seizures often occur, and one third of individuals also have absences. Seizure occurrence is more likely with sleep deprivation, fatigue, and alcohol withdrawal.

Onset is usually in adolescence, but seizures may begin or be diagnosed only in the early 20s. The typical abnormality on electroencephalography is bilateral multiple spike or polyspike and wave complexes at a rate of four to six per second, with anterior predominance. Photosensitivity occurs in about 30%, especially in women, but the two disorders appear to be inherited separately. Valproate is the drug of choice. Juvenile myoclonic epilepsy accounts for up to 26% of patients with idiopathic generalized epilepsy and up to 10% of all cases of epilepsy, but misdiagnosis and delayed diagnosis remain common. Patients may come to medical attention only after a generalized convulsion, and the history of much earlier myoclonic jerks is often obtained only retrospectively.

Autosomal Dominant Nocturnal Frontal Epilepsy: A Model of Idiopathic Partial Epilepsy Onset usually occurs in infancy. This disease is characterized by clusters of frequent brief partial seizures during sleep. Some patients also have rare diurnal seizures. The motor component of seizures predominates (paroxysmal dystonic postures, thrashing, deambulation). The symptoms can be limited to sudden arousals, and the level of awareness may be variably altered during attacks. Vocalizations or aura of various sorts may precede the motor manifestations. Misdiagnoses are frequent; there is particular confusion with familial parasomnias (nocturnal terrors, somnambulism). Seizures often persist throughout adulthood but may become less frequent and sometimes disappear. The course of the epileptic disorder may be severe in other individuals of the same family, with seizures refractory to conventional antiepileptic drugs. Neurological examination and structural imaging (MRI) are normal, and although seizures begin at an early age, intellectual development and behavior are usually normal. Genetic studies of families have discovered mutations affecting genes coding for subunits of the nicotinic cholinergic receptor.

Severe Myoclonic Epilepsy in Infancy: The Concept of Epileptic Encephalopathy The term epileptic encephalopathy characterizes severe epileptic conditions where the repetition of seizures and status epilepticus induce or aggravate cognitive and/or motor dysfunction. Severe myoclonic epilepsy in infancy, or Dravet’s syndrome, begins around 6 months of age in apparently normal infants. The first event may be an unremarkable or a prolonged febrile seizure. Then the child develops prolonged generalized or hemiclonic seizures, often triggered by fever, with frequent status epilepticus. Other seizure types, such as myoclonic, atypical absences, and focal seizures, are frequent. The electroencephalogram, which is normal interictally at the beginning, worsens with permanent generalized, focal, and multifocal abnormalities. In addition, progressive psychomotor delay, gait, and coordination disorders develop. In general, pharmacoresistance appears rapidly. The outcome is poor, with a 15% mortality rate. The physiopathology is not well understood, but a large proportion is associated with ion channel gene defects (mutations of SCN1A, a gene coding for a subunit of the sodium channel). The vast majority of severe myoclonic epilepsy in infancy is sporadic, with de novo mutations.

chapter 50 clinical spectrum Mesial Temporal Lobe Epilepsy: A Surgically Remediable Syndrome The temporal lobe is a vast lobe of the brain with distinct regions: a pole, a lateral aspect including peri-sylvian areas, and mesial structures including the amygdala, the hippocampal formations, and associated limbic cortices. Temporal lobe epilepsy may be caused by different etiologies—tumor, vascular malformations, or cortical dysplasias. However, in almost 50% of cases, hippocampal sclerosis is the major pathological substrate and is implicated in seizure generation, leading to the concept of mesial temporal lobe epilepsy. Patients have frequent antecedents of febrile seizures, often prolonged (complex febrile seizures). The onset of afebrile seizures occurs after a latency period of several years. The first manifestations can be subtle simple partial seizures (auras) with autonomic or psychic symptoms that may be unrecognized until the first secondarily generalized seizure. The clinical features of partial seizures include an aura, often epigastric, with autonomic or psychic symptoms followed by an alteration of consciousness, an arrest or staring reaction, oroalimentary automatisms, gestural automatisms, and limb dystonia; a postictal dysphasia may be present if the dominant hemisphere is implicated. Electroencephalography shows a temporal lobe interictal and ictal focus. The presence of hippocampal sclerosis, detectable by MRI, is strongly suggestive when the picture is not typical. Medical intractability is frequent, as is memory impairment. The surgical prognosis is good overall. However, mesial temporal lobe epilepsy is not a model of pure focal epilepsy; it is more of a regional disease.

Generalized Epilepsy With Febrile Seizure Plus: Familial Versus Conventional Epileptic Syndromes The concept of generalized epilepsy with febrile seizures plus was introduced by Scheffer and Berkovic to describe families in which febrile seizures coexist with epilepsy. In this heterogeneous familial context, some affected members exhibit a particular febrile seizure, termed febrile seizures plus, because the fits persist beyond the classic limit of 6 years of age. On the other hand, other family members may have typical febrile seizures, which disappear before the age of 6. Moreover, varying types of afebrile seizure are observed in affected individuals, most often generalized seizures, tonic-clonic, absences, atonic, tonic, and myoclonic seizures. Absence seizures are often atypical, with a longer duration and lower frequency than in typical childhood absence epilepsy. Electroencephalographic abnormalities usually consist of diffuse spike-wave patterns and photosensitivity may be present. Afebrile seizures may begin during childhood in association with the febrile seizures; this continuum between febrile and afebrile seizures is typical of the concept of generalized epilepsy with febrile seizures plus syndrome. Afebrile seizures may also appear after a seizure-free period or in subjects without a previous febrile seizure history. Seizures may cease around the age of 10 to 12 years, whereas in other patients seizures are persistent and difficult to treat. Hemiconvulsive, temporal, and frontal lobe seizures have, however, also been reported, extending the concept of generalized epilepsy with febrile seizures plus spectrum to partial

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seizures and further increasing its phenotypic diversity. This familial syndrome, which differs from conventional epileptic syndromes, has proved to be extremely fertile in terms of genetic characterization, and several ion channel genes, SCN1B, SCN1A, and GABRG2, have been implicated so far.

PROGNOSIS: FROM BENIGN CONDITIONS TO DEVASTATING DISEASES The evaluation of the prognosis and an appreciation of the degree of impairment caused by the epileptic condition are essential and should be based on both the nature of the syndrome and the characteristics of individual patients. After a first unprovoked seizure, the overall risk of relapse at 2 years ranges from 25% to 52%, with a median of 38%. In newly diagnosed epilepsy, the overall prognosis for full seizure control is very good, with more than 70% of patients achieving long-term remission, the majority within 5 years of diagnosis. Beyond these global estimates of prognosis, more precise information concerning outcome for a given individual should be based on a syndromic approach. The prognosis of the idiopathic generalized epilepsies is generally good. In absence epilepsies, the absence seizures are easily controlled by drug treatment and disappear in most of the patients during adolescence. Some generalized tonic-clonic events are possible later on. However, a late onset (juvenile absence epilepsy) or the presence of eyelid or perioral myoclonus indicates a higher risk of seizure persistence and necessitates longer treatment. In juvenile myoclonic epilepsy, the response to treatment is usually very good, but relapses occur in 90% of cases if treatment is discontinued. Epileptic encephalopathies carry a poor prognosis. Psychomotor development is impaired, and personality or psychiatric disorders are often present. Treatments are rarely efficacious, or only in a transitory manner, even with polytherapy. Cyclical periods of seizure aggravation occur with falls and injuries and sometimes with status epilepticus. Iatrogenic complications are frequent, with global slowing, somnolence, ataxia, and deterioration of cognitive impairment. The prognosis of symptomatic partial epilepsies is highly variable. The risk of pharmacoresistance to antiepileptic drugs is relatively high. This risk is influenced by the nature of the underlying brain lesion. For instance, the probability of being seizure free for a year with treatment is 50% to 60% in the case of poststroke epilepsy, whereas it decreases to 10% to 20% in cases of malformation of the cerebral cortex or of hippocampal sclerosis. People with epilepsy, despite an overall good prognosis for seizure control, have a greater risk of death compared with those without epilepsy. This increased risk is most evident in people with chronic epilepsy, particularly the young, and those with symptomatic epilepsy. Trauma, suicide, pneumonia, status epilepticus, and seizures cause death in people with epilepsy more frequently than in the general population. Sudden unexpected death in epilepsy is increasingly recognized, especially in persons with severe epilepsy. The mechanism of sudden unexpected death in epilepsy is unknown. Suggestions have been made that substandard care may contribute to the risk, but this theory needs to be formally investigated.

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Suggested Reading

K E Y

P O I N T S

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The expression of epileptic seizures is very diverse and depends on the function of the part of the brain that is involved by the abnormal neuronal discharge.

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The annual overall incidence of epilepsy is generally believed to be around 50 per 100,000 (range, 40 to 70 per 100,000 per year) in industrialized countries, but socioeconomically deprived people are at greater risk. In terms of prevalence, several studies conducted in different regions of the world have suggested that epilepsy affects 5 to 8 per 1000 population.

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A syndromic diagnosis relies on the grouping of information: on seizure type or types, pattern of recurrence or frequency, age at onset, personal and familial antecedents, natural history and other neurological and extraneurological manifestations.

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The International Classification of Seizures and International Classification of Epilepsies and Epileptic Syndromes are important consensus instruments that permit communication about this clinically very broad condition in a meaningful manner.

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The evaluation of the prognosis and an appreciation of the degree of impairment caused by the epileptic condition are essential and should be based on both the nature of the syndrome and the characteristics of individual patients.

Fish DE, et al (ed): The Treatment of Epilepsy. London: Blackwell Science (UK), 2004. Kotagal P, Luders H: The Epilepsies: Etiologies and Prevention. New York: Academic Press, 2001. Shorvon S: Handbook of Epilepsy Treatment. Boston: Blackwell Publishing, 2005. Schmidt D, Schachter SC: Epilepsy: Problem Solving in Clinical Practice. New York: Taylor & Francis, 1999.

CHAPTER

GENETICS ●

OF ●

●

51

EPILEPSY ●

John M. Lynch and Sanjay M. Sisodiya

Epilepsy is a heterogeneous group of conditions, with a very broad range of possible causes, manifesting as recurrent, unprovoked, clinical seizures, sometimes with additional neurological or extraneural features. It is the most common serious neurological disorder, affecting 5 per every 1000 people, and is associated with increased rates of mortality and morbidity in almost every sphere of life for affected patients. The types of epilepsy can be subdivided in a number of ways; classification schemes focus variously on seizure types, natural history, or etiology. Although there are many causes of epilepsy, it is likely that an individual’s genetic makeup contributes to or modulates, to some degree, the risk of developing epilepsy in response to another insult to the brain, whatever the nature of the insult. Genetic differences between individuals take a number of forms: there are rare variants, called mutations, each of which occurs in less than 1% of the population and usually in a far smaller percentage; there are more common variants, the most common type of which is known as single-nucleotide polymorphism (SNP), a variation occurring at a single nucleotide and seen in greater than 1% (and usually greater than 5%) of the population (Fig. 51–1). For most people with epilepsy, any genetic contribution to etiology is likely to arise from the additive, individually small effects of SNPs in a number of genes; understanding these effects requires analysis of large numbers of homogeneous groupings of patients and constitutes the field of population genetics. However, this area is only now beginning to be addressed by researchers in epilepsy. Most research to date on epilepsy genetics has concentrated on epilepsy caused by genetic mutations; almost by definition, such types of epilepsy are individually rare and even grouped together are unlikely to account for more than a small proportion of cases of epilepsy. The hope of research on these rare types of epilepsy caused by mendelian genetics is not only to inform disease management in affected individuals but also potentially to cast light on the genetics, pathophysiology, and management of epilepsies more broadly. In fact, this latter aim has yet to be realized, but certainly many epilepsies caused by single gene mutations are now known (Table 51–1) and account for a majority of the disorders covered in this chapter. Most of the genes implicated encode neuronal ion channels that directly affect neuronal excitability, or they function through alteration in ion flux; the finding that channelopathies cause seizures was a surprise initially, but it stands to reason because excitation and inhibition are fundamental

neuronal properties, and seizures are generally held to arise from a systems imbalance between excitation and inhibition. There are more than 200 genetically mediated conditions in which epilepsy is part of a broader phenotype. These conditions are not considered here; this chapter illustrates concepts of epilepsy genetics, drawing from genetic disorders in which the major and often sole manifestation is epilepsy. A glossary is given in Table 51–2.

MONOGENIC INHERITED EPILEPSIES This is the most researched and best understood facet of epilepsy genetics, because well-established genetic methods can relatively easily be applied to large kindreds with the clinical phenotype of epilepsy. The work has shown that even among or within families with a similar or identical mutation in a particular gene, there can be prominent differences in phenotypic expression: conversely, for individuals apparently suffering from an identical clinical type of epilepsy, there can be different underlying genetic abnormalities.

Generalized Epilepsies The broadest subdivisions of the epilepsies are that of generalized epilepsy, in which seizure discharges involve the majority of the cerebral hemispheres from the outset, and that of focal epilepsy, in which the seizure discharge starts focally (and may spread). Traditionally, it has been held that the genetic contribution to the epilepsies is greatest for the generalized epilepsies.

Juvenile Myoclonic Epilepsy This syndrome is characterized by the occurrence of myoclonic jerks, generalized tonic-clonic seizures, and absence seizures with onset in the early teens, normal magnetic resonance imaging findings, and a characteristic electroencephalographic pattern. Familial cases occur, and despite widespread acceptance that there is, even in sporadic cases, strong genetic susceptibility to juvenile myoclonic epilepsy (JME), only two responsible genes are known.1,2 Linkage has been described for JME in two regions of the short arm of chromosome 6 (6p12-11 and 6p21.3).3,4 Suzuki

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Subject 1

a

b

c c' d

e

f

g

a

b

c c' d

e

f

g

Subject 2

A chromosome is represented schematically in green for two subjects. Genes, including exons and introns, are represented in brown. Single-nucleotide polymorphisms (SNPs) are represented by the narrow vertical blue or yellow bars. Subjects 1 and 2 differ for a number of SNPs—for example, at position (a), Subject 1 has a blue bar and Subject 2 a yellow bar. Some SNPs may affect the function of the gene within which they lie, and the function of the protein encoded. SNPs affecting gene function may be at some distance to the gene itself. Thus, whether the SNP at position (c) is blue, as in Subject 1, or yellow, as in Subject 2, may determine, for example, whether or how a subject responds to a given drug. Such variants that cause alteration in a given clinical phenotype are known as "causal variants." Usually, the identity of a causal variant causing a given phenotype is unknown. Often, a nearby SNP, such as that in position (c'), may be known. If the identities of (c) and (c') usually vary together with a high degree of predictability (in which case they are said to be in linkage disequilibrium), then the state (blue or yellow, in this case) of the causal variant (c) might be predicted with a reasonable degree of certainty by typing (determining) the state of the associated variant SNP (c'). Haplotypes are combinations of a given set of SNPs. Usually, the identity of a larger set of SNPs of interest within a given genomic region can be predicted with reasonable certainty by typing a smaller representative subset of SNPs, affording a more economic strategy for studying genetic variation, including that associated with drug response: if the causal variant, or variants, is unknown but likely to reside within the larger set, its influence on drug response can usually be represented by typing the representative selection of SNPs (these representative SNPs are known as haplotype-tagging SNPs). This approach is now being adopted in some large population-based pharmacogenetic studies. ■

Figure 51–1. An illustration of some pharmacogenetic principles.

and associates (2004)2 examined 18 genes encoded in the linked 6p12-11 region. They discovered mutations in only one gene, EHFC1. They described five missense mutations in EHFC1, which encodes a protein with an EF-hand motif that cosegregated with epilepsy or electroencephalographic polyspike and wave activity in six unrelated families and was not detected in 382 control individuals. However, mutations were detected in only 6 of 44 families with JME examined. Although mutations in EHFC1 are the first described for JME, this study also highlights the underlying genetic heterogeneity of this condition. Genetic heterogeneity may also explain the variable mode of inheritance for JME. Elmslie and colleagues described linkage of JME to 15q14.5 Cossette and associates1 described autosomal dominant inheritance in a French-Canadian family with linkage to 5q34. This region includes the genes for a number of γ-amino butyric acid (GABA) receptor subunits and has since been shown to contain a causative mutation in the GABRA1 gene.

Generalized Epilepsy with Febrile Seizures Plus (GEFS+) Investigators have described families in which some members have febrile seizures persisting beyond the usually accepted upper age limit for the diagnosis of such seizures (6 years) and are thus denoted “febrile seizures plus”; other members of the same family may have generalized epilepsy. Within such families there can be wide phenotypic variability; febrile seizures, febrile seizures plus, generalized epilepsy, hemiconvulsive seizures, and temporal lobe or frontal lobe seizures may occur.

Some members with generalized or partial epilepsy may not have had febrile seizures or suffer from a number of different seizure types, and some members may have febrile seizures but never suffer another seizure beyond the age of 6. Generalized epilepsy with febrile seizures plus (GEFS+) has an autosomal dominant pattern of inheritance with reduced (70% to 80%) penetrance. GEFS+ displays genetic heterogeneity, inasmuch as mutations in different ion channel genes can give rise to similar phenotypes. The most frequent site of mutation in patients with febrile seizures plus (57%) is the in the SCN1A gene6; some mutations probably result in defective fast inactivation of channel gating and neuronal hyperexcitability. Mutations causing GEFS+ have also been described in SCN1B, SCN2A, and the GABA receptor gene GABRG2 (see Table 51–1). GABAA receptors contain an integral chloride channel that mediates synaptic inhibition. There are specific binding sites for GABA, barbiturates, benzodiazepines, and steroids. Bowser and associates reported altered kinetics and benzodiazepine sensitivity of a GABA receptor subunit mutation, GABRG2 R43Q, in a family with childhood absence epilepsy and febrile seizures.7 GEFS+ may possibly be more correctly termed autosomal dominant epilepsy with febrile seizures plus because of the large degree of phenotypic variability within families.8

Severe Myoclonic Epilepsy in Infancy (Dravet’s Syndrome) Severe myoclonic epilepsy in infancy (SMEI), or Dravet’s syndrome, is rare. Individuals with previously normal development

chapter 51 genetics of epilepsy

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T A B L E 51–1. Genetics of Monogenic Inherited Epilepsies Epileptic Disorder

Mode of Inheritance

Monogenic Epileptic Syndromes of Early Life Benign familial neonatal convulsions (BFNC)

AD

Benign familial neonatal infantile seizures (BFNIS) Benign familial infantile convulsions (BFIC)

Idiopathic Partial Epilepsies Autosomal dominant nocturnal frontal-lobe epilepsy

Locus

Gene

Protein

20q (EBN1) 8q (EBN2) 2q

KCNQ2 KCNQ3 SCN2A

Voltage-gated K channel Voltage-gated K channel α2 Subunit of the voltage-gated Na channel

AD

19q 16p 2q

Unknown Unknown Unknown

Unknown Unknown Unknown

AD

20q13.2 15q24 1 (pericentromere) 10q

CHRNA4 Unknown CHRNB2 LGI1

α4 Subunit of nAChR Unknown β2 Subunit of nAChR Epitempin

2qter 22q 16p

Unknown Unknown Unknown

Unknown Unknown Unknown

6p12-11 6p21.3 5q34 15q14 3q26 8q24 2p 8q13-21 (FEB1) 19p (FEB2) 2q23-24 (FEB3) 5q14-15 (FEB4) 6q22-24 (FEB5)

EHFC1 Unknown GABRA1 Unknown CLCN2 Unknown Unknown Unknown Unknown Unknown Unknown Unknown

EHFC1 protein Unknown α1 Subunit of the GABAA receptor Unknown ClC-2 (voltage-gated chloride channel) Unknown Unknown Unknown Unknown Unknown Unknown Unknown

19q (GEFS+1) 2q31 (GEFS+2) 2q31 5q31 (GEFS+3) 2q31 5q31

SCN1B SCN1A SCN2A GABRG2 SCN1A GABRG2

β1 Subunit of the voltage-gated Na channel α1 Subunit of the voltage-gated Na channel α2 Subunit of the voltage-gated Na channel γ2 Subunit of the GABAA receptor α1 Subunit of the voltage-gated Na channel γ2 Subunit of the GABAA receptor

AD

Familial lateral temporal-lobe epilepsy with auditory symptoms (ADPEAF) Familial partial epilepsy with variable foci

AD

Familial rolandic epilepsy with paroxysmal exercise-induced dystonia and writer’s cramp

AR

Idiopathic Generalized Epilepsies Juvenile myoclonic epilepsy

Idiopathic generalized epilepsies Benign adult familial myoclonic epilepsy Familial Febrile Seizures

AD

AD AD

AD AD AD AD AD

Generalized Epilepsy with Febrile Seizures Plus (GEFS+) AD AD AD AD Severe Myoclonic Epilepsy in Infancy De novo or transmitted

Modified from Gourfinkel-An I, Baulac S, Nabbout R, et al: Monogenic idiopathic epilepsies. Lancet Neurol 2004; 3:209-218. AD, autosomal dominant; AR, autosomal recessive; GABA, γ-amino butyric acid; K, potassium; Na, sodium; nAChR, nicotinic acetylcholine receptor.

develop severe epilepsy in their first year of life, initially with myoclonic seizures, cognitive decline, and ataxia; subsequently, myoclonic seizures may abate and other seizure types predominate. Patients frequently suffer febrile seizures and status epilepticus. Mutations in SCN1A, accounting for 35% of sporadic cases9 and GABRG2 in only one familial case,10 have been discovered to underlie SMEI. Of interest is that different mutations in the same gene (SCN1A) can cause both familial epilepsy with a relatively mild phenotype and sporadic epilepsy with a devastating one.

on day 2 or 3 after birth, usually remitting spontaneously by 8 months of age, and is not associated with any psychomotor impairment. However, approximately 11% of these patients subsequently develop epilepsy. It was the first idiopathic epilepsy to be genetically linked. Causative mutations have been identified in voltage-gated potassium channel genes (KCNQ2 and KCNQ3) (Fig. 51–2).11-16 Of interest is that mutations in the homologous KCNQ1 gene result in the long QT and Jervell– Lange-Nielsen cardioauditory syndromes.17,18

Benign Familial Infantile Convulsions Focal Epilepsies Benign Familial Neonatal Convulsions This is an autosomal dominant condition with high penetrance. It is characterized by the development of multiple seizure types

An autosomal dominant disorder, this is characterized by convulsions beginning at 3 to 12 months of age, with a very good prognosis. There has been strong linkage to chromosomal locus 19q in five Italian families.19 Benign familial infantile convulsion has been also been linked to chromosomal locus 2q20 and is reported with paroxysmal dyskinesias in another condi-

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K+ channel

Na+ Ca2+

Na+ channel

GABAAR

Cl- channel

Na+

Cl-

Cl-

Extracellular

β2α1/2

β2α

α γ2

Intracellular K+ ADNFLE ■

BFNC

GEFS+ SMEI BFNIS

GEFS+ ADJME

ADIGE

Figure 51–2. Voltage-gated or ligand-gated channels involved in genetically determined epilepsies. AchR, acetylcholine receptor; GABAAR, γ-amino butyric acid A receptor; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; BFNC, benign familial neonatal convulsions; GEFS+, generalized epilepsy with febrile seizures plus; SMEI, severe myoclonic epilepsy in infancy; BFNIS, benign familial neonatal-infantile seizures; ADJME, autosomal dominant juvenile myoclonic epilepsy; ADIGE, autosomal dominant idiopathic generalized epilepsy. (From Gourfinkel-An I, Baulac S, Nabbout R, et al: Monogenic idiopathic epilepsies. Lancet Neurol 2004; 3:209-218.)

T A B L E 51–2. Glossary of Epilepsy Genetics Terms SCN1A SCN1B SCN2A GABA KCNQ CLCN CHRNA4 LGI1 Gene Allele SNP Mutation Autosome Locus Linkage GEFS+ SMEI JME BFNC ICCA ADNFLE BFNIS ADPEAF ARFGEF2 BIG2 GPCR

α1 Subunit of the voltage-gated sodium channel β1 Subunit of the voltage-gated sodium channel α2 Subunit of the voltage-gated sodium channel γ-Amino butyric acid Voltage-gated potassium channel Voltage-gated chloride channel α4 Subunit of the nicotinic acetylcholine receptor Leucine-rich gene, glioma inactivated A segment of DNA that normally specifies a functional polypeptide or gene product One of several alternative forms of a gene or DNA sequence at a specific locus Single-nucleotide polymorphism, where more than one variant (allele) occurs at a locus with a frequency greater than 1% Change within a gene or DNA sequence due to base substitution, deletion or insertion occurring at a frequency < 1% and usually much less Any chromosome other than the sex chromosomes X and Y A unique chromosomal location The tendency of genes to be inherited together as a consequence of their physical proximity Generalized epilepsy with febrile seizures plus Severe myoclonic epilepsy of infancy Juvenile myoclonic epilepsy Benign familial neonatal convulsions Infantile convulsions and choreoathetosis Autosomal-dominant nocturnal frontal lobe epilepsy Benign familial neonatal-infantile seizures Autosomal dominant familial lateral temporal lobe epilepsy with auditory features Adenosine diphosphate (ADP)–ribosylation factor guanine nucleotide exchange factor 2 Brefeldin A (BFA): inhibited GEF2 protein G protein–coupled receptor

tion, infantile convulsions and choreoathetosis, which has been linked to chromosomal region 16p12.21

Benign Familial Neonatal-Infantile Convulsions Mutations in SCN2A have been described in two families22 with convulsions commencing at 2 days to 3.5 months of age.

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy In this disorder, seizures usually occur during sleep, often commencing in childhood, and are often misdiagnosed as a movement disorder. Frequently, it can be successfully treated with carbamazepine, but sometimes there is pharmacoresistance. The seizures have prominent motor manifestations, including hypermotor activity and dystonic posturing. Penetrance is high (~70%). Mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (CHRNA4, CHRNB2)23,24 have been described in some but not all kindreds, which again illustrates the genetic heterogeneity that may underlie an apparently simple and homogeneous phenotype.

Familial Lateral Temporal Lobe Epilepsy The most common form of epilepsy of temporal lobe origin arises from the mesial temporal lobe and is caused by hippocampal sclerosis (see “Complex Inheritance of Epilepsy” section). Epilepsy arising from the lateral temporal lobe is less common. In either case, it is usually sporadic, with no indication of an underlying causative genetic mutation. Autosomal dominant partial epilepsy with auditory features is a rare, familial lateral temporal lobe epilepsy syndrome with penetrance of approximately 60% to 70%. Brief auditory hallucinations are often described in its phenotypic spectrum but are not invariably present. Although it is a genetically heterogeneous condition, underlying mutations in LGI1, which encodes the leucine-rich glioma-inactivated factor 1 (also referred to as

chapter 51 genetics of epilepsy

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Figure 51–3. A, Coronal magnetic resonance imaging (MRI) section, demonstrating bilateral periventricular heterotopia (arrows). The signal intensity from the heterotopia is the same as that from normal cortex. B, Unilateral nodules of heterotopia (arrows) in a different case. C, On macroscopic pathological study in another case, the nodules can be seen abutting the lateral ventricles bilaterally. Inset, A cortical section showing white matter in violet: Nodules of gray matter are set within white matter (stars), or subcortical heterotopia, a pathological process well shown on the axial MRI (D): The heterotopia in the right frontal lobe extends to the ventricle. (Modified from Sisodiya SM: Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004; 3:29-38.)

T A B L E 51–3. Genetics of Progressive Myoclonic Epilepsies Disorder Neuronal ceroid lipofuscinosis Infantile Late infantile Finnish variant late infantile Variant late infantile Juvenile Northern epilepsy Adult (Kufs disease) Lafora’s disease Sialidosis Unverricht-Lundborg disease Juvenile GM2 gangliosidosis type III Myoclonus epilepsy with ragged red fibers (MERRF)

Gene

Protein

CLN1 CLN2 CLN5 CLN6 CLN3 CLN8 — EPM2A EPM2B (NHLRC1) NEU1 CSTB (EPM1) EPM1B

Palmitoyl-protein thioesterase 1 (PPT1) Tripeptidyl peptidase 1 (TPP1) Novel membrane protein Novel membrane protein Novel membrane protein Novel membrane protein — Laforin Malin Neuraminidase 1 Cystatin B Unknown β-N-acetylhexosaminidase A (deficiency) tRNALys

MTTK

tRNALys, transfer ribonucleic acid that codes for lysine.

epitempin), have been discovered.25 This finding is of particular interest because the gene does not encode a channel and is the first to be associated with idiopathic focal epilepsy.

Progressive Myoclonus Epilepsies Progressive myoclonus epilepsies are a heterogeneous group of conditions characterized by the triad of worsening myoclonic seizures, generalized tonic-clonic seizures, and progressive intellectual decline; in many subtypes, additional features are observed (e.g., photosensitivity, mitochondrial cytopathic manifestations). Many underlying genetic mutations have now been identified (Table 51–3).

Focal Epilepsies Caused by Malformations of Cortical Development Abnormal development of the brain is an important cause of epilepsy, particularly epilepsy that is refractory to drug treat-

ment. Such malformations can often be identified by magnetic resonance imaging in vivo (Figs. 51–3 to 51–5). In fact, magnetic resonance imaging can be used as a phenotyping tool, allowing the identification of other family members with a malformation who might not have epilepsy. In turn, this allows traditional linkage genetic studies to be undertaken. This strategy has revealed a group of gene mutations that are now known to cause brain malformation that may manifest with epilepsy; of additional importance, these genes are clearly also implicated in normal brain development, and much has been learned about human brain development from such studies (Table 51–4).

Febrile Seizures Simple febrile seizures occur at 6 months to 6 years of age with fever, typically greater than 38.5° C, without evidence of central nervous system infection. They consist of brief generalized, clonic, tonic-clonic, or atonic seizures and generally do not

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Figure 51–4. A, On axial magnetic resonance imaging (MRI), bilateral perisylvian polymicrogyria is shown. The gray-white matter interface is clear and in some regions appears excessively folded. The sylvian fissures themselves are widened and abnormally configured. B, Parasagittal reformatted image shows the excess digitations in perisylvian gray matter (arrow). C, Histological section shows an excessive number of small gyri, with fusion of the molecular layers (star). The overlying cortex appears smooth. D, A case of schizencephaly, with a cleft through the cortical mantle (white arrow), and subjacent periventricular gray matter. Demonstrating such clefts, and indeed polymicrogyria, may require reformatting of high-resolution MRI data. (Modified from Sisodiya SM: Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004; 3:29-38.)

A ■

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E

Figure 51–5. A, Typical case of bilateral subcortical band heterotopia, with simplified gyration of the surface cortex, a thin strip of underlying white matter (short arrow), and a thick subcortical band (long arrow). The innermost gray-white matter interface is indistinct. B, Macroscopic histological section exhibits the thin strip of white matter (short black arrow) and the subcortical band (long white arrow), illustrating how the term double cortex arose. C, Another histological section, also stained violet for white matter, shows a thin subcortical gray matter band, appearing much paler and containing neurons. There may be an anterior-posterior gradient in the brain abnormality, as shown in images from one individual affected less severely anteriorly (D) and more severely posteriorly (E); this gradient is known to be governed by the underlying mutation (LIS1 or DCX). (Modified from Sisodiya SM: Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004; 3:29-38.)

T A B L E 51–4. Some Brain Malformations and Their Reported Genes Malformation

Locus

Gene

Protein

Periventricular heterotopia

Xq28 5p 20 16q12.2-21 Xq22.3-q23

FLNA

Filamin A

ARFGEF2 GPR56 DCX

BIG2 GPCR doublecortin

17p13.3 7q22 Xp22.13 Xq22.3-q23 10q26.1

LIS1 Reln ARX DCX EMX2

LIS1 protein Reelin ARX Doublecortin EMX2 protein, a transcriptional regulator

9q34 16p13.3

TSC1 TSC2

Hamartin Tuberin

Bilateral frontoparietal polymicrogyria Subcortical band heterotopia Lissencephaly

Schizencephaly Disorders of differentiation Tuberous sclerosis

chapter 51 genetics of epilepsy necessitate prophylactic antiepileptic treatment. Estimates of the prevalence of febrile seizures vary from 2% to 5% in North America and Europe26,27 to 7% to 14% in Japan.28 However, prospective follow-up studies have shown that patients who suffer febrile seizures, especially complex febrile seizures, have a greater risk of developing epilepsy than do children who do not suffer such seizures. Epilepsy has a prevalence of 0.5% to 1% in the population, but afebrile seizures occur in 2% to 7% of patients who had febrile seizures.29,30 It is estimated that 11% of patients with generalized epilepsy and 5% to 6% with partial epilepsies other than temporal lobe epilepsy have suffered febrile seizures.31 Some studies suggest that 25% of patients with temporal lobe epilepsy have had febrile seizures.31 Chromosomal studies of large families with febrile seizures, with or without additional epilepsy, have identified four loci with autosomal dominant inheritance and incomplete penetrance: FEB1 on 8q13-21,32 FEB2 on 19p,33,34 FEB3 on 2q23-24,35 and FEB5 on 6q22-24.36 A locus for FEB4 was found on 5q14-15 from a nonparametric analysis of 47 families.37 No underlying mutations have yet been identified.

another illustration of the complexity of such work, a large replication study has failed to support this intriguing finding.45

CONCLUSIONS Epilepsy is a complex group of disorders. In a few cases, gene mutation causes epilepsy. These rare mutations can point to important candidate genes, common variation in which may have a potential role in epilepsy among the general population either in combination with other similarly variant genes and/or in interaction with the environment. Continuing research with familial epilepsies and population genetics will shed more light on the extent of the genetic contribution to epilepsy and genetic variation in antiepileptic drug response. Much work remains to be done even when an underlying mutation or association is proven; the mechanisms whereby gene changes mediate their effects are still rarely understood.

K E Y COMPLEX INHERITANCE OF EPILEPSY Although of great interest, mendelian genetics in epilepsy have a limited application: most patients with epilepsy are likely to display a more complex genetic contribution to their condition, possibly with oligogenic or polygenic inheritance. Such cases are very unlikely to demonstrate dominant, recessive, or Xlinked patterns of inheritance. Theories of population genetics are successfully being applied to the study of these more common epilepsy types. To date, most investigators have examined preselected (candidate) genes and attempted to identify associations between common variation (typically SNPs) in these genes and epilepsy phenotypes. Pal and associates38 postulated that changes in the BRD2 (RING3) gene may alter neural development and that subsequent interaction with other susceptibility genes for JME may provide a framework for inheritance of JME as a complex disease. Mesial temporal lobe epilepsy that is refractory to drug treatment is often associated with hippocampal sclerosis and a history of febrile seizures. SNPs in many genes (e.g., the interleukin-1β gene,39 the prodynorphin gene,40 GABBR1,41 the prion protein gene42) have been reported as associated with temporal lobe epilepsy, hippocampal sclerosis, or febrile seizures. However, none of these data have yet reliably survived attempts to replicate initial reports.43 This demonstrates the major difficulty with such population genetic association studies. One of the major difficulties in epilepsy is understanding why patients with apparently the same type of epilepsy show major differences in pharmacosensitivity. Population genetics studies facilitate pharmacogenetics, in which the genetic basis for individual response to drugs is examined. Pharmacoresistance may be dependent on the type of epilepsy, any underlying structural abnormality (e.g., brain malformation or lesion), drug absorption, drug metabolism, or the presence of drug transporter proteins. Successes with pharmacogenetics have highlighted associations between pharmacoresistance and common genetic variation in the gene ABCB1 encoding Pglycoprotein, a broad-spectrum drug transport protein.44 In

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P O I N T S

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Epilepsy encompasses a wide number of disorders for which an individual’s genetic constitution modulates or contributes to, in various degrees, risk of developing epilepsy in response to another insult to the brain.

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Most individuals with epilepsy probably display both a complex genetic susceptibility and an interplay of gene-gene and gene-environment interactions.

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Monogenic inherited epilepsies are rare and typically manifest with mendelian inheritance, usually with varying degrees of penetrance and expression among families.

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Primary generalized epilepsies are considered to have a greater genetic contribution than does focal epilepsy.

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For most people, any genetic contribution to seizure etiology and response to antiepileptic drug treatment is likely to arise from additive, individually small effects of variants in a number of genes.

Suggested Reading Baulac S, Gourfinkel-An I, Nabbout R, et al: Fever, genes and epilepsy. Lancet Neurol 2004; 3:421-430. Cavalleri GL, Lynch JM, Depondt C, et al: Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here? Brain 2005; 128:1832-1840. Gourfinkel-An I, Baulac S, Nabbout R, et al: Monogenic idiopathic epilepsies. Lancet Neurol 2004; 3:209-218. Gutierrez-Delicado E, Serratosa JM: Genetics of the epilepsies. Curr Opin Neurol 2004 17:147-145. Sisodiya SM: Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004; 3:29-38.

References 1. Cossette P, Liu L, Brisebois K, et al: Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002; 31:184-189.

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2. Suzuki T, Delgado-Escueta AV, Aguan K, et al: Mutations in EHFC1 cause juvenile myoclonic epilepsy. Nat Genet 2004; 36:842-849. 3. Liu AW, Delgado-Escueta AV, Gee MN, et al: Juvenile myoclonic epilepsy in chromosome 6p12-p11: locus heterogeneity and recombinations. Am J Med Genet 1996; 63:438-446. 4. Sander T, Bockenkamp B, Hildman T, et al: Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. Neurology 1997; 49:842-847. 5. Elmslie FV, Rees M, Williamson MP, et al: Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet 1997; 6:13291334. 6. Baulac S, Gourfinkel-An I, Nabbout R, et al: Fever genes and epilepsy. Lancet Neurol 2004; 3:421-430. 7. Bowser DN, Wagner DA, Czajkowski C, et al: Altered kinetics of a GABAA receptor subunit mutation [gamma 2(R43Q)] found in human epilepsy. Proc Natl Acad Sci U S A 2002; 99:1517015175. 8. Ito M, Nagafuji H, Okazawa H, et al: Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the Na+-channel α1 subunit gene, SCN1A. Epilepsy Res 2002; 48:15-23. 9. Nabbout R, Gennaro E, Dalla Bernardina B, et al: Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 2003; 60:1961-1967. 10. Harkin LA, Bowser DN, Dibbens LM, et al: Truncation of the GABA(A)-receptor γ2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 2002; 70:530-536. 11. Singh NA, Charlier C, Stauffer D, et al: A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998; 18:25-29. 12. Biervert C, Schroeder BC, Kubisch C, et al: A potassium channel mutation in neonatal human epilepsy. Science 1998; 279:403-406. 13. Lerche H, Bievert C, Alekov AK, et al: A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol 1999; 46:305-312. 14. Dedek K, Fusco L, Teloy N, et al: Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res 2003; 54:21-27. 15. Charlier C, Singh NA, Ryan SG, et al: A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998; 18:53-55. 16. Hirose S, Zenri F, Akiyoshi H, et al: A novel mutation of KCNQ3 (c.925T→C) in a Japanese family with benign familial neonatal convulsions. Ann Neurol 2000; 47:822-826. 17. Wang Q, Curran ME, Splawski I, et al: Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12:17-23. 18. Neyroud N, Tesson F, I Denjoy I, et al: A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997; 15:186-189. 19. Guipponi M, Rivier F, Vigevano F, et al: Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q. Hum Mol Genet 1997; 6:473-477. 20. Malacarne M, Gennaro E, Madia F, et al: Benign familial infantile convulsions: mapping of a novel locus on chromosome 2q24 and evidence for genetic heterogeneity. Am J Hum Genet 2001; 68:1521-1526. 21. Caraballo R, S Pavek S, Lemainque A, et al: Linkage of benign familial infantile convulsions to chromosome 16p12q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet 2001; 68:788794.

22. Heron SE, Crossland KM, Andermann E, et al: Sodiumchannel defects in benign familial neonatal-infantile seizures. Lancet 2002; 360:851-852. 23. Steinlein OK, Mulley JC, Propping P, et al: A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995; 11:201203. 24. Fusco MD, A Becchetti A, Patrignani A, et al: The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet 2000; 26:275-276. 25. Kalachikov S, Evgrafov O, Ross B, et al: Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 2002; 30:335-341. 26. Hauser WA: The prevalence and incidence of convulsive disorders in children. Epilepsia 1994; 35(Suppl 2):S1S6. 27. Hauser WA, Annegers JF, Rocca WA: Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 1996; 71:576586. 28. Tsuboi T: Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 1984; 34:175-181. 29. Annegers JF, Hauser WA, Elveback LR, et al: The risk of epilepsy following febrile convulsions. Neurology 1979; 29:297-303. 30. Verity CM, Golding J: Risk of epilepsy after febrile convulsions: a national cohort study. BMJ 1991; 303:1373-1376 [Erratum in BMJ 1992; 304:147]. 31. Hamati-Haddad A, Abou-Khalil B: Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions. Neurology 1998; 50:917-922. 32. Wallace RH, Berkovic SF, Howell RA, et al: Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21. J Med Genet 1996; 33:308-312. 33. Johnson EW, Dubovsky J, Rich SS, et al: Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. Hum Mol Genet 1998; 7:63-67. 34. Kugler SL, Stenroos ES, Mandelbaum DE, et al: Hereditary febrile seizures: phenotype and evidence for a chromosome 19p locus. Am J Med Genet 1998; 79:354-361. 35. Peiffer A, Thompson J, Charlier C, et al: A locus for febrile seizures (FEB3) maps to chromosome 2q23-24. Ann Neurol 1999; 46:671-678. 36. Nabbout R, Prud’homme JF, Herman A, et al: A locus for simple pure febrile seizures maps to chromosome 6q22-q24. Brain 2002; 125:2668-2680. 37. Nakayama J, Hamano K, Iwasaki N, et al: Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Hum Mol Genet 2000; 9:87-91. 38. Pal DK, Evgrafov OV, Tabares P, et al: BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet 2003; 73:261-270. 39. Kanemoto K, Kawasaki J, Yuasa S, et al: Increased frequency of interleukin-1β–511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion. Epilepsia 2003; 44:796-799. 40. Stogmann E, Zimprich A, Baumgartner C, et al: A functional polymorphism in the prodynorphin gene promotor is associated with temporal lobe epilepsy. Ann Neurol 2002; 51:260263. 41. Gambardella A, Manna I, Labate A, et al: GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe epilepsy. Neurology 2003; 60:560-563. 42. Walz R, Castro RM, Velasco TR, et al: Surgical outcome in mesial temporal sclerosis correlates with prion protein gene variant. Neurology 2003; 61:1204-1210.

chapter 51 genetics of epilepsy 43. Cavalleri GL, Lynch JM, Depondt C, et al: Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here? Brain 2005; 128:18321840. 44. Siddiqui A, Kerb R, Weale ME, et al: Association of multidrug resistance in epilepsy with a polymorphism in the drug-

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transporter gene ABCB1. N Engl J Med 2003; 348:14421448. 45. Tan NC, Heron SE, Scheffer IE, et al: Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology 2004; 63:1090-1092.

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ASSESSMENT AND MANAGEMENT PRINCIPLES ●

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Philippe Ryvlin, Sylvain Rheims, and Pierre Thomas

By virtue of their capacity to divert the functionality of neural networks into clinically overt discharges, epileptic seizures represent a fascinating window onto brain functions and also the source of a virtually infinite variety of ictal manifestations. The epilepsies encompass a large variety of syndromes reflecting a multitude of brain lesions as well as gene and protein dysfunction that results in neuronal hyperexcitability. An ever-increasing understanding, described in an exponentially growing number of dedicated textbooks, translates into a capacity for more precise diagnosis and optimization of syndrome-dependent management, compounded by the flurry of antiepileptic drugs made available for seizure treatment in the last two decades. However, the unique complexity of this common neurological disorder has created a major gap in knowledge between the few specialists who manage to keep comprehensively abreast of the multiple facets of seizures and epilepsies and most other physicians, including the majority of those primarily involved in the management of patients with newly diagnosed seizures. It is not possible to familiarize general practitioners, pediatricians, general physicians, or even general neurologists with the entire spectrum of epileptic disorders. On the other hand, it is dangerous to oversimplify the problem of seizures by ignoring major challenges that result from the diversity of epileptic disorders. Facing this dilemma, our aim is to provide a practical and effective guide to the diagnosis and management of the epilepsies for physicians who do not intend to become specialists in the field but are required to offer the best possible care to their patients with epilepsy. This chapter therefore. concentrates on general issues, rules, and procedures that help prevent misdiagnosis or inappropriate management rather than listing all seizure types and epilepsy syndromes, illustrating points with typical examples. More detailed information regarding specific types of epilepsy syndromes and their etiologies is provided in other chapters in this section. This chapter also concentrates on the diagnosis and management of newly affected patients. The diagnosis of epileptic seizures and epilepsy often proves difficult, reflected by an average delay of several years between the first seizure and accurate diagnosis. In juvenile myoclonic epilepsy, where subtle myoclonic jerks often precede the occurrence of a first generalized tonic-clonic seizure (GTCS) by many

years, this average delay lies between 6 and 15 years. Similarly, epilepsy is unlikely to be diagnosed in patients with simple partial seizures solely characterized by experiential auras or by distressing rising epigastric sensations, with the latter often wrongly considered manifestations of an anxiety disorder. Overall, it is believed that up to 20% of patients with epilepsy remain undiagnosed. Conversely, many patients with nonepileptic seizures are falsely considered to have epilepsy. Approximately 20% of patients seen at epilepsy referral centers for drug-resistant attacks eventually prove to have psychogenic nonepileptic seizures. The mean delay to diagnosis of this somatoform condition is around 7 years, implying that many patients with psychogenic nonepileptic seizures will inappropriately take antiepileptic medication, which by itself may result in serious adverse events. All of these pitfalls can be readily avoided with accurate observation and description of seizure semiology. When the epileptic origin of seizures has been ascertained, another major diagnostic issue remains to be dealt with—identification of the epileptic syndrome. Identification is important so that the most appropriate treatment can be recommended and an accurate prognosis given. For example, idiopathic generalized epilepsy can be aggravated by the majority of antiepileptic drugs used for treating partial epilepsy and must therefore be distinguished from the latter. Another important example is the early identification of temporal lobe epilepsy with magnetic resonance imaging (MRI) signs of hippocampal sclerosis. This diagnosis predicts a high risk of developing refractoriness to antiepileptic drugs and suggests timely consideration of presurgical evaluation with a view to epilepsy surgery. Failure to do so will expose the patients to the danger of recurrent seizures and associated socioprofessional and familial stigmas for many years, if not decades. In the above two examples, the diagnosis of epileptic syndromes largely depends on the clinical description of seizures, the age at onset, and a detailed family and personal history. However, two other investigations greatly contribute to a correct diagnosis: electroencephalography which plays a major role in differentiating idiopathic generalized epilepsy from other forms of epilepsy, and more generally in defining epileptic syndromes, and MRI, which is the most sensitive way to detect an epileptogenic brain lesion.

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DIAGNOSIS STEP 1: DEFINING THE SEIZURE TYPE(S) The diagnosis of seizure type(s) relies mainly on a detailed chronological description of ictal signs and symptoms by the patient, relatives, and any other available witnesses. Other investigations are often unnecessary in arriving at an accurate diagnosis.

stimuli, physicians should equally be prepared for such oddities that primarily reflect the potential for any cortical neural network to generate seizures, including those involved in allocating times and dates to events in living experience. One general rule applies to epilepsy—The more odd the experiential or behavioral phenomena, the more likely that they are of epileptic origin provided the presence of core features of an epileptic seizure are present (see later). Although counterintuitive, the “theatrical” semiology of psychogenic attacks usually proves less dramatic than that of partial seizures.

Investigating the Seizure Episode One can compare the process of gathering all potentially relevant information about a seizure episode with a detective investigation. Indeed, it is of primary importance to get a vivid, movie-like, corroborated description of the “seizure scene,” as if one had actually been there, to avoid neglecting potentially informative details. This approach is limited in specific situations such as unwitnessed nocturnal attacks that often leave patients amnesic of entire episodes, including the duration of any postictal confusion. But, in the majority of cases, patients can precisely describe their activity until seizure onset. It is useful to ascertain whether a patient was standing and for how long, whether engaged in conversation or in any other purposeful action, or whether an object was being held. Such contextual information provides a basis for interpretation of all subsequent changes in motor activity and behavior and might disclose a significant precipitating factor. The latter may operate on a time scale that varies from a few seconds in reflex seizures to about 20 minutes in the typical form of vasovagal syncope. Other seizure-favoring factors that operate on a larger time scale, such as sleep deprivation, alcohol withdrawal, or mood disorders, must also be sought, together with relevant past-history—they are discussed in the section on etiology.

Searching for Seizure-Precipitating Factors Seizure-precipitating factors are not always reported by patients spontaneously and so must be specifically sought. In the most common type of photosensitive epilepsy, the identification of a triggering stimulus may be trivial in some situations, such as stroboscopic lightning at a dance party or a video game session, but can be harder to detect in the case of alternating sun exposure when driving along a line of trees or looking at an object characterized by a pattern of repetitive high-contrast figures. Similarly, in the much rarer primary reading epilepsy, an affected adolescent or young adult will not necessarily recognize the role played by reading aloud until several seizures occur under similar circumstances. Detailing patient activity prior to seizure onset offers the best opportunity for a physician to detect a seizure-triggering factor. Apart from these examples, a variety of other sensory or cognitive stimuli may occasionally precipitate partial or generalized seizures. These include sudden unexpected noise responsible for startle-induced seizures, listening to specific pieces of music, playing chess, performing mental arithmetic, programming a particular gesture, and virtually any other mental process. One of our patients used to experience temporal lobe seizures when he heard or saw something related to the “past,” like an old song or a movie from the 1950s, regardless of their relation to his personal memories. Although patients may feel reluctant to consider or report such odd

Validating the Core Features of Epileptic Seizures Once the context of a seizure episode has been ascertained, and prior to its detailed description, one should confirm the presence of the core features that characterize almost all epileptic fits, such as an abrupt onset, a short duration of several seconds to a few minutes, and a stereotyped sequence of ictal signs and symptoms. 1. In patients aware of seizure onset, its abruptness is often compared with a switch-like change in mental state. However, this impression may be blurred when repetitive auras precede the occurrence of a full-blown seizure, requiring separate differentiation of the characteristics of aura and seizure. In patients unaware of seizure onset, witnesses usually testify to the abruptness of onset of abnormal ictal behavior. 2. The duration of epileptic seizures is typically several seconds for the shortest episodes, such as generalized atonic seizures or absences, to a few minutes in complex partial seizures of temporal lobe origin. There are exceptions. Myoclonic jerks that characterize juvenile myoclonic epilepsy can last less than a second. Conversely, occipital lobe seizures are prone to last 5 minutes or longer, in particular, those encountered in the early-onset form of benign epilepsy of childhood with occipital paroxysms (Panayiotopoulos syndrome) and in occipital partial epilepsy symptomatic of cortical dysplasia. Ring chromosome 20 is another disorder characterized by prolonged ictal episodes, which can culminate in nonconvulsive status epilepticus. By definition, status epilepticus and epilepsia partialis continuans represent specific epileptic entities of longer duration. 3. In contrast to its extraordinary diversity within the epilepsy population, seizure semiology is very stereotyped in individual patients. There is a remarkable reproducibility of the spatiotemporal distribution and frequency pattern of epileptic discharges within a given brain, as demonstrated by intracerebral electroencephalographic recordings in patients with drug-resistant partial epilepsy. In patients who report several seizure types (typically two or three), common features should be evaluated to ascertain that each seizure type remains stereotyped. Typically, patients with partial epilepsy can alternately have isolated auras (corresponding to simple partial seizures with sensory, autonomic, or psychic symptoms), complex partial seizures (characterized by an impairment of consciousness), and secondary generalized seizures. In some patients, all or part of an aura may precede complex partial and secondary generalized seizures, providing clear-cut evidence of a unique and stereotyped ictal onset for all seizure types. In others, such a conclusion may be hindered by amnesia for the aura following a

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prolonged seizure with impairment or loss of consciousness. Similarly, patients with both daytime and nocturnal seizures may recollect the onset of the former but not of the latter. In such cases, stereotyped ictal signs common to the various seizure types can be described by relatives or witnesses. In contrast to partial epilepsy, idiopathic generalized epilepsies are characterized by a small number of seizure types (absence, tonic-clonic, and myoclonic seizures) that are stereotyped both within and across patients. They might also be associated in the same individual, depending on the exact epileptic syndrome. The reproducibility of ictal semiology is more difficult to assess in patients with multifocal epilepsies, epileptic encephalopathies, or Lennox-Gastaut syndrome, in which a variety of epileptic networks appear to coexist and to evolve over time. This limitation does not hinder the identification of an epileptic origin for these severe seizure disorders. Finally, it is worth noting that seizure semiology can be modified by antiepileptic drugs. For instance, partial epilepsies will often be revealed by a secondary generalized tonicclonic seizure, whereas treated seizures may be only partial. 4. The spontaneous description of a seizure episode(s) provided by a patient is often far less informative than directed questioning. As stated, patients can be unaware of the relevance of various symptoms, such as the matinal myoclonic jerks of juvenile myoclonic epilepsy, or feel reluctant to report odd or embarrassing auras that invite specific inquiry. Priming may be needed to prompt recollection of blurred memories of seizure onset. Thus, following a spontaneous narrative from a patient, it is recommended that the presence of the following list of symptoms should be specifically asked for: abnormal olfactory, gustatory, auditory or visual illusions or hallucinations, vertigo, paraesthesias or other somatosensory manifestations including changes in body perception, pelvic, abdominal, epigastric, thoracic or throat sensations, urinary urge, thirst, tachycardia, breathing difficulties, involuntary muscle contractions or movements, perceptive or expressive language impairments, prolonged déjà vu or déjà vécu or dreamy states, inappropriate emotions including fear, distress, joy, or sadness, and any other strange or bizarre symptoms. When present, such symptoms should be investigated in the greatest possible detail and ordered chronologically according to their ictal sequence. In some patients, however, the aura remains indefinable. Patients rarely remember specific gestures, automatisms, or behaviors in their seizures, even though they can be verbally and appropriately responsive at the time of their manifestation. Report of such ictal signs by a patient usually reflects descriptions provided by relatives rather than personal recollections of an episode. Conversely, informative memories can be retrieved from the postictal period. After brief loss of awareness, patients will recover with a feeling of having been “disconnected” for a few seconds. This represents the only perception associated with absence seizures. Other patients notice a postictal deficit such as Todd’s paralysis, traces of urination or of tongue biting, and can have headache or postconvulsion myalgia. However, nonspecific fatigue and sleepiness represent the most frequent postictal symptoms. When a generalized tonic-clonic seizure is suspected, the first postictal memory is extremely helpful in determining the duration of postictal amnesia. In a typical GTCS that has required

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medical attention, a patient will remember awakening while already in medical care, either on site, in the ambulance, or in the intensive care unit. This often contrasts with witness accounts that the patient regained consciousness before the arrival of medical care, thus reflecting the gap between restored responsiveness and restored short-term memory following GTCS. When no detailed description of a seizure is available and patients fail to recollect an aura, a long postictal amnesia represents the most robust sign distinguishing GTCS from syncope given that both can result in urination, tongue biting (although usually lateral tongue only in GTCS), and clonic movements (although usually only a few jerks in syncope versus 30 seconds or longer in GTCS).

“Desperately Seeking” a Witness to the Seizure(s) Witnessed accounts of seizures often provide essential information, complementary to that reported by patients. Even in simple partial seizures characterized by a rising epigastric sensation, witnesses can notice subtle oroalimentary automatisms (chewing or lip-smacking) of which patients are unaware. This example is particularly striking because the sole presence of oroalimentary automatisms allows a firm conclusion about the epileptic origin of a condition that might otherwise be considered an anxiety disorder, inasmuch as the scalpelectroencephalogram is usually normal in such types of limbic seizure. Spontaneous narrative by nonmedical observers can be inadequate, so direct questioning is also needed. Efforts should always be made to directly question witnesses. A single telephone call can prove much more fruitful than costly medical examinations. The critical questions relate to the first detectable abnormal sign witnessed and whether there was any warning from the patient. Was there any detectable blush or pallor, change in respiration rate or facial expression, or head deviation? Were the eyes open with a fixed orientation or responsive to external stimulation (in favor of partial seizures), closed (in favor of nonepileptic seizures), or rolled upward (suggesting GTCS or syncope)? Were the arms still, or in a peculiar posture or gesture, or were they rhythmically moving? If a patient fell, was the fall abrupt or progressive, forward or backward, with legs bent or stretched, and was the fall followed by general hypotonia or hypertonia? If “convulsions” are reported, their duration, type, and the amplitude of limb movements must be specified to distinguish GTCS from convulsive syncope and psychogenic attacks. In GTCS, clonic movements are characterized by tonic contractions of moderate amplitude that last approximately 30 seconds. In convulsive syncope, only one to five irregular clonic movements are observed during a few seconds. In psychogenic “convulsion-like” episodes, rhythmic limb movements typically resemble a large-amplitude tremor developing in the context of neutral or decreased muscular tone and often lasting several minutes. If a seizure is primarily characterized by a lack of responsiveness, particular attention should be paid to the presence of automatisms, which, though often noticed, are infrequently reported spontaneously by witnesses. The diagnostic value of oroalimentary automatisms has been mentioned, the same is true for manual, pedal, and verbal automatisms, which all strongly suggest an epileptic origin for seizures. These automatic activities tend to imitate seemingly natural or

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purposeful gestures or speech, although they usually appear meaningless or inappropriate during a seizure. They must be distinguished from elementary motor activity leading to posture, change in muscle tone, clonic jerk, or a scream. In the 1989 classification of seizures and epilepsies, automatisms are specifically associated with complex partial seizures. In fact, as previously described, subtle automatisms may also occur during simple partial seizures and, at times, during absence seizures.

Classifying the Seizure Episode Based on all the information gathered through investigation of a seizure episode, three clinical situations should be distinguished, providing a framework for the diagnostic process: ■ The episode was primarily marked by a complete loss of con-

sciousness with a fall if the patient was standing and may have progressed to “convulsions.” ■ The episode was primarily characterized by an impairment of consciousness without fall or convulsion, that could be described as a secular “absence.” ■ The episode consisted mainly of abnormal “sensations” with preserved consciousness.

Seizures Associated With Complete Loss of Consciousness, a Fall, and Convulsive Features This category includes “primary” GTCS, secondary generalized partial seizures, and the much less frequent generalized tonic, atonic, or clonic seizures. Distinction between primary and secondary generalized tonic-clonic seizures has important therapeutic consequences and can pose a difficult diagnostic problem. Differential diagnosis primarily includes syncope and psychogenic nonepileptic seizure.

“Primary” Generalized Tonic-Clonic Seizures These typically start with a 10- to 20-second tonic phase characterized by a vocalization, intense tonic flexion, and then extension of all four limbs; the eyes roll upward, and apnea, which is responsible for subsequent cyanosis. The hypertonia intermittently resolves, giving rise to the clonic phase, which lasts approximately 30 seconds, and to the drooling of saliva. Clonic movements are characterized by tonic contractions of moderate amplitude and progressively decreasing frequency that finally cease. Patients remain hypotonic for several minutes; they may urinate and then resume loud labored breathing, reflecting the prior accumulation of bronchial and salivary secretions. Traces of tongue biting can then be observed. Their location on one or both sides of the tongue is highly suggestive of a GTCS, whereas biting the tip of the tongue can result from any traumatic fall. The long duration of postictal amnesia has been previously mentioned. Once patients recover, they may complain of diffuse muscle pain reflecting the intensity of tonic-clonic contractions, but the possibility of a seizure-induced shoulder dislocation should not be overlooked. An important feature of primary GTCS is the lack of ictal signs or symptoms that suggest a partial onset. However, tonic head deviation may occur at the onset of primary GTCS, representing the only “focal” sign in this seizure type. In addition, patients with juvenile myoclonic epilepsy sometimes remem-

ber presenting bursts of increasingly intense generalized myoclonic jerks prior to the onset of GTCS. As detailed later, these myoclonic jerks represent another type of generalized seizure, with preserved consciousness, and should not be interpreted as an aura.

Secondary Generalized Partial Seizures The identification of this seizure type relies primarily on a description of ictal signs or symptoms preceding the generalized tonic-clonic phase (other than head deviation and generalized myoclonic jerks, which might occur in primary GTCS). These include auras that are reported by patients and the accounts by witnesses of abnormal behavior or focal motor activity (loss of awareness, automatisms, posture, and clonic movements). The presence of a postictal focal deficit and, in particular, lateralized Todd’s paralysis has comparable value. In some instances such evidence will be lacking, but patients report past episode(s) of clear-cut partial seizures, indirectly suggesting the partial onset of GTCS. However, in a significant proportion of patients, no clinical indication of such partial seizure is available, but other investigations, particularly electroencephalography or MRI, provide evidence of an epileptogenic focal brain abnormality that eventually leads to a diagnosis of partial epilepsy.

Generalized Tonic, Atonic, and Clonic Seizures These are much less frequent than GTCS and typically are observed in children. Tonic and atonic seizures are responsible for abrupt traumatic falls and are usually encountered in epileptic encephalopathies.

Differential Diagnoses ■ Syncope can result from various pathophysiological mech-

anisms with a common endpoint being a decrease in cerebral perfusion responsible for acute cerebral and brainstem dysfunction. Vasovagal syncope is the most frequent and can be mistaken for GTCS. It typically occurs in adolescents and young adults following emotionally salient stimuli (pain, sight of blood during venous puncture, warm and enclosed atmosphere) or after standing motionless for prolonged periods (related to progressive venous blood sequestration in the lower limbs). Thus, vasovagal syncope usually occurs in the standing position and often aborts if a patient lies down in the early phase of an attack. More rarely, vasovagal syncope will occur in a seated patient at the end of a meal, triggered by digestion-induced splanchnic blood sequestration. Prodromes include vertigo, visual and auditory disturbances, nausea, sweating, and the feeling of an imminent fainting or death. Intense pallor and general hypotonia follow, resulting in a progressive nontraumatic fall and loss of consciousness, with eyes closed or rolled upward. At times, syncope might progress to brief axial hypertonia associated with a few irregular clonic limb movements (fewer than six), “convulsive syncope.” Urination and biting of the tip of the tongue can occur, but normal consciousness is restored much more rapidly than in GTCS. Thus, detailed analysis of all signs and symptoms usually results in a clear distinction of syncope from GTCS, even in the presence of clonic movements, urination, and tongue biting. When necessary, a tilt test can be used to confirm the diagnosis of vasovagal syncope. Cardiogenic syncope represents a less

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frequent form of attack, observed in older patients with cardiovascular pathology but no other precipitating factors. It is characterized by a more abrupt loss of consciousness and fall. ■ Psychogenic nonepileptic seizures (psychogenic nonepileptic seizures) can mimic several seizure types including GTCS. They can be precipitated by a stressful event, typically in a patient with a history of child abuse. They can also occur in epileptic patients making the differential diagnosis more difficult. In psychogenic nonepileptic seizures resembling GTCS, patients are unlikely to report an aura and are usually evasive regarding activity prior to seizure onset. A nontraumatic fall can be seen in standing patients, but psychogenic nonepileptic seizures occur more frequently in patients who are seated or lying down. No tonic phase is observed (nor is vocalization, apnea, or cyanosis), and clonic movement proper is not seen. Abnormal movements typically consist of erratic movements of the limbs associated with pelvic thrusts or tremor like agitation of the entire body, while the eyes remain closed and characteristically show active resistance to opening. The movements often last several minutes with a waxing and waning evolution. In the postictal period, patients may be calm, motionless, and unresponsive with closed eyes, or they break into tears and are distressed. No postictal confusion, urinary incontinence, or tongue biting are observed. The triggers for and termination of psychogenic nonepileptic seizures are both highly suggestible. ■ Simulated seizures are distinguished from psychogenic nonepileptic seizures by the intention to mislead others. Secondary benefits should be obvious to evoke this diagnosis, which is nevertheless difficult unless acknowledged by a patient explicitly.

Seizures Primarily Characterized by an Impairment of Consciousness Seizures predominantly characterized by an impairment of consciousness, or lack of responsiveness, are often referred to as “absences.” The term is easily understood but carries a risk of misclassification of seizure type and, in turn, epileptic syndrome. An isolated impairment of consciousness can be a generalized absence seizure or a complex partial seizure, evoking diagnoses of idiopathic generalized epilepsy and partial epilepsy, respectively. This distinction parallels that between primary GTCS and secondary generalized seizures. Psychogenic nonepileptic seizures can also mimic this form of attack. To describe seizures primarily characterized by an impairment of consciousness, without inferring their mode of onset, the term “dialeptic” has been proposed, the use of which is to be encouraged within the medical community. In its original definition, based on detailed observations of video-recorded attacks, dialeptic seizure excludes episodes where lack of responsiveness is associated with marked automatisms or other abnormal motor activity (the latter being referred to as motor seizures with several subtypes). In real life, however, seizure descriptions rely on witnesses who usually place more emphasis on the lack of responsiveness than on associated motor signs, describing these episodes also as absences. The duration of impairment of consciousness and accompanying symptoms can provide clues about the underlying seizure

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type, although this criterion has many exceptions. The distinction between the two main forms of dialeptic seizure often relies on other features, in particular, the age at onset, seizure frequency, and electroencephalographic findings. Absence seizures are included in the category of generalized seizure and primarily encountered in childhood absence epilepsy. Typical absence seizures are characterized by an abrupt impairment of consciousness lasting 5 to 30 seconds, followed by immediate and full restoration of normal consciousness. Decreased attention or alertness, emotion, and hyperventilation are predisposing factors. Patients usually remain motionless without change in muscular tone, gait, or stance if standing. Subtle eyelid or perioral 3-Hz myoclonus can be observed, as can manual automatisms during longer lasting episodes (more rarely, autonomic signs or axial hypotonia). Most characteristically, typical absences recur from ten to several hundred times a day in childhood absence epilepsy. They can be overlooked by teachers and parents who conclude that a child is simply inattentive. Absence seizures are less frequent in the juvenile form of absence epilepsy and in other idiopathic generalized epilepsies such as juvenile myoclonic epilepsy. Atypical absence seizures represent a less frequent form of generalized absence seizure usually encountered in the epileptic encephalopathies. They are less abrupt, of longer duration, and associated with more marked tonic, atonic, or myoclonic features than typical absences. Motor signs are often asymmetrical and can result in atraumatic falls. Complex partial seizures can resemble absence seizures in a minority of patients, especially when originating in prefrontal regions resulting in isolated dialeptic seizures of short duration. However, complex partial seizures can be easily distinguished from absences in the majority of patients because of the presence of one or more of the following ictal signs or symptoms: ■ Preceding aura (including all forms of simple partial ■ ■ ■ ■ ■ ■ ■ ■

seizures described further) Patient warning (vocalization) at seizure onset Partial responsiveness Lack of motionless staring Marked motor, verbal, or oroalimentary automatisms Focal dystonic, tonic, clonic, or atonic motor manifestation Clear-cut emotional or autonomic signs Duration over 30 seconds Postictal deficit, urinary urgency, thirst, nose wiping, or confusion

The large variety of ictal complex partial seizure manifestations cannot be detailed herein, nor the distinctive features of temporal, frontal, parietal, occipital, or insular seizures. These descriptions that are of relevance for localization of seizure onset zones in epilepsy surgery candidates are addressed in Chapters 54.

Differential Diagnosis (Psychogenic Nonepileptic Seizures, Parasomnia) ■ Psychogenic nonepileptic seizures can resemble dialeptic

seizures especially in patients who have suffered or observed such seizures in others. Automatisms are very unlikely to occur in psychogenic nonepileptic seizures, but tremor-like focal limb movements can be associated with apparent

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impairment of consciousness. Eye closure with active resistance to opening remains a very suggestive sign of psychogenic nonepileptic seizures in this form of nonepileptic seizure. ■ Parasomnias can be confused with nocturnal seizures, although patients with somnambulism and nocturnal terror attacks typically remember their dreams once awoken, whereas patients with nocturnal seizures usually do not recollect psychic experiences associated with their ictal behavior. Misdiagnosis usually results from partial seizures being regarded as parasomnias; this is especially so in the three main types of attack described in nocturnal frontal lobe epilepsy—paroxysmal arousal, nocturnal paroxysmal dystonia, and episodic nocturnal wandering. The abrupt onset and termination of these seizures and the typical movements observed in nocturnal paroxysmal dystonia characterized by pelvic and bimanual or bipedal repetitive movements, including pelvic thrusts, bicycling, and kicking often associated with vocalizations, usually point to the epileptic origin of an attack.

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Seizures Primarily Characterized by Abnormal Sensations with Preserved Consciousness Simple partial seizures represent the main form of epileptic attack with preserved consciousness. Generalized myoclonic seizures are characterized by failure to recognize myoclonic jerks despite preserved consciousness to the extent that they may remain unreported by patients. The differential diagnoses range from generalized anxiety disorder with panic attack to presyncopal states, hypoglycemia, transient ischemic attacks, migraine with aura, and gastrointestinal disorders in children. Misdiagnosis is usually due to a failure to identify the epileptic origin of attacks rather than the opposite, but one should be aware of possible comorbidity. Simple partial seizures can result in a great variety of sensory illusions and hallucinations (olfactory, gustatory, auditory, visual, somatosensory, vestibular) that can range from elementary to highly elaborated perceptions (music) including complex psychic experiences such as déjà vu, déjà vécu, and other dreamy states. Inner body sensations are also very frequent, especially rising epigastric and often distressing sensations, as well as pelvic, abdominal, thoracic, and throat manifestations. Emotional manifestations are usually negative, such as fear, and there can be various autonomic signs, including tachycardia, flushing, and breathing difficulties. Unlike automatisms, focal tonic or clonic movements can be recognized by patients during a simple partial seizure. Among rare and odd symptoms that are misinterpreted by both patients and physicians, one should be aware of out-ofbody experiences and heautoscopy (when patients see their own bodies from a distant visual perspective or mirror images of themselves); ecstatic seizures often compared with divine experiences, possibly at the origin of prophecies; orgasmic attacks most usually described as painful; and gelastic seizures characterized by unmotivated and irrepressible laughter that is often symptomatic of a hypothalamic hamartoma.

Differential Diagnoses of Simple Partial Seizures ■ Presyncopal states of vasovagal origin have been described

in a previous section. The distinction from epileptic seizures

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relies on the presence of specific precipitating factors; progressive onset, intense pallor, and a combination of sensory and vegetative symptoms. Whereas many of these symptoms can occur together during seizures, the specific combination of vertigo, visual and auditory disturbances, nausea, sweating, and a feeling of imminent fainting or death is very unlikely to result from an epileptic fit. Panic attacks are primarily characterized by the progressive onset of intense unmotivated fear and agitation associated with increased heart and respiratory rates, thoracic pain and feeling of an imminent death, paraesthesias, sweating, and nausea. Hypoglycemia typically results in hunger, epigastric pain, pallor, and sweating at times associated with neurological deficits. In severe hypoglycemia, usually precipitated by drugs in diabetic patients, symptoms can be followed by an authentic epileptic seizure. A blood glucose assay readily identifies this disorder. Transient ischemic attacks raise two potential sources of misdiagnosis: (1) Some partial seizures are characterized by an isolated ictal aphasia or focal limb deficit (negative motor manifestation) lasting from several seconds to a few minutes that can be wrongly diagnosed as a transient ischemic attack. These rare seizure types are usually symptomatic of an MRI-detectable brain lesion located in a specific cortical region (Broca’s area, inferior dorsolateral premotor cortex, mesial aspect of the precentral and postcentral regions). (2) Conversely, a transient ischemic attack can precipitate a seizure, leading to an erroneous diagnosis of postictal Todd’s paralysis and failure to diagnose the underlying ischemic etiology. In both of these circumstances, a vascular workup is recommended. Migraine with aura clearly differs from simple partial seizures by its progressive onset, slow propagation, and the long duration of aura reflecting spreading cortical depression whose speed approximates 3.5 mm/min within the visual cortex. The characteristics of visual migrainous auras also differ from those of occipital epileptic seizures, with noncolored hallucinations moving from peripheral to central portions of the visual field in migraine and colored hallucinations, static or growing from center to periphery, in epilepsy. Misdiagnosis can result from the fact that partial seizures; in particular, those originating in the occipital lobe, can be associated with severe postictal migraine. Gastrointestinal disorders, and especially gastric reflux, can be wrongly diagnosed in young children with epileptic seizures primarily characterized by epigastric discomfort or vomiting. The lack of a clear-cut positional or feeding precipitating factor, the presence of associated automatisms or lack of responsiveness, and epileptiform electroencephalographic abnormalities prevent such misdiagnosis.

Generalized myoclonic seizures are described in this section because they are associated with fully preserved consciousness. However, due to their benign features, this type of seizure almost never leads to medical attention or to spontaneous complaint by patients interviewed after a first GTCS. They are primarily encountered in juvenile myoclonic epilepsy and characterized by single or repetitive brief bilateral and symmetrical jerks of proximal limb segments, typically the shoulders, leading to the release of held objects (most likely those

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used during washing and breakfast due to their morning time of occurrence). Falls may occur when the lower limbs are affected.

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entiate between generalized and focal seizures depending on the scalp distribution.

Laboratory Investigations of Seizure Episodes

DIAGNOSIS STEP 2: IDENTIFYING THE EPILEPTIC SYNDROME

Laboratory investigations are often unnecessary to conclude that a fit is of epileptic origin or to precisely define the seizure type. There are, however, situations where the lack of information or inaccuracy of patient memories and witness accounts of seizures justifies a search for biological and electroencephalographic markers of a recent seizure.

The identification of an epileptic syndrome helps to determine seizure prognosis and to decide on the most appropriate treatment. Diagnosis is primarily based on seizure type(s), the age at onset, electroencephalographic findings, and any potential etiological factors suggested by past history or neuroimaging.

Biological Markers of Epileptic Seizures

Information Needed to Identify an Epileptic Syndrome (in Addition to Seizure Type)

Creatine kinase is typically elevated in the hours following a GTCS, reflecting muscular exhaustion resulting from sustained ictal hypertonia. The levels of the enzyme remain normal in syncope and psychogenic nonepileptic seizures. Prolactin release peaks 15 minutes after the end of a GTCS or of a temporal lobe complex partial seizure, reflecting the propagation of ictal discharges into the hypothalamus. The relatively low magnitude of this release needs to be compared with a baseline value obtained in the same individual at the same hour on another day.

Electroencephalography Electroencephalography is an essential and necessary tool to establish the diagnosis of epileptic syndromes once the epileptic origin of seizures has been ascertained. However, electroencephalography has several limitations for identification of seizure type: ■ The presence of interictal epileptiform electroencephalo-

graphic abnormalities (spikes, sharp waves, spikes and waves) favors an epileptic origin of a seizure but does not exclude a nonepileptic attack, because a few percent of normal individuals demonstrate incidental electroencephalographic findings of these types. Conversely, interictal electroencephalograms often prove normal in epileptic patients, of whom 15% will consistently fail to show epileptiform abnormalities on repeat investigation. ■ Ictal electroencephalography is very rarely obtained on a first recording unless the patient has very frequent absence seizures, or attacks precipitated by hyperventilation or intermittent photic stimulation, in which case it usually provides clear-cut evidence of seizure type. The electroencephalogram can also prove inconclusive in patients with epileptic foci that are localized on the mesial surface of the brain. These include two previously discussed forms of frequently misdiagnosed seizure type: simple partial seizures of mesial temporal origin giving rise to isolated epigastric sensations and nocturnal paroxysmal dystonia of mesial frontal origin. In contrast to these limitations a postictal electroencephalogram has the advantage of being more readily obtained than an ictal electroencephalogram, while still demonstrating abnormalities such as postictal slow waves that are directly related to a preceding seizure (Fig. 52–1). When present, such slow waves strongly support an epileptic origin for attacks and may differ-

Familial History The familial history can reveal various forms of genetic susceptibility to seizures and epilepsy. An autosomal dominant transmission is observed in rare and heterogeneous conditions such as nocturnal frontal lobe epilepsy, generalized epilepsy with febrile seizures plus, benign familial neonatal or infantile convulsions, a peculiar form of juvenile myoclonic epilepsy, and tuberous sclerosis. Recessive and maternal transmission occurs in various rare forms of progressive myoclonic epilepsy, whereas some abnormalities of neuronal migration are characterized by X-linked transmission. Idiopathic generalized epilepsy is often found in several members of the same family; the basis for this is believed to be polygenic transmission. The affected members of the same family can present with different forms of idiopathic generalized epilepsy, or even other types of epileptic syndrome such as primary reading epilepsy.

Past History A past history of perinatal insult, complicated febrile seizures, meningitis and other central nervous system infections, severe head trauma, and any other neurological disorders should be sought, for they might represent the etiology of nonidiopathic partial epilepsy. Perinatal insults include all events that might have resulted in ischemic, hypoxic, or traumatic brain lesions, in particular, premature or prolonged delivery. Complicated febrile seizures represent 5% of all febrile seizures, which themselves affect 4% to 5% of all children. Febrile seizures are complicated when one of the four following criteria is present: occurrence before the age of 9 months, duration longer than 20 minutes, unilateral or asymmetrical clonic movements, and postictal neurological deficit. The risk of developing temporal lobe epilepsy after a complicated febrile seizure is about 50%, whereas it is only 2.5% after a simple febrile seizure. Severe head trauma results in post-traumatic epilepsy in 0.5% to 5% of cases. One should distinguish early posttraumatic seizures occurring during the first week from posttraumatic epilepsy that develops later, although the former is a risk factor for the latter. The delay between head trauma and the onset of post-traumatic epilepsy is less than 1 year in 60% of cases, less than 3 years in 80%, and less than 10 years in

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FP2–F10 F10–T10 T10–TP10 TP10–O2

FP2–F8 F8–T4 T4–T6 T6–O2 FP2–F4 F4–C4 C4–P4 P4–O2 ECG FP1–F9 F9–T9 T9–TP9 TP9–O1

FP1–F7 F7–T3 T3–T5 T5–O1 FP1–F3 F3–C3 C3–P3 P3–O1 ■

Figure 52–1. Postictal slow waves.

95%. The severity of head trauma is assessed by the presence of the following criteria: penetrating open trauma (associated with a 30% risk of developing post-traumatic epilepsy), intracranial hematoma, any type of computed tomography (CT) scan or MRI-detectable brain lesion, prolonged neurological deficit, coma or post-traumatic amnesia greater than 24 hours, and depressed skull fracture. Meningitis, meningoencephalitis, and brain abscess are frequent causes of partial epilepsy. Neurocysticercosis is the leading cause in Latin America. HIV infection is commonly associated with epileptogenic opportunistic brain infections in developing countries. A great variety of other neurological disorders can give rise to epilepsy including stroke, brain tumors, vascular malformations, multiple sclerosis, and Alzheimer’s disease. Systemic autoimmune diseases also favor the development of epilepsy, including specific conditions such as Hashimoto’s and celiac diseases (see later).

Age at Onset Age at onset is a major diagnostic criterion in the vast majority of idiopathic or generalized epilepsy syndromes. The main exceptions are cryptogenic and symptomatic partial epilepsies, which can occur at virtually any age. Table 52–1 provides an overview of the age-dependent syndromes by increasing age at onset.

T A B L E 52–1. Overview of the Age-Dependent Syndromes by Increasing Age at Onset Benign familial neonatal convulsions: At day 2 or 3 Benign neonatal convulsions: At day 5 Early myoclonic encephalopathy with or without suppression bursts: Around 3 months Severe myoclonic epilepsy of infancy (Dravet’s syndrome): Before 1 year Infantile spasms (West’s syndrome): Before 1 year Benign myoclonic epilepsy in infants: 1-2 years Myoclonic-astatic epilepsy (Doose’s syndrome): 6 months to 6 years Lennox-Gastaut syndrome: Highest incidence at 3-5 years (2-8) Epilepsy with continuous spikes and waves during slow wave sleep: Around 4 years Benign epilepsy of childhood with occipital paroxysms: Mean age 5 years (2-8) Epilepsy with myoclonic absences: Around 7 years Childhood absence epilepsy: School-aged children, highest incidence at 7 years Benign epilepsy of childhood with centrotemporal spikes: Mean age 9 years (3-13) Juvenile absence epilepsy: Around puberty Juvenile myoclonic epilepsy: Highest incidence at 12-17 years (6-25) Primary reading epilepsy: Mean age 18 years

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Neurological and General Examinations These examinations are normal in the great majority of patients with idiopathic and cryptogenic epilepsy. Conversely, children with epileptic encephalopathies usually show developmental delay, justifying a thorough neuropsychological assessment. Symptomatic epilepsies can be associated with any type of neurological dysfunction depending on the number, size, and location of any underlying brain lesion(s). Other physical findings, in particular, skin abnormalities, are also found in certain specific epileptogenic disorders such as tuberous sclerosis or Sturge-Weber syndrome.

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Electroencephalography Electroencephalography is a mandatory investigation in all epileptic disorders including first unprovoked seizure, where it helps determine the risk of subsequent attacks. As previously mentioned, a postictal electroencephalogram performed within 6 hours of a seizure is likely to be more informative than interictal electroencephalogram and should be obtained in patients hospitalized for de novo epilepsy. Standard electroencephalography typically lasts 20 minutes, including periods of hyperventilation and intermittent photic stimulation. Hyperventilation favors the occurrence of all types of interictal electroencephalographic abnormalities and can precipitate absences as well as partial seizures. It also elicits physiological slow waves, at times of very high amplitude, in children and young adults. Intermittent photic stimulation can also be responsible for physiological photomyogenic electroencephalographic responses, which should be distinguished from the abnormal photoparoxysmal response, which is characterized by generalized spike-and-wave or polyspike-and-wave discharges that can culminate in a clinically overt seizure (Fig. 52–2). Photoparoxysmal response is observed mainly in juvenile myoclonic epilepsy and in the rare, purely photosensitive epilepsies. Photoparoxysmal response can also be seen in nonepileptic patients, especially in family members of juvenile myoclonic epilepsy probands. In children, longer recordings are often needed to obtain essential information provided by sleep recordings at this age. Sleep stages 1 and 2 can facilitate the appearance of interictal abnormalities, especially in idiopathic partial and generalized epilepsies. Sleep recording is also mandatory to detect the syndrome of continuous spikes-and-waves during sleep as well as the tonic ictal discharges that characterize LennoxGastaut syndrome. In some instances, a 24-hour ambulatory electroencephalogram is needed to thoroughly investigate all states of vigilance, associated with polygraphic recording of muscle activity and respiratory rate when necessary. Inhospital video-electroencephalographic monitoring lasting several hours to 1 or 2 weeks may be needed to characterize some seizures fully, especially if electrical or clinical data are insufficient to permit classification of seizure type or the underlying syndrome. Patients with epilepsy can show epileptiform abnormalities, including focal or generalized, symmetrical or asymmetrical spikes (duration less than 80 milliseconds), sharp waves (duration, 80 to 200 milliseconds), polyspike, spike-and-wave, and polyspike-and-wave complexes that can be isolated or assembled into rhythmic bursts or discharges of various durations, amplitudes, and frequencies (Fig. 52–3). When lasting more

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R. Trap. ■

Figure 52–2. Photoparoxysmal response with generalized polyspike and waves elicited by intermittent photic stimulation in juvenile myoclonic epilepsy.

than a few second(s), these rhythmic epileptiform patterns constitute ictal discharges. Bilateral symmetrical generalized spike-and-wave discharges with a frequency that is equal to or higher than 3 Hz are characteristic of typical absence seizures and more generally of idiopathic generalized epilepsies (Fig. 52–4). Conversely, bilateral asymmetrical generalized spikeand-wave discharges with a frequency that is equal to or lower than 2.5 Hz are seen in atypical absence seizures and cryptogenic or symptomatic generalized epilepsies (Fig. 52–5). Generalized tonic or tonic-clonic seizures are characterized by a diffuse flattening of the electroencephalogram, reflecting a very high frequency discharge of low amplitude. Various types of focal ictal discharges are seen at the onset of partial seizures,

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Figure 52–3. Generalized 3-Hz spike and wave discharge during an absence seizure in childhood absence epilepsy.

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Figure 52–4. Left frontal spikes and sharp waves (F3) in cryptogenic frontal lobe epilepsy.

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Figure 52–5. Bilateral asymmetrical generalized spike-and-wave discharges with a frequency lower than 2.5 Hz during an atypical absence seizure in Lennox-Gastaut syndrome.

including rhythmic spikes, sharp waves, or slow waves, as well as low-amplitude fast-activity discharges (Fig. 52–6). Patients with epilepsy can also show nonepileptiform, and thus less specific electroencephalographic findings, such as intermittent slow waves. Permanently abnormal background activity or a slow wave focus that is poorly or not reactive to external stimuli suggests an underlying encephalopathy or brain lesion.

Neuroimaging Neuroimaging must be performed in the majority of patients with epilepsy, unless clinical and electroencephalographic data have allowed a confident diagnosis of an idiopathic partial or generalized epileptic syndrome. ■ Although CT scanning is much less sensitive than MRI in

the identification of epileptogenic brain lesions such as hippocampal sclerosis, malformations of cortical development, cavernous angiomas, and low-grade tumors, it has two important applications: CT remains the method of choice for investigating newly diagnosed patients in an emergency setting. Indeed,

based on the fact that 1% of de novo seizures are symptomatic of brain lesions requiring rapid neurosurgical management, including subdural and intracerebral hematomas and brain abscess, a CT scan without contrast enhancement is recommended in the immediate management of patients with newly diagnosed seizures associated with any of the following criteria: a partial seizure, age greater than 40, a focal neurological abnormality, persisting headache or confusion, fever, HIV infection, recent head trauma, anticoagulant treatment, and cancer. In addition, CT scanning may be more sensitive than MRI in detecting calcifications, such as those observed around the ventricles in tuberous sclerosis, or the occipital calcifications associated with celiac disease (Fig. 52–7). ■ MRI is the gold standard for neuroimaging of the nonidio-

pathic epilepsies. It should be performed at 1.5 T or higher, by a radiologist familiar with the special sequences and slices orientations for optimal investigation of epileptic disorders. A standard epilepsy protocol should typically include a three-dimensional 1-mm3 resolution T1-weighted sequence as well as T2-weighted and FLAIR images in the axial and coronal planes, the latter perpendicular to the long axis of the hippocampus. Provided such a protocol, MRI can detect

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FP2–F10 F10–T10 T10–TP10 TP10–O2 SO2–FP2 FP2–F8 F8–T4 T4–T6 T6–O2 FP2–F4 F4–C4 C4–P4 P4–O2 ECG FP1–F9 F9–T9 T9–TP9 TP9–O1 SO1–FP1 FP1–F7 F7–T3 T3–T5 T5–O1 FP1–F3 F3–C3 C3–P3 P3–O1 EOG ■

Figure 52–6. Right temporal lobe discharge during a temporal lobe seizure.

abnormalities in up to 80% of patients with temporal lobe epilepsy and approximately two thirds of patients with nonidiopathic epilepsies. The most frequently encountered epileptogenic brain lesions are hippocampal sclerosis (Fig. 52–8), gliotic scars following various cerebral insults, lowgrade tumors, and, in particular, dysembryoplasic neuroepithelial tumors, gangliogliomas, oligodendrogliomas, cavernous angiomas, and malformations of cortical development, including cortical dysplasia, heterotopia, and polymicrogyria. ■ Many other investigations can occasionally be useful for the identification of a specific disease underlying an epileptic disorder, including biochemical and ophthalmological tests, as well as skin or muscle biopsy.

A Systematic Approach to the Classification of Epileptic Syndromes This section provides a practical guide to syndrome classification using core and specific features that characterize the main forms of epileptic disorder. Six major clinical situations should be distinguished:

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Figure 52–7. Bilateral occipital calcifications in celiac disease with occipital lobe epilepsy.

1. 2. 3. 4. 5. 6.

Epilepsies occurring before the age of 6 Idiopathic epilepsies Nonidiopathic partial epilepsies Occasional seizures Progressive myoclonic epilepsies Autoimmune and endocrinological seizure disorders

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Figure 52–8. MRI sign of hippocampal sclerosis with atrophy and increased T2 signal of the left hippocampus.

Epileptic Syndromes in Neonates, Infants, and Children Younger Than 6 Years Epilepsies occurring before the age of 6 include a great variety of rare disorders, many of which are associated with a grave prognosis. The very benign syndromes of neonatal convulsions that remit spontaneously and rapidly after a few days stand apart, provided an underlying metabolic dysfunction has been ruled out, The majority of epileptic syndromes encountered in infancy and early childhood, in particular, those manifesting with a generalized myoclonic or tonic component, lead to severe epilepsy associated with encephalopathy or developmental delay of varying severity. These include early myoclonic encephalopathy, early-infantile epileptic encephalopathy with suppression burst (Otahara’s syndrome), severe myoclonic epilepsy of infancy (Dravet’s syndrome), infantile spasms (West’s syndrome), and Lennox-Gastaut syndrome. These conditions necessarily require the expertise of a child neurologist or epileptologist and are not dealt with further in this chapter. The same expertise is needed to distinguish these disorders from less severe forms of epilepsy such as myoclonic-astatic epilepsy (Doose’s syndrome), benign myoclonic epilepsy in infants, and all forms of cryptogenic or symptomatic partial epilepsies that might occur at this age. Many of these disorders, including Otahara’s, West’s, and Lennox-Gastaut syndromes, can result from surgically treatable brain lesions and thus require expert MRI investigation.

Idiopathic Epilepsies of Late Childhood and Adolescence The idiopathic epilepsies, in particular, childhood absence epilepsy, juvenile myoclonic epilepsy, and benign childhood epilepsy with centrotemporal spikes,1 represent the most prevalent epileptic syndromes of childhood and adolescence. They should be identifiable by any physician involved in the care of patients with epilepsy, inasmuch as specific treatments exist for these syndromes.

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Idiopathic epilepsies are typically age related and characterized by a benign evolution. In addition, the generalized forms of idiopathic epilepsy are usually associated with familial history of idiopathic generalized epilepsy, although not necessarily a similar epileptic syndrome, and a favorable response to valproate. Childhood absence epilepsy occurs in school-aged children of normal intelligence and is characterized by very frequent typical absence seizures, up to several hundred per day, that can be elicited by hyperventilation. Electroencephalography demonstrates generalized 3-Hz spike-and-wave discharges and otherwise normal background activity. Evolution is usually benign under appropriate treatment, with disappearance of absences during adolescence, but breakthrough GTCS might occur at that age in 40% of patients. Juvenile myoclonic epilepsy has a peak incidence between 12 and 17 years but can occur more rarely in younger children and adults. Generalized myoclonic seizures, described in detail in a previous section of this chapter, are an invariant feature of this epileptic syndrome. Bilateral myoclonic jerks are typically experienced on awakening without associated loss of consciousness and are often not reported spontaneously by patients. GTCS are seen in 90% of patients often preceded by repetitive myoclonic jerking. From 10% to 15% of patients also suffer absence seizures. Clinical or electroencephalographic photosensitivity is present in 30% to 40% of patients. Sleep deprivation and alcohol intake can be triggering factors, especially for GTCS. Interictal electroencephalography shows generalized or asymmetrical polyspike-and-wave discharges at 3 Hz or faster. In contrast to most other idiopathic epilepsies, juvenile myoclonic epilepsy remains drug dependent during adulthood, with seizure relapse in 90% of patients who withdraw treatment. Benign childhood epilepsy with centrotemporal spikes is the most frequent epileptic syndrome of childhood with an age at onset ranging between 3 and 13 years. Seizures are typically sleep-related and characterized by tonic-clonic contraction of one side of the face and ipsilateral tongue and pharyngeallaryngeal muscles, ictal anarthria, and profuse dribbling at times preceded by somatosensory symptoms in the same body parts, and preserved consciousness. Secondary involvement of the ipsilateral upper limb can also be seen, as well as secondary generalization. Interictal electroencephalography shows typical high-amplitude, slow biphasic centrotemporal spikes, with a characteristic tangential dipolar distribution (Fig. 52–9). Spikes greatly increase in frequency and often become bilateral during sleep. Antiepileptic drug treatment can be avoided if seizures are brief and appear only during sleep.

Nonidiopathic Partial Epilepsies Nonidiopathic partial epilepsies represent between 50% and 60% of all epilepsies and occur across the entire life span. The seizure type varies greatly as a function of the cortical regions involved by an ictal discharge and often provides information about the most likely side and lobe of onset. Such information is useful in interpretation of the relationship between an MRIdetected abnormality and associated seizures or can help in detection of subtle brain lesions or malformations of cortical development. The multiple forms of nonidiopathic partial epilepsies need to be distinguished because specific management issues arise in this frequent disorder. For instance, mesial

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Figure 52–9. Typical high-amplitude slow biphasic right centrotemporal spikes in benign childhood epilepsy with centrotemporal spikes.

temporal lobe epilepsy with MRI changes of hippocampal sclerosis is characterized by a high rate of pharmacoresistance that is estimated to lie between 60% and 90% and shows an excellent response to epilepsy surgery in 80% of operated patients (Fig. 52–9). Despite these figures, the majority of patients with mesial temporal lobe epilepsy are referred for presurgical evaluation after an average delay of 15 to 20 years, primarily because the epileptic syndrome has not been properly assessed. Mesial temporal lobe epilepsy often develops in children, adolescents, or young adults with a past history of complex febrile convulsions. Among the many different signs and symptoms that can occur during temporal lobe seizures, the following ictal sequence is the most suggestive of mesial temporal lobe epilepsy: initial distressing, rising epigastric sensation sometimes associated with déjà vu or a dreamy state, early oroalimentary automatism followed by loss of awareness, upper limb motor automatisms ipsilateral to seizure onset with contralateral arm dystonia and ipsilateral head deviation, postictal nose wiping, and confusion with no or rare secondary generalization. Ictal verbal automatisms and postictal aphasia can also occur depending on the side of ictal onset. Hippocampal sclerosis can be readily detected on MRI provided that the appropriate sequences, slice thickness, and orientation are used to show clear-cut atrophy and an increased T2 and FLAIR signal within the hippocampus. Interictal electroencephalography often demonstrates anterior temporal spikes and intermittent slow waves but may also be normal.

Occasional Seizures Occasional seizures must be distinguished from all of the above conditions as they usually do not require antiepileptic treatment but rather control of a provocative agent or situation.2 The latter includes intake of excessive alcohol; of illicit drugs such as cocaine, codeine, amphetamines, and phencyclidine; and of many psychotropic drugs including antipsychotics, antidepressants, and lithium. Abrupt abstinence of alcohol, benzodiazepines, and barbiturates in chronic abusers can also precipitate a seizure. In contrast to alcohol-related seizures, alcohol-related epilepsy is characterized by relapsing partial or generalized seizures appearing in a chronic alcohol-abuser, independent of acute alcohol toxicity or sudden abstinence. It usually requires antiepileptic drug treatment. Sleep deprivation can also elicit seizures. Similarly, patients with obstructive sleep apnea syndrome can have nocturnal seizures that are better controlled by treatment of sleep apnea than by antiepileptic drugs. Finally, seizures can be provoked by acute metabolic dysfunction, including, hypoglycemia, hyponatremia, hypocalcemia, and hepatic and renal failure. Nonketotic hyperglycemia is one particular such disorder that can complicate preexisting diabetes but also often occurs in patients without prior history of hyperglycemia. This specific metabolic disorder is responsible for reflex motor seizures triggered by active or passive posture or movements that can

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progress to epilepsia partialis continua. Biochemical testing shows hyperglycemia of varying severity without associated ketosis. MRI is normal. Antiepileptic treatments are ineffective, whereas normalization of glycemia by insulin rapidly leads to seizure control.

Progressive Myoclonic Epilepsies Progressive myoclonic epilepsies include a variety of rare genetic seizure disorders associated with progressive neurological impairment, primarily characterized by action myoclonus and cerebellar dysfunction.3 They are thus of special interest to neurologists despite their rarity. Progressive myoclonic epilepsies at an early stage are often mistakenly diagnosed as juvenile myoclonic epilepsy, due to seemingly comparable age and seizure types at onset. However, a detailed analysis of the myoclonic jerks and neurological examination differentiate the two forms of myoclonic epilepsy, allowing anticipation of the far more severe prognosis of progressive myoclonic epilepsies. Various types of seizures can occur in these disorders, including generalized myoclonic seizures but also GTCS, atypical absences, and partial seizures that predominantly originate in the occipital lobe. However, the main clinical feature of progressive myoclonic epilepsy is the presence of action myoclonus that needs to be actively searched for. This movement disorder progressively worsens over years, together with the development of cerebellar dysfunction and cognitive impairment of varying severity, depending on the underlying etiology. Five diseases account for the great majority of progressive myoclonic epilepsies: Unverricht-Lundborg disease, myoclonic epilepsy with ragged red fibers, adult neuronal ceroid-lipofuscinosis (Kufs’ disease), Lafora’s disease, and sialidosis. Unverricht-Lundborg disease is the most common cause of adult progressive myoclonic epilepsy with the highest prevalence around the Baltic and Mediterranean seas. Evolution is slow and cognitive impairment is usually mild or absent, but the condition can be significantly aggravated by phenytoin. The diagnosis is confirmed by detection of the EMP1 mutation in the cystatin B gene on chromosome 6. Myoclonic epilepsy with ragged red fibers occurs at every age and results in progressive myoclonic epilepsy of varying severity, at times associated with neuropathy, extrapyramidal or pyramidal signs, and cardiac or hepatic dysfunction. Increased lactate can be observed in blood and cerebrospinal fluid, and muscle biopsy shows ragged red fibers in 90% of cases. The diagnosis is confirmed by detection of the MTTK mutation on mitochondrial DNA, accounting for the maternal line transmission. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes is another mitochondrial disorder that is more rarely associated with a progressive myoclonic epilepsy phenotype. Lafora’s disease is primarily characterized by rapid neurological deterioration, leading to death within 10 years of onset. Transient blindness associated with occipital seizures is often described. Lafora bodies can be observed on skin biopsy, and the EMP2A mutation of the laforin gene is detected in 80% of cases. Kufs’ disease is the adult form of neuronal ceroid lipofuscinosis and can be associated with a variety of nonspecific clinical patterns. Skin biopsy shows intracellular lipofuscin inclusion, whereas an important genetic heterogeneity

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hinders the detection of the underlying mutations in clinical practice. Sialidosis has a juvenile or adult onset and is often responsible for a relatively pure and slowly progressive action myoclonus. However, GTCS, ataxia, and visual impairment associated with a characteristic cherry-red spot in the fundus can be observed. The diagnosis is confirmed by detection of a mutation on the NEU 1 gene.

Autoimmune and Endocrinological Seizure Disorders These disorders are infrequent conditions whose special interest lies in the fact that they are diagnosed by specific biochemical tests and need specific treatment. Celiac disease is associated with epilepsy in 3.5% to 5.5% of cases. Seizures typically originate in the occipital lobe, where bilateral calcifications are often observed (see Fig. 52–8). It is to be distinguished from Sturge-Weber syndrome, where the calcified occipital pial angiomata are usually unilateral. Epilepsy is often the presenting manifestation of this disorder, before the occurrence of intestinal symptoms. Diagnosis is confirmed by the detection of IgA endomysial antibodies. A glutenfree diet is then required, although its impact on epilepsy remains controversial. Hashimoto’s disease can be responsible for an encephalopathy that combines seizures, myoclonus, and varying degrees of progressive cognitive impairment, confusion, and pyramidal signs. It usually manifests in the fifth decade. Partial seizures, most often arising from the temporal lobe, GTCS, and absence status might occur. MRI frequently shows hyperintense T2 lesions. The diagnosis is confirmed by positive anti-thyroid G and P antibodies, whereas thyroid function is normal in 66%. Corticosteroids are often spectacularly effective in this condition. Several other rare forms of autoimmune limbic encephalitis have been described based on the demonstration of specific antibodies, including anti-Hu, which is found in paraneoplastic syndromes and those directed toward voltage-gated potassium channels, or the more recently discovered anti-neuropil antibodies. Recognizing these conditions has important therapeutic consequences as they can respond dramatically to corticosteroids.4

CONCLUSION A practical guide to classify epileptic syndrome in neurological practice is to distinguish six major clinical situations: 1. Epilepsies occurring before the age of 6. These include a great variety of rare disorders, many of which are associated with a grave prognosis and require the expertise of a child neurologist or epileptologist. 2. Idiopathic epilepsies, and in particular childhood absence epilepsy, juvenile myoclonic epilepsy, and benign childhood epilepsies with centrotemporal spikes, represent the most prevalent epileptic syndromes in childhood and adolescence. They should be identifiable by any physician involved in the care of patients with epilepsy, because specific treatments exist for these disorders. 3. Nonidiopathic partial epilepsies represent between 50% and 60% of all epilepsies and occur across the entire life span.

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Once the partial origin of seizures has been ascertained, a search for an underlying etiology is needed, including assessment of any surgically treatable brain lesions. 4. Occasional seizures must be distinguished from all of the above conditions as they usually require control of a provocative agent or situation rather than antiepileptic treatment. 5. Progressive myoclonic epilepsies include a variety of rare genetic seizure disorders associated with progressive neurological impairment, primarily characterized by action myoclonus and cerebellar dysfunction. They are thus of special interest to neurologists despite their rarity. 6. Autoimmune and endocrinological seizure disorders

K E Y ●

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The diagnosis of seizure and of the seizure type relies mainly on a detailed chronological description of ictal signs and symptoms by the patient, relatives, and any other available witnesses. It is of primary importance to get a vivid, movie-like, corroborated description of the seizure scene, as if one had actually been there. The core features that characterize almost all epileptic fits are an abrupt onset, a short duration of several seconds to a few minutes, and a stereotyped sequence of ictal signs and symptoms.

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When no detailed description of a seizure is available and patients fail to recollect an aura, a long postictal amnesia represents the most robust sign distinguishing GTCS from syncope given that both can result in urination, tongue biting (although usually lateral tongue only in GTCS), and clonic movements (although usually only a few jerks in syncope versus 30 seconds or longer in GTCS).

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The identification of an epileptic syndrome helps to determine seizure prognosis and to decide on the most

appropriate treatment. Diagnosis is primarily based on seizure type(s), age at onset, electroencephalographic findings, and any potential etiological factors suggested by past history or neuroimaging. ●

Electroencephalography is a mandatory investigation in all epileptic disorders including first unprovoked seizure, where it helps determine the risk of subsequent attacks. A postictal electroencephalogram performed within 6 hours of a seizure is likely to be more informative than interictal electroencephalography and should be obtained in patients hospitalized for de novo epilepsy.

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Neuroimaging, and in particular MRI, needs to be performed in the majority of patients with epilepsy, unless clinical and electroencephalographic data have allowed a confident diagnosis of an idiopathic partial or generalized epileptic syndrome.

ACKNOWLEDGMENTS We wish to thank Renzo Guerrini and Richard Frackowiak for their help on this chapter.

References 1. Callenbach PM, van den Maagdenberg AM, Frants RR, et al: Clinical and genetic aspects of idiopathic epilepsies in childhood. Eur J Paediatr Neurol 2005; 9:91-103. 2. Delanty N, Vaughan CJ, French JA: Medical causes of seizures. Lancet 1998; 352:383-390. 3. Shahwan A, Farrell M, Delanty N: Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol 2005; 4:239-248. 4. Lang B, Dale RC, Vincent A: New autoantibody mediated disorders of the central nervous system. Curr Opin Neurol 2003; 16:351-357.

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Edward B. Bromfield

Treatment of epilepsy begins as soon as the diagnosis is made. Typically, this occurs after the second unprovoked seizure, but ancillary data, such as neuroimaging and electroencephalographic (EEG) recording, may support the diagnosis after a single seizure (see Chapters 50 and 52). On the other hand, the diagnosis could be inappropriate after even several seizures, if each can be plausibly regarded as provoked or acutely symptomatic of another condition, as in the case of repeated episodes of alcohol withdrawal or hypoglycemia (described as “occasional seizures” in Chapter 52). Of note is that the seizure risk in some clinical situations is sufficiently high that theoretically epilepsy could be suspected even before a single seizure has occurred; however, one practical argument against this approach is the observation that none of the tested antiepileptic drugs reliably prevents the first seizure in this circumstance. The mainstay of treatment is the use of antiepileptic drugs (AEDs), although, as mentioned, these probably do not prevent the development of epilepsy and could perhaps better be termed “antiseizure drugs,” because they do suppress seizures in established epilepsy; the older term anticonvulsant is no longer widely used because of the observation that many seizures do not involve convulsive movements. The first successful treatment, bromides, was introduced in the mid-19th century but proved to be too toxic for continued use. Phenobarbital has been used since the early 20th century, and phenytoin, the first AED identified by means of systematic testing, since 1938. Most drugs introduced before 1993 were variations of barbiturate, hydantoin, or benzodiazepine structures, but several novel medications have been identified and marketed since then. A relatively small number of comparative studies have failed to demonstrate major differences in efficacy, when used in appropriate situations, among the many approved AEDs. There are, however, major distinctions in common side effects, risk of serious idiosyncratic reactions, pharmacokinetics, drug interactions, and cost, and these differences help inform drug choices. Approximately half of all patients with newly diagnosed epilepsy (58% if idiopathic, 44% if symptomatic or cryptogenic) respond to the first well-tolerated drug administered, and about two thirds eventually achieve complete seizure control. Any of the remaining third, or those in whom seizure control is achieved at the cost of unacceptable side effects, are potential candidates for alternative therapies. These include vagus nerve stimulation (brain stimulation is under active study); resective brain surgery; disconnection procedures; dietary therapies,

including variations of the ketogenic diet; and certain supplements or herbal therapies.

TREATMENT WITH ANTIEPILEPTIC DRUGS Principles of use are outlined as follows: 1. Differences among drugs in efficacy are lesser than differences in pharmacokinetics, interactions, likely adverse effects, and cost. 2. There are several options for nearly every clinical situation. 3. Unless a rapid therapeutic effect is essential, a low starting dosage and slow titration rate should be chosen. This is especially true in the treatment of elderly or ill patients. 4. In general, the dosage should be increased until, after an adequate observation period, it is established that seizures are controlled or until dose-related side effects develop; in the latter case, the dosage should be decreased to the previous level, and the response should be monitored. If seizures are not controlled, another appropriate AED should be initiated and titrated up, usually while the first drug is tapered. 5. In rare cases, increases in dosage may result in worsening of seizures. The dosage should be reduced, and the drug will probably need to be replaced by an alternative AED. 6. For both ethical and logistical reasons, new AEDs are invariably tested as adjunctive therapy in adults with medically intractable partial seizures. Evidence of effectiveness in other settings is generally based on smaller studies that may or may not be well controlled, and it leads to regulatory approval for other uses in only a minority of cases. Therefore, off-label use is justifiable either if approved AEDs are not successful or if the risk of using the off-label alternative appears lower than that of the approved AED. 7. The most common drug interactions involving AEDs are based on induction or, less commonly, inhibition of the hepatic mixed-function oxidase or cytochrome P450 enzyme system. As a group, the older AEDs have much stronger effects on this system than do the newer drugs, although several of the latter are substrates whose metabolism is affected by addition or withdrawal of the older drugs. 8. Serum drug concentrations can be useful in verifying compliance or in providing an initial target for patients with infrequent seizures, but if used mechanically as a guide to dosing, they can hinder rather than help in achieving the goal of treatment: no seizures and no side effects (and ulti-

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mately, optimizing quality of life). Even with the older AEDs, published therapeutic ranges have limited scientific support, and individuals may have therapeutic responses or adverse effects either below or above these ranges. For the newer AEDs, therapeutic ranges are even more provisional but are included in the following discussions for completeness.

Use of Specific Antiepileptic Drugs AEDs may be categorized in several ways. Mechanistic classifications are logical but of limited clinical relevance, in that several drugs work by more than one mechanism and many work by mechanisms that are unknown or poorly understood. Perhaps the most useful classification concerns spectrum of action: 1. The first group of AEDs includes those that are effective against partial seizures, including simple and complex partial seizures, as well as secondarily generalized seizures. Most if not all of these also prevent primarily generalized tonic-clonic seizures; however, they are not effective against, and may worsen, other generalized seizure types, including absence and myoclonic seizures. Drugs in this class include carbamazepine, phenytoin, phenobarbital, primidone, gabapentin, oxcarbazepine, pregabalin, and tiagabine. 2. The second group includes those that can be viewed as “broad spectrum” AEDS, with activity against a variety of generalized as well as partial seizures. The traditional drug with this characteristic is valproate. There is evidence supporting a similar broad spectrum for the newer drugs lamotrigine, topiramate, levetiracetam, zonisamide, felbamate, and the older drug, methsuximide. 3. The third group includes drugs that do not easily fit in the above categories, including ethosuximide, a narrow spectrum AED with established efficacy against only typical generalized absence seizures. (Interestingly, the closely related drug methsuximide, as noted, has a broader spectrum and is effective against partial seizures as well.) There are also other, less commonly used adjunctive drugs that have different medical uses, such as acetazolamide and perhaps allopurinol. Finally, there are medications used in specific situations, including seizure clusters and status epilepticus, alcohol withdrawal and other drug-related seizures, and specific pediatric syndromes, such as infantile spasms. These include intravenous, sublingual, and rectal benzodiazepines, anesthetic agents, adrenocorticotropic hormone (ACTH), and pyridoxine.

Drugs for Partial and Tonic-Clonic Seizures Carbamazepine Advantages of carbamazepine are that it is considered a firstchoice drug for partial and tonic-clonic seizures; it has a long history of use; and slow-release preparations allow twice-daily dosing. Disadvantages are (1) the need to titrate slowly to avoid dose-related adverse effects and (2) pharmacokinetic interactions (cytochrome P450 enzyme inducer and substrate). Major dose-related adverse effects include dizziness, diplopia, nausea, sedation, mild leukopenia, hyponatremia, and bradyarrhythmias (elderly). Idiosyncratic adverse effects are

rash (including Stevens-Johnson syndrome), agranulocytosis, hepatic failure, pancreatitis, and lupus-like syndrome. Chronic adverse effects include osteopenia (possibly preventable with vitamin D and calcium supplementation). Carbamazepine has teratogenic effects, including a 0.5% to 1% incidence of neural tube defects (it is unclear whether extra folate prevents these), although data have shown that the risk is not elevated very much. The initial dosage should be 100 to 200 mg at bedtime or 100 mg twice a day, and the dosage is increased after 3 to 7 days to 200 mg twice a day. Blood values should be checked after 1 week on this dosage: carbamazepine level, complete blood cell count and differential, electrolytes (Na), and perhaps albumin and aspartate transaminase. The dosage should be increased at 3- to 7-day intervals to a level of 4 to 12 mg/L; this level should be rechecked in 4 to 6 weeks, because autoinduction may necessitate further increases. The usual maintenance dosages in adults are 600 to 1600 mg/day, up to 2400 mg/day; in children, the starting dosage is 5 to 10 mg/kg/day, and the maintenance dosage is 15 to 20 mg/kg/day, up to 30 mg/kg/day. With regard to pharmacokinetics, the half-life is 12 to 20 hours (shorter with enzyme-inducing drugs; autoinduction also occurs, with the level falling after 2 to 6 weeks on a stable dosage), and protein binding is 70% to 80%. The usual therapeutic range is 4 to 12 mg/L. Preparations of carbamazepine include Tegretol tablets, 100 and 200 mg; generic 200-mg tablets; a generic suspension of 100 mg/5 mL (which can solidify in tube feedings); and slow-release preparations, including Tegretol-XR in 100-, 200-, and 400-mg caplets and Carbatrol in 200- and 300-mg capsules.

Oxcarbazepine Advantages of oxcarbazepine include its rapid titration, twicedaily dosing, minor interactions, and no known hepatic or hematological adverse effects; it was approved as initial monotherapy for partial seizures. Disadvantages include dose-related effects similar to those of carbamazepine; although it is only a weak cytochrome P450 inducer, it can lower hormone (e.g., contraceptive) levels. Oxcarbazepine is very similar chemically to carbamazepine but is not converted to epoxide metabolite, which is believed to account for many adverse effects of carbamazepine. Major adverse effects include dose-related dizziness, diplopia, hyponatremia, somnolence, ataxia, and gastrointestinal upset. An idiosyncratic adverse effect is rash (25% crossreactivity with carbamazepine). No chronic adverse effects are known. Teratogenic risk with oxcarbazepine is unknown (lack of epoxide metabolite may suggest that oxcarbazepine is preferable over carbamazepine). Initiation should be at 150 to 300 mg twice daily, increasing by 300 to 600 mg every 1 to 2 weeks to a target of 1200 to 2400 mg/day. Pediatric (age >4 years) dosages are 8 to 10 mg/kg/day, titrated to 20 to 40 mg/kg/day. Of importance is that conversion from carbamazepine can be rapid, over 1 day to 2 weeks, at a ratio of 300 mg of oxcarbazepine to 200 mg of carbamazepine. With regard to pharmacokinetics, the half-life is 2 hours, but the drug is converted to an active monohydroxy-derivative, whose half-life is 8 to 10 hours. Protein binding is 40%.

chapter 53 drug treatment The therapeutic range is 10 to 35 mg/L (monohydroxyderivative). Preparations include Trileptal tablets, 150, 300, and 600 mg, and Trileptal syrup, 300 mg/5 mL.

Phenytoin Advantages of phenytoin are that it is arguably still a first-choice drug for partial and tonic-clonic seizures, although it is used much less in Europe than in the United States. It also has a long history of use; a long duration of action, especially with slowrelease preparations (dosing is usually twice daily but can be daily); and there is a parenteral loading option. It is effective against generalized tonic as well as tonic-clonic seizures, although it is not effective against absence or myoclonic seizures. Disadvantages include its zero-order kinetics; pharmacokinetic interactions (strong cytochrome P450 inducer); chronic cosmetic effects; and other adverse effects. Major dose-related adverse effects are dizziness, ataxia, diplopia, and nausea. Idiosyncratic adverse effects are rash, including Stevens-Johnson syndrome; blood dyscrasias; hepatic failure; and lupus-like syndrome. Chronic adverse effects include gingival hyperplasia, hirsutism, osteopenia, pseudolymphoma, possibly lymphoma, and possibly cerebellar degeneration. Phenytoin is teratogenic, causing a nonspecific doubling of the risk of major congenital malformations and a higher incidence of cosmetic anomalies. In adults in nonemergency situations, the drug can be loaded orally; two doses of 500 mg or three doses of 300 mg can be taken 4 to 6 hours apart. Parenteral loading can be achieved intravenously (15 mg/kg, or 20 mg/kg for status epilepticus, not more than 50 mg/minute; the precursor drug fosphenytoin may be preferable for status epilepticus). When loading is not needed, an estimated maintenance dosage of 300 to 400 mg/day can be initiated, usually in two doses; blood levels should be checked in 1 to 2 weeks. Because of zero-order kinetics, increases must be proportionately lower as the level rises; for example, if the steady-state level on 300 mg/day is 12 mg/L, then 330 mg/day, a 10% dose increase, may be sufficient to raise the level to 15 mg/L, a 25% increase. The pediatric dosage is 4 to 5 mg/kg/day, up to 8 mg/kg or more, depending on level. With regard to pharmacokinetics, the half-life (level-dependent) is 20 to 30 hours when the usual therapeutic range is used; protein binding is 90% (higher with renal failure or hypoalbuminemia). The usual therapeutic range is 10 to 20 mg/L (arguably 5 to 25 mg/L). Preparations include Dilantin tablets, 50 mg; Dilantin and generic extended-release capsules, 30 and 100 mg; a suspension, 125 mg/5 mL (must be adequately mixed in the bottle); and Phenytek capsules, 200 and 300 mg.

Gabapentin Advantages of gabapentin include its ability to be rapidly titrated, the facts that it is relatively well tolerated and has no pharmacokinetic interactions, and its additional uses (for neuropathic pain). Disadvantages include the recommendation of three- to four-times-daily dosing (although it can be given twice daily);

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it is also perceived as less efficacious than other AEDs, although data are conflicting. Major dose-related adverse effects include sedation, dizziness, and ataxia. Idiosyncratic adverse effects include weight gain, rash (rare), behavioral changes in children, and myoclonus. There are no known chronic adverse effects. Teratogenic risk with gabapentin is unknown. Initiation should be at 300 mg at bedtime, increasing by 300 mg every 1 to 7 days to a target of 1800 to 3600 mg/day; in elderly patients, at 100 at bedtime or twice daily, increasing in 100- to 200-mg increments; in pediatric patients (aged >3 year), at 10 to 20 mg/kg/day, increasing to a target of 30 to 60 mg/day. With regard to pharmacokinetics, the half-life is 5 to 7 hours (but brain kinetics are probably slower). There is no protein binding. The provisional therapeutic range is 4 to 16 mg/L. Preparations include Neurontin capsules, 100, 300, and 400 mg; Neurontin tablets, 600 and 800 mg; and Neurontin solution, 250 mg/5 mL. Generic gabapentin tablets are also available.

Pregabalin Advantages of pregabalin include the lack of pharmacokinetic interactions, additional uses (for neuropathic pain), and the ability for twice-daily dosing (although three times daily may be better tolerated). The disadvantage is that relatively slow titration is needed, to avoid sedation. Major dose-related adverse effects include sedation, dizziness, ataxia, and blurred vision. Idiosyncratic adverse effects include weight gain, edema, and rash (rare). There are no known chronic adverse effects. Teratogenic risk with pregabalin is unknown. Initiation should be at 50 or 75 mg at bedtime or twice daily, increasing by a similar amount every 4 to 7 days to a target of 300 twice daily if tolerated. With regard to pharmacokinetics, the half-life is 6 hours (but brain kinetics are probably slower). There is no protein binding. The provisional therapeutic range is unknown. Preparations include Lyrica capsules, 25, 50, 75, 100, 150, 200, 225, and 300 mg.

Tiagabine Advantages of tiagabine are that it may have antianxiety or analgesic effects and it can sometimes be given twice daily. Disadvantages include its sedating effects, the risk of nonconvulsive status epilepticus; and the fact that it is a cytochrome P450 substrate. Major dose-related adverse effects include dizziness, somnolence, nausea, and cognitive slowing. Idiosyncratic adverse effects include rash, mood changes, and generalized nonconvulsive status epilepticus (with dosages of 48 mg/day or greater). There are no known chronic adverse effects. Teratogenic risk with tiagabine is unknown. Initiation should be at 4 mg at bedtime, increasing by 4 to 8 mg/day weekly to a target of 36 to 54 mg/day, taken twice or three times daily. Titration should be at 2 to 8 mg/day, increasing by 2 to 8 mg/day at weekly intervals to a target of 24 to 56 mg/day in two to four doses. In pediatric patients (aged >12 years), the initial dosage is 4 mg/day, increasing by 4 mg/week to a target of 20 to 32 mg/day.

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With regard to pharmacokinetics, the half-life is 4 to 9 hours; protein binding is 96%. The provisional therapeutic range is unknown. Preparations include Gabitril, 2-, 4-, 12-, and 16-mg tablets.

Vigabatrin Advantages of vigabatrin are that it is very effective against partial seizures and against infantile spasms in patients with tuberous sclerosis. A disadvantage is that it may exacerbate generalized epilepsies. Major dose-related adverse effects include sedation, dizziness, and diplopia. Idiosyncratic adverse effects include psychiatric disturbances. Chronic adverse effects include retinal toxicity (which causes visual field defects that are detectable in high proportion with detailed testing, although they are often asymptomatic) and weight gain. Teratogenic risk with vigabatrin is unknown. In adults, vigabatrin should be initiated at 1 g/day and increased by 1 g/day weekly to a target of 3 to 4 g/day, taken twice daily; in children, the initial dosage should be 40 mg/ kg/day, taken twice daily, and increased to a target of 40 to 150 mg/kg/day. With regard to pharmacokinetics, the half-life is 5 to 8 hours, but the biological effect (γ-amino butyric acid transaminase inhibition) lasts days; protein binding is 0%. The provisional therapeutic range is unknown. Preparations include Sabril, 500-mg tablets, and a powder sachet, 500 mg.

against myoclonic seizures, and that it is effective against tremor at low doses. Disadvantages include the facts that it is possibly more sedating than phenobarbital alone; it must be taken in divided doses, usually three or four times daily; and that it is a cytochrome P450 inducer. Primidone is metabolized to phenobarbital. Major dose-related, idiosyncratic, and chronic adverse effects are the same as those of phenobarbital. Primidone is teratogenic, with similar risk of major congenital malformation. Initiation should be at 100 to 125 mg at bedtime, increasing by 125 to 250 mg every 2 to 7 days to a target of 500 to 1500 mg/day. In pediatric patients, the initial dosage is 50 mg/day, increasing to 10 to 25 mg/kg/day. With regard to pharmacokinetics, the half-life is 6 to 22 hours (72 to 168 hours for phenobarbital metabolite); cytochrome P450 inducers promote conversion to phenobarbital. The usual therapeutic range is 5 to 12 mg/L (10 to 40 mg/L for phenobarbital metabolite). Preparations include Mysoline and generic tablets, 50 and 250 mg, and a generic suspension, 250 mg/5 mL.

Drugs for Generalized Seizures, Including Absence and Myoclonic, as Well as Tonic-Clonic These also are effective against partial seizures.

Phenobarbital

Valproate

Advantages of phenobarbital include a long half-life (daily dosing) and its low cost. Disadvantages include cognitive and behavioral side effects and drug interactions (it is a cytochrome P450 inducer). Major dose-related adverse effects include sedation, depression, and cognitive impairment. Idiosyncratic adverse effects include rash, hyperactivity (in children), hepatic failure (rare), and aplastic anemia (rare). Chronic adverse effects include osteoporosis and connective tissue disorders (e.g., frozen shoulder). Phenobarbital is teratogenic, causing a two- to threefold increase over baseline in major congenital malformations. Initiation should be at 90 to 250 mg/day; up to 20 mg/kg (<100 mg/hour for status epilepticus) can be loaded intravenously, but sedation is universal. Steady-state levels should be checked in 2 to 3 weeks (4 to 5 weeks if valproate is taken concurrently). The pediatric dosage is 2 to 7 mg/kg/day. With regard to pharmacokinetics, the half-life is 72 to 168 hours (less in children, more when coadministered with valproate). The usual therapeutic range is 10 to 40 mg/L (arguably 5 to 30 mg/L). Preparations include generic tablets 15, 30, 60 (or 62.5), and 100 mg; a generic suspension, 15 or 20 mg/5 mL; and a generic parenteral formulation, 30, 60, and 130 mg/mL.

Advantages of valproate include its long history of use and the fact that it is the best established broad-spectrum AED; its concomitant effects on migraine and bipolar illness; and the fact that slow-release preparations allow twice- or possibly oncedaily dosing. Disadvantages include its acute and chronic adverse effects, particularly weight gain, and its interactions (it is a cytochrome P450 inhibitor and also competes for protein binding sites). Major dose-related adverse effects include gastrointestinal upset, anorexia, tremor, and thrombocytopenia. Idiosyncratic adverse effects include pancreatitis (in up to 1 per 200 patients), hepatic failure (especially in infants receiving polytherapy), stupor and coma, depression, rash, hyperammonemia, and thrombocytopenia or thrombocytopathy. Chronic adverse effects include weight gain, hair loss or change in texture, and possibly polycystic ovarian syndrome. Valproate has teratogenic effects, including a 1% to 2% incidence of neural tube defects. Initiation should be at 250 mg twice or three times daily, increasing by 250 to 500 mg weekly to a target of 750 to 2000 mg/day (higher if the patient is also taking enzymeinducing drugs). The pediatric dosage should begin at 10 to 15 mg/kg/day, increasing by 5 to 10 mg/kg weekly to 15 to 30 mg/kg/day (maximum, 60 mg/kg/day). With regard to pharmacokinetics, the half-life is 10 to 20 hours; up to 95% of the drug is protein bound, a lower percentage at higher doses; as a partial cytochrome P450 inhibitor, it causes elevation particularly of phenobarbital and lamotrigine levels. The usual therapeutic range is 50 to 120 mg/L.

Primidone Advantages of primidone are that the parent compound may have efficacy beyond that of phenobarbital metabolite, at least

chapter 53 drug treatment Preparations include Depakene or generic valproic acid capsules, 250 mg; generic syrup, 250 mg/5 mL; Depakote delayed-release tablets, 125, 250, and 500 mg; Depakote Sprinkles slow-release capsules, 125 mg; Depakote-ER extendedrelease capsules, 250 and 500 mg; and Depacon intravenous infusion, 100 mg/5 mL.

Lamotrigine Advantages of lamotrigine include its broad spectrum of coverage, including Lennox-Gastaut syndrome. It is well tolerated and relatively nonsedating; it is approved as monotherapy (for partial seizures) when transitioned from an enzymeinducing AED; and it can be taken twice daily. Disadvantages are that slow titration is needed to minimize rash risk, and patients taking lamotrigine are susceptible to enzyme induction. Major dose-related adverse effects include dizziness, ataxia, and drowsiness (or insomnia). Idiosyncratic adverse effects include rash in 5% to 10% of patients (including a 0.1% incidence of Stevens-Johnson syndrome, which is higher in children), and hypersensitivity syndrome. No chronic adverse effects are known. Teratogenicity is likely at higher dosages, particularly cleft palate. Initiation with enzyme-inducing AEDs should be at 50 mg/day for 2 weeks; then the dosage is increased, first to 50 mg twice daily for 2 weeks and then by 50 to 100 mg weekly to a target of 300 to 500 mg/day. Initiation with enzyme-inducing AEDs plus valproate should be at 25 mg every other day for 2 weeks; then the dosage is increased, first to 25 mg every day for 2 weeks and then by 25 to 50 mg every 1 to 2 weeks to a target of 100 to 300 mg/day. For (off-label) initial monotherapy or when added to non–enzyme-inducing AEDs without valproate, the initial dosage is 25 mg every other day for 2 weeks or 25 mg every day for 2 weeks, followed by 25 mg twice daily for 2 weeks and then increased by 25 to 50 mg/day every 1 to 2 weeks. For pediatric patients (aged >2 years) with enzymeinducing AEDs, the initial dosage should be 2 mg/kg/day for 2 weeks, increasing by similar amount to 5 to 15 mg/kg/day; with valproate, the initial dosage should be 0.1 to 0.2 mg/kg/day for 2 weeks, increasing by 0.5 mg/kg/day to a target of 1 to 5 mg/kg/day. With regard to pharmacokinetics, lamotrigine is a cytochrome P450 substrate; the half-life is approximately 24 hours alone (or combination of enzyme-inducing drugs and valproate), 15 hours with enzyme-inducing drugs, and 60 hours with valproate and no enzyme-inducing drugs. The therapeutic range is 4 to 16 mg/L. Preparations include Lamictal tablets, 25, 100, 150, and 200 mg, and generic chewable dispersible tablets, 5, 10, and 25 mg.

Topiramate Advantages of topiramate are its broad spectrum of coverage, including Lennox-Gastaut syndrome; its effectiveness at low dosages in some patients; and twice-daily dosing. Disadvantages include the need for slow titration to minimize CNS adverse effects; and its interference at high dosages with oral contraceptives in some patients.

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Major dose-related adverse effects include cognitive slowing, word-finding difficulties, paresthesias, and dizziness. Idiosyncratic dose-related effects include rash, gastrointestinal upset, narrow-angle glaucoma, irritability, and metabolic acidosis. Chronic adverse effects include renal stones (in 1% to 2% of patients, a lower percentage of women) and weight loss. Teratogenic risk with topiramate is unknown. Initiation should be at 25 mg/day, increasing by 25 mg/day per 1 to 2 weeks to a target of 200 mg/day or higher. In pediatric patients (aged ≥2), the dosage should start at 1 to 3 mg/kg/day, increasing by similar amount every 1 to 2 weeks to 5 to 9 mg/kg/day. Pharmacokinetics are renal and hepatic; patients are susceptible to enzyme induction; and phenytoin levels may become slightly elevated. The therapeutic range is 5 to 20 mg/L provisionally. Preparations include Topamax tablets, 25, 100, and 200 mg; Topamax Sprinkles capsules, 15 and 25 mg.

Levetiracetam Advantages of levetiracetam include the fact that the starting dose is therapeutic; its efficacy; its lack of interactions; and twice-daily dosing. Disadvantages include irritability and other less common psychobehavioral effects and the fact that its broad spectrum of coverage is not well documented. Major dose-related adverse effects include sedation and dizziness. Idiosyncratic adverse effects include gastrointestinal intolerance, depression, and irritability. No chronic adverse effects are known, apart from clinically insignificant decreases in hemoglobin or WBC count. The teratogenic risk of levetiracetam is unknown. Initiation should be at 250 to 500 mg twice daily, increasing by 500 mg/day every 1 to 2 weeks to a target of 1000 to 3000 mg/day. In pediatric patients (aged >12), the dosage should start at 10 to 20 mg/kg/day, increasing by 5 to 10 mg/kg/day every 1 to 2 weeks to a target of 40 mg/kg/day. With regard to pharmacokinetics, excretion is renal; the half-life is 6 to 8 hours, but levetiracetam is water soluble, which suggests that the brain kinetics are slower. The therapeutic range is 10 to 40 mg/L provisionally. Preparations include Keppra tablets, 250, 500, and 750 mg.

Zonisamide Advantages of zonisamide include its broad spectrum of coverage and its long half-life, which allows once-daily dosing (although twice-daily dosing is recommended). Disadvantages include the need for slow titration and sedation. Major dose-related adverse effects include fatigue, confusion, and dizziness. Idiosyncratic adverse effects include rash (can progress to Stevens-Johnson syndrome; zonisamide probably does not cross-react with sulfa antibiotics) and hypohidrosis (in children). Chronic adverse effects include renal stones and weight loss. Teratogenic risk with zonisamide is unknown. The dosage should begin at 100 mg/day for 2 weeks and then increase by 100 mg every 2 weeks to a target of 400 mg/day. In pediatric patients, the dosage should begin at 2 to 4 mg/kg/day,

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increasing by similar amount every 1 to 2 weeks to a target of 8 mg/kg/day. With regard to pharmacokinetics, zonisamide is a cytochrome P450 substrate; its half-life is 60 hours alone but 25 to 30 hours with enzyme inducers. The therapeutic range is 20 to 40 mg/L provisionally. The preparation is Zonegran, 100-mg capsules, and generic zonisamide 100-mg capsules.

Methsuximide Advantages of methsuximide include its broad spectrum of coverage, including partial seizures, and its long half-life; dosing is usually twice daily but can be once daily. Disdvantages include the need for slow titration, CNS side effects, and the drug’s lack of familiarity to many clinicians. Major dose-related adverse effects include sedation and headache. Idiosyncratic adverse effects include rash (including Stevens-Johnson syndrome), psychiatric difficulties, gastrointestinal upset, lupus-like syndrome, and leukopenia. No chronic adverse effects are known. Teratogenicity with methsuximide is unknown. With regard to pharmacokinetics, the half-life of the active metabolite, N,N-desmethylmethsuximide, is 34 to 80 hours in adults and 16 to 45 hours in children; the level can be lowered by enzyme inducers; phenytoin levels may become elevated and carbamazepine levels decreased. The initial dosage should be 300 mg at bedtime for 1 to 2 weeks, increasing by 300 mg every 1 to 2 weeks to a target of 900 to 1200 mg/day. In pediatric patients, the initial dosage should be 150 mg/day, increasing by 150 mg/day. The therapeutic range is 10 to 40 mg/L (N,N-desmethylmethsuximide). Preparations include Celontin capsules, 150 and 300 mg.

Felbamate Advantages of felbamate include its broad spectrum of coverage, including Lennox-Gastaut syndrome. It is efficacious and nonsedating, and it is approved as initial monotherapy (for partial seizures). Dosing can be twice daily, although three times daily is usually better tolerated. Disadvantages include drug interactions and the risk of potentially fatal aplastic anemia (1 per 5000 patients) and hepatic failure (1 per 10,000 patients). Major dose-related adverse effects include anxiety, insomnia, fatigue, and ataxia. Idiosyncratic adverse effects include rash, aplastic anemia, and hepatic failure. One chronic adverse effect is weight loss. Teratogenicity with felbamate is unknown. With regard to pharmacokinetics and interactions, the halflife is 15 to 20 hours but shortened by enzyme inducers. Felbamate may act as an enzyme inhibitor, elevating phenytoin, valproate, and phenobarbital levels; however, it reduces carbamazepine levels. The initial dosage should be 600 mg twice daily, increasing by 600 mg/day weekly to a target of 2400 to 4800 mg/day. In pediatric patients, the initial dosages should be 10 to 15 mg/kg/day, increasing to 20 to 40 mg/kg/day. The therapeutic range is 40 to 100 mg/L provisionally. Preparations include Felbatol tablets, 400 mg, and Felbatol suspension, 600 mg/5 mL.

Drugs with a Narrow Spectrum of Action or for Use in Specific Situations Ethosuximide Advantages of ethosuximide include its long half-life, which usually enables twice-daily dosing, and its effectiveness against absence seizures. Disadvantages include narrow spectrum, with absence seizures the only well-established target. Major dose-related adverse effects include sedation and headache. Idiosyncratic adverse effects include rash, psychiatric decompensation, gastrointestinal upset, and lupus-like syndrome. No chronic adverse effects are known. Teratogenicity with ethosuximide is not known. The initial dosage should be 250 mg twice daily, increasing by 250 mg/day at weekly intervals to a target of 500 to 1000 mg/day. In pediatric patients (aged >3 years), the initial dosage should be 250 mg/day, increasing by 250 mg/week to a target of 15 to 20 mg/kg/day. With regard to pharmacokinetics, ethosuximide is metabolized hepatically, and there is no protein binding; its half-life is 30 to 60 hours. The therapeutic range is 40 to 100 mg/L. Preparations include Zarontin capsules, 250 mg, and Zarontin solution, 250 mg/5 mL, as well as generic 250-mg tablets.

Acetazolamide Advantages of acetazolamide are that it is well tolerated; it is typically used adjunctively for absence seizures, but it may be used for partial seizures and intermittently for catamenial (menses-related) seizure exacerbations. Disdvantages include its probable low efficacy; it should not be used with topiramate or zonisamide (because renal stones can result). Major dose-related adverse effects include paresthesias, weakness, hyponatremia, and hypokalemia. Idiosyncratic adverse effects include anorexia, rash, and blood dyscrasias. One chronic adverse effect is osteomalacia. Acetazolamide is teratogenic, likely increasing the risk of congenital malformation. With regard to pharmacokinetics, the half-life is 2 to 13 hours. The initial dosage should be 250 to 500 mg/day, increasing to 500 to 1000 mg/day (twice or three times daily). In pediatric patients, the initial dosage is 4 mg/kg/day, increasing over several weeks to 8 to 30 mg/kg/day. No therapeutic range has been determined. Preparations include Diamox tablets, 125 and 250 mg; Diamox slow-release tablets, 500 mg; suspension 50 mg/mL; and generic acetazolamide, 100-mg and 200-mg tablets.

Benzodiazepines These differ from each other mainly by pharmacokinetics and available routes of administration. Adverse effects include mainly sedation and slowed cognition, as well as ventilatory suppression when given intravenously.

Clonazepam This drug is used as adjunctive therapy for myoclonic and atonic seizures and less often for partial seizures. Its half-life is 20 to 40 hours, shortened by enzyme inducers; the initial

chapter 53 drug treatment dosage is 0.5 mg once or twice daily, increasing by 0.5 mg/day every 3 to 7 days to a target of 1.5 to 4 mg/day. Preparations include Klonopin or generic tablets, 0.5, 1, and 2 mg. An intravenous formulation is available in Europe.

Clorazepate This drug is used in the same way as clonazepam (although it is approved for partial seizures). The nordiazepam metabolite half-life is 55 to 100 hours; the initial dosage is 3.75 mg twice to three times daily, increasing by 3.75 to 7.5 mg every week to a target of 15 to 45 mg/day. Preparations include Tranxene or generic tablets, 3.75, 7.5, and 15 mg, and Tranxene-CR slowrelease tablets, 11.25 and 22.5 mg.

Diazepam Diazepam is rarely used orally but widely used intravenously for status epilepticus and rectally for acute repetitive seizures. The half-life of its active metabolite, desmethyldiazepam, is 20 to 40 hours, but when the drug is given intravenously, it is redistributed out of the brain into other fatty tissues; it is also highly protein bound (99%). Therefore, when it is given intravenously, although onset of action is extremely rapid (1 to 2 minutes), duration of action is only 15 to 20 minutes. Preparations include a 5 mg/mL solution and a rectal gel (Diastat), dosages of which are according to age and weight, which is available in rectal syringes that can be adjusted to yield doses between 2.5 and 20 mg.

Lorazepam Lorazepam is administered intravenously for status epilepticus; its onset of action (4 to 5 minutes) is slightly slower than that of diazepam, but it remains in the brain much longer, with a duration of action of 4 to 10 hours. Protein binding is 90%. Oral lorazepam is rarely used long term, but it can be given sublingually for seizure clusters, especially if the patient is too awake between seizures to tolerate rectal diazepam gel. Preparations include Ativan or generic tablets, 0.5, 1, and 2 mg, and solution, 0.5, 1, or 2 mg/mL.

Midazolam Midazolam is administered intravenously for status epilepticus as an alternative to diazepam or lorazepam and as an infusion when status epilepticus becomes refractory. Its half-life is 1 to 2 hours. Preparations include Versed or generic vials, 1 mg/mL or 5 mg/mL.

Nitrazepam Nitrazepam is used primarily for infantile spasms; it is not available in the United States. The dosages are 1 mg/kg in children and 0.5 mg/kg in adults, given in one or two doses.

Clobazam Clobazam is less sedating than other benzodiazepines; it is not available in the United States. The dosage is 10 to 30 (up to 50) mg/day in one or two doses.

Fosphenytoin A water-soluble pro-drug of phenytoin, fosphenytoin may be given more quickly (up to 150 mg phenytoin equivalents/

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minute in adults) and without fear of tissue necrosis in case of extravasation; it may also be given intramuscularly in nonemergency situations. Although it is not given in a propylene glycol vehicle, which has been believed to be largely responsible for the hypotensive effects of phenytoin, studies have not demonstrated a lower rate of this complication with fosphenytoin.

COMMON CLINICAL SITUATIONS AND SPECIFIC SYNDROMES Approaches to common clinical situations and to specific syndromes are discussed as follows, presented when possible in order of the usual age at manifestation (see Chapter 52 for clinical and diagnostic considerations).

Neonatal Seizures The first priority is to identify and treat any reversible infectious or metabolic cause. While waiting for blood test results to return, some clinicians administer in a stepwise manner 2 to 4 mL/kg of 25% glucose, 50 to 100 mg of pyridoxine (ideally during EEG recording), 1 to 2 mL/kg of 10% calcium gluconate (over minutes during electrocardiographic monitoring), and 0.1 to 0.2 mL/kg of 50% magnesium sulfate. If ventilation and other autonomic functions are unaffected, some clinicians elect to observe or treat only with benzodiazepines. However, treatment is usually initiated with phenobarbital or phenytoin. Phenobarbital is given in two 10-mg/kg boluses at 2 to 3 mg/kg/minute, followed by additional boluses as needed. If this is unsuccessful, phenytoin may also be given in two 10-mg/kg boluses, no faster than 2 mg/kg/minute. Phenobarbital is maintained orally at 5 mg/kg/day; levels are monitored frequently because of more rapid and varied metabolisms in newborns than in older children. Variations in phenytoin absorption, as well as in metabolism, in neonates complicate its use in oral maintenance. There is experimental evidence that topiramate may have a neuroprotective role in neonatal seizure management, but recommendations must be withheld until further research.

West’s Syndrome (Infantile Spasms) If no etiology of seizures is found, pyridoxine deficiency, a very rare but dramatically treatable cause, should be considered. Pyridoxine, 100 to 200 mg, should be administered intravenously during EEG recording; if this is the etiology, the EEG recording should improve within minutes. The mainstay of treatment, however, remains ACTH, which often produces seizure control and EEG improvement within days. ACTH may be given intramuscularly at 40 IU daily for 2 weeks and, if seizures continue, increased by 10 IU weekly until seizures are controlled or until a maximum of 80 IU/day is reached. After seizures stop, the dosage can be continued for a month and then tapered by 10 IU/week. If seizures recur, the previously effective dosage is resumed. Blood pressure, stool guaiac, electrolytes, calcium level, phosphorus level, glucose level, and signs of infection must be monitored. Alternatives, typically used when ACTH fails or is not tolerated, include prednisone, valproate, clonazepam, lamotrigine, topiramate, felbamate, and tiagabine. Valproate can be initiated

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at 15 mg/kg/day in three doses and increased in 5- to 10mg/kg/day weekly increments. Clonazepam is begun at 0.01 to 0.03 mg/kg/day in three doses, increasing by 0.25 to 0.50 mg every three days to a target of 0.1 to 0.2 mg/kg/day. The AED vigabatrin, an inhibitor of γ-amino butyric acid catabolism, is unavailable in the United States, but it can be dramatically effective, especially when the spasms are caused by tuberous sclerosis.

Lennox-Gastaut Syndrome A variety of the broad-spectrum AEDs have shown efficacy in the treatment of Lennox-Gastaut syndrome, although responses are rarely dramatic. Valproate has traditionally been used, although the risk of hepatic failure is a concern in patients younger than 2 years, and felbamate also carries a risk of hepatic and bone marrow toxicity; topiramate and lamotrigine are likely to be safer. Clonazepam is sometimes given adjunctively, although sedation and behavioral effects limit its use. Levetiracetam, zonisamide, acetazolamide, and methsuximide are worthy of consideration but have not been studied formally. Narrow-spectrum drugs such as phenytoin and carbamazepine may be given for tonic-clonic seizures, and phenytoin may also help control tonic and perhaps atonic seizures. There is considerable evidence that the ketogenic diet can be effective in Lennox-Gastaut syndrome, with 30% to 50% of patients showing dramatic or convincing responses, and some children have been able to discontinue AEDs and show functional improvements that are maintained for a year or more, although long-term data are limited. For patients with potentially injurious drop spells, corpus callosotomy is an option, and the vagus nerve stimulator has demonstrated efficacy against Lennox-Gastaut syndrome in retrospective studies. Finally, there are anecdotal reports in which immunomodulating treatments such as ACTH, intravenous immunoglobulin, or plasmapheresis have had at least transient efficacy in treating this and other severe and refractory pediatric epilepsy syndromes.

Febrile Convulsions Preventive treatment with standard AEDs is no longer recommended for febrile convulsions. Aside from acetaminophen for fever control and treatment of the underlying illness, treatment options after a first febrile convulsion include diazepam, 0.3 mg/kg, given orally every 8 hours at onset of subsequent fever or potential febrile illness; an alternative is rectal diazepam gel, in dosages according to the age and weight of the patient, per package insert.

Benign Epilepsy with Centrotemporal Spikes Because of the benign course of this condition, not all pediatric neurologists treat patients with this syndrome, although most do once a secondarily generalized seizure occurs. Any AED effective against partial seizures can be used. Carbamazepine has been traditionally given, but gabapentin is also effective. Treatment can often be stopped after 1 to 2 years of seizure control, even if the EEG recording remains abnormal.

Childhood Absence Epilepsy Ethosuximide, valproate, and lamotrigine are equally effective against absence seizures; for children with absence seizures only, however, ethosuximide is still considered the drug of choice because of a lower risk of serious adverse effects. If tonicclonic seizures are present, then valproate or lamotrigine is preferable, because ethosuximide must be used with another AED that will treat the tonic-clonic seizures. If ethosuximide, valproate, or lamotrigine does not adequately control the absence seizures, then combinations of these may be used; topiramate, zonisamide, and levetiracetam may ultimately prove to be effective as well.

Juvenile Myoclonic Epilepsy and Related Syndromes Valproate is still considered the first-choice drug for these conditions, although in obese men or in women, the risks of weight gain and teratogenicity may argue for an alternative. Lamotrigine is often effective, although in some patients, myoclonic seizures may not respond or may even worsen. (When phenytoin or especially carbamazepine is given, worsening of absence and myoclonic seizures is relatively common, although these drugs may be useful adjuncts for tonic-clonic seizures.) Topiramate, zonisamide, and levetiracetam may be effective alternatives as well. Finally, counseling on the need to obtain adequate sleep and to avoid use of alcohol and other psychoactive substances, as well as to maintain medication compliance, is an important part of treatment.

Alcohol and Drug Withdrawal–Related Seizures Benzodiazepines are the mainstay of treatment for alcohol and benzodiazepine withdrawal and may also be used, along with phenobarbital, for barbiturate withdrawal. Lorazepam, 2 to 4 mg, can be administered intravenously or intramuscularly every 2 to 4 hours as needed to minimize withdrawal symptoms without causing excessive sedation. Phenytoin is typically not helpful unless status epilepticus develops. Referral to an appropriate substance abuse program should be attempted even if the chance of success is believed to be low.

LESIONAL EPILEPSY Although structural lesions account for fewer than half of all cases of epilepsy, this proportion is higher among patients with partial epilepsies and those with a later age at onset, especially after age 60. At younger ages, pathological specimens suggest that microscopic structural abnormalities, often disorders of cortical development, underlie many cases of at least medically intractable partial epilepsy, even in those with adolescent or adult onset. Other important pathological causes include neoplasm, especially benign brain tumors such as gangliogliomas, oligodendrogliomas, dysembryoplastic neuroepithelial tumors, and astrocytomas; infections, particularly parasitic infections such as cysticercosis, but also long-term sequelae of bacterial and viral meningoencephalitis; traumatic brain injury, especially penetrating but also closed-head injury if moderate or severe; stroke, both hemorrhagic and ischemic; and congenital

chapter 53 drug treatment or acquired vascular anomalies, such as arteriovenous malformations or cavernous angiomas. Clinical manifestations depend largely on the site of the lesion, although the correlation is far from perfect, inasmuch as the ictal discharge may start adjacent to rather than in the lesion (depending on lesion type) and may produce no symptoms or signs until it spreads within the hemisphere or even to the contralateral hemisphere. Lesions that produce either acute symptomatic seizures or later epilepsy are typically cortical or subcortical rather than deep. Frontoparietal lesions near the primary sensorimotor cortex typically produce contralateral somatosensory and motor phenomena, whereas lesions in other areas of the frontal lobe produce other manifestations: bilateral posturing if near the midline supplementary motor area, vigorous automatisms and emotional experiences with orbitofrontal and/or cingulate involvement. As a rule, frontal lobe epilepsies tend to produce frequent brief seizures that arise out of sleep and have a high propensity to generalize. Temporal lobe epilepsies differ, depending on whether the source is medial or lateral; medial temporal seizures are often characterized by a rising epigastric sensation or other autonomic disturbance. Emotional or olfactory auras may precede complex partial seizures that progress from motionless staring to oral automatisms. These complex partial seizures often last 2 to 3 minutes and are followed by postictal confusion. Lateral temporal lobe seizures are associated with auditory, language, or sometimes visual phenomena. Parietal and occipital lobe epilepsies may include partial seizures characterized by elementary or formed visual hallucinations or distortions of spatial perception, including vertigo.

Pathophysiology The mechanisms by which structural lesions produce neuronal hyperexcitability are not well understood and probably vary for different types of lesions. Disorders of cortical development, for example, include neurons that may have abnormal receptors, channels, or connections, whereas foreign tissue and destructive lesions may injure specific neurons or neuronal populations so as to decrease inhibition or increase excitation on a neuronal or network basis. With hemorrhagic lesions, iron itself can be epileptogenic when applied to the cortex.

Prognosis Prognoses for seizure control differ with lesion type and location. For example, mesial temporal sclerosis, a hippocampal lesion often associated with prolonged febrile convulsions in childhood and onset of partial seizures in adolescence or early adulthood, is frequently refractory to medical management but amenable to surgical treatment. Among patients with neoplasms, overall prognosis depends on likelihood of tumor growth or regrowth after resection, especially if recurrence is associated with malignant transformation, as can be seen with astrocytomas.

Diagnosis The diagnosis of structural lesions has been revolutionized by computed tomography and especially magnetic resonance

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imaging, which can reliably demonstrate not only neoplasms, abscesses, and vascular anomalies but also many disorders of cortical development and gliotic lesions such as mesial temporal sclerosis.

Treatment Any of the drugs effective against partial and tonic-clonic seizures can be used for lesional epilepsy; no drug specificity by location has been demonstrated. In the United States, carbamazepine and phenytoin are most commonly initiated, but in specific populations, valproate, lamotrigine, topiramate, gabapentin, levetiracetam, and oxcarbazepine may have advantages. (Of these, only valproate, topiramate, and oxcarbazepine are approved by the U.S. Food and Drug Administration as initial monotherapy.) It must be recognized, however, that a significant proportion of patients with lesional epilepsy do not respond to AEDs, and surgery should be strongly considered for any patient with a resectable lesion that can plausibly account for the epilepsy syndrome and whose seizures do not respond to two or more appropriate AEDs at reasonable dosages. In many cases, complete resection of the lesion alone renders the patient seizure free, and many such patients can eventually discontinue medication; it is likely that in some cases, the outcome is better if surrounding electrically abnormal tissue is also removed.

SPECIAL ISSUES RELATED TO EPILEPSY IN WOMEN Approximately 40% of all cases of epilepsy, or approximately 1,000,000 in the United States, occur in women of childbearing age. Issues that need to be considered include effects of hormones and pregnancy on epilepsy, influence of AEDs and seizures on pregnancy and pregnancy outcome, breastfeeding, and other child care issues. It is important to recognize that the enzyme-inducing drugs carbamazepine, phenytoin, phenobarbital, primidone, and, to a lesser extent, oxcarbazepine and topiramate can increase metabolism of hormones and cause failure of oral contraceptives. If no other effective contraceptive method is available, oral contraceptives can still be used, but only in medium- or high-dose pills, and the failure rate is still above baseline.

Pathophysiology Approximately one third of women with epilepsy, especially those with partial and perhaps temporal lobe seizures, report increased seizures shortly before menses or at ovulation. These so-called catamenial seizures probably reflect the important effects of hormones on neuronal excitability. In general, estrogens increase excitability and progesterones (particularly allopregnanolone) have inhibitory effects. The ratio of rising and falling levels of these two hormone classes probably accounts for the menstrual variation and may affect seizure fluctuations during and after menopause. On occasion, measurement of AED levels through the menstrual cycle reveals changes in absorption or metabolism that can account for the exacerbations. The mechanisms by which AEDs cause teratogenicity are not well understood and may be different for different

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AEDs. One hypothesis is that oxidative injury to fetal cells results from reactive AED metabolites. Folate deficiency is also associated with several AEDs and can adversely affect fetal cell division.

Prognosis Women with catamenial epilepsy may experience fewer seizures after menopause, although some report exacerbation during menopause. With regard to AED teratogenicity, monotherapy with the older drugs carbamazepine, phenytoin, and phenobarbital is associated with an approximate doubling of the rate of major congenital malformations from 2% to 3%, and monotherapy with valproate is associated with an approximate tripling of this rate, especially at higher doses. Because major organs are formed during the first trimester of gestation, risk of major malformations is not an issue beyond that time. The possibility of effects on neurobehavioral development posed by fetal exposure later in the pregnancy is under active investigation, and there is preliminary evidence that valproate may be problematic in this regard. During pregnancy, an estimated one third of epileptic women experience an increase in seizures, and it is unclear whether this proportion has declined since the 1990s with increased awareness of the need to increase drug dosages as pregnancy progresses. Seizures can adversely affect pregnancy either by causing falls and other accidents or, at least in the case of convulsive seizures, by producing fetal distress.

Diagnosis To establish the diagnosis of catamenial seizure exacerbations, the patient keeps a careful diary of seizures and menses. Close neurological and obstetrical follow-ups are needed to diagnose epilepsy-related pregnancy complications.

Treatment Catamenial seizure exacerbations can be treated by temporarily increasing the baseline AED dosage, especially if fluctuations in levels have been demonstrated; by adding acetazolamide, 250 to 1000 mg/day for 10 to 14 days, starting at midcycle; or by administering natural progesterone lozenges, 300 to 800 mg/day, during the second half of the cycle, tapering over 2 to 3 days after onset of menses. The latter treatment is under active study; potential adverse effects include depression, breast tenderness, and hypercoagulability. To minimize AED teratogenicity, an effective means of contraception must be used, and all women of childbearing age should be given supplemental folate; the optimal dose has not been determined, but at least 0.4 mg and perhaps as much as 5 mg should be given daily. In addition, polytherapy should be avoided whenever possible, and drug withdrawal before conception should be considered in women who have been seizure free for at least 2 years or in those for whom the diagnosis of epilepsy has not been established; in the latter case, video-EEG monitoring can enable the decision. In general, the most effective AED for the individual should be used at the lowest dosage that controls seizures, especially the secondarily or primarily generalized tonic-clonic seizures that are most likely to put

both mother and fetus at risk. Women with a family history of neural tube defects should probably not use valproate or carbamazepine if pregnancy is a possibility. Knowledge of potential teratogenic effects of the newer AEDs is facilitated by use of the AED pregnancy registries, of which there are several throughout the world, organized by geographical area. In North America, the patient herself must call the toll-free number, 1-888-233-2334 (1-888-AED-AED4). Treatment during pregnancy should include measurement of serum drug concentrations every 1 to 2 months, including free levels of highly protein-bound drugs. Total levels and, to a lesser extent, free levels tend to fall as pregnancy progresses, and dosages usually need to be increased; levels of lamotrigine and oxcarbazepine levels in particular are prone to decrease. Vitamin K, 10 to 20 mg/day, is sometimes recommended during the last month of pregnancy, especially to mothers taking enzyme-inducing drugs, and vitamin K is routinely given to newborns to prevent neonatal hemorrhage. Seizures during delivery, reported to occur in 1% to 4% of women with epilepsy, may be prevented by administration of AEDs parenterally when absorption is in doubt; use of parenteral or sublingual lorazepam can also be considered, although neonatal sedation is a risk. After delivery, serum drug concentrations rise over a period of days to weeks, and dosages typically need to be decreased to avoid toxicity. New mothers with epilepsy should be counseled to change diapers on the floor, not to bathe the baby alone, and to take other reasonable precautions consistent with the nature of the mother’s seizures. Although all AEDs can be found in breast milk, especially those that are not highly protein bound, specific risks have not been identified apart from sedation with barbiturates and benzodiazepines, and the benefits of breastfeeding probably outweigh the risks.

TOXEMIA OF PREGNANCY Toxemia of pregnancy, or eclampsia, is a situation-related syndrome occurring in the second half of pregnancy and consisting of systemic alterations, including hypertension with edema and/or proteinuria; coagulopathy and liver dysfunction are often present. Cerebral involvement is similar to that associated with hypertensive encephalopathy and includes headache and cerebral edema, often causing visual phenomena and partial or tonic-clonic seizures (probably secondarily generalized). Hyperreflexia is usually present. The presence of coma or seizures indicates progression from preeclampsia to eclampsia.

Pathophysiology The underlying mechanism of eclampsia is not known but may reflect alteration in endothelial function; effects on the brain are similar to those of hypertensive encephalopathy and probably relate to loss of autoregulation of cerebral blood flow, especially in posterior cerebral regions.

Prognosis Eclampsia carries a maternal mortality rate of 1% to 2%, and there are fetal complications in one third of cases.

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Diagnosis

Treatment

Eclampsia is diagnosed on the basis of clinical characteristics described previously, typically by the obstetrician.

Any of the traditional or newer AEDs discussed earlier may be used in the elderly population, but starting dosages should be lower, and dosages should be increased more slowly. In patients taking anticoagulants or other drugs whose metabolism is altered by enzyme inducers, such AEDs as phenytoin and carbamazepine must be used with caution, particularly by patients with cardiac rhythm disturbances; susceptibility to central nervous system adverse effects of barbiturates or benzodiazepines argues against use of these agents when alternatives exist. In patients taking multiple drugs for other conditions, AEDs with minimal drug-drug interactions, such as gabapentin, lamotrigine, or levetiracetam, should be strongly considered; drugs such as gabapentin and levetiracetam that are metabolized principally by the kidney should be given in dosages according to renal function, which declines with age.

Treatment The procedure essential to reversing the underlying eclamptic process is delivery of the baby. Seizures must still be treated, however, and in some cases, preventive treatment is justified. Traditionally, obstetricians have favored use of magnesium sulfate to treat or prevent eclamptic seizures, and neurologists have preferred the use of traditional AEDs such as phenytoin. Despite some methodological problems, studies since the 1990s have favored the obstetricians’ approach. Magnesium sulfate may be given intravenously at 20 mg of a 20% solution (4 g) over 4 minutes, with maintenance of 1 to 3 g/hour, or intramuscularly at 5 to 10 mg every 4 hrs; the dosage is titrated to a level of 3 to 5 mmol, and the patient is monitored for arreflexia and weakness that could herald ventilatory compromise. The addition of phenytoin, 15 to 20 mg/kg, can be considered, especially if seizures occur with adequate magnesium levels; lorazepam, 2 to 4 mg administered intravenously, can also be used in acute situations.

MEDICATION WITHDRAWAL

The incidences both of acute symptomatic seizures and of epilepsy increase after age 60, and in the oldest populations, new seizures occur at annual rates exceeding 100 per 100,000. The most common cause is stroke, both ischemic and hemorrhagic, but degenerative disorders, including Alzheimer’s dementia, and both metastatic and primary brain tumors are important contributors.

In general, patients who have had no seizures for at least 2 years can be considered for medication withdrawal; a seizure recurrence risk of 20% to 40% is acknowledged. Patients who had only one seizure type that responded promptly and was controlled for many years on modest dosages of one medication have the best prognosis, especially if they have normal neurological examination findings, imaging study results, and EEG recordings. Depending on lifestyle, however, this recurrence risk may be unacceptable, and many patients elect to continue medications. Furthermore, for patients whose epilepsy can be classified as part of a specific syndrome, such as benign epilepsy with centrotemporal spikes or juvenile myoclonic epilepsy, the syndrome itself may imply a lower or higher recurrence risk than the overall statistics quoted previously.

Pathophysiology

KETOGENIC DIET

The mechanisms by which these disease processes cause seizures and epilepsy depend on the type of insult and are not well understood.

A high-fat diet that produces metabolic changes mimicking starvation can produce complete or dramatic seizure reductions in 30% to 50% of children with multiple seizure types (usually cryptogenic or symptomatic generalized epilepsy syndromes). Short-term risks include weight loss, renal stones, acidosis, hemolytic anemia, lethargy, and elevated liver function values; treatment is usually initiated in the hospital and maintained with the assistance of a dietitian. Much less information is available concerning feasibility, effectiveness, and long-term safety in adults. More palatable modifications of this high-fat, low-carbohydrate diet, such as the “low glycemic index,” South Beach, and Atkins diets, are under study.

SEIZURES AND EPILEPSY IN ELDERLY PERSONS

Prognosis Overall prognosis depends on the specific cause and on comorbid conditions, but in most cases, seizures respond to AED treatment at least as well as in younger individuals.

Diagnosis Differential diagnosis of transient neurological dysfunction is similar to that discussed in Chapter 52, but in elderly patients, the likelihood of psychogenic nonepileptic seizures is lower than in younger patients, and the risk of such physiological causes as syncope or transient ischemic attack is higher. Prolonged electrocardiographic or video-EEG monitoring may be required for diagnosis. Among sleep disorders, rapid-eyemovement behavior disorder is a parasomnia that is much more common among elderly persons and is often associated with extrapyramidal movement disorders; polysomnography is required for diagnosis.

RESECTIVE SURGERY Among patients with medically refractory, location-related epilepsy, a significant proportion are candidates for resection of the epileptic focus. In appropriately selected patients, seizurefree rates range from 60% to 80%. The best prognosis is for patients with structural lesions, especially those with mesial temporal sclerosis. The key to a successful outcome is localization of a resectable epileptogenic region, for which a variety of structural and functional tests are used. These commonly

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include scalp-recorded ictal and interictal EEG recordings, usually with synchronized videography to clarify the ictal semiology; high-quality structural magnetic resonance imaging; positron emission tomography; single photon emission computed tomography (especially if an ictal tracer injection can be accomplished); formal neuropsychological testing; intracarotid amobarbital testing to lateralize language and memory; and, in select cases, magnetoencephalography and functional magnetic resonance imaging. If data are not concordant with regard to the likely epileptogenic and functional regions, intracranial recording with depth and/or subdural electrodes is often needed to identify these areas more definitively.

PALLIATIVE PROCEDURES For patients who are not candidates for resective surgery, several procedures have been shown to produce worthwhile benefit in many patients, although complete seizure remission is achieved in only a few. These include disconnection procedures such as corpus callosotomy (section of the major interhemispherical commissures, often the anterior two thirds of the corpus callosum), multiple subpial transections (shallow longitudinal cuts presumed to sever cortical-cortical connections while leaving intact the descending projection fibers needed to preserve function), or insertion of the vagus nerve stimulator. The vagus nerve stimulator, which delivers controllable stimulations at programmable intervals to the left vagus nerve, produces a 50% decrease in seizure frequency among 25% to 45% of patients who undergo implantation. Its use is approved for patients 12 years of age or older with partial seizures, but younger patients and those with generalized epilepsies may respond as well or better.

COMPLEMENTARY AND ALTERNATIVE THERAPIES Such activities as relaxation techniques, yoga, and exercise are under investigation, as are certain herbal medicines and dietary supplements. Although some of these may prove beneficial, and

although relaxation and related techniques appear safe, caution must be exercised, particularly with regard to herbal preparations, because some have potentially harmful effects (including lowering the seizure threshold) or may interact with AEDs.

K E Y

P O I N T S

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Most antiepileptic drugs can be grouped into one of two classes: (1) those effective against only focal and tonic-clonic seizures (either primarily or secondarily generalized) and (2) those effective against all seizure types, including absence and myoclonic seizures.

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Within each therapeutic class, major differences have not been demonstrated in efficacy, but there are significant differences in adverse effects, time necessary to achieve a therapeutic effect, drug interactions, and cost.

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Patients whose seizures do not respond to reasonable dosages of two or three AEDs should be considered for nonmedical treatments, including resective surgery or vagus nerve stimulation.

Suggested Reading Bromfield EB: Clinical use of anticonvulsants: a neurologist’s perspective. Harv Rev Psychiatry 2003; 11:257-268. Bromfield EB: Epilepsy. In Samuels MA, ed: Manual of Neurologic Therapeutics, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 65-75. Duncan JS, Sander JW, Sisodiya SM, et al: Adult epilepsy. Lancet 2006; 367:1087-1100. Spencer SS, Berg AT, Vickrey BG, et al: Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study. Neurology 2005; 65:912-918. Wyllie E, Gupta A, Lachhwani DK, eds: The Treatment of Epilepsy: Principles and Practice, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2005.

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MANAGEMENT OF STATUS EPILEPTICUS ●

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Padmaja Kandula and Cynthia Harden

Known case reports of epilepsy date as far back as the 16th century, but the term status epilepticus was first noted in the English language in 1868 in Bazire’s translation of Trousseau’s Lecture on Clinical Medicine1,2: “The status epilepticus is characterized, not by a single attack, but by a series of attacks . . . the stupor which succeeds the convulsions lasts from ten minutes to three-quarters of an hour at most. But before the stupor has passed away another attack, exactly similar to the first, supervenes, and is confounded with it. Now, as the third stage of an epileptic fit is not usually regarded as distinct from the convulsive stage, the patient seems to be still in a fit, although his comatose condition is only an effect of the fit. He has not therefore got over the disturbances caused by the first attack before a second occurs, then a third, a fourth, a fifth; and in proportion to the recurrence of the fits the cerebral congestion increases, the apoplectic coma is prolonged, and extends over a period varying from two to twenty-four hours, and after a time the patient does not recover his senses at all . . .” Although the basic definition of status epilepticus has not changed significantly over time, the understanding of the pathophysiology, etiology, and particularly treatment since the initial advent of the bromides has dramatically evolved. This chapter focuses on these aforementioned concepts, with particular emphasis on the advances in treatment of status epilepticus.

DEFINITION Status epilepticus is defined as continuous seizure activity lasting more than 30 minutes or two or more sequential seizures without full recovery of consciousness between seizures.3 However, most physicians agree that treatment should not be withheld if the manifestation does not conform to this 30-minute definition. Thus, new operational definitions, such as those by Lowenstein and colleagues, define generalized convulsive status epilepticus (GCSE) in adults and older children (>5 years old) as 5 minutes or more of continuous seizures or two or more discrete seizures between which there is incomplete recovery of consciousness.4

CLASSIFICATION Many different complicated classification schemes for status epilepticus have been proposed. In general, status epilepticus

can be defined on the basis of electrographic onset—specifically, partial versus generalized—or on clinical grounds (convulsive versus nonconvulsive) (Fig. 54–1). All forms of partial status epilepticus, such as complex partial status epilepticus, are classified clinically as nonconvulsive. The most common form of status epilepticus is GCSE and consists of tonic and/or clonic motor activity. This motor activity may be symmetrical or asymmetrical and clinically overt or subtle. There is associated alteration of consciousness and bihemispherical, generalized, ictal discharges (which maybe asymmetrical) on the electroencephalogram (EEG).5 If GCSE is allowed to progress, convulsive activity may become less apparent and clinical manifestations more subtle. Thus, the term subtle generalized convulsive status epilepticus has been used to denote twitching movements of the face, eyelids, trunk, and distal extremities or nystagmoid movements of the eyes in association with bilateral ictal discharges on EEG.6 Complex partial status epilepticus (Fig. 54–2) has the most varied clinical manifestation. Although the prevailing constant is the definite impairment of consciousness and very localized electrographic seizures, the extent of the impairment can be variable, ranging from mild alteration of consciousness with or without automatisms, waxing and waning confusion, and agitation with near-psychotic behavior to complete stupor.7-10 Absence status epilepticus is considered a nonconvulsive form of the condition and is often categorized as either typical or atypical absence status epilepticus. Both types are associated with paroxysms or loss of consciousness of abrupt onset and offset. However, typical absence status epilepticus is characterized by the hallmark 3-Hz spike-and-wave discharges on EEG (Fig. 54–3), a normal interictal background, and normal neurological examination findings. Atypical absence status epilepticus usually occurs in patients with underlying neurological dysfunction (Lennox-Gastaut syndrome) and is characterized by diffuse slow spike-and-wave discharges (<3 Hz) and an abnormal interictal background.11 Whatever the form, absence status epilepticus typically occurs more often in children and adolescents than in adults. Myoclonic status epilepticus as defined by Gastaut11 is divided into two subgroups. The first group includes primary generalized epilepsy characterized by massive bilateral myoclonic jerks that occur at irregular intervals and by preservation of consciousness. This is a rare form in comparison with the second group, which occurs in secondary (symptomatic) generalized

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Figure 54–1. Classification of status epilepticus.

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Figure 54–2. Electroencephalographic tracing in complex partial status epilepticus. Rhythmic evolving ictal activity is seen in the left hemisphere (odd-numbered contacts).

epilepsy in children and is associated with alteration of consciousness. Examples of this second group include myoclonicastatic epilepsy, Lennox-Gastaut syndrome, and epilepsy with myoclonic absences.12 In addition, there is a separate category of myoclonic status epilepticus that occurs in nonepileptic patients with acute or subacute encephalopathies.11 This category includes degenerative encephalopathies such as dyssynergia cerebellaris myoclonica of Ramsay Hunt, progressive myoclonic epilepsy, Lafora’s disease, and various toxic and metabolic (liver, renal insufficiency) encephalopathies.12

Myoclonic status epilepticus caused by anoxic encephalopathy has not been regarded as status epilepticus in the strictest sense11; however, some authorities have argued5 that this symptomatic myoclonic syndrome should instead be considered a subtle form of GCSE.12 Simple partial status epilepticus includes somatomotor, somatosensory, and aphasic status epilepticus. Somatomotor status epilepticus can occur during or at the onset of a somatomotor partial epileptic seizure (somatomotor simple partial status epilepticus in the strictest sense)11,13 or herald the

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Figure 54–3. Electroencephographic tracing in absence status epilepticus. Generalized spike-and-wave discharges are seen bilaterally.

presence of a metastatic embolus or asymptomatic sylvian or suprasylvian infarction in elderly persons.11,14 Ictal discharges are usually more pronounced in the rolandic area with definite preservation of consciousness.11 A well-known type of somatomotor status epilepticus is epilepsia partialis continua (Kojewnikoff’s epilepsy), characterized by segmental myoclonus between seizures. Lastly, somatomotor simple partial status epilepticus can accompany severe brain lesions in nonepileptic persons and is characterized by proximal limb or truncal myoclonus repeated approximately once per second in conjunction with periodic lateralized epileptiform discharges (PLEDs) on EEG.8 This syndrome occurs almost exclusively in the elderly population and most often represents a watershed infarct or, less frequently, metastatic tumor or brain contusion.11,15,16 Somatosensory status epilepticus is very rare and may in fact be residual activity after surgical resection of the primary epileptogenic area in medically refractory epilepsy.13 Aphasic or dysphasic status epilepticus is less frequent than somatomotor status epilepticus, but it is well documented in the literature.17-22 This syndrome is characterized by aphasia (either receptive or expressive), sometimes in association with alexia and agraphia, lasting from seconds to days. One special situation that deserves mention is simple partial status epilepticus in the context of hyperosmolar nonketotic hyperglycemia. Simple partial motor seizures can accompany medical symptoms such as polydipsia and loss of appetite. Osmolar values can be as high as 320 mmol, and in this

situation, the use of phenytoin is contraindicated because of its inherent ability to exacerbate hyperglycemia.13 In reality, although classification appears complex, classification is, to a great degree, of academic interest. In addition, exact classification may not be possible because one seizure type may evolve into another; for example, simple partial seizures may evolve into complex partial seizures. Classification then is based on the final full-blown symptoms of the seizure type. However, differentiation between convulsive and nonconvulsive status epilepticus (NCSE) can be helpful in determining aggressiveness of treatment (see later discussion).

INCIDENCE, ETIOLOGY, AND MORTALITY Multiple case series and large hospital-based retrospective studies of GCSE are noted in the literature.23-35 However, the true incidence of status epilepticus is not well defined, for multiple reasons, including clinically missed cases, variability in reporting, and inherent differences between populations. In initial hospital-based reports, Hauser31 estimated an annual incidence of 50,000 to 60,000 cases of status epilepticus in the United States. However, in a more recent prospective population-based study of status epilepticus,36 a higher U.S. incidence was estimated, approximately 100,000 to 150,000 patients with at least one episode of status epilepticus per year, according to extrapolation from community population data in Richmond, Virginia. Several

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retrospective and fewer prospective studies have been performed, and although methods of reporting and subpopulations of case studies are variable, a few generalizations can be drawn. First, the incidence of status epilepticus appears to be highest at the extremes of age: the young (1 to 12 months of age) and the elderly (>60 years of age).36,37 Recurrence, however, appears most common in the pediatric population.36 The Richmond study36 revealed a recurrence rate of 35% in the pediatric population versus 7% and 10% in the adult and elderly populations, respectively. Second, the major etiology for status epilepticus in the pediatric population overall appears to be systemic non–central nervous system infections.36 In adults, low antiepileptic drug levels, temporally remote symptomatic lesions (particularly cerebrovascular accident), and acute stroke accounted for the majority of cases.38 Thus, stroke, whether acute or subacute/chronic, accounted for 61% of cases of status epilepticus in the elderly population in the Richmond study.36 Third, the overall rate of mortality from status epilepticus appears to be approximately 15% to 22% in adults25,27,28,36 but much lower in children (5% to 11%).24,26,29 Fourth, death from status epilepticus is intricately linked with etiology, age, and duration of status epilepticus. Anoxia and hypoxia were much more common causes of status epilepticus in adults than in the pediatric population and were associated with the highest rates of mortality.36 The mortality rate is higher for status epilepticus lasting longer than 60 minutes (nearly 20%) than for status epilepticus lasting 30 to 59 minutes (<5% respectively).28

PHYSIOLOGICAL CHANGES IN GENERALIZED CONVULSIVE STATUS EPILEPTICUS Acute Systemic Complications of Generalized Convulsive Status Epilepticus Acute systemic effects of GCSE include cardiovascular alteration, acidosis, respiratory distress, hyperthermia, and renal failure secondary to rhabdomyolysis (Table 54–1). These physiological alterations occur in essentially two phases.39 Initially, the early phase of GCSE is characterized by sympathetic overdrive,40 but after 30 minutes, failure of homeostatic mechanisms causes initial physiological alterations to normalize or even move in the exact opposite direction.39 The most significant and most life-threatening changes occur within the cardiac system. Initially systemic hypertension predominates, along with tachycardia.41 Mean arterial blood pressure is elevated as a result of increased vascular resistance. However, later on, relative hypotension occurs, secondary to failure of splanchnic and renal constriction.42-44

T A B L E 54–1. Systemic Physiological Changes in Generalized Convulsive Status Epilepticus Initial hypertension, followed by hypotension Cardiac arrhythmias Hyperthermia Metabolic acidosis Central apnea and pulmonary edema Rhabdomyolysis Peripheral leukocytosis

Mortality is associated with the development of life-threatening arrhythmias in nearly 60% of patients with GCSE.45 Hyperthermia seen early on in GCSE in animal studies is not only associated with significant cerebellar damage but is also responsible for ischemic injury in outer cortical layers and hippocampus.46,47 Studies by Liu and associates48 in experimental rat models (kainic acid–induced seizures) demonstrated that decreasing temperature to 28° C decreased status epilepticus by 50%, and further reduction to 23° C abolished status epilepticus entirely. Increasing temperatures to 42° C uniformly resulted in death within 2 hours. Of most importance, decreasing temperature to 28° C prevented hippocampal cell loss, emphasizing the need to treat hyperthermia aggressively at the onset of status epilepticus.48 Derangements in blood chemistry are also seen. The natural occurrence of lactic acidosis is secondary to anaerobic metabolism in the setting of repetitive muscle activity from ongoing convulsions. Hyperglycemia occurs in the setting of increased levels of circulating catecholamines and exacerbates existing acidosis. Thus, supplemental glucose should be given only if true hypoglycemia exists.42,59 Respiratory changes include central apnea and pulmonary edema secondary to increased intravascular pressures within the pulmonary vasculature.43 Other systemic changes that may occur in GCSE include peripheral leukocytosis and possible rhabdomyolysis secondary to muscle injury from repetitive convulsions, producing subsequent acute tubular necrosis and possible renal failure.50

Central Nervous System Physiological Changes Essentially, the central nervous system changes reflect the eventual difficulty of the brain in keeping up with the ongoing metabolic demands induced by GCSE. Initially, cerebral blood flow increases profoundly to supply the brain with the necessary glucose and oxygen.51 However, late in status epilepticus (hours after onset of seizure activity), breakdown of the body’s homeostatic mechanisms (cerebrovascular autoregulation) occurs.46 In addition, mean arterial pressure starts to fall, which causes further drop in cerebral blood flow.51,52 An eventual mismatch between elevated cerebral metabolism and insufficient cerebral blood flow (supply/demand mismatch) occurs. As lactate accumulates, brain glucose levels decline47 and, in combination with decreased oxygenation at later stages of status epilepticus, contribute to ongoing hypoxia and anoxia.53

PATHOPHYSIOLOGY OF NEURONAL INJURY The aforementioned systemic alterations can contribute to neuronal injury, but the primary mechanisms leading to ongoing seizures and neuronal injury are at the cellular level. Although an eventual cerebral supply/demand mismatch occurs in the later stages of GCSE, neuronal injury occurs within 60 minutes.46,52 The combination of decreased γ-aminobutyric acid (GABA) neurotransmitter–mediated inhibition and abundance of glutamate excitation can lead to neuronal injury. Normal excitatory synaptic neurotransmission is essentially altered. Under normal circumstances, glutamate binds to postsynaptic non–N-methyl-D-aspartate (NMDA)–type glutamate receptors after its release from the axon terminal. This promotes sodium flow into the cell and produces depolarization, which results in

chapter 54 management of status epilepticus further propagation down the axon. However, in the case of status epilepticus, when glutamate binds to the postsynaptic NMDA receptor, the usual self-limited depolarization does not occur. Instead, prolonged depolarization occurs, because the magnesium ion that generally blocks the NMDA channel pore is displaced.42,53 Thus, calcium ions flow into the cell, causing intracellular accumulation of calcium, which leads to cell necrosis and apoptosis.42 Because NMDA receptors are located primarily in the limbic system, neuronal cell loss thus results in hippocampal injury.42

MANAGEMENT AND TREATMENT OF STATUS EPILEPTICUS The goal with any acute medical emergency is the timely diagnosis, management, and treatment of the problem. The longer

the duration of status epilepticus, the more subtle the motor manifestations,54 the later the electroencephalographic stage (impairing adequate detection of the syndrome),55 and the more refractory to pharmacological treatment the seizures will be54,56 (Fig. 54–4). Management is essentially divided into two sections: immediate general concerns to prevent the ongoing systemic complications described previously and specific pharmacotherapy to abort ongoing seizures. In general, the ABCs (airway, breathing, and circulation) of any acute medical problem should be addressed. A clear airway for the adequate passage of air is needed with availability of immediate endotracheal intubation if required. If ongoing convulsive motor activity causes hypoventilation, a paralytic agent may be needed temporarily to support respiration and prevent the patient from injuring himself or herself. Peripheral access also needs to be addressed immediately in order to initiate intravenous medication and ■

Acute Management of Status Epilepticus Intubate, IV access Blood pressure, ECG, temperature monitoring ± Cooling blanket if temperature > 40° C 50 mL of 50% glucose (adults) or 25% 2 mL/kg (child) if hypoglycemic Thiamine (100 mg) in deficiency states before glucose administration Serology for CBC, Na, K+, BUN, Cr, AED levels, toxicology screen, ABG

Lorazepam IV, 0.1, mg/kg (adults); 0.05-0.5 mg/kg (children)@ 2 mg/min Rectal diazepam, 0.5 mg/kg in children if no IV access

Obtain EEG to rule out NCSE

Convulsions cease

Convulsions persist

Fosphenytoin, 18-20 mg/kg PE IV load @ 150 mg/min (max 30 mg/kg) Monitor with ECG

Obtain EEG to rule out NCSE

Convulsions cease

Convulsions persist

Phenobarbital IV load, 20 mg/kg @ 100 mg/min; monitor BP OR Pentobarbital IV load, 5-15 mg/kg with infusion 0.5-5 mg/kg/hr OR Midazolam, 200 μg/kg IV load with infusion 0.75-10 μg/kg/min OR Propofol, 1-2 mg/kg IV load over 5-10 min with infusion of 1-15 mg/kg/hr Requires continuous EEG monitoring

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Figure 54–4. Protocol for management and treatment of generalized convulsive status epilepticus. ABG, arterial blood gases; AED, antiepileptic drug; BP, blood pressure; BUN, blood urea nitrogen; CBC, complete blood cell count; Cr, creatinine; ECG, electrocardiography; EEG, electroencephalogram; IV, intravenous; NCSE, nonconvulsive status epilepticus; PE, phenytoin equivalent.

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provide fluid resuscitation if needed. Two large-gauge intravenous catheters, or even a central catheter if peripheral access cannot be obtained, should be in place. Blood pressure, the electrocardiogram, and temperature should be monitored. Hypotension should be avoided, and agents to support blood pressure may be required temporarily. If significant hyperthermia develops (>40° C), a cooling blanket may be necessary to stabilize body temperature.57 Once the airway, breathing, and circulation are secure, blood chemistry profiles should be drawn for potentially reversible causes or exacerbating factors of status epilepticus. Fingerstick blood glucose should be tested, and 50 mL of 50% glucose bolus injection for adults and 2 mL/kg of 25% glucose for children should be administered if hypoglycemia exists. A glucose bolus should also be administered if hypoglycemia is suspected and a blood glucose level cannot be established in a timely manner. Thiamine (100-mg bolus) should be administered in individuals suspected of thiamine deficiency (e.g., alcoholic patients) before or simultaneously with glucose administration to prevent precipitating acute Wernicke’s encephalopathy. Blood samples should be analyzed for complete blood cell count, metabolic profile (sodium, potassium, blood urea nitrogen, creatinine, calcium, magnesium), antiepileptic drug levels if applicable, urine/serum toxicological levels, and arterial blood gases. Although the general measures have been described first, pharmacotherapy should be initiated in conjunction with them, as soon as peripheral vascular access is obtained. The ideal medication for status epilepticus should penetrate the blood-brain barrier quickly, have an immediate onset of action, have minimal side effects (minimal depression of consciousness and respiratory drive), and have a reasonably long half-life in order to prevent further episodes of status epilepticus. However, in reality, no ideal medication that meets all these requirements currently exists. The benzodiazepines, phenytoin, and phenobarbital have been used as first-line agents for aborting status epilepticus. The rationale for use of these agents for first-line therapy is the direct result mainly of four pivotal studies.58-61 Leppik and colleagues61 compared lorazepam with diazepam for the initial treatment of status epilepticus; 78 patients received either 10 mg of diazepam or 4 mg of lorazepam. No significant difference in terminating status epilepticus (58% with diazepam versus 78% with lorazepam) or latency of action (2 minutes for diazepam and 3 minutes for lorazepam) was noted.61 In 1988, Shaner and associates,59 in a randomized clinical trial, compared the efficacy of the combination of diazepam and phenytoin with phenobarbital alone in 36 patients with GCSE. Phenytoin was added to the phenobarbital regimen if seizures persisted for 10 minutes or more after therapy was initiated. Although phenobarbital aborted status epilepticus a little more quickly than did the combination, there was no statistical significance in the success frequency between the two treatments.59 However, these two studies paved the way for the Veterans Affairs cooperative trial (randomized, double-blind study)60 in 1998 in which four different treatment protocols were compared in 384 patients with overt (presumably early) status epilepticus and 134 patients with subtle (presumably late) status epilepticus. The four treatment regimens were as follows: (1) lorazepam, 0.1 mg/kg; (2) diazepam, 0.15 mg/kg, followed by 18 mg/kg of phenytoin; (3) phenytoin alone, 18 mg/kg; and (4) phenobarbital, 15 mg/kg. In the patients with overt status epilepticus, the best response (electroencephalo-

graphic and clinical termination of seizures within 20 minutes, and no seizure recurrence within 60 minutes, of therapy initiation) occurred in 64.9% of patients who received lorazepam alone, 58.2% of those who received phenobarbital alone, 55.8% of those who received diazepam with phenytoin, and 43.6% of those who received phenytoin alone. In the patients with subtle status epilepticus, overall response was much lower than in the patients with overt status epilepticus. The response rate was highest in the patients who received phenobarbital (24.2%), followed by those who received lorazepam (17.9%) and those who received diazepam and phenytoin (8.3%), and lowest in those who received phenytoin alone (7.7%). No statistically significant difference between recurrence during the 12-hour study, incidence of adverse effects, or 30-day outcome was noted. The authors concluded that lorazepam was more effective than phenytoin as initial intravenous treatment for overt GCSE. Although lorazepam was not found to be more efficacious than phenobarbital alone or diazepam and phenytoin combined, it was found to be easier to use.60 In the most recent randomized, double-blind trial, Alldredge and colleagues58 in 2001 evaluated intravenous benzodiazepine administration by paramedics for the treatment of out-of-hospital status epilepticus. In this trial, 205 patients were randomly assigned to receive intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. Status epilepticus was aborted in 59.1% of patients receiving lorazepam who arrived in the emergency department, in comparison with 42.6% of the diazepam recipients and 21.1% of the placebo recipients. The duration of status epilepticus was also shorter in the lorazepam recipients. On the basis of these data, most epileptologists would agree that lorazepam should be given first, followed by phenytoin/ fosphenytoin if seizures continue. Phenobarbital may be used as an alternative before initiation of full-dose anesthetics for individuals who have not responded to a benzodiazepine and subsequent phenytoin/fosphenytoin treatment. The following section focuses on the pharmacological properties, mechanism of action, side effects, and dosages of the first-line agents.

PHARMACOTHERAPY Benzodiazepines The benzodiazepines commonly used in the United States to treat status epilepticus include lorazepam (Ativan), diazepam (Valium), and midazolam (Versed). The agents in this class enhance GABA-mediated inhibition by binding to the benzodiazepine-binding site on the GABA receptor complex. Diazepam enters the brain rapidly because of its lipophilic quality; however, nearly 20 minutes later, it is rapidly distributed to other fatty tissues, which causes a fall of serum concentrations.58,62 Thus, duration of action is approximately 15 to 30 minutes.63 Side effects include respiratory suppression, hypotension, and sedation. Lorazepam is less lipid soluble but is distributed to other tissues over a longer period of time than is diazepam. Thus, lorazepam has a longer duration of effect (12 to 24 hours) but a slightly longer delay in reaching peak concentration (6 to 10 minutes) than does diazepam (1 to 3 minutes).63 Side effects are similar to those of diazepam. The recommended dosage of lorazepam in status epilepticus is 0.1 mg/kg in adults and 0.05 to 0.5 mg/kg in children (maximal

chapter 54 management of status epilepticus rate, 2 mg/minute).63,64 The recommended dosage of diazepam is 0.15 to 0.25 mg/kg in adults as an intravenous push and 0.1 to 1.0 mg/kg in children (maximal rate, 5 mg/minute).63,64 In children, in whom intravenous access may be difficult initially, rectal diazepam (Diastat) may be given at a dosage of 0.5 mg/kg.3 Midazolam is used mainly in Europe as a first-line agent, but it is used as an intravenous drip in refractory status epilepticus in the United States and hence is discussed elsewhere in this chapter (section on “Refractory Status Epilepticus”).

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adults and children at a maximal rate of 100 mg/minute.63,64 However, respiratory suppression, along with hypotension, can occur with phenobarbital infusion, particularly if benzodiazepines were administered previously. Thus, intravenous phenobarbital loading requires careful observation for hypotension and usually should be performed with the patient already intubated for airway support.

REFRACTORY STATUS EPILEPTICUS Phenytoin/Fosphenytoin Phenytoin has been shown to be effective in terminating generalized status epilepticus in 41% to 90% of patients in five unconPhenytoin’s main trolled retrospective studies.65-69 anticonvulsant mechanism of action involves blocking voltagesensitive, use-dependent sodium channels.70 However, the main disadvantages of this drug involve the limitation of rapid administration because of phenytoin itself and the propylene glycol diluent. The maximum rate of infusion is 50 mg/minute, which in a 70-kg individual would take nearly 30 minutes to administer. In addition, significant hypotension and arrhythmias can occur in elderly patients and in patients with known cardiac disease.70 Phlebitis and local irritation can also occur with intravenous administration, which further limits timely use in status epilepticus. In 1996, the U.S. Food and Drug Administration approved fosphenytoin for the treatment of status epilepticus. Fosphenytoin is a water-soluble prodrug of phenytoin that converts to phenytoin in 8 minutes.71-73 Approximately 1.5 mg of fosphenytoin is equivalent to 1 mg of phenytoin, and the dosage is expressed as phenytoin equivalents. Fosphenytoin can be infused at 150 mg phenytoin equivalents per minute. However, therapeutic concentrations of phenytoin (≥1 mg/L unbound) are attained within 10 minutes when either fosphenytoin or phenytoin is administered at maximal infusion rates. The recommended initial loading dosage of phenytoin is 15 to 20 mg/kg (no faster than 50 mg/minute) to a total maximum of 30 mg/kg. Fosphenytoin loading dosage is 18 to 20 mg/kg phenytoin equivalents administered at 150 mg/minute.64 The dosages are the same in children. In some patients, up to 30 mg/kg may be necessary to stop the seizures, but additional phenytoin/fosphenytoin has not proved helpful and in fact may be epileptogenic.74 Thus, either agent phenytoin or fosphenytoin may have a similar time to onset of effect.73 However, the significant advantage of fosphenytoin is the fewer local side effects (pain at injection site, phlebitis) that result in fewer infusion rate decreases, interruptions, or change of site.72 In addition, infusion of fosphenytoin at 150 mg/minute resulted in some decline in blood pressure, but this was not judged to be clinically significant, and so no adjustment of infusion rates was required. In addition, no significant cardiac arrhythmias have been associated with fosphenytoin.73 Rate of administration, however, should be slowed down regardless of which agent is used if hypotension, arrhythmias, or prolongation of the QT interval on electrocardiogram should occur.

Phenobarbital Although many actions at the cellular level have been reported for phenobarbital, evidence suggests that the main anticonvulsant effect is enhancement of GABA-mediated inhibition.75 Phenobarbital can be given at a loading dosage of 20 mg/kg in

There is no general consensus regarding the definition of what constitutes refractory status epilepticus. There is discrepancy between duration of seizure activity and number of failed medications. As a general guideline, status epilepticus that is not responsive to the measures described previously (benzodiazepine, phenytoin/fosphenytoin, phenobarbital) should be considered refractory. To date, there are no prospective randomized trials comparing medication choices for refractory status epilepticus. However, in the Veterans Affairs study, nearly 55% of patients who had overt status epilepticus did not respond to first-line therapeutic agents (benzodiazepines, phenytoin, phenobarbital); the cumulative rate of response to a second first-line agent was 7%, and that to a third first-line agent, 2.3%. Addition of phenobarbital for individuals who did not respond to lorazepam and phenytoin therapy was effective in only 5%.60,76 Thus, a case can be made to start early intravenous anesthetic drips in patients who have not responded to initial benzodiazepine and phenytoin/fosphenytoin therapy. Pentobarbital is probably the best-studied intravenous drip used for refractory status epilepticus.77-84 Pentobarbital (sodium-5-ethyl-5,1-methylbutyl barbiturate) binds to the GABAA receptor and thus augments GABAergic transmission, resulting in anticonvulsant and sedative-hypnotic effects.80 Pentobarbital has an onset of action of 15 to 20 minutes and a half-life of 20 to 60 hours.80 Pentobarbital-induced coma has proved effective in treating refractory status epilepticus,78 although depression of cardiac contractility and vascular tone, leading to profound hypotension (necessitating pressor support), are major side effects.80 The protocol adopted by clinicians for pentobarbital-induced coma is based on the standardized protocol of Lowenstein and colleagues.83 Pentobarbital is initially administered at a loading intravenous dose of 5 to 15 mg/kg over an hour, followed by a maintenance infusion of 0.5 to 5 mg/kg/hour, titrated to burst-suppression. To ensure adequate respiration, the patient should be electively intubated before barbiturate induction of coma. Infusion should be slowed down if profound hypotension occurs, with addition of pressor agents if needed. Although this treatment is efficacious, the side effects of profound hypotension with barbiturate coma have led to a search for alternative anesthetic intravenous agents, including midazolam and propofol. Midazolam is a water-soluble benzodiazepine with a relatively short half-life of 4 to 6 hours.85 Midazolam has been used in the intensive care unit for sedation and also in the operating room for preoperative induction of anesthesia in patients. Possible anticonvulsant effects were seen in animal studies initially,86-88 and since the early 1990s, a number of small case series and reports have been published about the use of midazolam infusion for refractory status epilepticus.86,89-92 A major disadvantage with midazolam infusion is tachyphylaxis. After 1 to 2 days, the

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dosage of the infusion must be increased substantially to maintain seizure control.92 With prolonged infusion, the drug accumulates as a result of an increase in elimination half-life, potentially leading to increasing difficulty in returning patients back to alertness.93 Initial studies suggest that midazolam may have fewer hypotensive effects than those observed with highdose pentobarbital-induced coma.86,90,94 A protocol commonly used to treat refractory status epilepticus with midazolam was developed at the University of California, San Francisco.86 As in pentobarbital infusion, the patient should be intubated and continuous electroencephalographic monitoring should be in place. The initial loading dose is 200 μg/kg as a slow intravenous bolus, followed by 0.75 to 10 μg/kg/minute infusion. Titration of the infusion is based on electroencephalographic monitoring, the primary endpoint being suppression of electrographic seizures. The infusion should be discontinued after 12 to 24 hours of electroencephalographic monitoring and reinstated if seizures recur.86 However, because of the small number of patient studies in case series and reports, and because there have been no randomized prospective clinical trials to date, definite conclusions about dosing and efficacy cannot be drawn. In addition, electrographic endpoints differ among studies (complete suppression on EEG versus suppression of clinical/electrographic seizures) and not all of the investigators used continuous EEGs to monitor patients (and thus potentially missed electrographic seizures). Propofol (2,6-diisopropylphenol), like midazolam, has been used for the induction and maintenance of anesthesia and also sedation in intensive care units. Propofol activates the GABAA receptor but is also a global central nervous system depressant.95 Propofol has an even shorter duration of action than midazolam because of its highly lipophilic nature and large volume of distribution. Thus, propofol is rapidly taken up by the brain and in turn rapidly eliminated. In contrast to midazolam, there is no accumulation with prolonged infusion. A rare complication that deserves mention is the “propofol infusion syndrome” seen in pediatric patients. This syndrome consists of metabolic acidosis, rhabdomyolysis, and cardiovascular collapse.96 Hence, propofol is contraindicated in children. Stecker and associates97 proposed an initial loading dose of 1 to 2 mg/kg over 5 to 10 minutes, followed by a maintenance infusion of 1 to 15 mg/kg/hour, titrated to induce electrographic burst suppression. It is recommended to slowly taper propofol infusions by 5% of the maintenance infusion per hour to prevent rebound of seizures on discontinuation.97 Multiple small case series advocating propofol’s efficacy in treating refractory status epilepticus have also been cited in the literature.97-105 In one small open-label, randomized study, investigators compared the outcome of patients treated with propofol versus pentobarbital infusion.97 It appeared that the time until attainment of control of refractory status epilepticus was longer (12 minutes) with pentobarbital than with propofol (2.6 minutes). However, propofol was not significantly better than pentobarbital in treatment of refractory status epilepticus in this study.97 One small (14-patient) retrospective comparison of propofol and midazolam infusion for refractory status epilepticus did not reveal differences in clinical and electrographic seizure control.106 Unfortunately, the same problems in drawing conclusions about midazolam’s efficacy also apply to propofol. From this discussion, a few general points can be made. If any of the anesthetic intravenous infusions are used for refractory status epilepticus, continuous electroencephalography should be used to ensure cessation of both clinical and electrographic

seizures. It is reasonable to try either midazolam or propofol infusion as third-line treatment (after benzodiazepine and phenytoin/fosphenytoin failure) to avoid potentially severe hypotensive effects from pentobarbital. However, if midazolam or propofol is ineffective in terminating status epilepticus within 1 hour, it is equally reasonable to initiate pentobarbital-induced coma, which has been shown to be effective in refractory status epilepticus (as discussed previously) despite hypotensive side effects. Finally, serum concentrations of phenytoin/fosphenytoin or phenobarbital (depending on whether phenobarbital was initiated before anesthetic drips) should be maintained in therapeutic ranges (20 μg/mL and 40 μg/mL, respectively) throughout anesthetic infusion. This measure is to prevent patients from regressing back into status epilepticus once eventual tapering of the anesthetic infusion is initiated. As indicated, more work is needed in three areas. First, depth of suppression on EEG and outcome with each of these three medications must be studied. A retrospective chart study by Krishnamurthy and Drislane107 suggested that deeper suppression correlated with better continued seizure control and survival. Second, the optimal electrographic endpoint of treatment also needs to be addressed. There is no consensus on how aggressively to treat persistent epileptiform discharges in those on anesthetic intravenous infusions for refractory status epilepticus. Most epileptologists would not consider PLEDs by themselves to be a manifestation of clinical seizures or status epilepticus. PLEDs have been seen in acute and subacute lesions (herpes simplex virus–related encephalitis, stroke, tumor, head trauma),108 as well as chronically.109 However, whether periodic epileptiform discharges occurring at a rate of 0.5 to 2 per second should be considered an ictal equivalent is still an area of debate. Some clinicians consider PLEDs or periodic epileptiform discharges that are present after a clear-cut clinical or electrographic seizure to be an ictal equivalent and treat them as such. Third, controlled, randomized prospective trials with head-to-head comparison of anesthetic infusions need to be conducted with similar subpopulations of patients.

NEW PHARMACOLOGICAL DEVELOPMENTS The intravenous formulation of valproic acid has generated much attention as a possible intravenous alternative agent for treatment of refractory status epilepticus. The exact mechanism of action of valproate is unknown. Valproate has been shown to increase brain GABA levels, reduce repetitive highfrequency firing by blocking voltage-sensitive sodium channels, activate calcium-dependent potassium clearance, and possibly decrease levels of excitatory amino acids such as aspartate.110 In reality, the contribution of each of these actions to valproate’s anticonvulsant effect is unknown. Very little literature exists about the use of intravenous sodium valproate (Depacon) for status epilepticus in adults and children. Depacon was approved in 1996 by the U.S. Food and Drug Administration for treatment of epilepsy with a recommended infusion rate of 20 mg/minute over 60 minutes, with a total maximum daily dose of 60 mg/kg/day. However, several studies have shown good tolerance by patients and relatively infrequent hypotension with more rapid infusion rates of up to 6 mg/kg/minute.111-116 In addition, loading doses achieving therapeutic concentrations with intravenous valproate sodium are about 25 to 30 mg/kg,113 and reports of better efficacy

chapter 54 management of status epilepticus with dosages as high as 30 to 40 mg/kg in children have been noted.117 In one series reported by Uberall and associates,117 41 children with refractory status epilepticus (failure of benzodiazepines, phenytoin, barbiturates) were given an initial loading dose of 20 to 40 mg/kg of intravenous valproate sodium over 1 to 5 minutes, with repetition after 10 to 15 minutes if necessary, followed by continuous intravenous infusion at 5 mg/kg/hour. After a 12-hour seizure free period, infusion was decreased to 1 mg/kg every 2 hours. Uberall and associates noted a response to intravenous valproate sodium (cessation of clinical and electrographic seizures) within 2 to 6 minutes by 65.9% of patients, response within 3 to 10 minutes after the second bolus by another 9.8%, and a response by one patient during the infusion. Overall, 32 (78%) of 41 patients responded to treatment. Success was highest in generalized tonic-clonic status epilepticus and for initial loading dosages between 30 and 40 mg/kg.117 In a retrospective study by Yu and colleagues,118 18 patients with status epilepticus were given an initial loading dose of 25 mg/kg of intravenous valproate at a rate of approximately 3 mg/kg/minute with cessation of seizures within 20 minutes of completion of the infusion. Patients tolerated the infusion well; one patient reported transient tremor afterward. However, this study was limited by design (retrospective), lack of stratification into seizure subtypes, and lack of electrographic confirmation of seizure cessation. A more recent retrospective study in adults of 63 patients revealed an overall efficacy of 63% when valproate was used as the first antiepileptic drug in 14 patients, the second in 20 patients, the third in 19 patients, and the fourth or fifth in 8 patients.119 Of the 63 patients, 3 experienced hypotension with intravenous infusion rates up to 500 mg/minute. Clinical experience is sparse with regard to the use of intravenous sodium valproate for status epilepticus. However, on the basis of the preceding discussion, it might be reasonable as a third- or fourth-line agent (after failure of benzodiazepines and phenytoin/fosphenytoin, and possibly phenobarbital) before anesthetic infusions (propofol, midazolam, pentobarbital) are initiated, especially in patients with baseline hemodynamic instability. With an infusion bolus rate of 6 mg/kg/minute and dosage of 25 to 30 mg/kg in an average 70-kg individual, intravenous sodium valproate can theoretically be administered in approximately 5 minutes. In addition, it may also be a reasonable option for patients in whom intubation is not being considered. Randomized, controlled clinical studies in both adults and children are needed to clarify the initial bolus dosage of intravenous valproate, its efficacy as an initial agent in status epilepticus, and its efficacy as a second- or third-line agent in treating refractory status epilepticus. Since 2003, anecdotal case reports of topiramate administered in suspension form (via nasogastric tube) for refractory status epilepticus have been published.120-122 Dosages ranged from 300 to 1600 mg/day.120-122 However, currently no definite conclusions can be made about efficacy. In addition, lack of an intravenous form poses a difficulty for acute administration. Other experimental medications that have been tried for refractory status epilepticus have included ketamine,123 inhalational anesthetics (desflurane, isoflurane),124-128 and lidocaine.129,130 Ketamine is an intravenous agent with a short half-life of 2 to 3 hours that in animal studies has shown anticonvulsant properties by causing NMDA receptor blockade.131 Isoflurane’s and desflurane’s antiepileptic effects may result from potentia-

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tion of GABAA inhibition. Both of these agents necessitate continuous electroencephalographic monitoring for dosage titration. Lidocaine has been tried mainly in Scandinavia and has an anticonvulsant effect primarily through blocking sodiumdependent channels, although the exact mechanism of action is not known.129 However, potential serious cardiac effects and proconvulsive action at higher doses pose serious risk in using this agent for refractory status epilepticus. One final point in treatment of GCSE involves electrographic assessment of the patient’s condition with medically stabilization (when convulsive activity has ceased). Ongoing NCSE has been observed in patients after GTCS (generalized tonic-clonic seizures) have ceased.132 In a study by DeLorenzo and associates,132 both continuous and intermittent ictal activity in NCSE were picked up within the first hour after GCSE was controlled.132 Therefore, although continuous electroencephalographic monitoring may not be feasible in all centers, a continuous 1-hour “follow-up” EEG, after GCSE has ceased and after initial pharmacotherapy has been initiated, should be obtained.

NONCONVULSIVE STATUS EPILEPTICUS The discussion up to this point has focused mainly on treatment of GCSE. Overall consensus is to treat GCSE aggressively because of associated high rates of morbidity and mortality. However, the incidence of and rate of mortality from NCSE are not so clear, and thus aggressiveness of therapy has not been uniform. In addition, diagnosis of NCSE itself poses a problem. Underrecognition of the problem can occur because diagnosis is based largely on electrographic data. Investigators have classified comatose patients in intensive care units with incidental findings of electrographic status epilepticus as having NCSE.133 Thus, in an effort to assess the morbidity and mortality in NCSE, Shneker and colleagues134 retrospectively reviewed a computerized database at their institution, identifying 100 consecutive cases of NCSE by the following characteristics: mental status, etiology, presence of complications, and electroencephalographic findings. Patients’ conditions were stratified into three categories according to etiology: acute medical, epilepsy, and cryptogenic. Overall, the rate of mortality was similar to that for GCSE (18%). The authors found the highest rate of mortality to be in the group with acute medical conditions (27%), in contrast to only 3% in the patients with known epilepsy (status epilepticus in patients with epilepsy).134 Again, as with GCSE, etiology was also closely linked to increased rates of mortality.36 In addition, patients with severe mental status impairment and acute complications also had increased mortality rates.134 Thus, the authors concluded that patients with epilepsy as the only cause of NCSE should probably not be routinely treated aggressively with anesthetic coma.134 Other authors have concluded that typical absence status epilepticus and complex partial status epilepticus should be treated with benzodiazepines or an intravenous agent, but anesthetic coma is not recommended. This is in contrast with NCSE in patients with coma, for which a more aggressive approach has been recommended.135 Ultimately, treatment of NCSE needs to be individually tailored to the underlying etiology, associated comorbidity, and individual response to initial first- and second-line therapy. It is clear that status epilepticus is a medical emergency and that timely treatment of both GCSE and NCSE is necessary.

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P O I N T S

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Status epilepticus is defined as continuous seizure activity for more than 30 minutes or two or more sequential seizures without full recovery of consciousness between seizures.

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The incidence of status epilepticus is highest in the elderly (>60 years old) and in young children (<1 year old).

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The rate of mortality from GCSE is 15% to 22%.

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Mortality in GCSE is dependent on the underlying etiology, age of the patient, and duration of seizure activity.

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Neuronal injury in status epilepticus is caused largely by decreased γ-aminobutyric acid (GABA) inhibition and abundant glutamate excitation.

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Management of status epilepticus includes instituting appropriate pharmacotherapy and targeting systemic complications.

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NCSE may follow GCSE, and thus electrographic assessment (EEG) of each patient is needed in order to appropriately manage status epilepticus.

Suggested Reading Arzimanaglou A, Hirsch E, Nehlig A, et al: Epilepsy and neuroprotection: an illustrated review. Epilept Disord 2002; 4:173-182. Husain AM, Mebust KA, Radtke RA, et al: Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis. J Clin Neurophysiol 1999; 16:51-58. Logroscino G, Hesdorffer DC, Cascino GD, et al: Long-term mortality after a first episode of status epilepticus. Neurology 2002; 58:537-541. Shorvon S: Definition, classification, and frequency of status epilepticus. In Shorvon S, ed: Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, UK: Cambridge University Press, 1994, pp 21-33. Treiman DM, Walton NY, Kendrick C: A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res 1990; 5:49-60.

References 1. Hunter RA: Status epilepticus: history, incidence and problems. Epilepsia 1959; 60:162-188. 2. Trousseau A: Lecture of clinical medicine. In Bazire PV (trans): Lectures on Clinical Medicine Delivered at the HôtelDieu, Paris, vol 1. London: New Sydenham Society, 1868, pp 53-54. 3. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993; 270:854-859. 4. Lowenstein DH, Bleck TP, Macdonald RL: It’s time to revise the definition of status epilepticus. Epilepsia 1999; 40:120122. 5. Treiman DM: Generalized convulsive status epilepticus in the adult. Epilepsia 1993; 34(Suppl 1):S2-S11. 6. Treiman DM, DeGiorgio CM, Salisbury SM, et al: Subtle generalized convulsive status epilepticus. Epilepsia 1984; 25:653. 7. Williamson P: Complex partial status epilepticus. In Engel J, Pedley TA, eds: Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997, pp 681-699.

8. Lowenstein DH, Aminoff MJ: Clinical and EEG features of status epilepticus in comatose patients. Neurology 1992; 42:100-104. 9. Tomson T, Lindom U, Nilsson BY: Nonconvulsive status epilepticus in adults: thirty-two consecutive patients from a general hospital population. Epilepsia 1992; 33:829-835. 10. Tomson T, Svanborg E, Wedlund JE: Nonconvulsive status epilepticus: high incidence of complex partial status. Epilepsia 1986; 27:276-285. 11. Gastaut H: Classification of status epilepticus. Adv Neurol 1983; 34:15-35. 12. Ohtahara S, Ohtsuka Y: Myoclonic status epilepticus. In Engel J, Pedley TA, eds: Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997, pp 725-729. 13. Wieser, H-G: Simple partial status epilepticus. In Engel J, Pedley TA, eds: Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997, pp 709-723. 14. Gastaut H, Boudouresques G, Gastaut JL, Michel B, et al: Jacksonian epileptic seizures as inaugural manifestations of sylvian infarctus. In Boulay G, Moseley IF, eds: Computerized Axial Tomography in Clinical Practice. New York: Springer Verlag, 1977, pp 237-245. 15. Chatrian G, Shaw C, Leffman H: The significance of periodic lateralized epileptiform discharges on EEG: an electrographic, clinical, and pathologic study. Electroencephalogr Clin Neurophysiol 1964; 17:177-193. 16. Naquet R, Franck G, Vigouroux R: Decharge paroxystique du carrefour parieto-temporo-occipital [Paroxysmal discharge from the parieto-temporo-occipital junction]. Zentralbl Neurochir 1915; 4/5:153-180. 17. De Pasquet E, Gaudin E, Bianchi A, et al: Prolonged and monosymptomatic dysphasic status epilepticus. Neurology 1976; 26:244-247. 18. Gastaut H: Aphasia. The sole manifestation of focal status epilepticus [Letter]. Neurology 1979; 29:1638. 19. Hamilton N, Matthews T: Aphasia, the sole manifestation of focal status epilepticus. Neurology 1979; 29:745-748. 20. Vernea J: Partial status epilepticus with speech arrest. Proc Aust Assoc Neurol 1974; 11:223-228. 21. Racy A, Osborn MA, Vern BA, et al: Epileptic aphasia: first onset of prolonged monosymptomatic status epilepticus in adults. Arch Neurol 1980; 37:419-422. 22. Wells CR, Labar DR, Solomon GE: Aphasia as the sole manifestation of simple partial status epilepticus. Epilepsia 1992; 33:84-87. 23. Celesia GG: Prognosis in convulsive status epilepticus. In Delgado-Escueta A, Wasterlain C, Treiman D, et al, eds: Status Epilepticus: Mechanisms of Brain Damage and Treatment. New York: Raven Press, 1983, pp 55-59. 24. Aicardi J, Chevrie JJ: Convulsive status epilepticus in infants and children: a study of 239 cases. Epilepsia 1970; 11:187197. 25. Aminoff NJ, Simon RP: Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980; 69:657-666. 26. Maytal J, Shinnar S, Moshe SL, et al: Low morbidity and mortality of status epilepticus in children. Pediatrics 1989; 83:323-331. 27. DeLorenzo R, Towne AR, Pellock JM, et al: Status epilepticus in children, adults, and the elderly. Epilepsia 1992; 33(Suppl 4):515-525. 28. Towne AR, Pellock JM, Ko D, et al: Determinants of mortality in status epilepticus. Epilepsia 1994; 5:27-36. 29. Dunn DW: Status epilepticus in children: etiology, clinical features, and outcome. J Child Neurol 1988:3:167-173. 30. Leppik IE: Status epilepticus. Clin Ther 1985; 7:272-278. 31. Hauser WA: Status epilepticus: epidemiology considerations. Neurology 1990; 40(Suppl 2):9-12.

chapter 54 management of status epilepticus 32. Hauser WA: Status epilepticus: frequency, etiology, and neurologic sequelae. In Delgado-Escueta A, Wasterlain C, Treiman D, et al, eds: Status Epilepticus: Mechanisms of Brain Damage and Treatment. New York: Raven Press, 1983, pp 3-14. 33. Lowenstein DH, Alldredge BK: Status epilepticus at an urban public hospital in the 1980’s. Neurology 1992; 43:483-488. 34. Janz D: Conditions and causes of status epilepticus. Epilepsia 1961; 2:170-177. 35. Oxbury JM, Whitty CWM: Causes and consequences of status epilepticus in adults: a study of 86 cases. Brain 1971; 94:733744. 36. De Lorenzo R, Pellock JM, Towne AR, et al: Epidemiology of status epilepticus. J Clin Neurophysiol 1995; 12:316-325. 37. Hesdorffer DC, Logroscino G, Cascino G, et al: Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology 1998; 50:735-741. 38. Shinnnar S, Pellock JM, Moshe S, et al: In whom does status epilepticus occur: Age-related differences in children. Epilepsia 1997; 38:907-914. 39. Lothman EW: Pathophysiology of status epilepticus. J Clin Neurophysiol 1990; 40(Suppl 2):13-23. 40. Simon RP, Aminoff MJ, Benowitz NL: Changes in plasma catecholamines after tonic-clonic seizures. Neurology 1984; 34:255-257. 41. White PT, Grant P, Mosier J, et al: Changes in cerebral dynamics associated with seizures. Neurology 1961; 11:345-361. 42. Fountain NB, Lothman EW: Pathophysiology of status epilepticus. J Clin Neurophysiol 1995; 12:326-342. 43. Bayne LL, Simon RP: Systemic and pulmonary vascular pressures during generalized seizures in sheep. Ann Neurol 1997; 42:588-594. 44. Kreisman NR, Gauthier-Lewis ML, Conklin SG, et al: Cardiac output and regional hemodynamics during recurrent seizures in rats. Brain Res 1993; 626:295-302. 45. Boggs JG, Painter JA, DeLorenzo RJ: Analysis of electrocardiographic changes in status epilepticus. Epilepsy Res 1993; 14:87-94. 46. Meldrum BS, Brierly JB: Prolonged epileptic seizures in primates. Arch Neurol 1973; 28:10-17. 47. Blennow G, Brierley JB, Meldrum BS, et al: Epileptic brain damage: the role of systemic factors that modify cerebral energy metabolism. Brain 1978; 101:687-700. 48. Liu Z, Gatt A, Mikati M, et al: Effect of temperature on kainic acid–induced seizures. Brain Res 1993; 631:51-58. 49. Tomlinson FH, Anderson RE, Meyer FB: Effect of arterial blood pressure and serum glucose on brain intracellular pH, cerebral and cortical blood flow during status epilepticus in the white New Zealand rabbit. Epilepsy Res 1993; 14:123-137. 50. Singhal PC, Chugh KS, Gulatie DR; Myoglobinuria and renal failure after status epilepticus. Neurology 1978; 28:200-201. 51. Seisjo BK, Ingvar M, Folbergrova J, et al: Local cerebral circulation and metabolism in bicuculline-induced status epilepticus: relevance for development of cell damage. In Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al, eds: Status Epilepticus. New York: Raven Press, 1983, pp 217-230. 52. Meldrum BS: Metabolic factors during prolonged seizures and their relation to cell death. Adv Neurol 1983; 34:261-275. 53. Simon R, Pellock JM, DeLorenzo RJ: Acute morbidity and mortality of status epilepticus. In Engel J, Pedley TA, eds: Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997, pp 741-753. 54. Treiman DM, Meyers PD, Walton NY: DVA Status Epilepticus Cooperative Study Group. Duration of generalized convulsive status epilepticus: relationship to clinical symptomatology and response to treatment. Epilepsia 1992; 33(Suppl 3):66. 55. Treiman DM, Walton NY, Kendrick C: A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res 1990; 5:49-60.

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56. Treiman DM, Meyers PD: VA Epilepsy Cooperative Study Group. Utility of the EEG pattern as a predictor of success in the treatment of generalized convulsive status epilepticus. Epilepsia 1991; 32(Suppl 3):93. 57. Bleck TP: Management approaches to prolonged seizures and status epilepticus. Epilepsia 1999; 40(Suppl 2):S59-S63. 58. Alldredge BK, Gelb AM, Isaacs SM, et al: A comparison of lorazepam, diazepam, and placebo for the treatment of out-ofhospital status epilepticus. N Engl J Med 2001; 345:631-637. 59. Shaner DM, McCurdy SA, Herring Mo, et al: Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988; 38:202-207. 60. Treiman DM, Meyers PD, Walton NY, et al: A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998; 339:792-798. 61. Leppik IE, Derivan AT, Homan RW, et al: Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983; 249:1452-1454. 62. Ramsay RE, Hammond EJ, Perchalski RJ, et al: Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 1979; 36:535-539. 63. Treiman DM: Status epilepticus. In Resor J, Kutt H, eds: The Medical Treatment of Epilepsy. New York: Marcel Dekker, 1992, pp 183-193. 64. Treiman DM: Current treatment strategies is selected situations in epilepsy. Epilepsia 1993; 34(Suppl 5):S17-S23. 65. McWilliam PKA, Leeds MB: Intravenous phenytoin sodium in continuous convulsions in children. Lancet 1958; 2:11471149. 66. Wallis W, Kutt H, McDowell F: Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology 1968; 18:513-525. 67. Wilder BJ, Ramsay RE, Willmore LJ, et al: Efficacy of intravenous phenytoin in the treatment of status epilepticus: kinetics of central nervous system penetration. Ann Neurol 1977; 1:511-518. 68. Cranford RE, Leppik IE, Patrick B, et al: Intravenous phenytoin in acute treatment of seizures. Neurology 1979; 29:14741479. 69. Carter CH: Use of parenteral diphenylhydantoin sodium in control of status epilepticus. AMA Arch Neurol Psychiatry 1958; 79:136-137. 70. Glauser T, Graves N: Phenytoin and fosphenytoin. In Wyllie E, ed: The Treatment of Epilepsy. Philadelphia: Lippincott Williams & Wilkins, 2001, pp 853-868. 71. Allen FH, Runge RW, Legarda S: Safety, tolerance and pharmacokinetics of intravenous fosphenytoin in status epilepticus. Epilepsia 1995; 36(Suppl 4):90-94. 72. Browne TR, Kugler AR, Eldon MA: Pharmacology and pharmacokinetics of fosphenytoin. Neurology 1996; 46(Suppl 1):S3-S7. 73. Ramsey RE, DeToledo J: Intravenous administration of fosphenytoin: options for the management of seizures. Neurology 1996; 46(Suppl 1):S17-S9. 74. Osorio I, Reed RC: Treatment of refractory generalized tonicclonic status epilepticus with pentobarbital anesthesia after high-dose phenytoin. Epilepsia 1989; 30:464-471. 75. Prichard J, Ransom B: Phenobarbital: mechanism of action. In Levy R, Mattson R, Meldrum B, eds: Antiepileptic Drugs. New York: Raven Press, 1995, pp 359-369. 76. Treiman DM, Walton NY, Collins JF, et al: Treatment of status epilepticus if first drug fails [Abstract]. Epilepsia 1999; 40(Suppl 7):243. 77. Van Ness PC: Pentobarbital and EEG burst suppression in treatment of status epilepticus refractory to benzodiazepines and phenytoin. Epilepsia 1990; 31:61-67.

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78. Yaffe K, Lowenstein DH: Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology 1993; 43:895-890. 79. Orlowski JP, Erenberg G, Lueders H, et al: Hypothermia and barbiturate coma for refractory status epilepticus. Crit Care Med 1984; 12:367-372. 80. Rashkin MC, Youngs C, Penovich P: Pentobarbital treatment of refractory status epilepticus. Neurology 1987; 37:500-503. 81. Partinen M, Kovanen J, Nilsson E: Status epilepticus treated by barbiturate anesthesia with continuous monitoring of cerebral function. BMJ (Clin Res Ed) 1981; 282:520-521. 82. Young GB, Blume WT, Bolton CF, et al: Anesthetic barbiturates in refractory status epilepticus. Can J Neurol Sci 1980; 7:291-292. 83. Lowenstein DH, Aminoff MJ, Simon RP: Barbiturate anesthesia in the treatment of status epilepticus. Neurology 1988; 38:395-400. 84. Mirski MA, Williams MA, Hanley DF: Prolonged pentobarbital and phenobarbital coma for refractory generalized status epilepticus. Crit Care Med 1995; 23:400-404. 85. Reves JG, Fragen RJ, Vinik R, et al: Midazolam: pharmacology and uses. Anesthesiology 1985; 62:310-324. 86. Parent JM, Lowenstein DH: Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology 1994; 44:1837-1840. 87. Domino EF: Comparative seizure inducing properties of various cholinesterase inhibitors: antagonism by diazepam and midazolam. Neurotoxicology 1987; 8:113-122. 88. Raines A, Henderson TR, Swinyard EA, et al: Comparison of midazolam and diazepam by the intramuscular route for the control of seizures in a mouse model of status epilepticus. Epilepsia 1990:31:313-317. 89. Crisp CB, Gannon R, Knauft F: Continuous infusion of midazolam hydrochloride to control status epilepticus. Clin Pharmacol 1988; 7:322-324. 90. Kumar A, Bleck TP: Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 1992; 20:483488. 91. Cortina J, Ancillo P, Duarte J, et al: Intravenous midazolam suppression of complex partial status refractory to intravenous phenytoin and diazepam. Clin Neuropharmacol 1993; 16:468-470. 92. Noritoku DK, Sinha S: Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology 2000; 54:1366-1368. 93. Malacrida R, Fritz ME, Suter PM, et al: Pharmacokinetics of midazolam administered by continuous venous infusion to intensive care patients. Crit Care Med 1992; 20:1123-1126. 94. Rivera R, Segnini M, Baltodano A, et al: Midazolam in the treatment of status epilepticus in children. Crit Care Med 1993; 21:991-994. 95. Borgeat A, Wilder-Smith OHG, Suter PM: The non-hypnotic therapeutic applications of propofol. Anesthesiology 1994; 80:642-656. 96. Vasile B, Rasulo F, Candiani A, et al: The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29:1417-1425. 97. Stecker MM, Kramer TH, Raps EC, et al: Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998; 39:18-26. 98. Yanny HF, Christmas D: Propofol infusions for status epilepticus [Letter]. Anesthesia 1988; 43:514. 99. Wood PR, Browne GPR, Pugh S: Propofol infusion for the treatment of status epilepticus. Lancet 1988; 1:480-481. 100. Chilvers CR, Laurie PS: Successful use of propofol in status epilepticus. Anesthesia 1990; 45:995-996. 101. Mackenzie SJ, Kapadia F, Grant IS; Propofol infusion for control of status epilepticus. Anesthesia 1990; 45; 1043-1045.

102. Alia G, Natale E, Mattaliano A, et al: On two cases of status epilepticus treated with propofol [Abstract]. Epilepsia 1991; 32(Suppl 1):77. 103. Borgeat A, Wilder-Smith OH, Jallon P, et al: Propofol in the management of status epilepticus: a case report. Intensive Care Med 1994; 20:148-149. 104. Pitt-Miller PL, Elcock BJ, Maharaj M: The management of status epilepticus with a continuous propofol infusion. Anesth Analg 1994; 78:1193-1194. 105. Hantson P, VanBrandt N, Verbeeck R, et al: Propofol for refractory status epilepticus. Intensive Care Med 1994; 20:611-612. 106. Prasad A, Worrall B, Bertram E, et al: Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001; 42:380-386. 107. Krishnamurthy K, Drislane F: Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia 1999; 40:759-762. 108. Chatrian GE, Shaw CM, Leffman H: The significance of periodic, lateralizing epileptiform discharges in EEG: an electrographic, clinical, and pathological study. Electroencephalogr Clin Neurophysiol 1964; 17:177-193. 109. Westmoreland BF, Klass DW, Sharbrough FW: Chronic periodic lateralized epileptiform discharges. Arch Neurol 1986; 43:494-496. 110. Bourgeois B: Valproate. In Wyllie E, ed: The Treatment of Epilepsy. Philadelphia: Lippincott Williams & Wilkins, 2001, pp 843-851. 111. Ramsey RE, Cantrell D, Collins SD, et al: Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy. Epilepsy Res 2003; 52:189-201. 112. Sinha S, Naritoku DK: Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000; 55:722-724. 113. Venkataraman V, Wheless JW: Safety of rapid intravenous infusion of valproate loading in epilepsy patients. Epilepsy Res 1999; 35:147-153. 114. Wheless J, Venkataraman V: Safety of high intravenous valproate loading doses in epilepsy patients. J Epilepsy 1998; 11:319-324. 115. Naritoku DK, Mueed S: Intravenous loading of valproate for epilepsy. Clin Neuropharmacol 1999; 22:102-106. 116. Wheless JW, Vazquez BR, Kanner AM, et al: Rapid infusion with valproate sodium is well tolerated in patients with epilepsy. Neurology 2004; 63:1507-1508. 117. Uberall M, Trollman R, Wunsiedler U, et al: Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology 2000; 54:2188-2189. 118. Yu K, Mills S, Thompson N, et al: Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003; 44:724-726. 119. Limdi NA, Shimpi AV, Faught E, et al: Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005; 64:353-355. 120. Kahriman M, Minecan D, Kutluay E, et al: Efficacy of topiramate in children with refractory status epilepticus. Epilepsia 2003; 44:1353-1356. 121. Towne AR, Garnett LK, Waterhouse EJ, et al: The use of topiramate in refractory status epilepticus. Neurology 2003; 60:332-334. 122. Bensalem MK, Fakhoury TA: Topiramate and status epilepticus: report of three cases. Epilepsy Behav 2003; 4(6):757760. 123. Sheth R, Gidal B: Refractory status epilepticus: response to ketamine. Neurology 1998; 51:1765-1766. 124. Mirsattari S, Sharpe M, Young B: Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 2004; 61:1254-1259.

chapter 54 management of status epilepticus 125. Kofke WA, Young RSK, Davis P, et al: Isoflurane for refractory status epilepticus: a clinical series. Anesthesiology 1989; 71:653-659. 126. Kofke WA, Bloom MJ, Van Cott A, et al: Electrographic tachyphylaxis to etomidate and ketamine used for refractory status epilepticus controlled with isoflurane. J Neurosurg Anesthesiol 1997; 9:269-272. 127. Hughes DR, Sharpe MD, McLachlan RS: Control of epilepsia partialis continua and secondary generalized status epilepticus with isoflurane. J Neurol Neurosurg Psychiatry 1992; 55:739-740. 128. Sharpe MD, Young GB, Mirsattari S, et al: Prolonged desflurane administration for refractory status epilepticus. Anesthesiology 2002; 97:261-264. 129. De Giorgio C, Altman K, Hamilton-Byrd E, et al: Lidocaine in refractory status epilepticus: confirmation of efficacy with continuous EEG monitoring. Epilepsia 1992; 33:913-916.

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130. Pascual J, Sedano M, Polo J, et al: Intravenous lidocaine for status epilepticus. Epilepsia 1988; 29:584-589. 131. Lodge D, Johnson KM: Noncompetitive excitatory amino acid receptor antagonists. Trends Pharmacol Sci 1990; 11:81-86. 132. DeLorenzo RJ, Waterhouse EJ, Towne AR, et al: Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998; 39:833-840. 133. Towne AR, Waterhouse EJ, Boggs JG, et al: Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000; 54:340-345. 134. Shneker B, Fountain N: Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003; 61:1066-1073. 135. Walker MC: Diagnosis and treatment of nonconvulsive status epilepticus. CNS Drugs 2001; 15:931-939.

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HEADACHE PATHOGENESIS ●

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Michael L. Oshinsky

Headache is a broad term that encompasses most of the pain syndromes that involve the head and upper neck. Headache is much more than migraine alone, and facial pain is often included in the discussion of headache. The common feature of all these pain syndromes is that they involve the regions of the body innervated by the trigeminal nerve and the upper cervical nerves, as opposed to nonheadache pain syndromes, which involve the spinal nerves. This chapter discusses the pathogenesis of headache. We discuss the tissues in the periphery and the regions of the brain that are involved in generating and maintaining headache pain, with an emphasis on the pathophysiology of migraine. This emphasis on migraine is due to the advances that have been made in animal models of headache and functional imaging studies of patients with migraine. Migraine is a primary headache disorder arising from a brain dysfunction that leads to activation of the trigeminal vascular system. This review discusses developments in the understanding of the cellular and molecular aspects of migraine. Migraine is more than a pain disorder—there are multiple stages of a migraine attack. The prodrome may begin as early as 3 days before an attack; in some patients (≈14%) this leads to a visual or sensory aura. The prodrome phase is followed by the pain phase, which, untreated, can last from 4 to 72 hours. This is followed by the resolution phase, which is characterized by alleviation of the pain and a return to normal activity. Even during this interictal phase, auditory habituation1 and threshold measurements of magnetic stimulation of the cortex2 are different in migraineurs compared with healthy subjects; the blink reflex, however, is not different.3

ANATOMY OF HEADACHE Most animal research into migraine has focused on activation of dural nociceptors using electrical current or proinflammatory chemicals. Dural blood vessels and the dura itself are innervated by sensory neurons whose cell bodies are in the trigeminal ganglion. A single neurite emerges from the cell bodies of the sensory neurons in the trigeminal ganglion. This neurite bifurcates and projects out to the periphery and into the dorsal horn of the midbrain. Because sensory neurons in the trigeminal ganglion have only one neurite, both projections are classified as axons. Normally, we associate the direction of information transmission along this neuron from the

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periphery to the central nervous system, but glutamate and neuropeptides can also be released in the periphery. This can contribute to sensory trigeminal activation, blood vessel vasodilation, and plasma protein extravasation.4 Glutamate and neuropeptides, such as calcitonin gene–related peptide, can also be released in the trigeminal ganglion itself.5-7 These sites of release are important for the strong sensory activation required for the initiation of the migraine attack and as potential targets of migraine headache treatments. Significant in headache, the large blood vessels of the meninges are mainly innervated by Aδ and C type sensory fibers, which contain glutamate as well as neuropeptides. The fifth cranial nerve arises from the trigeminal ganglion and transmits all the somatic sensory information from the head, face, and dura to the trigeminal nucleus caudalis in the central nervous system. The trigeminal nerve has three divisions: ophthalmic, mandibular, and maxillary. Anterior structures of the head and face are innervated by the ophthalmic (first) division. Posterior regions of the head and neck are innervated by the upper cervical nerves. The trigeminal nerve enters the brainstem at the pontine level of the hindbrain and terminates in the trigeminal nucleus of the brainstem. Nociceptive input from the cervical nerves also activates the neurons in the trigeminal nucleus caudalis, which extends to the C2 spinal segment.8 The trigeminal nucleus is composed of the principal trigeminal nuclei and spinal trigeminal nuclei (subdivided into three regions: the nucleus oralis, the interpolaris, and the nucleus caudalis).9 The dorsal horn of the brainstem spinal trigeminal nucleus has a laminar structure homologous to the dorsal horn of the spinal cord. The primary afferents terminate in laminae I and II and, to a lesser extent, the deeper laminae III to V. The neurons of the deeper lamina project to the thalamus in the trigeminothalamic tract, which is homologous to the spinothalamic tract. Second-order neurons from the trigeminal spinal nuclei form the trigeminothalamic tract and project to other midbrain structures, such as the periaquaductal gray, as well as to the thalamus and hypothalamus (Fig. 55–1).

HEADACHE PAIN Migraine pain is caused by trigeminal neurovascular activation.10 Neural events result in activation of nociceptive afferents and dilation of blood vessels on the dura. In patients with

chapter 55 headache pathogenesis migraine accompanied by aura, cortical spreading depression is the neural event that activated the nociceptors on the dura. Cortical spreading depression is really a spreading wave of cortical spreading excitation followed by long-lasting depression. In migraine patients without aura, the mechanism for the activation of the dural afferents is unknown. Trigeminal ganglion

Afferents

CNS

Prodrome

Before the contribution of neurogenic inflammation during the pain phase of migraine was demonstrated, the predominant theory of migraine was Harold Wolff’s vascular theory. Wolff postulated that migraine was a vascular disorder caused by a tightening (constriction) and sudden opening (dilation) of the blood vessels in the head. Research has shown that changes in blood flow are due to activation of afferents and the brain. This led to the neurogenic theory of migraine. During neurogenic inflammation, trigeminal afferent activation is accompanied by the release of vasoactive neuropeptides, including calcitonin gene–related peptide, substance P, and neurokinin A from the nerve terminals.10,15,16 These mediators produce vasodilation, sensitization of the nerve terminals, and extravasation of fluid into the perivascular space around the dural blood vessels (plasma protein extravasation) (Fig. 55–2). The nerve terminals become further excited due to a positive feedback loop. The afferents excite the blood vessels and other trigeminal nerve endings through glutamate and peptide release, and then the

Hypothalamus Thalamus

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Studies in humans and research on headache models in rats have elucidated three main components involved in headache pain: (1) the cranial blood vessels, (2) the trigeminal innervation of the vessels, and (3) the reflex connections of the trigeminal system with the cranial parasympathetic system.11 The key pathway for headache pain is trigeminovascular input from the meningeal vessels and the meninges.12 Brain imaging studies suggest that important modulation of the trigeminovascular nociceptive input stems from the dorsal raphe nucleus, the locus ceruleus, and the nucleus raphe magnus.13,14

PERIPHERAL MECHANISMS AND NOCICEPTOR ACTIVATION

Trigeminal nucleus caudalis

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Figure 55–1. Anatomy of a headache.

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Figure 55–2. Neurogenic inflammation.

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blood vessels further excite the sensitized afferent terminals. These afferents project in the central nervous system and terminate in the upper lamina of the dorsal horn. Some project to the deeper lamina.17,18 This strong sensory stimulation causes the induction of c-fos (an immediate-early gene product) in the secondary sensory neurons of the trigeminal nucleus caudalis in the brainstem.19 Substance P and calcitonin gene–related peptide further amplify the trigeminal terminal sensitivity by stimulating the release of bradykinin and other inflammatory mediators from mast cells. Prostaglandins and nitric oxide (a diffusible gas that acts as a neurotransmitter) are both endogenous neuromodulators that can sensitize nociceptors and the secondary sensory neurons in the trigeminal nucleus caudalis. There is evidence that inflammatory mediators, such as prostaglandin release in the central nervous system by microglia, may be more important than its release on the dura.20 Microglia are important modulators on sustained pain in chronic pain conditions.21 Cortical spreading depression (the mechanism of the visual aura) can also activate nociceptors of the trigeminal system through local changes in extracellular ion concentrations.22 Although the brain itself is largely insensate, pain can be generated by large cranial vessels and the dura mater, which receive nociceptor innervation. The involvement of the ophthalmic division of the trigeminal nerve and its overlap of structures innervated by branches of the C2 nerve roots explain the typical distribution of migraine pain over the frontal and temporal regions and the referral of pain to the parietal, occipital, and high cervical regions.

perceived in response to nonpainful stimuli). Peripheral sensitization is measured in minutes, up to 1 hour, whereas central sensitization is measured in hours to days. Peripheral sensitization produces an increase in pain sensitivity that is restricted to the site of inflammation—in the case of migraine, this is the dura. This results in the throbbing quality of migraine pain and its activation by movement.26 Sensitization of these neurons reduces their threshold to a level where blood vessel and cerebrospinal fluid pulsations are painful. Central sensitization is an activity-dependent increase in the excitability of neurons responsive to nociceptor inputs in the dorsal horn of the spinal cord due to nociceptor input. The increase in activity outlasts the initial afferent stimulation. Central sensitization is initiated by nociceptor afferent activation and is characterized by a reduction in activation threshold, increases in the magnitude of responsiveness, and an increase in receptive field. The prevailing theory is that most inputs received by dorsal horn neurons are subthreshold.27 The synaptic strength is too weak to evoke an action potential output. After a strong activation of nociceptive afferents in the periphery and a cascade of events associated with this activation, central sensitization is induced in the neuron of the deep lamina of the dorsal horn (laminae III to V), so that this input is now about threshold. These subthreshold inputs may be from Aδ or C fibers. The change in synaptic strength of the C fibers leads to the clinical symptom of hyperalgesia and an increase in the efficacy of Aδ fibers leads to allodynia. This has important implications for migraine treatment. Acute compounds must prevent central sensitization if they are to work early in an attack, and they have to reverse central sensitization if they are to be useful after allodynia has developed.

SENSITIZATION IN MIGRAINE Sensory sensitization is manifested in patients in two ways: hyperalgesia or allodynia. Hyperalgesia is present when lightly painful stimuli, such as a soft pinch, are perceived as very painful by the patient. Allodynia is the phenomenon wherein pain is perceived following a nonpainful stimulus. Clinicians have observed that during migraine attacks patients complain of increased pain with stimuli that would ordinarily be nonnociceptive.23 These stimuli include hair brushing, wearing a hat, showering, and resting the head on a pillow. Burstein and colleagues24 explored the development of allodynia in migraineurs. They measured pain thresholds for hot, cold, and pressure stimuli, both within the region of spontaneous pain and outside it. They found that as an attack progressed, cutaneous allodynia developed in the region of pain and then outside it at extracephalic locations in many migraine sufferers. Sensitization in migraine is important because patients with allodynia often fail to respond to triptans.25 Allodynia can be used as an outcome measure to evaluate the efficacy of migraine treatments. Sensitization of nociceptors, secondary sensory neurons in the trigeminal nucleus caudalis, or even the projection neurons in the thalamus are responsible for initiation and maintenance of the clinical symptoms of allodynia. The afferent or central neurons processing the sensory information may have an increased spontaneous discharge rate or increased responsiveness to both painful and nonpainful stimuli. The receptive fields of these neurons can expand, resulting in pain being felt over a greater part of the dermatome. This results in hyperalgesia (increased sensitivity to pain) and cutaneous allodynia (pain

PAIN MODULATION The nervous system contains networks that modulate nociceptive transmission.28 The trigeminal brainstem nuclear complex receives monoaminergic, enkephalinergic, and peptidergic projections from regions that are important in the modulation of nociceptive systems. A descending inhibitory neuronal network extends from the frontal cortex and hypothalamus through the periaquaductal gray to the rostral ventromedial medulla and the medullary and spinal dorsal horn. The rostral ventromedial medulla includes the raphe nuclei and the adjacent reticular formation and projects to the outer laminae of the spinal and medullary dorsal horn. Electrical stimulation or injection of opioids into the periaquaductal gray or rostral ventromedial medulla inhibits neuron activity in the dorsal horn. The periaquaductal gray receives projections from the insular cortex and the amygdala. These nuclei are believed to modulate the activity of the trigeminal nucleus caudalis and the dorsal horn neurons. Three classes of neurons have been identified in the rostral ventromedial medulla and periaquaductal gray. “OFF” cells pause immediately before the nociceptive reflex, whereas “ON” cells are activated.29 Neutral cells show no consistent changes in activation. Increased ON cell activity in the brainstem’s pain modulation system enhances the response to both painful and nonpainful stimuli. Headache may be caused, in part, by enhanced neuronal activity in the nucleus caudalis as a result of enhanced ON cell or decreased OFF cell activity. Other conditioned stimuli associated with pain and stress also can turn

chapter 55 headache pathogenesis on the pain system and may account, in part, for the association between pain and stress. Positron emission tomography and functional MRI in primary headaches, such as migraine and cluster headache, have demonstrated activations in the brain areas associated with pain, such as the cingulate cortex, the insulae, the frontal cortex, the thalamus, the basal ganglia, and the cerebellum. These areas are similarly activated when head pain is induced by injecting capsaicin into volunteers’ foreheads. In addition to the generic pain areas activated by the capsaicin injections, specific brainstem areas, such as the dorsal pons, are activated in episodic migraine.30

GENETICS AND MIGRAINE There is mounting evidence that migraine is a genetic disorder. For other headache disorders, such as familial hemiplegic migraine (FHM), there are very good data demonstrating inherited genes responsible for the disorder.31 Genome-wide screens have shown that there are several susceptibility loci associated with migraine, for example, on chromosomes 4q24, 6p12.2p21.1, 11q24, and 14q21.2-q22.3 and loci on 1q31 and Xq2428.32 None of these loci has been demonstrated to cause migraine as with the loci associated with familial hemiplegic migraine. Familial hemiplegic migraine is a rare autosomal dominantly inherited subtype of migraine with aura. Mutations in at least two genes result in the disorder (FMH1 [CACNA1A at 19p13] and FMH2 [ATP1A2 at 1q23]). The success in discovering several genes responsible for familial hemiplegic migraine has led to increased work on the genetic components of migraine. These studies should lead to new discoveries in this area.

SUMMARY Although clinical and basic science research has revealed many pieces of the puzzle of migraine pathophysiology, the full picture is still elusive. For example, we know that environmental and behavioral triggers, such as lack of sleep, too much sleep, fasting, and thirst, can initiate a migraine attack; however, the mechanism by which these triggers initiate the migraine is not clear.33 Many of these triggers are related to hypothalamic function. Most of the basic science research of migraine has focused on the pain phase of the disorder and has ignored the prodrome and resolution phases. In addition, although we have isolated genes that are associated with classic forms of inherited headache syndromes, such as familial hemiplegic migraine, we do not know how mutations in these genes lead to episodic headache disorders. Understanding these aspects of migraine and recognizing that it is more than just a pain disorder will be critical to fully elucidating its pathophysiology.

K E Y ●

P O I N T S

Migraine is a primary headache disorder arising from a brain dysfunction that leads to activation of the trigeminal vascular system.

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During migraine attacks, many patients complain of pain with stimuli that would ordinarily be nonnociceptive; this is called allodynia.

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The trigeminal brainstem nuclear complex receives monoaminergic, enkephalinergic, and peptidergic projections from regions that are important in the modulation of nociceptive systems.

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There is mounting evidence that migraine is a genetic disorder.

Suggested Reading Bolay H, Reuter U, Dunn AK, et al: Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8:136-142. Burstein R: Deconstructing migraine headache into peripheral and central sensitization. Pain 2001; 89:107-110. Knight Y: Brainstem modulation of caudal trigeminal nucleus: a model for understanding migraine biology and future drug targets. Headache Curr 2005; 2:108-118. Piovesan EJ, Kowacs PA, Oshinsky ML: Convergence of cervical and trigeminal sensory afferents. Curr Pain Headache Rep 2003; 7:377-383. Watkins LR, Milligan ED, Maier SF: Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol 2003; 521:1-21.

References 1. Ambrosini A, De PV, Afra J, et al: Reduced gating of middlelatency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing? Neurosci Lett 2001; 306:132-134. 2. Young WB, Oshinsky ML, Shechter AL, et al: Consecutive transcranial magnetic stimulation: phosphene thresholds in migraineurs and controls. Headache J Head Face Pain 2004; 44:131-135. 3. Kröner-Herwig B, Ruhmland M, Zintel W, et al: Are migraineurs hypersensitive? a test of the stimulus processing disorder hypothesis. Eur J Pain 2005; 9:661-671. 4. Omote K, Kawamata T, Kawamata M, et al: Activation of peripheral NMDA-nitric oxide cascade in formalin test. Anesthesiology 2000; 93:173-178. 5. Neubert JK, Maidment NT, Matsuka Y, et al: Inflammationinduced changes in primary afferent-evoked release of substance P within trigeminal ganglia in vivo. Brain Res 2000; 871:181-191. 6. Holland GR: Sympathetic-sensory axon to axon contacts in the dental pulp. Proc Finn Dent Soc 1989; 85:375-378. 7. Amir R, Devor M: Chemically mediated cross-excitation in rat dorsal root ganglia. J Neurosci 1996; 16:4733-4741. 8. Piovesan EJ, Kowacs PA, Oshinsky ML: Convergence of cervical and trigeminal sensory afferents. Curr Pain Headache Rep 2003; 7:377-383. 9. Strassman AM, Vos BP, Mineta Y, et al: Fos-like immunoreactivity in the superficial medullary dorsal horn induced by noxious and innocuous thermal stimulation of facial skin in the rat. J Neurophysiol 1993; 70:1811-1821. 10. Reuter U, Bolay H, Jansen-Olesen I, et al: Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001; 124:2490-2502.

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11. Bolay H, Reuter U, Dunn AK, et al: Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8:136-142. 12. Burstein R: Deconstructing migraine headache into peripheral and central sensitization. Pain 2001; 89:107-110. 13. Hadjikhani N, Sanchez DR, Wu O, et al: Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001; 98:4687-4692. 14. Knight Y: Brainstem modulation of caudal trigeminal nucleus: a model for understanding migraine biology and future drug targets. Headache Curr 2005; 2:108-118. 15. Goadsby PJ, MacDonald GJ: Extracranial vasodilation mediated by vasoactive intestinal polypeptide (VIP). Brain Res 1985; 329:285-288. 16. May A, Buchel C, Bahra A, et al: Intracranial vessels in trigeminal transmitted pain: a PET study. Neuroimage 1999; 9:453460. 17. Jacquin MF, Chiaia NL, Haring JH, et al: Intersubnuclear connections within the rat trigeminal brainstem complex. Somatosens Mot Res 1990; 7:399-420. 18. Hayashi H: Morphology of terminations of small and large myelinated trigeminal primary afferent fibers in the cat. J Comp Neurol 1985; 240:71-89. 19. Mitsikostas DD, Sanchez del Rio M: Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev 2001; 35:20-35. 20. Levy D, Burstein R, Strassman AM: Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 2005; 58:698-705. 21. Watkins LR, Milligan ED, Maier SF: Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol 2003; 521:1-21. 22. Wei F, Dubner R, Ren K: Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite

23.

24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation. Pain 1999; 80:127141. Burstein R, Cutrer MF, Yarnitsky D: The development of cutaneous allodynia during a migraine attack. Clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000; 123:1703-1709. Burstein R, Yarnitsky D, Goor-Aryeh I, et al: An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614-624. Burstein R, Levy D, Jakubowski M: Effects of sensitization of trigeminovascular neurons to triptan therapy during migraine. Rev Neurol (Paris) 2005; 161:658-660. Burstein R, Jakubowski M: Implications of multimechanism therapy: when to treat? Neurology 2005; 64(10 Suppl 2):S16S20. Ji RR, Kohno T, Moore KA, et al: Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003; 26:696-705. Millan MJ: Descending control of pain. Progr Neurobiol 2002; 66:355-474. Fields HL, Malick A, Burstein R: Dorsal horn projection targets of ON and OFF cells in the rostral ventromedial medulla. J Neurophysiol 1995; 74:1742-1759. Goadsby PJ: Neuroimaging in headache. Microsc Res Tech 2001; 53:179-187. Haan J, Kors EE, Vanmolkot KRJ, et al: Migraine genetics: an update. Curr Pain Headache Rep 2005; 9:213-220. Kors EE, Haan J, Van Den Maagdenberg AMJM, et al: Recent findings in headache genetics. Curr Opin Neurol 2004; 17:283288. Burstein R, Jakubowski M: Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol 2005; 493:9-14.

CHAPTER

56

MIGRAINE ●

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Stephen D. Silberstein

Migraine is a primary episodic headache disorder characterized by various combinations of neurological, gastrointestinal, and autonomic changes. The word migraine is derived from the Greek word “hemicrania” (Galen, circa 200 AD).1 Diagnosis is based on the headache’s characteristics and associated symptoms.2 The International Headache Society diagnostic criteria for headache disorders (1988)3 have been revised (2004) and describe a total of seven subtypes of migraine.4 Data in this chapter5 are from the Technical Reports of the Agency for Healthcare Policy and Research,6-9 the U.S. Headache Consortium Guidelines,10,11 and the triptan meta-analysis.12

EPIDEMIOLOGY Migraine prevalence rates are similar and stable in European countries and in the United States.13 In the United States, according to one study, 17.6% of women and 6% of men had had one migraine attack in the previous year.14 A second study 10 years later had similar prevalence estimates (Fig. 56–1).15 Migraine prevalence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%.16 After puberty, the prevalence increases more rapidly in girls than in boys. It increases until approximately age 40, then declines. The prevalence is lowest among Asian-Americans, intermediate among African-Americans, and highest among white persons.16 In the United States, migraine prevalence decreases as household income increases.14,16,17 Migraine substantially affects quality of life. The World Health Organization ranks migraine among the world’s most disabling medical illnesses.18 Approximately 28 million Americans have severe, disabling migraine headaches.15 Migraine’s annual cost to employers is approximately $13 billion, and related annual medical costs exceed $1 billion.16 Instruments to quantify migraine disability include the Migraine Disability Assessment Scale19 and the Headache Impact Test.20

PATHOPHYSIOLOGY Genetics Migraine is a group of familial disorders with a genetic component. Familial hemiplegic migraine (FHM) is an autosomal

dominant disorder characterized by attacks of migraine, with and without aura, and hemiparesis. The gene has been mapped to chromosome 19p13 in approximately two thirds of cases.21,22 The defect arises from at least 10 different missense mutations in the CACNA1A gene, which codes for the α1 subunit of a voltage-dependent P/Q Ca2+ channel.23 The same gene is associated with episodic ataxia with cerebellar vermix atrophy.21 Ptype neuronal Ca2+ channels mediate 5-hydroxytriptamine (5-HT) and excitatory neurotransmitter release. Dysfunction may impair 5-HT release and predispose patients to migraine attacks or impair their self-aborting mechanism. Voltage-gated P/Q-type calcium channels mediate glutamate release, are involved in cortical spreading depression (CSD), and may be integral in initiating the migraine aura (Fig. 56–2).24 A second gene has been mapped to chromosome 1q21-23. The defect is due to a mutation in the α2 subunit of the Na/K pump.25

Aura The migraine aura was believed to be caused by cerebral vasoconstriction and the headache by reactive vasodilation.26 This explained the headache’s throbbing quality and its relief by ergots. It is now believed that the migraine aura is caused by neuronal dysfunction, not ischemia; ischemia rarely, if ever, occurs. Headache often begins while cortical blood flow (CBF) is reduced27-29; thus, headache is not caused by simple reflex vasodilation.30,31 The migrainous fortification spectrum corresponds to an event moving across the cortex at 2 to 3 mm/minute.32 Noxious stimulation of the rodent cerebral cortex produced a spreading decrease in electrical activity that moved at 2 to 3 mm/minute (CSD).33 CSD is characterized by shifts in cortical steady-state potential; transient increases in potassium, nitric oxide, and glutamate levels; and transient increases in CBF, followed by sustained decreases.27 The aura is associated with an initial hyperemic phase followed by reduced CBF, which moves across the cortex (spreading oligemia).34 Olesen and colleagues34,35 found 17% to 35% reductions in posterior CBF, which spread anteriorly at 2 to 3 mm/minute. It crossed brain areas supplied by separate vessels and is thus not caused by segmental vasoconstriction.35 Reduced CBF persisted from 30 minutes to 6 hours, and then CBF slowly returned to baseline or even increased. The rates of

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Migraine prevalence (%)

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migraine by sex. (From Lipton RB, Stewart WF, Diamond S, et al: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646-657.)

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Figure 56–1. Adjusted age-specific prevalence of

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Figure 56–2. Cortical spreading depression (CSD). The relationship between CSD and headache in migraine with aura. CSD releases H+, K+, and other agents, including arachidonic acid (AA) and nitric oxide (NO), in the extracellular space of the neocortex. These agents diffuse toward local blood vessels and depolarize perivascular trigeminal terminals, which, in turn, causes activation of the caudal portion of the trigeminal nucleus (TGN) in the brainstem. At the same time, collateral axons of activated neurons in the trigeminal ganglion (TGG) release proinflammatory peptides in the meninges and their vessels, which leads to a local inflammatory reaction. The activation from the superior salivatory nucleus (SSN) and reaching meningeal blood vessels via the sphenopalatine ganglion (SPG). The perception of pain is mediated by higher order projections from the TGN. The dashed lines between TGN, SSN, and regions generating the pain indicate that these connections either are unknown or have not been depicted.

progression of spreading oligemia are similar to those of migrainous scotoma and CSD, which suggests that they are related.31,33,36 Additional studies28,29,37-40 support the hypothesis that CSD produces the aura.27 During visual auras, CBF decreased 15% to 53%, cerebral blood volume decreased 6% to 33%, and mean transit time increased 10% to 54% in the occipital cortex contralateral to where the aura was experienced. The perfusion defect moved anteriorly.29 The absence of diffusion abnormalities suggests that ischemia does not occur during the aura.41 Blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (MRI) reflects the relative concentration of deoxyhemoglobin in venous blood. Visual stimulation was used to trigger headache in migraineurs.37 A wave of increased BOLD signal (reflecting hyperoxygenated blood) and then decreased BOLD signal (possibly reflecting neuronal metabolic flow coupling) propagated into the contiguous occipital cortex at 3 to 6 mm/minute. When visual stimulation was used to test the visual cortex response, the BOLD signal and the BOLD response to visual activation diminished after progression of the visual aura.30 Magnetoencephalography demonstrates changes that are consistent with CSD in migraineurs but not in controls.42,43 Using transcranial magnetic stimulation (which applies magnetic fields of increasing intensity) to evaluate occipital cortex excitability, Aurora and associates44 and Young and coworkers,45 but not Afra and colleagues,46 found that phosphenes were generated in migraineurs at lower thresholds than in controls and that it was easier to visually trigger headaches in subjects with lower thresholds. Other evidence of increased central nervous system (CNS) excitability comes from studies of visual and brainstem auditory evoked potentials.47 Migraine with aura may be caused by neuronal hyperexcitability, which perhaps arises from cortical disinhibition.

Headache Headache probably results from the activation of meningeal and blood vessel nociceptors in combination with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Reflex connections to the cranial parasympathetic nerves form the trigeminoautonomic reflex. Activation results in vasoactive intestinal polypeptide release and vasodilation.31

chapter 56 Migraine Trigeminal sensory neurons contain substance P, calcitonin gene–related peptide (CGRP), and neurokinin A.48 Stimulation results in release of substance P and CGRP from sensory C-fiber terminals49 and neurogenic inflammation.50 The neuropeptides interact with the blood vessel wall, producing dilation, plasma protein extravasation, and platelet activation.51 One study suggests that neurogenic inflammation occurs in humans.52 Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization) that then respond to previously innocuous stimuli, such as blood vessel pulsations,53 causing, in part, the pain of migraine.54 Central sensitization can also occur. After meningeal irritation, expression of c-fos (a marker for neuronal activation) occurs in the trigeminal nucleus caudalis55 and in the dorsal horn at the C1 and C2 levels.56,57 Superior sagittal sinus stimulation results in release of CGRP but not substance P.58 This is important: Levels of CGRP, not substance P, is elevated in external jugular venous blood during migraine.59 Sumatriptan reduced elevated CGRP levels in a migraine attack and in experimental animals during trigeminal ganglion stimulation.60,61 CGRP may play a role in migraine headache.62,63 A potent specific CGRP antagonist64 has been reported to be effective in acute migraine treatment.65 Applying an “inflammatory soup” to the dura sensitizes second-order trigeminovascular neurons (increased spontaneous activity and response to mechanical and thermal skin stimulation).53 Triptans administered early prevented central sensitization: Dural and facial receptive fields did not expand; spontaneous activity, mechanical sensitivity, and thermal sensitivity did not increase. Late triptan intervention did not reverse central sensitization but shrank the expanded dural receptive fields and normalized intracranial mechanosensitivity. Central sensitization may play a key role in maintaining the headache.66,67 Affected patients often develop cutaneous allodynia (nonpainful stimuli are experienced as painful) during migraine attacks because of trigeminal sensitization.66 Triptans can prevent but not reverse cutaneous allodynia.67 Cutaneous allodynia can be used to predict triptans’ effectiveness.66 In the absence of allodynia, triptans completely relieved the headache and blocked the development of allodynia. In 90% of attacks with established allodynia, triptans provided little or no headache relief and did not suppress allodynia. However, late triptan therapy eliminated peripheral sensitization (throbbing pain aggravated by movement), even when pain relief was incomplete and allodynia was not suppressed.66 Early intervention may work by preventing cutaneous allodynia and central sensitization. Brainstem activation occurs in migraine without aura. On positron emission tomography, patients with right-sided migraine headache showed increased regional CBF in the left brainstem. 68 Sumatriptan relieved the headache and associated symptoms but did not normalize brainstem regional CBF. This suggests that activation is caused by factors other than, or in addition to, increased activity of the endogenous antinociceptive system. A second report corroborated these findings.69 A link exists between the migraine aura and headache. CSD activates trigeminovascular afferents, causing a long-lasting increase in middle meningeal artery blood flow and plasma protein extravasation within the dura mater.70 CSD results in upregulation of inducible nitric oxide synthetase and inflammatory cytokines. This mechanism couples meningeal blood flow and neurogenic inflammation to CSD but does not explain headache ipsilateral to the aura.31,70

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Serotonin (5-HT) Receptors and Migraine Treatment There are seven classes of 5-HT receptors: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.71 In humans, there are five 5HT1 receptor subtypes: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5HT1F.72 The 5-HT1B receptor is located on intracranial blood vessels and CNS neurons. The 5-HT1D receptor is located on CNS neurons and trigeminal nerve endings. The 5-HT1F receptors are located on trigeminal nerve endings.73 Ergots and triptans act at the 5-HT1B, 5-HT1D, and, in part, 5-HT1F receptors. They constrict extracerebral intracranial vessels, inhibit trigeminal neurons, and block transmission in the trigeminal nucleus. They minimally constrict human coronary arteries. They block plasma protein extravasation50 by activating prejunctional trigeminal 5-HT1D and 5-HT1F heteroreceptors, blocking neuropeptide release. Plasma protein extravasation can be also be blocked by nonsteroidal anti-inflammatory drugs (NSAIDs),74 γ-aminobutyric acid (GABA) agonists,75,76 neurosteroids,77 substance P antagonists,78 and the endothelin antagonist bosentan.79 Dihydroergotamine and the centrally penetrant triptans label the nuclei in the brainstem and spinal cord that are involved in pain transmission and modulation.80 The caudal trigeminal nucleus is activated by stimulation of the sagittal sinus, and this activity is transmitted to the thalamus. Ergots and triptans suppress this activation.

Conclusion The migraine aura is probably caused by CSD. Headache probably results from activation of meningeal and blood vessel nociceptors in combination with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Stimulation results in the release of substance P and CGRP from sensory Cfiber terminals and neurogenic inflammation.51 Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization), which then respond to previously innocuous stimuli, such as blood vessel pulsations, causing, in part, the pain of migraine. Central sensitization of trigeminal nucleus caudalis neurons can also occur. Central sensitization may play a key role in maintaining the headache. Brainstem activation also occurs in migraine without aura, partly as a result of increased activity of the endogenous antinociceptive system. The migraine aura can trigger headache; CSD activates trigeminovascular afferent vessels. Stress can also activate meningeal plasma cells via a parasympathetic mechanism, leading to nociceptor activation.81 Migraine may be a result of a change in processing of pain and sensory input. The aura is triggered in the hypersensitive cortex (as a result of CSD). Headache is generated by central pain facilitation and neurogenic inflammation. Central sensitization, mediated in part by supraspinal facilitation, can occur. Decreased antinociceptive system activity and increased peripheral input may be present.

DESCRIPTION OF THE MIGRAINE ATTACK The migraine attack can consist of premonitory, aura, headache, and resolution phases. Premonitory symptoms occur in 20% to 60% of migraineurs, hours to days before headache onset. They may include psychological, neurological,

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constitutional, or autonomic features, such as depression, cognitive dysfunction, and bouts of food cravings.82 Migraineurs who reported having premonitory symptoms were able to accurately predict 72% of their full-blown headaches. The most common premonitory symptoms were feeling tired/weary (72%), difficulty concentrating (51%), and stiff neck (50%). Poor functioning was commonly predictive of headache.83

Aura The migraine aura consists of focal neurological symptoms that precede, accompany, or (rarely) follow an attack. Aura usually develops over 5 to 20 minutes; lasts less than 60 minutes; can be visual, sensory, or motor; and may involve language or brainstem disturbances.3 Headache usually follows within 60 minutes of the end of the aura. Patients can have multiple aura types; most patients with a sensory aura also have a visual aura.84 Auras vary in complexity. Simple auras include scotomata, simple flashes (phosphenes), specks, geometrical forms, and shimmering in the visual field. More complicated visual auras include teichopsia or fortification spectra (the characteristic aura of migraine), metamorphopsia, micropsia, macropsia, zoom vision, and mosaic vision. Paresthesias are often cheiroaural: Numbness starts in the hand, migrates up the arm, and jumps to involve the face, lips, and tongue.2,85 Weakness is rare, occurs in association with sensory symptoms, and is unilateral.86 Apraxia, aphasia, agnosia, states of altered consciousness associated with déjà vu or jamais vu, and elaborate dreamy, nightmarish, trancelike, or delirious states can occur.82

Headache Phase The median migraine attack frequency is 1.5 per month.14 The typical headache is unilateral, of gradual onset, throbbing (85%),87 moderate to marked in severity, and aggravated by movement.3 Pain may be bilateral (40%) or may start on one side and become generalized. It lasts 4 to 72 hours in adults and 2 to 48 hours in children.3 During the headache, anorexia is common. Nausea occurs in almost 90% of patients, and vomiting occurs in about one third.88 Sensory hypersensitivity results in patients’ seeking a dark, quiet room.2,88 Blurry vision, nasal stuffiness, hunger, tenesmus, diarrhea, abdominal cramps, polyuria, facial pallor, sensations of heat or cold, and sweating may occur. Depression, fatigue, anxiety, nervousness, irritability, and impairment of concentration are common. Symptom complexes may be generated by linked neuronal modules.89

Resolution Phase After the headache, many patients feel tired, “washed out,” irritable, and listless and may have impaired concentration, scalp tenderness, or mood changes. Some patients feel unusually refreshed or euphoric after an attack; others experience depression and malaise.

FORMAL DIAGNOSTIC CRITERIA The International Headache Society subdivides the disorder into migraine with aura and migraine without aura.4,90 To

diagnose migraine without aura (Table 56–1), five attacks must have occurred. No single feature is mandatory, but recurrent episodic attacks must be documented.3 Migraine persisting for more than 3 days defines “status migrainosus.”3,4 Migraine with aura is subdivided into migraine with typical aura, migraine with prolonged aura, hemiplegic migraine, basilar-type migraine, and migraine with acute-onset aura (Table 56–2.) The International Headache Society classification now allows the association of aura with other headache types. Prolonged aura lasts from 1 hour to 1 week; persistent aura lasts for more than 1 week (but resolves). If neuroimaging demonstrates a stroke, a migrainous infarction has occurred. Periodic neurological dysfunction (scintillating scotomata and recurrent sensory, motor, and mental phenomena) can occur without headache.91 Visual phenomena, which are usually benign, occurred in 1.33% of women and in 1.08% of men in a general population sample.92 Scintillating scotomata, numbness, aphasia, dysarthria, and motor weakness may occur for the first time after age 45 and be confused with transient ischemic attacks of cerebrovascular origin.93 In general, migrainous symptoms are slower to develop (>5 minutes) and consist of positive and negative phenomena.

T A B L E 56–1. Migraine without Aura: Diagnostic Criteria At least five attacks Headache attack lasts 4 to 72 hours (untreated or unsuccessfully treated) Headache has at least two of the following characteristics: Unilateral location Pulsating quality Moderate or severe intensity Aggravation by routine physical activity (e.g., walking or climbing stairs) During headache at least one of the following: Nausea and/or vomiting Photophobia and phonophobia Not attributed to another disorder

T A B L E 56–2. Migraine with Aura (Classic Migraine): Diagnostic Criteria At least two attacks Migraine aura fulfills criteria for typical aura, hemiplegic aura, or basilar-type aura Not attributed to another disorder Typical aura: Fully reversible visual and/or sensory and/or speech symptoms but no motor weakness Homonymous or bilateral visual symptoms, including positive features (e.g., flickering lights, spots, lines) or negative features (e.g., loss of vision), and/or unilateral sensory symptoms, including positive features (e.g., visual loss, pins and needles) and/or negative features (e.g., numbness) At least one of the following At least one symptom develops gradually over ≥5min and/or different symptoms occur in succession Each symptom lasts ≥5 minutes and ≤60 minutes Headache that meets criteria for migraine without aura begins during the aura or follows aura within 60 minutes

chapter 56 Migraine MIGRAINE VARIANTS Basilar-type migraine aura has brainstem symptoms: ataxia, vertigo, tinnitus, diplopia, nausea and vomiting, nystagmus, dysarthria, bilateral paresthesia, and a change in the level of consciousness and cognition.3 The diagnosis should be considered when patients have paroxysmal brainstem disturbances. Some authorities have suggested that hemiplegic migraine should be diagnosed if weakness is present.86 Ophthalmoplegic migraine results from an idiopathic inflammatory neuritis.94 There is enhancement of the cisternal segment of the oculomotor nerve, followed by resolution over several weeks as symptoms resolve. Hemiplegic migraine can be sporadic or familial.2 Attacks are frequently precipitated by minor head injury.86 FHM is an autosomal dominant, genetically heterogeneous disorder with variable penetration. FHM includes attacks of migraine without aura, migraine with typical aura, and episodes of prolonged aura, fever, meningismus, and impaired consciousness.23 Headache may precede the hemiparesis or be absent. Hemiparesis onset may be abrupt and simulate the effects of a stroke. In 20% of unselected families whose members have FHM, patients have cerebellar symptoms and signs (nystagmus, progressive ataxia). All have mutations within CACNA1A.22 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain caused by a Notch3 gene mutation on chromosome 19.95,96 CADASIL mutations are highly stereotyped missense mutations within epidermal growth factor–like repeats in the extracellular domain of Notch3. Mutations lead to loss or gain of a cysteine, thereby creating an odd number of cysteines within a given epidermal growth factor domain.97 Notch3 expression is restricted to smooth muscle cells, and normal proteolysis of the Notch3 receptor generates a 210-kD extracellular fragment and a 97-kD intracellular fragment. Patients with CADASIL accumulate excess Notch3 ectodomain (i.e., the 210-kD fragment) within the cerebral vasculature, apparently because of impaired clearance of the receptor from the surface of vascular smooth muscle cells and pericytes. Most cases are inherited in an autosomal dominant manner, but a de novo symptomatic mutation, Arg182Cys, has been reported.98 Symptoms include recurrent subcortical lacunar infarctions (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%).99 MRI scans of at-risk individuals are often abnormal, with extensive areas of increased white matter T2 signals. The arteriopathy involves the media of small cerebral arteries and, to a lesser extent, extracerebral arteries, including skin arterioles. In skin biopsy, abnormal patches of agranular osmiophilic material within the basal membranes of vascular smooth muscle cells are diagnostic.97 A commercial genetic test is available for the most common CADASIL mutations. It currently has a false-negative rate of at least 20% because it screens only mutational hot spots located in exons 3, 4, 11, and 18. Scanning all 23 exons that encode all 34 epidermal growth factor–like repeat sequences is considered the most accurate test for CADASIL, but it is time-consuming and costly.

TREATMENT Migraine varies widely in its frequency, severity, and impact on the patient’s quality of life. A treatment plan should account

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not only for the patient’s diagnosis, symptoms, and any coexistent or comorbid conditions but also for the patient’s expectations, needs, and goals.100,101 Migraine treatment begins with making a diagnosis,2 explaining it to the patient, and developing a treatment plan that considers coincidental or comorbid conditions.101 Headache calendars record headache duration, severity, and treatment response. Comorbidity indicates an association between two disorders that is more than coincidental. Conditions that occur in migraineurs with a higher prevalence than would be expected include stroke, epilepsy, Raynaud’s disease, and affective disorders, which include depression, mania, anxiety, and panic disorder. Possibly associated disorders include essential tremor, mitral valve prolapse, and irritable bowel syndrome. The pharmacological treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Acute treatment is an attempt to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used a maximum of 2 to 3 days a week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability.

Pharmacotherapy for the Acute Migraine Headache Acute treatment can be specific (ergots and triptans), or nonspecific (analgesics and opioids) (Table 56–3). Nonspecific medications control the pain of migraine or other pain disorders, whereas specific medications are effective in migraine (and certain other) headache attacks but are not useful for nonheadache pain disorders. Triptans are effective in the range of mild, moderate, and severe migraine attacks.102 Treatment choice depends on attack severity, frequency, associated symptoms, coexistent disorders, prior treatment response, and the medication’s efficacy, its potential for overuse, and adverse events. A nonoral route of administration and an antiemetic should be considered for severe nausea or vomiting.11 Injections provide rapid relief. Headaches can be stratified by severity and disability (on the Migraine Disability Assessment Scale or Headache Impact Test). Analgesics are used for mild to moderate headaches.11 Triptans and dihydroergotamine are first-line drugs for severe attacks and for less severe attacks that do not adequately respond to analgesics.11 Patients with moderate or severe headaches with moderate or severe disability (according to the Migraine Disability Assessment Scale score) who were given a triptan did better than patients given aspirin and metoclopramide.103 Early intervention prevents escalation and may increase efficacy.104 Triptans can prevent the development of cutaneous allodynia, and cutaneous allodynia is predictive of triptans’ effectiveness.66 Before the clinician decides that a drug is ineffective, at least two attacks should be treated. It may be necessary to change the dose, formulation, or route of administration or add an adjuvant. When the response is inadequate, the headache recurs, or adverse events are bothersome, a medication change may be needed. Limiting acute treatment to 2 to

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T A B L E 56–3. Acute Medications: Efficacy, Adverse Events, Relative Contraindications, and Indications Comorbid Condition

3 days a week can prevent medication-overuse headache. When headaches are very frequent, early intervention may not be appropriate. All treatment occasionally fails; therefore, rescue medications (opioids, neuroleptics, and corticosteroids) are needed. They provide relief but often limit function by causing sedation or other adverse events.

Drug

Relative Contraindication

Relative Indication

Acetaminophen (Paracetamol) Aspirin

Liver disease

Pregnancy

Kidney disease Ulcer disease PUD Gastritis (age <15) Kidney disease PUD Gastritis Use of other sedative History of medication overuse Sensitivity to caffeine Uncontrolled HTN, CAD, PVD Drug or substance abuse Parkinson’s disease Prolonged QTc

CAD Transient ischemic attack

Nonspecific Medication

Arthritis

Analgesics and Nonsteroidal Anti-inflammatory Drugs

NSAIDs Butalbital, caffeine, and analgesics Caffeine adjuvant Isometheptene Opioids Neuroleptics

Dihydroergotamine Injections Intranasal instillation Ergotamine Tablets Suppositories

Triptans Almotriptan (tablets) Eletriptan (tablets) Frovatriptan (tablets) Naratriptan (tablets) Rizatriptan (tablets) Zolmitriptan (tablets, intranasal) Sumatriptan (subcutaneous injection, intranasal instillation, tablets)

— — — Pregnancy Rescue medication Nausea Vomiting Pregnancy Rescue medication

CAD PVD Uncontrolled HTN

Orthostatic hypotension Prominent nausea or vomiting

Prominent nausea or vomiting CAD PVD Uncontrolled HTN

—

CAD PVD Uncontrolled HTN CAD PVD Uncontrolled HTN CAD PVD Uncontrolled HTN CAD PVD Uncontrolled HTN CAD PVD Uncontrolled HTN CAD PVD Uncontrolled HTN CAD PVD Uncontrolled HTN

—

Aspirin; ibuprofen; tolfenamic acid; naproxen sodium; acetaminophen; and acetaminophen, aspirin, and caffeine (Excedrin) combination are effective in acute migraine treatment.11,105,106

Barbiturate Hypnotics No randomized, placebo-controlled studies have established the efficacy of butalbital-containing agents.107 They are used in the United States but have been withdrawn from the market in many European countries. Because of the potential for medication-overuse headache and withdrawal, their use should be limited and carefully monitored.

Opioids Opioids are effective.2,11 However, because of the risk of medication overuse, they should be limited (<2 days a week) to patients who have severe, relatively infrequent headaches.108 They are used in the United States for patients who do not respond to simple analgesics (or cannot take ergots or a triptan) and as a rescue medication. They are often prescribed for pregnant women in the absence of controlled data.109

—

Neuroleptics and Antiemetics — — —

Prochlorperazine is relatively safe and effective for the treatment of migraine and associated nausea and vomiting.7,9,11,110,111 Droperidol, a parenteral neuroleptic, was effective in one placebo-controlled, double-blind trial, at a dose of 2.75 mg intramuscularly. Sedation, akathisia, and other extrapyramidal reactions can be treated with diphenhydramine or benzotropine.112

Prominent nausea or vomiting —

CAD, coronary artery disease; HTN, hypertension; NSAID, nonsteroidal antiinflammatory drug; PUD, peptic ulcer disease; PVD, peripheral vascular disease; QTc, corrected QT interval.

Specific Medication Ergots and triptans are potent 5-HT1B, 5-HT1D, and, in some cases, 5-HT1F receptor agonists. Ergots have much greater receptor affinity at 5-HT1A, 5-HT2, adrenergic, and dopaminergic receptors than do triptans, and thus lead to more adverse events. All are indicated for acute migraine treatment. If the initial (appropriate) dose is not effective, it is unlikely that subsequent doses will be effective during the same attack, and rescue medications should be used. Contraindications include documented or suspected ischemic heart disease, Prinzmetal’s angina, uncontrolled hypertension, basilar or hemiplegic migraine, and pregnancy. Patients with sepsis, renal or hepatic failure, and cerebral or peripheral vascular disease should avoid ergots. There is little consensus as to how many risk factors

chapter 56 Migraine preclude triptan use and what constitutes an appropriate evaluation.113

Selective 5-HT1 Agonists (Triptans) Sumatriptan was the first triptan to be introduced. It was followed by zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan, all of which are more centrally penetrant than is sumatriptan. Eletriptan’s central penetrance is limited, inasmuch as it is a substrate for the P-glycoprotein pump114: P-glycoprotein pump inhibitors allow higher central penetrance. Data for all formulations of triptans are given in Table 56–4.11,12 All are effective, even if given after the onset of migraine, and may be more effective when pain is mild.115 They relieve head pain and nausea and vomiting. Efficacy is measured by 2-hour response rates and therapeutic gain (the difference between active drug and placebo; see Table 56–4). The drug is used to compensate for differences in placebo rates in different trials. Other measures include 2-hour pain-free rates and recurrence rates. Common adverse events include pain, tingling, flushing, and burning sensation at the subcutaneous injection site; warm or hot sensations; dizziness; paresthesias; somnolence; fatigue; sensation of heaviness; neck pain; and dysphoria.116,117 In the text, mainly nonoral formulations are discussed. Sumatriptan is available in 6-mg subcutaneous injection; 20-mg nasal spray; 25-, 50-, or 100-mg tablets; and 25-mg suppository.12,118 Subcutaneous sumatriptan has a rapid onset of action, reaching peak plasma concentrations within 12 minutes. The time of maximal concentration (Tmax) for oral sumatriptan is 2 hours. Bioavailability is 97% for subcutaneous

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injection, 19.2% for suppository, 15.8% for intranasal instillation, and 14.3% for tablet.116 The terminal elimination half-life is 2 hours. Sumatriptan is metabolized principally by the monoamine oxidase (MAO)-A; therefore, the oral, nasal, and suppository formulations are contraindicated in patients using MAO inhibitors. Subcutaneous sumatriptan (6 mg) produces a 1-hour response rate of 69%, with a therapeutic gain in 50%.119 The 1hour pain-free rate was 48% to 49%.120 Intranasal sumatriptan (20 mg) produced a 2-hour response rate of 61%, with a therapeutic gain in 31%.119,121 The 2-hour efficacy for the 25-mg sumatriptan suppository ranges from 64 to 72 (five studies).9 The pain-free rate ranged from 34% to 50%. In a comparative study, a combination (ergotamine, 2 mg, and caffeine, 100 mg) suppository was more effective than sumatriptan (73% versus 63%) but produced more adverse events.117 In Ferrari and associates’ meta-analysis of oral triptans, 100-mg sumatriptan was used as the standard.12 Zolmitriptan is available in 2.5- and 5-mg regular and orally disintegrating tablets and a 5-mg nasal spray. Zolmitriptan has a 40% oral bioavailability, has a Tmax of about 2.5 hours, and is metabolized by the cytochrome P-450 system to an active metabolite that is degraded by MAO-A. Patients taking MAO inhibitors are limited to a total dose of 5 mg/day. The nasal spray is absorbed in the nasopharynx; detectable blood levels appear within 5 minutes, and 40% of maximal concentration is achieved within 10 to 15 minutes.122,123 First-attack 2-hour headache response rates for 5 mg nasal spray are 69%, with a therapeutic gain in 38%.122-124 Naratriptan is available in 1- and 2.5-mg oral tablets. The recommended dose is 2.5 mg. Bioavailability is 60% to 70%, Tmax is 2 hours (outside an attack), and the terminal

T A B L E 56–4. Triptans

Drug* Almotriptan Eletriptan 40 mg 80 mg Frovatriptan (2.5 mg) Naratriptan 24% (21%-27%)‡ Rizatriptan 5 mg 10 mg Zolmitriptan 2.5 mg 5 mg 5 mg IN Sumatriptan 50 mg 100 mg 20 mg (IN) 6 mg (SC)§

Headache Response (2 Hours)

Therapeutic Gain (2 Hours)

Pain-Free Frequency (2 Hours)

Pain-Free Therapeutic Gain (2 Hours)

Recurrence Rate

61% (57%-65%)

25% (14%-36%)

36% (32%-40%)

21% (17%-25%)

26% (22%-30%)†

60% (58%-64%) 66% (62%-70%) 42% (40%-44%) 49% (46%-92%)

35% (27%-41%) 42% (36%-48%) 17% (27%-44%) 22% (17%-27%)

27% (25%-29%) 33% (28%-38%) — 22% (20%-24%)

22% (18%-26%) 28% (23%-33%) — 14% (11%-17%)

21% (18%-24%)† 20% (12%-28%)† — 21% (13%-28%)†

62% (60%-64%) 69% (67%-71%)

28% (23%-33%) 35% (30%-40%)

30% (28%-32%) 40% (38%-42%)

22% (20%-24%) 30% (27%-33%)

39% (36%-42%)† 37% (35%-39%)†

64% (59%-69%) 66% (62%-70%) 69% (62%-75%)

34% (27%-41%) 37% (30%-44%) 38% (30%-47%)

25% (21%-29%) 34% (30%-38%) 36% (29%-42%)

19% (14%-24%) 28% (23%-33%) 29% (22%-36%)

30% (26%-34%)† 34% (25%-43%)† 27% (20%-34%)†

63% (60%-64%) 59% (57%-61%) 61% (55%-78%) 69% (70%-88%) —

31% (24%-38%) 29% (25%-33%) 31% (28%-43%) 50% (38%-77%) —

28% (26%-30%) 29% (27%-31%) 27%-37% 48%-49% —

18% (12%-24%) 20% (18%-22%) 11%-28%

28% (29%-31%)† 30% (27%-33%)† —

43%-46%

—

Adapted from Ferrari et al,12 Tfelt-Hansen,119 Physicians’ Desk Reference,120 and Dahlöf.121 *All oral except as noted (IN, intranasal; SC, subcutaneous). † 2-24 hours. ‡ 4-24 hours. § Responses and gains reported for 1 hour, not 2.

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elimination half-life is 5 hours. Naratriptan is excreted largely as unchanged drug in the urine.125 Rizatriptan is available in 5- and 10-mg oral tablets and rapidly dissolving wafers. The recommended dose is 10 mg except for patients taking propranolol, which increases rizatriptan’s plasma concentration; for such patients, the recommended dose is 5 mg. The Tmax is 1 hour, bioavailability is 40% to 45%, and the plasma half-life is 2 to 3 hours. Rizatriptan is metabolized principally by MAO-A, metabolites being excreted in the urine. It should not be used by patients taking MAO inhibitors. Almotriptan is available in 6.25- and 12.5-mg oral tablets. The recommended dose is 12.5 mg, with a two-dose limit in a 24-hour period. Bioavailability is 70%, the Tmax is 1 to 3 hours, and mean half-life 3-4 hours. It is partially metabolized in the liver (MAO, 27%; cytochrome P-450 [3A4 and 2D6], 12%) to inactive metabolites. Almotriptan has no significant interaction with propranolol, selective serotonin reuptake inhibitors, or MAO inhibitors. Frovatriptan is available in 2.5-mg tablets. The daily limit is three tablets. Frovatriptan has a bioavailability of 22% in men and 30% in women. The Tmax is 2 to 3 hours. It is metabolized by P4540 (CYP-1A2) and excreted in the urine.126 The mean half-life is 26 hours. Eletriptan is available in 40- and 80-mg oral tablets. It has a 50% bioavailability and a half-life of 5 hours and is rapidly absorbed.127 Eletriptan interacts with drugs that are metabolized by cytochrome P-450 (including CYP-3A4). Adverse events are more common with 80-mg eletriptan than with other triptans. These seven triptans are safe (for patients without cardiovascular risk factors), effective, and appropriate first-line therapy for patients who have a moderate to severe migraine headache or for whom analgesics have failed to provide adequate relief. Although they are safe, no evidence supports their effectiveness during the aura phase of a migraine attack.128 Headache severity, rapidity of onset, and duration are important factors for deciding which triptan should be used. When the headache intensifies rapidly (<30 minutes), or when nausea and emesis are early and there are severe associated symptoms, nonoral administration is appropriate. Subcutaneous sumatriptan is the fastest and most effective. Sumatriptan or zolmitriptan nasal spray may provide a faster onset of action than do oral triptans, but sumatriptan nasal spray often has a disagreeable taste. The oral formulations can be divided into two classes. Almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan have the highest 2-hour efficacy, can provide headache relief within 30 to 60 minutes, and would be the first choice when patients require efficacy and speed of onset and do not have multiple recurrences. The meta-analysis suggests that almotriptan, eletriptan, and rizatriptan are most effective.12 Frovatriptan and naratriptan have lower 2-hour efficacy but produce fewer adverse events (as does almotriptan). Whether headache recurs less often with these drugs is controversial. Almotriptan, frovatriptan, and naratriptan are choices for patients who are prone to adverse events.129 All triptans have the same contraindications and safety concerns. None is safer than another; however, the response to triptans is often idiosyncratic. One triptan may work for one patient and cause no adverse events, and a different triptan may work for another patient. The triptan of choice is the one that

restores the patient’s ability to function by swiftly and consistently relieving pain and associated symptoms with minimal adverse events and without recurrence of symptoms.

Ergotamine and Dihydroergotamine The evidence supporting ergotamine’s efficacy is inconsistent.130 Some patients respond preferentially to rectal ergotamine.131 Dihydroergotamine can be administered intramuscularly, subcutaneously, or intravenously. The headache recurrence rate may be low (<20%), there are fewer adverse events, and it may be less likely than ergotamine to produce rebound headache.130 Limited efficacy evidence exists for dihydroergotamine nasal spray. No placebo-controlled trials have demonstrated the efficacy and safety of dihydroergotamine subcutaneously, intramuscularly, or intravenously as monotherapy. Repetitive intravenous dihydroergotamine is commonly used in North America to treat intractable headache.130,132

Corticosteroids Open-label studies have suggested that corticosteroids are effective. Hydrocortisone, methylprednisolone, and dexamethasone have been used.2

PREVENTIVE TREATMENT Preventive therapy is given in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability. Preventive treatment may prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions. Silberstein and colleagues retrospectively analyzed resource utilization information in a large claims database. The addition of migraine preventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. During the second 6 months after the initial preventive medication, as compared with the 6 months preceding preventive therapy, office and other outpatient visits with a migraine diagnosis decreased by 51.1%, emergency department visits with a migraine diagnosis decreased 81.8%, computed tomographic scans with a migraine diagnosis decreased 75.0%, MRI scans with a migraine diagnosis decreased 88.2%, and other migraine medication dispensations decreased 14.1%.133 Preventive medications reduce attack frequency, duration, or severity.2,134 According to the U.S. Headache Consortium Guidelines,10 indications for preventive treatment include the following: ■ Migraine that significantly interferes with the patient’s daily

routine despite acute treatment ■ Failure of, contraindication to, or troublesome adverse

events from acute medications ■ Acute medication overuse ■ Very frequent headaches (>2/week) (risk of medication

overuse) ■ Patient preference ■ Special circumstances, such as hemiplegic migraine or

attacks with a risk of permanent neurological injury Preventive measures are not used to nearly the extent they should be. In the American Migraine Study II, 25% of all people

chapter 56 Migraine with migraine, or more than 7 million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest.17 However, only 5% of all migraineurs currently use preventive therapy to control their attacks.135 Preventive medication groups include β-adrenergic blockers, antidepressants, calcium channel antagonists, serotonin antagonists, anticonvulsants, and NSAIDs. Choice is based on efficacy, adverse events, and coexistent and comorbid conditions (Table 56–5). It is started at a low dose and increased slowly until therapeutic effects develop or the ceiling dose is reached. A full therapeutic trial may take 2 to 6 months. Acute headache medications should not be overused. If headaches are well controlled, medication can be tapered and discontinued. Dose reduction may provide a better risk/benefit

T A B L E 56–5. Choices of Preventive Treatment in Migraine: Influence of Comorbid Conditions Comorbid Condition Drug

Relative Contraindication

Relative Indication

b Blockers

Asthma, depression CHF Raynaud’s disease Diabetes

HTN Angina

Antiserotonin Agents Pizotifen Obesity Methysergide Angina PVD Calcium-Channel Blockers Verapamil Constipation Hypotension Flunarizine Antidepressants TCAs

Parkinson’s disease

Mania Urinary retention Heart block

SSRIs

Mania

MAOIs

Unreliability of patient

Anticonvulsants Divalproex/ valproate

Liver disease Bleeding disorders

Gabapentin

Liver disease Bleeding disorders

Topiramate

Kidney stones

NSAIDs Naproxen

Ulcer disease Gastritis

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ratio. Women of childbearing potential should practice adequate contraception. Behavioral and psychological interventions used for prevention include relaxation training, thermal biofeedback combined with relaxation training, electromyographic biofeedback, and cognitive-behavioral therapy.136

Mechanism of Action of Preventive Medications Most migraine-preventive drugs were designed to treat other disorders. Serotonin antagonists were developed on the basis of the concept that migraine is caused by excess 5-HT. Antidepressants downregulate 5-HT2 and β-adrenergic receptors. Anticonvulsant medications decrease glutamate and enhance GABAA. Potential mechanisms of migraine-preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous system; enhancing antinociception; inhibiting CSD; inhibiting peripheral and central sensitization; blocking neurogenic inflammation; and modulating sympathetic, parasympathetic or serotonergic tone. Oshinsky showed that descending control from the upper brainstem, through serotonergic and noradrenergic systems, modulates the trigeminal nucleus caudalis and prevents central sensitization (personal communication). Moskowitz has recently shown that preventive medications given chronically, but not acutely, block CSD.137

Medication Orthostatic HTN

Migraine with aura HTN Angina Asthma Hypertension FHM Other pain disorders Depression Anxiety disorders Insomnia Depression OCD Refractory depression Mania Epilepsy Anxiety disorders Mania Epilepsy Anxiety disorders Mania Epilepsy Anxiety disorders Arthritis Other pain disorders

CHF, congestive heart failure; FHM, familial hemiplegic migraine; HTN, hypertension; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal antiinflammatory drug; OCD, obsessive-compulsive disorder; PVD, peripheral vascular disease; SSRI, serotonin-specific reuptake inhibitor; TCA, tricyclic antidepressant.

b Blockers β-Adrenergic blockers (also called β blockers), the most widely used class of drugs in prophylactic migraine treatment, are approximately 50% effective in producing a greater than 50% reduction in attack frequency. Rabkin and coworkers138 serendipitously discovered propranolol’s effectiveness in headache treatment in patients who were being treated for angina.139 Propranolol, nadolol, atenolol, metoprolol, and timolol are effective.8 Their relative efficacy has not been established; choice is based on β-adrenergic selectivity, convenience, adverse events, and patients’ reactions.2 β Blockers can produce behavioral adverse events, such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations; they should be avoided by patients who are depressed. Decreased exercise tolerance limits their use by athletes. Less common adverse events include impotence, orthostatic hypotension, and bradycardia. β Blockers are useful for patients with angina or hypertension. They are relatively contraindicated in patients with congestive heart failure, asthma, Raynaud’s disease, and insulin-dependent diabetes.

Antidepressants Antidepressants consist of a number of different classes of drugs with different mechanisms of action. The tricyclic antidepressants (TCAs) most commonly used for headache prophylaxis include amitriptyline, nortriptyline, doxepin, and protriptyline. Imipramine and desipramine have been used at times. With the exception of amitriptyline, the TCAs have not been vigorously evaluated; their use is based on anecdotal or uncontrolled reports. None have been approved for migraine.

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Antidepressants are especially useful for patients with comorbid depression and anxiety disorders. Amitriptyline (a TCA) is the only antidepressant whose efficacy has limited support.8 Adverse events include increased appetite, weight gain, dry mouth, and sedation; cardiac toxicity and orthostatic hypotension occasionally occur.140 There has been one trial with positive results for fluoxetine. Sexual dysfunction is a common adverse event.141 Amitriptyline is a tertiary amine TCA that is sedating and has antimuscarinic activity. Patients with coexistent depression are more tolerant and require higher doses of amitriptyline. It should be started at a dosage of 10 to 25 mg at bedtime. The dosage ranges from 10 to 400 mg/day. Doxepin is a sedating tertiary amine TCA. It should be started at a dosage of 10 mg at bedtime. The dose ranges from 10 to 300 mg a day. Nortriptyline is a secondary amine that is less sedating than amitriptyline. Nortriptyline is a major metabolite of amitriptyline. If insomnia develops, the drug should be taken earlier in the day or in divided doses. It should be started at a dosage of 10 to 25 mg at bedtime. The dosage ranges from 10 to 150 mg a day. Protriptyline is a secondary amine similar to nortriptyline. It should be started at a dose of 5 mg/day. The dose ranges from 5 to 60 mg a day.

Calcium-Channel Blockers The Agency for Healthcare Policy and Research analyzed 45 controlled trials.8 Flunarizine was effective, nimodipine produced mixed results, and the results of nifedipine were difficult to interpret. Verapamil was more effective than placebo in two of three trials, but both positive trials had high dropout rates, rendering the findings uncertain.2 Its most common adverse event is constipation. Flunarizine is the most effective drug of this class. It also has dopamine-blocking properties. Verapamil is available as a 40-, 80-, or 120-mg tablet or as a 120-, 180-, or 240-mg sustained-release preparation. It should be started at a dosage of 80 mg two to three times a day, with a maximum of 640 mg/day in divided doses. The most common adverse event is constipation; dizziness, nausea, hypotension, headache, and edema are less common. Bioavailability is 20%. The absorbed drug is tightly protein bound. Peak plasma levels occur in 5 hours; the half-life ranges from 2.5 to 7.5 hours. Flunarizine is not available everywhere. The dose is 5 to 10 mg/day. Adverse events include parkinsonism, depression, weight gain, somnolence, dry mouth, dizziness, and hypotension. The elimination half-life of flunarizine is 19 days.

Anticonvulsant Medications Anticonvulsant medication is increasingly recommended for migraine prevention because of placebo-controlled, doubleblind trials that have proved it to be effective. With the exception of valproic acid, topiramate, and zonisamide, anticonvulsants may interfere substantially with the efficacy of oral contraceptives.142,143 Nine controlled trials of five different anticonvulsants were included in the Agency for Healthcare Policy and Research Technical Report.145-151,153,154 Valproic acid is a simple eight-carbon, two-chain fatty acid with 80% bioavailability after oral administration. It is highly protein bound, with an elimination half-life of between 8 and

17 hours. Valproic acid possesses anticonvulsant activity in a wide variety of experimental epilepsy models. Valproate at high concentrations increases GABA levels in synaptosomes, perhaps by inhibiting its degradation; it enhances the postsynaptic response to GABA, and, at lower concentrations, it increases potassium conductance, producing neuronal hyperpolarization. Valproate turns off the firing of the 5-HT neurons of the dorsal raphe, which are implicated in controlling head pain. Divalproex sodium (500 to 1000 mg) and sodium valproate are effective, as is the extended-release formulation.8 Five studies provided strong and consistent support for the efficacy of divalproex sodium (approved by the U.S. Food and Drug Administration)146,147 and sodium valproate.150,151 Nausea, vomiting, and gastrointestinal distress are the most common adverse events of valproate therapy. These are generally selflimited and are slightly less common with divalproex sodium than with sodium valproate. On rare occasions, valproate administration is associated with severe adverse events, such as hepatitis or pancreatitis. The frequency varies with the number of concomitant medications used, the patient’s age and general state of health, and the presence of genetic and metabolic disorders. Valproate is teratogenic and should not be used by pregnant women or women considering pregnancy.152 In clinical trials, the most frequent adverse events were nausea (42%), alopecia (31%), tremor (28%), asthenia (25%), dyspepsia (25%), somnolence (25%), and weight gain (19%).153 Baseline liver function studies should be obtained, but follow-up studies are probably not needed for adults receiving monotherapy.152 Valproic acid is available as 250-mg capsules and as a syrup (250 mg/5 mL). Divalproex sodium is a stable coordination complex composed of sodium valproate and valproic acid in a 1:1 molar ratio. An enteric-coated form of divalproex sodium is available as 125-, 250-, and 500-mg capsules and a sprinkle formulation. It should be started at a dosage of 250 to 500 mg/day in divided doses, and then the dosage should be slowly increased. Serum levels should be monitored if there is a question of toxicity or compliance. (The usual therapeutic level is from 50 to 100 mg/mL.) The maximum recommended dosage is 60 mg/kg/day. An extended-release form of divalproex sodium demonstrated efficacy comparable with that of the tablet formulation. The adverse event profile in the clinical trial, however, showed almost identical adverse event rates for placebo and active treatment.154 Gabapentin (1800 to 2400 mg) showed efficacy in a placebocontrolled, double-blind trial only in a modified intent-to-treat analysis. Migraine attack frequency was reduced by 50% in about one third of patients.155 The most common adverse events were dizziness or giddiness and drowsiness. Topiramate was originally synthesized as part of a research project to discover structural analogs of fructose-1,6diphosphate capable of inhibiting the enzyme fructose-1,6bisphosphatase, thereby blocking gluconeogenesis, but it has no hypoglycemic activity. Topiramate is a derivative of the naturally occurring monosaccharide D-fructose and contains a sulfamate functionality. Topiramate was originally marketed for the treatment of epilepsy156; it is now approved by the U.S. Food and Drug Administration for treatment of migraine. It is associated with weight loss, not weight gain. In two large, double-blind, placebo-controlled, multicenter trials, topiramate, both 100 and 200 mg, was effective in reducing migraine attack frequency by 50% in half of the patients.157,158 Withdrawals from the study because of adverse events were

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common among the topiramate recipients but did not affect statistical significance. The most common adverse event was paresthesia, which was rated as mild to moderate in the majority of patients and limited treatment in only 8% of these subjects. The other most common adverse events were fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthesia and abdominal pain. The most common CNS adverse events were somnolence, insomnia, difficulty with memory, language problems, difficulty with concentration, mood problems, and anxiety. Renal calculi occur with a reported incidence of about 1.5%. A rare syndrome consisting of acute myopia in association with secondary angle-closure glaucoma has been reported. Topiramate therapy should be started at a dosage of 15 to 25 mg at bedtime and increased by 15 to 25 mg/week. The dosage should not be increased if bothersome adverse events develop; the increase should be delayed until they resolve (they usually do). If they do not resolve, the dosage should be decreased to the last tolerable amount and then increased by a lower increment more slowly. The goal is a dose of 50 to 100 mg/day given twice a day. It is the author’s experience that patients who tolerate the lower dosages with only partial improvement often experience increased benefit with higher doses. The dosage can be increased to 600 mg/day or higher. Divalproex and topiramate are useful for patients with epilepsy, anxiety disorder, or manic-depressive illness. These drugs can be used by patients with depression, Raynaud’s disease, asthma, and diabetes, circumventing the contraindications to β blockers.

MRI. The drug should be discontinued immediately on suspicion of pulmonary or cardiac retroperitoneal fibrosis.162 Cyproheptadine, an antagonist at the 5-HT2, histamine H1, and muscarinic cholinergic receptors, is widely used in the prophylactic treatment of migraine in children.162,165,166 Cyproheptadine is available as 4-mg tablets. The total dosage ranges from 12 to 36 mg/day (given two to three times a day or at bedtime). Common adverse events are sedation and weight gain; dry mouth, nausea, lightheadedness, ankle edema, aching legs, and diarrhea are less common. Cyproheptadine may inhibit growth in children167 and reverse the effects of selective serotonin reuptake inhibitors. Pizotifen, a benzocycloheptathiophene derivative, is a 5-HT2 receptor antagonist structurally similar to cyproheptadine.10 It is not available everywhere. According to the United States Headache Consortium guidelines,118 evidence was inconsistent for its efficacy. Analysis of the placebo-controlled trials suggested a large clinical effect that was statistically significant. Pizotifen was generally poorly tolerated.8 Substantial weight gain, tiredness, drowsiness, or a combination of these was frequently reported. Pizotifen was associated with a high rate of withdrawals from the study because of adverse events. Controlled and uncontrolled studies in Europe168 have shown this drug to be of benefit in 40% to 79% of patients. The dosage recommendation is 0.5 to 1 mg, one three times daily by titration. Adverse events include drowsiness, increased appetite, and weight gain.169

Serotonin Antagonists

Feverfew (Tanacetum parthenium) is a medicinal herb whose effectiveness has not been totally established.170 Riboflavin (400 mg) was effective in one placebo-controlled, double-blind trial; more than half the patients responded.171 A standardized extract (75 mg bid) of Petasites hybridus root (butterbur), a perennial shrub,16 was effective in a double-blind, placebocontrolled study.172 The most common adverse event was belching. Coenzyme Q10 was effective in one double-blind, placebo-controlled trial.173

The antiserotonin migraine-preventive drugs are potent 5-HT2B and 5-HT2C receptor antagonists. Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. It is a 5-HT2 receptor antagonist and 5-HT1B/5-HTD agonist. It was probably the first drug developed for migraine prevention,159 but its usefulness is limited by reports of retroperitoneal and retropleural fibrosis associated with longterm, mostly uninterrupted, administration.160 Methysergide is effective.8,161 Adverse events include transient muscle aching, claudication, abdominal distress, nausea, weight gain, and hallucinations. The major complication is rare (1 per 2500) retroperitoneal, pulmonary, or endocardial fibrosis.161 To prevent this, a 4-week medication-free interval is recommended after 6 months of continuous treatment.2,161 Methysergide is indicated for the treatment of migraine and cluster headache. The dosage ranges from 2 to 8 mg/day, the higher doses being given two or three times a day. Clinicians find that some patients can take higher doses, up to 14 mg a day, without adverse events and with higher efficacy.162 To minimize early adverse events, patients can start with a dose of 1 mg/day and increase the dose gradually by 1 mg every 2 to 3 days. Methysergide, in general, should not be taken continuously for long periods, because this may produce retroperitoneal fibrosis.160,163,164 Instead, the drug should be given for 6 months, stopped for 1 month, and then restarted. To avoid an increase in headache when methysergide is stopped, the patient should be weaned off the drug over a 1-week period. Some authorities use methysergide on a continuous basis with careful monitoring,162 which includes auscultation of the heart and yearly echocardiography, chest radiography, and abdominal

Natural Products

Newer Treatments Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists Schrader and associates174 conducted a double-blind, placebocontrolled, crossover study of lisinopril, an angiotensinconverting enzyme inhibitor. The treatment period was 12 weeks, with one 10-mg lisinopril tablet taken once daily for 1 week and then two 10-mg lisinopril tablets taken once daily for 11 weeks, followed by a 2-week washout period. Hours with headache, days with headache, days with migraine, and headache severity index were significantly reduced by 20% (95% confidence interval, 5% to 36%), 17% (5% to 30%), 21% (9% to 34%), and 20% (3% to 37%), respectively, with lisinopril, in comparison with placebo. Tronvik and colleagues175 performed a randomized, double-blind, placebo-controlled crossover study of candesartan (16-mg), an angiotensin II receptor blocker. The number of candesartan responders (reduction of 50% or more in comparison with placebo) was 18 (31.6%) of 57 for days with headache and 23 (40.4%) of 57 for

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days with migraine. Adverse events were similar in the two periods. In this study, candesartan was effective, with a tolerability profile comparable with that of placebo. Botulinum toxin type A (Botox) in dosages of 0, 25, or 75 U showed promising results in one placebo-controlled, doubleblind trial. It was injected into glabellar, frontalis, and temporalis muscles. The 25-U treatment was significantly better than placebo in reducing mean frequency of moderate to severe migraines during days 31 to 60, 50% reduction of incidence of all migraine at days 61 to 90, and reduction in all migraine at days 61 to 90.176

Setting Treatment Priorities The goals of preventive treatment are to reduce the frequency, duration, or severity of attacks, improve responsiveness to acute attack treatment, improve function, and reduce disability. Preventive treatment may also prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions. The preventive medications with the best documented efficacy are the β blockers, divalproex, and topiramate. The choice of drug is based on a drug’s proven efficacy, the physician’s informed belief about medications not yet evaluated in controlled trials, the drug’s adverse events, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders.2 The drug chosen should be the one that has the best risk/benefit ratio for the individual patient and takes advantage of the drug’s side effect profile.177,178 Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. An underweight patient would be a candidate for one of the medications that commonly produce weight gain, such as a TCA; in contrast, these drugs should be avoided by an overweight patient and the use of topiramate considered instead. Tertiary TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs or calcium channel or β blockers, but they could use divalproex or topiramate. In the athletic patient, β blockers should be used with caution. Medication that can impair cognitive functioning should be avoided when patients are dependent on their wits.177,178 In some instances, two or more conditions may be treated with a single drug. When migraine occurs with hypertension and/or angina, β blockers or calcium channel blockers may be effective for all conditions.179 For the patient with migraine and depression, TCAs or selective serotonin reuptake inhibitors may be especially useful.180 For the patient with migraine and epilepsy181 or migraine and bipolar illness,152,182 divalproex and topiramate are the drugs of choice. The pregnant migraineur who has a comorbid condition that necessitates treatment should be given a medication that is effective for both conditions and has the lowest potential for adverse events on the fetus. When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, β blockers should be used with caution in depressed migraineurs, whereas TCAs, neuroleptics, or sumatriptan may lower the seizure threshold and should be used with caution in the epileptic migraineur. Although monotherapy is preferred, it is sometimes necessary to combine preventive medications. Antidepressants are

often used with β blockers or calciums-channel blockers, and topiramate or divalproex sodium may be used in combination with any of these medications. Pascual and colleagues183 found that combining a β blocker and sodium valproate could lead to an increased benefit for patients with migraine that had previously been resistant to either drug alone. Fifty-two patients (43 women) with a history of episodic migraine with or without aura and previously unresponsive to β blockers or sodium valproate monotherapy were treated with a combination of propranolol (or nadolol) and sodium valproate in an open-label manner. Fifty-six percent had a greater than 50% reduction in days with migraine. This open-label trial supports the practice of combination therapy. Controlled trials are needed to determine the true advantage of this combination treatment in episodic and chronic migraine.

SUMMARY Migraine is an extremely common neurobiological headache disorder that is caused by increased CNS excitability. It ranks among the world’s most disabling medical illnesses. Diagnosis is based on the headache’s characteristics and associated symptoms. The economic effects and societal effects of migraine are substantial; it affects sufferers’ quality of life and impairs work, social activities, and family life. There are many acute and preventive migraine treatments on the market. Acute treatment is either specific (triptans and ergots) or nonspecific (analgesics). Disabling migraine should be treated with triptans. Increased headache frequency is an indication for preventive treatment, which decreases migraine frequency and improves quality of life. More treatments are being developed, which provides hope to the many sufferers whose condition is still uncontrolled.

K E Y

P O I N T S

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Migraine diagnosis is based on the headache’s characteristics and associated symptoms.

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Acute treatment is either specific (triptans and ergots) or nonspecific (analgesics).

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Increased headache frequency is an indication for preventive treatment, which decreases migraine frequency and improves quality of life.

References 1. Critchley M: Migraine: from Cappadocia to Queen Square. London: Heinemann, 1967. 2. Silberstein SD, Saper JR, Freitag F: Migraine: diagnosis and treatment. In Silberstein SD, Lipton RB, Dalessio DJ, eds: Wolff’s Headache and Other Head Pain, 7th ed. New York: Oxford University Press, 2001, pp 121-237. 3. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalalgia 1988; 8:1-96. 4. Headache Classification Committee of the International Headache Society: The International Classification of Headache Disorders, 2nd edition. Cephalalgia 2004; 24(Suppl 1): 9-160. 5. Ferrari MD: Migraine. Lancet 1998; 351:1043-1051.

chapter 56 Migraine 6. Goslin RE, Gray RN, McCrory DC, et al: Behavioral and physical treatments for migraine headache. Prepared for the Agency for Healthcare Policy and Research, Contract No. 29094-2025. Available from the National Technical Information Service, Accession No. 127946, February 1999. 7. Gray RN, McCrory DC, Eberlein K, et al: Parenteral drug treatments for acute migraine headache. Prepared for the Agency for Healthcare Policy and Research, Contract No. 29094-2025. Available from the National Technical Information Service, Accession No. 127862 (Technical Review 2.5), February 1999. 8. Gray RN, Goslin RE, McCrory DC, et al: Drug treatments for the prevention of migraine headache. Prepared for the Agency for Healthcare Policy and Research, Contract No. 290-942025. Available from the National Technical Information Service, Accession No. 127953 (Technical Review 2.3), February 1999. 9. Gray RN, McCrory DC, Eberlein K, et al: Self-administered drug treatments for acute migraine headache. Prepared for the Agency for Healthcare Policy and Research, Contract No. 290-94-2025. Available from the National Technical Information Service, Accession No. 127854 (Technical Review 2.4), February 1999. 10. Ramadan NM, Silberstein SD, Freitag FG, et al: Evidencebased guidelines of the pharmacological management for prevention of migraine for the primary care provider. Neurology 1999. 11. Matchar DB, Young WB, Rosenberg JA, et al: Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. Neurology 2000. 12. Ferrari MD, Roon KI, Lipton RB, et al: Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a metaanalysis of 53 trials. Lancet 2001; 358:1668-1675. 13. Stewart WF, Shechter A, Rasmussen RK: Migraine prevalence. A review of population-based studies. Neurology 1994; 44:S17-S23 14. Stewart WF, Lipton RB, Celentano DD, et al: Prevalence of migraine in the United States. JAMA 1992; 267:64-69. 15. Lipton RB, Diamond S, Reed M, et al: Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001; 41:638-645. 16. Lipton RB, Hamelsky SW, Stewart WF: Epidemiology and impact of headache. In Silberstein SD, Lipton RB, Dalessio DJ, eds: Wolff’s Headache and Other Head Pain, 7th ed. New York: Oxford University Press, 2001, pp 85-107. 17. Lipton RB, Stewart WF, Diamond S, et al: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646-657. 18. World Health Organization: World Health Report, 2001. Available at www.who.int/whr/en/. 19. Stewart WF, Lipton RB, Kolodner KB, et al: Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a population sample of migraine sufferers. Pain 2000; 88:41-52. 20. Ware JE, Bjorner JB, Kosinski M: Practical implication of item response theory and computerized adaptive testing. A brief summary of ongoing studies of widely used headache impact scales. Med Care 2000; 38:73-82. 21. Ophoff RA, Terwindt GM, Vergouwe MN: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNLA4. Cell Tiss Res 1996; 87:543-552. 22. Joutel A, Bousser MG, Biousee V: A gene for familial hemiplegic migraine maps to chromosome 19. Nat Genet 1993; 5:40-45. 23. Ducros A, Deiner C, Joutel A, et al: The clinical spectrum of familial hemiplegic migraine associated with mutations

24.

25.

26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42. 43. 44. 45.

46.

751

in a neuronal calcium channel. N Engl J Med 2001; 345: 17-24. Ferrari MD, Haan J: Genetics of headache. In Silberstein SD, Lipton RB, Dalessio DJ, eds: Wolff’s Headache and Other Head Pain, 7th ed. New York: Oxford University Press, 2001, pp 7384. De Fusco M, Marconi R, Silvestri L, et al: Haploinsufficiency of ATP1A2 encoding the Na(+)/K(+) pump α2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; 33:192-196. Wolff HG: Headache and other head pain. New York: Oxford University, 1963. Olesen J, Friberg L, Skyhoj-Olsen T: Timing and topography of cerebral blood flow, aura and headache during migraine attacks. Ann Neurol 1990; 28:791-798. Sanchez-del Rio M, Bakker D, Wu O, et al: Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19:701-707. Cutrer FM, Sorenson AG, Weisskoff RM, et al: Perfusionweighted imaging defects during spontaneous migrainous aura. Ann Neurol 1998; 43:25-31. Hadjikhani N, Sanchez delRio M, Wu O, et al: Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001; 98:4687-4692. Pietrobon D, Striessnic J: Neurobiology of migraine. Nat Rev Neurosci 2003; 4:386-398. Lashley KS: Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol 1941; 46:331-339. Leão AAP: Spreading depression of activity in cerebral cortex. J Neurophysiol 1944; 7:359-390. Olesen J, Larsen B, Lauritzen M: Focal hyperemia followed by spreading oligemia and impaired activation of RCBF in classic migraine. Ann Neurol 1981; 9:344-352. Olesen J: Cerebral and extracranial circulatory disturbances in migraine: pathophysiological implications. Cerebrovasc Brain Metab Rev 1991; 3:1-28. Milner PM: Note on a possible correspondence between the scotomas of migraine and spreading depression of Leão. Electroencephalogr Clin Neurophysiol 1958; 10:705. Cao Y, Welch KM, Aurora S, et al: Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 1999; 56:548-554. Andersen AR, Friberg L, Skyloj-Olsen T, et al: Delayed hyperemia following hypoperfusion in classic migraine. Single photon emission tomographic demonstration. Arch Neurol 1988; 45:154-159. Seto H, Shimizu M, Futatsuya R, et al: Basilar artery migraine. Reversible ischemia demonstrated by Tc-99m HMPAO brain SPECT. Clin Nucl Med 1994; 19:215-218. Woods RP, Iacoboni M, Mazziotta JC: Bilateral spreading cerebral hypoperfusion during spontaneous migraine headaches. N Engl J Med 1994; 331:1689-1692. Cutrer FM, O’Donnell A. Recent advances in functional neuroimaging. Curr Opin Neurol 1999; 12:255-259. Barkley GL, Tepley N, Nagel L, et al: Magnetoencephalographic studies of migraine. Headache 1990; 30:428-434. Bowyer SM, Aurora KS, Moran JE, et al: Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Ann Neurol 2001; 50:582-587. Aurora SK, Cao Y, Bowyer SM, et al: The occipital cortex is hyperexcitable in migraine: experimental evidence. Headache 1999; 39:469-476. Young WB, Oshinsky ML, Shechter AL, et al: Consecutive transcranial magnetic stimulation induced phosphene thresholds in migraineurs and controls [Abstract]. Neurology 2001; 56:A142. Afra J, Mascia A, Gerard P, et al: Interictal cortical excitability in migraine: a study using transcranial magnetic

752

47.

48.

49.

50.

51.

52. 53. 54. 55.

56.

57. 58. 59. 60.

61. 62.

63. 64. 65.

Section

XI

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stimulation of motor and visual cortices. Ann Neurol 1998; 44:209-215. Schoenen J, Thomsen LL: Neurophysiology and autonomic dysfunction in migraine. In Olesen J, Tfelt-Hansen P, Welch KMA, eds: The Headaches, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 301-312. Uddman R, Edvinsson L, Ekman R, et al: Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene–related peptide: trigeminal origin an co-existence with substance P. Neurosci Lett 1985; 62:131-136. Buzzi MG, Moskowitz MA, Shimizu T, et al: Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 1991; 30:11931200. Markowitz S, Saito K, Moskowitz MA: Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache. Cephalalgia 1988; 8:83-91. Dimitriadou V, Buzzi MG, Theoharides TC, et al: Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat dura mater and tongue following antidromic trigeminal stimulation. Neuroscience 1992; 48:187-203. Pappagalo M, Szabo Z, Esposito G, et al: Imaging neurogenic inflammation inpatients with migraine headaches. Neurology 2002; 52:274-275. Strassman AM, Raymond SA, Burstein R: Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996; 384:560-564. Moskowitz MA, Cutrer FM: Sumatriptan: a receptor-targeted treatment for migraine. Annu Rev Med 1993; 44:145-154. Nozaki K, Boccalini P, Moskowitz MA: Expression of c-fos–like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space. Neuroscience 1992; 49:669680. Kaube H, Keay K, Hoskin KL, et al: Expression of c-fos like immunoreactivity in the trigeminal nucleus caudalis and high cervical cord following stimulation of the sagittal sinus in the cat. Brain Res 1993; 629:95-102. Goadsby PJ, Hoskin KL: The distribution of trigeminovascular afferents in the non-human primate brain. J Anat 1997; 190:367-375. Zagami AS, Goadsby PJ, Edvinsson L: Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 1990; 16:69-75. Goadsby PJ, Edvinsson L, Ekman R: Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28:183-187. Goadsby PJ, Edvinsson L: The trigeminovascular system in migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33:48-56. Edvinsson L, Goadsby PJ: Neuropeptides in headache. Eur J Neurol 1998; 5:329-341. O’Connor TP, Van der Kooy D: Enrichment of vasoactive neuropeptide (calcitonin gene related peptide) in trigeminal sensory projection to the intracranial arteries. J Neurosci 1988; 8:2468-2476. O’Connor TP, vanderKooy D: Pattern of intracranial and extracranial projections of trigeminal ganglion cells. J Neurosci 1986; 6:2200-2207. Doods H, Hallermayer G, Wu D, et al: Pharmacological profile of BIBN-4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 2000; 129:420-423. Olesen J, Diener HC, Husstedt IW, et al: Calcitonin gene– related peptide (CGRP) receptor antagonist BIBN4096BS is effective in the treatment of migraine attacks [Abstract]. Cephalalgia 2003; 23:579.

66. Burstein R, Collins B, Bajwa Z, et al: Triptan therapy can abort migraine attacks if given before the establishment or in the absence of cutaneous allodynia and central sensitization: clinical and preclinical evidence [Abstract]. Headache 2002; 42:390-391. 67. Burstein R, Cutrer MF, Yarnitsky D: The development of cutaneous allodynia during a migraine attack: clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2001; 123:17031709. 68. Weiller C, May A, Limmroth V, et al: Brainstem activation in spontaneous human migraine attacks. Nat Med 1995; 1:658660. 69. Bahra A, Matharu MS, Buchel C, et al: Brainstem activation specific to migraine headache. Lancet 2001; 357:1016-1017. 70. Bolay H, Reuter U, Dunn AK, et al: Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8:136-142. 71. Hoyer D, Clarke DE, Fozard JR, et al: VII International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 1994; 46: 157-203. 72. Hartig PR, Hoyer D, Humphrey PPA, et al: Alignment of receptor nomenclature with the human genome: classification of 5HT-1B and 5HT1D receptor subtypes. Trends Pharmacol Sci 1996; 17:103-105. 73. Longmore J, Shaw D, Smith D, et al: Differential distribution of 5HT(1D)- and 5HT(1B)-immunoreactivity within the human trigeminocerebrovascular system: implications for the discovery of new antimigraine drugs. Cephalalgia 1997; 17:833-842. 74. Buzzi MG, Sakas DE, Moskowitz MA: Indomethacin and acetyl salicylic acid block neurogenic plasma protein extravasation in rat dura mater. Eur J Pharmacol 1989; 165:251-258. 75. Cutrer FM, Limmroth V, Ayata G, et al: Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin. Br J Pharmacol 1995; 116:3199-3204. 76. Lee WS, Limmroth V, Ayata C, et al: Peripheral GABA-A receptor mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation. Br J Pharmacol 1995; 116:1661-1667. 77. Limmroth V, Lee WS, Cutrer FM, et al: GABAA-receptor– mediated effects of progesterone, its ring-A–reduced metabolites and synthetic neuroactive steroids on neurogenic edema in the rat meninges. Br J Pharmacol 1996; 117:99-104. 78. Lee WS, Moussaoui SM, Moskowitz MA: Blockade by oral or parenteral RPR100893 (a nonpeptide NK1 receptor antagonist) of neurogenic plasma protein extravasation in guinea-pig dura mater and conjunctiva. Br J Pharmacol 1994; 112:920-924. 79. May A, Gijsman HJ, Wallnoefer A, et al: Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain 1996; 67:375-378. 80. Goadsby PJ, Gundlach AL: Localization of [3H]-dihydroergotamine binding sites in the cat central nervous system: relevance to migraine. Ann Neurol 1991; 29:91-94. 81. Kandere-Grzybowska K, Gheorghe D, Priller J, et al: Stressinduced dura vascular permeability does not develop in mast cell–deficient and neurokinin-1 receptor knockout mice. Brain Res 2003; 980:213-220. 82. Silberstein SD, Young WB: Migraine aura and prodrome. Semin Neurol 1995; 45:175-182. 83. Giffin NJ, Ruggiero L, Lipton RB, et al: A novel approach to the study of premonitory symptoms in migraine using an electronic diary. Neurology 2003; 60:935-940. 84. Russell MB, Olesen J: A nosographic analysis of the migraine aura in a general population. Brain 1996; 119:355-361.

chapter 56 Migraine 85. Silberstein SD, Lipton RB: Overview of diagnosis and treatment of migraine. Neurology 1994; 44:6-16. 86. Thomsen LL, Eriksen MK, Roemer SF, et al: A populationbased study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain 2002; 125:1379-1399. 87. Stewart WF, Schechter A, Lipton RB: Migraine heterogeneity: disability, pain intensity, attack frequency, and duration. Neurology 1994; 44:S24-S39. 88. Silberstein SD: Migraine symptoms: results of a survey of selfreported migraineurs. Headache 1995; 35:387-396. 89. Young WB, Peres MF, Rozen TD: Modular headache theory. Cephalalgia 2001; 21:842-849. 90. Draft International Headache Society Classification. Available at www.I-H-S.org (accessed February 9, 2006). 91. Whitty CWM: Migraine without headache. Lancet 1967; 2:283-285. 92. Wijman C, Wolf PA, Kase CS, et al: Migrainous visual accompaniments are not rare in late life: the Framingham Study. Stroke 1998; 29:1539-1543. 93. Fisher CM: Late-life migraine accompaniments—further experience. Stroke 1986; 17:1033-1042. 94. Mark AS, Casselman J, Brown D, et al: Ophthalmoplegic migraine: reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrastenhanced MR images. AJNR Am J Neuroradiol 1998; 19: 1887-1891. 95. Joutel A, Corpechot C, Ducros A, et al: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383:707-710. 96. Tournier-Lasserve E, Joutel A, Melki J: Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosomes. Nat Genet 1993; 3:256-259. 97. Joutel A, Vahedi K, Corpechot C, et al: Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997; 350:1511-1515. 98. Meschia JF, Brott TG, Brown RD Jr: Genetics of cerebrovascular disorders. Mayo Clin Proc 2005; 80:122-132. 99. Chabriat H, Vahedi K, Iba-Zizen MT, et al: Clinical spectrum of CADASIL: a study of seven families. Lancet 1995; 346:934939. 100. Silberstein SD: Migraine. Lancet 2004; 363:381-391. 101. Lipton RB, Silberstein SD: Why study the comorbidity of migraine? Neurology 1994; 44:4-5. 102. Lipton RB, Cady RK, O’Quinn S, et al: Sumatriptan treats the full spectrum of headache in individuals with disabling IHS migraine. Headache 1999; 40:783-791. 103. Lipton RB, Stewart WF, Stone AM, et al: Stratified care vs step care strategies for migraine. The disability in strategies of care (DISC) study: a randomized trial. JAMA 2000; 284:25992605. 104. Cady RK, Sheftell F, Lipton RB, et al: Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials. Clin Therap 2000; 22:1035-1048. 105. Lipton RB, Stewart WF, Ryan RE, et al: Efficacy and safety of the nonprescription combination of acetaminophen, aspirin, and caffeine in alleviating headache pain of an acute migraine attack: three double-blind, randomized, placebo-controlled trials. Arch Neurol 1998; 55:210-217. 106. Lipton RB, Baggish JS, Stewart WF, et al: Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, populationbased study. Arch Intern Med 2000; 160:3486-3492. 107. Silberstein SD, McCrory DC: Butalbital in the treatment of headache: history, pharmacology, and efficacy. Headache 2001; 41:953-967. 108. Silberstein SD, McCrory DC: Opioids. Cephalalgia 2000; 20:854-864.

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109. Silberstein SD: Migraine and pregnancy. Neurol Clin 1997; 15:209-231. 110. Callaham M, Raskin N: A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache 1986; 26:168-171. 111. Jones J, Sklar D, Dougherty J, et al: Randomized double-blind trial of intravenous prochlorperazine for the treatment of acute headache. JAMA 1989; 261:1174-1176. 112. Silberstein SD, Young WB, Mendizabal JE, et al: Acute migraine treatment with the dopamine receptor antagonist, droperidol: results of a randomized, double-blind, placebocontrolled, multicenter trial. Neurology 2003; 60:315-321. 113. Young WB, Mannix L, Adelman JU, et al: Cardiac risk factors and the use of triptans: a survey study. Headache 2000; 40:587-591. 114. Tatsuta T, Naito M, Oh-Hara T, et al: Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 1992; 267:20383-20391. 115. Lipton RB, Stewart WF, Cady R, et al: 2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study. Headache 2000; 40:783791. 116. Duquesnoy C, Mamet JP, Sumner D, et al: Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal, and intranasal administration. Eur J Pharm Sci 1998; 6:99-104. 117. Dahlöf C: Clinical efficacy and tolerability of sumatriptan tablet and suppository in the acute treatment of migraine: a review of data from clinical trials. Cephalalgia 2001; 21:912. 118. Silberstein SD: Practice Parameter—Evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology for the United States Headache Consortium. Neurology 2000; 55:754-762. 119. Tfelt-Hansen P: Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat. Cephalalgia 1998; 18:532-538. 120. Thomson Healthcare: Physicians’ Desk Reference, 57th ed. Montvale, NJ: Thomson PDR, 2003. 121. Dahlöf C: Sumatriptan nasal spray in the acute treatment of migraine: a review of clinical studies. Cephalalgia 1999; 19:769-778. 122. Shakra S, Yates Ra, Sorensen J, et al: Distribution and pharmacokinetics of zolmitriptan following administration by nasal spray [Abstract]. Neurology 2002; 58:A91. 123. Shakra S, Becker WJ, Lee D: Zolmitriptan nasal spray is effective, fast-acting, and well tolerated during both short and long-term treatment [Abstract]. Neurology 2002; 58:A414. 124. Charlesworth BR, Dowson AJ, Purdy A, et al: Speed of onset and efficacy of zolmitriptan nasal spray in the acute treatment of migraine: a randumized, double blind, placebo-controlled, dose-ranging study versus zolmitriptan tablet. CNS Drugs 2003; 17:653-667. 125. Gunasekara NS, Wiseman LR: Naratriptan. CNS Drugs 1997; 8:402-408. 126. Silberstein SD: Pharmacological profile and clinical characteristics of frovatriptan in the acute treatment of migraine: introduction. Headache 2002; 42:S45-S99. 127. Färkkilä M: A dose-finding study of eletriptan (UK-116,044) (5-30mg) for the acute treatment of migraine. Cephalalgia 1996; 16:387-388. 128. Bates D, Ashford E, Dawson R, et al: Subcutaneous sumatriptan during the migraine aura. Neurology 1994; 44:1587-1592. 129. Silberstein SD: Pharmacological profile and clinical characteristics of frovatriptan in the acute treatment of migraine. Headache 2002; 42:S45-S93.

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130. Silberstein SD, McCrory DC: Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 2003; 43:144-166. 131. Tfelt-Hansen P, Saxena PR, Dahlöf C, et al: Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 2000; 123:9-18. 132. Silberstein SD, Schulman EA, Hopkins MM: Repetitive intravenous DHE in the treatment of refractory headache. Headache 1990; 30:334-339. 133. Silberstein SD, Winner PK, Chmiel JJ: Migraine preventive medication reduces resource utilization. Headache J Head Face Pain 2003; 43:171-178. 134. Silberstein SD, Goadsby PJ: Migraine: preventive treatment. Cephalalgia 2002; 22:491-512. 135. Lipton RB, Scher AI, Kolodner K, et al: Migraine in the United States: epidemiology and patterns of health care use. Neurology 2002; 58:885-894. 136. Campbell JK, Penzien D, Wall EM: Evidenced-based guidelines for migraine headache: behavioral and physical treatments. Available at: http://www.aan.org/professionals/ practice/pdfs/g10089.pdf. 137. Ayata C, Jin H, Kudo C, et al: Suppression of cortical spreading depression in migraine prophylasis. Ann Neurol 2006; 59:652-661. 138. Rabkin R, Stables DP, Levin NW, et al: The prophylactic value of propranolol in angina pectoris. Am J Cardiol 1966; 18:370383. 139. Weber RB, Reinmuth OM: The treatment of migraine with propranolol. Neurology 1972; 22:366-369. 140. Saper JR, Silberstein SD, Lake AE, et al: Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 1994; 34:497-502. 141. Stein DJ, Hollander E: Sexual dysfunction associated with the drug treatment of psychiatric disorders: incidence and treatment. CNS Drugs 1994; 2:78-86. 142. Coulam CB, Annagers JR: New anticonvulsants reduce the efficacy of oral contraception. Epilepsia 1979; 20:519525. 143. Hansten PP, Horn JR: Drug interaction. Newsletter 1985; 5:710. 144. Kuritzky A, Hering R: Prophylactic treatment of migraine with long acting propranolol: a comparison with placebo. Cephalalgia 1987; 7:457-458. 145. Jensen R, Brinck T, Olesen J: Sodium valproate has prophylactic effect in migraine without aura: a triple-blind, placebocontrolled crossover study. Neurology 1994; 44:241-244. 146. Klapper JA: An open label crossover comparison of divalproex sodium and propranolol HCl in the prevention of migraine headaches. Headache Q 1995; 5:50-53. 147. Mathew NT, Saper JR, Silberstein SD, et al: Migraine prophylaxis with divalproex. Arch Neurol 1995; 52:281-286. 148. Rompel H, Bauermeister PW: Aetiology of migraine and prevention with carbamazepine (Tegretol). S Afr Med J 1970; 44:75-80. 149. Klapper JA: Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 1997; 17:103-108. 150. Hering R, Kuritzky A: Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992; 12:81-84. 151. Jensen R, Brinck T, Olesen J: Sodium valproate has a prophylactic effect in migraine without aura. Neurology 1994; 44:647-651. 152. Silberstein SD: Divalproex sodium in headache—literature review and clinical guidelines. Headache 1996; 36:547-555. 153. Silberstein SD, Collins SD: Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study. LongTerm Safety of Depakote in Headache Prophylaxis Study Group. Headache 1999; 39:633-643.

154. Freitag FG, Collins SD, Carlson HA, et al: A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology 2002; 58:1652-1659. 155. Mathew NT, Rapoport A, Saper J, et al: Efficacy of gabapentin in migraine prophylaxis. Headache 2001; 41:119-128. 156. Shank RP, Gardocki JF, Vaught JL, et al: Topiramate: preclinical evaluation of structurally novel anticonvulsant. Epilepsia 1994; 35:450-460. 157. Brandes JL, Jacobs DJ, Neto W, et al: Topiramate in the prevention of migraine headache: a randomized, double-blind, placebo-controlled, parallel study (MIGR-002) [Abstract]. Neurology 2003; 60:A238. 158. Mathew NT, Schmit TJ, Neto W, et al: Topiramate in migraine prevention: MIGR 001 [Abstract]. Neurology 2003; 60:A336. 159. Sicuteri R: Prophylactic and therapeutic properties of 1methyl-lysergic acid butanolamide in migraine. Int Arch Allergy Appl Immunol 1959; 15:300-307. 160. Graham JR, Suby HI, LeCompte PR, et al: Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med 1966; 274:360-368. 161. Silberstein SD: Methysergide. Cephalalgia 1998; 18:421-435. 162. Raskin NH: Headache, 2nd ed. New York: Churchill-Livingstone, 1988. 163. Graham J: Cardiac and pulmonary fibrosis during methysergide therapy for headache. Am J Med Sci 1967; 254:112. 164. Bana DS, MacNeal PS, LeCompte PM, et al: Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J 1974; 88:640-655. 165. Barlow CF: Headaches and Migraine in Children. Philadelphia: Lippincott, 1984. 166. Forsythe I, Hockaday JM: Management of childhood migraine. In Hockaday JM, ed: Migraine in Childhood. London: Butterworths, 1988, pp 63-74. 167. Smyth GA, Lazarus L: Suppression of growth hormone secretion by melatonin and cyproheptadine. J Clin Invest 1974; 54:116-121. 168. Peatfield R: Drugs acting by modification of serotonin function. Headache 1986; 26:129-131. 169. Capildeo R, Rose FC: Single-dose pizotifen, 1.5mg nocte: a new approach in the prophylaxis of migraine. Headache 1982; 22:272-275. 170. Vogler BK, Pittler MH, Ernst E: Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia 1998; 18:704-708. 171. Schoenen J, Jacquy J, Lenaerts M: Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998; 50:466-470. 172. Lipton RB, Gobel H, Wilks K, et al: Efficacy of petasites (an extract from petasites rhizome) 50 and 75mg for prophylaxis of migraine: results of a randomized, double-blind, placebo-controlled study [Abstract]. Neurology 2002; 58: A472. 173. Sandor PS, diClemente L, Coppola G, et al: Coenzyme Q10 for migraine prophylaxis: a randomized controlled trial [Abstract]. Cephalalgia 2003; 23:577. 174. Schrader H, Stovner LJ, Helde G, et al: Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo-controlled, crossover study. BMJ 2001; 322:19-22. 175. Tronvik E, Stovner LJ, Helde G, et al: Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 2003; 289:65-69. 176. Silberstein SD, Mathew N, Saper J, et al: Botulinum toxin type A as a migraine preventive treatment. Headache 2000; 40:445-450. 177. Silberstein SD, Lipton RB, Goadsby PJ: Migraine: diagnosis and treatment. In Silberstein SD, Lipton RB, Goadsby PJ, eds:

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178. 179. 180. 181.

Headache in Clinical Practice. Oxford, UK: Isis Medical Media, 1998, pp 61-90. Silberstein SD: Preventive treatment of migraine: an overview. Cephalalgia 1997; 17:67-72. Solomon GD: Management of the headache patient with medical illness. Clin J Pain 1989; 5:95-99. Silberstein SD, Lipton RB, Breslau N: Migraine: association with personality characteristics and psychopathology. Cephalalgia 1995; 15:337-369. Mathew NT, Saper JR, Silberstein SD, et al: Prophylaxis of migraine headaches with divalproex sodium. Arch Neurol 1995; 52:281-286.

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182. Bowden CL, Brugger AM, Swann AC: Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994; 271:918-924. 183. Pascual J, Leira R, Lainez JM: Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients. Cephalalgia 2003; 23:961-962.

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TENSION-TYPE HEADACHE ●

●

●

●

Messoud Ashina

Tension-type headache, the most common of the primary headaches,1,2 has tremendous socioeconomic effects.2,3 For many years, various terms such as tension headache, muscle contraction headache, psychomyogenic headache, stress headache, ordinary headache, essential headache, idiopathic headache, and psychogenic headache were used to characterize this common headache disorder. In 1988, the International Headache Society, to avoid using terminology with a specific pathophysiological implication, introduced the term tensiontype headache.4 The pathophysiology of tension-type headache is still far from clear, although advances in basic and clinical research have increased knowledge about the mechanisms underlying this disorder.5,6

DEFINITION The second edition of The International Classification of Headache Disorders (ICHD-II)7 subdivides tension-type headache into three main forms: 1. Infrequent episodic tension-type headache. 2. Frequent episodic tension-type headache. 3. Chronic tension-type headache. All forms are subdivided further into headache associated or not associated with pericranial tenderness. Diagnostic criteria are shown in Table 57–1.

EPIDEMIOLOGY The lifetime prevalence of tension-type headache is between 30% and 78%.1,2 Most affected patients (59%) reported tensiontype headache one day each month or less; 24% to 37% had headache several times each month; 10% had it weekly; and 2% to 3% of the population had chronic tension-type headache (≥15 days per month).8 The global prevalence of chronic tension-type headache is uniform (i.e., 2% to 3%). Unlike migraine headache, women are only slightly more affected than men, with a male/female ratio of 4 : 5.1,2,6

CLINICAL FEATURES Tension-type headache is diagnosed exclusively on the basis of the history and somatic and neurological examination findings.

The infrequent subtype has very little effect on the individual and does not represent a clinical or treatment challenge. However, frequent and chronic subtypes are always associated with considerable disability and high personal and socioeconomic costs. Patients usually complain of mild to moderate pain of varying duration in both the infrequent and frequent episodic forms of tension-type headache or of constant mild or moderate pain in the chronic form. The headache is bilateral, pressing or tightening pain, often described as feeling like “a pressure bandage around the head.” It is never associated with typical migrainous characteristics, such as aggravation by routine physical activity, severe nausea, vomiting, and severe photophobia or phonophobia. According to the ICHD-II criteria (see Table 57–1), patients with infrequent and frequent episodic tension-type headache have no more than one of the associated symptoms of photophobia or phonophobia. Mild nausea, photophobia, or phonophobia (no more than one of these symptoms) may be present in chronic tension-type headache.

ETIOLOGY AND PATHOPHYSIOLOGY Although there has been considerable progress in research on tension-type headache,5,6 the origin of pain in this prevalent primary headache is unknown. It has been suggested that both peripheral (nociception from myofascial tissue) and central (increased excitability of central nervous system) factors play a major role in the pathophysiology of tension-type headache. Epidemiological studies reported an increased familial risk in tension-type headache.9,10

Peripheral Factors Individuals who have been exposed to static or repetitive work for long periods of time may develop pericranial muscle tenderness and tension-type headache. Therefore, for many years the research on the mechanisms that lead to tension-type headache focused on peripheral or muscular factors. Increased pericranial myofascial tissue tenderness to manual palpation is the most prominent abnormal finding in patients with chronic tension-type headache.11-13 Painful impulses from these tissues may be referred to the head and perceived as headache, and myofascial mechanisms may therefore play a major role in the pathophysiology of tension-type headache.14 Possible excessive

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T A B L E 57–1. Diagnostic Criteria Infrequent Episodic Tension-Type Headache At least 10 episodes occurring on <1 day per month on average (<12 days per year) and fulfilling the next three criteria: Headache lasting from 30 minutes to 7 days Headache has at least two of the following characteristics: Bilateral location Pressing/tightening (nonpulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Headache is characterized by both of the following: No nausea or vomiting (anorexia may occur) No more than one of photophobia or phonophobia Not attributed to another disorder Frequent Episodic Tension-Type Headache At least 10 episodes occurring on ≥1 but <15 days per month for at least 3 months (≥12 and <180 days per year) and fulfilling the next three criteria: Headache lasting from 30 minutes to 7 days Headache has at least two of the following characteristics: Bilateral location Pressing/tightening (nonpulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Headache is characterized by both of the following: No nausea or vomiting (anorexia may occur) No more than one of photophobia or phonophobia Not attributed to another disorder Chronic Tension-Type Headache Headache occurring on ≥15 days per month on average for >3 months (≥180 days per year) and fulfilling the next three criteria: Headache lasts hours or may be continuous Headache has at least two of the following characteristics: Bilateral location Pressing/tightening (nonpulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Headache is characterized by both of the following: No more than one of photophobia, phonophobia or mild nausea Neither moderate or severe nausea nor vomiting Not attributed to another disorder

In summary, firm evidence for peripheral muscle pathology as a cause of muscle pain and chronic headache in tension-type headache is still lacking.

Central Factors Since the mid-1990s, there has been increasing interest in the role of central factors in tension-type headache. It has been shown that pressure pain detection and thresholds of tolerance of mechanical stimuli were decreased in chronic tension-type headache sufferers.20,21 Furthermore, Bendtsen and colleagues22 demonstrated that patients with chronic tension-type headache had a qualitatively altered pain perception. On the basis of these findings and data from basic pain research,23 it has been suggested that the central sensitization, and therefore the chronic pain state, in patients with chronic tension-type headache may result from sensitization at the level of the spinal dorsal horn, the trigeminal nucleus, or both, induced by prolonged nociceptive input from pericranial myofascial tissues.6 The hypothesis of central sensitization in tension-type headache is supported by experimental pharmacological studies. Animal studies have shown that sensitization of pain pathways may be caused by or associated with activation of nitric oxide synthase and the generation of nitric oxide.24 To test the hypothesis of central sensitization in tension-type headache, the antinociceptive effect of nitric oxide synthase inhibitors25,26 and the nociceptive effect of nitric oxide donor27 were investigated in patients with chronic tension-type headache. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine hydrochloride reduced headache and pericranial myofascial tenderness and hardness. Furthermore, the nitric oxide donor glyceryl trinitrate induced tension-type headache in these patients.27 These data suggest that nitric oxide plays an important role in the pathophysiology of chronic tension-type headache5 and that inhibition of nitric oxide synthase may become a novel principle in the treatment of this disorder. In summary, clinicians are beginning to understand some of the complex mechanisms leading to tension-type headache. It is hoped that this will lead to the development of more effective and specific treatment modalities.

Genetics pericranial muscle contraction, ischemia, and inflammation have been extensively studied in tension-type headache; however, electromyography with surface electrodes failed to demonstrate significantly increased activity.15-17 A microdialysis study reported altered blood flow regulation in tender skeletal muscles of patients with chronic tension-type headache during static work.18 The authors found no difference in locally increased interstitial lactate between patients and control subjects. This seems to rule out the presence of ischemia in the tender points of chronic tension-type headache patients during static exercise. It was hypothesized that increased excitability of neurons in the central nervous system may affect the regulation of muscle blood flow during static work.18 The microdialysis study also demonstrated that the interstitial concentration of inflammatory mediators in tender muscle did not differ between patients with chronic tensiontype headache and healthy subjects.19 These data indicate that tender points are not sites of ongoing inflammation.

A single genetic epidemiological study has investigated the familial aggregation of chronic tension-type headache in 122 probands recruited from a headache clinic.9 In comparison with the general population, first-degree relatives of the probands had a 3.1-fold increased risk of chronic tension-type headache, whereas spouses had no increased risk of chronic tension-type headache. It was suggested that an increased familial risk can be caused by both genetic and environmental factors.10

TREATMENT The current pharmacotherapy of tension-type headache is nonspecific and includes simple analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) for the episodic form and antidepressants for prophylaxis in the chronic form. Before any pharmacological or nonpharmacological therapy is initiated, an

chapter 57 tension-type headache accurate diagnosis must be established. Patients with frequent episodic or chronic tension-type headache should complete a 4-week diagnostic headache diary28 to confirm the diagnosis and to rule out possible medication overuse headache.

Acute Therapy Acute pharmacotherapy includes treating each episode of tension-type headache (i.e., infrequent and frequent episodic tension-type headache according to ICHD-II criteria). Simple analgesics and NSAIDs are the mainstays of acute tension-type headache therapy (Table 57–2). Aspirin and acetaminophen are the most commonly used analgesics. Randomized, controlled trials have demonstrated that acetaminophen, aspirin, and NSAIDs are effective in the treatment of single episodes of tension-type headache and should be included in the treatment of mild or moderate episodes (for review, see Ashina and Ashina29). Acetaminophen may be the first choice because of a better gastric side effect profile. More randomized, controlled, and comparative studies are needed to evaluate the efficacy and safety of combination analgesics in the treatment of infrequent and frequent episodic tension-type headache.29 Muscle relaxants are not considered effective because of insufficient studies and the risk of habituation30 and generally are not recommended. In addition, physicians should be aware of the risk of developing medication overuse headache as a result of frequent and excessive use of analgesics used in acute therapy. Recommended dosages of simple analgesics are shown in Table 57–2.

Preventive Therapy Preventive treatment is considered if a patient experiences a headache on 15 or more days each month (i.e., chronic tensiontype headache). Controlled randomized trials have demonstrated that amitriptyline has a statistically significant and clinically relevant effect in the prophylactic treatment of chronic tension-type headache.31-34 In addition, amitriptyline reduced secondary variables, such as headache duration and

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frequency, intake of analgesics, and myofascial tenderness.35 Amitriptyline should be considered the drug of first choice in the preventive treatment of chronic tension-type headache (see Table 57–2). Bendtsen and Jensen35 evaluated the efficacy of the noradrenergic and serotonergic antidepressant mirtazapine in 24 nondepressed patients with chronic tension-type headache in a randomized, double-blind, placebo-controlled, crossover trial. Mirtazapine reduced the area-under-the-headache curve (duration × intensity) by 34% more than placebo, and headache frequency, duration, and intensity in patients whose condition was difficult to treat, including patients who had not responded to amitriptyline. Mirtazapine was well tolerated. The efficacy was comparable with that of amitriptyline as reported in a previous study that used the same methods, but there were considerably fewer side effects. Mirtazapine should be considered the drug of second choice for the prophylactic treatment of chronic tension-type headache. In a randomized, double-blind, placebo-controlled, crossover trial, the selective serotonin reuptake inhibitor (SSRI) citalopram had no effect on patients with chronic tension-type headache.31 In a randomized, doubleblind, placebo-controlled, crossover trial, tizanidine was more effective than placebo at the end of the treatment period, and the authors suggested that tizanidine was effective in the preventive treatment of chronic tension-type headache in women.36 In another study, however, the effects of a modifiedrelease formulation of tizanidine in dosages up to 12 mg daily did not differ from those of placebo.37 In summary, more placebo-controlled trials are needed to demonstrate the possible efficacy of SSRIs and muscle relaxants in the preventive treatment of chronic tension-type headache. Data on the efficacy of botulinum toxin in the treatment of tension-type headache are based on a limited number of studies with several methodological reservations.29 No common consensus has been reached on the number of injection sites and dosages in clinical trials. The results demonstrate a need for additional randomized controlled trials with standard procedures before botulinum toxin can be recommended for the preventive treatment of chronic tension-type headache.

Nonpharmacological Therapy T A B L E 57–2. Recommended Dosages for Acute and Preventive Therapy of Tension-Type Headache Acute Therapy* 500 mg of aspirin 1000 mg of aspirin or 1000 mg of acetaminophen 200 mg of ibuprofen 25 mg of ketoprofen 400 mg of ibuprofen or 50 mg of ketoprofen Preventive Therapy 10-75 mg of amitriptyline daily 15-30 mg of mirtazapine daily Modified from Ashina S, Ashina M: Current and potential future drug therapies for tension-type headache. Curr Pain Headache Rep 2003; 7:466-474, with permission from BioMed Central. *For fewer than 15 headache days per month. Drugs used in acute therapy are classified hierarchically according to efficacy demonstrated in placebo-controlled trials. Dosages in preventive therapy are increased until efficacy or side effects are reported.

Behavioral approaches and physiotherapy are widely used as adjunct therapies and also, to a lesser extent, as an alternative to standard medication. The main goal of these approaches is to eliminate factors that are responsible for an increase in frequency and severity of tension-type headache. The question is whether there is a strong evidence-based effect of nonpharmacological therapy. Few studies have addressed these issues in a controlled design with properly classified patients with tension-type headache. Holroyd and associates38 reported that cognitive-behavioral (stress management) therapy had effectiveness comparable with that of amitriptyline in 41 patients with recurrent tension-type headache. In a large randomized, controlled trial, tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headacherelated disability than did placebo, but antidepressant medication yielded more rapid improvements in headache activity.39 Combined therapy was more likely to produce clinically significant reductions in headache index scores (in 64% of participants) than was antidepressant medication (in 38%), stress

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management therapy (in 35%), or placebo (in 29%). The authors concluded that combined therapy might improve outcomes in relation to monotherapy.39 Torelli and colleagues40 investigated the therapeutic effect of physiotherapy in 48 patients with frequent episodic tension-type headache or chronic tension-type headache. After a 4-week run-in period, patients were randomly assigned to either an 8-week period of standardized physiotherapy (group 1) or an 8-week observation period followed by an identical course of physiotherapy (group 2). After the physiotherapy, all patients were monitored for a 12-week follow-up period. Although the average number of days with headache per 4-week period was significantly reduced by physiotherapy in comparison with waiting list, severity and duration of headache, as well as drug consumption, did not differ. Interestingly, the number of responders was higher among patients with chronic tension-type headache than among patients with frequent episodic tension-type headache.40 In summary, to verify the effectiveness of nonpharmacological treatment strategies, more well-designed randomized controlled trials, which should be reported according to the Consolidated Standards of Reporting Trials guidelines, are needed.41

CONCLUSION AND RECOMMENDATIONS Tension-type headache is an important primary headache in terms of its high prevalence. The frequent episodic and chronic subtypes are associated with considerable disability and represent a therapeutic challenge. It is recommended that patients with frequent episodic and chronic tension-type headache complete a diagnostic headache diary to rule out possible medication overuse headache. Simple analgesics and NSAIDs are the mainstays in the acute therapy of tension-type headache. Amitriptyline should be considered the drug of first choice in the preventive treatment of chronic tension-type headache. If the patient does not respond to amitriptyline, mirtazapine should be attempted. If side effects are a major concern, mirtazapine may also be a first-choice drug. The SSRIs may be considered for patients with concomitant depression if amitriptyline and mirtazapine are not tolerated. The psychological and behavioral approaches and physiotherapy may be used as adjuncts to standard medication.

K E Y

P O I N T S

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Tension-type headache is the most common type of primary headache. The lifetime prevalence of tension-type headache is between 30% and 78%. Tension-type headache is the least studied of the primary headache disorders, despite the fact that it has a tremendous socioeconomic effect.

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Tension-type headache is diagnosed exclusively on the basis of the history and somatic and neurological examinations.

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The current pharmacotherapy of tension-type headache is nonspecific and includes simple analgesics and NSAIDs for the episodic form and the tricyclic antidepressant amitriptyline for the chronic form.

Suggested Reading Ashina M: Neurobiology of chronic tension-type headache. Cephalalgia 2004; 24:161-172. Bendtsen L: Central sensitization in tension-type headache— possible pathophysiological mechanisms. Cephalalgia 2000; 20:486-508. Holroyd KA, O’Donnell FJ, Stensland M, et al: Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA 2001; 285:22082215. The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24(Suppl 1):9-160. Olesen J, Tfelt-Hansen P, Welch KMA, eds: The Headaches, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000.

References 1. Rasmussen BK, Jensen R, Schroll M, et al: Epidemiology of headache in a general population—a prevalence study. J Clin Epidemiol 1991; 44:1147-57. 2. Schwartz BS, Stewart WF, Simon D, et al: Epidemiology of tension-type headache. JAMA 1998; 4:381-383. 3. Rasmussen BK, Jensen R, Olesen J: Impact of headache on sickness absence and utilisation of medical services: a Danish population study. J Epidemiol Commun Health 1992; 46:443446. 4. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders. Cephalalgia 1988; 8(Suppl 7):1-96. 5. Ashina M: Neurobiology of chronic tension-type headache. Cephalalgia 2004; 24:161-172. 6. Bendtsen L: Central sensitization in tension-type headache— possible pathophysiological mechanisms. Cephalalgia 2000; 20:486-508. 7. The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24(Suppl 1):9-160. 8. Jensen R: Diagnosis, epidemiology, and impact of tension-type headache. Curr Pain Headache Rep 2003; 7:455-459. 9. Ostergaard S, Russell MB, Bendtsen L, et al: Comparison of first degree relatives and spouses of people with chronic tension headache. BMJ 1997; 314:1092-1093. 10. Russell MB, Iselius L, Ostergaard S, et al: Inheritance of chronic tension-type headache investigated by complex segregation analysis. Hum Genet 1998; 102:138-140. 11. Bendtsen L, Jensen R, Jensen NK, et al: Pressure-controlled palpation: a new technique which increases the reliability of manual palpation. Cephalalgia 1995; 15:205-210. 12. Jensen R, Bendtsen L, Olesen J: Muscular factors are of importance in tension-type headache. Headache 1998; 38:1017. 13. Lipchick GL, Holroyd KA, Talbot F, et al: Pericranial muscle tenderness and exteroceptive suppression of temporalis muscle activity: a blind study of chronic tension-type headache. Headache 1997; 37:368-376. 14. Olesen J: Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs. Pain 1991; 46:125-132. 15. Jensen R: Pathophysiological mechanisms of tension-type headache: a review of epidemiological and experimental studies. Cephalalgia 1999; 19:602-621. 16. Schoenen J, Gerard P, De Pasqua V, et al: EMG activity in pericranial muscles during postural variation and mental activity in healthy volunteers and patients with chronic tension type headache. Headache 1991; 31:321-324.

chapter 57 tension-type headache 17. Schoenen J, Gerard P, De Pasqua V, et al: Multiple clinical and paraclinical analyses of chronic tension-type headache associated or unassociated with disorder of pericranial muscles. Cephalalgia 1991; 11:135-139. 18. Ashina M, Stallknecht B, Bendtsen L, et al: In vivo evidence of altered skeletal muscle blood flow in chronic tension-type headache. Brain 2002; 125:320-326. 19. Ashina M, Stallknecht B, Bendtsen L, et al: Tender points are not sites of ongoing inflammation—in vivo evidence in patients with chronic tension-type headache. Cephalalgia 2003; 23:109-116. 20. Bendtsen L, Jensen R, Olesen J: Decreased pain detection and tolerance thresholds in chronic tension-type headache. Arch Neurol 1996; 53:373-376. 21. Schoenen J, Bottin D, Hardy F, et al: Cephalic and extracephalic pressure pain thresholds in chronic tension-type headache. Pain 1991; 47:145-149. 22. Bendtsen L, Jensen R, Olesen J: Qualitatively altered nociception in chronic myofascial pain. Pain 1996; 65:259-264. 23. Woolf CJ, Doubell TP: The pathophysiology of chronic pain— increased sensitivity to low threshold A beta-fiber inputs. Curr Opin Neurobiol 1994; 4:525-534. 24. Meller ST, Gebhart GF: Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993; 52:127-136. 25. Ashina M, Bendtsen L, Jensen R, et al: Possible mechanisms of action of nitric oxide synthase inhibitors in chronic tensiontype headache. Brain 1999; 122:1629-1635. 26. Ashina M, Lassen LH, Bendtsen L, et al: Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial. Lancet 1999; 353:287-289. 27. Ashina M, Bendtsen L, Jensen R, et al: Nitric oxide–induced headache in patients with chronic tension-type headache. Brain 2000; 123:1830-1837. 28. Russell MB, Rasmussen BK, Brennum J, et al: Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 1992; 12:369-374. 29. Ashina S, Ashina M: Current and potential future drug therapies for tension-type headache. Curr Pain Headache Rep 2003; 7:466-474.

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30. Jensen R: Tension-type headache. Curr Treat Options Neurol 2001; 3:169-180. 31. Bendtsen L, Jensen R, Olesen J: A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J Neurol Neurosurg Psychiatry 1996; 61:285-290. 32. Gobel H, Hamouz V, Hansen C, et al: Chronic tension-type headache: amitriptyline reduces clinical headache-duration and experimental pain sensitivity but does not alter pericranial muscle activity readings. Pain 1994; 59:241-249. 33. Diamond S, Baltes BJ: Chronic tension headache—treated with amitriptyline—a double-blind study. Headache 1971; 11:110-116. 34. Lance JW, Curran DA: Treatment of chronic tension headache. Lancet 1964; 42:1236-1239. 35. Bendtsen L, Jensen R: Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache. Cephalalgia 2000; 20:603-610. 36. Fogelholm R, Murros K: Tizanidine in chronic tension-type headache: a placebo controlled double-blind cross-over study. Headache 1992; 32:509-513. 37. Murros K, Kataja M, Hedman C, et al: Modified-release formulation of tizanidine in chronic tension-type headache. Headache 2000; 40:633-637. 38. Holroyd KA, Nash JM, Pingel JD, et al: A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches. J Consult Clin Psychol 1991; 59:387-393. 39. Holroyd KA, O’Donnell FJ, Stensland M, et al: Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA 2001; 285:22082215. 40. Torelli P, Jensen R, Olesen J: Physiotherapy for tension-type headache: a controlled study. Cephalalgia 2004; 24:29-36. 41. Begg C, Cho M, Eastwood S, et al: Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996; 276:637-639.

CHAPTER

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CHRONIC DAILY HEADACHE ●

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Marcelo E. Bigal and Richard B. Lipton

Chronic daily headache (CDH) of long duration is a clinical syndrome defined by headaches that occur for 4 hours a day or more on 15 days or more a month for more than 3 months.1,2 CDH is one of the most common and disabling headache presentations in headache specialty care centers; it afflicts 4% to 5% of the general population.3,4 Many patients with CDH are severely impaired.5 CDH sufferers also have higher disability than those with episodic migraine.6 As a syndrome, CDH was not included in the first or the second edition of the International Classification of Headache Disorders (ICHD).7,8 As a consequence, several separate proposals for its classification have emerged. Silberstein’s and Lipton’s criteria have been most widely used2 (unpublished data). The S-L criteria divide primary CDH into transformed migraine, chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua and subclassify each of these into subtypes “with medication overuse” or “without medication overuse” (Table 58–1). Of these, only CTTH was included in the ICHD-I7 classification, whereas the ICHD-II8 has detailed diagnostic criteria for all four types of primary CDH of long duration. The term chronic migraine was introduced in place of transformed migraine and has a very different definition, as discussed later in this chapter. Although the ICHD-II is a vast improvement, recent studies show that it remains cumbersome for the classification of CDH in adults.9 This chapter focuses on CDH and its subtypes as defined by Silberstein’s and Lipton’s criteria. We also present proposed criteria for transformed migraine that are still under discussion by the International Headache Society. Whenever appropriate, we correlate these S-L criteria with the ICHD-II. We then focus on transformed migraine and discuss transformed migraine as the result of episodic migraine that has progressed over time. We finish by highlighting the strategies for the treatment of CDH and potential strategies for avoiding the development of CDH.

EPIDEMIOLOGY OF THE CHRONIC DAILY HEADACHE The epidemiology of CDH has been described in a number of population samples based in Europe, Asia, and the United States (Table 58–2).3,4,10,11 The prevalence of CDH is remarkably con-

sistent among studies, ranging from 2.4% (Norway) to 4.7% (Spain). In the United States, the prevalence is 4.1%. From 35% to 50% of CDH sufferers in the population have transformed migraine. The incidence of CDH was investigated in a prospective study in the United States. Among subjects with episodic headaches at baseline, 3% developed CDH within 1 year.12 The incidence among migraine sufferers in subspecialty care is 13%. Clinic-based studies show that CDH affects up to 80% of the patients presenting in a headache clinic.13-16 In this setting, transformed migraine is by far the most common type of CDH. In a study by Mathew and associates,14 77% of the patients with CDH had transformed migraine. In our clinic, transformed migraine represented 87.4% of the cases of CDH seen in a headache specialty center.13

CLINICAL CHARACTERIZATION Transformed Migraine/Chronic Migraine Patients with transformed migraine have a history of migraine. Sufferers usually report a process of transformation over months or years, and as headache frequency increases, associated symptoms become less severe and frequent.13-16 The process of transformation frequently ends in a pattern of daily or nearly daily headache that resembles CTTH, with some attacks of full migraine superimposed.2 In the clinical setting, migraine transformation is most often related to acute medication overuse, but transformation may occur without overuse.17 In the general population, most cases of transformed migraine are not related to medication overuse.12 Multiple risk factors may be involved in these cases (see section risk factors for the development of CDH). The International Headache Society proposed criteria for the diagnosis of transformed migraine: (1) Headache frequency is 15 days or more per month for 3 months or more, with an average headache duration of more than 4 hours/day (if untreated); (2) the headache fulfills criteria for migraine without aura, on 8 or more of the headache days; and (3) the headache does not meet criteria for CTTH, hypnic headache, hemicrania continua, or NDPH (Table 58–3).

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The terms transformed migraine and chronic migraine have been used synonymously in the past, but this is no longer appropriate: Chronic migraine has a specific definition in the ICHD-II, which does not recognize transformed migraine as a separate entity.8 One main difference exists between the S-L–AHS (transformed migraine) and ICHD-II (chronic migraine) systems: The ICHD-II criteria for chronic migraine require that headaches meeting criteria for migraine without aura occur on at least 15 days a month. To classify transformed migraine, the S-L–AHS criteria require at least 15 days of headache (not necessarily migraine), in which at least 50% of the days fulfill criteria for migraine or probable migraine.

Chronic Tension-Type Headache CTTH (see Table 48–3) represents one half of the CDH cases found in population studies but just a small fraction of those found in specialty clinics. It is the only CDH that was addressed by the ICHD-I as a single diagnosis.7 The criteria remained little changed in the ICHD-II.8 Despite the International Headache

T A B L E 58–1. The Classification of the Chronic Daily Headaches* According to Silberstein’s and Lipton’s2 Criteria 1.8 Transformed Migraine 1.8.1 With overuse 1.8.2 Without overuse 2.2 Chronic Tension-Type Headache 2.2.1 With overuse 2.2.2 Without overuse 4.7 New Daily Persistent Headache 4.7.1 With overuse 4.7.2 Without overuse 4.8 Hemicrania Continua 4.8.1 With overuse 4.8.2 Without overuse *Daily or near-daily headache lasting ≥4 hours for ≥15 days/month.

Society criteria distinguishing between episodic headache and CTTH, this headache remains surprisingly poorly studied. This can be explained partially by the confusion between CTTH and transformed migraine with a low frequency of superimposed migraine attacks. The prevalence of CTTH is markedly lower than that of episodic tension-type headache (ETTH), the most prevalent primary headache disorder. Its 1-year prevalence estimates range from 1.7% to 2.2%.18,19 The female preponderance of CTTH is greater than that of ETTH. In the United States, the prevalence of CTTH was reported to be 2.8 among women and 1.4 among men, with an overall gender prevalence ratio of 2.0.20 The prevalence of CTTH increases with age. The distinguishing pain features of CTTH are bilateral location, nonpulsating quality, mild to moderate intensity, and lack of aggravation by routine physical activity. The pain is not accompanied by nausea, although the presence of either photophobia or phonophobia (but not both) does not exclude the diagnosis. If the CDH develops abruptly (de novo), patients are said to have NDPH.

New Daily Persistent Headache Daily headache (see Table 58–3) may begin without a history of evolution from episodic headache. Regardless of the phenotype, Silberstein’s and Lipton’s system classifies such headache as NDPH.2 NDPH is characterized by the relatively abrupt onset of an unremitting primary CDH in a patient without a previous headache syndrome. The new onset of this primary daily headache is the most important feature. The clinical features of the pain are not considered in making the diagnosis, which requires only the absence of a history of evolution from migraine or ETTH. Silberstein’s and Lipton’s classification allows the diagnosis of NDPH in patients with either migraine or ETTH if these disorders do not increase in frequency to give rise to NDPH. The ICHD-II addresses NDPH as a single diagnosis in those with a new-onset CDH that resembles CTTH.8 A new-onset CDH with migrainous features cannot be classified as NDPH

T A B L E 58–2. Prevalence of Very Frequent Headaches in Adult Populations According to Silberstein’s and Lipton’s2 Criteria Prevalence (%) Author*

Country

Scher et al (1998)3 Castillo et al (1999)4 Wang (1999) Hagen (2000) Ho (2001) Lu (2001) Prencipe (2001) Lantéri-Minet (2003) Takeshima (2004)

United States Spain China Norway Singapore Taiwan Italy France Japan

N 13,343 1,883 1,533 51,383 2,096 3,377 833 10,585 5,758

Case Definition

Age Range

All Chronic Headaches

CTTH

≥15/month ≥15/month, ≥4 hr/day ≥15/month, ≥6 months ≥15/month >180/year ≥15/month, ≥4 hr/day ≥15/month Daily CTTH only

18-65 ≥14 ≥65 ≥20 ≥12 ≥15 ≥65 ≥15 ≥20

4.1 4.7 3.9 2.4 3.3 3.2 4.4 3.0 —

2.2 2.2 2.7 — — 1.4 2.5 — 2.1

TM

Female/Male Prevalence Ratio

Analgesic Overuse (%)†

1.3 2.4 1.0 — — 1.7 1.6 — —

1.8 8.7 3.1 1.6 — 2.3 2.4 2.6 —

— 25 25 — — 34 38 — —

Modified from Scher AI, Stewart WF, Lipton RB: Migraine and headache. A meta-analytic approach. In Crombie IK, ed: Epidemiology of Pain. Seattle: IASP Press, 1999, pp 159-170. *Ordered by year of publication, oldest to most recent. † Analgesic overuse based on Silberstein’s45 criteria. CTTH, chronic tension-type headache; TM, transformed migraine.

chapter 58 chronic daily headache

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T A B L E 58–3. Diagnostic Criteria for Primary Chronic Daily Headaches According to the International Classification of Headache Disorders (2004) Criteria and Silberstein’s and Lipton’s2 Criteria Headache

S-L–AHS

ICHD-II

Transformed migraine/ chronic migraine

Transformed Migraine Headache frequency ≥15 days/month for 3 months Average headache duration of ≥4 hours/day (if untreated) Headache fulfilling HIS criteria for migraine without aura (1.1), migraine with aura (1.2), or probable migraine (1.6), on ≥50% of the headache days Does not meet criteria for IHS chronic tension-type headache (2.3), hypnic headache (4.5), hemicrania continua (4.7) or new daily persistent headache (4.8) Not attributed to another disorder Average headache frequency ≥15 days/month (180 days/year) for ≥6 months and fulfilling the next three criteria: At least two of the following pain characteristics: 1. Pressure or tightening quality 2. Mild or moderate severity (may inhibit but does preclude activities) 3. Bilateral location 4. No aggravation by walking stairs or similar routine physical activity Both of the following: 1. No vomiting 2. *** No more than one of the following: nausea, photophobia, phonophobia

Chronic Migraine (Appendix) Description: Migraine headache ≥15 days per month for ≥3 months and no drug overuse Diagnostic criteria: Headache fulfilling criteria C and D for migraine without aura (1.1) on ≥18 days/month for >3 months Not attributed to another disorder

Chronic tensiontype headache

New daily persistent headache

Average headache frequency >15 days/month for >1 month Average headache duration >4 hours/day (if untreated); frequently constant without medication but may fluctuate No history of tension-type headache or migraine which increases in frequency and decreases in severity in association with the onset of new daily persistent headache (over 3 months) Acute onset (developing over <3 days) of constant unremitting headache Headache is constant in location (needs to be tested) Does not meet any criteria for hemicrania continua (4.8)

Hemicrania continua

Headache present for at least 1 month and fulfilling the next three criteria: Unilateral headache Pain has all three of the following qualities: 1. Continuous but fluctuating severity 2. Pain exacerbations of at least moderate severity 3. Lack of precipitating mechanisms Either absolute response to indomethacin or one of the following features with severe pain exacerbation: 1. Conjunctival injection 2. Lacrimation 3. Nasal congestion 4. Rhinorrhea 5. Ptosis 6. Eyelid edema 7. Idiopathic stabbing headache

At least 10 episodes fulfilling the next five criteria; number of days with such headache ≥15 days per month for at least 3 months (≥180 days per year) continuously Headache lasts hours or may be continuous; at least two of the following pain characteristics: 1. Pressing/tightening (nonpulsating) quality 2. Mild or moderate intensity (may inhibit but does not preclude activities) 3. Bilateral location 4. No aggravation by walking stairs or similar routine of physical activity Both of the following: 1. No more than one of the following: photophobia, phonophobia, or mild nausea 2. No moderate or severe nausea and no vomiting Use of analgesics or other acute medication on ≤10 days per month Not attributed to another disorder Headache that, within 3 days of onset, fulfills the next three criteria: Headache is present daily, and is unremitting, for >3 months At least two of the following pain characteristics: 1. Bilateral location 2. Pressing/tightening (nonpulsating) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity such as walking or climbing Both of the following: 1. No more than one of the following: photophobia, phonophobia, or mild nausea 2. Neither moderate or severe nausea nor vomiting Not attributed to another disorder Headache present for at least 2 months and fulfilling the next four criteria: Unilateral headache without side shift Pain has the following qualities: 1. Daily and without pain-free periods 2. Moderate severity but with exacerbations when it becomes severe Complete response to indomethacin At least one of the following autonomic features in association with exacerbations of pain on the affected side: 1. Conjunctival injection and/or lacrimation 2. Nasal congestion and/or rhinorrhea 3. Ptosis and/or miosis Not attributed to another disorder

ICHD-II, International Classification of Headache Disorders, 2nd ed.; IHS, International Headache Society; S-L, Silberstein and Lipton.

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according to the ICHD-II criteria, whereas Silberstein and Lipton’s classification allows this diagnosis in patients with headache features of migraine or ETTH if the disorder arises abruptly.

Hemicrania Continua Hemicrania continua (see Table 58–3) is an uncommon primary headache disorder first described as a syndrome by Sjaastad and Spierings.21 This daily, continuous, strictly unilateral headache is defined by its absolute response to therapeutic doses of indomethacin. Pain is moderate, with exacerbations of severe pain, and autonomic symptoms accompany these exacerbations, although less prominently than in cluster headache and chronic paroxysmal hemicrania.

PATHOPHYSIOLOGY Chronic Daily Headache as the Result of Progression of Disease Although the source of pain in primary CDH is unknown and may be dependent on the subtype, research findings suggest that the following mechanisms, alone or in combination, contribute to the process:22 (1) abnormal excitation of peripheral nociceptive afferent fibers in the meninges; (2) enhanced responsiveness of trigeminal nucleus caudalis neurons; (3) decreased pain modulation from higher centers such as the periaqueductal gray matter; (4) spontaneous central pain generated by activation of the “on cells” in the medulla; (5) decreased serotonin levels; and (6) central sensitization. There is evidence that a subgroup of migraine sufferers may have a clinically progressive disorder.23 Herein we analyze evidence that support the concept that migraine progresses within attacks and also as a disease, evolving to transformed migraine. Figure 58–1 summarizes theoretical concepts on this regard. An imaging study has shown that iron deposition occurs in the periaqueductal gray area in subjects with chronic headaches.24 The periaqueductal gray area is related to the descending analgesic network and is important in controlling pain and providing endogenous analgesia. It is also closely related to the trigeminal nucleus. In this study, the iron levels were higher in migraine sufferers than in controls and higher

30 25 20 15 10 5 0

Baseline Follow-up

Group 1 ■

Group 2

Figure 58–1. Evolution of the frequency of headache in subjects that stopped (group 1) or continued analgesic overuse (group 2) after 1 year of follow-up. The number represents the number of headaches per day in a month.

in CDH headache sufferers than in migraineurs. These findings may be directly attributable to iron-catalyzed, free-radical cell damage. The authors suggested that iron deposition may reflect progressive neuronal damage related to recurrent migraine attacks. It can be hypothesized that repetitive central sensitization of the trigeminal neurons is correlated with iron deposition in the periaqueductal gray area and, therefore, migraine attacks predispose to disease progression. Evidence of migraine progression also comes from a neuroimaging study.25 Kruit and colleagues used a cross-sectional design to study Dutch adults aged 30 to 60 years. They showed that male subjects who had migraine with aura were at an increased risk of posterior circulation infarction. In addition, women who had migraine with or without aura were at a higher risk of deep white matter lesions than were controls. The white matter lesions increased with attack frequency, possibly demonstrating progression of the disease. Finally, in a longitudinal epidemiological study, Scher and associates12 showed that 3% of individuals with episodic headache (headache frequency, 2 to 104 days per year) progressed to CDH over the course of 1 year. The authors concluded that the incidence of CDH in subjects with episodic headache is 3% per year. Burstein and colleagues26 showed that approximately 75% of migraine sufferers develop central sensitization (sensitization of the second order trigeminal neuron, which is clinically manifested by the development of cutaneous allodynia) during the course of a migraine attack. Central sensitization appears to be associated with triptan refractoriness. Central sensitization explains the progression of attacks but also may play a role in the progression of the disease itself. It is suggested that repeated central sensitization episodes are associated with permanent neuronal damage, preventive treatment refractoriness, and disease progression.26-28

Risk Factors for the Development of Chronic Daily Headache Limited evidence exists about risk factors for migraine progression. One study revealed that the prevalence of CDH decreased slightly with age and increased in women (odds ratio, 1.65; 95% confidence interval, 1.3 to 2.0) and in divorced, separated, or widowed individuals (odds ratio, 1.50; 95% confidence interval, 1.2 to 1.9).11,12 CDH prevalence was inversely associated with educational level. Subjects with less than a high school education had more than a threefold risk of CDH in comparison with those with a graduate school–level education (odds ratio, 3.56; 95% confidence interval, 2.3 to 5.6). CDH was also associated with a self-reported physician’s diagnosis of arthritis (odds ratio, 2.50; 95% confidence interval, 1.9 to 3.3) or diabetes (odds ratio, 1.51; 95% confidence interval, 1.01 to 2.3), with previous head trauma, and with medication overuse.12 Of importance is that the risk of new-onset CDH increased nonlinearly with baseline headache frequency; elevated risk was limited primarily to controls with more than about two headaches per month. Finally, the stronger risk factor for the development of CDH was obesity (odds ratio, 5.53; 95% confidence interval, 1.4 to 21.8), a risk factor confirmed in another population study.29

chapter 58 chronic daily headache Chronic Daily Headache and Medication Overuse In most clinical studies of CDH, overuse of analgesics or other acute-care medications figures prominently.4,14,15,30 A number of issues with this association evoke controversy. Is overuse a significant factor in transforming episodic headache into CDH? Or is the frequently observed overuse merely a response to chronic pain itself? Although medication rebound has not been demonstrated in placebo-controlled trials, withdrawal headache has been shown in a controlled trial of caffeine withdrawal.31 Diener and Limmroth,32 using individual studies plus meta-analysis, found that the time required for the development of CDH was approximately 5 years of exposure to medication and a history of primary headache for 10 years before that. A patient develops CDH, according to Diener and Limmroth32 and Katsarava and colleagues,33 after consuming a critical dose of a single medication or a combination of medications for an extended period of time, which is shortest for triptans (1 to 2 years), longer for ergots (3 years), and longest for analgesics (5 years). Acute withdrawal of the offending medications worsens headache for a finite time, usually from 3 days to 3 weeks. Both preventive and acute-care treatments for the primary headache usually fail if use of the offending medication or medications is not terminated.34 In an attempt to better understand the relationship between medication overuse and refractory headaches, Wilkinson and coworkers35 looked for CDH in 28 patients who underwent total colectomy for ulcerative colitis. All migraineurs who overused opioids developed CDH (19%), whereas no nonmigraineurs who overused opioids did so. Bahra and associates36 showed that when nonsteroidal anti-inflammatory drugs are used daily in large doses for medical conditions, such as rheumatoid arthritis, they do not induce CDH in subjects without preexisting primary headache disorders. Both studies established two principles of medication overuse headache: (1) Even when the overused medication is used for reasons other than headache, it may still be associated with the development of CDH, and (2) acute medication overuse induces CDH only in those predisposed (i.e., those with preexisting episodic migraine).

THE TREATMENT OF CHRONIC DAILY HEADACHE Principles of Treatment As with other lifelong illness, several fundamental management considerations are important for treatment success in patients with CDH.37 Patients suffering from long-duration CDH often present not only with acute medication overuse but also with psychiatric and somatic comorbidity, low frustration tolerance, and physical and emotional dependence. In patients with primary CDH, it is important to identify the subtype of CDH and evaluate for the presence of analgesic overuse and comorbid conditions. A combination of pharmacological, nonpharmacological, behavioral, and sometimes physical interventions is usually necessary for a favorable outcome. The essential features of an effective treatment regimen include a combination of the following steps: 1. Educate the patient, and establish expectations and a followup plan.

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2. Use nonpharmacological therapies when appropriate: ■ Biofeedback and relaxation therapy ■ Cognitive behavioral therapy ■ Individual/family counseling as necessary ■ Dietary instructions, chronobiological therapy, and sleep hygiene ■ Daily exercise program 3. Identify, address, and treat psychiatric and somatic comorbid conditions. 4. Discontinue use of all potentially offending medications and caffeine through outpatient or inpatient detoxification procedures. 5. Institute a program of acute care and preventive pharmacological therapy. Discussing the nonpharmacological treatment of CDH, as well as the treatment of comorbid disorders, is beyond the scope of this chapter. Herein we focus on the outpatient treatment of medication overuse and basic prospects to treat and prevent the development of CDH.

Treatment of Medication Overuse Most studies suggest the benefit and necessity of detoxifying the patient by weaning from the overused medication (when present), followed by an intensive, long-term treatment plan.38-40 Many patients who discontinue their overused medications experience considerable improvement; if they do not experience improvement, their condition is usually difficult to treat effectively. The evolution of the frequency of headache, in a comparison of patients who stopped using excessive analgesics with those who did not, as seen in a tertiary care setting after longterm follow-up, is displayed in Figure 58–1.41 Basically, there are three outpatient approaches to detoxification. One approach is to taper the overused medication gradually while an effective preventive therapy is established. The second strategy is to abruptly discontinue the overused drug, institute a transitional medication (medication bridge) to break the cycle of headache, and subsequently taper the transitional medication. The third approach is to combine the two strategies by eliminating the rebound medication rapidly and adding a preventive medication rapidly but also supplying a temporary bridge, to give the patient the maximal chance to improve without drastically worsening first. No matter what medication is being tapered, a very useful technique is to use a 3- to 7-day tapering schedule of oral steroids: prednisone, starting at 60 mg/day; dexamethasone, starting at 4 to 12 mg/day. The mechanism of action is unknown but presumed to be related to decreased neurogenic inflammation in the meninges. A second adjunctive therapy is to use a short course of daily triptans in patients who are not overusing them. For example, a patient could use daily naratriptan (2.5 mg twice a day) for 7 days. One study showed that transitional therapy with naratriptan was as effective as transitional therapy with prednisone, and both were more effective than just tapering off the overused medication.42 For medications containing butalbital compounds or opioids, abrupt discontinuation may be followed by severe abstinence syndrome. Thereby, for patients suspected of overusing butalbital compounds, it is important to calculate the

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average daily dose of medication in order to slowly taper over time. One approach is to reduce the dosage by one tablet every 3 to 5 days. A more controlled approach is to replace the overused butalbital with longer-acting phenobarbital, from which it is easier to withdraw. For each 100-mg dose of butalbital, an equivalent dose would be 30 mg of phenobarbital in divided doses throughout the day. Once this switch has been made, phenobarbital can be tapered 15 to 30 mg/day, thereby avoiding withdrawal.37 For opioids, one approach is to taper the opioid 10% to 15% every day over 7 to 10 days. It usually helps to add clonidine, 0.05 or 0.1 mg two or three times a day, during opioid withdrawal. This prevents withdrawal symptoms (probably by decreasing the release of norepinephrine) and, if given in high enough doses, can speed the detoxification process. Clonidine can be given either by tablet or transcutaneously. During opioid withdrawal, lack of ability to fall and stay asleep may prevent appropriate medication reduction. Various sleep-promoting medications, including tricyclic antidepressants, atypical antipsychotics, tizanidine, benzodiazepines, and zolpidem, may help.37

Establishing an Effective Preventive Treatment Most of the commonly used preventive agents for primary CDH have not been evaluated in well-designed double-blind studies. They are usually the same medications tried for migraine prevention. Table 58–4 summarizes the medications commonly used in CDH. The choice of a preventive drug is based on its proved efficacy, the patient’s preferences and headache profile, the drug’s side effects, and the presence or absence of coexisting or comorbid disease. The clinician should select the drug with the best risk/benefit ratio for the individual patient and minimize the side effects that are most important to the patient. Table 58–5 summarizes an assessment of the efficacy of, safety of, and evidence for a number of agents that may be useful in the preventive treatment of CDH.

Prospects for Preventing Headache Progression On the basis of the most recent data, some episodic headaches (migraine, ETTH) are now conceptualized not just as an episodic disorder but as a chronic episodic and sometimes chronic progressive disorder. Ongoing research and new emerging therapeutic strategies should account for this change in the conceptual model of migraine and CDHs. Preventing disease progression in migraine has already been added to the traditional goals of relieving pain and restoring patients’ ability to function. Emerging treatment strategies to prevent disease progression include risk factor modification, use of preventive therapies, and possibly the use of triptans as early as possible in the course of a migraine attack (Table 58–6).

T A B L E 58–4. Selected Preventive Therapies for Migraine That May Be Used in the Treatment of Chronic Daily Headache Generic Treatment

Dosage

a2 Agonists Clonidine tablets Guanfacine tablets

0.05 to 0.3 mg/day 1 mg

Anticonvulsants Divalproex sodium tablets* Gabapentin tablets* Levetiracetam tablets Topiramate tablets* Zonisamide capsules

500 to 1500 mg/day 300 to 3000 mg 1500 to 4500 mg 50 to 200 mg 100 to 400 mg

Antidepressants MAOIs Phenelzine tablets TCA Amitriptyline tablets* Nortriptyline tablets SSRIs Fluoxetine tablets Sertraline tablets Paroxetine tablets Venlafaxine tablets Mirtazapine tablets

10 to 40 mg 25 to 100 mg 10 to 30 mg 37.5 to 225 mg 15 to 45 mg

b Blockers Atenolol tablets* Metoprolol tablets Nadolol tablets Propranolol tablets* Timolol tablets*

25 to 100 mg 50 to 200 mg 20 to 200 mg 30 to 240 mg 10 to 30 mg

Calcium Channel Antagonists Verapamil tablets* Nimodipine tablets Diltiazem tablets Nisoldipine tablets Amlodipine tablets

120 to 720 mg 40 mg tid 30 to 60 mg tid 10 to 40 mg qd 2.5 to 10 mg qd

Serotonergic Agents Methysergide tablets* Cyproheptadine tablets Pizotifen tablets*

2 to 12 mg 2 to 16 mg 1.5 to 3 mg

Miscellaneous Montelukast sodium tablets Lisinopril tablets Botulinum toxin A injection Feverfew tablets Magnesium gluconate tablets Riboflavin tablets Petasites

5 to 20 mg 10 to 40 mg 25 to 100 U (IM) 50 to 82 mg/day 400 to 600 mg/day 400 mg/day 75 mg bid

30 to 90 mg/day 30 to 150 mg 30 to 100 mg

*Evidence for moderate efficacy from at least two well-designed placebo-controlled trials. IM, intramuscularly; MAOI, monamine oxidase inhibitor; SSRI selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

chapter 58 chronic daily headache

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T A B L E 58–5. Choices of Preventive Treatment in Chronic Daily Headache

From Katsarava Z, Schneeweiss S, Kurth T, et al: Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62:788-790. *Ratings are on a scale from 1+ (lowest) to 4+ (highest) based on strength of evidence. MAOI, monamine oxidase inhibitor; OCD, obsessive-compulsive disorder; SSRI selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

T A B L E 58–6. Risk Factors for Chronic Daily Headache Development and Srategies to Address Them Not Readily Modifiable

K E Y ●

CDHs of long duration are characterized by primary headaches that occur at least 15 days a month for at least 4 hours per day on average. The CDHs are subdivided into transformed migraine, CTTH, NDPH, and hemicrania continua.

●

Transformed migraine is a complication of migraine progression. Risk factors for progressing from episodic migraine to transformed migraine include more than one migraine attack per week, obesity, medication overuse, stressful life events, sleep problems, head trauma, and high caffeine consumption.

●

The treatment of the CDH involves a combination of nonpharmacological strategies, detoxification (in patients who overuse acute-care medication), preventive treatment, and rescue medication.

Sex: female Low education/socioeconomic status Head injury Modifiable

Strategies to Address Modifiable Risk Factors

Attack frequency Central sensitization Obesity

Preventive treatment Early acute migraine interventions Diet Using preventive medications that do not increase weight Limiting the consumption of acute medications Preventive treatment Detoxification protocols Relaxation techniques Biofeedback Addressing depression when present Assessing sleep disturbances Treating sleep apnea when present

Medication overuse Stressful life events Snoring

P O I N T S

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Suggested Reading Bigal ME, Tepper SJ, Sheftell FD, et al: Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria. Headache 2004; 44:684691. Katsarava Z, Schneeweiss S, Kurth T, et al: Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62:788-790. Scher AI, Stewart WF, Liberman J, et al: Prevalence of frequent headache in a population sample. Headache 1998; 38:497-506. Silberstein SD, Lipton RB, Sliwinski M: Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology 1996; 47:871-875. Welch KM, Goadsby PJ: Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 2002; 15:287-295.

References 1. Silberstein SD, Lipton RB, Solomon S, et al: Classification of daily and near-daily headaches: proposed revisions to the IHS criteria. Headache 1994; 34:1-7. 2. Silberstein SD, Lipton RB, Sliwinski M: Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology 1996; 47:871-875. 3. Scher AI, Stewart WF, Liberman J, et al: Prevalence of frequent headache in a population sample. Headache 1998; 38:497506. 4. Castillo J, Muñoz P, Guitera V, et al: Epidemiology of chronic daily headache in the general population. Headache 1999; 39:190-196. 5. Spierings ELH, Ranke AH, Schroevers M, et al: Chronic daily headache: a time perspective. Headache 2000; 40:306310. 6. Bigal ME, Rapoport AM, Lipton RB, et al: Assessment of migraine disability using the Migraine Disability Assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache 2003; 43:336-342. 7. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalalgia 1988; 8(Suppl 7):1-96. 8. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Second Edition. Cephalalgia 2004; 24(Suppl 1):1-160. 9. Bigal ME, Tepper SJ, Sheftell FD, et al: Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria. Headache 2004; 44:684691. 10. Silberstein SD, Dodick D, Lipton RB, et al: Classifying migraine patients with primary chronic daily headache. Consensus statement from the American Headache Society. Headache. In press. 11. Scher AI, Stewart WF, Lipton RB: Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology 2004; 63:2022-2027. 12. Scher AI, Stewart WF, Ricci JA, et al: Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003; 106(1-2):81-89. 13. Bigal ME, Sheftell FD, Rapoport AM, et al: Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22:432-438. 14. Mathew NT, Reuveni U, Perez F: Transformed or evolutive migraine. Headache 1987; 27:102-106.

15. Spierings EL, Schroevers M, Honkoop PC, et al: Presentation of chronic daily headache: a clinical study. Headache 1998; 38:191-196. 16. Mathew NT: Transformed migraine. Cephalalgia 1993; 13(Suppl 12):78-83. 17. Bigal ME, Sheftell FD, Rapoport AM, et al: Chronic daily headache: identification of factors associated with induction and transformation. Headache 2002; 42:575-581. 18. Rasmussen BK, Olesen J: Epidemiology of migraine and tension-type headache. Curr Opin Neurol 1994; 7:264-271. 19. Lavados PM, Tenhamm E: Epidemiology of tension-type headache in Santiago, Chile: a prevalence study. Cephalalgia 1998; 18:552-558. 20. Schwartz BS, Stewart WF, Simon D, et al: Epidemiology of tension-type headache. JAMA 1998; 4:279:381-383. 21. Sjaastad O, Spierings EL: “Hemicrania continua:” another headache absolutely responsive to indomethacin. Cephalalgia 1984; 4:65-70. 22. Welch KM, Goadsby PJ: Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 2002; 15:287-295. 23. Scher AI, Lipton RB, Stewart W: Risk factors for chronic daily headache. Curr Pain Headache Rep 2002; 6:486-491. 24. Welch KMA, Nagesh V, Aurora SK, et al: Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001; 41:629-637. 25. Kruit MC, van Buchem MA, Hofman PA, et al: Migraine as a risk factor for subclinical brain lesions. JAMA 2004; 291:427-434. 26. Burstein R, Yarnitsky D, Goor-Aryeh I, et al: An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614-624. 27. Burstein R, Jakubowski M: Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol 2004; 55:27-36. 28. Yarnitsky D, Goor-Aryeh I, Bajwa ZH, et al: 2003 Wolff Award Presentation: possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache 2003; 43:704-714. 29. Bigal M, Liberman M, Lipton R: Body mass index and headache: associations with attack frequency, severity and disability. Neurology 2005; 61(Suppl 1):421-422. 30. Katsarava Z, Schneeweiss S, Kurth T, et al: Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62:788-790. 31. Silverman K, Evans SM, Strain EC, et al: Withdrawal syndrome after the double-blind cessation of the caffeine consumption. N Engl J Med 1992; 327:1109-1114. 32. Diener HC, Limmroth V: Medication-overuse headache: a worldwide problem. Lancet Neurol 2004; 3:475-483. 33. Katsarava Z, Fritsche G, Muessig M, et al: Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001; 57:1694-1698. 34. Rapoport A, Stang P, Gutterman DL, et al: Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996; 36:14-19. 35. Wilkinson SM, Becker WJ, Heine JA: Opioid use to control bowel motility may induce chronic daily headache in patients with migraine. Headache 2001; 41:303-309. 36. Bahra A, Walsh M, Menon S, et al: Does chronic daily headache arise de novo in association with regular use of analgesics? Headache 2003; 43:179-190. 37. Tepper SJ, Rapoport AM, Sheftell FD, et al: Chronic daily headache—an update. Headache Care 2004; 1:233-245. 38. Krymchantowski AV: Overuse of symptomatic medications among chronic (transformed) migraine patients: profile of drug consumption. Arq Neuropsiquiatr 2003; 61:43-47. 39. Grazzi L, Andrasik F, D’Amico D, et al: Behavioral and pharmacologic treatment of transformed migraine with analgesic overuse: outcome at 3 years. Headache 2002; 42:483-490.

chapter 58 chronic daily headache 40. Diener HC, Haab H, Peters C, et al: Subcutaneous sumatriptan in the treatment of headache during withdrawal from drug-induced headache. Headache 1991; 31:205-209. 41. Bigal ME, Rapoport AM, Sheftell FD, et al: Transformed migraine and medication overuse in a tertiary headache

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centre—clinical characteristics and treatment outcomes. Cephalalgia 2004; 24:483-490. 42. Krymchantowski AV, Moreira PF: Out-patient detoxification in chronic migraine: comparison of strategies. Cephalalgia 2003; 23:982-993.

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TRIGEMINAL AUTONOMIC CEPHALALGIAS: CLUSTER HEADACHE AND RELATED CONDITIONS ●

●

●

●

Peter J. Goadsby* The trigeminal autonomic cephalalgias (TACs) are a grouping of headache syndromes recognized in the second edition of the International Headache Society (IHS) classification.1 The term was coined to reflect the underlying pathophysiology of a prominent part of the phenotype of the acute attacks: namely, the excessive cranial parasympathetic autonomic reflex activation in response to nociceptive input in the ophthalmic division of the trigeminal nerve.2 The TACs are classified in section III of the second edition of the IHS classification1 and include cluster headache,3 paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) (Table 59–1).4 In an early draft, hemicrania continua was included5 but this was finally classified in Section IV, which is appropriate, given the availability of newer brain imaging data.6 This chapter covers the shared physiology of these disorders and then the clinical aspects of each one in turn. Agents that are useful for these disorders are discussed. More detail on older clinical trials and agents that are used but are not particularly effective can be found elsewhere.4

is mediated by antidromic activation of the trigeminal nerve, which accounts for 20% of the effect, and orthodromic activation through the cranial parasympathetic outflow via the facial cranial nerve (VII), which accounts for the other 80%.12 The afferent pathway of the trigeminal-parasympathetic reflex traverses the trigeminal root,12 synapses in the trigeminal nucleus, and then projects to neurons of the superior salivatory nucleus in the pons.13 There is a glutamatergic excitatory receptor in the pontine synapse14 and projection via the facial nerve15 without synapse in the geniculate ganglion. The greater superficial petrosal nerve supplies classic autonomic preganglionic fibers to the sphenopalatine (pterygopalatine in humans) and otic ganglia.16 The sphenopalatine synapse involves a hexamethonium-sensitive nicotinic ganglion.16 Cranial nerve VII activation is associated with release of vasoactive intestinal polypeptide (VIP)17 and blocked by VIP antibodies.18 Blood flow changes in the brain depend on the frequency of stimulation19,20 and are independent of cerebral metabolism.21 VIP is found in the sphenopalatine ganglion,22 as is nitric oxide synthase, which is also involved in the vasodilator mechanism.23

PATHOPHYSIOLOGY OF TRIGEMINAL AUTONOMIC CEPHALALGIAS

Human Studies

Any explanation of the pathophysiology of TACs must account for the two major shared clinical features that are characteristic of the conditions: trigeminal distribution pain and ipsilateral cranial autonomic features.2 The pain-producing innervation of the cranium projects through branches of the trigeminal and upper cervical nerves7,8 to the trigeminocervical complex,9 from which nociceptive pathways project to higher centers.10 A reflex activation of the cranial parasympathetic outflow provides the efferent loop.

Experimental Studies In the cat, stimulation of the trigeminal ganglion produces cranial vasodilation and release of neuropeptides, notably calcitonin gene–related peptide and substance P.11 The dilation *The work of the author referred to herein was supported by the Wellcome Trust and the Migraine Trust.

The basic science implies an integral role for the ipsilateral trigeminal nociceptive pathways in TACs and predicts some degree of cranial parasympathetic autonomic activation. The ipsilateral autonomic features monifest clinically, such as lacrimation, rhinorrhea, nasal congestion, and eyelid edema, are consistent with cranial parasympathetic activation and sympathetic hypofunction (ptosis and miosis). The latter is likely to be a neurapraxic effect of carotid wall swelling24,25 with cranial parasympathetic activation. Cranial autonomic symptoms to some degree are, therefore, normal physiological responses to cranial nociceptive input.26-28 Indeed, other primary headaches, notably migraine,29 or secondary headache, such as trigeminal neuralgia,30 or trigeminal dysesthesias31 would be expected to have cranial autonomic activation, and they do. The distinction between the TACs and other headache syndromes is the degree of cranial autonomic activation, not its presence alone.32 This is why some patients with migraine have minor cranial autonomic activation, which is termed cluster migraine, whereas most such patients have migraine with cranial autonomic activation. This reflex also explains the

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T A B L E 59–1. Differential Diagnosis of Trigeminal Autonomic Cephalalgias (TACs) Primary TACs

Similar Secondary Headaches

Secondary TACs

Cluster headache Paroxysmal hemicrania SUNCT syndrome

Tolosa-Hunt syndrome Maxillary sinusitis Temporal arteritis Raeder’s paratrigeminal neuralgia225 Trigeminal neuralgia

Cranial artery dissection226-228 or aneurysm229 Pseudoaneurysm of intracavernous carotid aneurysm230 Aneurysm of anterior communicating artery231 Basilar artery aneurysm232 Carotid aneurysm231 Occipital lobe AVM233 AVM of middle cerebral territory234 High cervical meningioma235 Unilateral cervical cord infarction236 Lateral medullary infarction237 Pituitary adenoma238 Prolactinoma231,239 Meningioma of the lesser wing of sphenoid240 Maxillary sinus foreign body241 Facial trauma242 Orbitosphenoidal aspergillosis243 Orbital myositis244 Head or neck injury245

AVM, arteriovenous malformation; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

curious report of a sense of aural fullness that patients with these syndromes may report if asked specifically and that has been reported clearly.33

Permitting Trigeminal-Parasympathetic Activation What is the basis for the prominence of cranial autonomic symptoms in the TACs? Is it a result of a central disinhibition of the trigeminal-autonomic reflex?32 Evidence from functional imaging studies—positron emission tomography studies in cluster headache34-36 (Fig. 59–1), and paroxysmal hemicrania36a and functional magnetic resonance imaging (MRI) studies in SUNCT (Fig. 59–2)37,38—have demonstrated ipsilateral posterior hypothalamic activation. Posterior hypothalamic activation seems specific to these syndromes and is not present in episodic39-41 or chronic42 migraine or in experimental ophthalmic trigeminal distribution head pain.43 Of interest is that in hemicrania continua, there is contralateral posterior hypothalamic activation, in contrast to substantially ipsilateral activation in cluster headache, and additional pontine and midbrain activation.6 There are direct hypothalamic-trigeminal connections,44 and the hypothalamus is known to have a modulatory role on the nociceptive and autonomic pathways, specifically trigeminovascular nociceptive pathways.45 Hence, the TACs involve abnormal activation in the region of the hypothalamus with subsequent trigeminovascular and cranial autonomic activation. Cranial autonomic features are not invariably linked with trigeminal pain and may persist after trigeminal nerve lesions.46

DIFFERENTIAL DIAGNOSIS OF TRIGEMINAL AUTONOMIC CEPHALALGIAS The primary TACs need to be differentiated from secondary TAC-producing lesions, from other primary headaches, and from each other (see Table 59–1). The differentiation from secondary causes is not a problem if patients undergo imaging, but

■

Figure 59–1. Brain imaging of cluster headache. Changes in the posterior hypothalamic gray area are revealed with positron emission tomography in patients with chronic cluster headache34 imaged during an acute attack triggered by nitroglycerin. (From May A, Bahra A, Buchel C, et al: Hypothalamic activation in cluster headache attacks. Lancet 1998; 352:275-278.)

it can be extremely difficult if they do not. MRI of the brain with attention to the pituitary fossa and cavernous sinus reveals most secondary causes. In view of the rarity of paroxysmal hemicrania and SUNCT, MRI is a reasonable part of the initial evaluation of such patients. The situation is more complex for cluster headache. There are no studies with clear findings. The impression from a cohort that now exceeds 700 (the National Hospital for Neurology and Neurosurgery, Queen Square, London) is that MRI would detect no more than 1 per 100 cases of lesions in episodic cluster headache (ECH), and so its routine

chapter 59 trigeminal autonomic cephalalgias use cannot be recommended. For chronic cluster headache (CCH), MRI seems reasonable, in view of the very difficult nature of the long-term management and developments in neuromodulation as a treatment,47 which then make brain imaging more complex. Among other primary headaches, migraine is the biggest problem in the differential diagnosis of cluster headache. Migraine can cluster, and despite the best descriptions of the IHS classification committee, short attacks do occur. Cranial autonomic symptoms are well reported,29 and the neuropeptide changes are substantially similar48 to those in cluster headache.49 The occurrence of attacks together does not seem to have the seasonal preponderance that is so typical of cluster

■

Figure 59–2. Brain imaging of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Changes in the posterior hypothalamic gray area with blood oxygenation level–dependent functional magnetic resonance imaging in a patient with SUNCT. (From May A, Bahra A, Buchel C, et al: Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999; 46:791-793.)

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headache,50,51 and this fact can be a useful differential diagnostic feature. This author regards the term cluster migraine as unhelpful and has yet to see a convincing case of a distinct biological entity usefully described by this name. Migraine could occur by chance in up to one third of cluster headache sufferers, in view of the peak female migraine prevalence and the generally accepted dominant inheritance pattern of migraine. The criterion for the effect of movement was added to the IHS description of cluster headache to sharpen the difference from migraine. The IHS committee hoped that this would draw attention to the fact that most patients with cluster headache feel restless or agitated,52 whereas most migraine patients are quiescent, as recognized in the first edition of the IHS classification.53 In clinical practice, this symptom and the periodicity are extremely helpful in establishing the differential diagnosis. The other feature of cluster headache, which is a feature of TACs in comparison with migraine, is that patients with TACs more often complain of unilateral, homolateral photophobia. In addition, triggering of headache quickly with alcohol, within 30 minutes, is more typical of cluster headache, whereas alterations in sleep patterns, eating, stress, or menses do not generally affect cluster headache. Warm environments seem to be a trigger in cluster headache, whereas barometric pressure change is a trigger of migraine.54 The TACs themselves (Table 59–2) can often be differentiated by the length of attack. This is certainly true when cluster headache is compared with SUNCT. The IHS criteria for TACs does betray an uncomfortable biological naivety with regard to the timing. The A, C, D, and E criteria are rather similar for each TAC (Tables 59–3 to 59–5). It would be easy to classify the attacks if those in SUNCT were up to 4 minutes long, those in paroxysmal hemicrania were 2 to 30 minutes long, and cluster headaches were 15 minutes and longer. The overlap then seems minimal. This seems wrong in absolute terms, because biology rarely provides such clear-cut rules, but it does provide a useful way to identify cases of sufficient similarity to make biological studies meaningful.

CLUSTER HEADACHE Cluster headache is a form of primary headache that is almost always unilateral and occurs in association with cranial auto-

T A B L E 59–2. Clinical Features of Trigeminal Autonomic Cephalalgias Feature

Cluster Headache

Paroxysmal Hemicrania

SUNCT Syndrome

Sex: female/male ratio Pain: type Severity Site Attack frequency Duration of attack Autonomic features

1:4 Stabbing, boring Severe to excruciating Orbit, temple, face One/alternate day to 8/day 15-180 minutes Yes

2:1 Throbbing, boring, stabbing Excruciating Orbit, temple 1-40/day 2-30 minutes Yes

Migrainous features*† Alcohol trigger Indomethacin effect

Yes Yes −

Yes No ++

1:2 Burning, stabbing, sharp Moderate to severe Periorbital 1/day to 30/hour 5-240 seconds Yes (prominent conjunctival injection and lacrimation) Yes No Νο

*Nausea, photophobia (often ipsilateral to the pain), or phonophobia. † Photophobia ipsilateral to the pain may be present.

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T A B L E 59–3. Diagnostic Criteria for Cluster Headache Cluster Headache (3.1) Diagnostic criteria: A. At least five attacks fulfilling criteria B to D B. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes if untreated C. Headache is accompanied by at least one of the following: 1. Ipsilateral conjunctival injection and/or lacrimation 2. Ipsilateral nasal congestion and/or rhinorrhea 3. Forehead and facial sweating 4. Ipsilateral eyelid edema 5. Ipsilateral forehead and facial sweating 6. Ipsilateral miosis and/or ptosis 7. A sense of restlessness or agitation D. Attacks have a frequency from one every other day to eight per day. E. Not attributed to another disorder Episodic Cluster Headache (3.2.1) Description: Occurs in periods lasting 7 days to 1 year, separated by remission periods lasting ≥1 month Diagnostic criteria: A. Fulfills criteria A to E for cluster headache B. At least two cluster periods lasting 7 to 365 days and separated by remission periods of ≥1 month Chronic Cluster Headache (3.2.2) Description: Attacks occur for >1 year without remission periods or with remission periods lasting <1 month Diagnostic criteria: A. Fulfills criteria A to E for cluster headache B. Attacks recur over >1 year without remission periods or with remission periods lasting <1 month

T A B L E 59–4. Diagnostic Criteria for Paroxysmal Hemicrania Paroxysmal Hemicrania (3.2) Diagnostic criteria: A. At least 20 attacks fulfilling criteria B to D B. Severe unilateral orbital, supraorbital, or temporal pain lasting 2 to 30 minutes C. Headache is accompanied by at least one of the following: 1. Ipsilateral conjunctival injection and/or lacrimation 2. Ipsilateral nasal congestion and/or rhinorrhea 3. Forehead and facial sweating 4. Ipsilateral eyelid edema 5. Ipsilateral forehead and facial sweating 6. Ipsilateral miosis and/or ptosis D. Attacks have a frequency of more than five per day for more than half the time, although periods with lower frequency may occur E. Attacks are prevented completely by therapeutic doses of indomethacin F. Not attributed to another disorder Episodic paroxysmal headache (3.2.1) Description: Occurs in periods lasting 7 days to 1 year separated by remission periods lasting 1 month or more Chronic paroxysmal headache (3.2.2) Description: Attacks occur for more than one year without remission periods or with pain-free remission periods lasting less than 1 month

nomic features. Most patients report a striking circannual and circadian periodicity. It is an excruciating syndrome and is probably one of the most painful conditions known to humans; affected women have described the attacks as being worse than childbirth.

T A B L E 59–5. Diagnostic Criteria for Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing (3.3) A. At least 20 attacks fulfilling criteria B to E B. Attacks of unilateral, orbital, supraorbital, or temporal stabbing or pulsating pain lasting 5 to 240 seconds C. Pain is accompanied by ipsilateral conjunctival injection and lacrimation D. Attacks occur with a frequency of 3 to 200 per day E. Not attributed to another disorder

Epidemiology The prevalence of cluster headache is estimated to be 0.4%,55 slightly higher than that of multiple sclerosis in the United Kingdom.56 The male/female ratio is 3.5 : 1 to 7 : 1.52,57 The male/female ratio has changed in case series since the early 1990s, with a trend toward a decreasing male preponderance; this is likely to be an ascertainment issue and not a real shift in female incidence. Cluster headache can begin at any age, although the most common age at onset is the third or fourth decade of life. Children as young as 4 years of age have been affected, but this is unusual.

Clinical Features A cluster headache or attack is an individual episode of pain that can last from a few minutes to hours. A cluster bout, or period, refers to the duration over which recurrent cluster attacks are occurring; it usually lasts weeks or months. A remission is the pain-free period between two cluster bouts.

The Cluster Attack With very few exceptions, cluster attacks are strictly unilateral, although the headache may alternate sides. The pain is excruciating. It is located mainly around the orbital and temporal regions, although any part of the head can be affected. The headache usually lasts 45 to 90 minutes, but the duration can range from 15 minutes to 3 hours. The onset and cessation are abrupt. Some patients experience interictal pain or discomfort.58 The signature feature of cluster headache is the association with autonomic symptoms, and it is extremely unusual for these not to be reported. According to the IHS diagnostic criteria,1 the attacks are accompanied by at least one of the following, which are present on the painful side: conjunctival injection, lacrimation, miosis, ptosis, eyelid edema, rhinorrhea, nasal blockage, forehead or facial sweating, or a sense of restlessness or agitation (see Table 59–2). The autonomic features are transient, lasting only for the duration of the attack, with the exception of partial Horner’s syndrome; in rare cases, ptosis or miosis may persist, especially after frequent attacks. The full range of typical migrainous symptoms are reported in a significant proportion of patients with cluster headache.52,59,60 Premonitory symptoms (tiredness, yawning), associated features (nausea, vomiting, photophobia, phonophobia), and aura symptoms have all been described in relation to cluster attacks. However, in contrast to migraine, cluster headache sufferers are usually restless and irritable, preferring

chapter 59 trigeminal autonomic cephalalgias to move about, looking for a movement or posture that may relieve the pain.52 The cluster attack frequency varies between one every alternate day to three daily, although some sufferers have as many as eight daily, and clinical experience suggests that even more are possible. The condition can have a striking circadian rhythmicity; some patients report that the attacks occur at the same time each day. Alcohol, nitroglycerin, exercise, and elevated environmental temperature are recognized precipitants of acute cluster attacks. Alcohol induces acute attacks, usually within an hour of intake, in most sufferers, in contrast with migraine sufferers, who generally have headache some hours after alcohol intake. Alcohol triggers attacks during a cluster bout but not in a remission. Allergies, food sensitivities, reproductive hormonal changes,52 and stress do not appear to have any significant role in precipitating attacks.

The Cluster Bout Cluster headache is classified according to the duration of the bout. About 80% to 90% of patients have ECH, which is diagnosed when they experience recurrent bouts, each with a duration of more than a week and separated by remissions lasting more than 1 month. The remaining 10% to 20% of patients have CCH, in which either no remission occurs within 1 year or the remissions last less than 1 month. In practice, the therapeutic issue is whether the breaks are long enough in any individual patient to warrant discontinuing preventive treatment. Most patients with ECH have one or two annual cluster periods, each lasting between 1 and 3 months. Some patients have a striking circannual periodicity with the cluster periods: The bouts occur in the same month of the year. In other patients, the cluster periods recur at regular intervals that are consistently different from 12 months. Although the durations of the cluster and remission periods vary between individuals, they remain relatively consistent within the same individual.

Natural History Although there is a paucity of literature on the long-term prognosis of cluster headache, the available evidence suggests that it is a lifelong disorder in most patients. In one study, in about 10% of patients with ECH, the condition evolved into CCH, whereas in one third of patients with CCH, it transformed into ECH.61 An encouraging piece of information for cluster headache sufferers is that a substantial proportion of them can expect to develop longer remission periods as they age.62

Treatment The management of cluster headache includes offering patients advice on general measures and treating them with abortive agents, preventive agents, and, in rare cases, surgery (Table 59–6).

General Measures and Patient Education Patients should be advised to abstain from taking alcohol during the cluster bout. Otherwise, dietary factors seem to have little importance in cluster headache. Anecdotal evidence suggests that patients should be cautioned against prolonged exposure to volatile substances, such as solvents and oil-based

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T A B L E 59–6. Treatment Effects on Trigeminal Autonomic Cephalalgias

Indomethacin effect Abortive treatment

Preventive treatment

Cluster Headache

Paroxysmal Hemicrania

SUNCT Syndrome

−

++

−

Sumatriptan, 6 mg SC or 20 mg NS Zolmitriptan, 5 mg NS Oxygen Verapamil Methysergide Lithium Prednisone Melatonin

Nil

Intravenous lidocaine

Indomethacin

Lamotrigine Topiramate Gabapentin

NS, nasally; SC, subcutaneously; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

paints. Patients should be instructed to avoid afternoon naps, because sleeping can precipitate attacks in some patients.

Abortive Agents The pain of cluster headache builds up very rapidly to such an excruciating intensity that most oral agents are absorbed too slowly to cure the pain within a reasonable period of time. The most efficacious abortive agents are non-oral.

Triptans Sumatriptan Subcutaneous sumatriptan, 6 mg, is the drug of choice in the abortive treatment of a cluster attack. A randomized, placebocontrolled, double-blind, crossover study of 39 patients63 showed that headache severity was reduced at 15 minutes in 74% of attacks in which sumatriptan was administered, in comparison with 26% who received placebo. Of patients who took sumatriptan, 36% were pain free within 10 minutes, in comparison with 3% who took placebo. Sumatriptan was well tolerated, and there were no serious adverse events. A further study demonstrated no significant advantage to doubling the dose to 12 mg, although there were more side effects.64 Two large clinical trials show that long-term subcutaneous sumatriptan administration is well tolerated by patients who have cluster headache with no evidence of tachyphylaxis.65,66 A randomized, placebo-controlled, double-blind, crossover study of 86 patients67 showed that the severity of the headache at 30 minutes was reduced in 56% of attacks in which sumatriptan nasal spray, 20 mg, was administered, in comparison with 26% for which placebo was given. This formulation offers the prospect of effectively treating up to three attacks in 24 hours, in comparison with the subcutaneous 6-mg injection, for which the indicated dosing schedule is two doses in 24 hours.

Zolmitriptan A double-blind, placebo-controlled trial compared the efficacy of oral zolmitriptan, 5 mg and 10 mg, to treat acute attacks in ECH and CCH.68 With headache response defined as a 2-point

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reduction on a 5-point pain intensity scale, 30-minute response rates in ECH were 29%, 40%, and 47% after placebo and 5 mg and 10 mg of zolmitriptan, respectively. The difference reached statistical significance only for 10-mg zolmitriptan in comparison with placebo. The efficacy of oral zolmitriptan in ECH is modest and does not approach the efficacy or speed of subcutaneous sumatriptan or oxygen; therefore, its utility in clinical practice is limited. It may be considered for patients who cannot tolerate subcutaneous or intranasal sumatriptan and oxygen or for those who desire oral medications. The intranasal formulation of zolmitriptan might be more appropriate for acute cluster headache because of its better overall pharmacokinetics,69 and a recent controlled trial has demonstrated its efficacy.

Oxygen Oxygen inhalation is a safe and effective method for the acute treatment of cluster headache. Its mechanism of action remains unclear. Horton was the first to discover that inhaling 100% oxygen at the onset of attacks alleviates cluster headache pain.70 Kudrow71 noted a significant relief from cluster pain in 75% of 52 randomly selected outpatients treated with 100% oxygen administered through a facial mask at a rate of 7 L/minute for 15 minutes. Oxygen at 6 L/minute for 15 minutes was compared with air inhalation in a double-blind crossover study of 19 sufferers.72 Eleven patients used both gases. Of 16 patients who used oxygen, 9 (56%) perceived complete or substantial relief in 80% or more of their cluster attacks, in comparison with only 1 (7%) of 14 patients who used air. Inhalation of 100% oxygen at 7 to 12 L/minute is usually rapidly effective in relieving pain. It should be inhaled continuously for 15 to 20 minutes through a non-rebreathing facial mask. Patients need to be informed that they should cover any apertures on the facial mask. When oxygen inhalation is initiated as soon as the attack starts, the attack is often aborted rapidly and entirely,71 although some patients find oxygen completely effective if taken when the pain is at maximal intensity.73 Up to 25% of patients note that oxygen simply delays the attack for minutes to hours rather than completely aborting it.71 The great advantage of oxygen is that it has no established side effects. It can be readily combined with other abortive and preventive treatments. It can be used several times daily, as opposed to subcutaneous or intranasal sumatriptan, which can be used a maximum of only two or three times daily, respectively. The major drawback to oxygen inhalation treatment is the practical limitation imposed by the bulky equipment, and although small portable cylinders are available, most patients find these cumbersome and inconvenient.

Topical local anesthetics: lidocaine (lignocaine) Kittrelle and colleagues74 first reported that lignocaine solution applied topically to the region of the pterygopalatine fossa alleviated the pain of the cluster attack. In an open-label trial of intranasal lignocaine 4% solution, four of five patients obtained rapid relief of nitroglycerin-induced cluster headache. Lignocaine was also effective in relieving spontaneous attacks. Robbins75 reported on the use of 4 to 6 sprays of lidocaine 4% in the nostril ipsilateral to the painful side in an open-label trial in 30 patients. Lidocaine (10%) applied bilaterally for 5 minutes was reported to be effective in aborting nitroglycerin-induced cluster attacks in a double-blind, placebo-controlled study in nine patients.76

At the author’s institution, lidocaine solution, 20 to 60 mg, is given as nasal drops (4% to 6% lignocaine solution) and applied bilaterally in the region of the pterygopalatine fossa. To ensure that the solution reaches the pterygopalatine foramen, the patient is instructed to lie down horizontally as early as possible during an attack, with the head extending out of the bed, bent downward 30 to 45 degrees and rotated 20 to 30 degrees toward the side of the headache. The tip of the dropper is inserted above the rostral end of the inferior turbinate and pushed inward as deeply as possible before the drip is begun. The patient should be asked to maintain the position for 2 to 5 minutes. An alternative method of application is peg-pushing: a cotton swab on a peg is submerged in lidocaine before being applied to the region of the ipsilateral pterygopalatine foramen. Peg-pushing is, however, often reported by patients to considerably worsen the pain of cluster headache. In the author’s experience, intranasal lidocaine results in mild to moderate relief for some patients, although only a few patients obtain complete pain relief.

Ergotamine and dihydroergotamine Oral ergotamine is absorbed too slowly to be useful. It was widely recommended before the advent of the triptans, but it has little practical use in the modern treatment of acute cluster headache. Parenteral dihydroergotamine has been considered an effective abortive agent for cluster headache for some time.77,78 There are no controlled trials of injectable dihydroergotamine; however, clinical experience has demonstrated that intravenous administration provides prompt and effective relief of cluster headache within 15 minutes.79 Because of the frequency and the rapid peak intensity of cluster attacks, intravenous dihydroergotamine is not a feasible long-term solution. The intramuscular and subcutaneous routes of administration provide slower relief, although they have the advantage of being able to be self-administered. Dihydroergotamine nasal spray, 1 mg, has been studied in a double-blind, placebo-controlled, crossover trial in 25 patients.80 There was no difference in headache frequency or duration, but the pain intensity was significantly reduced with dihydroergotamine in comparison with placebo. The dosage used (1 mg) was lower than the recommended dosage for migraine (2 mg) and less than the currently available preparations of dihydroergotamine nasal spray (4 mg).

Analgesics Opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and combination analgesics have no routine role in the acute management of cluster headache. The pain of cluster headache builds up so rapidly and to such an excruciating intensity that most oral agents are absorbed too slowly to act within a reasonable period of time. Furthermore, problems with habituation and toxicity may develop with prolonged high-dosage treatment.

Somatostatin receptor antagonists Intravenous somatostatin (25 μg/minute for 20 minutes) was compared with ergotamine (250 μg intramuscularly) or placebo in a double-blind trial comprising 72 attacks in eight patients.81 Infusion of somatostatin significantly reduced the maximal pain intensity and the duration of pain in comparison with placebo and, to a degree, was comparable with intramuscular ergotamine. In another randomized, double-blind study,

chapter 59 trigeminal autonomic cephalalgias subcutaneous somatostatin was compared with ergotamine.82 Five patients were treated for three attacks by each of the drugs. Subcutaneous somatostatin and ergotamine were equally beneficial with regard to effects on maximal pain intensity and the pain area, but somatostatin was less effective in reducing the duration of pain. Matharu and associates compared subcutaneous octreotide (100 μg), a somatostatin receptor agonist, with a matching placebo in acute cluster headache.83 The primary endpoint was the headache response, defined as very severe, severe, or moderate pain becoming mild or nil at 30 minutes. Fifty-seven patients were recruited, of whom 46 provided efficacy data on attacks treated with octreotide and 45 with placebo. The headache response rate with subcutaneous octreotide was 52%, whereas the response with placebo was 36%. When the treatment outcome was modeled as a binomial in which response was determined by treatment and period effect, sex, and cluster headache type were other variables of interest, subcutaneous octreotide, 100 μg, was significantly superior to placebo (P < 0.01). More work in this area may produce a novel non-vasoconstrictor approach to the treatment of acute cluster headache.

Preventive Treatments The aim of preventive therapy is to rapidly suppress attacks and maintain that remission with minimal side effects until the cluster bout is over or for a longer period in patients with CCH.

Verapamil Verapamil was first reported to be an effective preventive agent for cluster headache by Meyer and Hardenberg.84 In an openlabel trial with verapamil at doses of 160 to 720 mg/day in five CCH patients, a reduction in the mean monthly headache frequency was reported in all patients. In another open-label trial with verapamil at doses of 240 to 600 mg/day for ECH and 120 to 1200 mg/day for CCH, an improvement of more than 75% was noted in 33 (69%) of 48 patients.85 A double-blind, crossover trial in which verapamil, 360 mg/day, was compared with the then standard prophylactic drug, lithium, 900 mg/day, each given for 8 weeks, demonstrated equivalent effects in the 24 CCH patients who completed the trial.86 Verapamil and lithium were superior to placebo. Verapamil caused fewer side effects and had a shorter latency period. In a double-blind, placebo-controlled trial, the efficacy of verapamil, 360 mg/day over a 2-week period, was evaluated in 26 patients with ECH.87 A statistically significant reduction in headache frequency and analgesic consumption occurred in the verapamil-treated patients, with a greater reduction in the second week of treatment. Verapamil is the preventive drug of choice for both CCH and ECH, the latter when the bout is sufficiently long to establish a suitable dose. Clinical experience has clearly demonstrated that higher doses are needed for cluster headache than for cardiological indications. Dosages commonly employed range from 240 to 960 mg/day in divided doses. Verapamil can cause heart block by slowing conduction in the atrioventricular node,88 as demonstrated by prolongation of the A-H interval.89 In observing for P-R interval prolongation on the electrocardiogram, clinicians can monitor potential development of heart block, although it is a coarse measure. No formal guidelines are available. After obtaining a baseline electrocardiogram, the

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author and colleagues start patients on 80 mg three times daily, and the total daily dose is increased in increments of 80 mg every 10 to 14 days. An electrocardiogram is obtained before each increment and at least 10 days after the last dose change. The dosage is increased until the cluster attacks are suppressed, side effects intervene, or the maximum dose of 960 mg/day is achieved. It is unproved clinical experience that standard preparations of verapamil are more effective than the modifiedrelease formulations.58,90 Constipation is the most common side effect, but dizziness, ankle swelling, nausea, fatigue, hypotension, and bradycardia may also occur. Gingival enlargement is a recognized problem that needs prompt attention from a dentist.91 β Blockers should not be given concurrently.

Lithium The effectiveness of lithium in psychiatric conditions of a cyclical nature, such as manic-depressive psychosis and seasonal affective disorder, led Ekbom92,93 to try this agent in five patients with cluster headache, three of whom had CCH and clearly benefited from lithium. Open-label trials have been reviewed.94 Collectively, in more than 28 clinical trials involving 468 patients, good to excellent results were found in 236 (78%) of 304 patients with CCH. The response to lithium in patients with ECH was less robust than in those with CCH; good efficacy was obtained in 103 (63%) of a total of 164 patients treated. In most unblinded trials, a lithium dose ranging from 600 to 1200 mg/day was used. Lithium was often effective at serum concentrations of 0.4 to 0.8 mEq/L, less than those usually required for the treatment of bipolar disorder. Some patients eventually become resistant to lithium.95 Lithium has also been evaluated in two randomized, doubleblind trials. A double-blind, crossover trial in which verapamil, 360 mg/day, was compared with lithium, 900 mg/day, each given for 8 weeks, demonstrated equivalent effects in the 24 patients with CCH who completed the trial86; verapamil and lithium were superior to placebo. In a double-blind, placebocontrolled, randomized, parallel-group trial of sustained-relief lithium with 27 patients with ECH, 13 received 800 mg/day, and 14 received placebo. Efficacy was assessed 1 week after treatment was begun.96 Cessation of attacks occurred in two patients in each group, and substantial improvement was noted in 6 (43%) of 14 patients taking placebo and 8 (62%) of 13 patients taking lithium. Lithium treatment was associated with a subjective improvement rate, but this was not statistically significant in comparison with placebo. The authors made an assumption at the onset of the trial that the placebo response would be zero. This is clearly incorrect for both acute attack and preventive treatment approaches in cluster headache.97 Lithium is an effective agent for cluster headache prophylaxis, although the response is less robust in ECH than in CCH. Most patients benefit from dosages between 600 and 1200 mg/day. Lithium has the potential for many side effects and has a narrow therapeutic window. Side effects include weakness, nausea, thirst, tremor, slurred speech, and blurred vision. Toxicity is manifested by nausea, vomiting, anorexia, diarrhea, neurological signs of confusion, nystagmus, ataxia, extrapyramidal signs, and seizures. Hypothyroidism and polyuria (nephrogenic diabetes insipidus) can occur with long-term use. Polymorphonuclear leukocytosis may occur and be mistaken for occult infection. Renal and thyroid function tests should be performed

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before and during treatment. The author and colleagues start patients on 300 mg twice per day and then titrate the dosage up until the cluster headaches are suppressed, side effects intervene, or the serum lithium level is in the upper part of the therapeutic range. The serum concentrations should be measured 12 hours after the last dose and should not exceed the upper level of the therapeutic range. Drug withdrawal at least once annually is advised, to detect the patients in whom CCH has transformed to ECH. The concomitant use of NSAIDs, diuretics, and carbamazepine is contraindicated.

Methysergide Methysergide is an ergot alkaloid that is an antagonist at 5hydroxytryptamine 2A (5-HT2A), 5-HT2B, and 5-HT2C receptors and an agonist at 5-HT1B/5-HT1D receptors. Methysergide was first reported to be effective in cluster headache by Sicuteri.98 Several authors subsequently confirmed this observation in open-label trials.99-105 The open-trials were reviewed by Curran and associates,106 who noted that methysergide, 3 to 12 mg/day, was effective in 329 (73%) of 451 patients with episodic cluster headache and chronic cluster headache. For treatment of cluster headache, methysergide is indicated in dosages up to 12 mg/day, if tolerated. To minimize side effects, patients can start with a low dosage and increase the dosage gradually. The author and colleagues start patients on 1 mg once daily and increase the daily dose by 1 mg every 3 days in a three-times-daily regimen until the daily dose reaches 5 mg; thereafter, the dosage is increased incrementally by 1 mg every 5 days. Common short-term side effects include nausea, vomiting, dizziness, muscle cramps, abdominal pain, and peripheral edema. Uncommon but troublesome side effects are caused by vasoconstriction (coronary or peripheral arterial insufficiency), which usually necessitate cessation of the drug. Prolonged treatment has been associated with retroperitoneal, pulmonary, pleural, and cardiac fibrotic reactions, although these are rare.107 Ideally, the drug should be used only by patients with short cluster bouts, preferably less than 3 to 4 months. If prolonged use is intended, the risk of fibrotic reactions can be minimized by taking the drug for 6 months, followed by a 1-month holiday before starting the drug again. To avoid a sudden increase in headache frequency when methysergide is stopped, the patient should be weaned off over a 1-week period. Some authorities administer methysergide continuously with careful monitoring, which includes auscultation of the heart and yearly echocardiogram, chest radiograph, and abdominal MRI. All patients receiving methysergide should remain under the supervision of the treating physician108 and should be examined regularly for the development of visceral fibrosis or vascular complications. Contraindications to methysergide use include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, and valvular heart disease.109

Ergots, triptans, and methysergide There is considerable controversy surrounding the use of ergot derivatives and triptans concomitantly with methysergide. This is not at all an easy subject. It is usually recommended that ergotamine or dihydroergotamine not be taken concomitantly

with methysergide, and other vasoconstrictive agents should be used with caution. Methysergide is an ergot derivative,110 but it is a weak vasoconstrictor in comparison with ergotamine.111 It is demethylated in vivo to methylergonovine, to which it may owe some of its activity.112 There are no reported prospective drug interaction studies between methysergide and sumatriptan. In some of the early clinical studies with sumatriptan, methysergide continued to be used.113 Eighty patients were taking either methysergide or pizotifen, both serotonin 5-HT2 antagonists. Thirty-eight had used sumatriptan injections, and 42 had used tablets. There was insufficient power to analyze this group, but they had a similar adverse event profile.113 The most worrisome case was that of a 43-year-old woman who experienced a myocardial infarction while taking methysergide and sumatriptan.114 She had a history of migraine without aura. She had controlled hypertension and atypical chest pain attributed to gastroesophageal reflux. Coronary angiography revealed a 50% block of the left anterior descending coronary artery, which was treated by stenting. In retrospect, sumatriptan should have been contraindicated in this patient because of the ischemic heart disease, although it might be argued that this was a difficult diagnostic issue. For cluster headache, the author and colleagues are unaware of any similar case. Thus, the combined use of ergot derivates or sumatriptan with methysergide must remain a clinical decision based on the balance of the very considerable benefit, particularly for sumatriptan and dihydroergotamine, and the concomitant use of methysergide, with each case judged on its merits.

Ergotamine Ekbom first reported the use of ergotamine tartrate for the prophylactic treatment of cluster headache in 1947.115 Sixteen patients were given ergotamine at a dose of 2 to 3 mg/day for 1 to 4 weeks, and 13 patients experienced considerable improvement. Later it was reported that a rectal suppository of ergotamine (2 mg) and caffeine (100 mg) or intramuscular injections of ergotamine (0.25 to 0.5 mg) at bedtime were effective in preventing nocturnal attacks.116 Ergotamine was widely used as the first-choice prophylaxis until the efficacy of lithium and verapamil became evident. Regular administration of ergotamine, 2 to 4 mg/day for 2 to 3 weeks, may be useful. If the patient has nocturnal attacks, 1 to 2 mg may be given at night in the form of tablets or suppositories.

Dihydroergotamine Repetitive intravenous dihydroergotamine administered in an inpatient setting over a period of 3 days has been reported to be very useful for some patients with both ECH and CCH. In a study of 54 patients with intractable cluster headache (23 episodic, 31 chronic), open-label use of repetitive intravenous dihydroergotamine rendered all patients headache free.117 At the 12-month follow-up, 83% and 39% of patients with ECH and CCH patients, respectively, remained free of headache.

Prednisolone (Prednisone) The use of corticosteroids in cluster headache was first reported by Horton,78 who found that cortisone at doses of 100 mg/day was effective in only 4 of 21 patients. The effectiveness of prednisolone (prednisone) in stopping bouts of cluster headache was established in a double-blind trial by Jammes.118 Couch and Ziegler119 reported that prednisolone (prednisone), 10 to

chapter 59 trigeminal autonomic cephalalgias 80 mg/day, employed in 19 patients with cluster headache (9 with ECH, 10 with CCH) provided greater than 50% relief in 14 patients (74%) and complete relief in 11 (58%) patients. Seventy-nine percent of patients reported headache recurrence when the prednisolone (prednisone) dosage was tapered. Corticosteroids are highly efficacious and the most rapid acting of the preventive agents. As in other disorders, the use of corticosteroids is contraindicated by a history of tuberculosis or psychotic disturbance. Caution has to be exercised because of the potential for serious side effects. In this regard, bony problems with steroid use have been reviewed, and the shortest course of prednisolone (prednisone) reported to be associated with osteonecrosis of the femoral head is a 30-day course. Courses of adrenocorticotrophic hormone have produced osteonecrosis after 16 days, and courses of dexamethasone, after 7 days.120 Thus, a tapering course of prednisolone (prednisone) for 21 days is prudent, with an excess risk for bony problems occurring if more than two courses are administered per year.120 The author and colleagues start patients on oral prednisolone (prednisone), 1 mg/kg, increasing the dosage to a maximum of 60 mg every day for 5 days, and thereafter decreasing the dosage by 10 mg every 3 days. Unfortunately, relapse almost invariably occurs as the dose is tapered. For this reason, steroids are used as an initial therapy in conjunction with preventive agents, until the latter are effective.

Topiramate In an open-label study of two patients with CCH, seven patients with ECH, and one patient with cluster headache–tic syndrome, treatment with topiramate was associated with rapid improvement.121 A topiramate dosage of 50 to 125 mg/day shortened the cluster period duration in all ECH patients and the total treated cluster period duration in four ECH patients. Topiramate induced remission in the two patients with CCH within 1 and 3 weeks, respectively. Only three patients reported mild side effects while taking topiramate in this study. Further openlabel studies followed this one.122-126 These favorable preliminary reports need to be followed up by properly controlled studies. In the interim, topiramate appears to be a reasonable treatment option for patients with otherwise refractory cluster headache, although its use may be limited by its side effect profile. Somnolence, dizziness, cognitive symptoms, and ataxia are commonly reported. Mood changes, psychosis, weight loss, and glaucoma have been reported. Paresthesias and nephrolithiasis can occur because of the weak carbonic anhydrase inhibition of the drug. The author and colleagues start patients on topiramate at low dosages (15 to 25 mg/day) and increase the dosage by small increments of 25 to 50 mg every 5 to 7 days, to minimize both the total daily dosage and the potential for side effects.

Melatonin Melatonin is a sensitive surrogate marker of circadian rhythm in humans and is under the control of the suprachiasmatic nucleus.127 Serum melatonin levels are reduced in patients with cluster headache, particularly during a cluster bout.128,129 On the basis of these observations, the striking circadian periodicity of cluster headache, and the importance of the hypothalamus in the pathogenesis of this disorder,34 the efficacy of melatonin has been evaluated as a prophylactic agent in cluster headache. Leone and coworkers130 performed a double-blind

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pilot study of melatonin versus placebo in the prophylaxis of cluster headache. Twenty patients with cluster headache (18 with ECH, 2 with CCH) participated in the study. The authors found that, in comparison with the run-in period, there was a reduction in the mean number of daily attacks and a strong trend toward reduced analgesic consumption in the melatonin recipients but not in the placebo recipients. Five melatonin recipients responded to the treatment, with cessation of cluster headaches after 5 days of treatment. No placebo recipient responded. The author and colleagues prescribe a daily dosage of 9 mg and have found it useful for some patients.

Other medicines often discussed Despite early promise from open-label experience, the results of a double-blind, placebo-controlled, parallel-group study of sodium valproate (1000 to 2000 mg/day) in the prophylaxis of cluster headache were negative.131 There were some issues with the study, although the result is not inconsistent with clinical experience. Gabapentin was first reported to be effective as a prophylactic agent in two case reports of cluster headache.132,133 Subsequently, Leandri and associates134 gave gabapentin, 900 mg/day, in an open-label manner to eight patients with ECH and four with CCH. All patients were rendered pain free within 8 days of initiating therapy. This remarkable effect is not obvious in practice. Baclofen, a γ-amino butyric acid (GABA) β receptor agonist, was evaluated in an open-label study of nine ECH patients.135 The patients received baclofen, 15 mg/day, for 2 days before the dose was increased to 30 mg/day. Six patients were rendered pain free within 1 week; one patient was substantially better at 1 week and became pain free by the end of the second week. The treatment was well tolerated. These results require further investigation with a larger number of patients in a double-blind study. Intranasal capsaicin was first reported by Sicuteri and coworkers to be beneficial as a prophylactic agent in cluster headache.136 In this open-label preliminary study, capsaicin, 300 μg, was applied once daily for 5 consecutive days into both nostrils of patients with cluster headache. The number of spontaneously occurring attacks was significantly reduced in the 60 days after the end of capsaicin treatment. The group subsequently reported their findings in 45 cluster headache patients (35 with ECH, 10 with CCH).137 A significant reduction in the number of attacks was observed during the 60-day observation period. Intranasal capsaicin produces an intense burning sensation, lacrimation, and rhinorrhea that last for approximately 20 minutes, although these symptoms progressively decrease and disappear after five to eight applications. Consequently, placebo-controlled studies are not easily performed, because patients are readily aware of what they are receiving. In a double-blind, placebo-controlled study of 13 patients, seven were treated with capsaicin 0.025% twice daily for 7 days in the nostril ipsilateral to the pain, and the six control patients received camphor 3% to simulate the painful irritation associated with topical capsaicin.138 The capsaicin-treated group experienced significantly less severe headaches during the 8 days after treatment than during the 7 days of treatment. This improvement was not observed in the placebo-treated group. In an attempted single-blind study designed to verify the difference in efficacy of treatment with nasal capsaicin, depending on the side of application, 26 patients with ECH received capsaicin on the symptomatic side, and 26 patients were treated

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on the nonsymptomatic side.139 Application of capsaicin on the symptomatic side had a temporary beneficial effect in most patients, but attacks occurred within 40 days in all patients. No benefit was observed with contralateral application. In a multicenter, vehicle-controlled study, patients with ECH were treated for 7 days; 18 received civamide 0.025% (25 μg), and 10 received placebo in a volume of 100 μL.140 They were evaluated in a 20-day post-treatment period. Although the number of headaches was reduced in the first seven days (−60% versus −26%), the overall effect at day 20 was not significant. Nasal burning sensation was common in the civamide recipients.

Greater occipital nerve blockade Anthony141 described the use of local anesthetic and corticosteroid injections around the greater occipital nerve homolateral to the pain. This procedure has been widely used but not subjected to systematic evaluation. It was reported that of 14 patients treated with greater occipital nerve injection, 4 had a good response, 5 had a moderate response, and 5 had no response.142 The author and colleagues find it a variable but sometimes effective strategy that, when performed by experienced clinicians, has almost no morbidity except about a 1% incidence of localized alopecia caused by fat atrophy at the injection site.143

Surgery This is a last-resort measure in treatment-resistant patients and should be considered only when the pharmacological options have been exploited to the fullest. Patients must be carefully selected. There is an emerging distinction between destructive procedures, which have historically been the only option, and neuromodulatory procedures. For the moment, the author and colleagues have abandoned destructive procedures, because they are irreversible, in favor of neuromodulatory approaches. Only patients whose headaches are exclusively unilateral should be considered for destructive surgery, because patients whose attacks have alternated sides are at risk of a contralateral recurrence after surgery. A number of procedures that interrupt either the trigeminal sensory or autonomic (cranial parasympathetic) pathways can be performed, although few are associated with long-lasting results, and the side effects can be devastating. The procedures that have been reported to show some success include trigeminal sensory rhizotomy via a posterior fossa approach,144,145 radiofrequency trigeminal gangliorhizolysis,146 and microvascular decompression of the trigeminal nerve with or without microvascular decompression of the nervus intermedius.147 Gamma knife treatment seems ineffective in view of its morbidity.148 Complete trigeminal analgesia may be required for the best results. Complications include diplopia, hyperacusis, jaw deviation, corneal anesthesia, and anesthesia dolorosa. Aggressive long-term ophthalmic follow-up is essential. Leone and colleagues149 reported the use of posterior hypothalamic neurostimulation in one patient and subsequently in a cohort of patients with CCH.47 The target was derived from brain imaging work in cluster headache,34 and this procedure has proved effective in those patients. Unfortunately, there is a risk of mortality associated with this procedure,150 which has led to some caution in its adoption. On the basis of a promising report of greater occipital nerve stimulation151 in other

headache forms, and effects particularly in migraine,42 trials of suboccipital nerve stimulation in cluster headache are being performed, again with promising early results. These nondestructive procedures need careful evaluation so that the best candidates are selected for their application in practice.

PAROXYSMAL HEMICRANIA Paroxysmal hemicrania, like cluster headache, is characterized by strictly unilateral, brief, excruciating headaches that occur in association with cranial autonomic features. Paroxysmal hemicrania differs from cluster headache mainly in the high frequency and shorter duration of individual attacks, although there is certainly overlap in these characteristics. However, paroxysmal hemicrania responds in a dramatic and absolute manner to indomethacin, which underlines the importance of distinguishing it from cluster headache, which is not responsive to indomethacin (see Table 59–4). Chronic paroxysmal hemicrania was first described by Sjaastad and Dale,152 when they reported a case they rather aptly named “a new treatable headache entity.” They consequently coined the term chronic paroxysmal hemicrania to describe this disorder.153 The initial cases described were characterized by daily headaches for years without remission. It subsequently became apparent that not all patients experienced a chronic, unremitting course; some patients had discrete headache bouts separated by prolonged pain-free remissions.2,154-156 This remitting pattern was named episodic paroxysmal hemicrania.154

Epidemiology Paroxysmal hemicrania is a rare syndrome. The prevalence of paroxysmal hemicrania is not known, but the relationship in comparison with cluster headache is reported to be approximately 1% to 3%.157 Cluster headache occurs in approximately 1 per 1000; the estimated prevalence of paroxysmal hemicrania is 1 per 50,000. The disorder has been reported in various parts of the world158,159 and affects different races.160 In contrast to cluster headache, paroxysmal hemicrania predominates in females by a sex ratio of 2.13 : 1 to 2.36 : 1.157,161 The condition usually begins in adulthood at the mean age of 34 years and in the range of 6 to 81 years.161

Clinical Features The attack profile of paroxysmal hemicrania is highly characteristic.2,157,161,162 The headache is strictly unilateral and without side shift in the majority of affected patients. However, the headache demonstrated side shift in four reported cases,163-166 and the pain was bilateral in one patient.167 The maximum pain is most often centered on the ocular, temporal, maxillary, and frontal regions; less often, the pain involves the neck, occiput, and retro-orbital regions. The pain occasionally radiates into the ipsilateral shoulder and arm. The pain is typically excruciating in severity and is described as a “clawlike,” throbbing, aching, or boring sensation. The headache usually lasts 2 to 30 minutes, although it can go on for as long as 2 hours (Fig. 59–3). Interictal discomfort or pain is present in as many as one third of patients.157 Attacks of paroxysmal hemicrania occur in association with ipsilateral cranial autonomic features.

chapter 59 trigeminal autonomic cephalalgias

Verbal rating scale (pain)

10

T A B L E 59–7. Lesions Reported to Produce a Paroxysmal Hemicrania–like Picture

8

Vascular Causes Aneurysms within the circle of Willis246 Parietal arteriovenous malformation247 Stroke: Middle cerebral artery infarct247 Occipital infarction248

6

4

Collagen Vascular Disease246

2

0 0 ■

783

100

200

300 Time (min)

400

500

Figure 59–3. Attack pattern in a patient with paroxysmal hemicrania.

Lacrimation, conjunctival injection, nasal congestion, or rhinorrhea frequently accompany the headache; eyelid edema, ptosis, miosis, and facial sweating are less frequently reported. Photophobia and nausea may accompany some attacks, although vomiting and phonophobia are rare. There exists one case report of a typical migrainous aura occurring in association with paroxysmal hemicrania attacks.168 During episodes of pain, approximately half the sufferers prefer to sit or lie still; the other half assume the pacing activity usually observed with cluster headache.157 The frequency of attacks ranges from 2 to 40 daily. The attacks occur regularly throughout the 24-hour period without the preponderance of nocturnal attacks that occur in cluster headache. Although the majority of attacks are spontaneous, approximately 10% of attacks are precipitated mechanically, either by bending or by rotating the head. Attacks may also be provoked by external pressure against the transverse processes of C4 to C5, the C2 root, or the greater occipital nerve. Alcohol ingestion triggers headaches in only 7% of patients.157 About 20% of patients have episodic paroxysmal hemicrania, which is diagnosed when there are clear remission periods that may last from a few weeks to years between bouts of attacks. The remaining 80% of patients have chronic paroxysmal hemicrania, which is diagnosed when the patients have daily attacks without any clear remission periods (see Table 59–4). Notably, in paroxysmal hemicrania, the chronic form dominates the clinical presentation, in contrast to cluster headache, in which the episodic form prevails.

Symptomatic Paroxysmal Hemicrania and Associations Secondary paroxysmal hemicrania is relatively common and can be caused by diverse pathological processes at various sites (Table 59–7). Paroxysmal hemicrania has been reported to occur in association with migraine,169 cluster headache,159,170-172 trigeminal neuralgia,173-176 and cough headache.177 Similar to cluster headache–tic syndrome, the paroxysmal hemicrania–tic

Tumors Frontal lobe tumor246 Gangliocytoma of the sella turcica249 Cavernous sinus meningioma250 Pituitary microadenoma251 Cerebral metastases of parotid epidermoid carcinoma252 Pancoast’s tumor253 Miscellaneous Maxillary cyst251 Intracranial hypertension254 Essential thrombocythemia255

syndrome is recognized, and treatment of both conditions is required.

Diagnostic Workup A good clinical history, a detailed neurological examination, and a therapeutic trial of indomethacin are all that are necessary to make a diagnosis of paroxysmal hemicrania. Because a relatively high number of symptomatic cases have been reported (see Table 59–7), MRI of the brain should be routinely performed in all patients with paroxysmal hemicrania. The therapeutic trial of oral indomethacin should be initiated at 25 mg three times daily; if there is no response or only a partial response after 5 days, the dosage should be increased to 50 mg three times daily for 5 days; if the index of suspicion is high and there is no or only a partial response, then the dosage should be further increased to 75 mg three times daily for 14 days. Complete resolution of the headache is prompt, usually occurring within 1 to 2 days of initiating the effective dose. Intramuscular injectable indomethacin, 50 to 100 mg (“indotest”) has been proposed as a diagnostic test for paroxysmal hemicrania.178 The indotest has the advantage that the diagnosis can be rapidly established, and although it needs further validation at this stage, it is, in the absence of a biological marker, likely to become the test of choice in TACs.

Management The treatment of paroxysmal hemicrania is prophylactic. Indomethacin is the treatment of choice. Complete resolution of the headache is prompt, usually occurring within 1 to 2 days of initiating the effective dose. The typical maintenance dosage ranges from 25 to 100 mg/day, but doses up to 300 mg/day are occasionally required. Dosage adjustments may be necessary to address the clinical fluctuations that occur in paroxysmal hemicrania. During active headache cycles, skipping or even delaying doses may result in the prompt recurrence of the headache.

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Gastrointestinal side effects secondary to indomethacin may be treated with antacids, misoprostol, histamine H2 receptor antagonists, or proton pump inhibitors and should always be considered for patients who require long-term treatment. The mechanism behind the absolute responsiveness to indomethacin is unknown. It appears to be independent of indomethacin’s effect on prostaglandin synthesis, inasmuch as other NSAIDs have little or no effect on paroxysmal hemicrania. The clinician faces a difficult challenge with patients who cannot tolerate indomethacin. No other drug is consistently effective in paroxysmal hemicrania. Drugs other than indomethacin reported to be partially or completely effective, mainly in isolated cases, include other NSAIDs such as aspirin,157,179 naproxen,180 and piroxicam β-cyclodextrin181; the cyclooxygenase-2 inhibitor celecoxib182; the calcium channel antagonists verapamil183,184 and flunarizine185; acetazolamide186; and corticosteroids.187 The author and colleagues have tried cyclooxygenase-2 inhibitors and verapamil with limited success. They have found greater occipital nerve block with depo-corticosteroids and local anesthetic to be useful.

SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING SUNCT syndrome, like the other TACs, manifests as a unilateral headache that occurs in association with cranial autonomic features. The features that distinguish it from the other TACs are (1) the presence of prominent conjunctival injection and lacrimation and (2) very brief-duration attacks that can occur very frequently. Both these features are present in the majority of patients. Because some patients have clinically the same problem, but either conjunctival injection or tearing is absent, the author and colleagues believe that the syndrome should be renamed short-lasting unilateral neuralgiform headache attacks (SUNA) with cranial autonomic features (Table 59–8) or that both forms should be recognized. SUNCT syndrome was described in 1978188 and more fully characterized in 1989.189

T A B L E 59–8. Short-Lasting Unilateral Neuralgiform Headache Attacks (SUNA) with Cranial Autonomic Symptoms SUNA (A3.3) Diagnostic criteria: A. At least 20 attacks fulfilling criteria B to E B. Attacks of unilateral orbital, supraorbital or temporal stabbing pain lasting from 2 seconds to 10 minutes C. Pain is accompanied by one of the following: 1. Conjunctival injection and/or tearing 2. Nasal congestion and or rhinorrhea 3. Eyelid edema D. Attacks occur with a frequency of one or more per day for more than half the time E. Not attributed to another disorder Episodic SUNA (A3.3.1) Description: SUNA attacks occurring for 7 days to 1 year with remission periods longer than 1 month Chronic SUNA (A3.3.2) Description: At least two attack periods lasting 7 days to 1 year, separated by remission periods of less than 1 month (untreated)

Epidemiology The prevalence of SUNCT syndrome is not known, although the extremely low number of reported cases suggests that it is rare. The disorder has a male predominance (36 male patients, 16 female patients) with a sex ratio of 2.1 : 1. The typical age at onset is between 40 and 70 years, although it ranges from 10 to 77 years.190

Clinical Features The pain of SUNCT is usually maximal in the ophthalmic distribution of the trigeminal nerve, especially the orbital or periorbital regions, forehead, and temple, although it may radiate to the other ipsilateral trigeminal divisions. Attacks are typically unilateral; however, three patients experienced the pain simultaneously on the opposite side.191 The pain is generally moderate to severe and described as stabbing, burning, pricking, or electric shock–like in character. The individual attacks are very brief, lasting between 5 and 250 seconds,192 although attacks lasting up to 2 hours each have been described.193-195 The paroxysms begin abruptly, reaching maximal intensity within 2 to 3 seconds; the pain is maintained at the maximal intensity before abating rapidly.191 Most patients are completely pain free between attacks, although some report a persistent, dull, interictal discomfort.195 The temporal pattern is quite variable, with symptomatic periods alternating with remissions in an erratic manner. Symptomatic periods generally last from a few days to several months and occur once or twice annually. Remissions typically last a few months, although they can range from 1 week to 7 years. Symptomatic periods appear to increase in frequency and duration over time.191 The attack frequency during the symptomatic phase varies greatly between sufferers and within an individual sufferer. Attacks may be as infrequent as once a day or less or as often as 30 attacks an hour. Acute headache episodes in SUNCT syndrome are accompanied by a variety of associated symptoms. The attacks are virtually always accompanied by both ipsilateral conjunctival injection and lacrimation. Ipsilateral nasal congestion, rhinorrhea, eyelid edema, ptosis, miosis, and facial redness or sweating are less commonly reported. These cranial autonomic symptoms, particularly conjunctival injection and lacrimation, are typically very prominent in SUNCT syndrome. The associated conjunctival injection and tearing usually begin 1 to 2 seconds after the onset of pain and may outlast the pain by a few seconds. Nausea, vomiting, photophobia, and phonophobia are not ordinarily associated with SUNCT syndrome. Unlike cluster headache, restlessness is not a feature of SUNCT syndrome.191 The majority of patients can precipitate attacks by touching certain trigger zones within the trigeminal innervated distribution and, occasionally, even from an extratrigeminal territory. Precipitants include touching the face or scalp, washing, shaving, eating, chewing, brushing the teeth, talking, and coughing.191 Unlike patients with trigeminal neuralgia, most patients with SUNCT have no refractory period.

SECONDARY SUNCT Secondary SUNCT has been reported in eight patients, seven of whom have had posterior fossa abnormalities. The secondary

chapter 59 trigeminal autonomic cephalalgias causes include homolateral cerebellopontine angle arteriovenous malformations in two patients,196,197 a brainstem cavernous hemangioma,198 a posterior fossa lesion in a patient with human immunodeficiency virus infection/acquired immunodeficiency syndrome,2 severe basilar impression causing pontomedullary compression in a patient with osteogenesis imperfecta,199 craniosynostosis resulting in a foreshortened posterior fossa,200 and ischemic brainstem201 or hemispheric202 stroke. The posterior fossa abnormalities emphasize the absolute need for cranial MRI in any suspected case of SUNCT. The author’s experience203 and other reported cases204,205 suggest that a SUNCT-like picture may be present with pituitary adenomas and that this is not related to tumor size.206

Differential Diagnosis The differential diagnosis of very brief headaches includes SUNCT (primary and secondary forms), trigeminal neuralgia, primary stabbing headache, and paroxysmal hemicrania. Differentiating SUNCT from trigeminal neuralgia can be challenging, because there is considerable overlap in the clinical phenotypes of the two syndromes. With both headaches, duration is short, attacks can have a high frequency, and clustering of attacks occurs. Both are principally unilateral headaches, and the trigger zones behave similarly. The usual onset is during middle or old age for both. However, there are a number of striking differences between these two syndromes (Table 59–9), awareness of which can aid in their differentiation.32,207 Primary (idiopathic) stabbing headache refers to brief sharp or jabbing pains in the head that occur either as a single episode or in brief repeated volleys. The pain is usually over the ophthalmic trigeminal distribution, whereas the face is generally spared. The pain usually lasts a fraction of a second but can persist for up to 1 minute, thereby overlapping with the phenotype of SUNCT, and recurs at irregular intervals (hours to days). In general, these headaches are easily distinguishable clinically because they differ in several respects: in primary stabbing headache, there is a female preponderance; the site and radiation of pain often vary between attacks; the majority of the attacks tend to be spontaneous; cranial autonomic features are absent; and the attacks commonly subside with indomethacin administration.208,209 SUNCT syndrome also has to be differentiated from shortlasting paroxysmal hemicrania. Paroxysmal hemicrania has a

T A B L E 59–9. Differentiating Features of Typical SUNCT and Trigeminal Neuralgia Feature

SUNCT

Trigeminal Neuralgia

Gender ratio (male/female) Site of pain Severity of pain

2.1 : 1 V1 Moderate to severe 5 to 250 Prominent Absent Partial

1:2 V2/V3 Very severe

Duration (seconds) Autonomic features Refractory period Response to carbamazepine

<5 Sparse or none Present Complete

SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

785

female preponderance; the attacks have a uniform distribution through day and night; the triggers differ from those in SUNCT; and the attacks are exquisitely responsive to indomethacin. If there is any diagnostic uncertainty, a trial of indomethacin is warranted.

Treatment Traditionally, SUNCT was believed to be highly refractory to treatment.210 Several categories of drugs used in other headache syndromes—namely, NSAIDs (including indomethacin), paracetamol (acetaminophen), 5-HT agonists (triptans, ergotamine, dihydroergotamine), β blockers, tricyclic antidepressants, calcium channel antagonists (verapamil, nifedipine), methysergide, lithium, prednisolone (prednisone), phenytoin, baclofen, and intravenous lignocaine—were reported to be ineffective.210 The author and colleagues have found intravenous lidocaine very effective in the acute suppression of SUNCT,211 although they are cautious of the neuropsychiatric side effects that are very common in these patients.212 Partial improvement with carbamazepine has been observed in several patients.193,194,210,213,214 Lamotrigine has been reported to be highly efficacious in a number of patients.215-219 Lamotrigine, given in an open-label manner at 100 to 300 mg/day, induced a complete remission in seven patients and produced about an 80% improvement in the other two patients. Although ultimate confirmation of lamotrigine’s utility in the treatment of this debilitating syndrome should come from a randomized, double-blind, placebocontrolled clinical trial, it is for now the treatment of choice. There are a number of reported cases of patients with SUNCT who responded completely to gabapentin,220-222 typically 900 to 2700 mg/day. Matharu and associates reported a patient who responded completely to topiramate, 50 mg/day.194 These observations clearly need to be confirmed in other cases. Nonetheless, given the debilitating nature of this headache, gabapentin and topiramate are reasonable second-line agents in patients in whom a trial of lamotrigine fails. Several surgical approaches have been tried for SUNCT syndrome. Anesthetic blockades of pericranial nerves have been reported to be ineffective.210 Black and Dodick reported two SUNCT cases that were refractory to various surgical procedures.223 The first patient underwent glycerol rhizotomy, Gamma knife radiosurgery, and microvascular decompression of the trigeminal nerve; the second patient underwent Gamma knife radiosurgery of the trigeminal root exit zone and two microvascular decompressions of the trigeminal nerve. Neither patient benefited from these procedures. In addition, the first patient suffered from anesthesia dolorosa and the second patient from unilateral deafness, chronic vertigo, and disequilibrium as a result of surgery. The author and colleagues have seen two patients who had failed to demonstrate a persistent response after trigeminal thermocoagulation and microvascular decompression (unpublished observations). Although there are some reports of successful procedures, none has had greater than 18 months’ follow-up, and the author and colleagues currently do not recommend destructive procedures at all. The most exciting developments in this area may mirror those in cluster headache, in view of a report that deep brain stimulation in the region of the posterior hypothalamic is useful in SUNCT.224

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P O I N T S

●

TACs encompass primary headaches whose features are short-lasting unilateral headache with cranial autonomic features, such as lacrimation, conjunctival injection, rhinorrhea, ptosis, and miosis.

●

Cluster headache is the most common of the TACs. Attacks last from 15 to 180 minutes. They respond well to oxygen and sumatriptan nasal spray or injection.

●

The attacks of paroxysmal hemicrania typically last from 2 to 30 minutes and are absolutely responsive to indomethacin.

●

SUNCT attacks last from 5 to 240 seconds. They are triggered and may respond to lamotrigine.

Suggested Reading Lance JW, Goadsby PJ: Mechanism and Management of Headache, 7th ed. New York: Elsevier, 2005. Matharu MS, Boes CJ, Goadsby PJ: Management of trigeminal autonomic cephalalgias and hemicrania continua. Drugs 2003; 63: 1637-1677. Matharu MS, Cohen AS, Boes CJ, et al: SUNCT syndrome: a review. Curr Pain Headache Rep 2003; 7:308-318. Pareja JA, Sjaastad O: SUNCT syndrome. A clinical review. Headache 1997; 37:195-202. Silberstein SD, Lipton RB, Goadsby PJ: Headache in Clinical Practice, 2nd ed. London: Martin Dunitz, 2002.

References 1. Headache Classification Committee of the International Headache Society: The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24(Suppl 1): 1-160. 2. Goadsby PJ, Lipton RB: A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases. Brain 1997; 120:193-209. 3. Goadsby PJ: Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol 2002; 1:37-43. 4. Matharu MS, Boes CJ, Goadsby PJ: Management of trigeminal autonomic cephalalgias and hemicrania continua. Drugs 2003; 63:1637-1677. 5. Olesen J: Revision of the International Headache Classification. An interim report. Cephalalgia 2001; 21:261. 6. Matharu MS, Cohen AS, McGonigle DJ, et al: Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004; 44:747-761. 7. McNaughton FL, Feindel WH: Innervation of intracranial structures: a reappraisal. In Rose FC, ed: Physiological Aspects of Clinical Neurology. Oxford, UK: Blackwell Scientific, 1977, pp 279-293. 8. Feindel W, Penfield W, McNaughton F: The tentorial nerves and localization of intracranial pain in man. Neurology 1960; 10:555-563. 9. Goadsby PJ, Hoskin KL: The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat 1997; 190:367-375.

10. May A, Goadsby PJ: The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 1999; 19:115-127. 11. Goadsby PJ, Edvinsson L, Ekman R: Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23:193-196. 12. Lambert GA, Bogduk N, Goadsby PJ, et al: Decreased carotid arterial resistance in cats in response to trigeminal stimulation. J Neurosurg 1984; 61:307-315. 13. Spencer SE, Sawyer WB, Wada H, et al: CNS projections to the pterygopalatine parasympathetic preganglionic neurons in the rat: a retrograde transneuronal viral cell body labeling study. Brain Res 1990; 534:149-169. 14. Nakai M, Tamaki K, Ogata J, et al: Parasympathetic cerebrovascular center of the facial nerve. Circ Res 1993; 72:470-475. 15. Goadsby PJ, Lambert GA, Lance JW: Effects of locus coeruleus stimulation on carotid vascular resistance in the cat. Brain Res 1983; 278:175-183. 16. Goadsby PJ, Lambert GA, Lance JW: The peripheral pathway for extracranial vasodilatation in the cat. J Auton Nerv Syst 1984; 10:145-155. 17. Goadsby PJ, Shelley S: High frequency stimulation of the facial nerve results in local cortical release of vasoactive intestinal polypeptide in the anesthetised cat. Neurosci Lett 1990; 112:282-289. 18. Goadsby PJ, Macdonald GJ: Extracranial vasodilatation mediated by VIP (vasoactive intestinal polypeptide). Brain Res 1985; 329:285-288. 19. Goadsby PJ: Characteristics of facial nerve elicited cerebral vasodilatation determined with laser Doppler flowmetry. Am J Physiol 1991; 260:R255-R262. 20. Seylaz J, Hara H, Pinard E, et al: Effect of stimulation of the sphenopalatine ganglion on cortical blood flow in the rat. J Cereb Blood Flow Metab 1988; 8:875-878. 21. Goadsby PJ: Effect of stimulation of the facial nerve on regional cerebral blood flow and glucose utilization in cats. Am J Physiol 1989; 257:R517-R521. 22. Uddman R, Tajti J, Moller S, et al: Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia. Brain Res 1999; 826:193-199. 23. Goadsby PJ, Uddman R, Edvinsson L: Cerebral vasodilatation in the cat involves nitric oxide from parasympathetic nerves. Brain Res 1996; 707:110-118. 24. Ekbom K, Greitz T: Carotid angiography in cluster headache. Acta Radiol 1970; 10:177-186. 25. May A, Buchel C, Bahra A, et al: Intra-cranial vessels in trigeminal transmitted pain: a PET study. Neuroimage 1999; 9:453-460. 26. Drummond PD, Lance JW: Pathological sweating and flushing accompanying the trigeminal lacrimation reflex in patients with cluster headache and in patients with a confirmed site of cervical sympathetic deficit. Evidence for parasympathetic cross-innervation. Brain 1992; 115:1429-1445. 27. Drummond PD: Autonomic disturbance in cluster headache. Brain 1988; 111:1199-1209. 28. May A, Buchel C, Turner R, et al: MR-angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation. J Cereb Blood Flow Metab 2001; 21:1171-1176. 29. Barbanti P, Fabbrini G, Pesare M, et al: Unilateral cranial autonomic symptoms in migraine. Cephalalgia 2002; 22:256259. 30. Benoliel R, Sharav Y: Trigeminal neuralgia with lacrimation or SUNCT syndrome? Cephalalgia 1998; 18:85-90. 31. Goadsby PJ, Edvinsson L, Ekman R: Cutaneous stimulation leading to facial flushing and release of calcitonin gene– related peptide. Cephalalgia 1992; 12:53-56.

chapter 59 trigeminal autonomic cephalalgias 32. Goadsby PJ, Matharu MS, Boes CJ: SUNCT syndrome or trigeminal neuralgia with lacrimation. Cephalalgia 2001; 21:82-83. 33. Boes CJ, Swanson JW, Dodick DW: Chronic paroxysmal hemicrania presenting as otalgia with a sensation of external acoustic meatus obstruction: two cases and a pathophysiologic hypothesis. Headache 1998; 38:787-791. 34. May A, Bahra A, Buchel C, et al: Hypothalamic activation in cluster headache attacks. Lancet 1998; 352:275-278. 35. May A, Bahra A, Buchel C, et al: PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000; 55:1328-1335. 36. Sprenger T, Boecker H, Tolle TR, et al: Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 2004; 62:516-517. 36a. Mathara MS, Cohen AS, Frackowiak RS, Goadsby PJ: Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol 2006; 59:535-545. 37. May A, Bahra A, Buchel C, et al: Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999; 46:791-793. 38. Cohen AS, Matharu MS, Kalisch R, et al: Functional MRI in SUNCT shows differential hypothalamic activation with increasing pain. Cephalalgia 2004; 24:1098-1099. 39. Weiller C, May A, Limmroth V, et al: Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1:658660. 40. Bahra A, Matharu MS, Buchel C, et al: Brainstem activation specific to migraine headache. Lancet 2001; 357:1016-1017. 41. Afridi S, Giffin NJ, Kaube H, et al: A PET study in spontaneous migraine. Arch Neurol 2005:in press. 42. Matharu MS, Bartsch T, Ward N, et al: Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 2004; 127:220-230. 43. May A, Kaube H, Buechel C, et al: Experimental cranial pain elicited by capsaicin: a PET-study. Pain 1998; 74:61-66. 44. Malick A, Burstein R: Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol 1998; 400:125144. 45. Bartsch T, Levy MJ, Knight YE, et al: Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004; 109:367-378. 46. Matharu MS, Goadsby PJ: Persistence of attacks of cluster headache after trigeminal nerve root section. Brain 2002; 175:976-984. 47. Franzini A, Ferroli P, Leone M, et al: Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches. The first reported series. Neurosurgery 2003; 52:1095-1101. 48. Goadsby PJ, Edvinsson L, Ekman R: Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28:183-187. 49. Goadsby PJ, Edvinsson L: Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 1994; 117:427-434. 50. Kudrow L: Cluster Headache: Mechanisms and Management. Oxford, UK: Oxford University Press, 1980. 51. Sjaastad O: Cluster Headache Syndrome. London: WB Saunders, 1992. 52. Bahra A, May A, Goadsby PJ: Cluster headache: a prospective clinical study in 230 patients with diagnostic implications. Neurology 2002; 58:354-361. 53. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(Suppl 7):1-96.

787

54. Cooke LJ, Rose MS, Becker WJ: Chinook winds and migraine headache. Neurology 2000; 54:302-307. 55. Sjaastad O, Bakketeig LS: Cluster headache prevalence. Vaga study of headache epidemiology. Cephalalgia 2003; 23:528533. 56. Ford HL, Gerry E, Johnson M, et al: A prospective study of the incidence, prevalence and mortality of multiple sclerosis in Leeds. J Neurol 2002; 249:260-265. 57. Manzoni GC: Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia 1998; 18:138-142. 58. Lance JW, Goadsby PJ: Mechanism and Management of Headache, 7th ed. New York: Elsevier, 2005. 59. Silberstein SD, Niknam R, Rozen TD, et al: Cluster headache with aura. Neurology 2000; 54:219-221. 60. Siow HC, Young WB, Peres MF, et al: Hemiplegic cluster. Headache 2002; 42:136-139. 61. Manzoni GC, Micieli G, Granella F, et al: Cluster headache— course over ten years in 189 patients. Cephalalgia 1991; 11:169-174. 62. Igarashi H, Sakai F: Natural history of cluster headache. Cephalalgia 1996; 16:390-391. 63. Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991; 325:322-326. 64. Ekbom K, Monstad I, Prusinski A, et al: Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study. Acta Neurol Scand 1993; 88:63-69. 65. Ekbom K, Krabbe A, Micelli G, et al: Cluster headache attacks treated for up to three months with subcutaneous sumatriptan (6 mg). Cephalalgia 1995; 15:230-236. 66. Gobel H, Lindner A, Heinze A, et al: Acute therapy for cluster headache with sumatriptan: findings of a one year long-term study. Neurology 1998; 51:908-911. 67. van Vliet JA, Bahra A, Martin V, et al: Intranasal sumatriptan is effective in the treatment of acute cluster headache—a double-blind placebo-controlled crossover study. Cephalalgia 2001; 21:270-271. 68. Bahra A, Gawel MJ, Hardebo J-E, et al: Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology 2000; 54:1832-1839. 69. Yates RA, Tateno M, Nairn K, et al: The pharmacokinetics of the antimigraine compound zolmitriptan in Japanese and Caucasian subjects. Eur J Clin Pharmacol 2002; 58:247252. 70. Horton BT: Histaminic cephalalgia: differential diagnosis and treatment. Proc Mayo Clin 1956; 31:325-333. 71. Kudrow L: Response of cluster headache attacks to oxygen inhalation. Headache 1981; 21:1-4. 72. Fogan L: Treatment of cluster headache: a double blind comparison of oxygen vs air inhalation. Arch Neurol 1985; 42:362363. 73. Igarashi H, Sakai F, Tazaki Y: The mechanism by which oxygen interrupts cluster headache. Cephalalgia 1991; 11(Suppl 11):238-239. 74. Kittrelle JP, Grouse DS, Seybold ME: Cluster headache: local anesthetic abortive agents. Arch Neurol 1985; 42:496498. 75. Robbins L: Intranasal lidocaine for cluster headache. Headache 1995; 35:83-84. 76. Costa A, Pucci E, Antonaci F, et al: The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache. Cephalalgia 2000; 20:85-91. 77. Friedman AP, Mikropoulos HE: Cluster headache. Neurology (Minneapolis) 1958; 8:653-663. 78. Horton BT: Histaminic cephalgia. Lancet 1952; 72:92-98. 79. Dodick DW, Rozen TD, Goadsby PJ, et al: Cluster headache. Cephalalgia 2000; 20:787-803.

788

Section

XI

Headache

80. Andersson PG, Jespersen LT: Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. Cephalalgia 1986; 6:51-54. 81. Sicuteri F, Geppetti P, Marabini S, et al: Pain relief by somatostatin in attacks of cluster headache. Pain 1984; 18:359-365. 82. Geppetti P, Brocchi A, Caleri D, et al: Somatostatin for cluster headache attack. In Pfaffenrath V, Lundberg PO, Sjaastad O, eds: Updating in Headache. Berlin: Spring-Verlag, 1985, pp 302-305. 83. Matharu MS, Levy MJ, Meeran K, et al: Subcutaneous octreotide in cluster headache—randomized placebo-controlled double-blind cross-over study. Ann Neurol 2004; 56:488-494. 84. Meyer JS, Hardenberg J: Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headache. Headache 1983; 23:266-277. 85. Gabai IJ, Spierings ELH: Prophylactic treatment of cluster headache with verapamil. Headache 1989; 29:167-168. 86. Bussone G, Leone M, Peccarisi C, et al: Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 1990; 30:411-417. 87. Leone M, D’Amico D, Attanasio A: Verapamil is an effective prophylactic for cluster headache: results of a double-blind multicentre study versus placebo. In Olesen J, Goadsby PJ, eds: Cluster Headache & Related Conditions. Oxford, UK: Oxford University Press, 1999, pp 296-299. 88. Singh BN, Nademanee K: Use of calcium antagonists for cardiac arrhythmias. Am J Cardiol 1987; 59:153B-162B. 89. Naylor WG: Calcium Antagonists. London: Academic Press, 1988. 90. Krabbe A, Steiner TJ: Prophylactic treatment of cluster headache. In Sjaastad O, Nappi G, eds: Cluster Headache Syndrome in General Practice: Basic Concepts. London: SmithGordon, 2000, pp 91-96. 91. Matharu MS, van Vliet JA, Ferrari MD, et al: Verapamilinduced gingival enlargement in cluster headache. J Neurol Neurosurg Psychiatry 2005; 76:124-127. 92. Ekbom K: Litium rid kroniska symptom av cluster headache. Opusc Med 1974; 19:148-156. 93. Ekbom K: Lithium in the treatment of chronic cluster headache. Headache 1977; 17:39-40. 94. Ekbom K, Solomon S: Management of cluster headache. In Olesen J, Tfelt-Hansen P, Welch KMA, eds: The Headaches, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 731-740. 95. Ekbom K: Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Headache 1981; 21:132-139. 96. Steiner TJ, Hering R, Couturier EGM, et al: Double-blind placebo controlled trial of lithium in episodic cluster headache. Cephalalgia 1997; 17:673-675. 97. Nilsson Remahl AIM, Laudon Meyer E, Cordonnier CS, et al: Placebo response rates in cluster headache trials. A review. Cephalalgia 2003; 23:504-510. 98. Sicuteri F: Prophylactic and therapeutic properties of lmethyl-lysergic acid butanolamide in migraine: preliminary report. Int Arch Allergy Appl Immunol 1959; 15:300-307. 99. Dalsgaard-Neilsen T: Uber die prophylaktische Behandlung der Migraine mit Deseril [On the prophylactic treatment of migraine with deseril]. Praxis 1960; 49:867-868. 100. Friedman AP: Clinical observations with 1-methyl-lysergic acid butanolamide (UML-491) in vascular headache. Angiology 1960; 11:364-366. 101. Graham JR: Use of a new compound, UML-491 (1-methyl-Dlysergic acid butanolamide), in the prevention of various types of headache. N Engl J Med 1960; 263:1273-1277. 102. Heyck H: Serotoninantagonisten in der behandlung der migraine und der erythroprosopalgic Bings oder des Horton-

103. 104. 105. 106. 107. 108. 109. 110.

111.

112. 113. 114.

115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126.

syndroms [Serotonin antagonists in the therapy of migraine and Bing’s erythroprosopalgia or the Horton syndrome.]. Schweiz Med Wochenschr 1960; 90:203-209. Friedman AP, Losin S: Evaluation of UML-491 in the treatment of vascular headache. Arch Neurol 1961; 4:241-245. Harris MC: Prophylactic treatment of migraine and histamine cephalgia with a serotonin antagonist (methysergide). Ann Allergy 1961; 19:500-504. Ekbom KA: Treatment of migraine, Horton’s syndrome and restless legs with deseril (UML-491). Acta Neurol Scand 1962; 38:313-318. Curran DA, Hinterberger H, Lance JW: Methysergide. Res Clin Stud Headache 1967; 1:74-122. Graham JR, Suby HI, LeCompte PR, et al: Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med 1966; 274:360-368. Raskin NH: Headache. New York: Churchill-Livingstone, 1988. Silberstein SD: Methysergide. Cephalalgia 1998; 18:421-435. Berde B, Schild HO: Ergot alkaloids and related compounds. In Born GVR, Eichler O, Farah A, et al, eds: Handbook of Experimental Pharmacology. Berlin: Springer-Verlag, 1978, vol 49. Garrison JC: Histamine, bradykinin, 5-hydroxytryptamine and their antagonists. In Gilman AG, Rall TW, Niles AS, et al, eds: The Pharmacological Basis of Therapeutics. New York: Pergamon Press, 1990, p 595. Saxena PR, De Boer MO: Pharmacology of antimigraine drugs. J Neurol 1991; 238:S28-S35. Blakeborough P, Fowler PA, Ashford EA: The use of sumatriptan in patients taking migraine prophylactic agents. Cephalalgia 1993; 13(Suppl):163. Liston H, Bennett L, Usher B, et al: The association of the combination of sumatriptan and methysergide in myocardial infarction in a premenopausal woman. Arch Intern Med 1999; 159:511-513. Ekbom K: Ergotamine tartrate orally in Horton’s “histaminic cephalalgia” (also called Harris’s ciliary neuralgia). Acta Psychiatr Scand 1947; (Suppl 46):106-113. Symonds CP: A particular variety of headache. Brain 1956; 79:217-232. Mather P, Silberstein SD, Schulman E, et al: The treatment of cluster headache with repetitive intravenous dihydroergotamine. Headache 1991; 31:525-532. Jammes JL: The treatment of cluster headaches with prednisone. Dis Nerv Syst 1975; 36:375-376. Couch JR, Ziegler DK: Prednisone therapy for cluster headache. Headache 1978; 18:219-221. Mirzai R, Chang C, Greenspan A, et al: The pathogenesis of osteonecrosis and the relationships to corticosteroids. J Asthma 1999; 36:77-95. Wheeler SD, Carrazana EJ: Topiramate-treated cluster headache. Neurology 1999; 53:234-236. Forderreuther S, Mayer M, Straube A: Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cepahalalgia 2002; 22:186-189. Mathew NT, Kailasam J, Meadors L: Prophylaxis of migraine, transformed migraine, and cluster headache with topiramate. Headache 2002; 42:796-803. Leone M, Dodick D, Rigamonti A, et al: Topiramate in cluster headache prophylaxis: an open trial. Cephalalgia 2003; 23:1001-1002. Lainez MJ, Pascual J, Pascual AM, et al: Topiramate in the prophylactic treatment of cluster headache. Headache 2003; 43:784-749. Rapoport AM, Bigal ME, Tepper SJ, et al: Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cephalalgia 2003; 23:69-70.

chapter 59 trigeminal autonomic cephalalgias 127. Brzezinski A: Melatonin in humans. N Engl J Med 1997; 336:186-195. 128. Waldenlind E, Gustafsson SA, Ekbom K, et al: Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987; 50:207-213. 129. Leone M, Lucini V, D’Amico D, et al: Twenty-four-hour melatonin and cortisol plasma levels in relation to timing of cluster headache. Cephalalgia 1995; 15:224-229. 130. Leone M, D’Amico D, Moschiano F, et al: Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16:494496. 131. El Amrani M, Massiou H, Bousser M-G: A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia 2002; 22:205-208. 132. Ahmed F: Chronic cluster headache responding to gabapentin: a case report. Cephalalgia 2000; 20:252-253. 133. Tay BA, Ngan Kee WD, Chung DC: Gabapentin for the treatment and prophylaxis of cluster headache. Reg Anesth Pain Med 2001; 26:373-375. 134. Leandri M, Luzzani M, Cruccu G, et al: Drug-resistant cluster headache responding to gabapentin: a pilot study. Cephalalgia 2001; 21:744-746. 135. Hering-Hanit R, Gadoth N: Baclofen in cluster headache. Headache 2000; 40:48-51. 136. Sicuteri F, Fusco BM, Marabini S: Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clin J Pain 1989; 5:49-53. 137. Sicuteri F, Faneiullaeci M, Nicolodi M, et al: Substance P theory: a unique focus on the painful and painless phenomena of cluster headache. Headache 1990; 30:69-79. 138. Marks DR, Rapoport A, Padla D: A double-blind placebocontrolled trial of intra-nasal capsaicin for cluster headache. Cephalalgia 1993; 13:114-116. 139. Fusco BM, Marabini S, Maggi CA, et al: Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 1994; 59:321-325. 140. Saper JR, Klapper J, Mathew NT, et al: Intranasal civamide for the treatment of episodic cluster headaches. Arch Neurol 2002; 59:990-994. 141. Anthony M: Arrest of attacks of cluster headache by local steroid injection of the occipital nerve. In Rose FC, ed: Migraine: Clinical and Research Advances. London: Karger, 1985, pp 169-173. 142. Peres MFP, Stiles MA, Siow HC, et al: Greater occipital nerve blockade for cluster headache. Cephalalgia 2002; 22:520-522. 143. Shields KG, Levy MJ, Goadsby PJ: Alopecia and cutaneous atrophy following greater occipital nerve infiltration. Neurology 2004; 63:2193-2194. 144. Kirkpatrick PJ, O’Brien M, MacCabe JJ: Trigeminal nerve section for chronic migrainous neuralgia. Br J Neurosurg 1993; 7:483-490. 145. Jarrar RG, Black DF, Dodick DW, et al: Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology 2003; 60:1360-1362. 146. Mathew NT, Hurt W: Percutaneous radiofrequency trigeminal gangliorhizolysis in intractable cluster headache. Headache 1988; 28:328-331. 147. Lovely TJ, Kotsiakis X, Jannetta PJ: The surgical management of chronic cluster headache. Headache 1998; 38:590-594. 148. Donnet A, Valade D, Regis J: Gamma knife treatment for refractory cluster headache: prospective open trial. J Neurol Neurosurg Psychiatry 2005; 76:218-221. 149. Leone M, Franzini A, Bussone G: Stereotatic stimulation of the posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001; 345:14281429.

789

150. Vandenheede M, Maertens de Noordhout AS, Remacle JM, et al: Deep brain stimulation of posterior hypothalamus in chronic cluster headache. Neurology 2004; 62(Suppl 5):A356. 151. Weiner RL, Reed KL: Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999; 2:217-222. 152. Sjaastad O, Dale I: Evidence for a new (?), treatable headache entity. Headache 1974; 14:105-108. 153. Sjaastad O, Dale I: A new (?) clinical headache entity “chronic paroxysmal hemicrania” 2. Acta Neurol Scand 1976; 54:140159. 154. Kudrow L, Esperanca P, Vijayan N: Episodic paroxysmal hemicrania? Cephalalgia 1987; 7:197-201. 155. Blau JN, Engel H: Episodic paroxysmal hemicrania: a further case and review of the literature. J Neurol Neurosurg Psychiatry 1990; 53:343-344. 156. Newman LC, Gordon ML, Lipton RB, et al: Episodic paroxysmal hemicrania: two new cases and a literature review. Neurology 1992; 42:964-966. 157. Antonaci F, Sjaastad O: Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 1989; 29:648-656. 158. Rapoport AM, Sheftell FD, Baskin SM: Chronic paroxysmal hemicrania: case report of the second known definite occurrence in a male. Cephalalgia 1981; 1:67-70. 159. Tehindrazanarivelo AD, Visy JM, Bousser MG: Ipsilateral cluster headache and chronic paroxysmal hemicrania: two case reports. Cephalalgia 1992; 12:318-320. 160. Joubert J, Powell D, Djikowski J: Chronic paroxysmal hemicrania in a South African black. A case report. Cephalalgia 1987; 7:193-196. 161. Newman LC, Goadsby PJ: The paroxysmal hemicranias, SUNCT syndrome, and hypnic headache. In Silberstein SD, Lipton RB, Dalessio DJ, eds: Wolff’s Headache and Other Head Pain. Oxford, UK: Oxford University Press, 2001, pp 310324. 162. Russell D: Paroxysmal hemicrania. In Olesen J, Goadsby PJ, eds: Cluster Headache & Related Conditions. Oxford, UK: Oxford University Press, 1999, pp 27-36. 163. Pelz M, Merskey H: A case of pre-chronic paroxysmal hemicrania. Cephalalgia 1982; 2:47-50. 164. Bogucki A, Szymanska R, Braciak W: Chronic paroxysmal hemicrania: lack of a pre-chronic stage. Cephalalgia 1984; 4:187-189. 165. Pradalier A, Dry J: [Chronic paroxysmal hemicrania. Treatment with indomethacin and diclofenac]. Therapie 1984; 39:185-188. 166. Pareja JA: Chronic paroxysmal hemicrania: dissociation of the pain and autonomic features. Headache 1995; 35:111113. 167. Pollmann W, Pfaffenrath V: Chronic paroxysmal hemicrania: the first possible bilateral case. Cephalalgia 1986; 6:55-57. 168. Matharu MS, Goadsby PJ: Post-traumatic chronic paroxysmal hemicrania (CPH) with aura. Neurology 2001; 56:273-275. 169. Pareja J, Pareja J: Chronic paroxysmal hemicrania coexisting with migraine. Differential response to pharmacological treatment. Headache 1992; 32:77-78. 170. Jotkowitz S: Chronic paroxysmal hemicrania and cluster. Ann Neurol 1978; 4:389. 171. Pearce SHS, Cox JGC, Pearce JMS: Chronic paroxysmal hemicrania, episodic cluster headache and classic migraine in one patient. J Neurol Neurosurg Psychiatry 1987; 50:1599. 172. Centonze V, Bassi A, Causarano V, et al: Simultaneous occurrence of ipsilateral cluster headache and chronic paroxysmal hemicrania: a case report. Headache 2000; 40:54-56. 173. Hannerz J: Trigeminal neuralgia with chronic paroxysmal hemicrania: the CPH-tic syndrome. Cephalalgia 1993; 13:361-364.

790

Section

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174. Caminero AB, Pareja JA, Dobato JL: Chronic paroxysmal hemicrania–tic syndrome. Cephalalgia 1998; 18:159-161. 175. Zukerman E, Peres MFP, Kaup AO, et al: Chronic paroxysmal hemicrania–tic syndrome. Neurology 2000; 54:1524-1526. 176. Martinez-Salio A, Porta-Etessam J, Perez-Martinez D, et al: Chronic paroxysmal hemicrania–tic syndrome. Headache 2000; 40:682-685. 177. Mateo I, Pascual J: Coexistence of chronic paroxysmal hemicrania and benign cough headache. Headache 1999; 39:437-438. 178. Antonaci F, Pareja JA, Caminero AB, et al: Chronic paroxysmal hemicrania and hemicrania continua. Parenteral indomethacin: the “Indotest.” Headache 1998; 38:122-128. 179. Kudrow DB, Kudrow L: Successful aspirin prophylaxis in a child with chronic paroxysmal hemicrania. Headache 1989; 29:280-281. 180. Durko A, Klimek A: Naproxen in the treatment of chronic paroxysmal hemicrania. Cephalalgia 1987; 7:361-362. 181. Sjaastad O, Antonaci F: A piroxicam derivative partly effective in chronic paroxysmal hemicrania and hemicrania continua. Headache 1995; 35:549-550. 182. Mathew NT, Kailasam J, Fischer A: Responsiveness to celecoxib in chronic paroxysmal hemicrania. Neurology 2000; 55:316. 183. Shabbir N, McAbee G: Adolescent chronic paroxysmal hemicrania responsive to verapamil monotherapy. Headache 1994; 34:209-210. 184. Evers S, Husstedt I-W: Alternatives in drug treatment of chronic paroxysmal hemicrania. Headache 1996; 36:429432. 185. Coria F, Claveria LE, Jimenez-Jimenez FJ, et al: Episodic paroxysmal hemicrania responsive to calcium channel blockers. J Neurol Neurosurg Psychiatry 1992; 55:166. 186. Warner JS, Wamil AW, McLean MJ: Acetazolamide for the treatment of chronic paroxysmal hemicrania. Headache 1994; 34:597-599. 187. Hannerz J, Ericson K, Bergstrand G: Chronic paroxysmal hemicrania: orbital phlebography and steroid treatment. A case report. Cephalalgia 1987; 7:189-192. 188. Sjaastad O, Russell D, Horven I, et al: Multiple neuralgiform unilateral headache attacks associated with conjunctival injection and appearing in clusters. A nosological problem. Proceedings of the Scandinavian Migraine Society. Arhus 1978; 31. 189. Sjaastad O, Saunte C, Salvesen R, et al: Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia 1989; 9:147-156. 190. Matharu MS, Cohen AS, Boes CJ, et al: SUNCT syndrome: a review. Curr Pain Headache Rep 2003; 7:308-318. 191. Pareja JA, Sjaastad O: SUNCT syndrome. A clinical review. Headache 1997; 37:195-202. 192. Pareja JA, Ming JM, Kruszewski P, et al: SUNCT syndrome: duration, frequency and temporal distribution of attacks. Headache 1996; 36:161-165. 193. Raimondi E, Gardella L: SUNCT syndrome. Two cases in Argentina. Headache 1998; 38:369-371. 194. Matharu MS, Boes CJ, Goadsby PJ: SUNCT syndrome: prolonged attacks, refractoriness and response to topiramate. Neurology 2002; 58:1307. 195. Pareja JA, Joubert J, Sjaastad O: SUNCT syndrome. Atypical temporal patterns. Headache 1996; 36:108-110. 196. Bussone G, Leone M, Volta GD, et al: Short-lasting unilateral neuralgiform headache attacks with tearing and conjunctival injection: the first symptomatic case. Cephalalgia 1991; 11:123-127. 197. Morales F, Mostacero E, Marta J, et al: Vascular malformation of the cerebellopontine angle associated with SUNCT syndrome. Cephalalgia 1994; 14:301-302.

198. De Benedittis G: SUNCT syndrome associated with cavernous angioma of the brain stem. Cephalalgia 1996; 16:503506. 199. ter Berg HWM, Goadsby PJ: Significance of atypical presentation of symptomatic SUNCT: a case report. J Neurol Neurosurg Psychiatry 2001; 70:244-246. 200. Moris G, Ribacoba R, Solar DN, et al: SUNCT syndrome and seborrheic dermatitis associated with craniosynostosis. Cephalalgia 2001; 21:157-159. 201. Penart A, Firth M, Bowen JRC: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) following presumed dorsolateral brainstem infarction. Cephalalgia 2001; 21:236-239. 202. van Vliet JA, Ferrari MD, Haan J: SUNCT syndrome resolving after contralateral hemispheric ischaemic stroke. Cephalalgia 2003; 23:235-237. 203. Levy MJ, Matharu MS, Goadsby PJ: Prolactinomas, dopamine agonist and headache: two case reports. Eur J Neurol 2003; 10:169-174. 204. Ferrari MD, Haan J, van Seters AP: Bromocriptine-induced trigeminal neuralgia attacks in a patient with pituitary tumor. Neurology 1988; 38:1482-1484. 205. Massiou H, Launay JM, Levy C, et al: SUNCT syndrome in two patients with prolactinomas and bromocriptine-induced attacks. Neurology 2002; 58:1698-1699. 206. Levy M, Jager HR, Powell MP, et al: Pituitary volume and headache: size is not everything. Arch Neurol 2004; 61:721725. 207. Sjaastad O, Kruszewski P: Trigeminal neuralgia and “SUNCT” syndrome: similarities and differences in the clinical picture. An overview. Functional Neurology 1992; 7:103-107. 208. Pareja JA, Ruiz J, Deisla C, et al: Idiopathic stabbing headache (jabs and jolts syndrome). Cephalalgia 1996; 16:93-96. 209. Pareja JA, Kruszewski P, Caminero AB: SUNCT syndrome versus idiopathic stabbing headache (jabs and jolts syndrome). Cephalalgia 1999; 19(Suppl 25):46-48. 210. Pareja JA, Kruszewski P, Sjaastad O: SUNCT syndrome: trials of drugs and anesthetic blockades. Headache 1995; 35:138142. 211. Matharu MS, Cohen AS, Goadsby PJ: SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia 2004; 24:985-992. 212. Gil-Gouveia R, Goadsby PJ: Neuropsychiatric side effects of lidocaine: examples from the treatment of headache and a review. Cephalalgia. In press. 213. Ertsey C, Bozsik G, Afra J, et al: A case of SUNCT syndrome with neurovascular compression. Cephalalgia 2000; 20:325. 214. Peatfield R, Bahra A, Goadsby PJ: Trigeminal-autonomic cephalgias (TACs). Cephalalgia 1998; 18:358-361. 215. Leone M, Rigamonti A, Usai S, et al: Two new SUNCT cases responsive to lamotrigine. Cephalalgia 2000; 20:845-847. 216. D’Andrea G, Granella F, Ghiotto N, et al: Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001; 57:1723-1725. 217. Gutierrez-Garcia JM: SUNCT syndrome responsive to lamotrigine. Headache 2002; 42:823-825. 218. Chakravarty A, Mukherjee A: SUNCT syndrome responsive to lamotrigine: documentation of the first Indian case. Cephalalgia 2003; 23:474-475. 219. Piovesan EJ, Siow C, Kowacs PA, et al: Influence of lamotrigine over the SUNCT syndrome: one patient follow-up for two years. Arq Neuropsiquiatr 2003; 61:691-694. 220. Graff-Radford SB: SUNCT syndrome responsive to gabapentin. Cephalalgia 2000; 20:515-517. 221. Porta-Etessam J, Martinez-Salio A, Berbel A, et al: Gabapentin (Neurontin) in the treatment of SUNCT syndrome. Cephalalgia 2002; 22:249. 222. Hunt CH, Dodick DW, Bosch P: SUNCT responsive to gabapentin. Headache 2002; 42:525-526.

chapter 59 trigeminal autonomic cephalalgias 223. Black DF, Dodick DW: Two cases of medically and surgically intractable SUNCT: a reason for caution and an argument for a central mechanism. Cephalalgia 2002; 22:201-204. 224. Leone M, Franzini A, D’Amico D, et al: Hypothalamic deep brain stimulation to relieve intractable chronic SUNCT: the first case. Neurology 2004; 62(Suppl 5):A356. 225. Goadsby PJ: Raeders Syndrome: “Paratrigeminal” paralysis of oculo-pupillary sympathetic. J Neurol Neurosurg Psychiatry 2002; 72:297-299. 226. Cremer P, Halmagyi GM, Goadsby PJ: Secondary cluster headache responsive to sumatriptan. J Neurol Neurosurg Psychiatry 1995; 59:633-634. 227. Leira EC, Cruz-Flores S, Leacock RO, et al: Sumatriptan can alleviate headaches due to carotid artery dissection. Headache 2001; 41:590-591. 228. Mainardi F, Maggioni F, Dainese F, et al: Spontaneous carotid artery dissection with cluster-like headache. Cephalalgia 2002; 22:557-559. 229. West P, Todman D: Chronic cluster headache associated with a vertebral artery aneurysm. Headache 1991; 31:210-212. 230. Koenigsberg AD, Solomon GD, Kosmorsky DO: Pseudoaneurysm within the cavernous sinus presenting as cluster headache. Headache 1994; 34:111-113. 231. Greve E, Mai J: Cluster headache-like headaches: a symptomatic feature? A report of three patients with intracranial pathologic findings. Cephalalgia 1988; 8:79-82. 232. Giffin N, Goadsby PJ: Basilar artery aneurysm with autonomic features: an interesting pathophysiological problem. J Neurol Neurosurg Psychiatry 2001; 71:805-808. 233. Mani S, Deeter J: Arteriovenous malformation of the brain presenting as a cluster headache—a case report. Headache 1982; 22:184-185. 234. Munoz C, Diez-Tejedor E, Frank A, et al: Cluster headache syndrome associated with middle cerebral artery arteriovenous malformation. Cephalalgia 1996; 16:202-205. 235. Kuritzky A: Cluster headache–like pain caused by an upper cervical meningioma. Cephalalgia 1984; 4:185-186. 236. de la Sayette V, Schaeffer S, Coskun O, et al: Cluster headache–like attack as an opening symptom of a unilateral infarction of the cervical cord: persistent anaesthesia and dysaesthesia to cold stimuli. J Neurol Neurosurg Psychiatry 1999; 66:397-400. 237. Cid C, Berciano J, Pascual J: Retro-ocular headache with autonomic features resembling “continuous” cluster headache in a lateral medullary infarction. J Neurol Neurosurg Psychiatry 2000; 69:134-141. 238. Tfelt-Hansen P, Paulson OB, Krabbe AE: Invasive adenoma of the pituitary gland and chronic migrainous neuralgia. A rare coincidence or a causal relationship? Cephalalgia 1982; 2:2528.

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239. Porta-Etessam J, Ramos-Carrasco A, Berbel-Garcia A, et al: Clusterlike headache as first manifestation of a prolactinoma. Headache 2001; 41:723-725. 240. Hannerz J: A case of parasellar meningioma mimicking cluster headache. Cephalalgia 1989; 9:265-269. 241. Scorticati MC, Raina G, Federico M: Cluster-like headache associated to a foreign body in the maxillary sinus. Neurology 2002; 59:643-644. 242. Lance JW: Mechanism and Management of Headache, 5th ed. London: Butterworth Scientific, 1993. 243. Heidegger S, Mattfeldt T, Rieber A, et al: Orbito-sphenoidal aspergillus infection mimicking cluster headache: a case report. Cephalalgia 1997; 17:676-679. 244. Lee MS, Lessell S: Orbital myositis posing as cluster headache. Arch Neurol 2002; 59:635-636. 245. Hunter CR, Mayfield FH: Role of the upper cervical roots in the production of pain in the head. Am J Surg 1949; 78:743749. 246. Medina JL: Organic headaches mimicking chronic paroxysmal hemicrania. Headache 1992; 32:73-74. 247. Newman LC, Herskovitz S, Lipton R, et al: Chronic paroxysmal headache: two cases with cerebrovascular disease. Headache 1992; 32:75-76. 248. Broeske D, Lenn NJ, Cantos E: Chronic paroxysmal hemicrania in a young child: possible relation to ipsilateral occipital infarction. J Child Neurol 1993; 8:235-236. 249. Vijayan N: Symptomatic chronic paroxysmal hemicrania. Cephalalgia 1992; 12:111-113. 250. Sjaastad O, Stovner LJ, Stolt-Nielsen A, et al: CPH and hemicrania continua: requirements of high dose indomethacin dosages—an ominous sign? Headache 1995; 35:363-367. 251. Gatzonis S, Mitsikostas DD, Ilias A, et al: Two more secondary headaches mimicking chronic paroxysmal hemicrania. Is this the exception or the rule? Headache 1996; 36:511-513. 252. Mariano HS, Bigal ME, Bordini CA, et al: Chronic paroxysmal hemicrania (CPH)–like syndrome as a first manifestation of cerebral metastasis of parotid epidermoid carcinoma: a case report. Cephalalgia 1999; 19:442. 253. Delreux V, Kevers L, Callewaert A: Hemicranie paroxystique inaugurant un syndrome de Pancoast [Paroxysmal hemicrania preceding Pancoast’s syndrome]. Rev Neurol 1989; 145:151-152. 254. Hannerz J, Jogestrand T: Intracranial hypertension and sumatriptan efficacy in a case of chronic paroxysmal hemicrania which became bilateral (the mechanism of indomethacin in CPH). Headache 1993; 33:320-323. 255. MacMillan JC, Nukada H: Chronic paroxysmal hemicrania. N Z Med J 1989; 102:251-252. 256. Silberstein SD, Lipton RB, Goadsby PJ: Headache in Clinical Practice, 2nd ed. London: Martin Dunitz, 2002.

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60

OTHER SECONDARY HEADACHE DISORDERS ●

●

●

●

Todd J. Schwedt and David W. Dodick

Although most patients who present to a physician with the chief complaint of headache have primary headache disorders, the clinician must always consider the possibility of a secondary headache. Thus, when evaluating a headache patient, the clinician must search for features that may serve as evidence for an underlying disorder. Such evidence may be found during the patient’s interview and physical examination. Although a list of these “red flags” is potentially exhaustive, common worrisome features include new-onset persistent or progressive headache, change in the characteristics of prior headaches, progressive nature, older age of the patient, worsening or precipitation by changes in posture or by the Valsalva maneuver, associated systemic or neurological symptoms, sudden and severe onset, and a history of trauma (Table 60–1). Abnormalities found on examination, including alterations in blood pressure, fever, neurological deficits, papilledema, and meningismus, may also raise this suspicion. Although there are many causes of secondary headache, which span the entire spectrum of a differential diagnosis, the secondary headaches can generally be divided into (1) those caused by cerebrovascular disorders, nonvascular intracranial disorders, disorders of the neck or cranial structures, and intracranial infection and (2) those that are secondary to disorders of homeostasis. Headaches occurring after trauma and those associated with ingestion or withdrawal of substances are not discussed in this chapter. Headaches secondary to idiopathic intracranial hypertension and low cerebrospinal fluid (CSF) levels are discussed elsewhere in this text.

HEADACHE SECONDARY TO CEREBROVASCULAR DISORDERS The intracranial vasculature is innervated by the sympathetic, parasympathetic, and sensory nervous systems (Fig. 60–1). The sensory system is the major conduit by which head pain is perceived after vascular stimulation. The majority of sensory nerves that innervate the anterior portion of the intracranial circulation terminate in the trigeminal nucleus caudalis, projecting via the first division of the trigeminal nerve, whereas those that innervate the posterior circulation terminate in the superior cervical ganglia and dorsal vagal ganglia.1-3 The density of sensory afferent vessels is greater in the posterior than anterior circulation, and thus stimulation of the posterior circulation is more likely to result in head pain.4-6

Direct stimulation of the intracranial vasculature and sinuses has been shown to cause activation of the trigeminal system. Stimulation of the superior sagittal sinus results in increased activity in the trigeminal nucleus caudalis, upper cervical dorsal horn, and thalamus.7 In addition, activation of orofacial excitatory receptive fields, mostly within the distribution of the first division of the trigeminal nerve, results in activation of thalamic neurons.8 The same thalamic neurons are also activated by stimulation of the superior sagittal sinus and/or the middle meningeal artery. Such evidence, in conjunction with a large body of additional data, characterizes the convergence and overlap within the trigeminovascular system. This continuity explains how nociceptive input at any part of the trigeminovascular system, including the intracranial vasculature, may result in pain in the head, face, and neck. Headaches commonly occur in association with cerebrovascular disorders, such as ischemic stroke, cervical artery dissection, intracranial aneurysm, subarachnoid hemorrhage (SAH), cerebral venous sinus thrombosis (CVST), giant cell arteritis (GCA), primary angiitis of the central nervous system (PACNS), and reversible cerebral vasoconstriction syndrome (RCVS). Headaches may also occur during or after interventional procedures of the intracranial vasculature, such as carotid endarterectomy, cerebral angiography, and coiling or clipping of intracranial aneurysms.

Ischemic Stroke Approximately 25% of patients with stroke develop associated headaches, at least one half of which occur before the onset of neurological deficits.9 However, such headaches commonly go unrecognized, being overshadowed by more worrisome focal neurological symptoms. Headaches associated with ischemic stroke can be quite varying in their characteristics. Patients who have a primary headache disorder may develop a headache that closely resembles their usual headache. In those without such a history, headaches are most often pressing or throbbing in quality. The location of the headache may correlate with the site of the stroke. When headaches are unilateral, they are generally ipsilateral to the side of the stroke.4 Frontal pain is more common with anterior circulation strokes, and occipital pain is more common with posterior circulation strokes. Headaches associated with stroke occur more frequently in young women and in persons with a history of migraine.10

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Headache Headaches are more common with large ischemic strokes and with strokes located in the territory of the posterior circulation, particularly those in the cerebellum.5,10 Headaches are much less common with subcortical infarctions, lacunar infarctions, and transient ischemic attacks.5,9

T A B L E 60–1. Headache Red Flags New-onset persistent or progressive headache Changes in the characteristics in comparison with previous headaches Sudden and severe at onset New headache in a patient older than 50 years Precipitated by changes in position or the Valsalva maneuver (cough, sneeze) Systemic symptoms: fever, chills, weight loss, transient visual obscurations History of recent trauma Focal neurologic symptoms or signs Meningismus Papilledema Fever, severe hypertension

NA NPY

Cervical Artery Dissection Headache is the most frequent presenting symptom of cervical artery dissection. Headache occurs with 60% to 95% of carotid artery dissections and with 70% of vertebral artery dissections.11 These headaches usually have a slow and gradual onset. However, about 20% of patients have a sudden and severe onset of pain consistent with that of a thunderclap headache.12 Headaches are typically located ipsilateral to the dissected artery. International Headache Society (IHS) diagnostic criteria stipulate that headaches considered secondary to cervical artery dissection must be ipsilateral to the dissection.13 Headaches associated with carotid dissection tend to be located in the ipsilateral frontotemporal region, lower face, jaw, or ear, whereas those of vertebral dissection are more often located in the parieto-occipital region. Patients with cervical artery dissection may also have neck pain. Neck pain occurs in 50% of patients

SP CGRP Ach NKA VIP PHI Sensory V1

Endothelin, NOS

Vg

V2

Parasympathetic

V3

TNC SPG

Sympathetic

VII Otic SCG

SSN To T2-3

■

Figure 60–1. Vascular innervation. Ach, acetylcholine; CGRP, calcitonin gene–related peptide; NA, noradrenaline; NKA, neurokinin A; NOS, nitric oxide synthase; NPY, neuropeptide Y; PHI, peptide histidine isoleucine; SCG, superior cervical ganglion; SP, substance P; SPG, sphenopalatine ganglion; SSN, superior salivatory nucleus; TNC, trigeminal nucleus caudalis; Vg, trigeminal ganglion; VIP, vasoactive intestinal polypeptide.

chapter 60 other secondary headache disorders with vertebral artery dissections and in 25% of patients with carotid artery dissections. Headaches associated with cervical artery dissections tend to be short-lived, with a median duration of 3 days. When longer lasting, headaches associated with carotid dissection usually resolve within 1 week, and those associated with vertebral dissection, by 5 weeks. Only an occasional patient develops persistent headaches after arterial dissection. It is uncommon for a patient with cervical artery dissection to present solely with a headache and/or neck pain. Most patients have additional neurological symptoms and signs, including amaurosis fugax, Horner’s syndrome, pulsatile tinnitus, dysgeu-

A

sia, diplopia, or other stroke manifestations. Classically, patients with carotid artery dissection present with Horner’s syndrome and unilateral hemicrania. The classic presentation of vertebral artery dissection is a young patient with new-onset hemicrania followed by a lateral medullary infarction. However, a wide variation in clinical presentation certainly exists. The diagnosis of cervical artery dissection may be accomplished by ultrasonography, magnetic resonance imaging (MRI), magnetic resonance angiography, computed tomographic angiography, and/or conventional catheter angiography (Fig. 60–2). MRI with diffusion sequences allows for

B

C ■

795

Figure 60–2. Carotid artery dissection. A, Magnetic resonance image axial cut with fat saturation technique, showing left internal carotid artery dissection. The classic “double lumen” is demarcated by the arrow. B and C, Magnetic resonance angiograms, showing gradual tapering of the left internal carotid artery (arrows).

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detection of cerebral infarction that may occur secondarily to decreased perfusion or emboli distal to the dissection site. The treatment of cervical artery dissection varies according to the clinical presentation and location of disease, but it may include clinical observation, anticoagulation, and/or surgical intervention, including the use of arterial stents. Asymptomatic cervical artery dissections generally do not necessitate any intervention, although antiplatelet therapy would be recommended by some authorities. Symptomatic dissections may be treated with antiplatelet therapy or anticoagulation to prevent thrombus formation and the potential for subsequent arteryto-artery embolism.14,15 Although some studies suggest that anticoagulation may be associated with a lower rate of recurrent transient ischemic attacks and stroke, there is no controlled evidence to support the use of any particular antiplatelet or antithrombotic treatment in these patients.16,17 Anticoagulation is associated with an increased risk of hemorrhage that in select situations, such as intradural extension of the dissection, may be a contraindication to its use. Patients with aneurysmal dilation, SAH, significant arterial stenosis, or progressive neurological sequelae despite medical management may require surgical intervention.18

Intracranial Aneurysms Headaches are common in patients with cerebral aneurysms. Headache is the presenting symptom of an unruptured intracranial aneurysm in 20% to 33% of patients.19,20 With the exception of a sentinel headache of the thunderclap type, no specific headache characteristics facilitate discovery of an unruptured aneurysm. Headaches may be focal or diffuse, unilateral or bilateral, anterior or posterior, and acute or gradual in onset.21 Therefore, it is imperative to check for associated neurological signs, such as cranial nerve palsies, that may provide evidence for an underlying lesion. The IHS diagnostic criteria for headaches secondary to saccular aneurysms stipulate that the headache must be acute and of new onset and must resolve within 72 hours (Table 60–2).13 It is necessary to rule out SAH and intracerebral hemorrhage as underlying etiologies. Thunderclap headaches occurring in patients with an unruptured intracranial aneurysm must be recognized as warnings of impending aneurysm rupture. This type of headache is discussed in more detail later in this chapter.

Subarachnoid Hemorrhage

type, sudden and severe at onset. Although there are numerous causes of thunderclap headaches, every patient who presents with this type of headache should be evaluated for SAH (Table 60–3, Fig. 60–3). Although there may be a focal pain distribution when the headache of SAH begins, the pain usually generalizes and becomes bilateral. Severe pain is usually short-lived, lasting 1 to 2 hours, followed by a less severe headache of longer duration. With small hemorrhages, headaches tend to resolve after 2 to 3 days, whereas those associated with larger hemorrhages last an average of 8 days. Neck stiffness and pain, elevated body temperature, and alterations of consciousness are common associated features. Additional neurological symptoms and signs include nausea and vomiting, focal motor deficits, seizures, coma, cranial nerve palsies, papilledema, ocular hemorrhages, visual field deficits, and paresthesias. A history of a sentinel or warning headache is reported by 10% to 43% of patients with aneurysmal SAH.23 A sentinel headache is similar to the headache of SAH, but it occurs days to weeks before aneurysm rupture. Sentinel headaches generally develop over a few seconds and reach maximal intensity within minutes. Common associated features of SAH, including stiff neck, focal neurological symptoms and signs, and alterations in consciousness, are usually absent. Sentinel headaches may be caused by small aneurysmal leakages or stretching of the aneurysm wall without seepage of blood into the subarachnoid space. Identifying a sentinel headache as a warning of future SAH may allow for identification of an unruptured aneurysm and the need for surgical or endovascular intervention, thus avoiding a potentially catastrophic hemorrhage. Unfortunately, sentinel headaches are often ignored by patients and physicians, or they are misdiagnosed. According to a review by Edlow and Caplan, up to 50% of patients with SAH are initially misdiagnosed.24 Misdiagnosis occurs because the diagnostician fails to recognize the full clinical spectrum of SAH, lacks knowledge regarding the sensitivity of brain computed tomography (CT), and either fails to perform lumbar puncture or misinterprets CSF results. CT of the brain is the first test in the evaluation of SAH (Fig. 60–4). CT is most sensitive early in the course of SAH. Its sensitivity is near 100% within the first 12 hours, but it decreases to approximately 50% by 1 week later.24-28 If CT yields negative results for SAH and does not provide an alternative diagnosis, lumbar puncture must be performed. Lumbar puncture evaluation should include measurement of opening pressure, cell count, visual inspection for xanthochromia, and spectrophotometry when available. When lumbar puncture is performed

Headache is common in patients with aneurysm rupture and occurs in association with nausea and vomiting in 75% of patients.22 SAH headaches are most often of the thunderclap T A B L E 60–3. Thunderclap Headache: Causes T A B L E 60–2. Headache Secondary to Intracranial Aneurysm: International Headache Society Diagnostic Criteria A. Any new acute headache, including thunderclap headache and/or painful third nerve palsy fulfilling criteria C and D B. Neuroimaging evidence of saccular aneurysm C. Evidence of causation by the saccular aneurysm D. Resolution of headache within 72 hours E. Subarachnoid hemorrhage, intracerebral hemorrhage, and other causes of headache ruled out by appropriate investigations

Subarachnoid hemorrhage Sentinel headache of subarachnoid hemorrhage Cervical artery dissection Acute hypertensive crisis Ischemic stroke Cerebral venous sinus thrombosis Pituitary apoplexy Spontaneous intracranial hypotension Retroclival hematoma Primary thunderclap headache Primary cough, sexual, and exertional headaches

chapter 60 other secondary headache disorders

797

Thunderclap headache

Brain CT—No contrast

SAH

Normal

Positive

CSF—Cell count/inspection for xanthachromia

Traumatic tap/uninterpretable results

Spectrophotometry (if available)

No bilirubin peak

Bilirubin peak ■

No SAH ■

SAH

Figure 60–4. Subarachnoid hemorrhage (SAH). Computed tomography without contrast material, axial cut, reveals extensive SAH.

Figure 60–3. Evaluation for subarachnoid hemorrhage (SAH). CSF, cerebrospinal fluid; CT, computed tomography.

at least 12 hours after the onset of hemorrhage, the sensitivity of spectrophotometry is greater than 95%.29

agulation has been shown to be safe and to result in reduction in the risk of death or morbidity.38 If patients deteriorate despite adequate anticoagulation, thrombolysis via local infusion of thrombolytics into the occluded sinus and/or mechanical disruption of the thrombus should be considered.39

Cerebral Venous Sinus Thrombosis Headache is the most common presenting symptom of CVST, occurring in 75% to 95% of patients.30,31 In addition to headaches, patients with CVST usually present with papilledema, seizures, bilateral focal deficits, and/or altered level of consciousness. However, about 15% of patients present with isolated headaches.30,32 The headaches of CVST may be localized or diffuse, persistent, exacerbated by the Valsalva maneuver, and positional, with worsening on recumbency. Headaches of CVST have a gradual, subacute onset. However, approximately 10% of patients present with a headache of severe and sudden onset.33 Approximately 25% of patients with CVST who have normal neurological examination findings also have a normal CT, but CT is normal in fewer than 10% of patients who have focal neurological signs.34,35 Lumbar puncture should be performed, and opening pressure should be measured. Although 30% to 50% of patients with CVST have a combination of lymphocytic pleocytosis, elevated red blood cell count, and elevated protein levels, approximately 40% exhibit only an elevated opening pressure.36,37 MRI with venography or conventional angiography are the diagnostic modalities of choice when CVST is suspected (Fig. 60–5). Anticoagulation is the treatment of choice for patients with CVST. Although anticoagulation carries the risk of promoting hemorrhage, it may prevent venous infarction, neurological worsening, and pulmonary embolism. Treatment with antico-

Giant Cell Arteritis GCA is manifested by headache, a tender scalp artery, and elevated inflammatory markers, and there is a potential for visual loss. GCA most often occurs in older individuals. To avoid possible complications, including anterior ischemic optic neuropathy and cerebral infarction, it is essential to recognize this disorder and treat it promptly. GCA should be suspected in all patients older than 50 years with new-onset, persistent headache. Suspicion is higher when classic associated features such as jaw claudication, polymyalgia rheumatica, and amaurosis fugax are present. However, there can be considerable variation in the presentation of GCA. Headache is the most common manifestation. It is the presenting symptom in 48% of patients with GCA and occurs at some point during the disease course in 90%.40 The headache of GCA may be quite variable in its quality and location and may closely resemble a primary headache disorder. Associated symptoms, in descending order of frequency, are listed in Table 60–4.41,42 Ophthalmological complications include amaurosis fugax, visual loss, diplopia, ptosis, visual hallucinations, orbital bruits, and acute ocular hypotony.43 Visual loss tends to occur early in the course of the disease. If one eye is affected, the second is often affected within 2 weeks but rarely after 2 months.43 Inflammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein level, are measured when

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A ■

B Figure 60–5. Cerebral venous sinus thrombosis. A, T1-weighted axial magnetic resonance image reveals venous infarction in the right temporal lobe. B, Magnetic resonance venography reveals right transverse sinus thrombosis.

GCA is suspected. Most patients with GCA have significant elevations in these inflammatory markers. The odds of a positive result of a temporal artery biopsy are increased 2.0 times when the ESR is 47 to 107 mm/hour, 2.7 times when the ESR is greater than 107 mm/hour, and 3.2 times when the C-reactive protein level is above 2.45 mg/dL.44 C-reactive protein level is more sensitive than ESR for the detection of GCA, and a combination of the two tests has the greatest specificity.44 Depending on the results of these laboratory tests and clinical suspicion for the disorder, temporal artery biopsy, the diagnostic “gold standard,” may be required. Although biopsy may be performed unilaterally or bilaterally, it is essential that the specimen be of adequate length in order to maximize test sensitivity. Treatment with steroids should not be delayed while biopsy is awaited. When the suspicion for GCA is high enough to plan a temporal artery biopsy, prednisone should be started immediately to decrease the risk of vascular complications, including visual loss. Furthermore, the yield of temporal artery

T A B L E 60–4. Giant Cell Arteritis: Associated Clinical Features Headache Temporal artery tenderness Jaw claudication Weight loss Polymyalgia rheumatica Visual symptoms: amaurosis fugax, visual loss, diplopia Absent temporal artery pulse Fever Joint pain Tongue claudication Pain with swallowing Limb claudication

biopsy is not significantly decreased when performed within 1 to 2 weeks of steroid initiation.45 Although temporal artery biopsy is considered the “gold standard” diagnostic test for GCA, as many as 15% of patients who meet clinical criteria for GCA have negative findings on temporal artery biopsies.46 Such patients are less likely to have jaw claudication, an abnormal temporal artery on physical examination, constitutional symptoms, and significant elevations in inflammatory markers.46,47 GCA is treated with high-dose steroids. The most common treatment is prednisone, beginning at 60 mg/day. Headaches usually resolve or significantly improve within the first few days of treatment. After symptoms abate and inflammatory markers normalize, prednisone is slowly tapered while the patient’s clinical symptoms, ESR, and C-reactive protein level are monitored. If headache returns or if the ESR or C-reactive protein level rises, the steroid dosage is increased. Although most patients can eventually discontinue the use of prednisone, some require chronic immunosuppression.

Primary Angiitis of the Central Nervous System and Reversible Cerebral Vasoconstriction Syndrome PACNS is a vasculitis that is limited to the central nervous system in its distribution. Patients usually present with a headache that is subacute or slowly progressive in onset, severe, and focal or diffuse.48,49 The headache may be accompanied by nausea and vomiting. However, it is usually associated with other neurological manifestations, including hemiparesis, mental impairment, dysphasia, or seizures.50 Symptoms of PACNS may fluctuate in their severity but eventually progress over time. This often leads to delayed diagnosis; as many as 40% of cases are diagnosed after symptoms have been present for more than 3 months.50 Systemic symptoms, such as fever and

chapter 60 other secondary headache disorders weight loss, occur much less commonly than with systemic vasculitides. The diagnosis of PACNS can be made through a combination of CSF analysis, angiography, or central nervous system biopsy. CSF analysis often reveals significantly elevated protein levels and white blood cell count in patients with pathologically confirmed PACNS.51 The classic finding on cerebral angiography is a pattern of alternating areas of segmental narrowing and ectasia, producing a beaded or sausage-like appearance. Pathological specimens reveal fibrinoid necrosis and infiltration of vessel walls by lymphocytes, multinucleated giant cells, and/or histiocytes.52 PACNS tends to be an aggressive disease and is uniformly fatal without treatment. Response to cytotoxic/immunosuppressive therapy is variable; remissions are possible in some patients. RCVS is a unifying diagnosis for a group of disorders characterized by reversible segmental cerebral vasospasm and more benign outcomes than those seen with PACNS. This includes thunderclap headache with vasospasm, benign angiopathy of the central nervous system, migrainous vasospasm or crash migraine, Call-Fleming syndrome, postpartum angiopathy, and drug-induced vasospasm.53-55 Patients with RCVS present with the acute onset of sudden and severe headache, consistent with thunderclap headache. Evaluation reveals normal or nearnormal CSF findings and reversible cerebral segmental vasospasm involving arteries of the circle of Willis. The diagnostic criteria for RCVS are (1) a thunderclap headache, (2) evidence of vasospasm of one or more arteries of the circle of Willis that reverses by 12 weeks after onset, and (3) normal or nearnormal CSF studies (Table 60–5). Patients may have a history of migraine, may be in the postpartum period, or have had exposure to certain drugs, including ergotamines, triptans, selective serotonin reuptake inhibitors, pseudoephedrine, cocaine, amphetamines, methylenedioxymethamphetamine (ecstasy), or bromocriptine.56-87 Patients with RCVS may differ in regard to the presence and/or severity of neurological deficits, imaging abnormalities, and circumstances at the time of symptom onset. Patients may present with thunderclap headache in isolation or in combination with changes in cognition or consciousness, motor deficits, sensory deficits, seizures, visual disturbances, ataxia, speech abnormalities, nausea, and/or vomiting. Because the angiographic appearance of segmental cerebral vasospasm in RCVS is identical to that seen in PACNS, these two entities must be differentiated, to avoid the unnecessary use of long-term immunosuppressants and cytotoxic agents in patients with RCVS. The clinical characteristic that best differentiates RCVS from PACNS is the acuity of headache onset and other clinical features. In contrast to patients with RCVS, who

T A B L E 60–5. Reversible Cerebral Vasoconstriction Syndrome: Diagnostic Criteria Severe headache of acute onset Normal or near normal cerebrospinal fluid examination findings Protein levels ≤ 70 mg/dL White blood cell count ≤ 20 cells/mm3 Normal glucose levels No evidence of subarachnoid hemorrhage Reversible cerebral segmental vasospasm involving arteries of the circle of Willis Reversibility must be documented ≤12 weeks after onset

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have a rapid onset of symptoms, patients with PACNS usually have a slowly progressive onset of disease and may accumulate new manifestations over weeks to months. Laboratory tests are also helpful in differentiating these two entities. Results of CSF analysis are markedly abnormal in approximately 80% of patients with PACNS but are generally normal in patients with RCVS.88 Cerebral imaging may appear normal in RCVS and usually appears abnormal in PACNS. In PACNS, MRI typically shows multifocal lesions secondary to ischemia or infarction distributed in the middle cerebral artery territory. Normal MRI, when diffusion and perfusion sequences are included, is uncommon in patients with symptomatic PACNS.89-92 In contrast, a greater proportion of patients with RCVS have normal brain MRI. However, abnormalities may be seen and are often consistent with posterior reversible leukoencephalopathy or watershed infarctions in the distribution of vasospastic blood vessels.93,94 RCVS cannot be differentiated from PACNS by the initial vascular imaging study, inasmuch as both show segmental vasospasm. However, even in the absence of any specific treatment, patients with RCVS have significant reversal of vasospasm within 4 weeks of symptom onset and complete normalization within several months.

Headache after Carotid Endarterectomy, Cerebral Angiography, and Coiling and Clipping of Intracranial Aneurysm Headaches are frequently encountered during and after procedures involving the cerebral vasculature. Such headaches have been described in association with carotid endarterectomy, cerebral angiography, and coiling and clipping of aneurysms.95-97 Patients with primary headache disorders are more likely to develop headaches in association with these procedures. In some patients, stimulation of the intracranial vasculature triggers a headache that is identical to the headache of their usual primary headache disorder. In others, a new headache with different characteristics develops. Although the characteristics of postprocedure headaches differ according to the intervention, all begin in close temporal relationship to the procedure. In addition, the headache is most often located ipsilateral to the site of intervention. Although postprocedure headaches may be selflimited, others may become chronic or may be manifestations of an underlying complication. For instance, after carotid endarterectomy, a severe unilateral headache, especially if associated with seizures and contralateral focal deficits, may be the manifestation of a hyperperfusion syndrome.

HEADACHE SECONDARY TO NONVASCULAR INTRACRANIAL DISORDERS Chiari Malformation Chiari type I malformation consists of downward herniation, of at least 3 to 5 mm, of the cerebellar tonsils through the foramen magnum (Fig. 60–6). In studies of patients with headache, Chiari type I malformation is found in 2.7% to 5.8%.98-100 Its prevalence in patients without headache is predicted to be 2 per 1000, but this would probably be higher if modern imaging modalities were used.101 Chiari type I malformation may be

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Headache T A B L E 60–6. Chiari I Malformation Headache: International Headache Society Diagnostic Criteria

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Figure 60–6. Chiari type I malformation. T1-weighted sagittal magnetic resonance image reveals cerebellar tonsillar herniation of approximately 1 cm.

associated with compression of the cervicomedullary junction, obstructive hydrocephalus, and syringomyelia.102 Patients with Chiari type I malformation can present with headache, lower cranial nerve palsies, scoliosis, sensory disturbance, or weakness.103,104 Although in most cases Chiari type I malformation is asymptomatic and diagnosed through an incidental MRI finding, headache is the most common presenting complaint.105,106 Head pain is most often described as a pressure sensation that worsens with increases in intracranial pressure and is located in the occipital or suboccipital region with radiation to the vertex, retro-orbitally, and to the neck.104,107,108 Many patients with Chiari type I malformation report headaches that occur after coughing, and more than one half of patients with coughinduced headache are found to have Chiari type I malformation.109 Headaches consistent with these characteristics, especially if associated with ocular disturbances, otoneurological dysfunction, or lower cranial nerve palsies, are suggestive of Chiari malformation. The IHS has defined diagnostic criteria for headache secondary to Chiari type I malformation (Table 60–6).13 Chiari malformation is diagnosed through MRI of the brain and cervical spinal cord, as indicated for evaluation for spinal cord syrinx. CSF flow studies may also be used to assess for suspected CSF obstruction at the cervicomedullary junction. The treatment of Chiari type I malformation is at times controversial, especially when patients have headache with no associated neurological features. Widely accepted indications for surgical intervention in such patients include spinal cord syrinx, cranial nerve deficits, gait instability, apnea, and torticollis.110,111 Surgical decompression may also be indicated for patients who have isolated headaches, meet criteria for Chiari headache, and are nonresponsive to conservative management. Studies have shown that most patients with headache secondary to Chiari

A. Headache characterized by at least one of the following and fulfilling criterion D: Precipitated by cough and/or the Valsalva maneuver Protracted (hours to days) occipital and/or suboccipital headache Associated with symptoms and/or signs of brainstem, cerebellar, and/or cervical cord dysfunction B. Cerebellar tonsillar herniation as defined by one of the following on craniocervical MRI: ≥5 mm caudal descent of the cerebellar tonsils ≥3 mm caudal descent of the cerebellar tonsils plus at least one of the following indicators of crowding of the subarachnoid space in the area of the craniocervical junction: Compression of the CSF spaces posterior and lateral to the cerebellum Reduced height of the supraocciput Increased slope of the tentorium Kinking of the medulla oblongata C. Evidence of posterior fossa dysfunction, based on at least two of the following: Otoneurological symptoms and/or signs (dizziness, disequilibrium, sensations of alteration in ear pressure, hypacusia or hyperacusia, vertigo, downbeat nystagmus, oscillopsia) Transient visual symptoms (spark photopsias, visual blurring, diplopia, or transient visual field deficits) Demonstration of clinical signs relevant to cervical cord, brainstem, or lower cranial nerves or of ataxia or dysmetria D. Headache resolves within 3 months after successful treatment of the Chiari malformation CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.

malformation have a reduction of symptoms after surgical intervention.111-113 However, caution must be observed in interpreting these outcomes because the studies have been retrospective and involved a small number of patients.

Intracranial Neoplasm Headache may be caused by the direct effects of an intracranial neoplasm, increased intracranial pressure secondary to such a neoplasm, carcinomatous meningitis, or secreting tumors of the hypothalamus or pituitary. Although as many as two thirds of patients with brain tumors report headaches, headache as an isolated and presenting clinical feature is uncommon, occurring in fewer than 10% of such patients.114 More often, patients present with focal neurological symptoms and signs and seizures.114 However, when headaches are associated with nausea, vomiting, or an abnormal neurological examination finding, or when there is a significant change in a patient’s prior headache pattern, the possibility of an underlying neoplasm must be investigated.115 Headaches secondary to the direct effects of an intracranial neoplasm may be progressive, localized, worse in the morning, and aggravated by increases in intracranial pressure caused by, for example, coughing and bending forward. In patients with unilateral head pain, the tumor is nearly always ipsilateral to the site of pain.115 According to IHS criteria, the headaches resolve within 7 days after surgical removal or volume reduction of the neoplasm or treatment with corticosteroids and must develop in temporal and usually spatial relation to the neoplasm.13 However, because it is often unknown when exactly

chapter 60 other secondary headache disorders a tumor first appeared, a temporal relationship may be difficult to determine in the clinical setting. Headaches may also be secondary to increased intracranial pressure or hydrocephalus caused by a tumor. Such headaches are often accompanied by nausea and vomiting and are made worse by transient increases in intracranial pressure during coughing, sneezing, and the Valsalva maneuver. They may occur episodically in discrete and acute episodes or have a slower, progressive onset. As with other secondary headaches, there should be a temporal relationship between the onset of head pain and hydrocephalus, and the headache should resolve with reversal of the hydrocephalus.13 Carcinomatous meningitis is also commonly associated with headache. Although there are not headache features that are specific for the headache of carcinomatous meningitis, the headache develops and/or worsens with advancing disease. In addition, headache should improve with intrathecal chemotherapy.13 Hormone-secreting tumors of the hypothalamus and pituitary may also result in secondary headache. Approximately two thirds of patients with pituitary tumors report an associated headache, with the association being strongest with prolactinomas.116,117 According to IHS criteria, such headaches are most often bilateral, frontotemporal, and/or retro-orbital13; if the headache is secondary to a pituitary lesion, there is evidence of increased secretion of prolactin, growth hormone, or adrenocorticotropic hormone associated with a microadenoma; and if it is secondary to hypothalamic dysfunction, there is clinical evidence of such dysfunction, including altered temperature regulation, thirst, appetite, emotional state, or consciousness. However, a wider variation in headache features than that allowed by IHS criteria certainly exists. Patients may develop headache in association with a pituitary tumor with or without hormonal hypersecretion. Headaches most commonly mimic chronic migraine, followed by episodic migraine, primary stabbing headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, cluster headache, and hemicrania continua.118 The majority of these headaches are severe in intensity and throbbing in quality.118 Both medical treatment to counteract tumor hypersecretion and surgical resection of the tumor often lead to headache amelioration.118

HEADACHE SECONDARY TO DISORDERS OF THE NECK OR CRANIAL STRUCTURES Cervicogenic Headache Cervicogenic headache refers to head pain that is generated from a source in the neck. According to IHS criteria, there is clinical, laboratory, and/or imaging evidence of an abnormality within the cervical spine or soft tissues of the neck,13 and pain is attributed to the neck on the basis of either clinical signs that implicate a source in the neck or resolution of the headache after blockade of cervical structures or their nerve supply. It is important to recognize that neck pain commonly occurs in patients with headache, and thus neck pain alone does not implicate the neck as the source of the pain. Neck pain and tenderness, a history of neck trauma, unilaterality of pain, shoulder pain, and decreased range of motion in the neck are not

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unique features of cervicogenic headache, and thus their presence does not necessitate a diagnosis of cervicogenic headache.119 Patients with a wide range of headache disorders, including the most common headaches, such as migraine, tension-type headache, and the trigeminal autonomic cephalgias, may exhibit these symptoms. Thus, although cervicogenic headache is not a diagnosis of exclusion, it is important to evaluate patients for the presence of migrainous and autonomic features, which are less common in patients with cervicogenic headache. Although not included in the current IHS diagnostic criteria, prior proposed criteria have suggested that the head pain of cervicogenic headache is most often unilateral, fluctuating or continuous, nonthrobbing, nonlancinating, moderate to severe, and beginning in the neck with spread to other areas of the head.120,121 Although the exact pathophysiology of cervicogenic headache is unknown, it is likely that pain is generated by structures innervated by the upper three cervical nerves.122 Nociceptive stimulation of the upper cervical nerves may cause activation of the trigeminovascular pathway via convergence in the trigeminal nucleus caudalis, which extends from the brainstem to the level of C2-C3. Such a trigeminocervical interaction, with convergence of upper cervical sensory afferent vessels and trigeminal sensory afferent vessels in the brainstem, can explain the phenomenon of trigeminal nerve–distributed head pain from primary nociceptive stimulation of the upper cervical nerves.123 In order to formally diagnose cervicogenic headache, diagnostic blockades should be performed and result in resolution of head pain. These may include anesthetic blockade of the greater occipital nerve, the lesser occipital nerve, the cervical zygapophyseal joints, the cervical segmental nerves, and the intervertebral disks.124 In accordance with strict diagnostic criteria, such blocks should be placebo-controlled, to account for the high placebo response rate of interventional procedures used in the treatment of pain.

Sinus Headache Because the sinuses and nasal mucosa are innervated by branches of the trigeminal nerve, it is easy to understand how sinus disease can result in facial and head pain.125,126 According to IHS diagnostic criteria for headache secondary to acute rhinosinusitis, headaches are frontal in location and associated with pain in the face, ears, or teeth13; there is clinical, laboratory, or radiographic evidence of acute sinusitis; and pain begins at the same time as the rhinosinusitis and resolves within 7 days of its successful treatment. Headache secondary to chronic sinusitis is not an entity recognized by the IHS. Caution must be exercised in considering the diagnosis of sinus headache. Both sinus-related symptoms and headache, which have relatively high frequencies in the general population, commonly coexist. However, their coexistence does not necessarily suggest a causative relationship. In addition, patients often inaccurately self-diagnose their head or face pain as “sinus headache.” A prospective analysis of patients with selfdiagnosed “sinus headache” found that 98% of cases met IHS diagnostic criteria for migraine or migrainous headache.127 Nonetheless, patients with active signs and symptoms of sinusitis and those with headaches that are correlated temporally with sinus disease should be evaluated for headaches of sinus

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origin. Such an evaluation must consider clinical manifestations of sinusitis in combination with the physical examination and radiological findings. CT is the imaging modality of choice. In interpreting sinus CT findings, it is important to avoid overinterpretation of minimal abnormalities, such as mild sinus mucosal thickening. This is especially pertinent in the absence of symptoms of active sinusitis. The clinician must remember that evidence for sinus abnormalities is found in 1.3% to 13.7% of patients undergoing imaging for headache and in 27% to 42.5% of asymptomatic patients undergoing CT for other reasons.98-100,128-130 Therefore, in headache patients without a clinical history or physical examination findings suggestive of active sinus disease, there is a poor correlation between facial and/or head pain and sinus imaging findings.131,132 However, when there is a high preimaging clinical suspicion for acute sinusitis and air-fluid levels or sinus opacification on imaging, and when patients meet nonimaging criteria for active sinus disease, antibiotic treatment may be warranted.133

HEADACHE SECONDARY TO INTRACRANIAL INFECTION Headache may occur secondary to intracranial infections, including meningitis, encephalitis, and intracranial abscess. Although headaches are quite common in patients with central nervous system infection, they are rarely the only manifestation. Associated features may include fever, focal neurological symptoms and signs, alteration in consciousness, nausea, vomiting, neck stiffness, photophobia, and back pain.134,135 However, an underlying infection must always be considered in the evaluation of a patient with headache, because of the morbidity and mortality that may be associated with a missed diagnosis. Although most patients with headaches secondary to an intracranial infection have other manifestations as well, those with indolent infections, as might be seen with fungal disease, more commonly present with isolated headaches. The diagnosis of headache secondary to an underlying intracranial infection depends on a temporal relationship between the development of the infectious process and the headache and resolution of the headache after successful treatment of the infection.13 In addition, there must be objective evidence of an underlying central nervous system infection. This is generally obtained through CSF examination, at times supplemented by neuroimaging, electroencephalography, and other laboratory tests.

HEADACHE SECONDARY TO DISORDERS OF HOMEOSTASIS Obstructive Sleep Apnea There exists a complex and multifaceted relationship between sleep and headache. Headache may be the result of disrupted sleep, such as that occurring with obstructive sleep apnea, periodic limb movements of sleep, and psychophysiological insomnia. Alternatively, significant head pain of any type may disrupt sleep. Third, there may be shared pathophysiological mechanisms underlying sleep and certain headache types, including hypnic headache (which occurs only during sleep), cluster

headache, and migraine headache. Although the exact mechanism of interaction between sleep and headache is often difficult to define, the relationship has long been recognized by clinicians. Headache is a common complaint of patients with obstructive sleep apnea, and “sleep apnea headache” is an IHS-defined headache type (Table 60–7). Nocturnal headaches and headaches noted on awakening are more common in patients with obstructive sleep apnea. Nondescript morning headache is reported by 36% to 58% of patients with sleep apnea, and it may be the presenting feature.136-138 More than 50% of patients with early morning headaches may be found to have identifiable sleep disorders, including obstructive sleep apnea.139,140 Headaches associated with sleep apnea tend to be mild to moderate in intensity, pressing or tightening in quality, frontal or frontotemporal in location, and unilateral or bilateral, and they last less than 2 hours.138 Treatment of obstructive sleep apnea headache by nocturnal oxygenation through the use of continuous positive airway pressure often eliminates these nocturnal or early morning headaches.141 Some studies but not others have identified a relationship between the apnea-hypopnea index and headache and another relationship between the nadir nocturnal oxygen concentration and headache.142 When these relationships do exist, they support the theory that physiological and cerebral hemodynamic effects of hypoxemia and/or hypercapnia associated with obstructive sleep apnea, as opposed to sleep disturbance, play a prominent role in the generation of headaches in such patients.143 However, patients with higher apnea-hypopnea indices may also have more frequent nighttime awakenings, leading to nonrestorative sleep and a form of sleep-deprivation headache.144 Patients with nocturnal or morning headaches without an identifiable underlying cause should be considered for polysomnography in search of a treatable sleep disorder. Suspicion for an underlying sleep abnormality is increased in patients with headache who have poorly defined headache characteristics, those with risk factors for obstructive sleep apnea (snoring, obesity), and certainly those who report poor or fragmented sleep and excessive daytime somnolence.

Hypertension Significant controversy regarding a possible association between hypertension and headache exists in the literature. Whereas some studies have concluded that headaches are more

T A B L E 60–7. Sleep Apnea Headache: International Headache Society Diagnostic Criteria A. Recurrent headache with at least one of the following characteristics and fulfilling criteria C and D: Occurs on >15 days per month Bilateral, pressing quality and not accompanied by nausea, photophobia, or phonophobia Each headache resolves within 30 minutes B. Sleep apnea (Respiratory Disturbance Index ≥5) demonstrated by overnight polysomnography C. Headache is present on awakening D. Headache ceases within 72 hours, and does not recur, after effective treatment of sleep apnea

chapter 60 other secondary headache disorders common in hypertensive patients, others have shown no correlation, and still others have concluded that high systolic and diastolic blood pressures are associated with a reduced risk of nonmigrainous headaches.145-147 Investigators using ambulatory blood pressure monitoring have not shown a correlation between blood pressure changes and the presence or absence of headache.148 Although the exact relationship is unclear, four distinct subclassifications of headache associated with hypertension have been suggested: acute hypertensive headache, chronic hypertensive headache, headache with malignant hypertension, and headache with hypertensive encephalopathy.149 Acute hypertensive headache occurs secondary to an abrupt increase in blood pressure. Headaches occur in approximately 20% of patients with hypertensive crisis and are most often described as throbbing and nondistinct.150 On occasion, such patients present with a thunderclap headache. Other manifestations of hypertensive crisis usually coexist and include faintness, dyspnea, chest pain, psychomotor agitation, focal neurological deficits, and epistaxis.150 Chronic hypertensive headache occurs secondary to long-standing hypertension, typically manifests on awakening in the morning, is located posteriorly, and improves on arising. Headache associated with malignant hypertension occurs generally when diastolic pressures are greater than 130 mm Hg and in the presence of papilledema. Headache may be the presenting feature of hypertensive encephalopathy with reversible neurological symptoms or of posterior reversible leukoencephalopathy syndrome.93,94 These patients usually have additional symptoms and signs, including nausea, vomiting, visual changes, altered mental status, seizures, and focal neurological signs.151,152 In patients with long-standing hypertension, hypertensive encephalopathy may not develop until pressures reach 250/150 mm Hg, whereas in those without a history of hypertension, values around 160/100 mm Hg may lead to encephalopathy.153 In addition, headache may occur in conjunction with hypertension in disorders such as pheochromocytoma, preeclampsia, eclampsia, and acute pressor response to exogenous agents.

K E Y

P O I N T S

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Although most patients with recurrent head pain have primary headaches, the clinician must consider the possibility of a secondary headache and must search for evidence of an underlying disorder.

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Clinical features that serve as potential evidence for a secondary headache include new-onset headache that persists or progresses, significant changes in the characteristics of a patient’s usual headaches, older age of the patient (>50 years), headache worsened or precipitated by changes in posture or by the Valsalva maneuver, sudden onset, presence of systemic or neurological symptoms, and a recent history of trauma.

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Abnormalities on examination that increase the suspicion of a secondary headache disorder include neurological deficits, papilledema, meningismus, elevated blood pressure, temporal artery tenderness, cranial bruits, and fever.

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Suggested Reading Dodick DW, Eross EJ, Parish JM: Clinical, anatomical, and physiologic relationship between sleep and headache. Headache 2003; 43:282-292. Edlow JA, Caplan LR: Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000; 342:29-36. Frishberg BM, Rosenberg JH, Matchar DB, et al: Evidence-based guidelines in the primary care setting: neuroimaging in patients with nonacute headache. Available at: www.aan.com/ professionals/practice/pdfs/gl0088.pdf (accessed March 13, 2006). Huston KA, Hunder GG, Lie JT, et al: Temporal arteritis. A 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 1978; 88:162-167. Lewis DW, Ashwal S, Dahl G, et al: Practice parameter: evaluation of children and adolescents with recurrent headaches. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002; 59:490-498.

References 1. Mayberg M, Langer RS, Zervas NT, et al: Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 1981; 213:228-230. 2. Keller JT, Beduk A, Saunders MC: Origin of fibers innervating the basilar artery of the cat. Neurosci Lett 1985; 58:263268. 3. Saito K, Moskowitz MA: Contributions from the upper cervical dorsal roots and trigeminal ganglia to the feline circle of Willis. Stroke 1989; 20:524-526. 4. Vestergaard K, Andersen G, Nielsen MI, et al: Headache in stroke. Stroke 1993; 24:1621-1624. 5. Kumral E, Bogousslavsky J, Van Melle G, et al: Headache at stroke onset: the Lausanne Stroke Registry. J Neurol Neurosurg Psychiatry 1995; 58:490-492. 6. O’Connor TP, van der Kooy D: Pattern of intracranial and extracranial projections of trigeminal ganglion cells. J Neurosci 1986; 6:2200-2207. 7. Goadsby PJ, Zagami AS, Lambert GA: Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 1991; 31:365-371. 8. Davis KD, Dostrovsky JO: Properties of feline thalamic neurons activated by stimulation of the middle meningeal artery and sagittal sinus. Brain Res 1988; 454:89-100. 9. Ferro JM, Melo TP, Oliveira V, et al: A multivariate study of headache associated with ischemic stroke. Headache 1995; 35:315-319. 10. Tentschert S, Wimmer R, Greisenegger S, et al: Headache at stroke onset in 2196 patients with ischemic stroke or transient ischemic attack. Stroke 2005; 36:e1-e3. 11. Silbert PL, Mokri B, Schievink WI: Headache and neck pain in spontaneous internal carotid and vertebral artery dissections. Neurology 1995; 45:1517-1522. 12. Mitsias P, Ramadan NM: Headache in ischemic cerebrovascular disease. Part I: clinical features. Cephalalgia 1992; 12:269274. 13. Headache Classification Committee of the International Headache Society: The International classification of headache disorders. Cephalalgia 2004; 24(Suppl 1):1-151. 14. Thanvi B, Munshi SK, Dawson SL, et al: Carotid and vertebral artery dissection syndromes. Postgrad Med J 2005; 81:383-388. 15. Stapf C, Elkind MSV, Mohr JP: Carotid artery dissection. Annu Rev Med 2000; 51:329-347.

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16. Lyrer P, Engelter S: Antithrombotic drugs for carotid artery dissection. Stroke 2004; 35:613-614. 17. Dziewas R, Konrad C, Drager B, et al: Cervical artery dissection—clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003; 250:1179-1184. 18. Muller BT, Luther B, Hort W, et al: Surgical treatment of 50 carotid dissections: indications and results. J Vasc Surg 2000; 31:980-988. 19. International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Engl J Med 1998; 339:1725-1733. 20. Solomon RA, Fink ME, Pike-Spellman J: Surgical management of unruptured intracranial aneurysms. J Neurosurg 1994; 80:440-446. 21. Raps EC, Rogers JD, Galetta SL, et al: The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol 1993; 50:265-268. 22. Fontanarosa PB: Recognition of subarachnoid hemorrhage. Ann Emerg Med 1989; 18:1199-1205. 23. Polmear A: Sentinel headaches in aneurysmal subarachnoid haemorrhage: what is the true incidence? A systematic review. Cephalalgia 2003; 23:935-941. 24. Edlow JA, Caplan LR: Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000; 342:29-36. 25. Morgenstern LB, Luna-Gonzales H, Huber JC Jr, et al: Worst headache and subarachnoid hemorrhage: prospective, modern computed tomography and spinal fluid analysis. Ann Emerg Med 1998; 32:297-304. 26. van der Wee N, Rinkel GJ, Hasan D, et al: Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after a negative scan? J Neurol Neurosurg Psychiatry 1995; 58:357-359. 27. Sidman R, Connolly E, Lemke T: Subarachnoid hemorrhage diagnosis: lumbar puncture is still needed when the computed tomography scan is normal. Acad Emerg Med 1996; 3:827-831. 28. Sames TA, Storrow AB, Finkelstein JA, et al: Sensitivity of new-generation computed tomography in subarachnoid hemorrhage. Acad Emerg Med 1996; 3:16-20. 29. Vermeulen M, Hasan D, Blijenberg BG, et al: Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry 1989; 52:826-828. 30. Terazzi E, Mittino D, Ruda R, et al: Cerebral venous thrombosis: a retrospective multicentre study of 48 patients. Neurol Sci 2005; 25:311-315. 31. de Bruijn SFTM, de Haan RJ, Stam J, et al: Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. J Neurol Neurosurg Psychiatry 2001; 70:105-108. 32. Cumurciuc R, Crassard I, Sarov M, et al: Headache as the only neurological sign of cerebral venous thrombosis: a series of 17 cases. J Neurol Neurosurg Psychiatry 2005; 76:1084-1087. 33. de Bruijn SFTM, Stam J, Kappelle LJ: Thunderclap headache as the first symptom of cerebral venous sinus thrombosis. CVST Study Group. Lancet 1996; 348:1623-1625. 34. Rao KCVG, Knipp HC, Wagner EJ: CT findings in cerebral sinus and venous thrombosis. Radiology 1981; 140:391-398. 35. Chiras J, Bousser MG, Medler JF, et al: CT in cerebral thrombophlebitis. Neuroradiology 1985; 27:145-154. 36. Bousser MG, Chiras J, Sauron B, et al: Cerebral venous thrombosis: a review of 38 cases. Stroke 1985; 16:199-213. 37. Barinagarrementeria F, Cantu C, Arredondo H: Aseptic cerebral venous thrombosis: proposed prognostic scale. J Stroke Cerebrovasc Dis 1992; 2:34. 38. Stam J, De Bruijn SF, DeVeber G: Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev 2002; (4):CD002005.

39. Canhao P, Falcao F, Ferro JM: Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis 2003; 15:159-166. 40. Solomon S, Cappa KG: The headache of temporal arteritis. J Am Geriatr Soc 1987; 35:163-165. 41. Huston KA, Hunder GG, Lie JT, et al: Temporal arteritis. A 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 1978; 88:162-167. 42. Hunder GG: Clinical features of GCA/PMR. Clin Exp Rheumatol 2000; 18(4, Suppl 20):S6-S8. 43. Cullen JF, Coleiro JA: Ophthalmic complications of giant cell arteritis. Surv Ophthamlol 1976; 20:247-260. 44. Hayreh SS, Podhajsky PA, Raman R, et al: Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997; 123:285-296. 45. Achkar AA, Lie JT, Hunder GG, et al: How does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) arteritis? Ann Intern Med 1994; 120:987-992. 46. Gonzalez-Gay MA, Garcia-Porrua C, Llorca J, et al: Biopsynegative giant cell arteritis: clinical spectrum and predictive factors for positive temporal artery biopsy. Semin Arthritis Rheum 2001; 30:249-256. 47. Smetana GW, Shmerling RH: Does this patient have temporal arteritis? JAMA 2002; 287:92-101. 48. Cupps TR, Moore PM, Fauci AS: Isolated angiitis of the central nervous system. Am J Med 1983; 74:97-105. 49. Calabrese LH, Mallek JA: Primary angiitis of the central nervous system. Medicine 1987; 67:20-39. 50. Calabrese LH, Furlan AJ, Gragg LA, et al: Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Cleve Clin J Med 1992; 59:293-306. 51. Calabrese LH, Gragg LA, Furlan AJ: Benign angiopathy: a distinct subset of angiographically defined primary angiitis of the central nervous system. J Rheumatol 1993; 20:2046-2050. 52. Parisi JE, Moore PM: The role of biopsy in vasculitis of the central nervous system. Neurology 1994; 14:341-348. 53. Calabrese LH, Gragg LA, Furlan AJ: Benign angiopathy: a distinct subset of angiographically defined primary angiitis of the central nervous system. J Rheumatol 1993; 20:2046-2050. 54. Hajj-Ali RA, Furlan A, Abou-Chebl A, et al: Benign angiopathy of the central nervous system: cohort of 16 patients with clinical course and long-term followup. Arthritis Rheum 2002; 47:662-669. 55. Call GK, Fleming MC, Sealfon S, et al: Reversible cerebral segmental vasoconstriction. Stroke 1988; 19:1159-1170. 56. Walsh JP, O’Doherty DS: A possible explanation of the mechanism of ophthalmoplegic migraine. Neurology 1960; 10: 1079-1084. 57. Dukes HT, Veith RG: Cerebral angiography during migraine prodrome and headache. Neurology 1964; 14:636-639. 58. Garnic JD, Schellinger D: Arterial spasm as a finding intimately associated with onset of vascular headache. Neuroradiology 1983; 24:273-276. 59. Masuzawa T, Shinoda S, Furuse M, et al: Cerebral angiographic changes on serial examination of a patient with migraine. Neuroradiology 1983; 24:277-281. 60. Lieberman AN, Jonas S, Hass WK, et al: Bilateral cervical and intracerebral vasospasm causing cerebral ischemia in a migrainous patient: a case of “diplegic migraine.” Headache 1984; 24:245-248. 61. Serdaru M, Chiras J, Cujas M, et al: Isolated benign cerebral vasculitis or migrainous vasospasm? J Neurol Neurosurg Psychiatry 1984; 47:73-76. 62. Monteiro P, Carneiro L, Lima B, et al: Migraine and cerebral infarction: three case studies. Headache 1985; 25:429-433. 63. Schon F, Harrison MJH: Can migraine cause multiple segmental cerebral artery constrictions? J Neurol Neurosurg Psychiatry 1987; 50:492-494.

chapter 60 other secondary headache disorders 64. Rothrock JF, Walicke P, Swenson MR, et al: Migrainous stroke. Arch Neurol 1988; 45:63-67. 65. Solomon S, Lipton RB, Harris PY: Arterial stenosis in migraine: spasm or arteriopathy? Headache 1990; 30:52-61. 66. Gomez CR, Gomez SM, Puricelli MS, et al: Transcranial Doppler in reversible migrainous vasospasm causing cerebellar infarction: report of a case. Angiology 1991; 42:152-156. 67. Sanin LC, Mathew NT: Severe diffuse intracranial vasospasm as a cause of extensive migrainous cerebral infarction. Cephalalgia 1993; 13:289-292. 68. Schluter A, Kissig B: MR angiography in migrainous vasospasm. Neurology 2002; 59:1772. 69. Farine D, Andreyko J, Lysikiewicz A, et al: Isolated angiitis of brain in pregnancy and puerperium. Obstet Gynecol 1984; 63:586-588. 70. Bogousslavsky J, Despland PA, Regli F, et al: Postpartum cerebral angiopathy: reversible vasoconstriction assessed by transcranial Doppler ultrasounds. Eur Neurol 1989; 29:102-105. 71. Geraghty JJ, Hoch DB, Robert ME, et al: Fatal puerperal cerebral vasospasm and stroke in a young woman. Neurology 1991; 41:1145-1147. 72. Janssens E, Hommel M, Mounier-Vehier F, et al: Postpartum cerebral angiopathy possibly due to bromocriptine therapy. Stroke 1995; 26:128-130. 73. Sugiyama Y, Muroi A, Ishikawa M, et al: A benign form of isolated angiitis of the central nervous system in puerperium: an identical disorder to postpartum cerebral angiopathy? Intern Med 1997; 36:931-934. 74. Ursell MR, Marras CL, Farb R, et al: Recurrent intracranial hemorrhage due to postpartum cerebral angiopathy: implications for management. Stroke 1998; 29:1995-1998. 75. Modi M, Modi G: Postpartum cerebral angiopathy in a patient with chronic migraine with aura. Headache 2000; 40:677681. 76. Kyung L, Sohn YH, Kim SH, et al: Basilar artery vasospasm in postpartum cerebral angiopathy. Neurology 2000; 54:20032005. 77. Ihara M, Yanagihara C, Nishimura Y: Serial transcranial color-coded sonography in postpartum cerebral angiopathy. J Neuroimaging 2000; 10:230-233. 78. Kubo S, Nakata H, Tatsumi T, et al: Headache associated with postpartum cerebral angiopathy: monitoring with transcranial color-coded sonography. Headache 2002; 42:297-300. 79. Geocadin RG, Razumovsky AY, Wityk RJ, et al: Intracerebral hemorrhage and postpartum cerebral vasculopathy. J Neurol Sci 2002; 205:29-34. 80. Konstantinopoulos PA, Mousa S, Khairallah R, et al: Postpartum cerebral angiopathy: an important diagnostic consideration in the postpartum period. Am J Obstet Gynecol 2004; 191:375-377. 81. Song JK, Fisher S, Seifert TD, et al: Postpartum cerebral angiopathy: atypical features and treatment with intracranial balloon angioplasty. Neuroradiology 2004; 46:1022-1026. 82. Henry PY, Larre P, Aupy M, et al: Reversible cerebral arteriopathy associated with the administration of ergot derivatives. Cephalalgia 1984; 4:171-178. 83. Meschia JF, Malkoff MD, Biller J: Reversible segmental cerebral arterial vasospasm and cerebral infarction: possible association with excessive use of sumatriptan and Midrin. Arch Neurol 1998; 55:712-714. 84. Singhal AB, Caviness VS, Begleiter AF, et al: Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 2002; 58:130-133. 85. Levine SR, Washington JM, Jefferson MI, et al: “Crack” cocaine–associated stroke. Neurology 1987; 37:1849-1853. 86. Reneman L, Habraken JB, Majoie CB, et al: MDMA (“ecstasy”) and its association with cerebrovascular accidents: preliminary findings. Am J Neuroradiol 2000; 21:1001-1007.

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87. Janssens E, Hommel M, Mounier-Vehier F, et al: Postpartum cerebral angiopathy possibly due to bromocriptine therapy. Stroke 1995; 26:128-130. 88. Calabrese LH, Mallek JA: Primary angiitis of the central nervous system—report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine 1987; 67:20-39. 89. Pomper MG, Miller TJ, Stone JH, et al: CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography. AJNR Am J Neuroradiol 1999; 20:7585. 90. Harris KG, Tran DD, Sickels WJ, et al: Diagnosing intracranial vasculitis: the roles of MR and angiography. AJNR Am J Neuroradiol 1994; 15:317-330. 91. Duna GF, Calabrese LH: Limitations of invasive modalities in the diagnosis of primary angiitis of the central nervous system. J Rheumatol 1995; 22:662-667. 92. Wasserman BA, Stone JH, Hellmann DB, et al: Reliability of normal findings on MR imaging for excluding the diagnosis of vasculitis of the central nervous system. AJR Am J Roentgenol 2001; 177:455-459. 93. Tang-Wai DF, Phan TG, Wijdicks EFM: Hypertensive encephalopathy presenting with thunderclap headache. Headache 2001; 41:198. 94. Dodick DW, Eross EJ, Drazkowski JF, et al: Thunderclap headache associated with reversible vasospasm and posterior leukoencephalopathy syndrome. Cephalalgia 2003; 23: 994. 95. Tehindrazanarivelo AD, Lutz G, PetitJean C, et al: Headache following carotid endarterectomy: a prospective study. Cephalalgia 1992; 12:380-382. 96. Ramadan NM, Gilkey SJ, Mitchell M, et al: Postangiography headache. Headache 1995; 35:21-24. 97. Schwedt TJ, Samples S, Rasmussen P, et al: New headache after endovascular or microsurgical treatment of intracranial aneurysm. Neurology 2005; 64(Suppl 1):A401. 98. Lewis DW, Dorbad D: The utility of neuroimaging in the evaluation of children with migraine or chronic daily headache who have normal neurological examinations. Headache 2000; 40:629-632. 99. Bass NE, Ruggieri PM, Cohen BH, et al: Clinical usefulness of magnetic resonance imaging in pediatric headache. Ann Neurol 1995; 38:527. 100. Schwedt TJ, Guo Y, Rothner AD: “Benign” imaging abnormalities in children and adolescents with headache. Headache 2006; 46:387-398. 101. Khurana RK: Headache spectrum in Arnold-Chiari malformation. Headache 1991; 31:151-155. 102. Carmel PW: Management of the Chiari malformations in childhood. Clin Neurosurg 1983; 30:385-406. 103. Greenlee JD, Donovan KA, Hasan DM, et al: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under age 6 years. Pediatrics 2002; 110:1212-1219. 104. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery 1999; 44:1005-1017. 105. Dure LS, Percy AK, Cheek WR, et al: Chiari type I malformation in children. J Pediatr 1989; 115:573-576. 106. Park JK, Gleason PL, Madsen JR, et al: Presentation and management of Chiari I malformation in children. Pediatr Neurosurg 1997; 26:190-196. 107. Kesler R, Mendizabal JE: Headache in Chiari malformation: a distinct clinical entity? J Am Osteopath Assoc 1999; 99:153156. 108. Sansur CA, Heiss JD, DeVroom HL, et al: Pathophysiology of headache associated with cough in patients with Chiari I malformation. J Neurosurg 2003; 98:453-458.

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109. Pascual J, Iglesias F, Oterino A, et al: Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology 1996; 46:1520-1524. 110. Haines SJ, Berger M: Current treatment of Chiari malformations types I and II: a survey of the Pediatric Section of the American Association of Neurological Surgeons. Neurosurgery 1991; 28:353-357. 111. Weinberg JS, Freed DL, Sadock J, et al: Headache and Chiari I malformation in the pediatric population. Pediatr Neurosurg 1998; 29:14-18. 112. Nohria V, Oakes WJ: Chiari I malformation: a review of 43 patients. Pediatr Neurosurg 1990; 16:222-227. 113. Dyste GN, Menezes AH, VanGilder JC: Symptomatic Chiari malformations. An analysis of presentation, management, and long-term outcome. J Neurosurg 1989; 71:159-168. 114. Vasquez-Barquero A, Ibanez FJ, Herrera S, et al: Isolated headache as the presenting clinical manifestation of intracranial tumors: a prospective study. Cephalalgia 1994; 14:270271. 115. Forsyth PA, Posner JB: Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993; 43:16781683. 116. Levy MJ, Jager HR, Powell M, et al: Pituitary volume and headache. Arch Neurol 2004; 61:721-725. 117. Abe T, Matsumoto K, Kuwazawa J, et al: Headache associated with pituitary adenomas. Headache 1998; 43:1678-1683. 118. Levy MJ, Matharu MS, Meeran K, et al: The clinical characteristics of headache in patients with pituitary tumours. Brain 2005; 128:1921-1930. 119. Taylor FR: Distinguishing primary headache disorders from cervicogenic headache: clinical and therapeutic implications. Headache Curr 2005; 2:37-41. 120. Sjaastad O, Fredriksen TA, Pfaffenrath V: Cervicogenic headache: diagnostic criteria. Headache 1990; 30:725-726. 121. Antonaci F, Ghirmai S, Bono S, et al: Cervicogenic headache: evaluation of the original diagnostic criteria. Cephalalgia 2001; 21:573-583. 122. Silverman SB: Cervicogenic headache: interventional, anesthetic, and ablative treatment. Curr Pain Headache Rep 2002; 6:308-314. 123. Bartsch T, Goadsby PJ: Anatomy and physiology of pain referral patterns in primary and cervicogenic headache disorders. Headache Curr 2005; 2:42-48. 124. van Suijlekon JA, Weber WEJ, van Kleef M: Cervicogenic headache: techniques of diagnostic nerve blocks. Clin Exp Rheumatol 2000; 18(Suppl 19):S39-S44. 125. Ng YT, Butler IJ: Sphenoid sinusitis masquerading as migraine headaches in children. J Child Neurol 2001; 16:882884. 126. Clerico DM: Sinus headaches reconsidered: referred cephalgia of rhinologic origin masquerading as refractory primary headaches. Headache 1995; 35:185-192. 127. Cady RK, Schreiber CP, Billings C: Subjects with selfdescribed “sinus” headache meet IHS diagnostic criteria for migraine [Abstract]. Cephalalgia 2001; 21:298. 128. Maytal J, Benkowski RS, Patel M, et al: The value of brain imaging in children with headaches. Pediatrics 1995; 96:413416. 129. Medina LS, Pinter JD, Zurakowski D, et al: Children with headache: clinical predictors of surgical space-occupying lesions and the role of neuroimaging. Radiology 1997; 202:819-824. 130. Alehan FK: Value of neuroimaging in the evaluation of neurologically normal children with recurrent headache. J Child Neurol 2002; 17:807-809. 131. Mudgil SP, Wise SW, Hopper KD, et al: Correlation between presumed sinusitis-induced pain and paranasal sinus com-

132.

133. 134. 135. 136. 137.

138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148.

149. 150. 151. 152. 153.

puted tomographic findings. Ann Allergy Asthma Immunol 2002; 88:223-226. Shields G, Seikaly H, Leboeuf M, et al: Correlation between facial pain or headache and computed tomography in rhinosinusitis in Canadian and U.S. subjects. Laryngoscope 2003; 113:943-945. Lanza DC, Kennedy DW: Adult rhinosinusitis defined. Otolaryngol Head Neck Surg 1997; 117:S1-S7. Lamonte M, Silberstein SD, Marcelis JF: Headache associated with aseptic meningitis. Headache 1995; 35:520-526. Scelsa SN, Lipton RB, Sander H, et al: Headache characteristics in hospitalized patients with Lyme disease. Headache 1995; 35:125-130. Dexter JD: Headache as a presenting complaint of the sleep apnea syndrome [Abstract]. Headache 1984; 24:171. Guilleminault C, van den Hoed J, Mitler MM: Clinical overview of the sleep apnea syndromes. In Guilleminault C, Dement WC, eds: Sleep Apnea Syndromes. New York: Alan R. Liss, 1978, pp 1-12. Alberti A, Mazzotta G, Gallinella E, et al: Headache characteristics in obstructive sleep apnea syndrome and insomnia. Acta Neurol Scand 2005; 111:309-316. Paiva T, Batista A, Martins P, et al: The relationship between headaches and sleep disturbances. Headache 1995; 35:590596. Paiva T, Farinha A, Martins A, et al: Chronic headaches and sleep disorders. Arch Intern Med 1997; 157:1701-1705. Poceta JS, Dalessio DJ: Identification and treatment of sleep apnea in patients with chronic headache. Headache 1995; 35:586-589. Rains J, Penzien D, Mohammed Y: Sleep and headache: morning headache associated with sleep disordered breathing [Abstract]. Cephalalgia 2001; 21:520. Dodick DW, Eross EJ, Parish JM: Clinical, anatomical, and physiologic relationship between sleep and headache. Headache 2003; 43:282-292. Blau JN: Sleep deprivation headache. Cephalalgia 1990; 10:157-160. Fuchs FD, Gus M, Moreira LB, et al: Headache is not more frequent among patients with moderate to severe hypertension. J Hum Hypertens 2003; 17:787-790. Cirillo M, Stellato D, Lombardi C, et al: Headache and cardiovascular risk factors: positive association with hypertension. Headache 1999; 39:409-416. Hagen K, Stovner LJ, Vaffen L, et al: Blood pressure and risk of headache: a prospective study of 22,685 adults in Norway. J Neurol Neurosurg Psychiatry 2002; 72:463-466. Kruszewski P, Bieniaszewski L, Neubauer J, et al: Headache in patients with mild to moderate hypertension is generally not associated with simultaneous blood pressure elevation. J Hypertens 2000; 18:437-444. Spierings ELH: Acute and chronic hypertensive headache and hypertensive encephalopathy. Cephalalgia 2002; 22:313-316. Zampaglione B, Pascale C, Marchisio M, et al: Hypertensive urgencies and emergencies. Prevalence and clinical presentation. Hypertension 1996; 27:144-147. Healton E, Burst J, Feinfield D, et al: Hypertensive encephalopathy and the neurologic manifestations of malignant hypertension. Neurology 1982; 32:127-132. Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494-500. Cortelli P, Grimaldi D, Guaraldi P, et al: Headache and hypertension. Neurol Sci 2004; 25:S132-S134.

CHAPTER

61

IDIOPATHIC INTRACRANIAL HYPERTENSION ●

●

●

●

Deborah I. Friedman*

Despite refinements in terminology and diagnostic criteria since it was initially described by Quincke in 1897, idiopathic intracranial hypertension (IIH) remains a disorder of uncertain pathogenesis.1 IIH most frequently affects obese women of childbearing age. It is suspected clinically in patients with headaches, transient obscurations of vision, intracranial noises, and papilledema, although the symptoms and severity of disease vary considerably. Prompt diagnosis and treatment are imperative because permanent visual field loss is common and blindness occurs in 10% of affected individuals. Medical and surgical treatments are available, although none is universally effective. The lack of evidence-based literature for IIH impedes the clinician’s ability to make well-informed choices regarding the available treatment options; prospective natural history data collection and a treatment trial are warranted.

EPIDEMIOLOGY IIH is nine times more common in women than in men, and the incidence of IIH in adolescents and adults seems to parallel the prevalence of obesity. Studies from Iowa and Louisiana in the 1980s revealed an incidence of 0.9 per 100,000 in the general population, rising to 3.5 per 100,000 in women 15 to 44 years old and 19.3 per 100,000 in women 20 to 44 years old whose weights were 20% or more above ideal.3 Similar incidence rates were found in population studies in Libya and Israel.4,5 However, as the percentage of the obese western population continues to rise, two studies suggest that the incidence of IIH has doubled since the 1980s.6,7 IIH in children occurs with equal frequency in boys and girls before puberty, although a secondary cause is often identified in children.8-11 There is no known race predilection. Its onset rarely occurs after the age of 50 years.12

DEFINITION The diagnostic criteria for IIH2 are as follows: 1. Symptoms, if present, that reflect only those of increased intracranial pressure (ICP) or papilledema. 2. Signs attributable only to increased ICP or papilledema. 3. Documented elevated ICP during lumbar puncture, measured in the lateral decubitus position. 4. Normal cerebrospinal fluid (CSF) composition. 5. No evidence of ventriculomegaly, mass, structural, or vascular lesion on magnetic resonance imaging (MRI) or contrast-enhanced computed tomography for typical patients and on MRI and magnetic resonance venography for all others. 6. Normal mental status. Certain conditions and exogenous agents produce a clinical syndrome indistinguishable from IIH. If a secondary cause of intracranial hypertension is identified, the syndrome is termed intracranial hypertension from a secondary cause.

*Supported by the National Eye Institute Grant 1K23EY015525 and a Research to Prevent Blindness Challenge Grant.

CLINICAL FEATURES Most patients with IIH are symptomatic, although they occasionally come to medical attention when asymptomatic papilledema is discovered on a routine ophthalmological examination.13 The most common symptom of IIH is headache, occurring in more than 90% of patients.14 The headache is usually daily, retro-ocular or bifrontal, and described as pressure-like. It may have migrainous features with pulsating pain, nausea, vomiting, photophobia, and phonophobia.14 Some patients have prominent posterior head pain, neck pain, or back pain.15 Superimposed medication overuse headache is not uncommon, inasmuch as patients self-medicate their headaches, which are often incapacitating. Visual symptoms are also common, including blurred vision, transient obscurations of vision, diplopia, and visual field loss/scotomata.14 Transient visual obscurations reflect brief episodes of optic nerve head ischemia caused by papilledema. They may be unilateral or bilateral and are described as partial or complete episodes of visual loss that last seconds to minutes. Transient visual obscurations are often precipitated by arising from a stooped position or rolling the eyes. They may occur many times during the day, and the vision is normal between events. Transient visual obscurations are not correlated with the severity of papilledema and are not predictive of visual loss.

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Patients often notice their enlarged physiological blind spot temporally “as if something was present to the side, but when I look, nothing is there.” Blurred vision and tunnel vision may also occur. In severe cases of IIH, visual loss may be acute and dramatic, leading to profound visual loss or blindness. Diplopia is generally binocular and horizontal, resulting from unilateral or bilateral sixth nerve palsy, a nonlocalizing sign of increased ICP. Pulsatile tinnitus occurs in 60% of patients and is often described as “hearing my heartbeat in my head” or a whooshing sound in one or both ears.16 It is often not voluntarily mentioned by the patient and should be queried for. Other symptoms include paresthesias, ataxia, radicular pain, arthralgias, impaired concentration, depression, and anxiety.17-19 The hallmark of IIH is papilledema that may be asymmetrical and is occasionally unilateral.20,21 Because the severity of papilledema factors into the overall treatment plan, it is useful to have a standardized grading system for it. The Frisén scale describes papilledema in stages that are clinically meaningful (Table 61–1).22 Important features to identify are the obscuration of the optic disc borders, presence of a grayish peripapillary halo, the obscuration of one or more segments of major

T A B L E 61–1. Papilledema Grading System (Frisén Scale22) Stage 0: Normal Optic Disc Blurring of nasal, superior, and inferior poles in inverse proportion to disc diameter Radial nerve fiber layer (NFL) without NFL tortuosity Rare obscuration of a major vessel, usually on the upper pole Stage 1: Very Early Papilledema Obscuration of the nasal border of the disc No elevation of disc borders Disruption of the normal radial NFL arrangement with grayish opacity accentuating nerve fiber bundles Normal temporal disc margin Subtle grayish halo with temporal gap (best seen with indirect ophthalmoscope) Concentric or radial retinochoroidal folds Stage 2: Early Papilledema Obscuration of all borders Elevation of the nasal border Complete peripapillary halo Stage 3: Moderate Papilledema Obscuration of all borders Elevation of all borders Increased diameter of the optic nerve head Obscuration of one or more segments of major blood vessels leaving the disc Peripapillary halo—irregular outer fringe with finger-like extensions Stage 4: Marked Papilledema Elevation of entire nerve head Obscuration of all borders Peripapillary halo Total obscuration on the disc of a segment of a major blood vessel Stage 5: Severe Papilledema Dome-shaped protrusions, representing anterior expansion of the optic nerve head Peripapillary halo is narrow and smoothly demarcated Total obscuration of a segment of a major blood vessel may or may not be present Obliteration of the optic cup

blood vessels as they cross the disc margin, and optic disc elevation/loss of the optic cup (Figs. 61–1 and 61–2). Hyperemia, vessel tortuosity, hemorrhages, exudates, cotton-wool spots, and optic nerve pallor are too variable to use for staging purposes. Severe papilledema may extend into the papillomacular bundle and macula, producing choroidal folds, macular edema, a macular star, and a central scotoma (Fig. 61–3). Mild papilledema may be difficult to discern with the direct ophthalmoscope, and stereoscopic viewing with indirect ophthalmoscopy or slit-lamp bi-microscopy is helpful for detecting subtle disc edema. Other conditions, such as optic disc drusen and tilted optic discs, may simulate the appearance of papilledema. Diagnostic techniques such as orbital echography, fluorescein angiography, and computed tomography are useful in such cases. There is probably much variability regarding the development of papilledema in relation to the onset of symptoms. In most patients, the papilledema probably precedes or coincides with symptom onset. However, there are patients who become symptomatic shortly before appreciable disc swelling is seen on ophthalmoscopy. Perhaps their visual changes arise from the effect of increased CSF pressure more posterior along the course of the optic nerve. Similarly, papilledema may evolve over hours or days to weeks.23,24 Cases of IIH without papilledema have been reported in the literature.25-27 This situation is possible in the acute phase before papilledema develops. The diagnosis is probably erroneous in many patients with chronic daily headaches and elevated CSF pressures, most of whom have overused medication.25 The diagnosis of IIH is best made in context with the expected constellation of symptoms and signs. Spontaneous venous pulsations are sometimes relied on to approximate ICP, because they generally disappear with CSF pressures greater than 250 mm H2O.28 Although the presence of spontaneous venous pulsations is reassuring, their absence is not informative as an isolated feature, inasmuch as about 25% of normal individuals lack them. Spontaneous venous pulsations are best viewed through the direct ophthalmoscope by observing the veins over the optic disc. Visual field defects are frequently present with IIH. An enlarged physiological blind spot, reflecting the swollen optic nerve head, is a nearly universal finding. Other common defects are inferonasal visual loss; generalized visual constriction; and central, arcuate, and altitudinal scotomas.29 Either automated or Goldmann perimetry is necessary to detect and quantify these defects. Central acuity is usually preserved with early papilledema; therefore, a decline in acuity early in the course of the disease is an ominous sign. This may result from optic nerve ischemia, optic nerve compression caused by papilledema, or macular edema. The most common ocular motility disturbance is a unilateral or bilateral lateral rectus palsy producing an esotropia. Other cranial nerve palsies, skew deviation, and global ophthalmoparesis are rare.30,31 The motility disorders generally resolve when the ICP is lowered.

DIAGNOSTIC TESTING Because the most important diagnostic consideration is a tumor, neuroimaging is mandatory for ruling out a spaceoccupying mass or ventriculomegaly. MRI is recommended

chapter 61 idiopathic intracranial hypertension

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B

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Figure 61–1.

Asymmetrical papilledema in a 54-year-old woman with constant daily headaches and transient obscurations of vision in the right eye from idiopathic intracranial hypertension. There is mild papilledema (Frisén stage 2) of the right optic nerve (A) and minimal papilledema (Frisén stage 1) of the left optic nerve (B). Her symptoms resolved after a diagnostic lumbar puncture. (Photography by Julie Howell.)

A ■

B Figure 61–2.

A and B, Chronic disc edema and bilateral disc pallor in an asymptomatic patient with 20/20 vision in both eyes. Perimetry shows slightly enlarged physiological blind spots, and the study results are otherwise normal. (Photography by Julie Howell.)

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A ■

B Figure 61–3.

Marked papilledema in a 12-year-old girl with minocycline-induced intracranial hypertension. She experienced retro-orbital headaches, photophobia, phonophobia, pulsatile tinnitus, and diplopia. There is Frisén stage 4 edema of the right optic nerve (A) and Frisén stage 5 edema of the left optic nerve (B). Note the hypervascularity of the optic nerves and the radial nerve fiber layer hemorrhages. The hemorrhages extend into the macular area in the left eye (B). Her symptoms and disc edema resolved after discontinuing the minocycline and a brief course of acetazolamide. (Photography by Julie Howell.)

unless there is a contraindication, the technology is unavailable, or the patient exceeds the gantry size or weight threshold. Ventricular size should be normal.32 There may be an empty sella, indicating long-standing increased ICP. An orbital MRI is not required for diagnosis but may be helpful, revealing protrusion of the optic papilla into the posterior aspect of the globe, flattening of the posterior sclerae, and dilation of the perineuronal subarachnoid space.33 The role of magnetic resonance venography in typical cases (overweight women of childbearing age) is controversial, but it is certainly recommended for ruling out venous sinus thrombosis in any atypical patient: slim patients, men, children without an apparent secondary cause, patients over age 45 years, and those not responding to therapy.34,35 Elliptic-centric–ordered three-dimensional gadolinium-enhanced MRI increases the sensitivity of magnetic resonance venography for detecting intracranial sinovenous stenosis.36 Spinal fluid examination with an opening pressure measurement is mandatory for diagnosing IIH. The CSF contents should be normal. The opening pressure, measured with the patient in the lateral decubitus position with the legs relaxed, is 250 mm H2O or greater in adults. Values between 200 and 249 mm H2O are not diagnostic.37 Many patients experience transient relief of the headache after a lumbar puncture, but some develop a low-pressure headache.

SECONDARY CAUSES Many conditions have been associated with increased ICP (Table 61–2). The only factors demonstrated in case-control

studies are weight gain and obesity.38 Other well-accepted factors include systemic retinoids (vitamin A, isotretinoin, tretinoin), tetracyclines (tetracycline, minocycline, doxycycline), levonorgestrel (Norplant), corticosteroid withdrawal, human growth hormone, cerebral venous sinus thrombosis, mastoiditis, Behçet’s disease, renal failure, and obstructive sleep apnea. It is uncertain whether the medications represent true causative agents or produce an additional insult in predisposed patients.

PATHOPHYSIOLOGY Any unifying theory of IIH must explain (1) its predilection in obese women of childbearing age, (2) the lack of ventriculomegaly, and (3) the clinically identical syndrome produced by other etiologies, such as exogenous agents and venous sinus thrombosis. Although menstrual irregularities are common in women with IIH, no particular hormonal disturbance has been identified; irregular menses may be a co-association with obesity.39 The Monro-Kellie hypothesis compartmentalizes the intracranial contents into brain, blood, and CSF. ICP is normally maintained by a compliance factor arising from distension of meningeal membranes and compression of vascular volume. A resistance factor regulates CSF volume by venting CSF through the arachnoid granulations into the cerebral veins.40 Fifty percent of CSF are below the foramen magnum, and almost one half of that amount is absorbed in the spinal sac.41 Within the cranium, resistance factors are quickly exceeded, and so when CSF volume increases, compliance

chapter 61 idiopathic intracranial hypertension T A B L E 61–2. Conditions Associated with Increased Intracranial Pressure Obstruction to Venous Drainage Cerebral venous sinus thrombosis35,85,86 Aseptic state (hypercoagulable state)87 Septic (middle ear or mastoid infection) Bilateral radical neck dissection with jugular vein ligation Jugular vein tumor88,89 Superior vena cava syndrome Brachiocephalic vein thrombosis89 Increased right-sided heart pressure After embolization of arteriovenous malformation90 Endocrine Disorders Addison’s disease91 Hypoparathyroidism Obesity, recent weight gain38 Orthostatic edema63 Exogenous Agents Amiodarone92,93 Cytarabine93 Chlordecone (Kepone) Corticosteroids (particularly withdrawal)94-96 Cyclosporine97 Growth hormone98-102 Leuprorelin acetate (LH-RH analog)103 Levothyroxine (children)104,105 Lithium carbonate106 Nalidixic acid107,108 Levonorgestrel (Norplant)109,110 Sulfa antibiotics Tetracycline and related compounds111-120 Minocycline121-124 Doxycycline125 Vitamin A54,55,59,113 Vitamin supplements, liver Isotretinoin (Accutane)113,126-130 Tretinoin (for acute promyelocytic leukemia)131-134 Infectious or Postinfectious Process HIV infection135-137 Lyme disease138 After childhood varicella infection139,140 Other Medical Conditions Antiphospholipid antibody syndrome141-143 Behçet’s disease144-146 Occult craniosynostosis147 Polycystic ovary syndrome148 Sarcoidosis149 Sleep apnea72,150,151 Systemic lupus erythematosus152,153 Turner’s syndrome154 HIV, human immunodeficiency virus.

mechanisms fail and a small increase in volume results in a large increase in ICP.42,43 Some authors have proposed that increased cerebral venous pressure is the primary pathology in IIH, reversing the normal gradient between sinus and subarachnoid space and increasing the resistance to CSF flow across the arachnoid villi.44,45 Others have suggested that an abnormality in the cerebral microvasculature produces an elevation in cerebral blood volume, reflecting tissue swelling from increased total water content. However, increased brain water content or cerebral edema has never been proved in IIH.46 It is uncertain why the ventricles

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do not enlarge, but the venous system seems to be the distensible component manifesting increased pressure. Manometry has shown elevated CSF pressure in patients with IIH, and there is a reciprocal relationship between CSF pressure and pressure in the superior sagittal sinus and transverse sinus with IIH (i.e., removing CSF produces a decline in venous pressure).47 Both venous sinus thrombosis and venous sinus stenosis have been observed in patients with an IIH-like syndrome.35,48-50 Systemic (and subsequently intracranial) venous hypertension arising from abdominal obesity—that is, direct compression on the inferior vena cava by abdominal adipose tissue—has also been suggested.51,52 If this were the case, a much higher rate of IIH in general would be expected, especially among pregnant women. In fact, the incidence of IIH during pregnancy is no greater than that among age-matched control subjects.53 Hypervitaminosis A is one of the most extensively studied secondary causes of intracranial hypertension.54-59 The specific effect of toxic vitamin A level on CSF homeostasis is uncertain, but it may impair CSF outflow or produce a toxic effect on CSF absorption. Conflicting data have emerged with regard to serum retinol and retinol-binding protein levels in patients with IIH in comparison with unaffected subjects.60-62 The association of IIH with orthostatic edema, depression, and anxiety is suggestive of a possible neurotransmitter derangement.18,63 Although there is evidence in animal studies that 5-hydroxytriptamine and norepinephrine directly affect CSF production, these neurotransmitters have not been studied in humans.64-66 High levels of vasopressin, a hormone that regulates brain water content and raises ICP by increasing water transudation from cerebral capillaries in the choroid plexus epithelium and arachnoid villi, are present in the CSF of patients with IIH.67 Studies investigating serum levels of leptin, a hormone associated with obesity, showed no difference between patients with IIH and control subjects.

TREATMENT The treatment of IIH is generally coordinated by a neurologist (or neuro-ophthalmologist) and requires co-management with an ophthalmologist. The primary care physician and a neurosurgeon may also be involved in the patient’s care. Good communication between providers is crucial. The goals of treatment are to preserve vision and to alleviate symptoms. The treatment strategy depends on several variables: ■ ■ ■ ■

Presence and severity of symptoms, such as headache Degree of visual loss at presentation Progression of visual loss Detection of factors known to be associated with a poorer visual prognosis (i.e., high-grade papilledema with macular edema, venous sinus thrombosis, systemic hypertension) ■ Pregnancy ■ Identification of a treatable secondary cause There have been no prospective clinical treatment trials for IIH. All treatment recommendations are based on case series and clinical experience (class 3 evidence). Asymptomatic patients with mild papilledema may be monitored without specific treatment.

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Medical therapy is usually initiated when the diagnosis of IIH is made, but it is most useful when the primary problem is headache in the setting of good vision. On the basis of several retrospective studies suggesting that moderate weight loss is correlated with a reduction in papilledema, obese patients are advised to lose weight.67a,67b The only specific dietary regimen described in the literature is a modified low-calorie (400 to 1000 cal/day) rice-based diet, consisting of fruits, rice, vegetables and small amounts of meat, coupled with sodium restriction to less than 100 mg/day.68 Because many women with IIH also have orthostatic edema with retention of water or sodium, moderate limitation of salt and water intake is generally advised.63 Bariatric surgery may be considered when dietary weight loss is unsuccessful.51 In general, weight loss is considered a long-term management option and is not always successful in reducing ICP or alleviating symptoms. Carbonic anhydrase inhibitors prevent the secretion of CSF in the choroid plexus and have a mild diuretic effect. They may also contribute to weight loss by producing nausea and altering the taste of food. Acetazolamide is most commonly used. It reduces CSF production by 6% to 50%, but the reduction does not occur until more than 99.5% of choroid plexus carbonic anhydrase is inhibited.69,70 This requires doses of approximately 4 g/day, which is more than most people can tolerate. The side effects of acetazolamide, such as paresthesias, somnolence, and depression, often limit its use. Furosemide may also lower ICP by diuresis, reducing sodium transport into the brain, and by weak carbonic anhydrase inhibition. Early experience with topiramate in IIH is promising; it is a weak carbonic anhydrase inhibitor used for migraine prophylaxis and commonly produces weight loss.71 Corticosteroids are to be avoided because they have undesirable side effects (weight gain, fluid retention) and cause rebound intracranial hypertension as they are withdrawn. Patients with obstructive sleep apnea may experience improvement with weight loss and continuous positive airway pressure or bilevel positive airway pressure.72 If an exogenous agent that may be contributing to the condition is identified, it should be discontinued immediately if possible. However, additional treatment to lower the ICP may also be necessary. Patients with headache and good vision are managed with preventive headache medications. Many such patients have coexisting migraines and tension-type headaches that respond to the usual medication used to treat these conditions.73 Analgesic overuse should be avoided.

may fail to improve after aggressive medical and surgical interventions. The normal ventricular size in IIH presents a challenge to neurosurgeons during ventriculoperitoneal shunt placement. There are no reliable data comparing ventriculoperitoneal with lumboperitoneal shunts in this condition, although one study suggests that stereotactic ventriculoperitoneal shunting has a lower risk of shunt failure.74 The lumboperitoneal route is generally preferred in IIH, but it has limitations, including a high incidence of acquired Chiari type I malformation and lumbar radiculopathy. Moreover, the CSF pressure transmitted to the lumboperitoneal shunt valve is much higher in the standing and seated positions than in the supine position and is very different from that in the ventriculoperitoneal system. Although they “treat the primary problem” of increased ICP, shunts have a very high failure rate; more than one half of patients ultimately require one or more revisions, often within months after their initial shunt placement.75 Other complications of shunts include low pressure, infection, obstruction, and migration of the shunt catheter. Optic nerve sheath fenestration was first used to treat papilledema in 1872 and gained popularity for the treatment of IIH in the 1970s.75a The orbit may be entered medially or laterally, the conjunctiva is incised, one or more extraocular muscles are temporarily detached from the sclera, and the globe is rotated into view.76 Under microscopic viewing, the optic nerve sheath is fenestrated with several slits, or a window of dural tissue is removed. An efflux of CSF can generally be observed from the subarachnoid space with a successful decompression. The procedure immediately reduces pressure on the nerve by creating a filtration apparatus surrounding the orbital segment of the optic nerve. The long-term effectiveness may be related to the creation of a barrier by fibrous scar formation to protect the anterior optic nerve from the intracranial CSF pressure. The procedure is generally effective in stabilizing or improving vision and sometimes ameliorates headaches.77 A unilateral fenestration may improve vision in the contralateral eye. A repeat procedure is sometimes needed.78,79 Risks include transient or permanent visual loss, diplopia, and infection. Venous stents have been inserted in patients with documented transverse venous sinus obstructions with both a measurable pressure gradient and raised proximal venous sinus pressure. Preliminary studies revealed that some patients improved dramatically, whereas others experienced no benefit.50,80 Further investigation into this potential emerging treatment modality is needed.

Surgical Treatment

Idiopathic Intracranial Hypertension in Pregnancy

Surgery is used when severe optic neuropathy is present early in the course of the illness, when there is rapid deterioration of vision or when other forms of therapy fail to prevent visual loss. It is not recommended for the treatment of headaches alone. The decision to proceed with optic nerve sheath fenestration or a CSF diversion procedure depends to a large extent on the resources available locally. There are no comparative treatment trials of shunting versus optic nerve sheath fenestration surgery. Sometimes more than one type of procedure is needed. In patients with a sudden decline in vision, there is often an ischemic component to the visual loss, and vision

In women with a history of IIH, there is no contraindication to becoming pregnant, and there is no evidence of an increased risk to either the mother or the fetus in this circumstance.81,82 IIH may develop during pregnancy, although pregnancy is not an independent risk factor for IIH.53 IIH management during pregnancy is similar to that in a nonpregnant woman.83 Careful neuro-ophthalmological follow-up and repeated lumbar punctures are often satisfactory for monitoring during the gestational period. Acetazolamide may be used after 20 weeks of pregnancy. If vision deteriorates, corticosteroids, and optic nerve sheath fenestration or shunting may be employed. IIH

Medical Treatment

chapter 61 idiopathic intracranial hypertension arising during the peripartum period or after fetal loss raises the suspicion of venous sinus thrombosis.

PROGNOSIS The course of IIH is variable, and few prospective data are available. Most patients sustain little or no visual loss and have a monophasic course. Most patients have some degree of persistent visual field loss as determined by quantitative perimetry; it usually does not interfere with daily activities, but 10% of patients develop blindness.84 The papilledema does not always completely resolve, possibly because of gliotic changes of the nerve fiber layer. Many patients develop persistent headaches that necessitate treatment after the ICP normalizes.73 A small subgroup experiences a rapid onset of symptoms and abrupt visual decline, so-called malignant IIH. Patients may have marked papilledema, macular edema, and ophthalmoparesis at presentation. This course necessitates aggressive management; multiple surgical procedures may be necessary and may nonetheless be unsuccessful in reversing visual loss.

K E Y

P O I N T S

●

The incidence of IIH is rising as the population becomes more obese.

●

A key element of the examination of a patient with new or worsening headaches is ophthalmoscopy, to look for papilledema.

●

Visual loss remains a major morbid condition in IIH, with detectable visual field loss in most patients and blindness in 10%.

●

A team approach with a neurologist and ophthalmologist is necessary for managing this condition.

●

The primary goal of treatment is to preserve visual function.

Suggested Reading 1. Digre KB, Corbett JJ: Idiopathic intracranial hypertension (pseudotumor cerebri): a reappraisal. Neurologist 2001; 7:267. 2. Friedman DI: Pseudotumor cerebri. Neurol Clin North Am 2004; 22:88-131. 3. Sanders MD: The Bowman Lecture. Papilloedema: “The pendulum of progress.” Eye 1997; 11:267-294.

References 1. Quincke H: Uber meningitis serosa und verewandte zustande. Deutsche Zeitschr Nervenheilkunde 1897; 9:149-168. 2. Friedman DI, Jacobson DM: Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002; 59:1492-1495. 3. Digre KB, Corbett JJ: Idiopathic intracranial hypertension (pseudotumor cerebri): a reappraisal. Neurologist 2001; 7:267. 4. Kesler A, Gadoth N: Epidemiology of idiopathic intracranial hypertension in Israel. J Neuroophthalmol 2001; 21:12-14. 5. Radhakrishanan K, Sridharan R, Askhok PP, et al: Pseudotumor cerebri: incidence and pattern in north-eastern Libya. Acta Neurol 1986; 25:117-124.

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6. Garrett JH, Corbett JJ, Braswell R: The incidence of idiopathic intracranial hypertension in Mississippi. Presented at the annual meeting of the North American Neuro-Ophthalmology Society. Orlando, FL, 2004, p 269. 7. Jacobs DA, Corbett JJ, Balcer LJ: Annual incidence of idiopathic intracranial hypertension (IIH) in the Philadelphia area. Presented at the annual meeting of the North American Neuro-Ophthalmology Society. Orlando, FL, 2004, p 286. 8. Balcer LJ, Liu GT, Forman S, et al: Idiopathic intracranial hypertension: relation of age and obesity in children. Neurology 1999; 52:870-872. 9. Gordon K: Pediatric pseudotumor cerebri: descriptive epidemiology. Can J Neurol Sci 1997; 24:219-221. 10. Kesler A, Fattal-Valevski A: Idiopathic intracranial hypertension in the pediatric population. J Child Neurol 2002; 17:745748. 11. Cinciripini GS, Donahue S, Borchert MS: Idiopathic intracranial hypertension in prepubertal pediatric patients: characteristics, treatment and outcome. Am J Ophthalmol 1999; 127:178-182. 12. Bandyopadhyay S, Jacobson DM: Clinical features of late lifeonset pseudotumor cerebri fulfilling the Modified Dandy Criteria. J Neuroophthalmol 2002; 22:9-11. 13. Weig SG: Asymptomatic idiopathic intracranial hypertension in young children. J Child Neurol 2002; 17:239-241. 14. Wall M, George D: Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain 1991; 114:155-180. 15. Giuseffi V, Wall M, Spiegel PZ, et al: Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study. Neurology 1991; 41:239244. 16. Wall M, Giuseffi V, Rojas PB: Symptoms and disease associations in pseudotumor cerebri: a case-control study. Neurology 1989; 39:210. 17. Round R, Keane JR: The minor symptoms of increased intracranial pressure: 101 patients with benign intracranial hypertension. Neurology 1988; 38:1461-1464. 18. Kleinschmidt JJ, Digre KB, Hanover R: Idiopathic intracranial hypertension. Relationship to depression, anxiety, and quality of life. Neurology 2000; 54:319-324. 19. Groves MD, McCutcheon IE, Ginsberg LE, et al: Radicular pain can be a symptom of elevated intracranial pressure. Neurology 1999; 52:1093-1095. 20. Wall M, White WN II: Asymmetric papilledema in idiopathic intracranial hypertension. Prospective interocular comparison of sensory visual function. Invest Ophthalmol Vis Sci 1998; 39:132-142. 21. Huna-Baron R, Landau K, Rosenberg ML, et al: Unilateral swollen disc due to increased intracranial pressure. Neurology 2001; 56:1588-1590. 22. Frisén L: Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg Psychiatry 1982; 45:13-18. 23. Steffen H, Eifert B, Aschoff A, et al: The diagnostic value of optic disc evaluation in acute elevated intracranial pressure. Ophthalmology 1996; 103:1229-1323. 24. Pagani LF: The rapid appearance of papilledema. J Neurosurg 1969; 30:247-249. 25. Wang S-J, Silberstein SD, Patterson S, et al: Idiopathic intracranial hypertension without papilledema. A casecontrol study in a headache center. Neurology 1998; 51:245249. 26. Marcelis J, Silberstein SD: Idiopathic intracranial hypertension without papilledema. Arch Neurol 1991; 48:392-399. 27. Lipton HL, Michelson PE: Pseudotumor cerebri syndrome without papilledema. JAMA 1972; 220:1591-1592. 28. Kahn EA, Cherry GR: The clinical importance of spontaneous retinal venous pulsations. Med Bull (Ann Arbor) 1950; 16: 305-308.

814

Section

XI

Headache

29. Wall M, Hart WM Jr, Burde RM: Visual field defects in idiopathic intracranial hypertension (pseudotumor cerebri). Am J Ophthalmol 1983; 96:654-669. 30. Friedman DI, Forman S, Levi L, et al: Unusual ocular motility disturbances with increased intracranial pressure. Neurology 1998; 50:1893-1896. 31. Frohman LP, Kupersmith MJ: Reversible vertical ocular deviations associated with raised intracranial pressure. J Clin Neuroophthalmol 1985; 5:158-163. 32. Jacobson DM, Karanjia PN, Olson KA, et al: Computed tomography ventricular size has no predictive value in diagnosing pseudotumor cerebri. Neurology 1990; 40:1454-1455. 33. Brodsky MC, Vaphiades M: Magnetic resonance imaging in pseudotumor cerebri. Ophthalmology 1998; 105:1686-1693. 34. Cremer PD, Thompson EO, Johnston IH, et al: Pseudotumor cerebri and cerebral venous hypertension. Neurology 1996; 47:1602. 35. Biousse V, Ameri A, Bousser M-G: Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology 1999; 53:1537-1542. 36. Farb RI, Vanek I, Scott JN, et al: Idiopathic intracranial hypertension. The prevalence and morphology of sinovenous stenosis. Neurology 2003; 60:1418-1424. 37. Corbett JJ, Mehta MP: Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri. Neurology 1983; 33:1386-1388. 38. Ireland B, Corbett JJ: The search for causes of idiopathic intracranial hypertension. Arch Neurol 1990; 47:315-320. 39. Solberg Sørensen P, Gjerris F, Svenstrup B: Endocrine studies in patients with pseudotumor cerebri: estrogen levels in blood and cerebrospinal fluid. Arch Neurol 1986; 43:902-906. 40. Mann JD, Butler AB, Rosenthal JE, et al: Regulation of intracranial pressure in rat, dog, and man. Ann Neurol 1978; 3:156-165. 41. Sanders MD: The Bowman Lecture. Papilloedema: “The pendulum of progress.” Eye 1997; 11:267-294. 42. Jones HC, Lopman BA: The relation between CSF pressure and ventricular dilatation in hydrocephalic HTx rats. Eur J Pediatr Surg 1998; 8(Suppl 1):55-58. 43. Löfgren J, Swetnow NN: Cranial and spinal components of the cerebrospinal fluid pressure-volume curve. Acta Neurol Scand 1973; 49:599-612. 44. Johnston I, Paterson S: Benign intracranial hypertension: II. Cerebrospinal fluid pressure and circulation. Brain 1974; 97:301-312. 45. Johnston IH, Paterson A: Benign intracranial hypertension: I. Diagnosis and prognosis. Brain 1974; 97:289-300. 46. Wall M, Dollar JD, Sadun AA, et al: Idiopathic intracranial hypertension. Lack of histological evidence for cerebral edema. Arch Neurol 1995; 52:141-145. 47. King JO, Mitchell PJ, Thomson KR, et al: Manometry combined with cervical puncture in idiopathic intracranial hypertension. Neurology 2002; 58:26-30. 48. Repka MX, Miller NR: Papilledema and dural sinus obstruction. J Clin Neuroophthalmol 1984; 4:247-250. 49. Lam BL, Schatz NJ, Glaser JS, et al: Pseudotumor cerebri from cranial venous obstruction. Ophthalmology 1992; 99: 706-712. 50. Higgins JNP, Cousins C, Owler BK, et al: Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting. J Neurol Neurosurg Psychiatry 2003; 74:1662-1666. 51. Sugarman HJ, Felton WL, Salvant JB, et al: Effects of surgically induced weight loss on idiopathic intracranial hypertension in morbid obesity. Neurology 1995; 45:1655-1659. 52. Sugarman HJ, DeMaria EJ, Felton WL, et al: Increased intraabdominal pressure and cardiac filling pressure in obesityassociated pseudotumor cerebri. Neurology 1997; 49:507511.

53. Digre KB, Varner MV, Corbett JJ: Pseudotumor cerebri and pregnancy. Neurology 1984; 34:721-729. 54. Lombaert A, Carton H: Benign intracranial hypertension due to A-hypervitaminosis in adults and adolescents. Eur Neurol 1976; 14:340-350. 55. Feldman MH, Schlezinger NS: Benign intracranial hypertension associated with hypervitaminosis A. Arch Neurol 1970; 22:1-7. 56. Fishman R: Polar bear liver, vitamin A, aquaporins, and pseudotumor cerebri. Ann Neurol 2002; 52:531-533. 57. Baqui AH, de Francisco A, Arifeen SE, et al: Bulging fontanelle after supplementation with 25,000 IU of vitamin A in infancy using immunization contacts. Acta Paediatr 1995; 84:863-866. 58. Selhorst JB, Waybright EA, Jennings S, et al: Liver lover’s headache; pseudotumor cerebri and vitamin A intoxication. JAMA 1984; 252:3364. 59. Alemeyehu W: Pseudotumor cerebri (toxic effect of the “magic bullet”). Ethiop Med 1995; 33:265-270. 60. Warner JEA, Bernstein PS, Yemelyanov A, et al: Vitamin A in the cerebrospinal fluid of patients with and without idiopathic intracranial hypertension. Ann Neurol 2002; 52:647650. 61. Selhorst JB, Kulkanthrakorn K, Corbett JJ, et al: Retinolbinding protein in idiopathic intracranial hypertension (IIH). J Neuroophthalmol 2000; 20:250-252. 62. McDonald PN, Bok D, Ong DE: Localization of cellular retinol-binding protein and retinol-binding protein in cells comprising the blood-brain barrier of rat and human. Proc Natl Acad Sci U S A 1990; 87:4265-4269. 63. Friedman DI, Streeten DHP: Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis. Neurology 1998; 50:1099-1104. 64. Lindvall-Axelsson M, Mather C, Nilsson C, et al: Effect of 5hydroxytryptamine on the rate of cerebrospinal fluid production in rabbit. Exp Neurol 1988; 99:362-368. 65. Lindvall M, Edvinsson L, Owman C: Effect of sympathomimetic drugs and corresponding receptor antagonists on the rate of cerebrospinal fluid production. Exp Neurol 1979; 64:132-145. 66. Lindvall-Axelsson M, Nilsson C, Owman C, et al: Involvement of 5-HT1c receptors in the production of CSF from the choroid plexus. In Seylaz J, MacKenzie ET, eds: Neurotransmission and Cerebrovascular Function I. Amsterdam: Elsevier, 1989, pp 237-240. 67. Sørenson PS, Hammer M, Gjerris F: Cerebrospinal fluid vasopressin in benign intracranial hypertension. Ann Neurol 1984; 15:435-440. 67a. Kupersmith MJ, Gamell L, Turbin R, et al: Effects of weight loss on the course of idiopathic intracranial hypertension in women. Neurology 1998; 50:1094-1098. 67b. Johnson LN, Krohel GB, Madsen RW, et al: The role of weight loss and acetazolamide in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Ophthalmology 1998; 105:2313-2317. 68. Newberg B: Pseudotumor cerebri treated by the rice/reduction diet. Arch Intern Med 1974; 133:802-807. 69. Liu GT, Glaser JS, Schatz N: High-dose methylprednisolone and acetazolamide for visual loss in pseudotumor cerebri. Am J Ophthalmol 1994; 118:88-96. 70. Tschirgi RD, Frost RW, Taylor JL: Inhibition of cerebrospinal fluid formation by a carbonic anhydrase inhibitor, 2acetyl-1,3,4-thiadiazole-5-sulfonamide (Diamox). Proc Soc Exp Biol Med 1954; 87:373-376. 71. Eller P, Friedman DI: Topiramate for the treatment of idiopathic intracranial hypertension. Presented at the American Headache Society 45th Annual Scientific Meeting, Chicago, 2003.

chapter 61 idiopathic intracranial hypertension 72. Purvin VA, Kawasaki A, Yee RD: Papilledema and obstructive sleep apnea syndrome. Arch Ophthalmol 2000; 118:16261630. 73. Friedman DI, Rausch EA: Headache diagnoses in patients with treated idiopathic intracranial hypertension. Neurology 2002; 58:1551-1553. 74. Garton HJL: Cerebrospinal fluid diversion procedures. J Neuroophthalmol 2004; 24:146-155. 75. Eggenberger ER, Miller NR, Vitale S: Lumboperitoneal shunt for the treatment of pseudotumor cerebri. Neurology 1996; 46:1524-1530. 75a. McGirt MJ, Woodworth G, Thomas G, et al: Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and analysis of long term outcomes. J Neurosurg 2004; 101:627632. 76. Tse DT, Nerad JA, Andersen JW: Optic nerve sheath fenestration in pseudotumor cerebri: A lateral orbitotomy approach. Arch Ophthalmol 1988; 106:1458-1462. 77. Sergott RC, Savino PJ, Bosley TM: Modified optic nerve sheath decompression provides long-term visual improvement for pseudotumor cerebri. Arch Ophthalmol 1988; 106: 1384-1390. 78. Spoor TC, Ramocki JM, Madion MP, et al: Treatment of pseudotumor cerebri by primary and secondary optic nerve sheath decompression. Am J Ophthalmol 1991; 112:177-185. 79. Spoor TC, McHenry JG: Long-term effectiveness of optic nerve sheath decompression for pseudotumor cerebri. Arch Ophthalmol 1993; 111:632-635. 80. Owler BK, Parker G, Halmagyi GM, et al: Pseudotumor cerebri syndrome: venous sinus obstruction and its treatment with stent placement. J Neurosurg 2003; 98:1045-1055. 81. Digre KB, Varner MW, Corbett JJ: Pseudotumor cerebri and pregnancy. Neurology 1984; 34:721-729. 82. Huna-Baron R, Kupersmith MJ: Idiopathic intracranial hypertension in pregnancy. J Neurol 2002; 249:1078-1081. 83. Evans RW, Friedman DI: The management of pseudotumor cerebri during pregnancy. Headache 2000; 40:496-497. 84. Corbett JJ, Savino PJ, Thompson HS, et al: Visual loss in pseudotumor cerebri. Follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982; 39:461-474. 85. Daif A, Awada A, Al-Rajeh S, et al: Cerebral venous thrombosis in adults: a study of 40 cases from Saudi Arabia. Stroke 1995; 26:1193-1195. 86. Lam BL, Schatz NJ, Glaser JS, et al: Pseudotumor cerebri from cranial venous obstruction. Ophthalmology 1992; 99: 706-712. 87. McDonnell GV, Patterson VH, McKinstry S: Cerebral venous thrombosis occurring during an ectopic pregnancy and complicated by intracranial hypertension. Br J Clin Pract 1997; 51:194-197. 88. Kikuchi M, Kudo S, Wada M, et al: Retropharyngeal rhabdomyosarcoma mimicking pseudotumor cerebri. Pediatr Neurol 1999; 21:496-499. 89. Molina JC, Martinez-Vea A, Riu S, et al: Pseudotumor cerebri: an unusual complication of brachiocephalic vein thrombosis associated with hemodialysis catheters. Am J Kidney Dis 1998; 31:E3. 90. Kollar DC, Johnston IH: Pseudotumor after arteriovenous malformation embolisation. J Neurol Neurosurg Psychiatry 1999; 67:249-252. 91. Condulis N, Germain G, Charest N, et al: Pseudotumor cerebri: a presenting manifestation of Addison’s disease. Clin Pediatr 1997; 36:711-713. 92. Bourruat F-X, Regli F: Pseudotumor cerebri as a complication of amiodarone therapy. Am J Ophthalmol 1993; 116:776777.

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93. Fort JA, Smith LD: Pseudotumor cerebri secondary to intermediate-dose cytarabine HCl. Ann Pharmacother 1999; 33: 576-578. 94. Greer M: Benign intracranial hypertension. II. Following corticosteroid therapy. Neurology 1963; 13:439-441. 95. Liu GT, Kay MD, Bienfang DC, et al: Pseudotumor cerebri associated with corticosteroid withdrawal in inflammatory bowel disease. Am J Ophthalmol 1994; 117:352-357. 96. Walker AE, Adamkiewitz JJ: Pseudotumor cerebri associated with prolonged corticosteroid therapy. JAMA 1964; 188:779784. 97. Cruz OA, Fogg SG, Roper-Hall G: Pseudotumor cerebri associated with cyclosporine use. Am J Ophthalmol 1996; 122:436. 98. Blethen SL: Complications of growth hormone therapy in children. Curr Opin Pediatr 1995; 7:466-471. 99. Grancois I, Castells I, Silberstein J, et al: Empty sella, growth hormone deficiency and pseudotumour cerebri: effect of initiation, withdrawal and resumption of growth hormone therapy. Eur J Pediatr 1997; 156:69-70. 100. Koller EA, Stadel BV, Malozowski SN: Papilledema in 15 renally compromised patients treated with growth hormone. Pediatr Nephrol 1997; 11:451-454. 101. Malozozwski S, Tanner LA, Wysowski DK, et al: Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone. J Pediatr 1995; 126:996-999. 102. Rogers AH, Rogers GL, Bremer DL, et al: Pseudotumor cerebri in children receiving recombinant human growth hormone. Ophthalmology 1999; 106:1186-1190. 103. Boot JH: Pseudotumor cerebri as a side effect of leuprorelin acetate. Ir J Med Sci 1996; 165:60. 104. Campos SP, Olitsky S: Idiopathic intracranial hypertension after L-thyroxine therapy for acquired hypothyroidism. Clin Pediatr 1995; 34:334-337. 105. Raghavan S, DiMartino-Nardi J, Saenger P, et al: Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism. J Pediatr 1997; 130:478-480. 106. Saul RF, Hamburger HA, Selhorst JB: Pseudotumor cerebri secondary to lithium carbonate. JAMA 1985; 253:2869-2870. 107. Cohen DN: Intracranial hypertension and papilledema associated with nalidixic acid therapy. Am J Ophthalmol 1973; 76:680-682. 108. Mukherjee A, Dutta B, Lahiri M, et al: Benign intracranial hypertension after nalidixic acid overdose in infants. Lancet 1990; 335:1602. 109. Wysowski DK, Green L: Serious adverse events in Norplant users reported to the Food and Drug Administration’s MedWatch spontaneous reporting system. Obstet Gynecol 1995; 85:538-542. 110. Alder J, Fraunfelder F, Edwards R, et al: Levonorgestrel implants and intracranial hypertension. N Engl J Med 1995; 332:1720-1721. 111. Gardner K, Cox T, Digre K: Idiopathic intracranial hypertension associated with tetracycline use in fraternal twins: case report and review. Neurology 1995; 45:6-10. 112. Giles CL, Soble AR: Intracranial hypertension and tetracycline therapy. Am J Ophthalmol 1971; 72:981-982. 113. Lee AG: Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995; 55:165-168. 114. Meacock DJ, Hewer RL: Tetracycline and benign intracranial hypertension. BMJ 1981; 282:1240. 115. Minutello JS, Dimayuga RG, Carter J: Pseudotumor cerebri, a rare adverse reaction to tetracycline therapy. J Periodontol 1988; 58:848-851. 116. Maroon JC, Mealy J Jr: Benign intracranial hypertension. Sequel to tetracycline therapy in a child. JAMA 1971; 216: 1479-1480.

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117. Quinn AG, Singer SB, Buncic JR: Pediatric tetracyclineinduced pseudotumor cerebri. J AAPOS 1999; 3:53-57. 118. Ohlrich GD, Ohlrich JG: Papilloedema in an adolescent due to tetracycline. Med J Aust 1977; 1:334-335. 119. Pierog SH, Al-Salihi FL, Cinotti D: Pseudotumor cerebri—a complication of tetracycline treatment of acne. J Adolesc Health Care 1986; 7:139-140. 120. Stuart BH, Litt IF: Tetracycline-induced intracranial hypertension in an adolescent: a complication of systemic acne therapy. J Pediatrics 1978; 92:679-680. 121. Chiu AM, Chuenkongkaew WL, Cornblath WT, et al: Minocycline treatment and pseudotumor cerebri syndrome. Am J Ophthalmol 1998; 126:116-121. 122. Moskowitz T, Leibowitz E, Ronen M, et al: Pseudotumor cerebri induced by vitamin A combined with minocycline. Ann Ophthalmol 1993; 25:306-308. 123. Donnet A, Dufour H, Graziani N, et al: Minocycline and benign intracranial hypertension. Biomed Pharmacother 1992; 46:171-172. 124. Beran RG: Pseudotumor cerebri associated with minocycline therapy for acne. Med J Aust 1980; 1:323-324. 125. Lochhead J, Elston JS: Doxycycline induced intracranial hypertension. BMJ 2003; 326:641-642. 126. Fraunfelder FW, Fraunfelder FT, Edwards R: Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001; 132:299-305. 127. Fraunfelder FW, Fraunfelder FT, Corbett JJ: Isotretinoinassociated intracranial hypertension. Ophthalmology 2004; 111:1248-1250. 128. Bigby M, Stern RS: Adverse reactions to isotretinoin. A report for the Adverse Reaction Reporting System. J Am Acad Dermatol 1988; 18:543-552. 129. Roytman M, Frumkin A, Boyn TG: Pseudotumor cerebri caused by isotretinoin. Cutis 1988; 42:399-400. 130. Lebowitz MA, Berson DS: Ocular effects of oral retinoids. J Am Acad Dermatol 1988; 19:209-211. 131. Tallman MS, Andersen JW, Schiffer CA, et al: Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 2000; 95:90-95. 132. Viraben R, Mathieu C, Fontan B: Benign intracranial hypertension during etretinate therapy for mycosis fungoides. J Am Acad Dermatol 1985; 13:515-517. 133. Bonnetblanc JM, Hugon J, Dumas M, et al: Intracranial hypertension with etretinate. Lancet 1983; 2:974. 134. Visani G, Manfroi S, Tosi P, et al: All-trans-retinoic acid and pseudotumor cerebri. Leukemia Lymphoma 1996; 23:437442. 135. Javeed N, Shaikh J, Jayaram S: Recurrent pseudotumor cerebri in an HIV-positive patient. AIDS 1995; 9:817-819. 136. Prevett MC, Plant GT: Intracranial hypertension and HIV associated meningoradiculitis. J Neurol Neurosurg Psychiatry 1997; 62:407-409. 137. Schwartz S, Husstedt IW, Georgiadis D, et al: Benign intracranial hypertension in an HIV-infected patient: headache as the only presenting sign. AIDS 1995; 9:657-658.

138. Kan L, Sood SK, Maytal J: Pseudotumor cerebri in Lyme disease: a case report and literature review. Pediatr Neurol 1998; 18:439-441. 139. Konrad D, Kuster H, Hunzinker UA: Pseudotumor cerebri after varicella. Eur J Pediatr 1998; 157:904-906. 140. Lahat E, Leshem M, Barzilai A: Pseudotumor cerebri complicating varicella in a child. Acta Paediatr 1998; 87:13101311. 141. Sussman J, Leach M, Greaves M, et al: Potentially prothrombotic abnormalities of coagulation in benign intracranial hypertension. J Neurol Neurosurg Psychiatry 1997; 62:229-233. 142. Kesler A, Ellis MG, Reshef T, et al: Idiopathic intracranial hypertension and anticardiolipin antibodies. J Neurol Neurosurg Psychiatry 2000; 68:379-380. 143. Leker RR, Steiner I: Anticardiolipin antibodies are frequently present in patients with idiopathic intracranial hypertension. Arch Neurol 1998; 55:817-820. 144. Kalbian VV, Challis MT: Behçet’s disease: Report of twelve cases with three manifesting as papilledema. Am J Med 1970; 49:823-829. 145. Teh LS, O’Connor GM, O’Sullivan MM, et al: Recurrent papilloedema and early onset optic atrophy in Behçet’s syndrome. Ann Rheum Dis 1990; 49:410-411. 146. Graham EM, Al-Akshar R, Sanders MD, et al: Benign intracranial hypertension in Behçet’s syndrome. J Neuroophthalmol 1980; 1:73-76. 147. Martinez-Lage JF, Alamo L, Poza M: Raised intracranial pressure in minimal forms of cranial synostosis. Childs Nerve Syst 1999; 15:11-15. 148. Au Eong KG, Hariharan S, Chua EC, et al: Idiopathic intracranial hypertension, empty sella turcica and polycystic ovary syndromes—a case report. Singapore Med J 1997; 38:129130. 149. Pelton RW, Lee AG, Orengo-Nania SD, et al: Bilateral optic disk edema caused by sarcoidosis mimicking pseudotumor cerebri. Am J Ophthalmol 1999; 127:229-230. 150. Wolin MJ, Brannon WL, Kay MD, et al: Disk edema in an overweight woman (clinical conference). Surv Ophthalmol 1995; 39:307-314. 151. Miller JJ, Thomas D, Lynn JL, et al: Sleep disorders: a risk factor for pseudotumor cerebri (PTC). Invest Ophthalmol Vis Sci 2000; 41:S313. 152. Green L, Vinker S, Amital H, et al: Pseudotumor cerebri in systemic lupus erythematosus. Semin Arthritis Rheum 1995; 25:103-108. 153. Horoshovski D, Amital H, Katz M, et al: Pseudotumor cerebri in SLE. Clin Rheum 1995; 14:708-710. 154. Sybert VP, Bird TD, Salk DJ: Pseudotumor cerebri and Turner syndrome. J Neurol Neurosurg Psychiatry 1985; 48:164-166.

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62

LOW CEREBROSPINAL FLUID HEADACHE ●

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●

●

Bahram Mokri

BACKGROUND AND TERMINOLOGY

CLINICAL MANIFESTATIONS

In 1938, Schaltenbrand used the term aliquorrhea to describe the spontaneous occurrence of an entity manifested by very low cerebrospinal fluid (CSF) opening pressures and orthostatic headaches, among other features.1,2 Sometimes referred to as Schaltenbrand’s headaches, this later came to be known as spontaneous intracranial hypotension.3 It is now realized that practically all cases of spontaneous intracranial hypotension result from spontaneous CSF leaks,4 often at the level of the spine (particularly the thoracic spine5) and only rarely at the skull base. CSF leak leads to CSF volume depletion. Terms such as spontaneous CSF leak, CSF hypovolemia, and CSF volume depletion have been used interchangeably with spontaneous intracranial hypotension, because some patients with this disorder have consistently normal CSF opening pressures.5,6 True hypovolemic state (reduced total body water), CSF shunt overdrainage, dural holes or tears as the result of lumbar puncture, epidural catheterization, surgery, and trauma all may lead to loss of CSF volume. In this chapter, we focus on spontaneous CSF leaks.

Headache is the most common manifestation. It is “classically” orthostatic (present in upright position, relieved by recumbency).3,5 It is often not throbbing, but it may be throbbing; it is often bilateral, but it may be unilateral; and it is often aggravated or sometimes even triggered by Valsalva-type maneuvers. The headache may be frontal, fronto-occipital, holocephalic, or occipital. Not all headaches in CSF leaks are orthostatic, and variability is substantial (Table 62–1).5,13-17 Furthermore, not all orthostatic headaches result from CSF leaks. For example, they can be the dominant clinical manifestation in some patients with postural tachycardia syndrome.18

ETIOLOGY OF SPONTANEOUS CEREBROSPINAL FLUID LEAKS The cause of spontaneous CSF leaks often remains undetermined, but two etiologic factors should be considered: trivial trauma and weakness of the dural sac. Some patients report a history of trivial trauma, such as coughing, pushing, trivial falls, lifting, and sports activities. Evidence for weakness of the dural sac is accumulating. Meningeal diverticula are seen more frequently in patients with spontaneous CSF leaks. Increased frequency of meningeal diverticula and also CSF leaks have been reported in Marfan’s syndrome.7-9 Some patients with spontaneous CSF leaks show stigmata of the disorders of a connective tissue matrix (e.g., marfanoid features, hyperflexible joints, hyperextensible skin).5,10 In uncommon instances, a dural tear from a spondylotic spur or disc herniation11,12 may cause dural defect and CSF leak.

CLINICAL MANIFESTATIONS OTHER THAN HEADACHES Many of the patients with spontaneous CSF leaks have one or, often, more symptoms in addition to the headaches (Table 62–2).3,5,19-32 Proposed mechanisms of clinical manifestations in CSF leaks and intracranial hypotension are listed in Table 62–3.3,5,19-34

DIAGNOSIS Cerebrospinal Fluid Examination Considerable variability, not only between different patients but also in the same patient if multiple taps are performed at different times, is to be expected. The opening pressure is typically low, sometimes unmeasurable, and sometimes it is “low normal” or even consistently within normal limits. Analysis reveals the following characteristics: ■ Color: often clear, occasionally xanthochromic. ■ Protein concentration: normal or elevated (protein concen-

trations up to 100 mg/dL are common, and a concentration up to 1000 mg/dL has been reported).15

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T A B L E 62–1. Headache Variations in Cerebrospinal Fluid (CSF) Leaks

T A B L E 62–3. Mechanisms of Clinical Manifestations or Cerebrospinal Fluid Volume Depletion

Orthostatic headaches may be preceded by neck pain or interscapular pain or both or by lingering nonorthostatic headaches. With chronicity, sometimes the orthostatic features may dampen and the headache may be transformed into chronic lingering headaches that are present even in recumbency.5 Sometimes the headaches may have an acute thunderclap-like onset mimicking a subarachnoid hemorrhage13 before orthostatic features are recognized. In rare cases, a paradoxical postural headache (headache present in recumbency, relieved in upright position) may occur.14 Sometimes a second-half-of-the-day headache may occur. Typically, patients are headache free in the morning, but by later morning or early afternoon, they develop a headache that would increase in severity if the patients continued to be up and about; the headaches decrease clearly or vaguely in recumbency.15 Exertional headaches occur in isolation or are accompanied by some of the other clinical manifestations of CSF leaks and without any orthostatic features.16 With intermittent CSF leaks, the headaches may appear and disappear for variable periods of time. Sometimes patients with documented CSF leaks and low CSF pressures and typical MRI abnormalities may have no headache at all—the acephalgic form.18

Clinical Manifestation

Proposed Mechanism

Headache

Descent of the brain, stretch and distortion of pain-sensitive suspending structures of the brain3,5,33,34,34a Stretching or compression of related cranial nerves19-23 Stretching of eighth cranial nerve or pressure changes in perilymphatic fluid of the inner ear5,25 Distortion of pituitary stalk24

Cranial nerve palsies Dizziness, change in hearing Galactorrhea and increased prolactin Radicular upper limb symptoms Encephalopathy, stupor, coma Cerebellar ataxia, parkinsonism Frontotemporal dementia Gait disorder

Stretching of cervical nerve roots or irritation by dilated epidural venous plexus5,26 Diencephalic compression27-29 Compression of posterior fossa and deep midline structures30 Compression of frontotemporal lobes32 Spinal cord venous congestion31

MRI, magnetic resonance imaging.

T A B L E 62–2. Clinical Features Other Than Headaches Interscapular or neck pain (sometimes orthostatic), low back pain Nausea, sometimes emesis, often orthostatic Horizontal diplopia (unilateral or bilateral sixth cranial nerve palsy)19 Cochleovestibular manifestations (dizziness, change in hearing, tinnitus)3,5,20 Photophobia, visual blurring Upper limb numbness or pain5 Rare manifestations: facial numbness or weakness, diplopia due to third or fourth cranial nerve palsy,20-23 galactorrhea,24 Menière’s disease–like manifestations,25 upper limb radiculopathy,26 encephalopathy,27 stupor,28 coma,29 parkinsonism,30 ataxia, incontinence, gait unsteadiness,31 frontotemporal dementia32

Therefore, images at 24 or even 48 hours reveal either absence or paucity of activity over the cerebral convexities.35-37 This finding is the most common cisternographic abnormality in CSF leaks. Detection of parathecal activity that may point to the level or approximate site of the leak, although more desirable, is noted much less commonly (Fig. 62–1). Furthermore, meningeal diverticula, if large enough, may appear as foci of parathecal activity. Another cisternographic observation in CSF leaks is the early appearance of radioactivity in the kidneys and urinary bladder (<4 hours versus 6 to 24 hours), indicative of early entrance of extravasated isotope into the venous system and its early renal clearance and early appearance in the urinary bladder.

Head Computed Tomography ■ Glucose concentration: never low. ■ Leukocyte count: normal or elevated (pleocytosis with

counts up to 50 cells/mm3 is common, and a count up to 222 cells/mm3 has been reported).5 ■ Erythrocyte count: normal or elevated (difficult and traumatic taps are common in this disorder, and epidural venous plexus may be dilated). ■ Cytological and microbiological profiles: always negative.

Head computed tomography (CT) only infrequently shows subdural fluid collections or increased tentorial enhancement and overall is of very limited diagnostic value in this disorder.

Magnetic Resonance Imaging Magnetic resonance imaging (MRI) has truly revolutionized the diagnosis of spontaneous CSF leaks and has been instrumental in recognizing its broad clinical spectrum. Head and spine MRI abnormalities are listed in Table 62–4.

Radioisotope Cisternography Indium 111 is the radioisotope of choice. This is introduced intrathecally, typically through a lumbar puncture, and its movement is monitored by sequential scanning at various intervals, up to 24 or even 48 hours. Normally, by 24 hours (but often earlier), substantial radioactivity can be detected over the cerebral convexities. When a spinal CSF leak exists, the activity typically does not extend much beyond the basal cisterns.

Computed Tomographic Myelography Computed tomographic myelography (CTM) is myelography with water-soluble contrast material, followed by CT, typically at each spinal level, unless the myelogram itself or a previous cisternography or spine MRI reliably pointed to a more limited area of the spine to be investigated. CTM may show extraarachnoid and extradural extravasation of contrast material

chapter 62 low cerebrospinal fluid headache ■

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(and therefore, the CSF) and so far is the most reliable test for locating the actual site of CSF leakage. It also shows meningeal diverticula and dilated nerve root sleeves and helps identify whether a noted meningeal diverticulum is the actual site of the CSF leak (Figs. 62–2B,C and 62–5).5 This test, like cisternography, also provides an opportunity to measure CSF opening pressure. The rate of CSF leakage (fast-flow or slow-flow) may create special diagnostic challenges.

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Figure 62–1.

Indium 111 cisternography in a patient with spontaneous cerebrospinal fluid (CSF) leak. Note parathecal activity at 2 hours pointing to the level of CSF leak. At 24 hours, there is paucity of activity over the cerebral convexities, although activity can be seen in the spinal canal and, in particular, the basal cisterns.

Figure 62–2.

Composite figure pertaining to a patient with spontaneous cerebrospinal fluid (CSF) leak. A, T1-weighted gadolinium-enhanced coronal image while CSF leakage is active. Note diffuse pachymeningeal gadolinium enhancement (upper arrows) and enlargement of the pituitary gland (lower arrow). Also note that the optic chiasm above the pituitary gland is flattened and that the perichiasmatic cistern is partially obliterated. The patient has a large meningeal diverticulum, as seen in myelography (B) and computed tomographic myelography (C), believed to be source of the CSF leakage. After surgical treatment, along with disappearance of symptoms, all of the abnormalities on magnetic resonance imaging also reversed (D). (From Mokri B: Intracranial hypertension after treatment of spontaneous cerebrospinal fluid leaks. Mayo Clin Proc 2002; 77:1241-1246. Reprinted with permission of the Mayo Foundation for Education and Research.)

Fast-Flow Cerebrospinal Fluid Leaks In this situation, after the myelogram and by the time of CT, a substantial amount of contrast has leaked and has spread across several spinal levels, making it virtually impossible to locate the exact site of the leakage. Dynamic CTM38 is often effective in solving this problem. In this technique, CT is performed immediately after intrathecal injection of contrast material, and high-speed multidetector spiral CT (which allows obtaining

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T A B L E 62–4. MRI Abnormalities in Cerebrospinal Fluid Leaks Head MRI Diffuse pachymeningeal enhancement: the most common head MRI abnormality; may be thick or thin but is typically uninterrupted, nonnodular, bilateral, both supratentorial and infratentorial, and without leptomeningeal involvement (see Fig. 62–2A)5,41,54 Descent (“sagging” or “sinking”) of the brain: manifested by descent of cerebellar tonsils, which may mimic Chiari type I malformation (see Fig. 62–3)55; by obliteration of prepontine or perichiasmatic cisterns; by crowding of the posterior fossa; and by flattening of the optic chiasm (see Figs. 62–2A and 62–3) Enlargement of pituitary gland: sometimes may mimic pituitary adenoma or hyperplasia (see Fig. 62–2A)56,57 Subdural fluid collections: may be unilateral but are often bilateral, are usually hygromas but may be or may become hematomas Engorged cerebral venous sinuses58 Decrease in size of the ventricles, “ventricular collapse”2 Spine MRI Extra-arachnoid fluid collection:59,60 often extends across several spinal levels; therefore, usually does not enable determination of the exact site of the leak (see Fig. 62–4) Extradural extravasation of fluid: typically extends across fewer levels and, when seen, is more likely to point to the site or approximate site of the leak Meningeal diverticula: may be single or multiple, small or large; may or may not be the site of the CSF leakage (see Fig. 62–4) Spinal pachymeningeal enhancement61 Engorgement of spinal epidural venous plexus62 MRI, magnetic resonance imaging.

many cuts in a short period of time) is used. This technique is quite effective in detecting fast-flow CSF leaks as well as leaks from multiple sites.

Slow-Flow Cerebrospinal Fluid Leaks When the leaks are slow, even after CTM, not enough contrast material has leaked to allow detection. A delayed CT, 3 to 4 hours after the initial one, sometimes reveals the site of the leak. Magnetic resonance myelography (spine MRI after intrathecal introduction of gadolinium), a test that awaits more

■

Figure 62–3.

T1-weighted midline sagittal view in a patient with spontaneous cerebrospinal fluid leak shows descent of the cerebellar tonsils and crowding of posterior fossa.

confirmation and experience, may also prove to be helpful, inasmuch as images delayed as long as 72 or even 96 hours may be obtained.39

MECHANISMS OF MAGNETIC RESONANCE IMAGING ABNORMALITIES CSF volume depletion leads to (1) ventricular collapse and decrease in the size of the ventricles and (2) sinking of the brain (and, therefore, descent of the cerebellar tonsils [Fig. 62–3], decrease in the sizes of prepontine and perichiasmatic cisterns, flattening of the optic chiasm, and crowding of the posterior fossa). Furthermore, the loss of CSF volume, according to the

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Figure 62–4.

Spine magnetic resonance imaging in a patient with spontaneous cerebrospinal fluid leak. A, Extra-arachnoid fluid extending across several spinal levels (arrows). B, Meningeal diverticulum (arrows). (From Mokri B: Spontaneous cerebrospinal fluid leaks: from intracranial hypotension to cerebrospinal fluid hypovolemia—evolution of a concept. Mayo Clin Proc 1999; 74:11131123. Reprinted with permission of the Mayo Foundation for Education and Research.)

chapter 62 low cerebrospinal fluid headache ■

Monro-Kellie doctrine,40 mandates replacement of the depleted CSF volume, which is accomplished mainly by an intracranial venous hypervolemia. This results in (1) meningeal venous hyperemia, leading to diffuse pachymeningeal enhancement with gadolinium (leptomeninges have blood-brain barriers, but pachymeninges do not and, therefore, it is only the pachymeninges that enhance)41; (2) enlargement of the pituitary gland as the result of pituitary hyperemia; and (3) engorgement of cerebral venous sinuses. Subdural fluid collections are also volume-compensatory phenomena. At the spine level, CSF volume depletion and relative collapse of the spinal dura lead to engorgement of the epidural venous plexus.15

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Figure 62–5.

Water-soluble myelography and computed tomographic myelography in spontaneous cerebrospinal fluid leaks. A, Myelogram shows a meningeal diverticulum (arrows). B, Computed tomographic myelography shows a meningeal diverticulum at T7 (arrow). C, Extraarachnoid collections of contrast, giving the “dog ears” appearance on axial image. D, Leakage of contrast toward the paraspinal soft tissues (arrow). (A, B, and D from Mokri B: Spontaneous cerebrospinal fluid leaks: from intracranial hypotension to cerebrospinal fluid hypovolemia—evolution of a concept. Mayo Clin Proc 1999; 74:11131123. C from Mokri B, Piepgras DG, Miller GM: Syndrome of orthostatic headaches and diffuse pachymeningeal gadolinium enhancement. Mayo Clin Proc 1997; 72:400-413. All reprinted with permission of the Mayo Foundation for Medical Education and Research.)

Decreased CSF pressure

CSF hypovolemia

CONSIDERABLE VARIABILITY In spontaneous CSF leaks, clinical manifestations (including headaches), imaging findings, and CSF abnormalities (including opening pressures, which may range from unmeasurable to entirely normal) exhibit considerable variability. The core pathogenetic factor in this disorder is loss of CSF volume (CSF hypovolemia), which is the independent variable, whereas CSF pressures, imaging abnormalities, and clinical manifestations are variables dependent on the CSF volume (Fig. 62–6).4

TREATMENT A variety of treatment modalities have been advocated in the management of patients with intracranial hypotension or spontaneous CSF leaks (Table 62–5). Some of these are based on previous experience with post–lumbar puncture headaches rather than direct experience with spontaneous CSF leaks.

Clinical manifestations

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Figure 62–6.

MRI abnormalities

Cerebrospinal fluid (CSF) hypovolemia as the independent variable in CSF leaks. CSF pressures, magnetic resonance imaging abnormalities, and clinical manifestations substantially vary as variables dependent on CSF volume. (From Mokri B: Spontaneous cerebrospinal fluid leaks: from intracranial hypotension to cerebrospinal fluid hypovolemia—evolution of a concept. Mayo Clin Proc 1999; 74:1113-1123. Reprinted with permission of the Mayo Foundation for Medical Education and Research.)

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T A B L E 62–5. Treatment of Cerebrospinal Fluid Leaks Bed rest Hydration/overhydration Caffeine, theophylline Steroids Abdominal binder Epidural blood patch Continuous epidural saline infusion Epidural infusion of dextran Epidural injection of fibrin glue (fibrin sealant) Cerebrospinal fluid shunting Intrathecal fluid infusion Surgery

Sporadic reports on the effectiveness of epidural injection of fibrin glue48 are encouraging. It can be an alternative when EBPs fail. Surgery in well-selected cases is effective and can be tried when conservative and less invasive approaches, such as EBPs, have failed.49 The surgery, however, may not be entirely straightforward, mostly as the result of the complexity of the anatomy of the leak. Besides, occasional patients have leaks at multiple sites.38 It is essential to determine the site of the CSF leak and perform a thorough preoperative workup before surgery is undertaken.

PROGNOSIS Fortunately, in some patients, the leak stops or slows spontaneously and the symptoms resolve. Bed rest has been traditionally recommended. Because many such patients have orthostatic symptoms, they tend to remain recumbent much of the time anyway. Hydration (or, more precisely, overhydration), another traditionally advocated measure, is often tried, with variable results and essentially undetermined efficacy. An occasional patient may report a definite although nondurable improvement with intravenous fluid infusion. Caffeine and theophylline, according to some studies,42 are mildly effective, but this effectiveness is doubtful to be impressive or durable. Some patients report definite improvement with steroids, but many do not. It is unlikely that a substantial and durable improvement will occur with a course of corticosteroid therapy, and chronic corticosteroid use carries the recognized risks of many side effects. Sporadic reports of successful results with epidural saline infusion exist,43 but the experience is limited. This procedure can be tried, but with limited expectations, in patients in whom repeated epidural blood patches (EBPs) have failed. Reports, mostly anecdotal,44 have mentioned the efficacy of epidural dextran injections. Intradural fluid infusions have been effective but typically only for as long as the CSF volume loss is thus compensated. However, in rare cases of rapid deterioration with obtundation or coma, intrathecal fluid injections may prove helpful.45 Overall, the concern is about complications such as infections in sustained epidural and intrathecal infusions. EBP has emerged as the treatment of choice for patients in whom initial conservative management has failed.46,47 The effect of EBP may be transient or sustained. EBP has an early effect that is simply a volume replacement resulting from the tamponade effect of the volume of the epidurally introduced blood, as well as a latent effect related to complete or partial sealing of the leak. A durable response is noted in approximately one third of patients with each EBP.47 Thus, many patients may require more than one EBP. The efficacy of EBP in spontaneous CSF leaks is much less than what is seen in post–lumbar puncture headaches or even in the leaks that may follow epidural catheterizations. This difference is related mostly to the complex anatomy of the spontaneous CSF leaks (often not a simple rent or hole) but also to the site of the leak (which may not be in the posterior aspect of the dura or may be distant from the site where EBP is delivered).

Most patients make a complete recovery either spontaneously, with conservative management, or with more invasive therapeutic approaches, such as EBP, epidural injection of fibrin glue (fibrin sealant), or surgery. Sometimes, however, all attempts to stop the leak may fail. A few patients experience recurrences within varying intervals, sometimes after several years. The exact rate of recurrence is not known. Overall, patients with underlying disorders of connective tissue matrix and multiple meningeal diverticula may be more prone to recurrences or leakage from more than one site and from more than one level, but this has not been formally studied.

COMPLICATIONS The major complication of spontaneous CSF leak is the development of symptomatic unilateral or bilateral subdural hematomas, which may create significant therapeutic challenges.50,51 Cerebral venous sinus thrombosis, an uncommon complication of spontaneous CSF leak, has been occasionally reported.52 After treatment of spontaneous CSF leaks, whether by EBP or by surgery, sometimes a symptomatic rebound syndrome of intracranial hypertension may develop.53 This is typically selflimited. Treatment with acetazolamide has shown encouraging results.

K E Y

P O I N T S

●

Spontaneous intracranial hypotension nearly always results from spontaneous CSF leaks, typically at the spine level and only rarely at the skull base. The traditional theories of increased CSF absorption or decreased CSF production have never been substantiated. The disorder is far more common than was believed as recently as the mid-1990s.

●

There is considerable variability in clinical manifestations (including headaches), in imaging findings, and in CSF findings (including CSF pressures that can be normal). CSF volume depletion (CSF hypovolemia), rather than decreased CSF pressure, appears to be the pathogenetic core factor and the independent variable. CSF pressures, clinical manifestations, and MRI abnormalities are variables dependent on CSF volume.

chapter 62 low cerebrospinal fluid headache ●

The anatomy of spontaneous CSF leaks is often complex and different from a simple hole or rent. This disorder should not be equated with post–lumbar puncture headaches.

●

Clinical stigmata of disorders of connective tissue matrix can be seen in a notable minority of patients. This probably plays a role in the weakness of the dural sac, formation of meningeal diverticula, and pathogenesis of spontaneous CSF leaks.

●

Not all headaches in spontaneous CSF leaks are orthostatic, and not all orthostatic headaches result from CSF leaks or indicate intracranial hypotension, although most do.

●

The rate of CSF leakage in spontaneous CSF leaks may vary considerably. Fast-flow and slow-flow leaks, as well as intermittent leaks, each present special diagnostic challenges.

●

EBP has emerged as the treatment of choice for patients in whom initial conservative management fails. Epidural injection of fibrin sealant is a reasonable alternative, particularly if EBPs fail. Surgery may be considered for patients in whom less invasive measures have failed and only when the site of the leak has been thoroughly identified.

References 1. Schaltenbrand G: Neure anschauungen zur pathophysiologie der liquorzirkulation. Zentrablbl Neurochir 1938; 3:290-300. 2. Schaltenbrand G: Normal and pathological physiology of the cerebrospinal fluid circulation. Lancet 1953; 1:805-808. 3. Chung SJ, Kim JS, Lee MC: Syndrome of cerebrospinal fluid hypovolemia: clinical and imaging features and outcome. Neurology 2000; 55:1321-1327. 4. Mokri B: Spontaneous cerebrospinal fluid leaks: from intracranial hypotension to cerebrospinal fluid hypovolemia—evolution of a concept. Mayo Clin Proc 1999; 74:1113-1123. 5. Mokri B, Piepgras DG, Miller GM: Syndrome of orthostatic headaches and diffuse pachymeningeal gadolinium enhancement. Mayo Clin Proc 1997; 72:400-413. 6. Miyazawa K, Shiga Y, Hasegawa T, et al: CSF hypovolemia vs intracranial hypotension in “spontaneous intracranial hypotension syndrome.” Neurology 2003; 60:941-947. 7. Davenport RJ, Chataway SJ, Warlow CP: Spontaneous intracranial hypotension from a CSF leak in a patient with Marfan’s syndrome. J. Neurol Neurosurg Psychiatry 1995; 59:516-519. 8. Fukutake T, Sakakibara R, Mori M, et al: Chronic intractable headache in a patient with Marfan’s syndrome. Headache 1997; 37:291-295. 9. Schriver I, Schievink WI, Godfrey M, et al: Spontaneous spinal cerebrospinal fluid leaks and minor skeletal features of Marfan’s syndrome: a microfibrillonopathy. J Neurosurg 2002; 96:483-489. 10. Mokri B, Maher CO, Sencakova D: Spontaneous CSF leaks: underlying disorder of connective tissue. Neurology 2002; 58:814-816. 11. Eros EJ, Dodick DW, Nelson KD: Orthostatic headache syndrome with CSF leak secondary to bony pathology of the cervical spine. Cephalalgia 2002; 22:439-443. 12. Winter SCA, Maartens NF, Anslow P, et al: Spontaneous intracranial hypotension due to thoracic disc herniation. J Neurosurg 96(3, Suppl):343-345. 13. Schievnik WI, Wijdicks EFM, Meyer FB, et al: Spontaneous intracranial hypotension mimicking aneurysmal subarachnoid hemorrhage. Neurosurgery 2001; 48:513-157.

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14. Mokri B, Aksamit AJ, Atkinson JLD: Paradoxical postural headache in spontaneous CSF leaks. Cephalalgia 2004; 24:883886. 15. Mokri B: Low cerebrospinal fluid pressure syndromes. Neurol Clin North Am 2004; 22:55-74. 16. Mokri B: Spontaneous CSF leaks mimicking benign exertional headaches. Cephalalgia 2002; 22:780-783. 17. Mokri B, Atkinson JLD, Piepgras DG: Absent headaches despite CSF volume depletion (intracranial hypotension). Neurology 2000; 55:573-575. 18. Mokri B, Low PA: Orthostatic headaches without CSF leak in postural tachycardia syndrome. Neurology 2003; 61:980982. 19. Horton JC, Fishman RA: Neurovisual findings in the syndrome of spontaneous intracranial hypotension from dural cerebrospinal fluid leak. Ophthalmology 1994; 101:244-251. 20. Brady-McCreery K, Spiedel S, Hussein MAW, et al: Spontaneous intracranial hypotension with unique strabismus due to third and fourth cranial neuropathies. Binocul Vis Strabismus Q 2002; 17:43-48. 21. Follens I, Evans PA, Tassignon MJ: Combined fourth and sixth cranial nerve palsy after lumbar puncture: a rare complication. Bull Soc Belge Ophthalmol 2001; 281:29-33. 22. Warner GT: Spontaneous intracranial hypotension causing a partial third cranial nerve palsy: a novel observation. Cephalalgia 2002; 22:822-823. 23. Ferrante E, Svaino A, Briuschia A, et al: Transient oculomotor cranial nerve palsy in spontaneous intracranial hypotension. J Neurosurg Sci 1998; 42:177-179. 24. Yamamoto M, Suehiro T, Nakata H, et al: Primary low cerebrospinal fluid pressure syndrome associated with galactorrhea. Intern Med 1993; 32:228-321. 25. Portier F, de Minteguiaga C, Racy E, et al: Spontaneous intracranial hypotension: a rare cause of labyrinthine hydrops. Ann Otol Rhinol Laryngol 2002; 111:817-820. 26. Albayram S, Wasserman BA, Yousem DM, et al: Intracranial hypotension as a cause of radiculopathy from cervical epidural venous engorgement: case report. AJNR Am J Neuroradiol 2002; 23:618-621. 27. Beck CE, Rzk NW, Kiger LT, et al: Intracranial hypotension presenting with severe encephalopathy: case report. J Neurosurg 1998; 89:470-473. 28. Pleasure SJ, Abosch A, Friedman J, et al: Spontaneous intracranial hypotension resulting in stupor caused by diencephalic compression. Neurology 1998; 50:1854-1857. 29. Evans RW, Mokri B: Spontaneous intracranial hypotension resulting in coma. Headache 2002; 24:159-160. 30. Pakiam AS, Lee C, Lang AE: Intracranial hypotension with parkinsonism, ataxia, and bulbar weakness. Arch Neurol 1999; 56:869-872. 31. Nowak DA, Radiek SO, Zinner J, et al: Broadening of the clinical spectrum: unusual presentation of spontaneous cerebrospinal fluid hypovolemia: case report. J Neurosurg 2003; 98:903-907. 32. Hong M, Shah GV, Adams KM, et al: Spontaneous intracranial hypotension causing reversible frontotemporal dementia. Neurology 2002; 58:1285-1287. 33. Fay T: Mechanism of headache. Arch Neurol Psychiatry 1937; 37:471-474. 34. Mokri B: Cerebrospinal fluid volume depletion and its emerging clinical/imaging syndromes. Neurosurg Focus 2000; 9(1, article 6). 34a. Fishman RA: Cerebrospinal Fluid in Diseases of the Nervous System, 2nd ed. Philadelphia: WB Saunders, 1992, pp 84-87, 152-155. 35. Benamer M, Tainturier C, Graveleau P, et al: Radionuclide cisternography in spontaneous intracranial hypotension. Clin Nucl Med 1998; 23:150-151.

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36. Bai J, Yokoyama K, Kinuya S, et al: Radionuclide cisternography in intracranial hypotension syndrome. Ann Nucl Med 2002; 16:75-78. 37. Spell L, Boulin A, Tainturier C, et al: Neuroimaging features of spontaneous intracranial hypotension. Neuroradiology 2001; 43:622-627. 38. Leutmer PH, Mokri B: Dynamic CT myelography: a technique for localizing high-flow spinal cerebrospinal fluid leaks. AJNR Am J Neuroradiol 2003; 24:1711-1714. 39. Tali ET, Ercan N, Krumina G, et al: Intrathecal gadolinium (gadopentetate dimeglumine). Enhanced magnetic resonance myelography and cisternography. Results of a multicenter study. Invest Radiol 2002; 37:152-159. 40. Mokri B: The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology 2001; 56:1746-1748. 41. Fishman RA, Dillon WP: Dural enhancement and cerebral displacement secondary to intracranial hypotension. Neurology 1993; 43:609-611. 42. Vilmig ST, Titus F: Low cerebrospinal fluid pressure. In Olesem J, Tfelt-Hansen P, Welch KMA, eds: The Headache. New York: Raven Press, 1993, pp 687-695. 43. Gibson BE, Wedel DJ, Faust RJ, et al: Continuous epidural saline infusion for the treatment of low CSF pressure headache. Anesthesiology 1988; 48:789-791. 44. Aldrete JA: Persistent post-dural–puncture headache treated with epidural infusion of dextran. Headache 1994; 34:265-267. 45. Binder DK, Dillon WP, Fishman RA: Intrathecal saline infusion in the treatment of obtundation associated with spontaneous intracranial hypotension. Technical case report. Neurosurgery 2002; 51:830-837. 46. Duffy PJ, Crosby ET: The epidural blood patch. Resolving the controversies. Can J Anaesth 1999; 46:878-886. 47. Sencakova D, Mokri B, McClelland RL: The efficacy of epidural blood patch in spontaneous CSF leaks. Neurology 2001; 57:1921-1923. 48. Cru JBP, Gerritse BM, Van Dongen RTM, et al: Epidural fibrin glue injection stops persistent postdural puncture headache. Anesthesiology 1999; 91:576-577. 49. Scheivink WI, Morreale VM, Atkinson JLD, et al: Surgical treatment of spontaneous spinal cerebrospinal fluid leaks. J Neurosurg 1998; 88:243-246.

50. De Noronha RJ, Sharrack B, Hadjivassiliou M, et al: Subdural hematoma: a potentially serious consequence of spontaneous intracranial hypotension. J Neurol Neurosurg Psychiatry 2003; 74:752-755. 51. Augustin J, Proust F, Verdure L, et al: [Bilateral chronic subdural hematoma: spontaneous intracranial hypotension?]. Neurochirurgie 2003; 49:47-50. 52. Berroir S, Grabli D, Heran F, et al: Cerebral venous sinus thrombosis in two patients with spontaneous intracranial hypotension. Cerebrovasc Dis 2004; 17:9-12. 53. Mokri B: Intracranial hypertension after treatment of spontaneous cerebrospinal fluid leaks. Mayo Clin Proc 2002; 77:12411246. 54. Pannullo SC, Reich JB, Krol G, et al: MRI changes in intracranial hypotension. Neurology 1993; 43:919-926. 55. Atkinson JLD, Weinshenker BG, Miller GM, et al: Acquired Chiari I malformation secondary to spontaneous spinal cerebrospinal fluid leakage and chronic intracranial hypotension syndrome in seven cases. J Neurosurg 1988; 88:237-242. 56. Mokri B, Atkinson JLD: False pituitary tumor in CSF leaks. Neurology 2000; 55:573-575. 57. Alvarez-Linera J, Escribano J, Benito-Leon J, et al: Pituitary enlargement in patients with intracranial hypotension syndrome. Neurology 2000; 55:1895-1897. 58. Bakshi R, Mechtler LL, Kamran S, et al: MRI findings in lumbar puncture headache syndrome: abnormal duralmeningeal and dural venous sinus enhancement. Clin Imaging 1999; 23:73-76. 59. Rabin BM, Roychowdhury S, Meyer JR, et al: Spontaneous intracranial hypotension: spinal MRI findings. AJNR Am J Neuroradiol 1998; 19:1034-1039. 60. Chiapparini L, Farina L, D’Incerti L, et al: Spinal radiological findings in nine patients with spontaneous intracranial hypotension. Neuroradiology 2002; 44:143-150. 61. Moayeri NN, Henson JW, Schaefer PW, et al: Spinal dural enhancement on magnetic resonance imaging associated with spontaneous intracranial hypotension. J Neurosurg 1998; 88:912-918. 62. Mokri B: Headaches caused by decreased intracranial pressure: diagnosis and management. Curr Opin Neurol 2003; 16:319326.

CHAPTER

63

HYDROCEPHALUS, INCLUDING NORMAL-PRESSURE HYDROCEPHALUS ●

●

●

●

Noojan J. Kazemi, Andrew H. Kaye, and Elsdon Storey

Hydrocephalus is an abnormal enlargement of the ventricles caused by an excessive accumulation of cerebrospinal fluid (CSF) that results from a disturbance of its flow, absorption, or, uncommonly, secretion. Advances in neuroimaging and measurement of clinical CSF parameters have allowed early recognition of hydrocephalus and a better understanding of this pathological process. However, treatment of hydrocephalus has not been significantly affected by these advances, and various procedures for diversion of CSF from the ventricles to another body compartment continue to be the mainstay of surgical therapy.

CEREBROSPINAL FLUID PRODUCTION, FLOW, AND ABSORPTION Hydrocephalus is a disturbance of CSF circulation. Average CSF production is 0.44 mL/minute, corresponding to a total of about 500 mL/day1 (see Gjerris, 2000). The normal volume of CSF is approximately 150 mL. CSF is secreted by the epithelial cells of the choroid plexus, through an energy-dependent process involving ion pumps and enzyme systems.2 Specifically, an adenosine triphosphate–dependent, ouabain-sensitive sodium-potassium exchange pump at the apical (CSF) surface of the choroidal cells drives secretion, with water entering via aquaporin 1 channels, after the accumulation of sodium and chloride. The (passive) import of sodium into the choroidal cells from the pericapillary space is necessarily coupled with that of chloride, itself exchanged for bicarbonate. Carbonic anhydrase inhibitors, by reducing available bicarbonate, indirectly reduce CSF formation. CSF production is relatively independent of intracranial pressure (ICP), whereas, in patent CSF pathways and venous systems, CSF absorption is proportional to ICP. ICP is therefore determined by the pressure at which the rate of absorption rate balances the rate of production.1 CSF is also produced through transependymal bulk flow from the brain parenchyma itself.3,4 There is a marked diurnal variation in CSF production, with an increase at night to as high as twice diurnal values at 2:00 A.M.5 CSF flow and circulation are maintained by the arterial systolic pulsations of the brain and by continuous CSF secretion, as well as by changes in central venous pressure through respiration. These mechanisms combine as a “CSF pump.”

The arachnoid villi of the dural sinuses are traditionally regarded as the main site of CSF absorption.6 However, perineural lymphatic pathways, including those at the cribriform plate, and transependymal pathways, with absorption into capillaries or venules in the brain parenchyma, may also contribute.7,8 These alternative routes of CSF absorption may become increasingly important in hydrocephalus. The CSF circulation is shown in Figure 63–1. Flow is from the lateral ventricles through the foramen of Monro into the third ventricle, via the aqueduct of Sylvius into the fourth ventricle and then via its outlets (foramina of Luschka and Magendie) into the subarachnoid space and basal cisterns. CSF then circulates throughout the spinal subarachnoid space and basal cisterns up through the tentorial hiatus. It flows over the cerebral hemispheres and is absorbed at the sites identified previously.

HYDROCEPHALUS Classification and Etiology Hydrocephalus has a variety of etiologies, outlined in the following sections. In most cases, it is caused by obstruction of CSF circulation or reduced absorption of CSF. In rare cases, there is overproduction of CSF (see Kaye, 2005). Hydrocephalus can be classified into obstructive or communicating types. Obstructive hydrocephalus results from obstruction to CSF flow within the ventricles. In communicating hydrocephalus, as originally defined, there is communication between the ventricles and the lumbar CSF, but CSF flow over the surface of the brain is obstructed, or there is a failure of absorption of CSF.

Obstruction of Cerebrospinal Fluid Circulation Sites and common causes of obstruction within the ventricular system (obstructive hydrocephalus) are as follows: ■ Lateral ventricle obstruction by tumors, including basal

ganglia gliomas, and thalamic gliomas. ■ Third ventricle obstruction, caused by colloid cysts or other

tumors of the third ventricle.

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Scalp and skull

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Arachnoid granulation

■

Subarachnoid space Choroid plexus, lateral ventricle

Superior sagittal sinus

Choroid plexus, third ventricle

Figure 63–1.

Flow pattern of cerebrospinal fluid within the ventricles of the brain and the surrounding subarachnoid space. (From Burt AM: Textbook of Neuroanatomy. Philadelphia: WB Saunders, 1993, Fig. 9–4.)

Lateral ventricle Interventricular foramen of Monro

Superior cistern (cistern ambiens)

Third ventricle

Straight sinus

Interpeduncular cistern Chiasmatic cistern Cerebral aqueduct

Fourth ventricle

Pontine cistern

Choroid plexus, fourth ventricle

Foramen of Magendie Cerebellomedullary cistern (cisterna magna)

Subarachnoid space, spinal cord

■ Obstruction of the aqueduct of Sylvius, either by congenital

stenosis or secondary to lesions such as pineal tumors (Fig. 63–2). ■ Fourth ventricular obstruction caused by posterior fossa tumors, such as medulloblastomas, ependymomas, and acoustic neuromas. CSF flow may also be obstructed at the basal cisterns, often as a result of congenital developmental abnormalities, such as those associated with spina bifida.

Reduction of Cerebrospinal Fluid Absorption Reduced CSF absorption through the arachnoid granulations may be caused by ■ Infection or meningitis. This can lead to adhesive arach-

noiditis and permanent fibrosis of the CSF absorptive surfaces.9 This is a common cause of hydrocephalus in children. Newborns are particularly at risk because of severe inflammatory responses to leptomeningeal infection by agents, including Haemophilus influenzae, Streptococcus pneumoniae, and group B streptococci.10 ■ Cerebral hemorrhage. Both subarachnoid hemorrhage and intraventricular hemorrhage may result in adhesive arachnoiditis. Intraventricular hemorrhage is often associated with prematurity and is a frequent cause of hydrocephalus in infants.2 ■ Carcinomatous meningitis (see Pattisapu, 2001).11

■

Figure 63–2.

Hydrocephalus secondary to a pineal tumor. (Copyright Andrew H. Kaye.)

chapter 63 hydrocephalus, including normal-pressure hydrocephalus ■ Various other, uncommon causes of reduced CSF absorp-

tion, including maternal malnutrition and an increase in CSF viscosity caused by high CSF protein content.11

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Adult-Onset Hydrocephalus Adult onset hydrocephalus may be acute or chronic.

Acute adult hydrocephalus

Overproduction of Cerebrospinal Fluid Choroid plexus papillomas are rare ventricular tumors that can produce excessive volumes of CSF. In some cases, the hydrocephalus persists despite tumor resection, which is probably related to chronic pressure changes or proteinaceous debris within the spinal fluid. This tumor type is the only known cause of overproduction of CSF10,12 (see also Kaye, 2005.)

Clinical Presentation Infantile Hydrocephalus The incidence of infantile hydrocephalus is approximately 3 to 4 per 1000 births. Most cases arise from congenital abnormalities or from intraventricular hemorrhage associated with premature birth.10,13 The incidence of hydrocephalus occurring as an isolated congenital disorder is 1 to 1.5 per 1000 births. The most common congenital cause of hydrocephalus is stenosis of the aqueduct of Sylvius. The incidence of this abnormality is increased in children with a Chiari type II malformation. Hydrocephalus also occurs with spina bifida and myelomeningoceles. Its incidence in this context varies from 1.5 to 2.9 per 1000 births; however, this rate is decreasing with improved prevention through folate supplementation and prenatal screening for spina bifida (see Kaye, 2005). Congenital atresia of the foramina of Luschka and Magendie (Dandy-Walker cyst) is a rare cause of congenital hydrocephalus.11,14,15 Hydrocephalus can also occur as a component of numerous genetic disorders (see Online Mendelian Inheritance in Man at www.ncbi.nlm.gov/entrez/query.fcgi?db=OMIM for an up-to-date listing of such syndromes). The best characterized is X-linked, with aqueduct stenosis, and accompanied by mental retardation, caused by mutations in the L1CAM gene. The acquired forms of hydrocephalus occur most frequently after intracranial bleeding (particularly in premature infants), as a complication of meningitis, and secondary to tumors. The marked improvement in the survival of premature infants of very low birth weight has resulted in an increase in the numbers of infants with hydrocephalus resulting from perinatal intracranial hemorrhage.10 Major clinical features of hydrocephalus in infants include: 1. Failure to thrive. 2. Delayed developmental milestones. 3. Increased skull circumference (compared with normal growth curves). 4. Tense fontanelles. 5. “Cracked pot” sound on skull percussion. 6. A “copper-beaten” appearance of the skull on plain radiographs. 7. Transillumination of the cranial cavity with light. 8. Impaired conscious level and vomiting in severe cases. 9. The “setting-sun” appearance due to eyelid retraction and impaired upward gaze from third ventricular pressure on the midbrain tectum (Parinaud’s syndrome). 10. Thin scalp with dilated veins.

Acute hydrocephalus most frequently occurs in patients with mass lesions causing obstruction to the ventricular system; however, it can also arise from many other causes. There may also be acute deterioration in patients with long-standing (previously “compensated”) chronic hydrocephalus. The major presenting features of acute onset hydrocephalus are symptoms and signs of raised ICP. The most important feature is deterioration of conscious state. Other features that may be seen include: ■ ■ ■ ■ ■

headache vomiting papilledema sixth nerve palsy: a so called false localizing sign impairment of upward gaze, caused by compression of the rostral tectum by the enlarged third ventricle

Chronic adult hydrocephalus In chronic hydrocephalus, the symptoms of raised ICP are only very gradually progressive, and late diagnosis is common. Onset can occur in adolescence; deteriorating school performance is a result of headaches, failing mental function, memory loss, and behavioral disturbances. Endocrine abnormalities such as infantilism and precocious puberty can occur in association with chronic hydrocephalus in older children and adolescents, as a result of disturbance of the hypothalamus and possibly compression of the pituitary gland (see Kaye, 2005). If the condition is unrecognized, progressive visual failure occurs secondarily to papilledema with subsequent optic atrophy. One chronic form of hydrocephalus more commonly seen in older patients is normal-pressure hydrocephalus (NPH), described in a later section of this chapter.

Radiological Investigations The most important investigation is either a computed tomographic (CT) scan or magnetic resonance imaging (MRI) of the brain (Figs. 63–3 and 63–4), which demonstrate enlargement of the ventricles. The type and cause of the hydrocephalus may also be determined on imaging.12 For example, an enhanced CT scan or MRI may demonstrate a tumor obstructing the ventricles. In communicating hydrocephalus, all the ventricles are dilated, whereas in obstructive hydrocephalus caused by a lesion at or above the level of the aqueduct of Sylvius, the fourth ventricle is of normal size. MRI is particularly helpful when performed in the sagittal plane, because it may demonstrate aqueduct stenosis and lesions around the third ventricle. Flow of CSF through the aqueduct can be determined through the use of dedicated flow sequences on MRI.16,17 Ultrasonography through the open anterior fontanelle is useful in assessing ventricular size in infants and may obviate the need for repeated CT scans. Records of the head circumference and its comparison with body weight and length percentile charts are an integral part of the postnatal follow-up of any child.

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Surgical Management External drainage An external ventricular drain may be required as an urgent treatment for acute hydrocephalus associated with rapid deterioration of consciousness level, occurring with ventricular hemorrhage, acute infection, or a cerebral mass lesion.19 Because acute hydrocephalus is a surgical emergency, a temporary drain can be used. In addition to drainage of CSF, any intraventricular blood that is present can be drained, and ICP can be monitored as well.20,21

Internal shunting

■

Figure 63–3.

Brain computed tomographic scan, demonstrating hydrocephalus of the lateral and third ventricles, caused by aqueduct stenosis. (Copyright Andrew H. Kaye.)

In adult neurology, the question often arises as to whether dilated ventricles are a result of atrophy of the brain parenchyma (sometimes termed hydrocephalus ex vacuo) or are a result of acquired hydrocephalus (typically NPH, discussed later). A number of features are suggestive of a diagnosis of hydrocephalus rather than atrophy, including enlargement of the temporal horns (however, hippocampal and parahippocampal atrophy in Alzheimer’s disease can look similar), a convex third ventricle with dilated anterior recesses, an acute rather than obtuse angle between the frontal horns on axial scans, enlargement of the ventricles out of proportion to sulcal enlargement (or frank sulcal effacement), and periventricular smooth high signal on fluid-attenuated inversion recovery imaging (representing transependymal edema).18

Treatment Hydrocephalus is mainly treated surgically, by diverting CSF from the ventricular system to either the subarachnoid space or to another compartment within the body. Medical treatment is designed to manipulate the ICP while the need for a definitive shunting procedure is determined. If there is a rapid neurological deterioration in patients, a shunt or ventriculostomy may need to be performed as an emergency procedure to relieve raised ICP.

The usual method of CSF diversion is a ventriculoperitoneal shunt, in which a catheter is placed into the lateral ventricle and is connected through a burr hole to a valve, which is itself attached to a catheter threaded subcutaneously down to the abdomen and inserted into the peritoneal cavity (Fig. 63–5).22 Alternative sites for CSF drainage such as the atrium, pleural cavity, or ureter have now been largely abandoned except in special circumstances: for example, when prior peritoneal scarring or multiple abdominal operations leads to reduced absorptive capacity. It is occasionally necessary to place the shunt into the pleural cavity. A lumboperitoneal shunt involves drainage of the CSF from the lumbar theca rather than the ventricle. This type of shunt can be considered only in patients with communicating hydrocephalus. A catheter is threaded percutaneously into the lumbar theca and then tunneled subcutaneously to the anterior abdominal wall and placed into the peritoneal cavity. The practical advantage of this shunt system is that the brain is not manipulated. However, this shunt is not as reliable as a ventriculoperitoneal shunt and is more difficult to assess if the patient develops malfunction of a shunt.22,23 There is a wide variety of shunt systems with different conformations. However, almost all have been designed around valve systems that are designed to open at a particular level of ICP, although some, such as the Hakim and Sophy valves, are programmable transcutaneously. One of the major dilemmas for the neurosurgeon is the selection of the shunting system that best fits the needs of a particular patient.

Shunt Complications The principal causes of shunt malfunction are infection, occlusion, intracranial hemorrhage, and overdrainage. The risk of shunt failure is greatest within the first year of insertion, estimated to be 10% to 20%, depending on the underlying cause of the hydrocephalus. The subsequent failure rate is about 5% per year after this.24,25 Infection is a dreaded complication, especially in patients who are shunt dependent. The infection rate has significantly decreased as a result of improved surgical technique, more stringent asepsis, and possibly the use of antibioticimpregnated shunts, as well as intraoperative prophylactic antibiotics,26 and the overall infection rate in children is now about 3%.27 Important risk factors associated with infection include suboptimal surgical technique, prolonged operating time,28,29 multiple surgical revisions,29 skin abrasion,30 and ventriculoatrial shunting.28,31 Although the treatment of shunt infection is

chapter 63 hydrocephalus, including normal-pressure hydrocephalus

A ■

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B Figure 63–4.

Brain magnetic resonance imaging (MRI), demonstrating obstructive hydrocephalus in a patient. A, Axial T1-weighted MRI showing dilated lateral ventricles. B, Coronal T1-weighted MRI with arrow pointing to dilated third ventricle. (Copyright Andrew H. Kaye.)

complex, the most commonly accepted method involves immediate removal of the shunt device, along with ventriculostomy.19,28,29 One suggested protocol for the replacement of the shunt then requires a minimum of three negative CSF cultures and the absence of fever for at least 24 hours before reinsertion.19,28,32 Shunt occlusion may result from blockage of the ventricular catheter, malfunction or blockage of the valve, or obstruction of the peritoneal catheter. In the majority of cases, the site of occlusion is the ventricular portion.19 Shunt occlusion can arise from tissue debris, hematoma, or plugging by choroid plexus and ependymal cells.19,33 The slit-ventricle syndrome occurs when overdrainage leads to collapse of the ventricular walls surrounding the apertures at the ventricular end of the shunt.34 This then leads to repeated shunt blockage, because the CSF flow is intermittently obstructed through a cycle of ventricular collapse and dilatation. In this condition, raised ICP and marginally dilated ventricles are evident on CT scanning. This condition occurs predominantly but not exclusively in the pediatric population. In the case of burr hole–flushing valve systems, such as Pudenz-style valves, compression of the valve may be helpful in determining the position of obstruction. If the ventricular end is blocked, the contents of the pump can be expressed, but the valve refills only slowly. If the blockage lies in the valve or the peritoneal catheter, the valve is usually not compressible (see Kaye, 2005). Intracranial hemorrhage after the insertion of a ventriculoperitoneal shunt may occur either in the brain parenchyma

or in the subdural space. A subdural hematoma is particularly likely to occur in patients with long-standing severe hydrocephalus, in whom rapid decompression and collapse of the ventricles may result in tearing of the cortical bridging veins. Consequently, patients should remain initially supine after insertion of a shunt, to reduce the risk of sudden decompression occurring with elevation of the cerebral venous sinuses in relation to the right atrium. Attempts have been made to overcome this condition and that of shunt overdrainage with the use of an anti-siphon device that prevents excessive drainage with postural changes. However, antissiphon devices have also been associated with insufficient drainage and are not routinely used.35

Endoscopic surgery Third ventriculostomy, originally performed by Walter Dandy in 1922, was one of the first surgical treatments for hydrocephalus. Endoscopic third ventriculostomy through the lamina terminalis or the ventricular floor establishes communication between the ventricular system and the subarachnoid space.19,36 Therefore, the procedure is useful for patients with obstructive hydrocephalus who maintain a normal subarachnoid space: that is, predominantly those with aqueduct stenosis.19,36 In patients who undergo endoscopic third ventriculostomy, ICP occasionally remains high immediately after the procedure, with substantial reduction around the fourth day after surgery. This time course is indicative of the physiological changes that adjust CSF circulation to new flow conditions.37,38

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Headache Mannitol can also be used in combination with diuretics, such as furosemide, and/or carbonic anhydrase inhibitors, such as acetazolamide, which reduce CSF production22,42 (see also earlier section). There is no evidence that steroids are effective in the treatment of hydrocephalus, other than by reducing vasogenic edema associated with mass lesions that contribute to hydrocephalus.19

NORMAL-PRESSURE HYDROCEPHALUS

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Figure 63–5.

Pathway of ventriculoperitoneal shunt. (Copyright Andrew H. Kaye.)

Hydrocephalus with ventriculomegaly in a single lateral ventricle may arise secondarily to obstruction of the foramen of Monro. This condition may also be treated through endoscopic procedures such as fenestration of the septum pellucidum. Such a technique may preclude the need for shunting.19,39

Medical Treatment Medical management is occasionally used in patients with selflimited hydrocephalus. It includes both patient positioning and pharmaceutical means for the manipulation of ICP. The placement of the head at 30 degrees in relation to the rest of the body helps venous drainage and downward displacement of the CSF pressure40; because there are no valves in the dural sinus/jugular system, a flat or head-down posture results in transmitted right atrial backward pressure, raising venous backward pressure to CSF absorption, as well as intracranial venous volume. Restriction of fluid is indicated, because hypervolemia may contribute to raised ICP by elevating central venous pressure. Osmotic diuretics such as mannitol reduce ICP, with a maximum effect within the first 20 to 60 minutes. This effect results predominantly from the dehydration of brain parenchyma secondary to the increase of osmotic pressure in the vascular space (but not the brain),41 although hyperosmolality does reduce CSF formation to some extent.

NPH, first described by Hakim and Adams in 1965,43 is characterized by the triad of gait disturbance, urinary incontinence, and cognitive changes that may occasionally progress to a subcortical-type dementia (for a more detailed review, see Vanneste, 2000). Gait impairment and postural instability are usually the first symptoms of NPH and are also the most responsive to shunting.44 The gait is sometimes described as “apraxic,” but this constitutes very loose usage of the term; “frontal gait disorder” is probably preferable. The gait abnormalities themselves are not specific; slower velocity, shorter and more varying strides, reduced ground clearance and ankle dorsiflexion during the swing phase, and increased base of gait (step width) are all seen.45 There may be postural instability with frequent falls, gait ignition failure, or freezing (typically unresponsive to levodopa).44 Pyramidal signs, including extensor plantar responses, may be seen in the lower limbs.44 Urinary urgency, arising from impairment of frontal inhibitory pathways, is almost always present, but urinary incontinence is a relatively late feature.44 The detrusor muscle is unstable and hyperreflexic on urodynamic studies, but sphincteric function is normal.44,46 The urinary dysfunction may also improve on shunting.46 NPH is an uncommon cause of dementia.44 Indeed, dementia is an inapposite term for the cognitive impairment that may be seen in NPH, which often fails to meet any of the usual diagnostic criteria for dementia. Furthermore, some patients have no cognitive impairment at all. Dementia, if present, is the least likely of the three classic symptoms to improve with shunting,44 although cognitive improvement at 6 to 12 months, particularly in memory (word list acquisition) and psychomotor speed, has been convincingly demonstrated prospectively on careful testing.48 The pattern of cognitive impairment is typically that of subcortical dysfunction, with impaired working memory (the ability to manipulate data in consciousness) and slowed information processing and psychomotor speed.44 This is different from the profile in Alzheimer’s disease, and, indeed, visuoconstructional difficulties and executive dysfunction are predictive of a lower chance of cognitive improvement after shunting (and, by implication, a lower likelihood of actual NPH).48 The Mini-Mental State Examination is not particularly sensitive to the type of cognitive impairment observed in NPH,44 and measures such as the Trail Making Test or the HIV Dementia Scale,49,50 with their emphasis on aspects of cognition impaired by subcortical processes, are probably preferable screening tools.

Pathophysiology Although the condition is named normal pressure because lumbar puncture typically demonstrates a CSF pressure within

chapter 63 hydrocephalus, including normal-pressure hydrocephalus the normal range, there is experimental evidence that an initial stage of raised CSF pressure resulting from impaired CSF flow leads to ventricular enlargement.51 This disparity between ventricular and convexity CSF later diminishes, although episodic CSF pressure elevations persist, and continuous monitoring of the ICP frequently reveals abnormal ICP wave formation (predominantly so-called B waves), especially at night (see Edwards et al, 2004, and Kaye, 2005). Increased transmantle pressure and a “water hammer” effect from increased CSF pulse pressure waves have also been suggested as contributing factors.44 Neurological impairment in NPH is probably a result of progressive impairment of the periventricular microcirculation, with impaired perfusion secondary to compression and stretching of arterioles and venules.52 This may explain the increased prevalence of concomitant subcortical ischemic vascular disease and its etiological risk factors (such as hypertension) in NPH.45,54

Etiology Perhaps as much as 50% of NPH may be secondary to causes of impaired extraventricular CSF flow.44 The commonest cause is traumatic subarachnoid hemorrhage,53 but spontaneous subarachnoid hemorrhage and meningitis may also be responsible. The cause or causes of the remaining idiopathic cases are unknown; there is no histological evidence for the leptomeningeal “fibrosis” sometimes suggested as an explanation.44 Although secondary NPH can develop at any age, idiopathic NPH typically manifests in the sixth or seventh decades.54

Diagnosis The diagnosis of (shunt-responsive) NPH is difficult, because no single feature is reliably predictive of worthwhile improvement on shunting. Furthermore, although substantial improvement after shunting is seen in 30% to 50% of patients with idiopathic NPH, with 29% showing long-term improvement, there is a 6% to 8% chance of death or permanent neurological deficit.44,54 Factors associated with a greater likelihood of shunt responsiveness include a secondary cause (worthwhile improvement being seen in 50% to 70%), gait impairment preceding cognitive changes, and a short history of cognitive decline to only a mild or moderate level.44,54 Adverse factors include severe cognitive decline; cognitive decline as the first symptom; and MRI showing marked atrophy, extensive white matter involvement (subcortical ischemia), or both. Not surprisingly, in view of the difficulties of the diagnosis and the potential complications of shunting, numerous investigative techniques have been employed in an attempt to improve the accuracy of decision making in this area. Radiological investigations may demonstrate ventriculomegaly, and certain radiological features favor a diagnosis of hydrocephalus over atrophy (see “Radiological Investigations” section). However, in the presence of coexistent cortical atrophy, the diagnosis may be difficult to establish. Although marked atrophy is an adverse prognostic feature, moderate atrophy does not exclude the possibility of shunt responsiveness. CSF flow through the aqueduct is hyperdynamic in NPH, appearing as a flow void. This may be quantitated with phasecontrast cine–magnetic resonance flow imaging and has been claimed to be well correlated with findings of ICP monitoring

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and to be predictive of response to shunting with more than 80% accuracy,55,56 although other studies have failed to show this.44 Radioisotope cisternography may demonstrate disturbed flow, with stasis in the ventricles. However, the results are not successfully predictive of shunt outcome and do not add to the accuracy of clinical plus CT assessment.44,54 CSF drainage via single or repeated large-volume (40- to 50-mL) lumbar puncture or temporary external lumbar drainage catheter (for several days) may result in improvement in symptoms such as the gait disturbance and, more particularly, in gait velocity and stride length.45 The CSF tap test is widely used, probably because of its simplicity: It can be performed as an outpatient procedure. Although a positive result may be predictive of response to shunting, a negative result cannot be used to rule out the condition, because of its poor negative predictive value.44,54 Continuous lumbar CSF drainage may yield more accurately predictive results,57 but it has a number of potential complications44 and requires an inpatient stay. A number of more complicated assessment procedures have been reported. Continuous CSF pressure monitoring is not widely available, but there is good evidence that the frequent occurrence of B waves is predictive of shunt responsiveness, whereas their absence is a poor prognostic factor.44 Resistance to CSF outflow, measured during lumbar infusion of artificial CSF, produces very good diagnostic information when performed by some, but not all, clinicians.44,54 The technique apparently requires considerable technical expertise.

Treatment There are no randomized controlled trials of CSF shunting for NPH.58 A systematic review of the existing literature (largely small retrospective case series), published in 2001, revealed that 59% of patients (range, 24% to 100%) improved after shunting, with prolonged improvement in 29% (range, 10% to 100%), complications in 38% (range, 5% to 100%), a requirement for reoperation in 22% (range, 0% to 47%), and death or permanent neurological deficit in 6% (range, 0% to 35%).54 Vanneste reached similar conclusions in 2000.44 It is nevertheless apparent that symptoms may resolve almost completely if the correct diagnosis is made and shunting is successful. In such patients, the amount of CSF drainage and the valve pressure setting necessary to achieve therapeutic benefit vary considerably. Hence, it may be appropriate to use a valve that is adjustable, in order for the pressure and CSF drainage to be tailored to the patient’s physiological requirements. Such “programmable” valves have been used effectively in the treatment of NPH, but overshunting may lead to subdural hematoma. In some cases, a lumboperitoneal shunt may offer an effective solution.

K E Y

P O I N T S

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Hydrocephalus may be obstructive, as when there is obstruction to flow of CSF through the ventricular system, or it may be communicating, with either failure of CSF absorption or CSF obstruction outside the ventricles.

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Hydrocephalus can manifest acutely with deterioration of conscious state in children and adults.

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Treatment usually involves diverting CSF from the ventricles to another compartment with shunting or, increasingly, through an endoscopic technique to divert the CSF circulation.

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NPH occurs predominantly in older adults and is characterized by the triad of cognitive impairment, gait disturbance, and urinary urgency or incontinence. It may be improved by shunting, although the selection of patients most likely to benefit remains imperfect.

Suggested Reading Edwards RJ, Dombrowski SM, Luciano MG, et al: Chronic hydrocephalus in adults. Brain Pathol 2004; 14:325-336. Gjerris F: Hydrocephalus in adults. In Kaye AH, Black PMcL, eds: Operative Neurosurgery. London: Churchill Livingstone, 2000, pp 1235-1247. Kaye AH: Raised intracranial pressure and hydrocephalus. In: Essential Neurosurgery. Malden: Blackwell Publishing, 2005, pp 27-39. Pattisapu JV: Etiology and clinical course of hydrocephalus. Neurosurg Clin North Am 2001; 36:651-659. Vanneste JA: Diagnosis and management of normal pressure hydrocephalus. J Neurol 2000; 247:5-14.

References 1. Lorenzo AV, Page LK, Watters GV: Relationship between cerebrospinal fluid formation, absorption and pressure in human hydrocephalus. Brain 1970; 93:679-692. 2. Garton H, Piatt J: Hydrocephalus. Pediatr Clin North Am 2004; 51:305-325. 3. Milhorat TH, Hammock MK, Fenstermacher JD, et al: Cerebrospinal fluid production by the choroid plexus and brain. Science 1971; 173:330-332. 4. Pollay M, Stevens A, Estrada E, et al: Extracorporeal perfusion of choroid plexus. J Appl Physiol 1972; 32:612-617. 5. Nilsson C, Stahlberg F, Gideon P, et al: The nocturnal increase in CSF production is inhibited by a β1-receptor antagonist. Am J Physiol 1994; 267:R1445-R1448. 6. Weed LH: Forces concerned in the absorption of the cerebrospinal fluid. Am J Physiol 1935; 114:40-45. 7. Mollanji R, Bozanovic-Sosic R, Silver I, et al: Intracranial pressure accommodation is impaired by blocking pathways leading to extracranial lymphatics. Am J Physiol Regul Integr Comp Physiol 2001; 280:R1573-R1581. 8. Greitz D: Cerebrospinal fluid circulation and associated intracranial dynamics. A radiologic investigation using MR imaging and radionuclide cisternography. Acta Radiol Suppl 1993; 386:1-23. 9. Dodge PR, Swartz MN: Bacterial meningitis—a review of selective aspects. II. Special neurologic problems, postmeningitic complications and clinicopathological correlations. N Engl J Med 1965; 272:954. 10. Pattisapu JV: Etiology and clinical course of hydrocephalus. Neurosurg Clin North Am 2001; 36:651-659. 11. Squier MV: Pathological approach to the diagnosis of hydrocephalus. J Clin Pathol 1997; 50:181-186. 12. Bradley WG: Diagnostic tools in hydrocephalus. Neurosurg Clin North Am 2001; 36:661-684. 13. Rekate H: Treatment of Hydrocephalus. Principles and Practice of Pediatric Neurosurgery. New York: Thieme, 1999.

14. Raimondi AJ: Pediatric Neurosurgery: Theoretical Principles— Art of Surgical Techniques. New York: Springer Verlag, 1987. 15. Chahlavi A, El-Babaa SK, Luciano MG: Adult-onset hydrocephalus. Neurosurg Clin North Am 2001; 36:753-760. 16. Bradley WG, Kortman KE, Burgoyne B: Flowing cerebrospinal fluid in normal and hydrocephalic states: appearance on MR images. Radiology 1986; 159:611-616. 17. Citrin CM, Sherman JL, Gangarose RE, et al: Physiology of the CSF flow-void sign: modification by cardiac gating. AJNR Am J Neuroradiol 1987; 148:205-208. 18. Grossman RI, Yousem DM: Neurodegenerative diseases and hydrocephalus. In: Neuroradiology: The Requisites, 2nd ed. St. Louis: Mosby, 2003, pp 369-409. 19. Arriada N, Sotelo J: Review: treatment of hydrocephalus in adults. Surg Neurol 2002; 58:377-384. 20. Auer LM, Mokry M: Disturbed cerebrospinal fluid circulation after subarachnoid haemorrhage and acute aneurysm surgery. Neurosurgery 1990; 26:804-809. 21. Bogdahn U, Lau W, Hassel W, et al: Continuous-pressure controlled external ventricular draining for treatment of acute hydrocephalus—evaluation of risk factors. Neurosurgery 1992; 31:898-903. 22. Kanev OM, Park TS: The treatment of hydrocephalus. Neurosurg Clin North Am 1993; 4:611-624. 23. Bondurant CP, Jimenez DF: Epidemiology of cerebrospinal fluid shunting. Pediatr Neurosurg 1995; 23:254-258. 24. Drake JM, Saint-Rose C: The Shunt Book. New York: Blackwell Science, 1995. 25. Drake JM: Ventriculostomy for treatment of hydrocephalus. Neurosurg Clin North Am 1993; 4:657-666. 26. Choux M, Genitori L, Lang D, et al: Shunt implantation: reducing the incidence of shunt infection. J Neurosurg 1992; 77:875-880. 27. Davis SE, Levy ML, McComb JG, et al: Does age or other factors influence the incidence of ventriculoperitoneal shunt infections? Pediatr Neurosurg 1999; 30:253-257. 28. Moores LE, Ellenbogen RG: Cerebrospinal fluid shunt infections. In Osenbach RK, Zeidman SM, eds: Infections in Neurological Surgery. Diagnosis and Management. Philadelphia: Lippincott-Raven, 1999, pp 199-207. 29. Morrissette I, Gourdeau M, Francoeur J: CSF shunt infections: a fifteen-year experience with emphasis on management and outcome. Can J Neurol Sci 1993; 20:118-122. 30. Pople IK, Bayston R, Hayward RD: Infection of cerebrospinal fluid shunts in infants: a study of etiological factors. J Neurosurg 1992; 77:29-36. 31. Walters BC, Hoffman HJ, Hendrick EB, et al: Cerebrospinal fluid shunt infection. Influences on initial management and subsequent outcome. J Neurosurg 1984; 60:1014-1021. 32. Venes JL: Infections of CSF shunt and intracranial pressure monitoring devices. Infect Dis Clin North Am 1989; 3:289-299. 33. Del Bigio MR: Biological reactions to cerebrospinal fluid shunt devices: a review of cellular pathology. Neurosurgery 1998; 42:319-326. 34. Blount JP, Campbell JA, Haynes SJ: Complications in ventricular cerebrospinal fluid shunting. Neurosurg Clin North Am 1993; 4:633-656. 35. Czosnyka Z, Czosnyka M, Richards HK, et al: Posture-related overdrainage: comparison of the performance of 10 hydrocephalus shunts in vitro. Neurosurgery 1998; 42:327-333. 36. Grant JA, McLone DG: Third ventriculostomy: a review. Surg Neurol 1997; 47:210-212. 37. Schwartz TH, Ho B, Prestigiacomo CJ, et al: Ventricular volume following third ventriculostomy. J Neurosurg 1999; 91:20-25. 38. Schwartz TH, Yoon SS, Cutruzzola FW, et al: Third ventriculostomy: post-operative ventricular size and outcome. Minim Invasive Neurosurg 1996; 39:122-129.

chapter 63 hydrocephalus, including normal-pressure hydrocephalus 39. Gangemi M, Maiuri F, Donati PA, et al: Endoscopic surgery for monoventricular hydrocephalus. Surg Neurol 1999; 52:246251. 40. Sotelo J, Rubalcava MA, Gomez-Llata S: A new shunt for hydrocephalus that relies on CSF production rather than on ventricular pressure: initial clinical experiences. Surg Neurol 1995; 43:324-332. 41. James HE: Methodology for the control of intracranial pressure with hypertonic mannitol. Acta Neurochir (Wein) 1980; 51:161-172. 42. Gilmore H: Medical treatment of hydrocephalus. In Scott RM, ed: Hydrocephalus. Baltimore: William & Wilkins, 1990, pp 3746. 43. Hakim S, Adams RD: The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure: observations on cerebrospinal fluid hydrodynamics. J Neurol Sci 1965; 2:307-372. 44. Vanneste JAL: Diagnosis and management of normal-pressure hydrocephalus. J Neurol 2000; 247:5-14. 45. Stolze H, Kuhtz-Buschbeck JP, Drücke H, et al: Gait analysis in idiopathic normal pressure hydrocephalus—which parameters respond to the CSF tap test? Clin Neurophysiol 2000; 111:1678-1686. 46. Ahlberg J, Norlén L, Blomstrand C, et al: Outcome of shunt operation on urinary incontinence in normal pressure hydrocephalus predicted by lumbar puncture. J Neurol Neurosurg Psychiatry 1988; 51:105-108. 47. Duinkerke A, Williams MA, Rigamonti D, et al: Cognitive recovery in idiopathic normal pressure hydrocephalus after shunt. Cogn Behav Neurol 2004; 17:179-184. 48. Thomas G, McGirt MJ, Woodworth G, et al: Baseline neuropsychological profile and cognitive response to cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Disord 2005; 20:163-168.

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49. Power C, Selnes OA, Grim JA, et al: The HIV Dementia Scale: a rapid screening test. J AIDS 1995; 8:273-278. 50. van Harten B, Courant MN, Scheltens P, et al: Validation of the HIV Dementia Scale in an elderly cohort of patients with subcortical cognitive impairment caused by subcortical ischaemic vascular disease or a normal pressure hydrocephalus. Dement Geriatr Cogn Disord 2004; 18:109-114. 51. James AE, Burns B, Flor WF, et al: Pathophysiology of chronic communicating hydrocephalus in dogs (Canis familiaris): experimental studies. J Neurol Sci 1975; 24:151-178. 52. Del Bigio MR, Bruni JE: Changes in periventricular vasculature of rabbit brain following induction of hydrocephalus and after shunting. J Neurosurg 1988; 69:115-120. 53. Krauss JK, Regel JP, Vach W, et al: Vascular risk factors and arteriosclerotic disease in idiopathic normal-pressure hydrocephalus of the elderly. Stroke 1996; 27:24-29. 54. Hebb AO, Cusimano MD: Idiopathic normal pressure hydrocephalus: a systematic review of diagnosis and outcome. Neurosurgery 2001; 49:1166-1186. 55. Poca MA, Sahuquillo J, Busto M, et al: Agreement between CSF flow dynamics in MRI and ICP monitoring in the diagnosis of normal pressure hydrocephalus: sensitivity and specificity of CSF dynamics to predict outcome. Acta Neurochir Suppl 2002; 81:7-10. 56. Egeler-Peerdeman SM, Barkhof F, Walchenbach R, et al: Cine phase-contrast MR imaging in normal pressure hydrocephalus patients: relation to surgical outcome. Acta Neurochir (Wien) Suppl 1998; 71:340-342. 57. Marmarou A, Young HF, Aygok GA, et al: Diagnosis and management of idiopathic normal-pressure hydrocephalus: a prospective study in 151 patients. J Neurosurg 2005; 102:987-997. 58. Esmonde T, Cooke S: Shunting for normal pressure hydrocephalus (NPH). Cochrane Database Syst Rev 2005; (3):CD003157.

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TRIGEMINAL NEURALGIA AND OTHER FACIAL PAIN ●

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Alan Stiles and James Evans

HISTORICAL CONSIDERATIONS Trigeminal neuralgia has been identified in the medical literature as the classic neuropathic pain syndrome. The first known description was made in the first century A.D. by Aretaeus. Many physicians have penned descriptions of this affliction; the first to comprehensively describe it was John Locke in 1677. He described the condition of one such patient: “. . . such violent and exquisite torment, that it forced her to such cries and shrieks as you would expect from one upon the rack, to which I believe hers was an equal torment, which extended itself all over the right side of her face and mouth. When the fit came there was, to My Lady’s own expression of it, as it were a flash of fire all of a sudden shot into all of those parts, and at every one of those twitches which made her shriek out, her mouth was constantly drawn to the right side towards the right ear by repeated convulsive motions, which were constantly accompanied by her cries. . . . These violent fits terminated on a sudden and then My Lady seemed to be perfectly well. . . .” (John Locke and Kenneth Dewhurst)1,2 John Hunter (1728-1793), an English physiologist and surgeon, described trigeminal neuralgia in his A Practical Treatise on the Diseases of the Teeth in 1778 as follows: “This pain is seated in some one part of the Jaws. As simple pain demonstrates nothing, a Tooth is often suspected, and is perhaps drawn out; but still the pain continues, with this difference however, that it now seems to be in the root of the next Tooth: it is then supposed either by the patient or the operator, that the wrong Tooth was extracted; wherefore, that in which the pain now seems to be, is drawn, but with as little benefit. I have known cases of this kind, where all the Teeth of the affected side of the Jaw, have been drawn out, and the pain has continued in the Jaw; in others, it has had a different effect, the sensation of pain has become more diffused, and has at last, attacked the corresponding side of the tongue. In the first case, I have known it recommended to cut down upon the Jaw, and even to perforate and cauterize it, but all without effect. Hence it should appear, that the pain, in question, does not arise from any disease in the part, but entirely a nervous affection.”2a

William Osler (1849-1919) eloquently captured the clinical essence of trigeminal neuralgia in his own words: “In advanced cases the paroxysms follow one another rapidly and without assignable cause, and in the intervals the patient may never be quite free from pain. They are inaugurated by almost any form of external stimulus, by a draught of air, by movement of the facial muscles or of the tongue in speaking, by touching the skin, particularly over those points from which the pain seems to take its origin, by the act of swallowing, especially when the pain involves the mucous membrane field of distribution of the nerve. It is not a self-limited disease. In some instances the neuralgia reaches such a frightful intensity that it renders the patient’s life insupportable. In former years suicide was not an uncommon consequence.”3

THE CLINICAL SYNDROME Trigeminal neuralgia is a severe, almost exclusively unilateral, neuropathic pain located within the distribution of the trigeminal nerve, manifesting as paroxysmal, high-intensity, stabbing pain lasting seconds. Each attack may be followed by a refractory period, a period of relief that lasts seconds, minutes, or even hours. The burst of pain can occur spontaneously or can be triggered by stimulating a specific area of the face, known as a trigger zone. Trigger zones can be difficult to locate: They exist anywhere within the trigeminal distribution, including intraorally. The trigger zone is located in the same division of the trigeminal nerve as the pain. For this reason, patients characteristically avoid touching the face, washing, shaving, biting, chewing, or any other maneuver that stimulates the trigger zones and produces the pain.4 This avoidance is an invaluable clue to the diagnosis. With almost every other facial pain syndrome, patients massage, abrade, or apply heat and cold to the painful area; however, in trigeminal neuralgia, exactly the opposite occurs: Patients avoid any stimulation of the face or mouth. The pain is often characterized as an “electric shock” and is typically accompanied by a unilateral grimace; hence the designation tic douloureux. The pain may occur daily for weeks or months and then cease, sometimes for years, before returning; these intervals are known as periods of remission. Although this pain has been clinically described for centuries, the etiology of trigeminal neuralgia and the other

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cranial neuralgias is not fully understood. For years, the integrity of the myelin sheath has been the focal point of investigation; however, the only agreement is that there is a dysfunction of the trigeminal sensory system.5 Trigeminal neuralgia is classified as primary (idiopathic or type 1) or secondary (type 2), which is caused by compression or irritation, tumor, or disease, such as multiple sclerosis. Intermittent trigeminal neuralgia is uncommon in multiple sclerosis, with an incidence of between 1% and 2%.6,7 Conversely, the incidence of multiple sclerosis among patients with trigeminal neuralgia is approximately 3%. Patients with multiple sclerosis and trigeminal neuralgia typically have a history of classic trigeminal neuralgia, except that the trigeminal neuralgia appears at a younger age when patients have multiple sclerosis than when the disease occurs in its idiopathic form. Some patients with multiple sclerosis present with recurrent episodes of face pain that are generally long lasting, not stabbing or lancinating, and without associated trigger zones. These patients are assumed to not have true trigeminal neuralgia but a form of atypical facial pain. Trigeminal neuralgia can be the first manifestation of multiple sclerosis, but this is rare. Most patients who have trigeminal neuralgia in association with multiple sclerosis have significant physical signs of multiple sclerosis for many years before the facial pain begins. Most, for example, have paraparesis or paraplegia, which are disorders of sensory function. Bilateral trigeminal neuralgia occurs more often than expected in patients with multiple sclerosis. On rare occasions, trigeminal neuralgia may be a manifestation of brainstem disease and has been reported to result from pontine infarction.8 Neoplasms involving the trigeminal nerve generally produce constant neuropathic pain associated with sensory loss. Animal models have not been able to reproduce the pain of trigeminal neuralgia, and this limits clinicians’ ability to study the condition on a basic science level.

TESTING The diagnosis of trigeminal neuralgia is made from the clinical history. No medical testing is available to confirm the diagnosis; however, some authorities have mentioned a response to carbamazepine as being “diagnostic.” When the condition is found, magnetic resonance imaging is recommended, to rule out secondary causes. Typically, the neurologic examination findings are normal. Clinically, the onset of trigeminal neuralgia is generally after age 50, although it can occur at any age. Twice as many women as men are affected. There is usually no sensory loss in “idiopathic” trigeminal neuralgia as measured by ordinary sensory testing, although some clinicians refer to occasional sensory findings.9-12 In contrast, sensory disturbances in the distribution of the trigeminal nerve are relatively common when patients have multiple sclerosis or a structural lesion involving the trigeminal nerve or roots. Such sensory loss may even involve the inside of the mouth. Some clinicians have postulated that trigeminal neuralgia left untreated may become more atypical, accompanied by sensory disturbances and constant pain.13 Fromm and colleagues described 18 patients whose initial trigeminal pain was not characteristic of neuralgia but suggestive of a toothache or sinus pain and frequently lasted several hours.14 Often this pain was set off by jaw movements or by

drinking hot or cold liquids. Then, at a later time, ranging from several days to 12 years, more typical trigeminal neuralgia developed in the same general area as the initial pain. Six of these patients became pain free while taking carbamazepine or baclofen. The authors designated the problem pretrigeminal neuralgia. This neuralgia must be differentiated from trigeminal tumors, atypical facial pain, atypical odontalgia, and facial migraine, among other entities. A magnetic resonance imaging scan emphasizing the middle and posterior fossae is recommended as a diagnostic study in this situation. In rare instances, trigeminal neuralgia is accompanied by hemifacial spasm. The combination has been designated tic convulsif.15 Tic convulsif is characterized by periodic contractions of one side of the face, accompanied by great pain. It may be confused with the facial contortions on the involved side that can accompany the paroxysms of true trigeminal neuralgia.15 Painful tic convulsif is reported to be more severe in women than in men. It may begin in or around the orbicularis oculi as fine intermittent myokymia, with some spread thereafter into the muscles of the lower part of the face. On occasion, strong spasms involve all of the facial muscles on one side almost continuously. In rare cases, the face becomes weak, and some of the facial muscles atrophy. Tic convulsif is usually indicative of a tumor, ectatic dilation of the basilar artery, or a vascular malformation compressing the trigeminal and facial nerves.16

DIFFERENTIAL DIAGNOSIS Cluster-Tic Syndrome Both trigeminal neuralgia and cluster headache in the same individual have been termed “cluster-tic syndrome.”17-23 In these cases, the entities are treated separately, and each is controlled with different medications.17,24 In some cases, surgical decompression of the trigeminal nerve has been successful in alleviating the pain.25,26 Secondary causes must be considered in all of these cases.27,28

Glossopharyngeal Neuralgia Glossopharyngeal neuralgia is even rarer than trigeminal neuralgia. Clinically, the pain is similar to that of trigeminal neuralgia except that the distribution includes cranial nerve IX, the glossopharyngeal nerve, and the auricular (otic variety) and pharyngeal (cervical variety) branches of the vagus nerve. The pain is described as severe, transient, stabbing, or burning and is felt in the ear, the base of the tongue, the tonsillar fossa, or the area beneath the angle of the jaw, where it can be mistaken for trigeminal neuralgia affecting the third division of the trigeminal nerve. Rotation of the head, chewing, and swallowing may be triggers. The attacks of pain generally come in paroxysms and are lightning-like, but some patients have a more constant sore-throat sensation. Severe bradycardia, hypotension, or transient asystole, resulting in syncope or convulsions, may occur in some patients with glossopharyngeal neuralgia.29,30 Secondary causes must be ruled out with magnetic resonance imaging, and similar medications used for trigeminal neuralgia may work for this disorder as well.31-34

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(A) Is present daily and persists for most or all of the day, but may also appear attack-wise and with remissions. (B) Is confined at onset to a limited area on one or both sides of the face. May spread to the upper and lower jaws, or to a wider area of the face or neck. Can have different pain qualities and be perceived as superficial or deep, but is altogether poorly localized. (C) Is not associated with sensory loss or other physical signs, but often associated with dysesthesia. (D) Laboratory investigations, including X-rays of the face and jaws, do not demonstrate relevant abnormality. Comment: Pain may be initiated by operation or injury to the face, teeth, or gums but persists without any demonstrable cause. ■

Pfaffenrath and colleagues’40 suggested modifications of the International Headache Society diagnostic criteria for atypical facial pain.

Figure 64–1.

Geniculate Neuralgia

(I) Facial pain of unknown origin (atypical facial pain) (A) Neuropathic pain (i) Intermittent (a) Trigeminal neuralgia (b) Glossopharyngeal neuralgia (c) Occipital neuralgia (d) Nervus intermedius neuralgia, etc. (ii) Continuous (a) Trigeminal dysesthesia (b) Trigeminal dysesthesia, sympathetically maintained (B) Myofascial pain

Geniculate neuralgia is an extremely painful disorder affecting the sensory part of the seventh cranial nerve, described as trigeminal neuralgia of the nervus intermedius.35 The pain is described as a severe stabbing pain deep within the ear.

Idiopathic Stabbing Headache Idiopathic stabbing headache was first described as a “jabs and jolts syndrome” by Sjaastad and associates in 1979.36 Clinically, the pain is ultrashort, lasting less than one second; it can be located anywhere in the head but usually not in the facial region. It occurs as a stabbing pain or a series of recurring stabs. The frequency at which this occurs is extremely erratic, and there are no triggers. Idiopathic stabbing headache is a primary benign headache that is clinically relevant to the diagnosis of trigeminal neuralgia because nearly two thirds of patients find indomethacin to be helpful.37

Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing (SUNCT) SUNCT is characterized as unilateral moderate to severe orbital stabbing pain that lasts for 5 to 250 seconds and may occur up to 40 or more times a day.38 The pain is accompanied by autonomic features, the most significant of which are the tearing and conjunctival injection. Attacks have been known to be precipitated by chewing, by swallowing, by touching of the nose or eyelids, or by certain neck movements. SUNCT is refractory to medical management and does not respond to indomethacin or traditional treatments for trigeminal neuralgia.

■

Figure 64–2.

Graff-Radford’s proposed classification for features of facial pain of unknown cause.41

eating and talking, are rarely affected, except when pain is intraoral. Some patients have a history of trauma or a dental or surgical procedure before the onset of pain. In 1993, Pfaffenrath and colleagues suggested modifying the International Headache Society diagnostic criteria for atypical facial pain (Fig. 64–1).40 Because Pfaffenrath and colleagues’ criteria could apply to pain symptoms of separate etiologies, clinicians further categorize these pains according to their specialty in hopes of a better understanding of the condition, as well as in directing treatment toward correcting the cause of the pain. Facial pain of unknown cause was also categorized by Graff-Radford, who proposed an outline to help clinicians compartmentalize their clinical findings and to create a more uniform approach to treating these disorders with limited knowledge of the etiology (Fig. 64–2).41

TREATMENT

Atypical Facial Pain

Medical Management

Atypical facial pain or facial pain of unknown cause is characterized by a deep burning or aching sensation that is continuous and poorly localized. The pain may be unilateral or bilateral and does not necessarily follow the distribution of the peripheral nerves. It may be accompanied by sensory changes, such as allodynia, dysesthesia, and paresthesia.39 The usual sufferers are middle-aged women. Sleep and facial functions, such as

Initial management of trigeminal neuralgia is medical, and surgical therapy should be considered if medical treatment fails or cannot be tolerated and if secondary causes are found during the initial workup.42,43 It is important to discuss all treatment options with the patient early in the treatment process. A neurosurgical consultation early in the medical management of the patient allows the patient time to understand the multiple

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treatment options. It is impossible to predict which patients may not respond to medications, and so it is imperative that they understand treatment options before desperately seeking surgery after months of failed medication trials. Patient preference for either medical or surgical treatment as first-line therapy must be a part of the decision making as well, and this can be facilitated by having an early consultation with a neurosurgeon. The medical treatment of trigeminal and other cranial neuralgias is based on the capacity of the drugs employed to decrease nerve hyperexcitability either peripherally or centrally. Clinically pharmacological therapies are aimed at providing rapid and sustainable pain relief with a minimum of side effects. Unfortunately, the clinical trials in trigeminal neuralgia are not adequate to enable clinicians to fully understand each medication’s effect on this disease. Each patient is evaluated individually, with age, other systemic illnesses, and previous tried medications taken into account, and then medication choices can be made. Treatment is usually begun with an antiepileptic medication that has proved antineuralgic properties. The initial dose should be low and titrated up gradually, with close clinical monitoring, until either the maximum tolerated or pain-free dose is attained. For years, the “gold standard” has been carbamazepine, 100 mg to 200 mg two or three times daily, which provides benefit in more than 75% of patients. Today there are multiple medications from which to choose, but a response to carbamazepine has been described as being almost diagnostic. If, because of side effects, the initial medication is not tolerated, then an alternative medication is employed. For example, if carbamazepine is not tolerated, other medications, including baclofen,44-50 sodium valproate,51 gabapentin,52-56 lamotrigine,58,54-61 oxcarbazepine,62-66 topiramate,62,67,68 felbamate,69 zonisamide, vigabatrin, pregabalin, and clonazepam,70,71 are sometimes effective, but the therapeutic efficacy of most of these agents has not been adequately studied formally. There is a continuing need for new antineuralgic medications because of the limited tolerance and limited efficacy of the agents already available.5 Clinicians who have monitored patients with trigeminal neuralgia for more than a few years realize that the disease often goes into remission, and a patient may enter remission during a treatment course. If the patient has been without an attack for several months, the current medication can be slowly tapered, and if the patient has entered a remission period, no medication is necessary until the remission period ends. Patient compliance with medication regimens is essential to determine what benefit, if any, is being achieved. Patients with trigeminal neuralgia often taper the medication themselves when they achieve sustained pain relief, only to have the pain start again. It is important to counsel patients that they must be extremely compliant to achieve maximum benefit from medications. Botulinum toxin, specifically type A, has been described as effective in one case report and two open label studies.72-74 Placebo-controlled clinical trials are needed to confirm these findings. The methodology in regard to the exact location injected and the units used, as well as the duration of effect, needs to be better studied before treatment recommendations can be made. If only limited benefit is realized with one medication and side effects preclude additional dosing, a second medication

may be used. Often a combination of antiepileptic medications is needed to achieve freedom from pain. Surgical options may be considered after multiple medication failures, patient intolerance of side effects, or pain escalation. If the patient has consulted with a surgeon early in the treatment phase, this transition is easier for both the patient and the treating physicians, is achieved in a more timely manner, and limits the patient’s suffering.

Surgical Management Surgical treatment of trigeminal neuralgia is considered for patients in whom medical treatment has failed or who are unable to tolerate medical treatment because of side effects. Failure of medical therapy is a relative term that takes into account the number, action duration, maximal dosage, and intolerable side effects of medications used to attempt to control the pain of trigeminal neuralgia. On occasion, patients who are so significantly impaired by pain that they are rendered unable to chew or drink may be offered surgery before medical treatment fails, or even begins, so as to avoid the prolonged time that may be associated with titrating medications to therapeutic doses. Burchiel separated the diagnosis of trigeminal neuralgia into type 1 and type 2 trigeminal neuralgia.75 Type 2 cases are believed to be caused by arterial and/or venous compression of the trigeminal nerve in the area of transition from central to peripheral myelin (O-R zone) near the root entry zone of the nerve to the brainstem. Operations such as microvascular decompression directly address the underlying pathology. Microvascular decompression requires a general anesthetic and retrosigmoid craniotomy/craniectomy and therefore has historically been reserved for young, healthy patients. Other surgical interventions for trigeminal neuralgia are directed at other areas along the course of the trigeminal pathway, such as the trigeminal tracts in the brainstem, the retrogasserian nerve root, the trigeminal (gasserian) ganglion, or the peripheral trigeminal nerve distributions (V1 to V3). In addition to microvascular decompression, the most common surgical interventions for trigeminal neuralgia include Gamma knife radiosurgery (GKRS) treatment of the cisternal portion of the trigeminal nerve and percutaneous procedures directed at the gasserian ganglion or retrogasserian trigeminal nerve root. GKRS produces a radiation-induced injury of the trigeminal nerve. The percutaneous techniques include glycerol (retro-) gasserian rhizotomy, radiofrequency rhizotomy, and balloon compression of the trigeminal nerve. These procedures produce chemical, thermal, and physical injuries, respectively, to the trigeminal nerve or ganglion. The percutaneous procedures, GKRS, and microvascular decompression are addressed individually in the following few paragraphs. Percutaneous glycerol retrogasserian rhizotomy, otherwise known as a glycerol rhizotomy, is widely used for patients with type 1, type 2, or multiple sclerosis–related trigeminal neuralgia. Historically, this procedure was done with absolute alcohol75,76 or phenol and subsequently with a phenol/glycerol mixture injected into the trigeminal cistern. Subsequently, Hakanson reported that glycerol alone (without phenol) could relieve facial pain with less facial sensory loss.77 Approximately 90% of patients achieved complete/immediate pain relief after glycerol injection, and 77% maintained

chapter 64 trigeminal neuralgia and other facial pain good/excellent pain control over an approximately 10-year follow-up.78,79 Facial sensory loss may occur after glycerol rhizotomy; its severity is mild in 32% to 48%, moderate in 13%, and dense in 6%.79,80 Facial dysesthesia has been reported in approximately 2% to 22% of patients79 and anesthesia dolorosa in fewer than 1%.80 Transient perioral herpes outbreak is seen in 3.8% to 37% of patients up to 1 week postoperatively.79,80 Aseptic meningitis has been reported in 0.6% to 1.5% of patients.79,80 Intraoperative vasovagal response can occur in 15% to 20% of cases but does not usually necessitate aborting of the procedure.80,81 Percutaneous balloon compression of the trigeminal nerve is based on the concept of squeezing, manipulating, or compressing the trigeminal nerve. Surgeons in the 1950s and 1960s reported that patients in whom the trigeminal nerve was traumatized during surgery seemed to have a better outcome with regard to pain relief. In 1983, Mullan and Lichtor reported a percutaneous technique for compression of the gasserian ganglion by a Fogarty catheter.81 Percutaneous balloon compression is mainly indicated for patients with type 1 or 2 (classic or idiopathic) trigeminal neuralgia and multiple sclerosis–related trigeminal neuralgia. As with the other percutaneous techniques, pain relief after percutaneous balloon compression of the trigeminal nerve is usually immediate, but it can be delayed for as long as 1 week after the procedure. Numbness in the V2 and V3 distribution is the norm (occurring in approximately 80% of patients), but this is typically mild and often improves with time to the point at which it is not a major problem. Most patients have some degree of jaw or pterygoid weakness, which is usually mild and often resolves over weeks to months. In rare cases, the unilateral symptomatic jaw weakness is permanent. Because of the possibility of permanent jaw weakness, this procedure is contraindicated for patients with pre-existing contralateral jaw weakness, in whom “drop jaw” can result. Theoretically, this can also be a problem when this procedure is performed bilaterally, as in some patients with multiple sclerosis. Another, more rare complication is diplopia from compression of the fourth and sixth cranial nerves. Pain relief is immediate in 92% to 100% of patients, and reported recurrence rates are 19% to 32% over 5 to 20 years.82,83 Severe sensory loss or dysesthesias occur in 3% to 20% of patients.82,83 Masseter or jaw weakness occurs in 3% to 16% of patients, although most such cases improve or resolve after 1 year.82,83 Transient diplopia has been reported to occur in 1.6% of patients.83 To our knowledge, corneal anesthesia and anesthesia dolorosa have not been reported. Radiofrequency trigeminal (retrogasserian) rhizotomy is the third percutaneous procedure used to treat trigeminal neuralgia. The theory behind the use of radiofrequency to produce lesions of the trigeminal nerve is that it may selectively injure/destroy the unmyelinated or poorly myelinated nociceptive nerve fibers and spares the (heavily) myelinated fibers that serve touch, proprioception, and motor function. The procedure consists of a low-current stimulation to determine the proper position of the electrode at the offending trigeminal nerve fibers, followed by the creation of a permanent lesion with higher current to generate enough temperature to destroy the selected nerve fibers. A mild paresthesia in the distribution of the facial pain is the goal of radiofrequency treatment. Significant dysesthesia or sensory loss is reported in approximately 6% to 28% of patients,

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and loss of the corneal reflex may occur in 3% to 8% of patients, depending on the technique employed.84-86 In treatment of ophthalmic-distribution trigeminal neuralgia, the risk of corneal anesthesia and keratitis is certainly greater. Trigeminal nerve motor weakness has been reported after radiofrequency treatment in up to 14% of patients; however, it is most often mild and transient.84-86 The risk of anesthesia dolorosa has been reported in 0.5% to 1.6% of patients.84-86 Rare complications of carotid artery injury, stroke, diplopia, meningitis, seizures, and death have been reported. After radiofrequency, 88% to 99% of patients obtain immediate pain relief; recurrence rates of 20% to 27% over 9- to 14year follow-ups have been reported.84,85 Patients with a more dense sensory loss from the radiofrequency lesion have a lower recurrence rate but are subject to greater complications from dysesthesias and analgesia. One clinician reported that after recurrence of pain, 81% of patients obtained “good or excellent” pain relief with a second radiofrequency treatment.84 GKRS is the only noninvasive “surgical” treatment of trigeminal neuralgia. It is a same-day procedure that is performed in the outpatient radiosurgery center. Treatment delivery can take 45 to 90 minutes, depending on the age of the cobalt sources in the Gamma knife system being used. After the treatment is completed, the head frame is removed, and bandages are placed over the pin sites. The patient is observed in the radiosurgery center, to ensure complete recovery from any residual intravenous sedation, and is discharged the same day. Although GKRS can be performed with the patient under general anesthesia, a particular advantage of this technique is that it can be done with minimal intravenous sedation. Drawbacks are the cost of purchasing and maintaining the radiosurgery device and the latency period between treatment and facial pain improvement. Pain relief typically occurs after a latency period of 4 to 12 weeks after treatment; a range of 1 day to 13 months after treatment has been reported. The rates of pain control and recurrence of trigeminal neuralgia have been rather variable between reports. The variability probably results from the use of different pain scales to report outcome, followup duration, number of patients unavailable for follow-up, prior surgical treatment, the size and placement of the radiation dosage, and the maximal radiation dose. An excellent response (complete pain relief without medication) and a good response (50% to 90% improved pain with or without medication) can be achieved in 57% to 86% of patients at 1 year after radiosurgery treatment.87,88 As with most surgical treatments for trigeminal neuralgia, recurrence of facial pain after GKRS increases with time after treatment. Pain recurrence rates of 23%, 33%, 39%, and 44% have been reported 1, 2, 3, and 5 years after radiosurgery treatment, respectively.89,90 Mild or tolerable facial numbness occurs in 25% to 29% of patients, and significant numbness or dysesthesia can occur in 12% to 18% of patients.87,91 Complications of facial weakness, trigeminal motor weakness, and anesthesia dolorosa have not been reported. Greater doses of radiation are correlated with both higher rates of pain control and higher rates of complications, which consist mostly of facial numbness and bothersome facial dysesthesias. Patients who experience more facial numbness seem to have a better chance of pain control.87 Repeat radiosurgery for patients with recurrent pain has also been reported, with approximately 50% excellent or good pain relief and an increased rate of facial sensory loss within a limited followup period.92 Long-term follow-up studies of more than 10 to

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20 years are needed. The ideal Gamma knife dose and treatment strategy, as well as the role of other radiosurgery modalities, such as linear accelerator, remain to be determined. Microvascular decompression is the only medical or surgical intervention that directly addresses the presumed underlying pathology of classic trigeminal neuralgia: focal vascular compression of the trigeminal nerve near the brainstem root entry zone. The procedure requires a general anesthetic. With the use of the intraoperative microscope, the arachnoid membrane surrounding the trigeminal nerve is opened, and the nerve is explored from the brainstem to the entrance of the nerve to Meckel’s cave, where the trigeminal nerve ganglion (gasserian ganglion) is located. Under microscopic and endoscopic visualization, microdissection is performed to mobilize any arteries or veins compressing the trigeminal nerve. One or more Teflon sponges are then placed between the dissected blood vessels and the trigeminal nerve to prevent continued vascular compression of the trigeminal nerve. Veins compressing the trigeminal nerve can frequently be cauterized and divided. The compression is usually arterial, most commonly a branch of the superior cerebellar artery.93 However, venous compression alone or a combination of arterial and venous compression may also occur.94,95 When offending vessels are identified and decompressed, most patients obtain immediate relief from their facial pain. Rates of immediate pain relief as high as 90% to 98% have been reported after microvascular decompression. Barker and associates reported Jannetta’s large series of microvascular decompression procedures with up to 10-year follow-ups and defined outcome as “excellent” if at least 98% pain relief was achieved without the need for medications and “good” if at least 75% pain relief was achieved with only intermittent need for pain medication.96 In that series, an excellent or good early postoperative outcome was achieved in 98% of patients. This number decreased to approximately 84% and 67% after 1- and 10-year follow-ups, respectively. Tronnier and coworkers reported that 64% of their patients were pain free 20 years after microvascular decompression.97 Whether there is continued recurrence of facial pain with time is debated. Some clinicians have reported the majority of recurrences early (within 2 years after microvascular decompression), whereas others have reported a more constant rate of recurrence at 3.5% annually in one series.98,99 Surgical complications associated with microvascular decompression have diminished since brainstem and cranial nerve intraoperative neurophysiological monitoring has been in regular use. Complications of microvascular decompression may include cerebellar injury (0.45%), transient facial numbness (15%), mild persistent facial numbness (12%), significant facial numbness (1.6%), facial dysesthesia (0% to 3.5%), hearing loss (<1%), transient or permanent facial weakness (<1%), cerebrospinal fluid leakage (1.5% to 2.5%), hematoma (0.5%), and mortality (0.3%).93,100,101 Lower morbidity rates have been reported from high-volume centers and from surgeons performing a large number of procedures.101 When no arterial or venous compression is identified, the trigeminal nerve may be “traumatized” by stroking or squeezing the nerve with microinstruments; however, the resulting pain relief is only temporary, and such manipulation can be associated with trigeminal dysesthesias. Some surgeons have advocated partial sectioning of the sensory portion of the

trigeminal nerve for negative-yield explorations or during repeat surgical exploration of the nerve for recurrent pain after microvascular decompression.98,102,103 Since the 1960s, microvascular decompression has been the standard to which each of the other surgical treatments for classic trigeminal neuralgia has been compared. An experienced surgeon, however, may use any of the techniques outlined in this chapter to manage trigeminal neuralgia successfully. Each procedure has its own attributes and limitations, and the procedure selected must be based on the patient’s individual situation. Therefore, from a surgical perspective, patients with trigeminal neuralgia are probably best managed at centers that are able to offer a variety of interventions, including one or more percutaneous techniques, GKRS, and microvascular decompression.

COMPLICATIONS AND PITFALLS Diagnosis is extremely important in treating trigeminal neuralgia. A thorough history, clinical examination, and diagnostic imaging are the mainstays of diagnosing facial pain. When all information has been collected, a treatment plan can be formulated. Pharmacotherapy must be used in a systematic manner, with each medication tested to its fullest potential. All cases should be evaluated from both medical and surgical standpoints soon after the diagnosis is made, to ensure that the patient fully understands all available options before making his or her ultimate choice. Problems arise with one-sided approaches that may delay the ultimate goal of relieving the patient’s pain. Multiple therapies have been discussed here, and navigating these options has to be done on a case-by-case basis with the patient, medical specialists, and surgeons all working together.

CONCLUSIONS Arriving at a clinical diagnosis is often flawed and results in multiple consultations, misguided treatments, and, in some cases, unnecessary procedures; however, once a diagnosis of trigeminal neuralgia is made, many therapeutic options become available. The initial treatment is medical management, and with newer agents becoming available, there are many possibilities for monotherapy or even polypharmacy to greatly lessen the pain. Surgical interventions are available for patients who are intolerant of medication therapy or whose pain is extreme and unremitting. Secondary causes must always be explored, because if they are present, surgical interventions may supersede medical options. Each of the medications and each of the surgical procedures is associated with side effects and potential risks. These pitfalls must be weighed on the basis of each individual’s medical conditions, lifestyle, age, personal preference, and past therapies. The patient needs to be well informed about both the medical and the surgical options as soon as the diagnosis is made. This allows time for the treatment plan to be tailored to the individual. It is inappropriate to withhold surgical or medical options until one modality has failed. The patient should be required to consult with both surgeons and medical specialists as part of the initial evaluation. This allows for a planned therapeutic attack, leading to timely and effective pain relief.

chapter 64 trigeminal neuralgia and other facial pain

K E Y

P O I N T S

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For centuries, trigeminal neuralgia has been described clinically; however, the etiology of trigeminal neuralgia and the other cranial neuralgias remains elusive.

●

Initial management of trigeminal neuralgia is medical, and surgical therapy should be considered if medical treatment fails or cannot be tolerated and if secondary causes are found during the patient’s initial workup.

●

Failure of medical therapy is a relative term that takes into account the number, action duration, maximal dosage, and intolerable side effects of medications used to attempt to control the pain of trigeminal neuralgia.

●

Surgical interventions are available for patients who are intolerant of medication therapy or whose pain is extreme and unremitting. Secondary causes must be sought, because surgical interventions may supersede medical options if secondary causes are present.

●

All cases should be evaluated from both medical and surgical standpoints soon after the diagnosis is made, to ensure that the patient fully understands all available options before making his or her choice of treatment.

●

In some cases, a combination of medical and surgical interventions may be necessary to control the pain of trigeminal neuralgia.

Suggested Reading Fisher A, Zakrzewska JM, Patsalos PN: Trigeminal neuralgia: current treatments and future developments. Expert Opin Emerg Drugs 2003; 8:123-143. Lovely TJ, Jannetta PJ: Microvascular decompression for trigeminal neuralgia. Surgical technique and long-term results. Neurosurg Clin North Am 1997; 8:11-29.

References 1. Locke J: The celebrated Locke as a physician. Lancet 1829; 2:367. 2. Locke J: Letters to Dr. Mapletoft: Letter VII, Paris, 9th August 1677; Letters IX and X, Paris, 4th December 1677. Eur Magazine 1789; (February):85, 185-190, 186. 2a. Hunter J: A Practical Treatise on the Diseases of the Teeth: Intended as a Supplement to the Natural History of Those Parts. London: J. Johnson, 1778. 3. Osler W: The Principles and Practice of Medicine, 8th ed. New York: Appleton, 1912. 4. Dalessio DJ: Trigeminal neuralgia. A practical approach to treatment. Drugs 1982; 24:248-255. 5. Fisher A, Zakrzewska JM, Patsalos PN: Trigeminal neuralgia: current treatments and future developments. Expert Opin Emerg Drugs 2003; 8:123-143. 6. Harris W: Rare forms of paroxysmal trigeminal neuralgia, and their relation to disseminated sclerosis. BMJ 1950; 2:10151019. 7. Hooge JP, Redekop WK: Trigeminal neuralgia in multiple sclerosis. Neurology 1995; 45(7):1294-1296.

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8. Kim JS, Kang JH, Lee MC: Trigeminal neuralgia after pontine infarction. Neurology 1998; 51:1511-1512. 9. Dubner R, Sharav Y, Gracely RH, et al: Idiopathic trigeminal neuralgia: sensory features and pain mechanisms. Pain 1987; 31:23-33. 10. Terrence CF: Differential diagnosis of trigeminal neuralgia. In Fromm GH, ed: The Medical and Surgical Management of Trigeminal Neuralgia. New York: Futura, 1987, pp 43-63. 11. Nurmikko TJ: Altered cutaneous sensation in trigeminal neuralgia. Arch Neurol 1991; 48:523-527. 12. Sinay VJ, Bonamico LH, Dubrovsky A: Subclinical sensory abnormalities in trigeminal neuralgia. Cephalalgia 2003; 23:541-544. 13. Burchiel KJ, Slavin KV: On the natural history of trigeminal neuralgia. Neurosurgery 2000; 46:152-154. 14. Fromm GH, Graff-Radford SB, Terrence CF, et al: Pretrigeminal neuralgia. Neurology 1990; 40:1493-1495. 15. Cushing H: The major trigeminal neuralgias and their surgical treatment, based on experiences with 332 gasserian operations. The varieties of facial neuralgia. Am J Med Sci 1920; 160:157. 16. Harsh GR, Wilson CB, Hieshima GB, et al: Magnetic resonance imaging of vertebrobasilar ectasia in tic convulsif. Case report. J Neurosurg 1991; 74:999-1003. 17. Monzillo PH, Sanvito WL, Peres MF: [Cluster-tic syndrome: two case reports]. Arq Neuropsiquiatr 1996; 54:284-287. 18. Monzillo PH, Sanvito WL, Da Costa AR: Cluster-tic syndrome: report of five new cases. Arq Neuropsiquiatr 2000; 58:518521. 19. Mulleners WM, Verhagen WI: Cluster-tic syndrome. Neurology 1996; 47:302. 20. Alberca R, Ochoa JJ: Clustertic syndrome. Neurology 1994; 44:996-999. 21. Klimek A: Cluster-tic syndrome. Cephalalgia 1987; 7:161-162. 22. Klimek A. [“Cluster-tic syndrome” with a report of our case]. Neurol Neurochir Pol 1987; 21:161-163. 23. Watson P, Evans R: Cluster-tic syndrome. Headache 1985; 25:123-126. 24. Pascual J, Berciano J: Relief of cluster-tic syndrome by the combination of lithium and carbamazepine. Cephalalgia 1993; 13:205-206. 25. Kreiner M: Use of streptomycin-lidocaine injections in the treatment of the cluster-tic syndrome. Clinical perspectives and a case report. J Craniomaxillofac Surg 1996; 24:289-292. 26. Solomon S, Apfelbaum RI, Guglielmo KM: The cluster-tic syndrome and its surgical therapy. Cephalalgia 1985; 5:83-89. 27. Leone M, Curone M, Mea E, et al: Cluster-tic syndrome resolved by removal of pituitary adenoma: the first case. Cephalalgia 2004; 24:1088-1089. 28. Ochoa JJ, Alberca R, Canadillas F, et al: Cluster-tic syndrome and basilar artery ectasia: a case report. Headache 1993; 33:512-513. 29. Ferrante L, Artico M, Nardacci B, et al: Glossopharyngeal neuralgia with cardiac syncope. Neurosurgery 1995; 36:58-63. 30. Ozenci M, Karaoguz R, Conkbayir C, et al: Glossopharyngeal neuralgia with cardiac syncope treated by glossopharyngeal rhizotomy and microvascular decompression. Europace 2003; 5:149-152. 31. Luef G, Poewe W: Oxcarbazepine in glossopharyngeal neuralgia: clinical response and effect on serum lipids. Neurology 2004; 63:2447-2448. 32. Rozen TD: Trigeminal neuralgia and glossopharyngeal neuralgia. Neurol Clin 2004; 22:185-206. 33. Saviolo R, Fiasconaro G: Treatment of glossopharyngeal neuralgia by carbamazepine. Br Heart J 1987; 58:291-292. 34. Ringel RA, Roy EP III: Glossopharyngeal neuralgia: successful treatment with baclofen. Ann Neurol 1987; 21:514515.

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35. Pulec JL: Geniculate neuralgia: diagnosis and surgical management. Laryngoscope 1976; 86:955-964. 36. Sjaastad O, Egge K, Horven I, et al: Chronic paroxysmal hemicranial: mechanical precipitation of attacks. Headache 1979; 19:31-36. 37. Pareja JA, Ruiz J, de Isla C, et al: Idiopathic stabbing headache (jabs and jolts syndrome). Cephalalgia 1996; 16:93-96. 38. Sjaastad O, Saunte C, Salvesen R, et al: Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia 1989; 9:147-156. 39. Turp JC, Gobetti JP: Trigeminal neuralgia versus atypical facial pain. A review of the literature and case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81:424432. 40. Pfaffenrath V, Rath M, Pollmann W, et al: Atypical facial pain—application of the IHS criteria in a clinical sample. Cephalalgia 1993; 13(Suppl 12):84-88. 41. Graff-Radford SB: Facial pain. Curr Opin Neurol 2000; 13:291-296. 42. Zakrzewska JM, Patsalos PN: Drugs used in the management of trigeminal neuralgia. Oral Surg Oral Med Oral Pathol 1992; 74:439-450. 43. Sidebottom A, Maxwell S: The medical and surgical management of trigeminal neuralgia. J Clin Pharm Ther 1995; 20:3135. 44. Parmar BS, Shah KH, Gandhi IC: Baclofen in trigeminal neuralgia—a clinical trial. Indian J Dent Res 1989; 1:109113. 45. Fromm GH, Terrence CF: Comparison of L-baclofen and racemic baclofen in trigeminal neuralgia. Neurology 1987; 37:1725-1728. 46. Baker KA, Taylor JW, Lilly GE: Treatment of trigeminal neuralgia: use of baclofen in combination with carbamazepine. Clin Pharm 1985; 4:93-96. 47. Hershey LA: Baclofen in the treatment of neuralgia. Ann Intern Med 1984; 100:905-906. 48. Fromm GH, Terrence CF, Chattha AS: Baclofen in the treatment of trigeminal neuralgia: double-blind study and longterm follow-up. Ann Neurol 1984; 15:240-244. 49. Steardo L, Leo A, Marano E: Efficacy of baclofen in trigeminal neuralgia and some other painful conditions. A clinical trial. Eur Neurol 1984; 23:51-55. 50. Fromm GH, Terrence CF, Chattha AS, et al: Baclofen in trigeminal neuralgia: its effect on the spinal trigeminal nucleus: a pilot study. Arch Neurol 1980; 37:768-771. 51. Peiris JB, Perera GL, Devendra SV, et al: Sodium valproate in trigeminal neuralgia. Med J Aust 1980; 2:278. 52. Cheshire WP Jr: Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study. J Pain 2002; 3:137-142. 53. Solaro C, Messmer UM, Uccelli A, et al: Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis. Eur Neurol 2000; 44:45-48. 54. Carrazana EJ, Schachter SC: Alternative uses of lamotrigine and gabapentin in the treatment of trigeminal neuralgia. Neurology 1998; 50:1192. 55. Sist T, Filadora V, Miner M, et al: Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology 1997; 48:1467. 56. Khan OA: Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology 1998; 51:611-614. 57. Leandri M, Lundardi G, Inglese M, et al: Lamotrigine in trigeminal neuralgia secondary to multiple sclerosis. J Neurol 2000; 247:556-558. 58. Canavero S, Bonicalzi V: Lamotrigine control of trigeminal neuralgia: an expanded study. J Neurol 1997; 244:527.

59. Lunardi G, Leandri M, Albano C, et al: Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia. Neurology 1997; 48:1714-1717. 60. Canavero S, Bonicalzi V, Ferroli P, et al: Lamotrigine control of idiopathic trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1995; 59:646. 61. Zakrzewska JM, Chaudhry Z, Nurmikko TJ, et al: Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain 1997; 73:223-230. 62. Solaro C, Uccelli MM, Brichetto G, et al: Topiramate relieves idiopathic and symptomatic trigeminal neuralgia. J Pain Symptom Manage 2001; 21:367-368. 63. Zakrzewska JM, Patsalos PN: Long-term cohort study comparing medical (oxcarbazepine) and surgical management of intractable trigeminal neuralgia. Pain 2002; 95:259-266. 64. Grant SM, Faulds D: Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs 1992; 43:873-888. 65. Patsalos PN, Elyas AA, Zakrzewska JM: Protein binding of oxcarbazepine and its primary active metabolite, 10hydroxycarbazepine, in patients with trigeminal neuralgia. Eur J Clin Pharmacol 1990; 39:413-415. 66. Zakrzewska JM, Patsalos PN: Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1989; 52:472-476. 67. Gilron I, Booher SL, Rowan JS, et al: Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple crossover pilot study. Clin Neuropharmacol 2001; 24:109112. 68. Zvartau-Hind M, Din MU, Gilani A, et al: Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology 2000; 55:1587-1588. 69. Cheshire WP: Felbamate relieved trigeminal neuralgia. Clin J Pain 1995; 11:139-142. 70. Caccia MR: Clonazepam in facial neuralgia and cluster headache. Clinical and electrophysiological study. Eur Neurol 1975; 13:560-563. 71. de Negrotto OV, Dalmas JF, Negrotto A: [Trigeminal neuralgia. Treatment with clonazepam]. Acta Neurol Latinoam 1974; 20:139-145. 72. Piovesan EJ, Teive HG, Kowacs PA, et al: An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology 2005; 65:1306-1308. 73. Turk U, Ilhan S, Alp R, et al: Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol 2005; 28:161-162. 74. Allam N, Brasil-Neto JP, Brown G, et al: Injections of botulinum toxin type a produce pain alleviation in intractable trigeminal neuralgia. Clin J Pain 2005; 21:182-184. 75. Burchiel KJ: A new classification for facial pain. Neurosurgery 2003; 53:1164-1166. 76. Hartel F: Uber die intracranielle Injektionbehandlung der Trigeminusneuralgie. Med Klin 1914; 10:582. 77. Hakanson S: Trigeminal neuralgia treated by the injection of glycerol into the trigeminal cistern. Neurosurgery 1981; 9:638-646. 78. Young RF: Glycerol rhizolysis for treatment of trigeminal neuralgia. J Neurosurg 1988; 69:39-45. 79. Jho HD, Lunsford LD: Percutaneous retrogasserian glycerol rhizotomy. Current technique and results. Neurosurg Clin North Am 1997; 8:63-74. 80. Blomstedt PC, Bergenheim AT: Technical difficulties and perioperative complications of retrogasserian glycerol rhizotomy for trigeminal neuralgia. Stereotact Funct Neurosurg 2002; 79:168-181. 81. Mullan S, Lichtor T: Percutaneous microcompression of the trigeminal ganglion for trigeminal neuralgia. J Neurosurg 1983; 59:1007-1012.

chapter 64 trigeminal neuralgia and other facial pain 82. Brown JA, Gouda JJ: Percutaneous balloon compression of the trigeminal nerve. Neurosurg Clin North Am 1997; 8:5362. 83. Skirving DJ, Dan NG: A 20-year review of percutaneous balloon compression of the trigeminal ganglion. J Neurosurg 2001; 94:913-917. 84. Nugent GR: Radiofrequency treatment of trigeminal neuralgia using a cordotomy-type electrode. A method. Neurosurg Clin North Am 1997; 8:41-52. 85. Taha JM, Tew JM Jr: Treatment of trigeminal neuralgia by percutaneous radiofrequency rhizotomy. Neurosurg Clin North Am 1997; 8:31-39. 86. Kanpolat Y, Savas A, Bekar A, et al: Percutaneous controlled radiofrequency trigeminal rhizotomy for the treatment of idiopathic trigeminal neuralgia: 25-year experience with 1,600 patients. Neurosurgery 2001; 48:524-532. 87. Pollock BE, Phuong LK, Gorman DA, et al: Stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2002; 97:347-353. 88. Kondziolka D, Lunsford LD, Flickinger JC: Stereotactic radiosurgery for the treatment of trigeminal neuralgia. Clin J Pain 2002; 18:42-47. 89. Petit JH, Herman JM, Nagda S, et al: Radiosurgical treatment of trigeminal neuralgia: evaluating quality of life and treatment outcomes. Int J Radiat Oncol Biol Phys 2003; 56:11471153. 90. Maesawa S, Salame C, Flickinger JC, et al: Clinical outcomes after stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2001; 94:14-20. 91. McNatt SA, Yu C, Giannotta SL, et al: Gamma knife radiosurgery for trigeminal neuralgia. Neurosurgery 2005; 56:1295-1301. 92. Hasegawa T, Kondziolka D, Spiro R, et al: Repeat radiosurgery for refractory trigeminal neuralgia. Neurosurgery 2002; 50:494-500.

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93. Lovely TJ, Jannetta PJ: Microvascular decompression for trigeminal neuralgia. Surgical technique and long-term results. Neurosurg Clin North Am 1997; 8:11-29. 94. Lee SH, Levy EI, Scarrow AM, et al: Recurrent trigeminal neuralgia attributable to veins after microvascular decompression. Neurosurgery 2000; 46:356-361. 95. Matsushima T, Huynh-Le P, Miyazono M: Trigeminal neuralgia caused by venous compression. Neurosurgery 2004; 55:334-337. 96. Barker FG, Jannetta PJ, Bissonette DJ, et al: The long-term outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med 1996; 334:1077-1083. 97. Tronnier VM, Rasche D, Hamer J, et al: Treatment of idiopathic trigeminal neuralgia: comparison of long-term outcome after radiofrequency rhizotomy and microvascular decompression. Neurosurgery 2001; 48:1261-1267. 98. Burchiel KJ, Clarke H, Haglund M, et al: Long-term efficacy of microvascular decompression in trigeminal neuralgia. J Neurosurg 1988; 69:35-38. 99. Elias WJ, Burchiel KJ: Trigeminal neuralgia and other neuropathic pain syndromes of the head and face. Curr Pain Headache Rep 2002; 6:115-124. 100. McLaughlin MR, Jannetta PJ, Clyde BL, et al: Microvascular decompression of cranial nerves: lessons learned after 4400 operations. J Neurosurg 1999; 90:1-8. 101. Kalkanis SN, Eskandar EN, Carter BS, et al: Microvascular decompression surgery in the United States, 1996 to 2000: mortality rates, morbidity rates, and the effects of hospital and surgeon volumes. Neurosurgery 2003; 52:1251-1261. 102. Klun B: Microvascular decompression and partial sensory rhizotomy in the treatment of trigeminal neuralgia: personal experience with 220 patients. Neurosurgery 1992; 30:49-52. 103. Bederson JB, Wilson CB: Evaluation of microvascular decompression and partial sensory rhizotomy in 252 cases of trigeminal neuralgia. J Neurosurg 1989; 71:359-367.

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65

ALZHEIMER’S DISEASE ●

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●

●

John G. F. Boughey and Neill R. Graff-Radford

DEFINITION Alzheimer’s disease is a progressive degenerative brain disease defined by both a clinical component and a pathological component: 1. Clinically, the disease involves impairment of anterograde memory (learning of new information) and deficits in one or several of the following cognitive domains: language, visuospatial ability, praxis, and executive functioning. 2. Histopathologically, there are senile plaques composed of extracellular amyloid deposits and neurofibrillary tangles composed of intraneuronal tau protein. Two excellent sets of clinical criteria with good clinicopathological correlation are given in Tables 65–1 and 65–2.

EPIDEMIOLOGY Alzheimer’s disease causes about 70% of cases of dementia.1 In the Framingham study, Bachman and colleagues reported that the incidence of Alzheimer’s disease increases from 3.5 per 1000 per year between the ages of 65 and 69 to 72.8 per 1000 per year at ages 85 to 89 years.2 Bachman and colleagues found that the incidence of Alzheimer’s disease doubled with every 5 years of age. Alzheimer’s disease prevalence is low among persons younger than 65 years, but it increases to 10% to 30% among persons older than 85.3 In 1907, when Alois Alzheimer described the disease named for him, mean life expectancy was 42 years; since then, in developed countries, life expectancy has greatly increased.4 For example, in the United States, 50% of persons are expected to live past 75 and 25% past 85. With age being such an important risk factor and so many people living into the high-risk ages, the prevalence of Alzheimer’s disease has greatly increased; it is 4.5 million in the United States, according to the 2000 census.5 Because of the staggering cost of caring for patients with Alzheimer’s disease (estimated at $100 billion annually in the United States6) and because “baby boomers” are reaching the high-risk period, it can be argued strongly that the world should invest heavily in finding ways to prevent this disease. In fact, Brookmeyer and associates7 predicted that if the onset of the disease is delayed by an average of 5 years, the present-day U.S. prevalence of Alzheimer’s disease would

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remain constant (at 4.5 million) instead of increasing to an anticipated 13 million in 2047.

RISK AND PUTATIVE PROTECTIVE FACTORS FOR ALZHEIMER’S DISEASE Table 65–3 lists risk factors and Table 65–4 the putative protective factors for Alzheimer’s disease.

Genetics Researchers have discovered three genes that, if they have undergone mutation, cause early-onset Alzheimer’s disease. Although they account for fewer than 1% of cases of Alzheimer’s disease, the knowledge of how these genes probably cause Alzheimer’s disease has been helpful for understanding the pathogenesis of this disease. Table 65–5 lists the genes from the Alzheimer Disease and Frontotemporal Dementia Mutation Database and tabulates for each gene the number of mutations and families reported. By January 2005, investigators had reported a total 404 families with 189 different mutations in these three genes. Many studies (summarized in a meta-analysis by Farrer and colleagues8) have established apolipoprotein E4 (ApoE4) as an important risk factor for Alzheimer’s disease. ApoE is a lipoprotein that carries cholesterol and has three forms: ApoE2, ApoE3, and ApoE4. The allelic prevalence varies in different ethnic groups. Table 65–6 reveals that persons with Alzheimer’s disease have a higher prevalence of ApoE4. Although community-based studies do not show ApoE4 as a risk factor for Alzheimer’s disease in African American patients, a large clinically based series reported that it is.9 One of Graff-Radford and colleagues’ findings in that report was that ApoE4 is associated with early-onset risk. In the community-based studies, there were very few early-onset cases. There is strong evidence that there are undiscovered genetic factors related to late-onset Alzheimer’s disease.10 Although many candidate genes have been proposed, associations have often not been reproduced by different investigators. Therefore, researchers are working on refining their techniques and working out the pitfalls in case-control methods. Difficulties in the studies so far include heterogeneity of populations, the

chapter 65 alzheimer’s disease T A B L E 65–1. DSM-IV Criteria for Alzheimer’s Disease

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T A B L E 65–2. NINCDS-ARDA Criteria for Diagnosis of Probable Alzheimer’s Disease Criteria for Diagnosis of Probable Alzheimer’s Disease Dementia established by clinical examination, documented by a standard test of cognitive function (e.g., Mini-Mental State Examination, Blessed Dementia Scale), and confirmed by neuropsychological tests Significant deficiencies in two or more areas of cognition: for example, word comprehension and task-completion ability Progressive deterioration of memory and other cognitive functions No loss of consciousness Onset from age 40 to 90, typically after 65 No other diseases or disorders that could account for the loss of memory and cognition Support for Diagnosis of Probable Alzheimer’s Disease Progressive deterioration of specific cognitive functions: language (aphasia), motor skills (apraxia), and perception (agnosia) Impaired activities of daily living and altered patterns of behavior A family history of similar problems, particularly if confirmed by neurological testing The following laboratory results: Normal cerebrospinal fluid (lumbar puncture test) Normal EEG test of brain activity Evidence of cerebral atrophy in a series of CT scans

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 1994); HIV, human immunodeficiency virus.

possible complexity of the factors causing the disease, the fact that many of the controls are probably susceptible themselves to the disease (as they age), and the fact that the effect size is too small to detect with the size of the samples used.

Amyloid Hypothesis When Alzheimer described the disease histologically, he noted the deposition of a substance in the form of plaques that was later identified as the β amyloid protein (Aβ) by Glenner and Wong.11 Subsequently, many lines of evidence have led to the hypothesis that brain deposition of this protein causes Alzheimer’s disease. Aβ is produced by the sequential proteolytic cleavage of the amyloid precursor protein (APP) (coded for on chromosome 21) by enzymes known as secretases (Fig. 65–1). There are two pathways, one of which leads to the production of the Aβ peptides and the other does not. In the amyloidogenic pathway, the first step involves cleavage of APP at the amino terminus by an aspartyl protease (β-secretase), resulting in the formation of soluble APPβ and a membrane-bound APP carboxy terminal fragment (CTF-β). Cleavage of this CTF-β by γ-secretase results in the formation of Aβ peptides of variable length, including a 40–amino acid Aβ peptide (Aβ40) and a 42–amino acid peptide (Aβ42). The γ-secretase cleavage requires the presence of two membrane proteases, presenilin-1 and presenilin-2; it is thought that these presenilins may, in fact, be part of the γsecretase complex. Other parts of this complex include nicastrin, a type I membrane protein that was originally purified, and two other membrane proteins, APH-1 and PEN-2. Together with presenilin, these three components appear to constitute a minimal functional γ-secretase complex. It is also possible that

Other Features Consistent with Alzheimer’s Disease Plateaus in the course of illness progression CT findings normal for the person’s age Associated symptoms, including depression, insomnia, incontinence, delusions, hallucinations, weight loss, sexual problems, and significant verbal, emotional, and physical outbursts Other neurological abnormalities, especially in advanced disease, including increased muscle tone and a shuffling gait Features That Decrease the Likelihood of Alzheimer’s Disease Sudden onset Such early symptoms as seizures, gait problems, and loss of vision and coordination Adapted from McKhann, G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS/ADRDA Work Group under the auspices of Department of Health Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939-944. CT, computed tomographic; EEG, electroencephalographic; NINCDS-ADRDA, National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease Related Disorders Association.

T A B L E 65–3. Risk Factors for Alzheimer’s Disease Aging32 Family history33 Genetic factors Genes causing early-onset Alzheimer’s disease34-36 Apolipoprotein E37 Late-onset genes38 Down’s syndrome39 Female gender40 Head injury41,42 Factors associated with atherosclerosis43: Apolipoprotein E Hypercholesterolemia Hypertension Diabetes mellitus Hyperhomocysteinemia Metabolic syndrome Smoking Systemic inflammation Increased fat intake Obesity

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T A B L E 65–4. Putative Protective Factors for Alzheimer’s Disease

T A B L E 65–7. Factors Supporting the Amyloid Hypothesis as a Cause of Alzheimer’s Disease

Education44 Keeping the mind active during aging45 Nonsteroidal anti-inflammatory drugs46 Statins47 Hormone replacement therapy48,49 Homocysteine50 Niacin51 Physical activity52 Alcohol53 Fat intake54 Antioxidants55

Amyloid is found in the brains of all patients with Alzheimer’s disease. There are three genes that, if they have undergone mutation, cause early-onset Alzheimer’s disease, and all increase Aβ production.56 Patients with Down’s syndrome have trisomy 21. The amyloid precursor protein gene is located on chromosome 21. All patients with Down’s syndrome who live past age 40 develop the pathology of Alzheimer’s disease. Also, patients with Down’s syndrome have an increased production of Aβ from birth.57-59 Patients with apolipoprotein E4 have increased deposition of Aβ in their brains.60 First-degree relatives of patients with Alzheimer’s disease have increased plasma Aβ levels.61 When the double-transgenic mouse model of TG2576 (the amyloid mouse) is crossed with the P301L (tau mouse), the tau pathology is accelerated in their progeny; this is evidence of an interaction between these two fundamental pathological processes of Alzheimer’s disease.16 Low levels of CSF Aβ are correlated with Alzheimer’s disease, which suggests that the disease occurs when large amounts of Aβ have been deposited in the brain.

T A B L E 65–5. Genes Related to Early-Onset Alzheimer’s Disease Gene

Number of Mutations

Total Number of Families Published

18 141 10

48 280 16

APP PSEN1 PSEN2

Aβ, β amyloid protein; CSF, cerebrospinal fluid.

Based on Alzheimer Disease and Frontotemporal Dementia Mutation Database, maintained by Marc Cruts and Roos Rademakers (www.molgen.ua.ac.be/ADMutations/, accessed June 8, 2006). APP, amyloid precursor protein; PSEN, presenilin.

APP PROCESSING ␣-pathway

P3

CTF␥ ␥-secretase

sAPP␣

T A B L E 65–6. Apolipoprotein (Apo) Genotypes Related to Alzheimer’s Disease in Different Population Groups, Divided into Cases and Controls Ethnic Group

ApoE2 (%)

ApoE3 (%)

ApoE4 (%)

White Cases Controls

3.9 8.4

59.4 77.9

36.7 13.7

African American Cases Controls

7.7 8.3

59.1 72.7

32.2 19.0

Japanese Cases Controls

2.7 4.2

69.5 86.9

27.8 8.9

CTF␤ ␣-secretase APP ␤-secretase

sAPP␤

CTF␤ ␥-secretase

␤-pathway ■

Based on data from Farrer LA, Cupples LA, Haines JL, et al: Effects of age, sex and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997; 278:1349-1356.

these “accessory” proteins are involved in substrate presentation. The non-amyloidogenic pathway is carried out by αsecretase, which cleaves the APP protein in the middle into soluble APPα and CTF-β, which, in turn, is cleaved by γ-secretase into P3 and CTF-γ (see Fig. 65–1). Aβ42 constitutes less than 10% of the total secreted amyloid protein and is more likely to form fibrils than is Aβ40.12 Aβ42 is found in the brains of all patients with Alzheimer’s disease, and Aβ40 is found in two thirds.13 Both accumulate as extracellular plaques consisting of β-pleated sheets, but before plaque formation, a combination of fewer Aβ molecules form

A␤

CTF␥

Figure 65–1. Amyloid precursor protein (APP) processing pathways. CTF, carboxy terminal fragment; sAPP, soluble amyloid precursor protein.

oligomers, which may mediate the neurotoxic effects seen in Alzheimer’s disease. Understanding of the generation of Aβ has proceeded at a faster rate than understanding of the pathways that lead to neuronal dysfunction and death. Aβ may be neurotoxic directly, may initiate inflammation, may cause oxidative stress, or may affect calcium homeostasis, or it may lead to a combination of all of these. Table 65–7 lists some of these factors supporting the amyloid hypothesis.

Arguments against the Amyloid Hypothesis The anatomical distribution of the tangle (tau) pathology is correlated better with the clinical picture than is distribution of the Aβ plaques.14 Because of this, some authors have proposed that tau, rather than Aβ, is the cause of the disease. Furthermore, there are many patients with extensive Aβ plaques who

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Figure 65–3. Dense amyloid core plaque stained with thioflavin S.

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Figure 65–2. Gross appearance of the brain of a patient with Alzheimer’s disease. (Courtesy of Dennis Dickson, MD.)

are not demented. Their condition is referred to as pathological aging in the literature.15 Because tau pathology is accelerated in the double-transgenic mouse16 by Aβ deposition, it is possible that Aβ deposition may be partially responsible for the tau pathology. Also, in the cases of early-onset Alzheimer’s disease, such as those caused by the APP mutations, there is typical tau pathology. Thus, attributing the disease exclusively to either the Aβ or tau pathology is incorrect; rather, it is much more likely that both pathological processes are involved. In further studies, investigators should work out how they interact, rather than ruling out one. Other important factors found in brains of patients with Alzheimer’s disease, including oxidative stress, inflammation, cell loss, apoptosis, and synapse loss, are probably crucial in the pathogenesis. Many researchers are studying the relationship of these factors to the amyloid and tau pathology.

PATHOLOGY A definite diagnosis of Alzheimer’s dementia requires histopathological confirmation. On gross examination (Fig. 65–2), the brain weight varies between 900 and 1200 g. The loss of brain weight is more marked in the early-onset form of Alzheimer’s disease, whereas in the late-onset form, there is substantial overlap with findings in age-matched controls. The temporal and parietal lobes

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Figure 65–4. Neurofibrillary tangle stained with thioflavin S. (Courtesy of Dennis Dickson, MD.)

are more affected than the frontal lobes. The occipital lobe may be involved but is relatively spared in the majority of cases. On examination, the diseased brain may appear normal in the early stages, but closer inspection usually reveals temporal lobe atrophy of its medial aspect with thinning of the cortical mantle. Other features include enlargement of the third and lateral ventricles, normal pigmentation of the substantia nigra, and pallor of the locus ceruleus in advanced cases. Alteration of pigmentation in the brainstem raises the possibility of other neurodegenerative disease (for example, Lewy body disease). In Alzheimer’s disease, the olfactory bulb is consistently smaller than expected. On occasion, atrophy may be asymmetrical or focal, and cases of Alzheimer’s disease with focal atrophy may be associated with focal cognitive deficits such as progressive aphasia, Balint’s syndrome, or frontal dementia. The cardinal histopathological lesions of Alzheimer’s disease are senile plaques composed of extracellular amyloid deposits (Fig. 65–3) and neurofibrillary tangles composed of intraneuronal tau protein aggregates (Fig. 65–4). The plaques are

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detected by silver staining (Bielschowsky stain) or by specialized amyloid stains (thioflavin S, Congo red). The β-pleated sheet structure gives rise to the staining characteristics: that is, a birefringent apple-green appearance under polarized light. Some plaques are “diffuse,” and these may be present in nondemented individuals. These plaques do not have dystrophic neurites (nerve endings containing tau protein), unlike the “cored” or neuritic plaques, which have deposition of extracellular amyloid surrounded by tau-containing neurites. Neurofibrillary tangles are filamentous inclusions that are intraneuronal and are composed of hyperphosphorylated aggregates of the microtubule-associated protein tau. Electron microscopy reveals that tau consists of a paired helical filament structure. Initially, tau collects in the nucleus and becomes aggregated into paired helical filaments, after which it may be attached to the protein ubiquitin. These tau tangles affect the microtubules, which, in turn, interfere with neuronal and dendrite/axonal transport. The neurons die and are surrounded by phagocytes removing the debris. Eventually, the tangles become extracellular structures.

PATHOLOGICAL DIAGNOSTIC CRITERIA Histopathological changes seen in patients with Alzheimer’s disease may overlap with changes seen in a nondemented elderly persons and may occur in patients with other neurodegenerative disease also (e.g., vascular dementia, Lewy body dementia). Different criteria are used in pathological assessment of Alzheimer’s disease cases. They include the Khachaturian criteria, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Guidelines for the Diagnosis of Alzheimer’s Disease, and the National Institute on Aging–Ronald and Nancy Reagan Institute criteria.17-19 With the Khachaturian criteria, the age of the patient is compared with the density of the plaque count; this method tends to overestimate the frequency of Alzheimer’s disease. Major limitations of this method include a failure to distinguish between different plaque types and the lack of inclusion of neurofibrillary tangles in the analysis. The CERAD criteria, which are widely used and reproducible between different laboratories,20 involve the following: ■ Macroscopic features, such as brain weight, regional

Nonamyloid Components of Plaques The plaques show evidence of inflammation because they are associated with activated microglial cells, components of the complement cascade, α1-antichymotrypsin, and proinflammatory cytokines. Activated microglial cells are most evident in dense-cored plaques, especially those with Aβ40. In addition to their association with senile plaques, microglial cells are activated throughout the brain in Alzheimer’s disease. Microglial activation is correlated with the degree of neurofibrillary degeneration in the hippocampus, where microglial cells may be responding to neuronal and synaptic degeneration and loss. Other nonamyloid components localized to senile plaques include components of the extracellular matrix, such as proteoglycans, amyloid P component (a serum-derived protein, present in virtually all types of amyloid deposits, which has been shown to accumulate in cerebral amyloid deposits, possibly because of alterations in the blood-brain barrier), and apolipoprotein E, which is derived from astrocytes. Other Alzheimer’s disease–associated pathological changes include the following: 1. Amyloid deposition in cerebral blood vessels, known as cerebral amyloid angiopathy. 2. Granulovacuolar degeneration, which is not specific for Alzheimer’s disease; it is also seen in very old persons (>100 years old), in amyotrophic lateral sclerosis dementia– parkinsonism complex of Guam, in Down’s syndrome, and in Pick’s disease. It is characterized by a vesicle with a central basophilic granule that is seen in the hippocampal pyramidal neurons. 3. Hirano bodies, seen in the area CA1 and the subiculum of the hippocampus, consisting of eosinophilic rod-shaped structures lying adjacent to pyramidal neurons. 4. Increased density of fibrous astrocytes in the cortex of patients with Alzheimer’s disease. 5. Neuronal and synaptic loss in the area CA1 layer of the hippocampus, entorhinal cortex, anterior olfactory nucleus, and amygdala.

atrophy, atrophy of specific regions (hippocampus, entorhinal cortex), the presence of lacunar infarcts, and the color of the substantia nigra and locus ceruleus. ■ Histological sampling/staining of six anatomical regions (middle frontal gyrus, superior and middle temporal gyri, anterior cingulate gyrus, inferior parietal lobule, hippocampus and entorhinal cortex, and the midbrain, including the substantia nigra). These are stained with one or more of the following: hematoxylin/eosin, thioflavin S, a silver stain (modified Bielschowsky), and/or Congo red. The CERAD classification involves three steps: (1) A semiquantitative measurement of neuritic plaque density is made and then compared with a reference, and the score is categorized as none, sparse, moderate, or frequent. (2) Maximal plaque densities in the frontal, temporal, and parietal neocortex are then compared with references for the patient’s age, which yields an age-related plaque score. (3) This score is then used in conjunction with the patient’s history (absence/presence of dementia) to allow categorization of the patient as normal or as having possible, probable, or definite Alzheimer’s disease. As with the Khachaturian method, the classification in the CERAD criteria does not use neurofibrillary tangle density. The National Institute on Aging–Ronald and Nancy Reagan Institute criteria19 constitute the most recent attempt to solve the disadvantages of the first two classifications. They include an age-related plaque score and a staging of neurofibrillary tangle pathology (Braak’s staging system); combination of the two yields an estimate of the likelihood that a patient has Alzheimer’s disease, which is classified as high, intermediate, or low probability.

DIAGNOSIS The diagnosis of Alzheimer’s disease in the clinic comprises a complete history, a complete physical examination, laboratory studies, special tests, and a neuropsychological evaluation. There is a continuum from normal aging to dementia, including an entity called mild cognitive impairment. Published criteria for this entity are listed in Table 65–8.

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T A B L E 65–8. Criteria for Mild Cognitive Impairment

T A B L E 65–9. Causes of Dementia

Memory complaint, preferably corroborated by informant Impaired memory function for age and education Preserved general cognitive function Intact activities of daily living Not demented

Degenerative Causes Alzheimer’s disease Lewy body dementia Frontotemporal dementia Semantic dementia Progressive nonfluent aphasia Frontal dementia Corticobasal degeneration Progressive supranuclear palsy Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) Multiple system atrophy Huntington’s disease

Adapted from Petersen RC, Smith GE, Waring SC, et al: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303-308.

History With regard to patients with dementia, physicians should obtain the history from both the patient and an informant. In fact, patients with memory difficulty may be unaware and even deny they have a memory problem (this is a form of anosognosia). While documenting the history, physicians should keep the differential diagnosis in mind (see Table 65–9).

Determine the Presenting Symptoms The informant should be asked with an open-ended question what abnormalities he or she noticed first and later, with specific questions to evaluate specific cognitive areas, such as memory.

Time Course of the Disease The informant should be asked when he or she first noticed a problem and whether the onset was slowly progressive, stepwise, or acute.

Cognitive Domains Memory The informant should be asked whether he or she thinks the patient has a memory problem and, if so, whether he or she can give specific examples. Then the clinician should probe specifically with such questions as “Does the patient ask the same questions again?” “Does the patient have trouble remembering details of recent events?” “Does the patient often not know the date?”

Visuospatial Domain The clinician should ask whether the patient becomes lost while driving, has difficulty recognizing faces, or becomes lost in his or her own home or other familiar environments.

Attention and Concentration

Vascular Causes Single strategic stroke Multiple strokes Multiple lacunes Small-vessel disease Amyloid angiopathy Subarachnoid hemorrhage Superficial siderosis Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Subdural hematoma Infectious Causes Acute and chronic fungal and bacterial meningitis Sequelae of herpes encephalitis Other viral encephalitis HIV dementia Neurosyphilis Transmissible prion disease Subacute sclerosing panencephalitis (SSPE) Progressive multifocal leukoencephalopathy (PML) Toxic, Metabolic, and Deficiency States Medications (see Table 65–10) Glue sniffing Heavy metal ingestion (e.g., mercury) Hypothyroidism Vitamins B12, B1, B3, and B6 deficiency Organ failure (heart, lung, kidney, and liver) Substance abuse Psychiatric Causes Mood disorder (depression, bipolar disorder) Psychosis Neurological Diseases Anoxic brain damage Cerebral neoplasm Limbic encephalitis Head injury Multiple sclerosis Hydrocephalus Leukodystrophies (e.g., metachromatic leukodystrophy and adrenoleukodystrophy) Hashimoto’s encephalopathy Nonvasculitic autoimmune inflammatory meningoencephalitis HIV, human immunodeficiency virus.

The clinician should ask whether the patient has a short attention span or limited ability to concentrate.

Language

Executive Function

The clinician should ask whether the patient has developed a problem finding words or has a problem understanding conversation.

The clinician should ask whether the patient has difficulty making decisions or cannot complete tasks such as keeping a checkbook or organizing papers for tax preparation.

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Psychiatric Factors

Hearing and Vision

Depression

The clinician should ask whether the patient has deficits in these areas.

The clinician should ask whether the patient has lost interest in, or enjoyment of, activities; has become withdrawn; has gained or lost weight; is not taking part in usual activities; and whether he or she is sad or tearful, experiencing a feeling of hopelessness.

Family History

Anxiety The clinician should ask whether the patient is upset when separated from the caregiver and whether the patient is nervous, short of breath, sighing, or tense.

Psychosis The clinician should determine whether the patient experiences visual or auditory hallucinations or exhibits delusions. Patients often believe that a loved one is stealing from them, or they may suspect that burglars are trying to steal their property.

The clinician should document a careful history regarding dementia in first-degree relatives (parents, siblings, and children) and any other relatives (grandparents, aunts, uncles, and cousins). If there is a history of dementia, the clinician should try to establish age at onset, symptoms, and specific etiology (e.g., through an autopsy report).

Medical Conditions That May Contribute to Dementia The clinician should inquire about whether the patient has cardiovascular disease; hypertension; hypercholesterolemia; vitamin B12 deficiency; diabetes; thyroid disease; incontinence; and substance abuse, including alcohol, tobacco, and recreational drugs.

Personality Change and Disinhibition The clinician should ask the informant whether the patient’s personality has changed and, if so, what has the informant noticed. The informant should discuss whether the patient shows anger or acts in a socially inappropriate way and whether the patient uses coarse language or exhibits inappropriate behavior in public.

Agitation and Aggression The clinician should ask whether the patient is stubborn and whether he or she refuses help from others.

Sleep This history is best obtained from a bed partner. The clinician should ask whether the patient has difficulty going to sleep, waking up, and going back to sleep; whether the patient is sleeping in the daytime; whether the patient snores or experiences apneic episodes; whether the patient has dream enactment behavior (acts out dreams at night); and whether the patient sleeps during the day and remains awake at night.

Activities of Daily Living These activities can be divided into personal and instrumental. Examples of personal activities are the patient’s ability to perform bathroom chores and to dress. Examples of instrumental activities are using the telephone, writing a check, and preparing a meal.

Motor Activities The clinician should determine whether the patient has trouble walking, writing, cutting food, or swallowing; whether the patient has fallen; and whether the patient has a tremor.

Other Neurological Disease That May Contribute to Dementia A history of stroke, head injury, seizures, multiple sclerosis, or cardiac arrest should be documented.

Medication The patient and the informant should provide a list of all prescription and nonprescription medications and food supplements. Ideally, they should bring the containers of all the medications and supplements the patient takes. Table 65–10 contains a list of medications that may adversely affect cognition.

Examination The patient should be given a standardized short mental status test such as the Kokmen Short Test of Mental Status21 (Table 65–11) or the Mini-Mental State Examination. The patient’s anterograde memory should be tested with questions about current events or famous persons, such as the current president’s and spouse’s names and previous presidents’ and their spouses’ names. (The clinician should be sure that the patient has been exposed to this information.) Cardiovascular risk factors such as hypertension, arterial bruits, arrhythmias, and heart murmurs should be documented. A full neurological examination should be completed. The clinician should pay attention to focal deficits such as visual field cuts, pareses, sensory loss, and ataxia. The patient should be evaluated for extrapyramidal problems such as hypokinesia, rigidity, masklike facies, micrographia, and glabellar reflex. The clinician should examine the patient’s gait, looking at step size, speed of walking, arm swing, ability to turn, and how far apart the legs are. The presence of palmomental and snout reflexes is not particularly helpful because these are common in normal individuals. The grasp reflex occurs late in the course of the disease.

chapter 65 alzheimer’s disease T A B L E 65–10. Drugs with Cognitive Side Effects Antibiotics Anticholinergic agents

Anticonvulsants

Psychotropic agents

Analgesics Cardiac agents

Hypnotics

Antineoplastic agents Antiparkinson agents

Miscellaneous agents

Metronidazole Antihistamines (diphenhydramine) Atropine Benztropine Oxybutynin Tolterodine Phenobarbital Phenytoin Carbamazepine Valproic acid Levetiracetam Topiramate Antidepressants Heterocyclic (imipramine, nortriptyline) Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors (citalopram) Other (bupropion, trazodone) Antimanic agents Lithium Typical antipsychotics Haloperidol, phenothiazines Atypical antipsychotics Quetiapine, olanzapine, risperidone Amphetamines Dextroamphetamine, methylphenidate Opiates Salicylates β Blockers Clonidine Digitalis Methyldopa Reserpine Procainamide Barbiturates Benzodiazepines Nonbenzodiazepines (zolpidem) Chloral hydrate 5-Fluorouracil Amantadine Levodopa Dopamine agonists Selegiline Tacrolimus Cyclosporine Cimetidine Bromides Alcohol Baclofen Metoclopramide

Special Tests The following tests are indicated in the routine workup of a patient with dementia: laboratory studies, including complete blood cell count and measurements of thyroid-stimulating hormone; measurement of vitamin B12 levels and rapid plasma reagin; and neuroimaging (computed tomography or magnetic resonance imaging). Other tests may be ordered as the clinical situation dictates. It is not necessary to perform a lumbar puncture in the routine assessment of a patient with Alzheimer’s disease,22,23 but it is indicated when the following diagnoses are suspected: central nervous system infection, prion disease, hydrocephalus in the presence of normal cerebrospinal fluid pressure, and nonvasculitic autoimmune inflammatory menin-

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goencephalitis. Lumbar puncture should also be considered when the manifestation is atypical: for example, a rapid course or an early onset of disease. Cerebrospinal fluid can be analyzed for markers of prion disease (14-3-3 protein) and Alzheimer’s disease (tau protein and Aβ42 level). Neuropsychological test results characterize the pattern of cognitive strengths and weaknesses and, in this way, are helpful in diagnosis. Also, in mild cases, they may be helpful in determining whether there is a deficit. Furthermore, these tests may be used in monitoring patients over time.

Markers for Alzheimer’s Disease “The Consensus Report of the Working Group on: ‘Molecular and Biochemical Markers of Alzheimer’s Disease’ ”24 proposed that a diagnostic marker for Alzheimer’s disease should have as many of the following features as possible: ■ Ability to detect a fundamental feature of Alzheimer’s

neuropathology. ■ Validated in neuropathologically confirmed cases. ■ Precise (able to detect Alzheimer’s disease early in its course ■ ■ ■ ■

and distinguish it from other dementias). Reliable. Noninvasive. Simple to perform. Inexpensive.

To date, the best markers are a combination of the cerebrospinal fluid tau and Aβ42 proteins. In an excellent review, Blennow and Hampel25 noted that the sensitivity and specificity for cerebrospinal fluid tau protein are 81% and 90%, respectively, and for cerebrospinal fluid Aβ42 protein, they are 86% and 90%, respectively. Because the clinical diagnosis without these markers is close to these measurements, most physicians do not use these markers routinely.

Neuroimaging: Distinguishing Cognitively Normal Individuals from Patients with Alzheimer’s Disease Different imaging modalities can be used to distinguish cognitively normal persons from patients with Alzheimer’s disease. Using structural magnetic resonance imaging, investigators have reported that with regard to visual inspection of anteromedial temporal lobe atrophy, the sensitivity is 83% to 85% and the specificity is 96% to 98% in distinguishing clinically diagnosed Alzheimer’s disease cases from controls.26 It is possible to outline the areas of interest in Alzheimer’s disease, such as the hippocampus, and to use this information for diagnosis and longitudinal change over time. An example is shown in Figure 65–5. Temporal and parietal hypometabolism characterize the typical positron emission tomography (PET) findings in Alzheimer’s disease. Published estimates of PET sensitivity and specificity, in which pathologically verified cases of Alzheimer’s disease were distinguished from controls by functional imaging, have ranged from 63% to 82%.27 It is now possible to image Alzheimer’s disease plaques and tangles directly with carbon 11 or fluorine 18 isotopes. Using the Pittsburgh B compound (Fig. 65–6), researchers imaged amyloid plaques and were able to distinguish patients with Alzheimer’s disease from controls in most cases.28

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T A B L E 65–11. Kokmen Short Test of Mental Status

From Kokmen E, Naessens JM, Offord KP: A short test of mental status: description and preliminary results. Mayo Clin Proc 1987; 62:281-288.

T A B L E 65–12. Medications for Alzheimer’s Disease Class

Name

Dosage

Disease Stage

Comment

Cholinesterase inhibitors

Donepezil Rivastigmine

5-10 mg/day Start 1.5 mg twice/day Target dose, 6 mg twice/day 4-12 mg twice/day or 8-24 mg/day (extended release) Start 5 mg/day Target dose, 10 mg twice/day

Mild/moderate Mild/moderate

Once-a-day dosing Inhibits butyrylcholinesterase; requires gradual titration Allosteric modulator of nicotinic receptor

Galantamine NMDA antagonist

Memantine

Mild/moderate Moderate/severe

Headache and transient confusion may occur

NMDA, N-methyl-D-aspartate.

MANAGEMENT Pharmacological Treatment Current pharmacological treatment involves use of a cholinesterase inhibitor, which increases brain acetylcholine concentrations. In 2003, the U.S. Food and Drug Administration approved the use of memantine, a glutamate receptor antagonist, for treatment of moderate to severe Alzheimer’s disease. These two classes of agents represent the mainstay of current treatment and are listed in Table 65–12. Memantine may be used with any of the cholinesterase inhibitors or on its own; if the patient cannot tolerate cholinesterase inhibitors it may be used alone.

Therapies in Development ■

Figure 65–5. Hippocampal atrophy in a case of Alzheimer’s disease. (From Sencakova D, Graff-Radford NR, Willis FB, et al: Hippocampal atrophy correlates with clinical features of Alzheimer disease in African Americans. Arch Neurol 2001; 58:1593-1597.)

One of the targets identified is the Aβ protein. Academic institutions and pharmaceutical companies are investigating a number of strategies. These include drugs that inhibit the enzymes that form Aβ: that is, γ-secretase and β-secretase inhibitors. Experimentally, immunizing transgenic mice may

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■

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Figure 65–6. Positron emission tomographic images of a brain from a patient with Alzheimer’s disease. AD, alzheimer’s disease; MR, magnetic resonance. (Courtesy of William Klunk, Chet Mathis, Steven DeKosky, and the University of Pittsburgh Imaging Group.)

prevent and remove amyloid from their brains; therefore, active and passive immunization are being investigated. One group has shown that heavy metal modulators, such as clioquinol, remove amyloid from the brain; this medication and newer generations of it are being investigated. Another strategy is to prevent amyloid from forming fibrils, and at present, such a medication has entered trials. Knowledge that some nonsteroidal anti-inflammatory agents decrease amyloid in the brains of transgenic mice has led to investigations of these agents. Some researchers are using antioxidant strategies.

can be offered a road test to evaluate their driving ability. Patients with a score of 1 or greater (equivalent to a MiniMental State Examination score of less than 25) are at great risk and should be advised not to drive.

Safety Issues

Wandering

Driving

If the patient has a tendency to wander, an identity bracelet may be obtained from a local branch of the Alzheimer’s Association.

Patients with memory impairment are at increased risk for automobile accidents and therefore should be made aware of this.29 The American Academy of Neurology guidelines on driving and Alzheimer’s disease indicate that persons with a Clinical Dementia Rating Scale (CDR) score of 0.5 are at increased risk for accidents, but the risk is no greater than that for other groups at high risk, such as men aged 18 to 25 years or those with blood alcohol levels exceeding 0.08%. Patients

Medication Supervision Health workers should advise patients and their caregivers to have an organized system for taking medication, such as having a “day of the week” medication organizer. The caregiver and the patient should share this responsibility.

Living Situation The health provider should assess the patient’s living situation to make sure the patient is safe. Advice should be tailored for each situation. Factors to consider include severity of the problem, amount of family support available, patients’ behav-

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iors, finances, and community options. Weapons should be removed or disabled. At the beginning, patients often live with a spouse or independently with regular monitoring by family members. Later, options include in-home respite care, day care, and assisted living facilities. In the later stages, the patient may need to be placed in a nursing home. Determining factors in making the decision to place a patient in a nursing home include severity of the disease, behavioral symptoms, incontinence, caregiver stress or ill health, and the family’s financial situation.

Mild Agitation

Durable Power of Attorney

Intervention

The health provider should ensure that the patient has designated a person with durable power of attorney for health decisions.

Management of mild agitation may require only an environmental intervention or a redirection by a caregiver, depending on the cause. Environmental interventions include the provision of a predictable routine for the patient, a noise-free environment with control of access to prevent wandering, pictures of family members in a patient’s room, use of a night light in the room, reassurance of the patient by a family member or caregiver with whom the patient is familiar, and encouragement of the patient to participate in recreational activities available in the facility. If agitation is either severe or prolonged, then medication is necessary. One review showed evidence that olanzapine and risperidone are efficacious, but the effects are modest, and there is an increased risk for stroke.30 Another report indicates that quetiapine in doses of 25 to 50 mg twice per day was not useful in institutionalized patients with agitation.31 At the time of writing, quetiapine has not been found to be associated with an increased risk of stroke and cardiovascular disease. The chapter authors often prescribe quetiapine as a first choice; higher doses are more frequently needed than those tested in the cited study.

Finances The family should create a situation so that the patient is less subject to financial errors, such as paying bills more than once or forgetting to pay them. Family members can oversee bill payment, or payment can be automated through a bank. Families should prevent exploitation of patients (which is all too common) and monitor investment decisions, another area of vulnerability.

Management of Agitation in Dementia Establishing a Cause Medical Infection (especially urinary infection), medication (particularly anticholinergics, analgesics, sedatives, and antipsychotics) (see Table 65–10), dehydration, electrolyte imbalance, constipation, pain, system dysfunction (biliary, cardiac, pulmonary, renal, and endocrine), and neurological dysfunction (cerebrovascular disease, seizure, and subdural hemorrhage) can affect the degree of agitation.

Environmental A noisy roommate, change of environment, social isolation, interruptions from staff, change of caregiver, room lighting, and temperature can affect the degree of agitation.

Sleep Disorders

Mild agitation may be disruptive and nonaggressive, with little risk of danger to patient/staff, and it may include wandering and repetitive movements.

Severe Agitation Severe agitation manifests as aggressive behavior with threat of physical harm to self or others, and it is not limited by verbal redirection (the affected person throws objects or food items, screams, grabs, bites, attempts to hit caregiver or to injure self).

K E Y

P O I N T S

●

Alzheimer’s disease is the commonest form of dementia.

●

There is mounting evidence that the Aβ42 protein is fundamental in the pathogenesis of Alzheimer’s disease.

●

The best way to attack this disease is to prevent it.

●

An important advance in imaging is the ability to visualize pathologic change with a PET scan and the Pittsburgh B compound.

●

So far, biomarkers have not improved the accuracy of the clinical diagnosis.

The clinician should establish the patient’s sleep quantity and quality (e.g., determine whether sleep is interrupted by apneic spells, dream enactment behavior, or restless leg syndrome).

Psychiatric The patient should be evaluated for mood disorder, psychosis, and anxiety disorder.

Grading Severity Management of agitation depends on severity, amount of disruption, and risk of physical harm to the patient or others.

Suggested Reading Doody RS, Stevens JC, Beck C, et al: Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1154-1156. Golde TE: Alzheimer disease therapy: can the amyloid cascade be halted? J Clin Invest 2003; 111:11-18. Hardy J: Toward Alzheimer therapies based on genetic knowledge. Annu Rev Med 2004; 55:15-25.

chapter 65 alzheimer’s disease Schenk D, Hagen M, Seubert P: Current progress in beta-amyloid immunotherapy. Curr Opin Immunol 2004; 16:599-606.

References 1. Fratiglioni L, Launer LJ, Andersen K, et al: Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000; 54:S10-S15. 2. Bachman DL, Wolf PA, Linn RT, et al: Incidence of dementia and probable Alzheimer’s disease in a general population: the Framingham Study. Neurology 1993; 43:515-519. 3. Mayeux R: Epidemiology of neurodegeneration. Annu Rev Neurosci 2003; 26:81-104. 4. Alzheimer A: Uber eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift Fur Pschiatrie und phychishGerichtliche Medizin (Berlin) 1907; 64:146-148. 5. Hebert LE, Scherr PA, Bienias JL, et al: Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003; 60:1119-1122. 6. Small G, Rabins P, Barry P, et al: Diagnosis and treatment of Alzheimer’s disease and related disorders. Consensus Statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 1997; 278:1363-1371. 7. Brookmeyer R, Gray S, Kawas C: Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88:13371342. 8. Farrer LA, Cupples LA, Haines JL, et al: Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium [Comment]. JAMA 1997; 278:1349-1356. 9. Graff-Radford NR, Green RC, Go RC, et al: Association between apolipoprotein E genotype and Alzheimer disease in African American subjects. Arch Neurol 2002; 59:594-600. 10. Ertekin-Taner N, Graff-Radford N, Younkin LH, et al: Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 2000; 290:2303-2304. 11. Glenner GG, Wong CW: Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984; 122:1131-1135. 12. Kanai M, Matsubara E, Isoe KEA: Longitudinal study of cerebrospinal fluid levels of tau, Ab1-40, and Ab1-42(3) in Alzheimer’s disease: a study in Japan. Ann Neurol 1998; 44:1726. 13. Gravina SA, Ho L, Eckman CB, et al: Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 1995; 270:70137016. 14. Arnold SE, Hyman BT, Flory J, et al: The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1991; 1:103-116. 15. Crystal H, Dickson D, Fuld P, et al: Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology 1988; 38:1682-1687. 16. Lewis J, Dickson DW, Lin WL, et al: Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001; 293:1487-1491. 17. Fillenbaum GG, Huber MS, Beekly D, et al: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part XIII. Obtaining autopsy in Alzheimer’s disease. Neurology 1996; 46:142-145.

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18. Khachaturian Z: Diagnosis of Alzheimer’s disease. Arch Neurol 1985; 42:1097-1105. 19. Newell KL, Hyman BT, Growdon JH, et al: Application of the National Institute on Aging (NIA)–Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease. J Neuropathol Exp Neurol 1999; 58:1147-1155. 20. Mirra S, Gearling M, McKeel D, et al: Interlaboratory comparison of neuropathology assessments in Alzheimer’s disease: a study of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). J Neuropathol Exp Neurol 1994; 53:303315. 21. Kokmen E, Naessens J, Offord K: A Short Test of Mental Status: description and preliminary results. Mayo Clin Proc 1987; 62:281-288. 22. Becker P, Feussner J, Mulrow C, et al: The role of lumbar puncture in the evaluation of dementia: the Durhar Veterans Administration/Duke University Study. J Am Geriatr Soc 1985; 33:392-396. 23. Hammestrom D, Zimmer B: The role of lumbar puncture in the evaluation of dementia: the University of Pittsburgh Study. J Am Geriatr Soc 1985; 33:397-400. 24. Consensus Report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s disease.” The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Neurobiol Aging 1998; 19:109-116 [Erratum in Neurobiol Aging 1998; 19:285]. 25. Blennow K, Hampel H: CSF markers for incipient Alzheimer’s disease [Review]. Lancet Neurol 2003; 2:605-613. 26. Wahlund LO, Julin P, Johansson SE, et al: Visual rating and volumetry of the medial temporal lobe on magnetic resonance imaging in dementia: a comparative study. J Neurol Neurosurg Psychiatry 2000; 69:630-635. 27. Hoffman JM, Welsh-Bohmer KA, Hanson M, et al: FDG PET imaging in patients with pathologically verified dementia. J Nucl Med 2000; 41:1920-1928. 28. Klunk WE, Engler H, Nordberg A, et al: Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004; 55:306-319. 29. Dubinsky RM, Stein AC, Lyons K: Practice parameter: risk of driving and Alzheimer’s disease (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology [Review]. Neurology 2000; 54:22052211. 30. Sink KM, Holden KF, Yaffe K: Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence [Review]. JAMA 2005; 293:596-608. 31. Ballard C, Margallo-Lana M, Juszczak E, et al: Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled trial. BMJ 2005; 330:874. 32. Mayeux R: Apolipoprotein E, Alzheimer disease, and African Americans [Comment]. Arch Neurol 2003; 60:161-163. 33. Green RC, Cupples LA, Go R, et al: Risk of dementia among white and African American relatives of patients with Alzheimer disease. JAMA 2002; 287:329-36. 34. Goate A, Chartier-Harlin M, Mullan M, et al: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s diseases. Nature 1991; 349:704-706. 35. Levy-Lehad E, Wijsman E, Nemens EEA: A familial Alzheimer’s disease locus on chromosome 1. Science 1995; 269:970973. 36. St. George-Hyslop P, Haines J, Rogaev E, et al: Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nat Genet 1992; 2:330-334. 37. Pericak-Vance M, Bebout J, Gaskell P, et al: Linkage studies in familial Alzheimer’s disease: evidence for chromosome 19 linkage. Am J Hum Genet 1991; 48:1034-1050.

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38. Kamboh MI: Molecular genetics of late-onset Alzheimer’s disease. Ann Hum Genet 2004; 68:381-404. 39. Schupf N, Kapell D, Nightingale B, et al: Specificity of the fivefold increase in AD in mothers of adults with Down syndrome. Neurology 2001; 57:979-984. 40. Andersen K, Launer LJ, Dewey ME, et al: Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurology 1999; 53:1992-1997. 41. Guo Z, Cupples LA, Kurz A, et al: Head injury and the risk of AD in the MIRAGE study. Neurology 2000; 54:1316-1323. 42. Plassman BL, Havlik RJ, Steffens DC, et al: Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 2000; 55:1158-1166. 43. Casserly I, Topol E: Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 2004; 363:1139-1146. 44. Snowdon DA, Kemper SJ, Mortimer JA, et al: Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Findings from the Nun Study. JAMA 1996; 275:528532. 45. Verghese J, Lipton RB, Katz MJ, et al: Leisure activities and the risk of dementia in the elderly. N Engl J Med 2003; 348:25082516. 46. Szekely C, Thorne J, Zandi PP, et al: Nonsteroidal antiinflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology 2004; 23:159-169. 47. Wolozin B, Kellman W, Ruosseau P, et al: Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000; 57:1439-43. 48. Shumaker SA, Legault C, Rapp SR, et al: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2651-2662. 49. Yaffe K, Sawaya G, Lieberburg I, et al: Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279:688-695.

50. Seshadri S, Beiser A, Selhub J, et al: Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346:476-483. 51. Morris MC, Evans DA, Bienias JL, et al: Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry 2004; 75:1093-1099. 52. Yaffe K, Barnes D, Nevitt M, et al: A prospective study of physical activity and cognitive decline in elderly women: women who walk [Comment]. Arch Intern Med 2001; 161:1703-1708. 53. Orgogozo JM, Dartigues JF, Lafont S, et al: Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol 1997; 153:185-192. 54. Morris MC, Evans DA, Bienias JL, et al: Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease [Comment]. Arch Neurol 2003; 60:940-946. 55. Morris MC, Evans DA, Bienias JL, et al: Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002; 287:32303237. 56. Scheuner D, Eckman C, Jensen M, et al: Secreted amyloid betaprotein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996; 2:864-870. 57. Graff-Radford N, Eckman C, O’Brien P, et al: Plasma amyloid β protein (Aβ) in Down’s syndrome (DS): implications for Alzheimer’s disease. Neurology 1997; 47:A378. 58. Schupf N, Patel B, Silverman W, et al: Elevated plasma amyloid beta-peptide 1-42 and onset of dementia in adults with Down syndrome. Neurosci Lett 2001; 301:199-203. 59. Tokuda T, Fukushima T, Ikeda S, et al: Plasma levels of amyloid β proteins Ab1-40 and Ab1-42(43) are elevated in Down’s syndrome. Ann Neurol 1997; 41:271-273. 60. Gearing M, Mori H, Mirra S: Aβ-peptide length and apolipoprotein E genotype in Alzheimer’s disease. Ann Neurol 1996; 39:395-399. 61. Graff-Radford N, Eckman C, Hutton M, et al: Plasma amyloid (Aβ) levels in relatives of Alzheimer’s disease patients. Neurology 1998; 48:A314.

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66

AMYOTROPHIC LATERAL SCLEROSIS ●

●

●

●

Kevin B. Boylan

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing stereotypic motor impairment, commonly known in the United States as Lou Gehrig’s disease, after the famous baseball player stricken with ALS in the 1930s.1 Jean-Martin Charcot’s 1874 description of clinical and pathological features of ALS remains largely accepted today.2 Clinical and basic research since Charcot’s time have further refined the clinical features in ALS and provide evidence that ALS has multiple causes.3 Also apparent is that a number of neurological disorders share certain features with ALS, complicating the diagnostic evaluation of suspected ALS in some patients. Epidemiological aspects of ALS are summarized in Table 66–1. ALS is by definition a progressive motor disorder affecting upper motor neurons (UMNs) and lower motor neurons (LMNs), typically culminating in life-threatening complications of respiratory muscle weakness within 3 to 4 years after onset.4 However, the relative extent of UMN and LMN involvement differs among patients. Individual variation in rate of progression also is seen in ALS, from rapid decline over a period of months in a small proportion of patients to slow progression over 20 to 30 years in rare cases. Current pharmacotherapy at best yields only modest increase in survival.5 Management remains mainly supportive, but the effect of these interventions on quality of life can be significant.6

Nomenclature Classic ALS is a mixed UMN and LMN disorder, but the term may also be applied to incomplete manifestations with only LMN or UMN signs or solely bulbar features. In “pure” form, however, these partial presentations also are recognized as disorders separate from ALS (Fig. 66–1).7 A proposed solution was to apply the general term motor neuron diseases to this range of presentations, ALS being one manifestation in the spectrum of adult motor neuron diseases (Table 66–2).8 Of the others, motor neuron disease with exclusively LMN features is classified as progressive muscular atrophy (PMA) 9; generalized, purely UMN disease is classified as primary lateral sclerosis (PLS); and progressive bulbar palsy (PBP) is a UMN and/or LMN disorder restricted to the bulbar region. Most patients presenting with these syndromes eventually develop the full clinical

picture of ALS, but approximately 10% of patients with adult motor neuron disease retain the diagnosis of PMA, PLS, or PBP.10 In life, these diagnoses are established on clinical grounds, because no confirmatory supportive test other than postmortem examination is available.11 The diagnostic challenge is exemplified by PMA, in which autopsy studies demonstrate UMN pathology, establishing the correct diagnosis of ALS. Diagnostic distinction is more than academic, inasmuch as prognosis differs for the various syndromes.12

Diagnostic Criteria The World Federation of Neurology Subcommittee on ALS in 1990 developed diagnostic criteria to standardize the assessment of patients with ALS for research trials. Referred to as the El Escorial criteria and first published in 1994, the guidelines divide the central nervous system into four regions—bulbar, cervical, thoracic, and lumbosacral—and rank the level of diagnostic certainty for ALS on the basis of signs found in each region (Table 66–3).13 Requirements for the diagnosis include the presence of UMN and LMN signs in multiple regions, evidence of progression, and absence of conditions that could otherwise account for the manifestation. Revised El Escorial criteria developed in 1998 and published in 2000 allow supportive evidence for the diagnosis of ALS to be obtained from electromyography (EMG) and created special guidelines for the diagnosis of familial ALS for cases in which confirmation by DNA testing is available (see Table 66–3).14 The El Escorial criteria in clinical practice can provide a framework for establishing the diagnosis of ALS, but they remain arbitrary guidelines. Patients’ conditions do not necessarily follow stepwise progression from the lower levels of diagnostic certainty to clinically definite ALS.15 Those without features required for a clinically definite diagnosis at presentation may die of the disease without developing signs that allow classification as clinically probable or definite ALS.

Internet Resources The knowledge base for ALS is rapidly evolving. Sources of current information on the diagnosis and management of ALS and ongoing research trials include several internet sites, some

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LMN

T A B L E 66–2. Nomenclature of Idiopathic Adult Motor Neuron Disease UMN

ALS Classic ALS PMA ■

PLS

Figure 66–1.

Theoretical relationships between amyotrophic lateral sclerosis (ALS) and other forms of idiopathic adult motor neuron disease: progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Indistinct boundaries between these entities reflect the possibility that these disorders may represent varied expression of the same underlying disease process. Most patients presenting with features of PBP, PMA, or PLS progress to develop the full clinical picture of ALS, although “pure” presentations of these conditions may occur. Lower motor neuron (LMN) signs predominate at one end of the spectrum, and upper motor neuron (UMN) signs predominate at the other. (Data from Desai J, Swash M: Essentials of diagnosis. In Kuncl RW, ed: Motor Neuron Disease. Philadelphia: WB Saunders, 2002, pp 1-20; and from Mitsumoto H, Chad D, Pioro E: History, terminology, and classification of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 3-17.)

T A B L E 66–1. Epidemiology of Amyotrophic Lateral Sclerosis Worldwide prevalence Annual incidence Male-to-female ratio Peak age at onset

≈4 per 100,000 1-2 per 100,000 ≈1.5-2.5 : 1.0 55-75 years

Data from Kondo K: Epidemiology of motor neuron disease. In Leigh PN, Swash M, eds: Motor Neuron Disease: Biology and Management. London: Springer-Verlag, 1995, pp 19-33; and from Mitsumoto H, Chad D, Pioro E: Epidemiology. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 18-33.

of which offer downloadable patient information. A selection of these is listed in Table 66–4.

CLINICAL FEATURES Weakness with related symptoms and signs in ALS reflects loss of cortical, brainstem, and spinal motor neurons.16 Cortical, or UMN, pathology results in characteristic weakness and in UMN signs such as weakness, hyperreflexia, and pathological reflexes such as Hoffmann and Babinski signs. Anterior horn cell loss produces weakness, atrophy, and fasciculations.10 Involvement of the corticobulbar tract produces UMN-type orofacial weakness and associated signs and symptoms, such as sialorrhea, dysphagia, and dysarthria. These symptoms, in addition to muscle atrophy, accompany involvement of brainstem motor nuclei. Dysarthria in ALS may have mainly spastic and/or flaccid qualities in relation to the degree of UMN and/or LMN dysfunction. Patients may gradually lose functional speech and become mute before or after significant respiratory muscle weakness develops. Airway protection may be compromised by impaired glottic closure. Glottic spasm may also occur.

Condition

Acronym

Features

Amyotrophic lateral sclerosis Progressive bulbar palsy Progressive muscular atrophy

ALS

Upper and lower motor neuron signs in limbs, trunk and bulbar regions

PBA

Upper and/or lower motor neuron signs in bulbar region only Lower motor neuron signs of limb and trunk musculature; bulbar involvement late if at all; no upper motor neuron signs Upper motor neuron signs in bulbar, limb and trunk regions; no lower motor neuron signs

Primary lateral sclerosis

PMA

PLS

From Strong M, Rosenfeld J: Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:136-143.

Initial motor deficits in ALS tend to arise focally, involving a single limb or orofacial muscles, and gradually extend to adjacent body regions.8 The ratio of patients with limb onset to those with bulbar onset is approximately 3:1.12,17,18 Diffuse onset of weakness is less common. With focal onset, deficits tend to progress to the corresponding opposite side of the body and ipsilaterally in a rostral or caudal direction.19 Rostral-caudal extension appears to occur more rapidly than caudal-rostral extension. Extension to a nonadjacent body region, such as from left lower limb to right upper limb, is atypical. Disease onset may be in the thoracic region, leading to stooped posture as a result of paraspinal muscle weakness and weakness of abdominal wall muscles.10,20 Fasciculations are characteristic of ALS but may be difficult to detect in some patients. Fasciculations appear to arise in the axon of diseased motor neurons in ALS but are not specific for the disorder; they are present in other chronic neurogenic disorders, endocrine/metabolic conditions, and in some normal persons.21-23 Those in normal persons, so-called benign fasciculations, tend to have restricted distribution, repetitively occurring in a single muscle rather than diffusely as in ALS. Exercise, stress, and fatigue may promote benign fasciculations in some healthy subjects. Normal neurological examination and electromyographic findings can provide assurance that fasciculations in this setting are benign.24 EMG may help identify fasciculation potentials that are not apparent on physical examination: for example, in obese patients.10

Cramps Muscle cramps are a common symptom in ALS but lack diagnostic importance, occurring in a variety of conditions and in otherwise normal subjects. Overexertion of weakened muscle can precipitate a cramp, such as use of forearm muscles in manual tasks. Cramps may also occur at rest, such as those in the calf muscles.

Dysphagia Nutritional compromise and weight loss can occur in patients with ALS as a result of oropharyngeal weakness and dysphagia.

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T A B L E 66–3. El Escorial Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis (ALS): Original and Revised Criteria Level of Certainty

Original Criteria (1994)

Revised Criteria (2000)

Definite ALS Definite familial ALS

LMN and UMN signs in 3 regions Not used

Probable ALS

LMN and UMN signs in at least 2 regions; regions may be different, but some UMN signs must in part be rostral to LMN signs Not used

LMN and UMN signs in 3 regions LMN and UMN signs in ≥1 region plus laboratory identification of DNA mutation associated with ALS LMN and UMN signs in at least 2 regions; regions may be different, but some UMN signs must in part be rostral to LMN signs

Probable ALS, laboratory supported Possible ALS Permits diagnosis of possible ALS in monomelic ALS, PLS, and PBP Suspected ALS

LMN and UMN signs in 1 region or UMN signs alone in >2 regions or LMN signs are rostral to UMN signs

LMN and UMN signs in only 1 region or UMN signs alone are found, plus signs of active and chronic denervation on EMG in at least 2 limbs LMN and UMN signs in 1 region or UMN signs alone in >2 regions or LMN signs are rostral to UMN signs and the diagnosis of probable ALS, laboratory supported, cannot be made

LMN signs alone in ≥2 regions

Deleted

Data from Brooks BR: El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical Limits of Amyotrophic Lateral Sclerosis” workshop contributors. J Neurol Sci 1994; 124(Suppl):96-107; and from Brooks BR, Miller RG, Swash M, et al: El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1:293-299. The guidelines divide the central nervous system into 4 regions: bulbar, cervical, thoracic, and lumbosacral. EMG, electromyography; PBP, progressive bulbar palsy; PLS, primary lateral sclerosis; LMN, lower motor neuron; UMN, upper motor neuron.

T A B L E 66–4. Internet Resources for Information on Amyotrophic Lateral Sclerosis (ALS) Resource

Information Provided

World Wide Web Address

Amyotrophic Lateral Sclerosis Association (United States) Amyotrophic Lateral Sclerosis/Motor Neurone Disease Association (United Kingdom) ALS Therapy Development Foundation (United States) GeneTests (United States)

Information on management of ALS; lists of ongoing research trials Information on management of ALS; links to ongoing research trials Extensive information on ongoing and completed medication studies in ALS Publicly funded medical genetics information; access to information on genetic testing for ALS Information on management of ALS; lists of ongoing research trials Information on ALS, including information in Spanish; information on ongoing research trials Includes El Escorial ALS diagnostic criteria

www.alsa.org

Muscular Dystrophy Association (United States) National Institute of Neurological Disorders and Stroke (United States) World Federation of Neurology Research Group on Motor Neuron Diseases

UMN and/or LMN involvement may occur in the distributions of cranial nerve nuclei V, VII, IX, X, and XII. Dysphagia is an early or presenting symptom in 10% to 30% of patients with ALS.10 Nearly all such patients eventually experience dysphagia.25 Recognition of this complication is important in avoiding weight loss, possible malnutrition, and aspiration. Nutritional balance and composition with adequate fluid intake should match estimated dietary needs and swallowing ability. Aspiration is a significant complication of oropharyngeal weakness, potentially leading to avoidance of certain foods or liquids and interfering with administration of oral medications.10 Symptoms of oropharyngeal weakness include fatigue with chewing, lodging of food in the gingival-buccal mucosa, sensation of food sticking in the throat when swallowing, coughing or choking during meals, sialorrhea, and leaking of liquids from the mouth during swallowing. Patients with severe oropharyngeal weakness may become at risk for aspiration of their own secretions.

www.mndassociation.org www.als-tdf.org www.geneclinics.org www.mdausa.org www.ninds.nih.gov www.wfnals.org

Pseudobulbar affect refers to recurrent, involuntary outbursts of laughter or crying triggered by circumstances that normally would not provoke an overtly emotional response. This symptom can be distressing for patients and caregivers. The cause appears to be bilateral interruption of pathways between UMNs and bulbar nuclei, possibly including the cerebellum.26 The incidence of pseudobulbar affect increases gradually during the course of the disorder. In a study of 73 patients with a relatively long mean duration of disease (8.5 years), 49% exhibited pseudobulbar affect.27 Respiratory dysfunction in ALS tends to develop insidiously, although relatively rapid development of respiratory failure is reported in some cases. In rare cases, respiratory failure is the presenting sign of ALS.28-30 Respiratory impairment in ALS stems mainly from LMN weakness of the diaphragm and respiratory accessory muscles (Table 66–5). Exertional dyspnea and fatigue can be early symptoms, although patients may be asymptomatic despite respiratory muscle weakness demonstra-

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T A B L E 66–5. Respiratory Muscles Affected by Amyotrophic Lateral Sclerosis Respiratory Phase

Muscle

Inspiration

Primary Diaphragm Accessory Sternocleidomastoid Trapezius Scalenes Parasternal and external intercostals Primary Mainly passive relaxation of diaphragm Accessory Internal intercostals Abdominal muscles

Expiration

Spinal Level C3-5 C2-3 C3-4 C4-8 T1-11

T1-12 T7-L1

From Krvickas L: Pulmonary function and respiratory failure. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 382-404.

ble on pulmonary function testing.31 Symptoms may be mitigated by reduced activity level.32 Dyspnea during conversation, frequent sighing, reduced speech volume, orthopnea, and weak cough can be indicators. Dyspnea with mild exertion or in association with meals is suggestive of significant respiratory muscle weakness. Postprandial dyspnea and orthopnea are attributable to pressure against the diaphragm from the abdominal contents.33 Physical signs of respiratory compromise include tachypnea, use of accessory muscles, and dyssynchrony of chest/abdominal muscle movement, including paradoxical inward abdominal movement during chest expansion.34 Changes in laboratory tests such as increased hematocrit and respiratory acidosis with reduced serum chloride levels are relatively late indicators of severe respiratory compromise in ALS.10 Significant respiratory muscle weakness can be overlooked if not sought in the history and pulmonary function testing. Early identification of clinically significant respiratory muscle involvement in ALS is important in order to allow the patient adequate time to make decisions regarding potential use of mechanical ventilatory support.10 Sleep disturbance in ALS can be exacerbated by depression, limited mobility interfering with comfortable positioning, and respiratory muscle weakness. Mechanisms of weakness-related sleep disturbance include paresis of respiratory muscles, mechanical obstructive sleep apnea caused by pharyngeal muscle weakness and resulting hypopharyngeal collapse, and/or weakness of vocal cord abduction.10,35,36 Specific inquiry regarding changes in sleep habits, ability to sleep comfortably supine, and recurrent morning headache may be needed to identify these conditions.

DIFFERENTIAL DIAGNOSIS A large number of disorders may enter into the differential diagnosis of suspected ALS.10 Differential diagnosis can be considered in terms of symptoms and by anatomical localization. An approach to a symptom-based differential diagnosis is shown

in Table 66–6. Specific disorders in relation to anatomical localization are discussed as follows. Patients with suspected ALS who have LMN signs but borderline or no UMN signs can be grouped by the anatomical level of primary pathology: anterior horn cell, peripheral motor axon, neuromuscular junction, and muscle. Several primary anterior horn cell diseases may resemble ALS with mainly LMN signs. All are less common than ALS. PMA, a sporadic LMN disorder, is one of these, occurring in about 10% of patients with motor neuron disease.37 ALS lacking UMN signs is clinically indistinguishable from PMA. Case series suggest that there are a higher male-to-female ratio in PMA and a better prognosis than in ALS, with longer survival and lower frequency of progression to significant bulbar dysfunction and respiratory compromise in PMA than in ALS. Ultimately, the determination that a patient with LMN disease has ALS rather than PMA can be made during the patient’s life only if UMN signs develop or at postmortem study through identification of pyramidal tract pathology.38-40 Adult-onset forms of the hereditary spinal muscular atrophies (SMA) may present diagnostic uncertainty of the type encountered with PMA.41 Several forms of adult-onset SMA are reported with autosomal recessive or autosomal dominant inheritance.42-44 Adult-onset SMA becomes apparent generally after age 20 years. Progression is slow, and the prognosis is better than that of ALS. Initial involvement typically is in the limbs. Generalized weakness may develop, but significant bulbar or respiratory weakness is rare. Kennedy’s disease, or spinobulbar neuronopathy, is an Xlinked inherited disorder in which LMN signs predominate.45,46 Progressive weakness affects bulbar and limb muscles with atrophy and fasciculations, the latter particularly in the orofacial muscles. Progression is slow and potentially compatible with a normal life span, but significant dysarthria, dysphagia, and respiratory impairment can develop. Gynecomastia and impotence may occur. Primary pathology involves LMNs, but sensory neurons also are involved. Sensory and other nonmotor abnormalities may be asymptomatic, however, and Kennedy’s disease is an important consideration in the differential of LMN presentations of ALS in men. Kennedy’s disease is caused by a trinucleotide (cytosine-adenine-guanine) repeat expansion in the X-linked androgen receptor gene.47 Needle electromyographic findings in Kennedy’s disease are similar to those of ALS, but in contrast to ALS, nerve conduction studies tend to show reduced sensory nerve action potential amplitudes.48 DNA testing for the trinucleotide mutation that causes the disorder can establish diagnosis of Kennedy’s disease. Other uncommon LMN disorders that may resemble ALS include brachial amyotrophic diplegia, a progressive LMN condition of the upper limbs, and monomelic amyotrophy, a progressive LMN disorder affecting a single extremity, usually an upper limb.37,49-53 These conditions tend to progress over a few years and then stabilize, without spread to other body regions. Natural history data suggest that progression of disease outside of the initially involved limb or limbs is unlikely if spread is not evident within a few years after onset. In rare cases, paraneoplastic motor neuron disease or motor neuronopathy occur with lymphoma.54,55 Weakness in most cases is exclusively LMN type, although some patients demonstrate probable or definite UMN signs that are compatible with ALS.56 Identification of lymphoma in this syndrome may be

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T A B L E 66–6. Symptom-Based Differential Diagnosis of Amyotrophic Lateral Sclerosis Peripheral Neuropathy

Symptom

Metabolic

Myopathy

NMJ

Fatigue; limb weakness; clumsiness

—

Inclusion body myositis

MG; LEMS

CIDP; MMN (esp. Cervical/ upper limb); lumbosacral mononeuropathy; brachial/ lumbosacral plexopathy

PLS; PMA

Head drop; stooped posture

—

Inflammatory myopathy; focal neck extensor myopathy congenital myopathy

MG

—

—

Dysarthria and/or dysphagia

—

Inflammatory MG myopathy; oculopharyngeal dystrophy

—

Dyspnea

—

Acid maltase deficiency

MG

—

Fasciculations —

Cramps

Electrolyte Metabolic disturbance; myopathy hypothyroidism; hypoadrenalism; uremia; pregnancy

Radiculopathy

Anterior Horn Cell

CNS Neurodegenerative Disorder

Neoplasm

Cerebrovascular

Parkinson’s disease

Spinal

Stroke

—

Parkinson’s disease

—

—

—

Bulbospinal neuronopathy

Parkinson’s disease

Foramen Stroke magnum; brainstem

GBS

—

Bulbospinal — neuronopathy; postpolio syndrome; PMA

—

—

—

MMN

Cervical/ lumbosacral

Benign; — bulbospinal neuronopathy; SMA

—

—

—

—

Cervical/ lumbosacral

Bulbospinal — neuronopathy; postpolio syndrome

—

—

Modified from Mitsumoto H, Chad D, Pioro E: The differential diagnosis of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 87-121. CIDP, chronic inflammatory demyelinating polyneuropathy; CNS, central nervous system; GBS, Guillain-Barré syndrome; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; MMN, multifocal motor neuropathy; NMJ, neuromuscular junction; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; SMA, spinal muscular atrophy.

difficult. Paraproteinemia is a useful marker and, if present, should prompt cerebrospinal fluid examination. Increased cerebrospinal fluid protein and/or oligoclonal bands warrant consideration of bone marrow examination. The neurological disorder may stabilize with treatment of the lymphoma.56,57 Postpolio syndrome is the recurrence of weakness in patients with a history of poliomyelitis a decade or more after the initial infection.58,59 New or ongoing instability and degeneration of previously affected motor units is suspected, but the primary cause is not established.60 Involved muscle groups tend to be those originally affected, but previously unaffected muscles may be included. Progression is slow; periods of stabilization may be interspersed. Bulbar and respiratory function can be affected. Fatigue and musculoskeletal pain are significant in many patients. UMN signs generally are not found, although Babinski’s sign may be present. EMG shows chronic and active neurogenic changes. No specific diagnostic test is available for postpolio syndrome; distinction from LMN-type ALS is based on slow progression, absence of UMN signs, and history of poliomyelitis. Hexosaminidase A deficiency, a form of GM2 gangliosidosis, is an autosomal recessive condition with a range of neuro-

logical phenotypes, depending on the degree of residual enzyme activity.61 Complete absence or profound deficiency of hexosaminidase A results in the fatal infantile disorder Tay-Sachs disease. Less severe deficiency of hexosaminidase A can produce various childhood-, juvenile-, or adult-onset phenotypes, including one resembling a progressive LMN disease.62,63 Onset in the latter is typically in childhood, but clinical manifestation may be delayed until adulthood. Hexosaminidase A deficiency with prominent LMN features can suggest a sporadic LMN disorder. Clinical features such as childhood onset, slow progression, and associated signs such as tremor or developmental delay readily distinguish hexosaminidase A deficiency from ALS. EMG shows signs of chronic motor denervation, but nerve conduction studies usually show sensory nerve involvement, and brain computed tomography or magnetic resonance imaging (MRI) reveals cerebellar atrophy, at variance with ALS. Multifocal motor neuropathy (MMN) with conduction block is a rare, immune-mediated disorder with a male-to-female ratio of 3 : 1 and mean age at onset of 40 years.64,65 The estimated incidence is 1 to 2 per 1,000,000, much lower than that of ALS. MMN can be an important consideration in the differential diagnosis ALS because of clinical overlap and the

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observation that up to 80% of affected patients respond to treatment. Weakness in MMN may be asymmetrical, beginning distally in the upper limbs. Tendon reflexes are usually reduced but may be retained and seem inappropriately brisk; pathological reflexes are not present. Nerve conduction studies show evidence of demyelination and conduction block in multiple motor nerves, generally not solely at common sites of entrapment. Needle electromyographic abnormalities may be similar to those of ALS but are found only in the territory of involved nerves, not diffusely.66 Approximately 50% of patients have serum immunoglobulin M antibodies that react with GM1 and other gangliosides.67,68 Elevated titers of ganglioside antibodies are found in some patients with ALS, but their presence nevertheless warrants thorough evaluation for possible motor conduction block. Monoclonal gammopathy may be associated with peripheral neuropathy or polyradiculoneuropathy with mainly motor features, resembling the LMN presentation of ALS.69 Affected patients may have a lymphoproliferative disease potentially amenable to treatment.70 This syndrome can be difficult to distinguish from primary LMN disorders if sensory symptoms/ signs are minimal or lacking. Muscle atrophy and fasciculations may be present, but UMN signs are not.71 Associated systemic features may be present and, when fully established, constitute the syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS). The monoclonal protein in these disorders usually is immunoglobulin G or Aκ, associated with one or more bony lesions (osteosclerotic or sclerotic/lytic). Nerve conduction studies compatible with demyelination and cerebrospinal fluid protein elevation potentially exceeding 100 mg/dL facilitate the distinction from ALS.70 Pathological significance of a monoclonal gammopathy in ALS can be difficult to establish, inasmuch as paraproteinemia is reported in nearly 10% of patients with motor neuron disorders in general, including clinically definite ALS.72 Other peripheral neuropathies that may resemble the LMN presentation of ALS include chronic inflammatory demyelinating polyneuropathy and unusual manifestations of GuillainBarré syndrome with minimal paresthesia or sensory signs.73,74 Elevated cerebrospinal fluid protein, evidence of demyelination on nerve conduction studies, and nerve biopsy, if indicated, readily distinguish these conditions from ALS.75 Neuromuscular junction disorders that share certain features with ALS include the autoimmune diseases myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS). Diffuse weakness may occur in both disorders, but myasthenia gravis has a predilection for ocular and bulbar muscles.76 Fasciculations are not a hallmark of either myasthenia gravis or LEMS. Motor nerve conduction studies of clinically weak muscles in myasthenia gravis tend to show a decrement on slow (2- to 3-Hz) repetitive stimulation. This may occur in ALS, but denervation on EMG distinguishes the latter. Unlike patients with ALS, approximately 85% of patients with myasthenia gravis have serum antibodies to the acetylcholine receptor, and approximately 40% of seronegative patients have antibodies that react with muscle-specific kinase.77,78 LEMS tends to produce limb girdle weakness with milder, if any, bulbar weakness. Increase in strength after repetitive use and autonomic dysfunction also are features of LEMS but not of ALS.79 Patients with LEMS tend to show an electromyographic decrement on slow repetitive stimulation. Motor ampli-

tudes generally are low, and increase by more than 100% on stimulation immediately after brief (10- to 15-second) exercise. LEMS may occur as a primary autoimmune condition, but more often is associated with underlying cancer, particularly small cell lung carcinoma. A high proportion of patients with LEMS carry serum antibody against P/Q-type calcium channels.80 Inclusion body myositis (IBM), polymyositis, and dermatomyositis are inflammatory muscle diseases that in adults produce gradually progressive weakness without fasciculations or UMN signs.81,82 Clinical findings in IBM in particular may superficially resemble ALS with LMN features. IBM affects particularly knee extensors and flexor forearm muscles; neck muscle weakness and dysphagia also may occur. Polymyositis and dermatomyositis cause mainly proximal weakness. Characteristic skin rash is typical of dermatomyositis. Weakness may be asymmetrical, especially in IBM. EMG in these inflammatory myopathies typically reveals fibrillation potentials and myopathic motor unit potentials. In IBM, chronic neurogenic motor unit potential abnormalities are not uncommon. Muscle biopsy demonstrates inflammatory changes in all three, with rimmed vacuoles, amyloid deposition, and filamentous intranuclear inclusions in IBM. If inflammatory myopathy is a diagnostic consideration, muscle biopsy is indicated. Other muscle disorders that may superficially resemble predominantly LMN presentations of ALS are listed in Table 66–7. Absence of fasciculations, myopathic features on EMG, and findings on muscle biopsy readily distinguish these from possible ALS.83 Neurological disease manifesting solely with UMN signs and no associated evidence of LMN pathology may indicate the initial stages of ALS. However, the differential diagnosis of this syndrome includes other forms of motor neuron disease, such

T A B L E 66–7. Muscle Disorders in the Differential Diagnosis of Suspected Amyotrophic Lateral Sclerosis (ALS) with Lower Motor Neuron Features* Disease

Features Distinct from ALS†,‡

Inclusion body myositis Polymyositis Dermatomyositis Myotonic muscular dystrophy Oculopharyngeal dystrophy

— — Rash Myotonia; characteristic facies Oculofacial signs generally established by the time limb weakness is symptomatic Generally does not progress to generalized weakness — — — — — — Ocular signs may distinguish this entity from ALS

Neck extensor myopathy (drop head syndrome) Nemaline myopathy Acid maltase deficiency McArdle’s disease Phosphofructokinase deficiency Debrancher deficiency Carnitine deficiency Mitochondrial myopathy

Modified from Mitsumoto H, Chad D, Pioro E: The differential diagnosis of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 87-121. *Electromyography and muscle biopsy are generally useful in distinguishing these disorders from ALS. † Fasciculations and upper motor neuron signs are not found in these disorders. ‡ As in ALS, mild creatine phosphokinase elevation may be present.

chapter 66 amyotrophic lateral sclerosis as PLS, and conditions dominated by UMN weakness and spasticity, such as hereditary spastic paraparesis. PLS is a rare sporadic disorder affecting corticobulbar and corticospinal neurons, found in 2% to 4% of patients in larger motor neuron disease series.84,85 The age at onset is similar to that of ALS.86 Spasticity and weakness may begin in the bulbar region or lower limbs, usually the latter. Physical findings may initially be asymmetrical (i.e., hemiparesis).86 Gradual progression to initially uninvolved regions is typical. The concept of PLS as a specific disease entity is supported by autopsy data demonstrating solely UMN pathology in patients given this diagnosis while alive.85,87 However, natural history data include reports of patients with an initial diagnosis of PLS who after years of follow-up developed LMN signs compatible with ALS.9 Furthermore, mild creatine kinase elevation is reported in some patients who otherwise meet criteria for diagnosis of PLS; needle EMG may reveal signs of active and chronic motor denervation; and muscle biopsy may demonstrate neurogenic changes.84,88 Also, patients given a diagnosis of PLS while alive may at postmortem demonstrate anterior horn cell disease.89 Nosology aside, it is clear that the diagnosis of PLS, even if LMN signs eventually develop, tends to progress more slowly than in patients meeting diagnostic criteria for ALS.84,85 Like that of ALS, diagnosis of PLS rests on history, clinical findings, and periodic reassessment. Hereditary spastic paraparesis causes a progressive spastic weakness of the lower limbs, rarely extending to the upper limbs and bulbar region.90-92 Inheritance may be autosomal dominant, autosomal recessive, or X-linked; more than 20 genetic loci are identified.93 Onset usually occurs in childhood or early adulthood, earlier than expected for ALS. Bulbar or significant upper limb involvement generally is not a feature of hereditary spastic paraparesis. Urinary symptoms and large fiber sensory involvement may occur, readily distinguishing hereditary spastic paraparesis from ALS. Mixed UMN and LMN or mainly UMN disorders resembling ALS are uncommon but are important to consider in the workup of patients with possible ALS. Spondylotic cervical spinal stenosis may produce myelopathy and associated LMN signs in the upper limbs.94,95 Thyrotoxicosis can produce a syndrome with mixed UMN and LMN signs attributed to combined myopathy, myelopathy, and motor neuropathy.94 Vitamin B12 deficiency, multiple sclerosis, syringomyelia, adrenal leukodystrophy, human T cell lymphotropic virus I myelopathy, and human immunodeficiency virus myeloneuropathy may superficially suggest ALS with UMN signs.96-102 Identification of these conditions is aided by signs and/or symptoms of neurological involvement beyond solely UMN and anterior horn cell pathology. Neurological disorders with motor features confined to the bulbar region may resemble a bulbar presentation of ALS. PBP, by definition a UMN and/or LMN disorder limited to bulbar muscles, is included in this differential diagnosis.103 Distinction of PBP from ALS with bulbar onset is established by the presence of LMN and/or UMN signs outside the bulbar region. Physical findings establishing the diagnosis of ALS usually develop in PBP. Disorders suggestive of bulbar-onset ALS that potentially cause mixed UMN/LMN signs include structural lesions such as tumors in the brainstem or foramen magnum.104 Cerebrovascular disease and demyelinating disease such as multiple sclerosis may produce similar signs and symptoms. Associated

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symptoms may help rule out ALS, but brain imaging, particularly MRI, as a rule is indicated.83 Cerebrovascular events can generally be ruled out on the basis of their acute onset and nonprogressive course, but some ALS patients report acute symptom onset, and early on it may be unclear whether the disorder is progressive. Exclusively bulbar weakness may occur in myopathic conditions, neuromuscular transmission disorders, cranial neuropathies, and brainstem structural or demyelinating diseases. Ptosis is characteristic of myopathies such as oculopharyngeal dystrophy and of neuromuscular transmission disorders such as myasthenia gravis.76,105 Ophthalmoparesis, similarly, is not present in ALS except in advanced disease, generally in ventilator-dependent patients approaching a locked-in state.106,107 A variety of conditions have been reported in rare instances to produce an ALS-like disorder. These include lead exposure or other heavy metal exposure, connective tissue disease such as Sjögren’s disease, Lyme disease, and hyperparathyroidism.108 Data supporting these associations are limited, and investigation of these diagnoses seems warranted only in the event of associated clinical or laboratory indications or, in the case of heavy metal toxicity, a history of exposure.

AMYOTROPHIC LATERAL SCLEROSIS WITH ATYPICAL FEATURES Patients with ALS occasionally have neurological findings in addition to UMN and LMN involvement, also referred to as ALSplus.14 These findings include dementia, extrapyramidal signs, autonomic features, and sensory signs and/or symptoms. Diagnosis of these syndromes as variants of ALS requires exclusion of potential causes for the variant features. Two of these, dementia and extrapyramidal features, are mentioned briefly here. Clinical management of motor aspects of the syndromes is similar to that of classic ALS. Dementia, characteristically a frontotemporal type, is reported in about 5% of patients with ALS, although data suggest that the incidence may be higher.18,109,110 Clinically similar familial and sporadic forms occur; one phenotype is linked to chromosome 9.111 Associated cognitive dysfunction includes impaired executive function, emotional lability, decreased speech output, perseveration, and disinhibition. These may develop before or concurrently with motor abnormalities in ALS or manifest after motor deficits are established. Extrapyramidal signs, including bradykinesia, rigidity, tremor, and postural instability may be present with features of ALS.112,113 One such ALS variant is the ALS-parkinsonismdementia complex of Guam, largely confined to western Pacific islands (Guam, New Guinea, and the Kii Peninsula of Japan).114,115 Patients with this form of ALS often have parkinsonism-dementia. Its occurrence outside of this geographic distribution has been reported,116-118 and its incidence on the western Pacific islands may be declining.119 The pathogenesis is not established; dietary exposure to a cycad-derived toxin may contribute. Other forms of ALS with extrapyramidal involvement include rare familial extrapyramidal syndromes.120,121

PATHOGENESIS The cause of sporadic ALS is unknown, although data are suggestive of an interaction of genetic and acquired mechanisms

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leading to neuronal death.1,122 Causative genes are identified for some inherited forms of ALS, but the molecular pathogenesis is not understood. ALS appears to be a multisystem disorder with selective vulnerability of UMNs and LMNs. Pathology of ALS is characterized by loss of LMNs in bulbar motor nuclei and the spinal anterior horn.16 UMN changes include myelin pallor in the corticospinal tract and variable pathological changes in motor cortex, such as loss of pyramidal neurons, including Betz cells, and motor cortex gliosis. LMN nuclei characteristically spared are those innervating external ocular muscles (cranial nerves III, IV, and VI) and those innervating pelvic floor/sphincter muscles (Onuf’s nucleus). Molecular pathogenesis of ALS appears to involve more than one distinct mechanism.1,3 Basic research data suggest that oxidative damage, neurofilament disorganization, glutamate excitotoxicity, formation of intracellular aggregates, and the failure of protein degradation are important components. It is unknown whether more than one independent mechanism is necessary and sufficient to cause sporadic ALS. Potential pathogenic mechanisms are referred to in relation to therapy in the following discussion. Genetic factors in ALS include disease-causing mutations in familial ALS and genes that appear to modify disease risk in sporadic ALS. About 10% of cases of ALS are familial, mostly autosomal dominant, although autosomal recessive and Xlinked familial ALS also occur.120,123 Genetic linkage is established for a growing number of familial ALS types (Table 66–8). Reports of families with ALS not linked to known loci indicate further heterogeneity. Approximately 20% of patients with familial ALS have ALS1, a mutation in the copper/zinc superoxide dismutase gene (SOD1) linked to chromosome 21q12.1.124 More than 100 pathogenic SOD1 mutations are known.125 Inheritance with all but one of these is autosomal dominant. The phenotype is compatible with classic ALS, but age at onset and severity may vary within families, and penetrance may be less than 100%.120

T A B L E 66–8. Familial Forms of Amyotrophic Lateral Sclerosis Type

Gene*

Locus

Inheritance

Comment

ALS1 ALS2 ALS3 ALS4 ALS5

SOD1 Alsin ? SETX ?

21q12.1 2q33-35 18q21 9q34 15q15-q22

AD AR AD AD AR

ALS6

?

16q12

AD

ALS7 ALS8

? VAPB

20ptel-p13 20q13.33

AD AD

ALS-FTD ALS-FTD

? MAPT

9q21-22 17q

AD AD

Classic ALS Juvenile onset Classic ALS Onset < age 25 years Juvenile or adult onset ALS with FTD in some affected patients Classic ALS Classic ALS or adult SMA FTD Variable extrapyramidal features

Modified from Kunst CB: Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet 2004; 75:933-947. See also Online Mendelian Inheritance in Man for *Updated information. Question marks denote gene not identified. AD, autosomal dominant; AR, autosomal recessive; FTD, frontotemporal dementia; SETX, senataxin; SMA, spinal muscular atrophy; SOD1, copper/zinc superoxide dismutase; VAPB, vesicle-associated membrane protein/synaptobrevin-associated membrane protein B.

Other genes account for the 80% of cases of familial ALS not linked to SOD1 (see Table 66–8).126-132 Better understanding of the molecular basis of familial ALS is expected to lead to improved understanding of the pathogenesis of sporadic ALS. The development of ALS or course of the disease in sporadic and familial ALS may be modified by genes that are not by themselves pathogenic. These include vascular endothelial growth factor120 and the survival motor neuron genes 1 and 2 on chromosome 5.133-136 Environmental factors have been considered as potential risk factors for ALS, but a pathogenic basis is not yet established for any of these.5,115 Putative dietary risks include high dietary fat, low fiber intake, and high dietary glutamate. Current smoking is associated with the threefold risk increase; past cigarette smoking confers a twofold risk. Athletic conditioning and reduced body mass index (BMI) may confer increased risk, although physical activity per se apparently does not.137 Risk is higher for urban dwellers. Isolated examples of geographic clustering of sporadic ALS raise questions of environmental or environmental-genetic factors, but no proved factors are identified. A slightly increased but unexplained risk of ALS is seen in military personnel.138 Necessary interaction of environmental factors in genetically susceptible individuals may underlie the failure to more strongly link specific environmental factors with sporadic ALS.

DIAGNOSTIC STUDIES Neurophysiological Evaluation Nerve conduction studies and EMG are central to establishing the diagnosis of ALS and investigating other possible diagnoses.139,140 In the revised El Escorial criteria, nerve conduction studies are required for the diagnosis of ALS “principally to define and exclude other disorders of peripheral nerve, neuromuscular junction and muscle that may mimic or confound the diagnosis of ALS. These studies should generally be normal or near normal.”14 In accordance with this guideline, nerve conduction data in ALS typically show normal sensory amplitudes, normal or reduced motor amplitudes, and normal conduction velocities and distal latencies.140 Abnormalities outside this range do not preclude ALS if accounted for by additional conditions, such as superimposed focal entrapment neuropathy. Evidence of motor conduction block should be sought, especially in patients with predominantly LMN features, because this is a key marker for multifocal motor neuropathy with conduction block (Fig. 66–2).141,142 Sensory responses in the latter disorder are expected to be normal. Marked motor denervation associated with reduced motor amplitude may be accompanied by mild motor conduction velocity slowing as a result of loss of fast conducting axons. Sensory amplitudes and distal latencies may be mildly abnormal in patients with ALS but should be interpreted cautiously, and alternative causes should be investigated. General guidelines for interpretation of nerve conduction abnormalities in ALS have been published.143 Repetitive motor nerve stimulation at low rates (i.e., 2 to 3 Hz) is indicated if myasthenia gravis or LEMS is a consideration. Decremental response is expected with stimulation of

chapter 66 amyotrophic lateral sclerosis Elbow Radial groove Supraclavicular fossa

5 mg

100 mA 2 mV

100 mA 2 mV

83.9 mA 2 mV ■

Figure 66–2.

Partial motor conduction block in a 56-year-old man with multifocal motor neuropathy and elevated ganglioside antibody titers, including immunoglobulin M antibody to GM1. Radial motor nerve conduction studies recorded from the extensor digitorum communis with surface stimulation and recording. Compound muscle action potential amplitude and area are reduced on stimulation at the radial groove in comparison with stimulation at the elbow. More severe reduction is apparent with supraclavicular fossa stimulation in comparison with the radial groove. The findings are compatible with demyelination that results in partial motor conduction block between the radial groove and elbow and, in addition, between the supraclavicular fossa and the radial groove. (From Olney RK, Lewis RA, Putnam TD, et al: Consensus criteria for the diagnosis of multifocal motor neuropathy. Muscle Nerve 2003; 27:117-121.)

clinically weak muscles in these disorders but is reported in ALS, particularly if motor amplitudes are low.144 In ALS, this defect apparently arises from the nerve terminal–neuromuscular junction. Associated signs of motor denervation on EMG distinguish this finding in ALS from neuromuscular junction disorders. Single fiber EMG may be useful if neuromuscular junction disease is suspected and standard EMG is not suggestive of motor denervation. Increase in amplitude of the motor response by more than 200%, immediately after isometric exercise (or 20- to 50-Hz stimulation), termed postexercise facilitation, is observed with LEMS.79 EMG aids in demonstrating the presence of LMN involvement in ALS and is central to published diagnostic guidelines used in establishing the diagnosis (Table 66–9; see Table 66–3).13,14,140 The revised El Escorial criteria advise electrophysiological studies to confirm signs of LMN dysfunction, identify electrophysiological evidence of LMN dysfunction in clinically uninvolved regions, and exclude other pathophysiological processes. Evidence of LMN dysfunction supports the diagnosis of ALS but is not itself diagnostic of the disorder, inasmuch as similar abnormalities can be found in a wide range of conditions that involve the LMN, including peripheral neuropathic, radicular, and anterior horn cell disorders.139 EMG in ALS generally demonstrates fasciculation potentials, fibrillation potentials, and long-duration, high-amplitude, and complex voluntary motor unit potentials with reduced recruit-

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ment (Fig. 66–3).139,140 Fibrillation and fasciculation potentials in particular are expected in ALS. Large and/or complex motor unit potentials reflect chronic motor denervation and reinnervation in affected motor units. Recruitment changes signal loss of motor units. In the investigation of possible ALS, examination of muscles that do not appear to be involved may reveal subclinical LMN involvement. Examination of thoracic paraspinal muscles and rectus abdominis is useful in identifying thoracic region motor denervation.20,145 Motor unit estimates refers to various neurophysiological techniques developed for quantification of the number of motor units in skeletal muscles.109 Motor unit estimates have been studied in the evaluation and follow-up of ALS, but their use remains primarily investigative.146 Motor evoked potentials have been studied as a means of identifying UMN pathology in ALS, although their role for this indication is not established.147,148 Somatosensory evoked potentials may be abnormal in ALS, but the sensitivity and utility of these techniques are significantly less than those of EMG.149,150 Neuroimaging studies in the evaluation of ALS aid in determining whether a disorder other than ALS may be present. Targeted on the basis of physical findings and EMG, brain and spinal MRI can enable detection of structural and vascular lesions and demyelination. Computed tomographic scanning and contrast myelography are alternatives for initial evaluation in patients unable to undergo MRI. Several MRI techniques have been investigated for their potential to demonstrate ALS-specific abnormalities.151-153 Brain MRI in ALS may reveal increased signal in the corticospinal tract using certain sequences, such as T2-weighted imaging and fluid-attenuated inversion recovery imaging sequences. Magnetic resonance spectroscopy allows localized, quantitative assessment of brain biochemistry and is reported to show signs of UMN involvement in proportion to clinical UMN signs. Data are suggestive of the utility of magnetic resonance diffusion tensor imaging or T1-weighted spin-echo magnetization transfer contrast-enhanced imaging for detecting corticobulbar and corticospinal abnormalities.154 However, the sensitivity and specificity of these imaging techniques are not yet established for routine use in the diagnostic evaluation of ALS.

Clinical Laboratory Testing Clinical laboratory testing is indicated in the evaluation of ALS in order to identify conditions other than ALS that may manifest similarly. Normal results aid in supporting the diagnosis of ALS. Standard tests also help to identify medically significant comorbid conditions. Specialized tests for neoplastic conditions or infectious diseases may be indicated, depending on history, clinical findings, and results of initial routine testing (Table 66–10).155

Muscle and Nerve Biopsy Neither muscle nor peripheral nerve biopsy is essential for the diagnosis of ALS. Muscle biopsy may be warranted to confirm the presence of LMN involvement or if workup results raise the possibility of primary muscle disease.14,156 Nerve biopsy may be indicated if peripheral nerve disease is suspected.14

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T A B L E 66–9. El Escorial Guidelines for Electrophysiological Testing in the Diagnosis of Amyotrophic Lateral Sclerosis (ALS) Nerve Conduction Studies Motor

Expected in ALS CV is normal unless CMAP is small

Sensory

Normal, but may be abnormal with peripheral nerve disease/ entrapment coexisting with ALS; lower limb sensory responses may be difficult to elicit in the elderly

Needle Electromyography (EMG) Signs of active and chronic denervation* on needle EMG examination in at least 2 of the 4 CNS regions

Features Suggestive of Other Diagnoses Evidence of motor conduction block CV < 70% of LLN DL > 30% above ULN F-wave or H-wave latency > 30% above ULN Decrement > 20% on repetitive stimulation Abnormal sensory nerve conduction studies (i.e., as a result of peripheral neuropathy, entrapment

Brainstem Cervical Thoracic Lumbosacral

≥1 Muscle; i.e., tongue, face, jaw ≥2 Limb muscles innervated by different roots/peripheral nerves Paraspinal region below T6 or abdominal muscles ≥2 Limb muscles innervated by different roots/peripheral nerves

Expected in ALS Normal

Features Suggestive of Other Diagnoses Evoked response latencies > 20% above ULN

Normal Normal

Significant abnormality Significant abnormality

Other Electrophysiological Testing Modality Somatosensory evoked potentials Autonomic testing Electronystagmography

Modified from Mitsumoto H, Chad D, Pioro E: Diagnostic evaluation of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 125-128. *Signs of active denervation: fibrillation potentials; positive sharp waves; signs of chronic denervation: large motor unit potentials; reduced recruitment (firing rates of individual potentials > 10 Hz), unstable motor unit potentials (see Fig. 66–3C); fasciculation potentials not required, but absence raises doubts regarding diagnosis. CMAP, compound muscle action potential; CNS, central nervous system; CV, conduction velocity; DL, distal latency; EMG, electromyographic; LLN, lower limit of normal; ULN, upper limit of normal.

MANAGEMENT Pharmacological Treatment Of the variety of therapeutic agents tested in clinical trials, none to date has yielded improvement in motor function or significantly slowed disease progression in ALS (Table 66–11),5 although the antiglutamate agent riluzole modestly extends survival.157 Drug development in ALS research has followed advances in basic research, especially since the 1990s. Availability of transgenic mouse and rat models for ALS that overexpress mutant forms of human copper/zinc superoxide dismutase (SOD1) and greater understanding of mechanisms contributing to neuronal death in ALS allow more systematic evaluation of potential therapies. A number of therapeutics ineffective in human studies were originally beneficial in mouse models of ALS. Differences in the pathogenesis of human ALS and animal models of the disease may be responsible for this inconsistency, although interspecies differences in response to the medication, and in some trials, the method of drug delivery or dosage may be relevant. Human studies of potential therapeutic agents extend from current concepts of disease pathogenesis in ALS, including excitotoxicity with excessive glutamate activity in the brain and spinal cord, neuroinflammation with microglial activation, and oxidative stress.

Excitotoxicity Only the glutamate antagonist riluzole has proved to alter the natural course of ALS, but its effect is small.5,158 Three large,

randomized clinical trials involving patients treated with riluzole at 100 mg/day demonstrated modestly increased survival but no effect on muscle strength. An American Academy of Neurology practice advisory on the treatment of ALS recommends that riluzole be offered to patients with ALS who do not require mechanical ventilation. Other drugs or compounds with potential antiexcitotoxic/ antiglutamate effects in ALS, including branched-chain amino acids, dextromethorphan, and the anticonvulsants lamotrigine, topiramate, and gabapentin, yielded no benefit in clinical trials. Increased cellular calcium concentrations that may accompany excitotoxicity prompted clinical trials of the calcium channel blockers verapamil and nimodipine, with negative results.

Neuroinflammation and Microglial Activation Expression of cyclooxygenase 2 is increased in the central nervous system in ALS, which led to consideration of cyclooxygenase 2 inhibitors as a potential treatment for ALS.5 One of these, celecoxib, slowed disease progression in a mouse model of ALS but showed no benefit in human patients with ALS. Minocycline is a tetracycline antibiotic with antiinflammatory effects also shown to be beneficial in ALS mice, and a clinical trial in human ALS is ongoing. Total lymphoid irradiation, cyclophosphamide, interferon, plasmapheresis, and intravenous immune globulin demonstrated no efficacy in human ALS.1,159,160

chapter 66 amyotrophic lateral sclerosis 50 uV

50 ms

50 uV

869

50uV

50 ms

50uV

50 ms

5 ms

B

A 200 uV

200 uV

10 ms

10 ms

5 ms

200 uV

1 mV

10 ms

*

C

D ■

Figure 66–3.

Examples of electromyographic findings in amyotrophic lateral sclerosis (ALS). A, left, Two fasciculation potentials recorded at 50-milliseconds/division sweep speed. Right, Same fasciculation potentials shown at left, at 5-milliseconds/division sweep speed, demonstrating prolonged duration of the first potential and normal duration of the second. Configuration of fasciculation potentials in ALS reflects the state of the motor unit generating the potential, and may be that of a normal motor unit potential or show evidence of chronic motor denervation. B, Fibrillation potentials: top, predominantly spike configuration; bottom, mixed positive wave and spike configuration. C, Abnormal voluntary motor unit potentials seen with chronic partial motor denervation and reinnervation. Top, Complex motor unit potentials. Bottom, Neurogenic reduced recruitment; high-amplitude motor unit potential firing at approximately 30 Hz. D, top, Unstable, complex motor unit potential firing at approximately 25 Hz. Bottom, motor unit potential shown at top; superimposed tracings demonstrate instability of firing, including variable presence of satellite potentials (asterisk).

Oxidative Stress A variety of antioxidants have been tested for therapeutic efficacy in ALS. Vitamin C and vitamin E were beneficial in SOD1 mice. Administration of vitamin E with riluzole in human ALS may have slowed disease progression, but survival was not affected.5,160 Antioxidant supplements of possible but as yet unproved benefit in ALS include vitamin C, coenzyme Q10, betacarotene, and N-acetylcysteine. In one review of antioxidant supplements, investigators found no evidence of efficacy in ALS.161 Whether this reflects general ineffectiveness of antioxidant treatment in human ALS, flawed clinical trial design, or lack of efficacy of the antioxidants tested is unresolved. These supplements appear to have a favorable safety profile, although questions regarding safety of vitamin E in doses of 400 IU/day

or higher have been raised.162 General guidelines regarding dosage in ALS have emerged (Table 66–12).5,163

Trophic Factors Neurotrophic growth factors are polypeptides shown to promote survival of motor neurons in animal models of ALS.5,160 Several have been studied in human patients with ALS, with mixed results. Insulin-like growth factor 1 yielded a modestly reduced rate of decline in a U.S. trial but not in a European study. A third trial of insulin-like growth factor 1 is under way in the United States to help resolve this discrepancy. Ciliary neurotrophic factor and brain-derived neurotrophic factor were ineffective in ALS clinical trials. Testing of glial-derived

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T A B L E 66–10. Clinical Laboratory Evaluation of Amyotrophic Lateral Sclerosis

T A B L E 66–11. Therapeutic Agents Studied in Amyotrophic Lateral Sclerosis (ALS)

Routine Studies Complete blood count Electrolyte measurements Liver function tests Fasting serum glucose measurement Creatinine measurement Thyroid function tests (TSH) Vitamin B12 level measurement Rapid plasma reagin Connective tissue disease screen (ANA, RF, ENA) Immunofixation electrophoresis of serum and urine

Agent

Results in ALS Clinical Trials

Antioxidant Betacarotene Coenzyme Q10 N-acetylcysteine Selegiline Vitamin C Vitamin E Calcium Channel Blocker Nimodipine Verapamil

All negative

Special Studies

Qualifiers

Ganglioside antibodies (GM1; asialo-GM1) Kennedy’s disease: androgen receptor CAG mutation DNA testing Leukocyte hexosaminidase A assay Anti-HIV antibody

Mainly LMN signs

Anti-inflammatory Celecoxib Cyclophosphamide Interferon Intravenous immune globulin Minocycline Levamisole Plasmapheresis Total lymphoid irradiation

Negative Negative Negative Negative Trial in progress Negative Negative Negative

Antiexcitotoxic Riluzole Branched-chain amino acids Dextromethorphan Gabapentin Lamotrigine Topiramate

Modest extension of survival (≈10%) Negative Negative Negative Negative Negative

Anti-HTLV I/II antibody Urine metals screen Adrenal myeloneuropathy: very-long-chain fatty acid levels Serum parathyroid hormone level

Mainly LMN signs, sensory symptoms/ signs, gynecomastia Mental changes, sensory symptoms/ signs HIV risk factors or workup suggests infectious disease Ascending myeloneuropathy; possible infectious disease Heavy metals exposure Onset < age 40 years, adrenal insufficiency, sensory symptoms/ signs Serum calcium level elevated

ANA, antinuclear antibody; CAG, cytosine-adenine-guanine; ENA, antibody to extractable nuclear antigen; HIV, human immunodeficiency virus; HTLV, human T cell lymphotropic virus; LMN, lower motor neuron; RF, rheumatoid factor; TSH, thyroid-stimulating hormone.

neurotrophic factor was suspended during phase 1 safety studies.

Other Pharmacological Agents Creatine extended survival in SOD1 mice, although the mechanism of action is not established. However, in two human ALS studies, creatine at 5 to 10 g/day showed no benefit.164 The antibiotic ceftriaxone in small, uncontrolled studies appeared to have no efficacy in human ALS, but more recent animal and in vitro data have prompted a reappraisal. A multicenter trial is planned.165-167

Stem Cells Replacement of damaged or lost neurons by stem cell therapy in ALS is intuitively attractive and holds promise as a potential treatment, but technical challenges remain.168 Anecdotal reports of successful application of this treatment in patients with ALS outside the United States have not been subject to controlled study.169

Symptomatic and Supportive Care Patients with ALS may experience a wide range of symptoms directly or indirectly linked to progressive weakness. Manage-

Trophic Factor BDNF CNTF GDNF IGF-1 Other Creatine Ceftriaxone

All negative

Negative Negative Withdrawn during phase 1 testing Efficacious in 1 of 2 trials; third trial under way Negative Trial in planning stages

Data from Cleveland DW, Rothstein JD: From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Natl Rev Neurosci 2001; 2:806-819; and from Carter GT, Krivickas LS, Weydt P, et al.: Drug therapy for amyotrophic lateral sclerosis: Where are we now? IDrugs 6:147-53, 2003. BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; GDNF, glial-derived neurotrophic factor; IGF-1, insulin-like growth factor 1.

T A B L E 66–12. Antioxidant Supplements Used to Treat Amyotrophic Lateral Sclerosis Supplement

Daily Dose Range

Betacarotene Coenzyme Q10 N-acetylcysteine Vitamin C Vitamin E

10-25,000 IU 50-300 mg 100-200 mg 500-1000 mg Up to 2000 IU

From Carter GT, Krivickas LS, Weydt P, et al.: Drug therapy for amyotrophic lateral sclerosis: where are we now? IDrugs 2003; 6:147-153; and from Pioro EP: Antioxidant therapy in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1(Suppl 4):5-12; discussion, Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1(Suppl 4):13-15.

chapter 66 amyotrophic lateral sclerosis ment of these can significantly affect quality of life. Commonly reported symptoms and their treatment are briefly reviewed as follows. Multidisciplinary ALS clinics, where available, can aid the primary neurologist in long-term care of patients with ALS. There is evidence that survival is improved for patients with ALS with whom this model of care is used.170 Hospice referral can aid patients and family members significantly in day-to-day care of patients approaching a terminal stage.4 Fatigue is common in ALS, potentially exacerbated by muscle weakness and overexertion, by sleep disturbance, and by conditions unrelated to ALS. The last contributor, such as hypothyroidism, cardiac disease, or primary pulmonary disease, should be considered. For some patients, counseling regarding energy conservation techniques may be helpful. Data suggest that modafinil may be helpful.5 The possibility of preexisting depression or depression associated with ALS should be explored; treatment is discussed later. Clinicians should inquire specifically about sleep disturbance, because patients may fail to recognize this as a cause of daytime fatigue. Management of sleep disturbance in ALS is briefly reviewed later. Fasciculations are found in nearly all patients with ALS but often are not bothersome enough to warrant treatment. Fasciculations themselves are not harmful. For suppression of fasciculations, anecdotal recommendations include gabapentin, phenytoin, carbamazepine, or lorazepam, but none has been of proved benefit in controlled trials.171,172 Muscle cramps involving the limbs and trunk may occur in ALS either in association with activity or spontaneously. Depending on severity, nocturnal lower limb cramps may improve with stretching exercises performed before retiring and with increased fluid intake. Medications that may be effective include quinine sulfate, baclofen, and tizanidine.171 Spasticity resulting in slowness of movement, gait and limb incoordination, and limb spasms can be intrusive symptoms. Injurious falls can be a significant problem for patients with axial and limb spasticity. Gait stability may be improved with ankle-foot orthoses.172 Medications include diazepam, baclofen, and tizanidine.171,172 Intrathecal baclofen administered by an implantable pump is a consideration in patients with an extended clinical course dominated by spasticity.173

Dyspnea The patient’s decision regarding mechanical ventilation is central to management of dyspnea in ALS.6 Counseling with regard to ventilatory support should be offered relatively early in the course of management, although timing of this discussion may be a sensitive issue for patients and caregivers. Periodic pulmonary function tests, including maximum inspiratory pressure, forced vital capacity, or vital capacity, provide important information regarding pulmonary function, and declining values offer a basis for discussion of respiratory management options. Mechanical ventilatory support includes invasive and noninvasive options (Table 66–13). Palliative approaches can be offered to patients who decline mechanical ventilatory support. Studies have suggested that survival and quality of life in ALS are improved with noninvasive mechanical ventilation.10,174,175 Negative- and positive-pressure options are available. Negative-pressure devices are less widely used but may be appropriate for some patients. The “iron lung” is an early example; portable equipment such as the chest cuirass is a more current alternative. Negative-pressure ventilation is not

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T A B L E 66–13. Management of Respiratory Muscle Weakness in Amyotrophic Lateral Sclerosis Treatment

Description and Rationale

Nonmechanical/terminal care techniques

Body positioning to elevate head and shoulders; reduce pressure of abdominal contents on diaphragm (i.e., elevate head of bed195) Treatment of reversible causes of dyspnea (i.e., pneumonia6) Oxygen by nasal cannula, 2-4 L/minute; may promote apnea if patient is retaining C02194 For terminal dyspnea, morphine sulfate: initially 2.5 mg intravenously/ subcutaneously/transdermally or oral equivalent by mouth, percutaneous endoscopic gastrostomy tube, or rectally (i.e., tablets, elixir 20 mg/mL, or rectal suppository) Chlorpromazine may be needed as antiemetic6,172,195

Mechanical techniques10 Negative pressure Positive pressure

Iron lung Chest cuirass Pneumojacket Noninvasive positive-pressure ventilation (i.e., bilevel positive airway pressure) Tracheostomy ventilation

appropriate for patients with significant bulbar weakness, because negative chest pressure breathing can lead to upper airway collapse. Positive-pressure ventilation includes noninvasive and invasive methods, the latter for patients unable to tolerate noninvasive ventilation or in whom it fails. Noninvasive ventilation is administered with a mask or other interface; invasive ventilation is by tracheostomy (Fig. 66–4). Noninvasive positive-pressure ventilation in ALS typically employs an inspiratory pressure set slightly higher than expiratory pressure, referred to as bilevel positive airway pressure (BiPAP). Ventilation by tracheostomy is indicated in patients unable to control upper airway secretions, in those unable to tolerate the BiPAP interface, or when adequate oxygenation cannot be achieved with BiPAP. Patients and caregivers tend to accept noninvasive ventilation better than ventilation by tracheostomy.6 The likelihood of accepting tracheostomy is greater in patients making an advance decision rather than during an acute episode of respiratory distress. It is appropriate in patients initiating noninvasive ventilation to consider whether they wish to proceed with tracheostomy should this become indicated. Patients opting for mechanical ventilation should have made a prior decision as to any circumstances under which they would want ventilatory support discontinued.4 Adjuncts to mechanical ventilation include management of potentially excess oral secretions, or sialorrhea, discussed later, and cough assistance techniques.176 Patients unable to generate an adequate cough may benefit from using a mechanical cough assistance device, which delivers air through the mouth, followed by rapid release, stimulating a cough.10,176 Sleep disturbance in ALS may be contributed to by a variety of factors. One of these is musculoskeletal pain from impaired mobility and improper positioning. An egg crate mattress pad,

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Figure 66–4.

Noninvasive mechanical ventilation by nasal pillow interface in a patient with amyotrophic lateral sclerosis. Mechanical ventilation without need for tracheostomy can be an option if oropharyngeal strength allows adequate airway protection. This man has relatively preserved speech and swallowing ability despite severe respiratory and limb muscle weakness.

pillows to facilitate positioning, or a hospital bed may improve sleep quality. Medications potentially helpful in promoting sleep include amitriptyline, diphenhydramine, and zolpidem.171 Sleep disturbance in ALS may also be associated with disturbed sleep architecture related to periodic leg movements or oxygen desaturation. Periodic leg movements may respond to dopamine agonists.172 Oxygen desaturation from upper airway obstruction can be investigated through the use of overnight oximetry or in a formal sleep study. Suspected respiratory muscle weakness resulting in sleep disturbance is perhaps more reliably evaluated by daytime measures of respiratory function, such as pulmonary function tests and arterial blood gas measurements.174 Treatment is by noninvasive positive pressure ventilation, typically BiPAP.172 Sialorrhea, or drooling, probably caused by mechanical impairment of swallowing, can be troublesome in ALS.6 Anticholinergic medications that reduce saliva production, such as glycopyrrolate, tricyclic antidepressants, or transdermal scopo-

lamine, may help but can produce unwanted side effects such as constipation. Botulinum toxin injection into the parotid or submandibular salivary glands inhibits saliva production but may lead to temporary weakness of adjacent muscles.177-179 Lack of systemic anticholinergic side effects is a potential advantage over standard medications. Irradiation of the salivary glands can permanently reduce saliva production, although some patients may find resulting xerostomia bothersome.180,181 A manual suction catheter offers another approach, used alone or in conjunction with other treatments.6 Portable suction machines are available. Dysphagia can be managed with dietary modification.6 A modified barium swallow study is indicated for investigation of possible aspiration in this setting, because the history may not enable reliable determination of aspiration risk. This evaluation may be facilitated by consultation with a speech pathologist. Some degree of weight loss in ALS can be expected because of denervation-related loss of muscle mass, but weight loss despite dietary intervention or aspiration warrants consideration of a percutaneous endoscopic gastrostomy tube (PEG) or percutaneous radiological gastrostomy (PRG).182-184 Early patient education regarding the rationale for PEG or PRG tube placement is important in helping to establish patient acceptance of the procedure. Ideally, a PEG or PRG tube should be placed before forced vital capacity falls below 50% of predicted in order to reduce the risk of pulmonary complications potentially associated with the procedure. However, patients with forced vital capacity less than 50% of predicted can safely undergo PEG or PRG tube placement while supported with noninvasive mechanical ventilation (BiPAP).185 Laryngospasm is an abrupt sensation of throat closure and inability to inhale.172 The sensation may be momentary and dissipates spontaneously but can be highly distressing to patients. Hyperactive gag reflex and sensitivity to gastric acid reflux may contribute. Antireflux and antacid agents may help.171 Lorazepam oral concentrate administered sublingually may abort acute attacks.172 “Thick phlegm” refers to the sensation of secretions in the back of the throat that cannot be cleared because of compromised cough strength.172 Guaifenesin, nebulized saline, or 10% acetylcysteine can be helpful. β Blockers have been recommended but may have less efficacy.

Dysarthria Intelligibility with mild to moderate dysarthria can be managed by maintaining face-to-face contact and reducing background noise.186 A speech pathologist can assist the patient and family in adaptive approaches.187 With more pronounced dysarthria, patients with adequate hand control may resort to written communication. Electronic devices, handheld or operated by standard personal computers, are available with speech synthesizer and text display capabilities. These augmentive and alternative communication (AAC) devices allow effective communication but can be physically demanding for patients, and communication with them tends to be relatively slow.172

Depression, Dementia, and Anxiety Depression should be inquired about during the course of care by direct questioning. There are no studies to indicate whether tricyclic antidepressants or selective serotonin reuptake

chapter 66 amyotrophic lateral sclerosis inhibitors differ in efficacy in ALS.171 The side effect profiles of the various drugs should be considered in initiating therapy, and the selective serotonin reuptake inhibitors may be better tolerated. Pseudobulbar affect may respond to fluvoxamine or amitriptyline.188,189 Data are suggestive of greater benefit with a combination of dextromethorphan and quinidine, 30 mg each twice daily.190 Dementia in ALS tends to be of the frontotemporal type, differing from that of Alzheimer’s disease.109 Efficacy of acetylcholinesterase inhibitors such as donezepil is uncertain. Data on rivastigmine in frontotemporal dementia raise the possibility that this agent may be beneficial, but its use in ALS dementia has not been studied.191 Cognitive dysfunction unrelated to dementia also may occur with chronic sleep disturbance caused by respiratory muscle weakness.192 Anxiety in ALS arising from psychological effects of the disease may by ameliorated by a caring, supportive relationship with the physician and by psychological or psychiatric counseling.193 If pharmacological treatment is needed, lorazepam or diazepam can help alleviate these symptoms.171 Anxiety resulting from hypoxia caused by terminal respiratory muscle weakness is discussed in the following section.

Terminal Care Terminal care includes management of symptoms stemming from respiratory failure and severe limb and trunk muscle weakness.6 These include dyspnea and related anxiety and pain potentially exacerbated by muscle cramps, spasticity, and positional effects of immobility. Detailed reviews of terminal care in ALS have been published.6,194,195 Communication with the patient, although potentially difficult because of progressive weakness, is an important part of management. Compassionate care with attention to psychological and spiritual support is central to providing effective treatment. Discussion of end-of-life matters with the patient and family is appropriate when clinically significant respiratory and bulbar involvement is apparent. Even if advance directives are already established, review of them is worthwhile, because the patient’s wishes may have changed with progression of the disease. An approach to terminal respiratory management is outlined in Table 66–13. Anxiety symptoms associated with respiratory failure can be controlled with lorazepam (i.e., 1 to 2.5 mg sublingually initially), diazepam or midazolam.6,195

Pain Management Pain management guidelines provided in the American Academy of Neurology Practice Parameter on the care of ALS include initial use of nonnarcotic analgesic/anti-inflammatory agents and antispasticity drugs and later use of opioids for pain refractory to these medications.6,194 Hospice referral should be considered, because hospice support can significantly improve quality of life during terminal care of ALS.6

PROGNOSIS Average survival in ALS is approximately 2.5 years after onset of limb symptoms and 1 year after onset of bulbar symptoms.5

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Survival is improved if the patient opts for mechanical ventilatory support and/or a gastrostomy feeding tube.183,196,197 Decline in motor function in ALS is generally linear, although the rate of decline varies among patients.198 The practical utility of prognostic factors derived from natural history studies is limited, although available data allow some generalizations. Better prognosis is reported with age younger than 55 years, onset of limb symptoms, manifestation with purely LMN or purely UMN signs, absence of pulmonary symptoms at onset, minimal fasciculations, and relatively mild motor impairment and/or extended time from symptom onset to diagnosis.198,199 Poor prognosis is associated with shortened time from symptom onset to diagnosis, rapid progression of early ALS symptoms, and rapid decline of pulmonary function.200-202 Familial forms of ALS in general appear to have a poorer prognosis than does sporadic ALS, although extended survival is reported with certain SOD1 mutations.198 Poor prognosis also is correlated with reduced compound muscle action potential amplitude on nerve conduction studies of the most affected limb.203 Decrement on repetitive stimulation is also suggestive of a poor prognosis.204,205 About 10% of patients with ALS survive 10 years or more.206 Survival in excess of three decades has been reported, but prolonged survival is not necessarily equated with milder disability, inasmuch as patients with severe impairment may experience extended survival.198 Patients in whom ALS develops and then appears to improve have been reported but are rare.207 LMN features predominated in these patients, and none had bulbar involvement; whether these patients in fact had ALS or a clinically similar disorder remains unresolved.198

K E Y

P O I N T S

●

ALS, or Lou Gehrig’s disease, is a disabling, slowly progressive neurodegenerative disorder affecting UMNs and LMNs with peak age at onset of 55 to 75 years.

●

The cause of ALS is not established, although research data are suggestive of an interaction of genetic and acquired mechanisms leading to neuronal death; about 10% of patients have familial ALS.

●

Although characteristic clinical findings readily establish the diagnosis of ALS, other neurological disorders with potentially similar features should be considered in the differential diagnosis.

●

Of therapeutic agents studied in clinical trials, none has improved motor function or significantly slowed disease progression in ALS, although the antiglutamate agent riluzole modestly extends survival.

●

Symptomatic and supportive care in ALS can significantly improve quality of life and improve survival. Multidisciplinary ALS clinics, where available, can aid the primary neurologist in the long-term care of patients with ALS.

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Suggested Reading Miller RG, Bradley WG, Gelinas D, et al: Amyotrophic Lateral Sclerosis. Continuum. American Academy of Neurology. Hagerstown, MD: Lippincott Williams & Wilkins 8:(4) August 2002. Brooks BR, Miller RG, Swash M, et al: El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1:293299. [Also available at: www.wfnals.org; accessed March 23, 2006] Cleveland DW, Rothstein JD: From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Natl Rev Neurosci 2001; 2:806-819. Forshew DA, Bromberg MB: A survey of clinicians’ practice in the symptomatic treatment of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:258-263. Miller RG, Rosenberg JA, Gelinas DF, et al: Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 1999; 52:1311-1323. Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998.

References 1. Cleveland DW, Rothstein JD: From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Natl Rev Neurosci 2001; 2:806-819. 2. Goldblatt D: Motor neuron disease: historical introduction. In Norris FH, Kurland LT, eds: Motor Neuron Diseases. Research on Amyotrophic Lateral Sclerosis and Related Disorders: Contemporary Neurology Symposia, vol 2. New York: Grune & Stratton, 1968, pp 3-11. 3. Strong M, Rosenfeld J: Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:136-143. 4. Borasio GD, Miller RG: Clinical characteristics and management of ALS. Semin Neurol 2001; 21:155-166. 5. Carter GT, Krivickas LS, Weydt P, et al: Drug therapy for amyotrophic lateral sclerosis: where are we now? IDrugs 2003; 6:147-153. 6. Miller RG, Rosenberg JA, Gelinas DF, et al: Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 1999; 52:13111323. 7. Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med 2001; 344:1688-1700. 8. Desai J, Swash M: Essentials of diagnosis. In Kuncl RW, ed: Motor Neuron Disease. Philadelphia: WB Saunders, 2002, pp 1-20. 9. Younger DS, Chou S, Hays AP, et al: Primary lateral sclerosis. A clinical diagnosis reemerges. Arch Neurol 1988; 45:1304-1307. 10. Krvickas L: Pulmonary function and respiratory failure. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 382-404. 11. Ince PG, Lowe J, Shaw PJ: Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology. Neuropathol Appl Neurobiol 1998; 24:104-117. 12. Norris F, Shepherd R, Denys E, et al: Onset, natural history and outcome in idiopathic adult motor neuron disease. J Neurol Sci 1993; 118:48-55.

13. Brooks BR: El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical Limits of Amyotrophic Lateral Sclerosis” workshop contributors. J Neurol Sci 1994; 124(Suppl):96-107. 14. Brooks BR, Miller RG, Swash M, et al: El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1:293-299. 15. Traynor BJ, Codd MB, Corr B, et al: Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch Neurol 2000; 57:1171-1176. 16. Ince PG: Neuropathology. In Brown RH Jr, Meininger V, Swash M, eds: Amyotrophic Lateral Sclerosis. London: Martin Dunitz, 2000, pp 83-112. 17. Gubbay SS, Kahana E, Zilber N, et al: Amyotrophic lateral sclerosis. A study of its presentation and prognosis. J Neurol 1985; 232:295-300. 18. Jokelainen M: Amyotrophic lateral sclerosis in Finland. II: clinical characteristics. Acta Neurol Scand 1977; 56:194-204. 19. Brooks BR: Design of clinical therapeutic trials in amyotrophic lateral sclerosis. In Rowland LP, ed: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases: Advances in Neurology, vol 56. New York, Raven Press, 1991, pp 521546. 20. Kuncl RW, Cornblath DR, Griffin JW: Assessment of thoracic paraspinal muscles in the diagnosis of ALS. Muscle Nerve 1988; 11:484-492. 21. Conradi S, Ronnevi LO, Norris FH: Motor neuron disease and toxic metals. Adv Neurol 1982; 36:201-231. 22. Roth G: Fasciculations and their F-response. Localisation of their axonal origin. J Neurol Sci 1984; 63:299-306. 23. Wettstein A: The origin of fasciculations in motoneuron disease. Ann Neurol 1979; 5:295-300. 24. Blexrud MD, Windebank AJ, Daube JR: Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol 1993; 34:622-625. 25. Robbins J: Swallowing in ALS and motor neuron disorders. Neurol Clin 1987; 5:213-229. 26. Parvizi J, Anderson SW, Martin CO, et al: Pathological laughter and crying: a link to the cerebellum. Brain 2001; 124: 1708-1719. 27. Gallagher JP: Pathologic laughter and crying in ALS: a search for their origin. Acta Neurol Scand 1989; 80:114-117. 28. Fromm GB, Wisdom PJ, Block AJ: Amyotrophic lateral sclerosis presenting with respiratory failure. Diaphragmatic paralysis and dependence on mechanical ventilation in two patients. Chest 1977; 71:612-614. 29. Hill R, Martin J, Hakim A: Acute respiratory failure in motor neuron disease. Arch Neurol 1983; 40:30-32. 30. Nightingale S, Bates D, Bateman DE, et al: Enigmatic dyspnoea: an unusual presentation of motor-neurone disease. Lancet 1982; 1:933-935. 31. Fallat RJ, Jewitt B, Bass M, et al: Spirometry in amyotrophic lateral sclerosis. Arch Neurol 1979; 36:74-80. 32. Kreitzer SM, Saunders NA, Tyler R, et al: Respiratory muscle function in amyotrophic lateral sclerosis. Chest 1978; 73:266267. 33. Gibson GJ: Diaphragmatic paresis: pathophysiology, clinical features, and investigation. Thorax 1989; 44:960-970. 34. Grinman S, Whitelaw WA: Pattern of breathing in a case of generalized respiratory muscle weakness. Chest 1983; 84:770-772. 35. Goldstein RS: Hypoventilation: neuromuscular and chest wall disorders. Clin Chest Med 1992; 13:507-521.

chapter 66 amyotrophic lateral sclerosis 36. Caselli RJ, Windebank AJ, Petersen RC, et al: Rapidly progressive aphasic dementia and motor neuron disease. Ann Neurol 1993; 33:200-207. 37. van den Berg-Vos RM, Visser J, Franssen H, et al: Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 2003; 126:1036-1047. 38. Mortara P, Chio A, Rosso MG, et al: Motor neuron disease in the province of Turin, Italy, 1966-1980. Survival analysis in an unselected population. J Neurol Sci 1984; 66:165-173. 39. Ince PG, Evans J, Knopp M, et al: Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology 2003; 60:1252-1258. 40. Iwanaga K, Hayashi S, Oyake M, et al: Neuropathology of sporadic amyotrophic lateral sclerosis of long duration. J Neurol Sci 1997; 146:139-143. 41. Pearn J: Autosomal dominant spinal muscular atrophy: a clinical and genetic study. J Neurol Sci 1978; 38:263275. 42. Rudnik-Schoneborn S, Rohrig D, Morgan G, et al: Autosomal recessive proximal spinal muscular atrophy in 101 sibs out of 48 families: clinical picture, influence of gender, and genetic implications. Am J Med Genet 1994; 51:70-76. 43. Somerville MJ, Hunter AG, Aubry HL, et al: Clinical application of the molecular diagnosis of spinal muscular atrophy: deletions of neuronal apoptosis inhibitor protein and survival motor neuron genes. Am J Med Genet 1997; 69:159165. 44. Harding AE, Thomas PK: Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J Med Genet 1980; 17:329-336. 45. Kennedy WR, Alter M, Sung JH: Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 1968; 18:671-680. 46. Harding AE, Thomas PK, Baraitser M, et al: X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 1982; 45:1012-1019. 47. La Spada AR, Wilson EM, Lubahn DB, et al: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352:77-79. 48. Olney RK, Aminoff MJ, So YT: Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy. Neurology 1991; 41:823-828. 49. Katz JS, Wolfe GI, Andersson PB, et al: Brachial amyotrophic diplegia: a slowly progressive motor neuron disorder. Neurology 1999; 53:1071-1076. 50. Hu MT, Ellis CM, Al-Chalabi A, et al: Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1998; 65:950-951. 51. Hirayama K, Tomonaga M, Kitano K, et al: Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry 1987; 50:285-290. 52. Hirayama K, Tokumaru Y: Cervical dural sac and spinal cord in juvenile muscular atrophy of distal upper extremity. Neurology 2000; 54:1922-1926. 53. de Visser M, Ongerboer de Visser BW, et al: Amyotrophy of the hands and pyramidal features of predominantly the legs segregating within one large family. J Neurol Sci 1988; 88:241-246. 54. Rowland LP, Schneck SA: Neuromuscular disorders associated with malignant neoplastic disease. J Chronic Dis 1963; 16:777-795. 55. Gordon PH, Rowland LP, Younger DS, et al: Lymphoproliferative disorders and motor neuron disease: an update. Neurology 1997; 48:1671-1678. 56. Younger DS, Rowland LP, Latov N, et al: Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann Neurol 1991; 29:78-86.

875

57. Rowland LP, Sherman WH, Latov N, et al: Amyotrophic lateral sclerosis and lymphoma: bone marrow examination and other diagnostic tests. Neurology 1992; 42:1101-1102. 58. Jubelt B, Cashman NR: Neurological manifestations of the post-polio syndrome. Crit Rev Neurobiol 1987; 3:199220. 59. Trojan DA, Cashman NR: Post-poliomyelitis syndrome. Muscle Nerve 2005; 31:6-19. 60. Dalakas MC, Elder G, Hallett M, et al: A long-term follow-up study of patients with post-poliomyelitis neuromuscular symptoms. N Engl J Med 1986; 314:959-963. 61. Johnson WG: The clinical spectrum of hexosaminidase deficiency diseases. Neurology 1981; 31:1453-1456. 62. Mitsumoto H, Sliman RJ, Schafer IA, et al: Motor neuron disease and adult hexosaminidase A deficiency in two families: evidence for multisystem degeneration. Ann Neurol 1985; 17:378-385. 63. Cashman NR, Antel JP, Hancock LW, et al: N-acetyl-β-hexosaminidase β locus defect and juvenile motor neuron disease: a case study. Ann Neurol 1986; 19:568-572. 64. Nagale SV, Bosch EP: Multifocal motor neuropathy with conduction block: current issues in diagnosis and treatment. Semin Neurol 2003; 23:325-334. 65. Nobile-Orazio E, Meucci N, Barbieri S, et al: High-dose intravenous immunoglobulin therapy in multifocal motor neuropathy. Neurology 1993; 43:537-544. 66. Bouche P, Moulonguet A, Younes-Chennoufi AB, et al: Multifocal motor neuropathy with conduction block: a study of 24 patients. J Neurol Neurosurg Psychiatry 1995; 59:3844. 67. Lange DJ, Trojaborg W, Latov N, et al: Multifocal motor neuropathy with conduction block: is it a distinct clinical entity? Neurology 1992; 42:497-505. 68. Pestronk A, Chaudhry V, Feldman EL, et al: Lower motor neuron syndromes defined by patterns of weakness, nerve conduction abnormalities, and high titers of antiglycolipid antibodies. Ann Neurol 1990; 27:316-326. 69. Kelly JJ Jr: Peripheral neuropathies associated with monoclonal proteins: a clinical review. Muscle Nerve 1985; 8:138150. 70. Ropper AH, Gorson KC: Neuropathies associated with paraproteinemia. N Engl J Med 1998; 338:1601-1607. 71. Rowland LP, Defendini R, Sherman W, et al: Macroglobulinemia with peripheral neuropathy simulating motor neuron disease. Ann Neurol 1982; 11:532-536. 72. Younger DS, Rowland LP, Latov N, et al: Motor neuron disease and amyotrophic lateral sclerosis: relation of high CSF protein content to paraproteinemia and clinical syndromes. Neurology 1990; 40:595-599. 73. Lewis RA, Sumner AJ, Brown MJ, et al: Multifocal demyelinating neuropathy with persistent conduction block. Neurology 1982; 32:958-964. 74. McKhann GM, Cornblath DR, Griffin JW, et al: Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China. Ann Neurol 1993; 33:333-342. 75. Barohn RJ, Kissel JT, Warmolts JR, et al: Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989; 46:878-884. 76. Drachman DB: Myasthenia gravis. N Engl J Med 1994; 330:1797-1810. 77. Keesey JC: Clinical evaluation and management of myasthenia gravis. Muscle Nerve 2004; 29:484-505. 78. McConville J, Farrugia ME, Beeson D, et al: Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55:580-584. 79. Mareska M, Gutmann L: Lambert-Eaton myasthenic syndrome. Semin Neurol 2004; 24:149-153.

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80. Lennon VA, Kryzer TJ, Griesmann GE, et al: Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 1995; 332:1467-1474. 81. Lotz BP, Engel AG, Nishino H, et al: Inclusion body myositis. Observations in 40 patients. Brain 1989; 112(Pt 3):727-747. 82. Dalakas MC: Polymyositis, dermatomyositis and inclusionbody myositis. N Engl J Med 1991; 325:1487-1498. 83. Mitsumoto H, Chad D, Pioro E: The differential diagnosis of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 87-121. 84. Le Forestier N, Maisonobe T, Spelle L, et al: Primary lateral sclerosis: further clarification. J Neurol Sci 2001; 185:95-100. 85. Pringle CE, Hudson AJ, Munoz DG, et al: Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain 1992; 115(Pt 2):495-520. 86. Gastaut JL, Bartolomei F: Mills’ syndrome: ascending (or descending) progressive hemiplegia: a hemiplegic form of primary lateral sclerosis? J Neurol Neurosurg Psychiatry 1994; 57:1280-1281. 87. Hudson AJ, Kiernan JA, Munoz DG, et al: Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis. Brain Res Bull 1993; 30:359364. 88. Kojan S, Goodwin W, Bryan WW, et al: Clinical and laboratory features of primary lateral sclerosis. J Child Neurol 2000; 15:200. 89. Brownell B, Oppenheimer DR, Hughes JT: The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry 1970; 33:338-357. 90. Fortini D, Cricchi F, Di Fabio R, et al: Current insights into familial spastic paraparesis: new advances in an old disease. Funct Neurol 2003; 18:43-49. 91. Fink JK: Progressive spastic paraparesis: hereditary spastic paraplegia and its relation to primary and amyotrophic lateral sclerosis. Semin Neurol 2001; 21:199-207. 92. Fink JK: The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 2003; 60:1045-1049. 93. Bouslam N, Benomar A, Azzedine H, et al: Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann Neurol 2005; 57:567-571. 94. Rowland LP: Diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1998; 160(Suppl 1):S6-S24. 95. Yamada M, Furukawa Y, Hirohata M: Amyotrophic lateral sclerosis: frequent complications by cervical spondylosis. J Orthop Sci 2003; 8:878-881. 96. Noseworthy JH, Heffernan LP: Motor radiculopathy—an unusual presentation of multiple sclerosis. Can J Neurol Sci 1980; 7:207-209. 97. Fisher M, Long RR, Drachman DA: Hand muscle atrophy in multiple sclerosis. Arch Neurol 1983; 40:811-815. 98. Matsuzaki T, Nakagawa M, Nagai M, et al: HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) with amyotrophic lateral sclerosis–like manifestations. J Neurovirol 2000; 6:544-548. 99. MacGowan DJ, Scelsa SN, Waldron M: An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2001; 57:1094-1097. 100. von Giesen HJ, Kaiser R, Koller H, et al: Reversible ALS-like disorder in HIV infection. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2002; 59:474; author reply, Neurology 2002; 59:474-475 [Erratum in Neurology 2002; 59:2009]. 101. Mariani C, Cislaghi MG, Barbieri S, et al: The natural history and results of surgery in 50 cases of syringomyelia. J Neurol 1991; 238:433-438. 102. Griffin JW, Goren E, Schaumburg H, et al: Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. I. Clin-

103.

104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114.

115.

116. 117. 118. 119.

120. 121. 122. 123. 124.

ical and endocrinologic aspects. Neurology 1977; 27:11071113. Mitsumoto H, Chad D, Pioro E: History, terminology, and classification of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 3-17. Sawaya RA: Foramen magnum meningioma presenting as amyotrophic lateral sclerosis. Neurosurg Rev 1998; 21:277280. Fan X, Rouleau GA: Progress in understanding the pathogenesis of oculopharyngeal muscular dystrophy. Can J Neurol Sci 2003; 30:8-14. Noseworthy JH, Rae-Grant AD, Brown WF: An unusual subacute progressive motor neuronopathy with myasthenia-like features. Can J Neurol Sci 1988; 15:304-309. Hayashi H, Kato S, Kawada A: Amyotrophic lateral sclerosis patients living beyond respiratory failure. J Neurol Sci 1991; 105:73-78. Kuncl RW: Errors in diagnosis. In Kuncl RW, ed: Motor Neuron Disease. London: WB Saunders, 2002, pp 21-38. Lomen-Hoerth C: Characterization of amyotrophic lateral sclerosis and frontotemporal dementia. Dement Geriatr Cogn Disord 2004; 17:337-341. Kondo K, Hemmi I: Clinical statistics in 515 fatal cases of motor neuron disease. Neuroepidemiology 1984; 3:129148. Hosler BA, Siddique T, Sapp PC, et al: Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 2000; 284:1664-1669. Qureshi AI, Wilmot G, Dihenia B, et al: Motor neuron disease with parkinsonism. Arch Neurol 1996; 53:987-991. Liang TW, Forman MS, Duda JE, et al: Multiple pathologies in a patient with a progressive neurodegenerative syndrome. J Neurol Neurosurg Psychiatry 2005; 76:252-255. Rodgers-Johnson P, Garruto RM, Yanagihara R, et al: Amyotrophic lateral sclerosis and parkinsonism-dementia on Guam: a 30-year evaluation of clinical and neuropathologic trends. Neurology 1986; 36:7-13. Armon C: Epidemiology of amyotrophic lateral sclerosis / motor neuron disease. In Shaw PJ, Strong MJ, eds: Motor Neuron Disorders: Blue Books of Practical Neurology. Philadelphia: Butterworth-Heinemann, 2003, pp 167-205. Gilbert JJ, Kish SJ, Chang LJ, et al: Dementia, parkinsonism, and motor neuron disease: neurochemical and neuropathological correlates. Ann Neurol 1988; 24:688-691. Hudson AJ: Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review. Brain 1981; 104:217-247. Schmitt HP, Emser W, Heimes C: Familial occurrence of amyotrophic lateral sclerosis, parkinsonism, and dementia. Ann Neurol 1984; 16:642-648. Waring SC, Esteban-Santillan C, Reed DM, et al: Incidence of amyotrophic lateral sclerosis and of the parkinsonismdementia complex of Guam, 1950-1989. Neuroepidemiology 2004; 23:192-200. Kunst CB: Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet 2004; 75:933-947. Furtado S, Payami H, Lockhart PJ, et al: Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). Mov Disord 2004; 19:622-629. Strong MJ, Lomen-Hoerth C, Caselli RJ, et al: Cognitive impairment, frontotemporal dementia, and the motor neuron diseases. Ann Neurol 2003; 54(Suppl 5):S20-S23. Siddique T, Lalani I: Genetic aspects of amyotrophic lateral sclerosis. Adv Neurol 2002; 88:21-32. Rosen DR, Siddique T, Patterson D, et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362:59-62.

chapter 66 amyotrophic lateral sclerosis 125. Andersen PM, Sims KB, Xin WW, et al: Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:62-73. 126. Chen YZ, Bennett CL, Huynh HM, et al: DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004; 74:1128-1135. 127. De Jonghe P, Auer-Grumbach M, Irobi J, et al: Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain 2002; 125:1320-1325. 128. Hand CK, Khoris J, Salachas F, et al: A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am J Hum Genet 2002; 70:251-256. 129. Chance PF, Rabin BA, Ryan SG, et al: Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet 1998; 62:633-640. 130. Hadano S, Hand CK, Osuga H, et al: A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001; 29:166-173. 131. Yang Y, Hentati A, Deng HX, et al: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 2001; 29:160-165. 132. Hentati A, Ouahchi K, Pericak-Vance MA, et al: Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998; 2:5560. 133. Cleveland JL: A new piece of the ALS puzzle. Nat Genet 2003; 34:357-358. 134. Lambrechts D, Storkebaum E, Morimoto M, et al: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 2003; 34:383-394. 135. Veldink JH, van den Berg LH, Cobben JM, et al: Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS. Neurology 2001; 56:749-752. 136. Corcia P, Mayeux-Portas V, Khoris J, et al: Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis. Ann Neurol 2002; 51:243-246. 137. Veldink JH, Kalmijn S, Groeneveld GJ, et al: Physical activity and the association with sporadic ALS. Neurology 2005; 64:241-245. 138. Weisskopf MG, O’Reilly EJ, McCullough ML, et al: Prospective study of military service and mortality from ALS. Neurology 2005; 64:32-37. 139. Daube JR: Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. Muscle Nerve 2000; 23:1488-1502. 140. Lambert EH, Mulder DW: Electromyography in amyotrophic lateral sclerosis. In Norris FH, Kurland LT, eds: Motor Neuron Diseases; Research on Amyotrophic Lateral Sclerosis and Related Disorders: Contemporary Neurology Symposia, vol 2. New York: Grune & Stratton, 1968, pp 135-153. 141. Chaudhry V, Corse AM, Cornblath DR, et al: Multifocal motor neuropathy: electrodiagnostic features. Muscle Nerve 1994; 17:198-205. 142. Olney RK, Lewis RA, Putnam TD, et al: Consensus criteria for the diagnosis of multifocal motor neuropathy. Muscle Nerve 2003; 27:117-121. 143. Cornblath DR, Kuncl RW, Mellits ED, et al: Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve 1992; 15:1111-1115. 144. Henderson RD, Daube JR: Decrement in surface-recorded motor unit potentials in amyotrophic lateral sclerosis. Neurology 2004; 63:1670-1674.

877

145. Cornblath DR, Kuncl RW, Rechthand E, et al: The value of rectus abdominal muscle electromyography [Letter]. Muscle Nerve 1987; 10:376. 146. Gooch CL, Shefner JM: ALS surrogate markers. MUNE. Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5(Suppl 1):104-107. 147. Osei-Lah AD, Mills KR: Optimising the detection of upper motor neuron function dysfunction in amyotrophic lateral sclerosis—a transcranial magnetic stimulation study. J Neurol 2004; 251:1364-1369. 148. Kaufmann P, Pullman SL, Shungu DC, et al: Objective tests for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS). Neurology 2004; 62:1753-1757. 149. Theys PA, Peeters E, Robberecht W: Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques. J Neurol 1999; 246:438442. 150. Mitsumoto H, Chad D, Pioro E: Electrodiagnosis. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 78-79. 151. Kaufmann P, Levy G, Thompson JL, et al: The ALSFRSr predicts survival time in an ALS clinic population. Neurology 2005; 64:38-43. 152. Kaufmann P, Mitsumoto H: Amyotrophic lateral sclerosis: objective upper motor neuron markers. Curr Neurol Neurosci Rep 2002; 2:55-60. 153. Kalra S, Arnold D: Neuroimaging in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:243-248. 154. da Rocha AJ, Oliveira AS, Fonseca RB, et al: Detection of corticospinal tract compromise in amyotrophic lateral sclerosis with brain MR imaging: relevance of the T1-weighted spinecho magnetization transfer contrast sequence. AJNR Am J Neuroradiol 2004; 25:1509-1515. 155. Mitsumoto H, Chad D, Pioro E: Diagnostic evaluation of ALS. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 125-128. 156. Cudkowicz M, Qureshi M, Shefner J: Measures and markers in amyotrophic lateral sclerosis. NeuroRx 2004; 1:273283. 157. Shefner JM: Multi-drug therapy in amyotrophic lateral sclerosis: combinations of multiple, untested drugs should not be used at this time. Muscle Nerve 2004; 30:676-678. 158. Miller RG, Mitchell JD, Lyon M, et al: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:191-206. 159. Meucci N, Nobile-Orazio E, Scarlato G: Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. J Neurol 1996; 243:117-120. 160. Miller R: Pharmacology and clinical trials. Continuum: Amyotrophic Lateral Sclerosis 2002; 8:56-81. 161. Orrell RW, Lane JM, Ross MA: Antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2004; (4):CD002829. 162. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al: Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142:37-46. 163. Pioro EP: Antioxidant therapy in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1(Suppl 4):5-12; discussion, Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1(Suppl 4):13-15. 164. Shefner JM, Cudkowicz ME, Schoenfeld D, et al: A clinical trial of creatine in ALS. Neurology 2004; 63:1656-1661. 165. Carelli V, Liguori R, Cordivari C, et al: Ceftriaxone is ineffective in ALS. Ital J Neurol Sci 1994; 15:66.

878

Section

XII

Neurodegenerative Diseases

166. Couratier P, Vallat JM, Merle L, et al: Report of six sporadic cases of ALS patients receiving ceftriaxone. Therapie 1994; 49:146. 167. Rothstein JD, Patel S, Regan MR, et al: Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005; 433:73-77. 168. Silani V, Cova L, Corbo M, et al: Stem-cell therapy for amyotrophic lateral sclerosis. Lancet 2004; 364:200-202. 169. Watts J: Controversy in China. Lancet 2005; 365:109110. 170. Traynor BJ, Alexander M, Corr B, et al: Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry 2003; 74:1258-1261. 171. Forshew DA, Bromberg MB: A survey of clinicians’ practice in the symptomatic treatment of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:258-263. 172. Sufit R, Miller R: Symptomatic management. Continuum: Amyotrophic Lateral Sclerosis 2002; 8:82-94. 173. Marquardt G, Lorenz R: Intrathecal baclofen for intractable spasticity in amyotrophic lateral sclerosis. J Neurol 1999; 246:619-20. 174. Bourke SC, Bullock RE, Williams TL, et al: Noninvasive ventilation in ALS: indications and effect on quality of life. Neurology 2003; 61:171-177. 175. Gelanis DF: Respiratory failure or impairment in amyotrophic lateral sclerosis. Curr Treat Options Neurol 2001; 3:133-138. 176. Perrin C, Unterborn JN, Ambrosio CD, et al: Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 2004; 29:5-27. 177. Giess R, Naumann M, Werner E, et al: Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2000; 69:121-123. 178. Winterholler MG, Erbguth FJ, Wolf S, et al: Botulinum toxin for the treatment of sialorrhoea in ALS: serious side effects of a transductal approach. J Neurol Neurosurg Psychiatry 2001; 70:417-418. 179. Tan EK, Lo YL, Seah A, et al: Recurrent jaw dislocation after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis. J Neurol Sci 2001; 190:95-97. 180. Andersen PM, Gronberg H, Franzen L, et al: External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis. J Neurol Sci 2001; 191:111-114. 181. Harriman M, Morrison M, Hay J, et al: Use of radiotherapy for control of sialorrhea in patients with amyotrophic lateral sclerosis. J Otolaryngol 2001; 30:242-245. 182. Mitsumoto H, Davidson M, Moore D, et al: Percutaneous endoscopic gastrostomy (PEG) in patients with ALS and bulbar dysfunction. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:177-185. 183. Chio A, Galletti R, Finocchiaro C, et al: Percutaneous radiological gastrostomy: a safe and effective method of nutritional tube placement in advanced ALS. J Neurol Neurosurg Psychiatry 2004; 75:645-647. 184. Thornton FJ, Fotheringham T, Alexander M, et al: Amyotrophic lateral sclerosis: enteral nutrition provision— endoscopic or radiologic gastrostomy? Radiology 2002; 224: 713-717. 185. Rio A, Leigh N: Noninvasive ventilation allows gastrostomy tube placement in patients with advanced ALS. Neurology 2001; 57:1351; discussion, Neurology 2001; 57:13511352. 186. Mitsumoto H, Chad D, Pioro E: Speech and communication management. In Mitsumoto H, Chad DA, Pioro EP, eds: Amy-

187. 188. 189. 190. 191. 192.

193.

194.

195. 196. 197.

198.

199. 200. 201. 202.

203. 204. 205. 206. 207.

otrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 405-420. Yorkston KM: Treatment efficacy: dysarthria. J Speech Hear Res 1996; 39:S46-S57. Schiffer RB, Herndon RM, Rudick RA: Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med 1985; 312:1480-1482. Iannaccone S, Ferini-Strambi L: Pharmacologic treatment of emotional lability. Clin Neuropharmacol 1996; 19:532-535. Brooks BR, Thisted RA, Appel SH, et al: Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004; 63:1364-1370. Moretti R, Torre P, Antonello RM, et al: Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging 2004; 21:931-937. Newsom-Davis IC, Lyall RA, Leigh PN, et al: The effect of noninvasive positive pressure ventilation (NIPPV) on cognitive function in amyotrophic lateral sclerosis (ALS): a prospective study. J Neurol Neurosurg Psychiatry 2001; 71:482-487. Mitsumoto H, Chad D, Pioro E: Symptomatic treatment. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 321-328. Bradley WG, Anderson F, Bromberg M, et al: Current management of ALS: comparison of the ALS CARE Database and the AAN Practice Parameter. The American Academy of Neurology. Neurology 2001; 57:500-504. Borasio GD, Voltz R, Miller RG: Palliative care in amyotrophic lateral sclerosis. Neurol Clin 2001; 19:829-847. Mazzini L, Corra T, Zaccala M, et al: Percutaneous endoscopic gastrostomy and enteral nutrition in amyotrophic lateral sclerosis. J Neurol 1995; 242:695-698. Aboussouan LS, Khan SU, Banerjee M, et al: Objective measures of the efficacy of noninvasive positive-pressure ventilation in amyotrophic lateral sclerosis. Muscle Nerve 2001; 24:403-409. Mitsumoto H, Chad D, Pioro E: Course and prognosis. In Mitsumoto H, Chad DA, Pioro EP, eds: Amyotrophic Lateral Sclerosis: Contemporary Neurology Series 49. Philadelphia: FA Davis, 1998, pp 151-163. Magnus T, Beck M, Giess R, et al: Disease progression in amyotrophic lateral sclerosis: predictors of survival. Muscle Nerve 2002; 25:709-714. del Aguila MA, Longstreth WT Jr, McGuire V, et al: Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003; 60:813-819. Chio A, Mora G, Leone M, et al: Early symptom progression rate is related to ALS outcome: a prospective populationbased study. Neurology 2002; 59:99-103. Turner M, Al-Chalabi A: Early symptom progression rate is related to ALS outcome: a prospective population-based study. Neurology 2002; 59:2012-2013; author reply, Neurology 2002; 59:2013. Daube JR: Electrophysiologic studies in the diagnosis and prognosis of motor neuron diseases. Neurol Clin 1985; 3:473493. Bernstein LP, Antel JP: Motor neuron disease: decremental responses to repetitive nerve stimulation. Neurology 1981; 31:204-207. Wang FC, De Pasqua V, Gerard P, et al: Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients. Neurology 2001; 57:897-899. Mulder DW, Howard FM, Jr.: Patient resistance and prognosis in amyotrophic lateral sclerosis. Mayo Clin Proc 1976; 51:537-541. Tucker T, Layzer RB, Miller RG, et al: Subacute, reversible motor neuron disease. Neurology 1991; 41:1541-1544.

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HUNTINGTON’S DISEASE ●

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Erika Driver-Dunckley and John N. Caviness

Huntington’s disease is an autosomal dominant, progressive neurodegenerative disease that typically manifests in adulthood. The prevalence is estimated at 5 to 10 per 100,000 individuals in the United States, 8 per 100,000 people in the United Kingdom, and 1 per 100,000 individuals in Japan. There is a high prevalence of Huntington’s disease, as a result of the founder effect, in several isolated populations of western European descent; these include the Lake Maracaibo region (700 per 100,000), Tasmania (17 per 100,000), and the island of Mauritius (46 per 100,000).1 The classic clinical triad of signs consists of chorea, dementia, and personality changes. Since its first description in 1872, Huntington’s disease has been identified as a trinucleotide repeat disorder and multiple treatment strategies have been attempted, but a successful cure has yet to be identified.

HISTORY Chorea was first described in the 1600s by Paracelsus, a notable alchemist, who described a peculiar disease characterized by writhing and sporadic movements and called “St. Vitus’s Dance.” At that time it was believed to be most likely caused by mass hysteria and religious superstition. It is now thought that this “dancing mania” of epidemic proportions throughout Europe may have been caused by Huntington’s disease, epileptic seizures, or ergot poisoning. In the 1840s, for the first time, Huntington’s disease was described in the medical literature as “chronic hereditary chorea.” It was not until 1872 that George Huntington (Fig. 67–1), an American physician who was only 22 years old, submitted his famous paper “On Chorea” to The Medical and Surgical Reporter.2 His research drew from the written observations of his father and grandfather. Huntington was able to explicitly point to genetic inheritance as the mode of transmission, and he noticed that the first symptoms usually appeared at an adult age and that they were usually accompanied by mental decline as well. Because of these significant observations and conclusions, the disease bears George Huntington’s name.3 In the early 1900s, researchers first noted that the brains of Huntington’s disease patients are destroyed as the disease progresses. They identified the caudate nucleus as the central target of brain cell death. In 1955, Americo Negrette, a Venezuelan physician, published a book describing communities in Lake Maracaibo (Fig. 67–2) with unusually high

numbers of individuals with chorea and reclassified their “dancing mania” as Huntington’s disease.4 More attention was brought to the disease when the famous songwriter and poet Woody Guthrie died of Huntington’s disease in 1967. Through extensive and prolonged research led by Nancy Wexler and others and the help of Lake Maracaibo residents through donation of blood samples, the gene for Huntington’s disease was finally identified in 1983 and localized in 1993.

GENETICS AND MOLECULAR PATHOGENESIS Huntington’s disease is an autosomal dominant disorder caused by an unstable cytosine-adenine-guanine (CAG) repeat expansion on chromosome 4 (4p16.3) (Fig. 67–3). Affected individuals have 37 to 86 repeats, whereas normal individuals have 11 to 34 repeats. The normal protein product is termed huntingtin and serves a role in intracellular trafficking and membrane recycling.5 This CAG repeat is unstable in gametes, and the number of trinucleotide repeats can therefore change with subsequent generations. Affected fathers are more likely to transmit a higher number of repeats because of the instability of the repeat in sperm DNA. This results in a higher number of cases of juvenile Huntington’s disease in the offspring of affected fathers. This is caused by the inverse relationship between number of repeats and age at onset.6 Spontaneous mutations were once considered rare, but with DNA analysis, more cases have been revealed. About one third of individuals share a common haplotype, but the other two thirds show evidence of a spontaneous mutation in the past.7 For asymptomatic individuals with a borderline number of repeats (opinions vary, but about 34 to 37), the consequence of the genetic test results remains inconclusive. The trinucleotide CAG codes for glutamine, and the increase in the polyglutamine tract prevents normal protein turnover, thereby resulting in protein aggregation (Fig. 67–4). The aberrant protein product is ubiquitinated but fails to be efficiently degraded, which leads to the formation of intranuclear inclusions that may disrupt mitochondrial processes and other functions.8,9 The mutant huntingtin is cleaved into fragments, and these fragments may have a primary role in huntingtin toxicity, including transcriptional dysregulation.10 Mutant huntingtin associates with a rapidly growing list of proteins. These “huntingtin-interacting proteins” are involved with numerous

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important cell functions, including transcription, trafficking, signaling, and metabolism.11 These findings, made within 10 years after the gene for Huntington’s disease was identified, have produced much excitement. Of more importance, researchers of Huntington’s disease are identifying agents that can interfere with the pathological effect of these mechanisms. This “drug pipeline” is forming rapidly, and new clinical trials are imminent.10

late-onset Huntington’s disease begins after the age of 50. Initial manifestations of Huntington’s disease include incoordination, occasional involuntary jerks, and difficulty with complex facial movements such as whistling or frowning. This is described as buccofacial apraxia and typically manifests before the chorea.12 Personality changes and difficulty with focusing may also manifest initially. Some affected individuals, particularly those with juvenile Huntington’s disease, never develop chorea but instead have an akinetic-rigid syndrome. Variants of Huntington’s disease are discussed later. Most cases are diagnosed on the basis of neurological symptoms, but 50% of patients develop behavioral changes or psychiatric symptoms first or concomitantly with the neurological changes.

CLINICAL FEATURES The average age at onset for Huntington’s disease averages 35 to 42 years. Juvenile-onset begins before 20 years of age, and

MOTOR FEATURES The classic neurological symptom seen in Huntington’s disease is chorea, and approximately 90% of patients are affected with

Caribbean Sea

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Caribbean Sea

VENEZUELA COLUMBIA BRAZIL

MARACAIBO Lake Maracaibo

VENEZUELA

BARRANQUITAS

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■

Figure 67–1. George Huntington.

Figure 67–2. Lake Maracaibo region. ■

Normal huntingtin Transcription

Huntingtin protein interactor

Loss of cellular function

x

Mutated huntingtin Caspase activation Transcription factors Nuclear translocation

Inclusions

Figure 67–3. The expression of mutated huntingtin causes cellular dysfunction. The mutated protein could disrupt protein interactions with the normal protein, which leads to the loss of function. This dysfunction leads to caspase activation, which cleaves the mutated huntingtin. The N-terminal fragment of mutated huntingtin is translocated to the nucleus and disrupts transcription of genes necessary for cortical and striatal survival and forms aggregates. (From Blum D, Hourez R, Galas MC, et al: Adenosine receptors and Huntington’s disease: implications for pathogenesis and therapeutics. Lancet Neurol 2:366-374, Figure 1.)

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eventually develop cognitive decline with an overall lowering of intelligence quotient. Through the development of standardized neuropsychometric testing, the dementia of Huntington’s disease has been further classified, and distinct patterns have been identified. Different testing batteries are applied at different centers, although typical testing includes the Wechsler Adult Intelligence Scale–Revised and the Halstead-Reitan Battery.12 Performances on the Controlled Word Association Test (COWAT), digit symbol test, and Stroop test commonly contain abnormalities. The pattern of dementia seen in Huntington’s disease is similar to that of the subcortical dementia of Parkinson’s disease and different from the pattern seen in Alzheimer’s disease.

PSYCHIATRIC FEATURES

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Figure 67–4. Striatal neuron with Htt inclusion body (center). (From Burton A: Inclusion bodies may be neuroprotective in Huntington’s disease. Lancet Neurol 3:699.)

it. In the beginning, the chorea may manifest only in the face or distal limbs and, over time, evolve into a more generalized form that may become dystonic. Although strength is preserved, sustained contraction may be interrupted by sudden relaxations also known as motor impersistence (“milkmaid’s grips”). Myoclonus and intention tremor occur in rare cases. The myoclonus seen is consistent with cortical reflex myoclonus.13 The classic gait of Huntington’s disease is characterized by incoordination with interrupting choreic movements. The severity of these movements can lead to the complete inability to walk and frequent falls. In early stages, affected individuals may have normal muscle tone, but over time they typically develop hypertonia of either extrapyramidal or pyramidal origins. Later in the course of the disease, individuals may develop bradykinesia and/or dystonia with or without rigidity. Patients develop dysarthria early in the disease and dysphagia later.12 Their speech may seem slow and irregular and eventually becomes disorganized and may even deteriorate to mutism. Eye movement dysfunction is almost uniform as Huntington’s disease progresses. Typically seen is a slowing down of saccades with some dysmetria and errors with tracking and convergence.14 Swallowing usually becomes impaired, and choking is often severe enough to incur risk of death.

COGNITIVE FEATURES The dementia of Huntington’s disease may appear before, during, or after the onset of motor symptoms. The pattern of dementia is consistent with frontal-subcortical dysfunction, with evidence of impairment in problem solving, judgment, attention, and concentration, but preservation of memory until late in the disease. All patients with Huntington’s disease

Personality changes of aggressiveness, impulsiveness, emotional lability, apathy, and irritability are the most common psychiatric features in this disease and can occur in as many as 59% of patients.12 Symptoms, such as being quick to anger and depression, can be characteristic early signs. Depression is the second most common psychiatric disorder in these patients and can affect as many as 30%; the suicide rate is as high as four to six times (8 to 20 times in patients older than 50 years) that of the general population.12,15 Psychosis occurs in 6% to 25% of patients.12 This psychosis has a pattern consistent with paranoid schizophrenia and is more common in juvenile-onset Huntington’s disease.

OTHER FEATURES Patients with Huntington’s disease may also suffer from autonomic dysfunction, including blood pressure alterations, hyperhidrosis, and bowel and bladder incontinence. Affected individuals may also have seizures, although this is more common in juvenile-onset Huntington’s disease.12 Weight loss is also common, even in patients without dysphagia, and can border on cachexia. The etiology of this is unknown, but in these patients, weight loss may be related to higher sedentary energy expenditure secondary to chorea or other involuntary muscle activity.16

VARIANTS There are two main variants of Huntington’s disease—Westphal’s variant and juvenile-onset Huntington’s disease—and they may overlap. Westphal’s variant was first described in 1883 and is characteristically an akinetic-rigid syndrome. This variant exists in two forms; a primary form with akineticrigidity from onset and a secondary form with chorea preceding the akinetic-rigid state. This variant is rarely seen in the adult-onset Huntington’s disease, but it occurs in 50% of juvenile-onset cases.12 Juvenile-onset Huntington’s disease is the diagnosis given to patients with symptom onset before age 20, and it can be further subdivided into childhood onset (onset before age 10) or adolescent onset. It is estimated that 5% to 10% of individuals with Huntington’s disease have symptoms before age 20 and only 3% before age 15.12 Studies have shown that 80% of juvenile-onset Huntington’s disease cases have an affected

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Figure 67–5. Basal ganglia motor pathways. ■

father.17 The majority of affected individuals have rigidity and associated pyramidal features, bradykinesia, or dystonic postures. Patients with the rigid juvenile-onset Huntington’s disease have a more rapid course of disease progress than do patients with juvenile-onset Huntington’s disease or the rigid adult-onset Huntington’s disease. Juvenile-onset Huntington’s disease patients may present with the classic chorea pattern seen in adult onset. They may also evince intellectual deterioration, behavioral changes, speech and ocular dysfunction, and cerebellar signs. Interestingly, seizures can occur in up to one half of these patients, typically later in the disease course, and may be refractory to medications. The myoclonus of Huntington’s disease is more common in juvenile-onset cases and has been documented to have a cortical origin.13

PATHOPHYSIOLOGY OF SIGNS AND SYMPTOMS The basal ganglia, through a series of feedback loops, are important for adjusting the velocity and amplitude of movements (Fig. 67–5). In Huntington’s disease, there is selective degeneration of the neurons of the indirect pathway in the striatum, leading to an imbalance between the inhibitory and excitatory pathways.18 This imbalance in turn leads to a decrease in the cortical motor pathways’ inhibitory influences, and an exaggerated facilitation of movement (chorea) occurs. This situation seems to be the opposite of what occurs in Parkinson’s disease; therefore, medications used to treat Parkinson’s disease, such as dopaminergic and anticholinergic drugs, will worsen the chorea of Huntington’s disease.18 The pathophysiology of the cognitive changes in Huntington’s disease is still being elucidated. Magnetic resonance imaging studies have shown subcortical atrophy, more so than cortical atrophy, to be correlated with cognitive dysfunction in patients with Huntington’s disease.19 Depression in Huntington’s disease can be primary or secondary. Primary depression results directly from neuronal degeneration in the caudate nucleus and its projections and can be observed early in the course of the disease.20 Secondary depression results from a disordered family environment, parental guilt for carrying the gene, or the fear of the impending devastating disease.20 One half the suicides that occur are committed by individuals with very early signs of disease who have not yet received a genetic diagnosis.15

Figure 67–6. Caudate atrophy.

DIFFERENTIAL DIAGNOSIS The diagnosis of Huntington’s disease may be easy if the patient has a documented family history of the disease; however, many patients who are referred for chorea lack genetic documentation. In preparing a differential diagnosis, it is important to ascertain a good medical history about childhood development, drug use or abuse, exposures, and associated neurological symptoms, as well as timing of their onset. This information can be used to help muddle through the long differential diagnosis of chorea (Table 67–1).

EVALUATION AND GENETIC TESTING With the advent of genetic testing, the certainty of the diagnosis of Huntington’s disease was made relatively simple. The cost of the test still remains high and may be an issue for patients without insurance or those in economic hardship. Ethical issues may also arise. Therefore, it is important to consider the following question before ordering gene testing. Does the patient to be tested have symptoms of Huntington’s disease? If so, and if there is a family history, then testing is considered confirmatory; if not, but there is a family history, then this is called asymptomatic testing. In asymptomatic testing, individuals need a full neurological evaluation and genetic counseling by a trained genetic counselor before making a decision to be tested.18 If the individual is disabled by signs and symptoms of Huntington’s disease, then genetic counseling is still needed but may be performed differently because of the clinical gravity of the situation. Other supplemental tests may include electroencephalography, which may show low-voltage waves, or magnetic resonance imaging, which typically reveals cortical and subcortical atrophy and significant caudate loss (butterfly ventricles) (Fig. 67–6). However, particularly early in the clinical manifestations of the disease, no computed tomographic or magnetic resonance imaging abnormalities may be detected.

TREATMENT OPTIONS There is currently no cure for Huntington’s disease or a treatment that has slowed the neurodegenerative process. In discussing treatment options with the patient, it is important to

chapter 67 huntington’s disease T A B L E 67–1. Differential Diagnosis of Chorea

T A B L E 67–2. Overall Treatment Guidelines

Developmental Physiological chorea of infancy Cerebral palsy

Neuroprotection (None Proved) Possibilities: minocycline, creatine, coenzyme Q10, remacemide, vitamin E

Hereditary Huntington’s disease Benign hereditary chorea Neuroacanthocytosis Wilson’s disease Ataxia telangiectasia Tuberous sclerosis Pantothenate kinase–associated neurodegeneration neurodegeneration with brain iron accumulation type 1 (PKAN/NBIA-1) (formerly known as Hallervorden-Spatz disease) Fahr’s syndrome (familial idiopathic cerebral calcification) Dentatorubral-pallidoluysian atrophy (DPRLA) Spinocerebellar ataxia type 3 Lesch-Nyhan Syndrome

Symptom Management Depression: SSRIs, venlafaxine, bupropion, mirtazapine Mood lability: valproic acid, carbamazepine (Tegretol), clonazepam, SSRIs Chorea: dopamine antagonists, dopamine depleters, clonazepam

Metabolic Hyperthyroidism Hypoparathyroidism Hypoglycemia, hyperglycemia Hyponatremia, hypernatremia Hypomagnesemia Hypocalcemia Nutritional (vitamins B1, B2, and B12 deficiencies) Drug-Induced Neuroleptics Dopaminergic medications Amphetamines Oral contraceptives Anticonvulsants Tricyclic antidepressants Anticholinergics Toxin-Induced Alcohol intoxication/withdrawal Anoxia Carbon monoxide poisoning Manganese Toluene Thallium Mercury Infectious Sydenham’s chorea Encephalitis lethargica Creutzfeldt-Jakob disease Postviral encephalitides Neurometabolic Lysosomal storage diseases Amino acid disorders Aging Senile chorea Buccal-oral-lingual dyskinesia Edentulous orodyskinesia in elderly patients Vascular Basal ganglia stroke Systemic Disorders Lupus erythematosus Polycythemia vera Chorea gravidarum Acquired hepatocerebral degeneration

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Supportive Care Speech, swallowing, and physical therapies Social counseling SSRI, selective serotonin reuptake inhibitor.

consider possible neuroprotective agents and current treatment trials, symptom management, and physical and social supportive care (Table 67–2). Although there have been significant advances in the elucidation of the genetics and molecular pathophysiology of Huntington’s disease, medical treatments are lagging behind. The search for a neuroprotective agent for Huntington’s disease, along with other neurodegenerative diseases, has been so far unsuccessful. Creatine, coenzyme Q10, vitamin E, and remacemide have all been tolerated by patients with Huntington’s disease but have not slowed functional decline.21-23 Higher dosages of coenzyme Q10, similar to what has yielded some preliminary success in Parkinson’s disease, await further testing. The tetracycline antibiotic minocycline, a caspase inhibitor with antiapoptotic properties, was first discovered to have neuroprotective effects in 1998 in an animal model for ischemia (Fig. 67–7).24 Since then, this medication has been studied in other diseases, such as amyotrophic lateral sclerosis, with some promising effects, although evidence of its benefit in the Huntington’s disease animal model has been conflicting.25 The Huntington Study Group demonstrated that minocycline is well-tolerated and safe in patients with Huntington’s disease.26 A promising 2-year pilot study showed that minocycline stabilized motor and cognitive changes while improving psychiatric symptoms.27 This study will help to motivate investigators in larger double-blind, placebo-controlled trials to evaluate the use of minocycline in Huntington’s disease further. The drug study pipeline for Huntington’s disease is providing potential new agents to be evaluated as treatment for Huntington’s disease. The disabling chorea of Huntington’s disease is best treated with dopamine antagonists, dopamine-depleting agents, or clonazepam. However, the threshold for treating the chorea in Huntington’s disease should be higher than for other symptoms, because possible side effects include worse balance, more difficulty swallowing, and exacerbation of depression. Because dopamine antagonists can cause severe side effects, they are usually initiated after a trial of clonazepam. The dopamine antagonists most frequently used are risperidone (Risperdal), 2 to 6 mg/day; fluphenazine (Prolixin), 0.5 to 5.0 mg/day; and haloperidol (Haldol), 0.5 to 5.0 mg/day, although their use may be limited by their extrapyramidal side effects.18 Medications such as quetiapine (Seroquel), olanzapine (Zyprexa), and clozapine (Clozaril) may have less severe extrapyramidal side effects,

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Figure 67–7. Peripheral and central functions of minocycline. Minocycline has immunomodulatory activity in the periphery and both immunomodulatory and neuroprotective capacities within the central nervous system (CNS). The likelihood of a direct action at the level of the blood-brain barrier has not been addressed thoroughly. MMP, matrix metalloproteinase. (From Yong VW, Wells J, Giuliani F, et al: The promise of minocycline in neurology. Lancet Neurol 2004; 3:744-751.)

Oligodendrocyte

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Inhibits activation of microglia Microglia Immunomodulatory activity

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although clozapine necessitates weekly blood evaluations and should be considered a more risky alternative than the other similar agents. Dopamine-depleting agents such as reserpine (Serapasil), 0.2 to 0.6 mg/day, and tetrabenazine (Nitoman), 50 to 200 mg/day, may also be used, although they are hard to obtain.18 No drug is currently approved in the United States for the treatment of Huntington’s disease, symptomatic or otherwise. Thus, all treatment is “off-label,” and patients and families should be informed of this. In addition, potential side effects are very real and dose limiting. For example, dopamine antagonists may cause disabling balance problems; exacerbation of depression, including suicide attempts; sedation; and tardive dyskinesia. Therefore, the indication for the treatment of involuntary movements should be strong, and follow-up is required on an ongoing basis to ensure that the benefits outweigh the side effects of these and other agents used in the treatment of Huntington’s disease. Depression may be treated with selective serotonin reuptake inhibitors or some of the newer antidepressants, such as bupropion (Wellbutrin), venlafaxine (Effexor), or mirtazapine (Remeron).18 Mood stabilization is best treated with valproic acid (Depakote) or carbamazepine (Tegretol).18 However, stronger agents and/or neuroleptic medication may be needed. It is important to enlist the help of a psychiatrist early on in the treatment plan to better manage the psychiatric symptoms.18 At every opportunity, the risk of suicide should be openly assessed with the patient and family. If such a risk is found, then a mental health referral should be sought. Nonpharmacological treatment is as important as pharmacological treatments in the treatment of Huntington’s disease. Involving speech and language pathologists to monitor speech

and swallowing function, along with physical therapists to evaluate and help improve gait and strength early in the course of the disease, is valuable in preventing serious falls or aspiration. All persons who spend time with patients who have Huntington’s disease should be trained in the Heimlich maneuver, because choking is a significant risk and cause of death. The future of treatment for Huntington’s disease may involve nondrug treatment in addition to agents that act on neurotransmitter receptors. Fetal cell transplantation, after 20 years of research, has been shown to be safe in humans, and one pilot study has indicated a possible benefit, although follow-up studies are needed.28 A promising treatment option for the disabling chorea of Huntington’s disease is deep-brain stimulation surgery, although further studies are needed.29 Laboratory studies have indicated that there may be neuroprotective effects with adenosine A1 agonists or A2A antagonists, and additional studies are under way.30

PROGNOSIS Unfortunately, Huntington’s disease is a neurodegenerative disease with only symptomatic treatment. As already mentioned, the suicide rate among individuals with Huntington’s disease is more than double that in the general population. Other causes of death in Huntington’s disease include aspiration or asphyxia from the severe dysphagia observed in advanced cases. Serious injuries may also be sustained from falls. The average age at death ranges from 51.4 to 56.9 years, and the average survival time from disease onset is 14 to 17 years.

chapter 67 huntington’s disease

K E Y

P O I N T S

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Huntington’s disease is a progressive autosomal dominant genetic disorder characterized by chorea, dementia, and personality changes.

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The genetic mutation is a variable expansion of trinucleotide repeats that results in polyglutamine tract expansion within the normal protein huntingtin.

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The diagnosis is supported by appropriate clinical symptoms, family history, and association with the Huntington’s disease mutation, and genetic counseling is always recommended before the genetic test is performed.

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No cure or treatment that slows progression has been found.

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Symptomatic therapy for various manifestations should be cautiously applied, and supportive treatment, counseling, and follow-up for depression are important.

Suggested Reading Bonelli RM, Hofmann P: A review of the treatment options for Huntington’s disease. Expert Opin Pharmacother 2004; 5:767776. Caviness JN: Huntington’s disease and other choreas. In Adler CH. Ahlskog JE, eds: Parkinson’s Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana Press, 2000, pp 321-330. Hersch SM: Huntington’s disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation. Curr Opin Neurol 2003; 16:501-506. Li S-H, Li X-J: Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 2004; 20:146-154.

References 1. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Huntington’s Disease Collaboration Research Group. Cell 1993; 72:971-983. 2. Huntington G: On chorea. George Huntington, M.D. J Neuropsychiatry Clin Neurosci 2003; 15:109-112. 3. Okun MS: Huntington’s disease: what we learned from the original essay. Neurologist 2003; 9:175-179. 4. Okun MS: Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela. Neurology 2004; 63:340-343. 5. Cattaneo E, Rigamonti D, Goffredo D, et al: Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci 2001; 24:182-188. 6. Fahn S: Huntington’s disease. In Rowland, LP, ed: Merritt’s Neurology, 10th ed. New York: Lippincott Williams & Wilkins, 2000, pp 659-662. 7. Myers RH, MacDonald ME, Koroshetz WJ, et al: De novo expansion of a (CAG)(n) repeat in sporadic Huntington’s disease. Nat Genet 1993; 5:168-173.

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8. DiFiglia M, Sapp E, Chase KO, et al: Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277:1990-1993. 9. Bates G: Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 2003; 361:1642-1644. 10. Hersch SM: Huntington’s disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation. Curr Opin Neurol 2003; 16:501-506. 11. Li S-H, Li X-J: Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 2004; 20:146154. 12. Haddad MS, Cummings JL: Neuropsychiatry of the basal ganglia. Psychiatr Clin North Am 1997; 20:791-807. 13. Caviness JN, Kurth M: Cortical myoclonus in Huntington’s disease associated with an enlarged somatosensory evoked potential. Mov Disord 1997; 12:1046-1051. 14. Lasker AG, Zee DS: Ocular motor abnormalities in Huntington’s disease. Vision Res 1997; 37:3639-3645. 15. Schoenfeld M, Myers RH, Cupples LA, et al: Increased rate of suicide among patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 1984; 47:1283-1287. 16. Pratley RE, Salbe AD, Ravussin E, et al: Higher sedentary energy expenditure in patients with Huntington’s disease. Ann Neurol 2000; 47:64-70. 17. Martin JB, Gusella JF: Huntington’s disease: pathogenesis and management. N Engl J Med 1986; 315:1267-1276. 18. Caviness JN: Huntington’s disease and other choreas. In Adler CH, Ahlskog JE, eds: Parkinson’s Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana Press, 2000, pp 321-330. 19. Starkstein SE, Brandt J, Bylsma F, et al: Neuropsychological correlates of brain atrophy in Huntington’s disease: a magnetic resonance imaging study. Neuroradiology 1992; 34:487-489. 20. Folstein SE: The psychopathology of Huntington’s disease. Res Publ Assoc Res Nerv Ment Dis 1991; 69:181-191. 21. Verbessem P, Lemiere J, Eijnde BO, et al: Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 2003; 61:925-930. 22. Huntington Study Group: A randomized placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001; 57:397-404. 23. Peyser CE, Folstein M, Chase GA, et al: Trial of D-alphatocopherol in Huntington’s disease. Am J Psychiatry 1995; 152:1771-1775. 24. Yrjanheikki J, Keinanen R, Pellikka M, et al: Tetracyclines inhibit microglial activation and are neuroprotective in global barin ischemia. Proc Natl Acad Sci U S A 1998; 95:1576915775. 25. Smith DL, Woodman B, Mahal A, et al: Minocycline and doxycycline are not beneficial in a model of Huntington’s disease. Ann Neurol 2003; 53:186-196. 26. Huntington Study Group: Minocycline safety and tolerability in Huntington disease. Neurology 2004; 63:547-549. 27. Bonelli RM, Hodl AK, Hofmann P, et al: Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 2004; 19:337-342. 28. Peschanski M, Dunnett SB: Cell therapy for Huntington’s disease, the next step forward. Lancet Neurol 2002; 1:81. 29. Moro E, Lang AE, Strafella AP, et al: Bilateral globus pallidus stimulation for Huntington’s disease. Ann Neurol 2004; 56:290-294. 30. Blum D, Hourez R, Galas MC, et al: Adenosine receptors and Huntington’s disease: implications for pathogenesis and therapeutics. Lancet Neurol 2003; 2:366-374.

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Nathaniel Robb Whaley and Ryan J. Uitti

The inherited ataxias are a heterogeneous group of neurodegenerative syndromes with a vast array of clinical signs and symptoms, both neurological and systemic. The clinical spectrum is wide and may range from “pure” cerebellar signs to constellations that include spinal cord syndromes, peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmological signs, psychiatric problems, and seizure disorders. Typically, inherited ataxias develop over years to decades; recessively inherited forms start in childhood and those dominantly inherited start in adulthood. Historically, these disorders were diagnosed with difficulty on the basis of clinical manifestations. Classification schemes, complicated by eponymous designations in the absence of genetically based information, further complicated the literature. Genetic advances, however, have aided in the classification and diagnosis of the inherited ataxias, identifying specific chromosomal defects or gene loci associated with a clinical phenotype in many instances.

with axonal neuropathy, Cayman’s ataxia, trichothiodystrophy, xeroderma pigmentosum, Cockayne’s syndrome, and ataxia with oculomotor apraxia.2,3 The ARCAs begin in infancy and early life. Ataxias may also be inherited by an X-linked or mitochondrial mode. Because the prevalence of X-linked and mitochondrial inherited ataxias are unknown and probably extremely rare, this chapter focuses on the more commonly encountered inherited ataxias: ARCAs and ADCAs. Pathophysiological clues for many of the inherited ataxias are known. A few of the ARCAs have been genetically characterized with pathogenesis resulting from the loss of function of specific cellular proteins crucial in metabolic homeostasis, cell cycle, or DNA repair. For the ADCAs, the pathogenesis often appears related to the production of a toxic or harmful protein.2

EPIDEMIOLOGY AND RISK FACTORS BRIEF DESCRIPTION The inherited ataxias are grouped (Table 68–1) by mode of inheritance: autosomal dominant, autosomal recessive, mitochondrial, and X-linked. More than 32 known autosomal dominant cerebellar ataxias (ADCAs) were known as of May 2006. The known ADCAs are designated as spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), episodic ataxia types 1 and 2, human spastic ataxia, and ataxia caused by mutations in the gene encoding fibroblast growth factor 14.1 These ataxias characteristically manifest symptomatically in adulthood. However, the phenomenon of anticipation occurs frequently because (1) many ADCAs occur on the basis of trinucleotide repeat expansion mutations, (2) the length of trinucleotide repeats may be correlated with symptomatic agerelated onset, and (3) trinucleotide repeats may undergo further expansion in subsequent generations. The autosomal recessive cerebellar ataxias (ARCAs) are less common than ADCAs. The two most common ARCAs are Friedreich’s ataxia and ataxia telangiectasia. Other less common ARCAs include ataxia with vitamin E deficiency (AVED), autosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS), abetalipoproteinemia, Refsum’s disease, infantile-onset spinocerebellar ataxia, spinocerebellar ataxia

Estimates of the prevalence of the ADCAs are restricted to a few epidemiological studies hindered by founder effects in the isolated geographical populations studied. The population studies do indicate that the prevalence of the ADCA subtypes varies among ethnic and geographical populations.1 Although the prevalence is probably underestimated at three cases per 100,000 people, ADCAs are relatively uncommon disorders.4 In comparison, the prevalence of Huntington’s disease is 5 to 10 cases per 100,000 people. The most common ADCA worldwide is spinocerebellar ataxia type 3, followed by types 2 and 6, type 1, type 8, and type 7.5,6 The prevalence of DRPLA is 0.25% to 2% among patients with ADCA and is especially prevalent in Japan.7 The remaining subtypes are very rare.6 The two most common ARCAs worldwide are Freidriech’s ataxia and ataxia telangiectasia. The prevalence of Friedreich’s ataxia is 2 to 4 cases per 100,000 people. The worldwide prevalence of ataxia telangiectasia is about 1 to 3 cases per 100,000 people. The prevalence of the remaining ARCAs is rare and/or unknown. The exact prevalence of X-linked and mitochondrial inherited ataxias is unknown but believed to be extremely low. For example, the estimated prevalence of all mitochondrial disorders (with and/or without ataxia) is 11.5 cases per 100,000 individuals.8

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T A B L E 68–1. Examples of Inherited Ataxias and Their Mode of Inheritance Mode of Inheritance Autosomal recessive

Autosomal dominant X-linked

Mitochondrial

Inherited Ataxias Friedreich’s ataxia, late-onset Friedreich’s ataxia, FARR, AVED, ARSACS, Cayman’s ataxia, abetalipoproteinemia, ataxia telangiectasia, AOA, SCAN, xeroderma pigmentosum, Cockayne’s syndrome, trichothiodystrophy, Joubert’s syndrome, Gillespie’s syndrome, Behr’s disease, Marinesco-Sjögren syndrome, and metabolic ataxias (urea cycle defects, aminoacidurias, peroxisomal disorders, disorders of pyruvate and lactate, Wilson’s disease, hyperammonemic ataxia, Niemann-Pick disease type C, sialidosis, Refsum’s disease, ceroid lipofuscinosis, leukodystrophies, cholestanolosis, and gangliosidosis) Spinocerebellar ataxias, DRPLA, episodic ataxia types 1 and 2, HSA, and FGF14 Sideroblastic anemia and spinocerebellar ataxia, cerebellar ataxia 2 syndrome, ataxia syndrome with extrapyramidal involvement, Arts syndrome, ataxia with tremor and cognitive decline, and Pelizaeus-Merzbacher allelic variant Leukodystrophy; MELAS; MERRF; NARP; Leigh’s syndrome; HAM; syndrome of ataxia, cataract, and diabetes mellitus; coenzyme Q10 deficiency; COX10 deficiency; cytochrome c oxidase I and II deficiency; pyruvate dehydrogenase disorders; and syndrome of sideroblastic anemia and spinocerebellar ataxia

ADCA, autosomal dominant cerebellar ataxia; AOA, ataxia with ocular motor apraxia; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; AVED, ataxia with vitamin E deficiency; COX10, cytochrome oxidase 10; DRPLA, dentatorubral-pallidoluysian atrophy; FARR, Friedreich’s ataxia with retained reflexes; FGF14, fibroblast growth factor 14 (mutation causing disease); HAM, hearing loss, ataxia, and myoclonus; HSA, human spastic ataxia; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke; MERRF, myoclonic epilepsy and ragged red fibers; NARP, neuropathy, ataxia, and retinitis pigmentosa; SCAN, spinocerebellar ataxia with axonal neuropathy.

50% chance of inheriting the disease, whereas a sister has a 50% chance of being a carrier. Mitochondrial disorders can result either from mutations in mitochondrial DNA that are maternally transmitted or from mutations in nuclear DNA that may follow either an autosomal dominant or an autosomal recessive pattern of inheritance.8

CLINICAL FEATURES The clinical features of the inherited ataxias overlap with phenotypical variability and differing manifesting features, even within families with a single inherited ataxia. However, cerebellar ataxia is a universal finding; the term refers to a disturbance in the coordination of voluntary movement that occurs independently of weakness and as a result of dysfunction of the cerebellum or its afferent or efferent pathways. Specifically, cerebellar ataxia comprises disorders in (1) the rate of initiation and cessation of movement (dyschronometria), (2) the amplitude of movement (dysmetria), (3) the combining of single movements (dyssynergia), (4) the speed of alternating movements (dysdiadochokinesia), and (5) the continuity of movement (manifested as static and kinetic tremor). These disorders in movement combine in varying degrees, producing cerebellar ataxia as a result. Cerebellar ataxia may affect all parts of the body, including the trunk, culminating in abnormalities in posturing, tone, gait, use of the extremities, speech, and eye movements. For the clinician evaluating a patient with a possible inherited ataxia, decisions regarding genetic testing for specific inherited ataxias can become difficult. Rather than list all the known signs and symptoms of each inherited ataxia, this chapter includes only distinguishing features of the ataxias that can aid clinicians in strategies for genetic testing of patients in whom an inherited ataxia is suspected.

The Autosomal Recessive Cerebellar Ataxias The main risk factor for the inherited ataxias is a family history of ataxia. Spontaneous mutations are rarely identified.6 A patient with an ADCA, the proband, typically has a parent with the disease. However, this, too, is not a universal finding, because the mutant allele may have decreased penetrance in the parent, onset of the disease may be late in the parent but early in the proband secondary to anticipation, an affected parent may die before the disease manifests, the proband’s background may be unknown because of adoption or unknown lineage, or symptoms in a family member may go unrecognized. The offspring of a proband with an ADCA have a 50% chance of developing the disease. The siblings and parents of a proband likewise have a 50% chance of developing the disease. The siblings of such a proband have the same risks at birth as the offspring of a proband; however, because of the early onset of the ARCAs, it is possible after childhood, if a sibling has not developed symptoms, to predict that the theoretical risk of being a carrier is 67% for asymptomatic siblings. If the mother of a male proband with one of the rare X-linked recessive inherited ataxias is asymptomatic, either she may be a carrier or the mutation occurred de novo in the proband. A brother of the proband with a mother who is a carrier has a

The ARCAs are rare, with the exceptions of Friedreich’s ataxia and ataxia telangiectasia. For simplification, they can be grouped etiologically (Table 68–2) as those resulting from potentially increased oxidative stress, those resulting from problems in DNA repair, and those caused by metabolic derangements. The more frequently encountered ARCAs are discussed in the following section; the features that may aid in determining diagnosis are highlighted. The ARCAs associated with oxidative stress include Friedreich’s ataxia and Friedreich’s ataxia–like syndromes, ataxias secondary to vitamin E deficiency, and Cayman’s ataxia. The most common of these is Friedreich’s ataxia. The classic clinical features include progressive gait and limb ataxia, dysarthria, absence of deep tendon reflexes, vibratory and proprioceptive sensory loss, and pyramidal weakness with a disease onset before 25 years of age.2 Symptomatic sensory loss typical of Friedreich’s ataxia helps to distinguish this ataxia from other spinocerebellar ataxias with severe reduction or loss of sensory action potentials without reduction of motor conduction velocities.9 About 25% of patients have an atypical manifestation after 25 years of age, called late-onset Friedreich’s ataxia, or with retained reflexes, known as Friedreich’s ataxia with retained reflexes, and/or slow disease progression. The skeletal, endocrine, and cardiovascular systems are affected; the disease

chapter 68 inherited ataxias T A B L E 68–2. Pathophysiology of Autosomal Recessive Cerebellar Ataxias Pathophysiology

Disease

Oxidative stress

Friedreich’s ataxia, late-onset Friedreich’s ataxia, FARR, AVED, ARSACS, Cayman’s ataxia, and abetalipoproteinemia Ataxia telangiectasia, AOA, SCAN, xeroderma pigmentosum, Cockayne’s syndrome, trichothiodystrophy Urea cycle defects, aminoacidurias, peroxisomal disorders, disorders of pyruvate and lactate, Wilson’s disease, hyperammonemic ataxia, Niemann-Pick disease type C, sialidosis, Refsum’s disease, ceroid lipofuscinosis, leukodystrophies, cholestanolosis, and gangliosidosis Joubert’s syndrome, Gillespie’s syndrome, Behr’s disease, Marinesco-Sjögren syndrome

DNA repair failure Metabolic causes

Congenital ataxia syndromes

AOA, ataxia with ocular motor apraxia; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; AVED, ataxia with vitamin E deficiency; FARR, Friedreich’s ataxia with retained reflexes; SCAN, spinocerebellar ataxia with axonal neuropathy.

manifests, respectively, as scoliosis and pes cavus, diabetes mellitus, and hypertrophic cardiomyopathy. Cardiomyopathy is a cardinal feature of Friedreich’s ataxia and detrimentally affects prognosis commonly, with early death secondary to heart failure or fatal arrhythmia. Optic neuropathy and sensorineural hearing may be present later in the disease. The pathogenesis of Friedreich’s ataxia involves a deficiency of a mitochondrial protein, frataxin, secondary to a guanine-adenine-adenine expansion. The genetic defect is believed to result in iron accumulation in mitochondria with oxygen-free radical production. The normal trinucleotide repeat range is estimated at 33 or fewer triplet repeats; pathological expansions range from 67 to 1000 triplets, with length inversely proportional to age at clinical onset, scoliosis, and cardiomyopathy.10 Unlike the ADCAs with trinucleotide repeats, Friedreich’s ataxia is not associated with anticipation. Patients with Friedreich’s ataxia become unable to walk within 11 years after disease onset and have a mean survival length of 36 years after onset of symptoms. Typically, more than two decades of life are spent in a debilitated motor state.11 To date, the size of the guanine-adenine-adenine pathological expansion has made development of transgenic animal models difficult. Several ARCAs are the result of vitamin E deficiency. Vitamin E is a potent lipid-soluble antioxidant absorbed by the small intestine and incorporated into chylomicrons before traveling to the liver, where it is packaged into very-low-density lipoproteins and circulated in the bloodstream. Malabsorption in the gut as a result of atresia, short gut syndrome, cholestasis, severe malnutrition, and cystic fibrosis can result in vitamin E deficiency and consequent neurological and multisystemic problems. The ARCAs resulting from vitamin E deficiency secondary to genetic causes include abetalipoproteinemia and AVED. Abetalipoproteinemia is caused by the absence of apolipoprotein B–containing lipoproteins, which prevents the incorporation of lipid-soluble vitamins such as A, K, and E into chylomicrons and thus into very-low-density lipoproteins. This syndrome starts in infancy with diarrhea and leads to a progressive clinical syndrome marked by gait ataxia, nystagmus, loss of deep

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tendon reflexes, impaired proprioception, and pigmentary retinal degeneration, a helpful distinguishing feature. Screening for this disorder reveals low cholesterol and triglyceride levels; absence of very-low-density lipoproteins; absence of lowdensity lipoproteins (LDLs); and low levels of vitamins A, E, and K. Acanthocytes can be seen in the peripheral blood smear. Management involves vitamin A, E, and K replacement, as soon as possible, to prevent or diminish neurological sequelae. AVED is a rare disorder with clinical manifestations similar to those of Friedreich’s ataxia. A patient with clinical features of Friedreich’s ataxia and negative genetic test results should be screened for AVED (with plasma vitamin E levels), especially because this syndrome is potentially treatable. Head titubation and dystonia are more common in AVED than in Friedreich’s ataxia; cardiomyopathy is a less frequent problem.2 The syndrome is caused by a defective transfer protein for α-tocopherol that prevents transfer of this most biologically active form of vitamin E to peripherally circulating lipoproteins.12 Oral vitamin E supplementation is the mainstay of treatment. Cayman’s ataxia is an ARCA found in a population on Grand Cayman Island. It involves a mutation of the Caytaxin protein, found almost exclusively in the central nervous system, and is believed to bind a ligand with similar properties to vitamin E in the central nervous system.3 It is characterized by early-onset hypotonia, cerebellar ataxia, and psychomotor retardation.3 There are seven inherited ataxias caused by defective DNA repair: ataxia telangiectasia, ataxia with oculomotor apraxia, spinocerebellar ataxia with axonal neuropathy, ARSACS, xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy. The most common of these is ataxia telangiectasia. Ataxia telangiectasia is typified by neurological, dermatological, and immunological symptoms starting in infancy or early childhood, with death in early adulthood. Neurological manifestations include cerebellar ataxia, slowed horizontal saccades, dystonic posturing, chorea, tics or jerks, dysphagia and choking, and peripheral neuropathy. The dermatological signs include oculocutaneous telangiectasia, premature graying of hair, and premature senile keratosis.12 Patients with ataxia telangiectasia have recurrent sinopulmonary infections secondary to derangement of cellular and humoral immunity (deficient immunoglobulin A levels). Malignancy and neoplasia are common, especially those involving hematological cells. The mutations associated with ataxia telangiectasia in the ataxia telangiectasia mutation gene lead to mutations in nuclear protein, which normally repairs DNA. Consequently, individuals with ataxia telangiectasia have a sensitivity to ionizing radiation—a diagnostic hallmark of ataxia telangiectasia.3 Almost all persons with ataxia telangiectasia have an elevated α-fetoprotein level; however, this is a nonspecific finding. Ataxia with oculomotor apraxia may be a separate syndrome. It lacks the immunological features and sensitivity to ionizing radiation seen in classic ataxia telangiectasia.2,13 Survival of patients with ataxia telangiectasia after age 30 is rare. ARSACS is a rare ARCA secondary to defective DNA repair found in parts of Quebec. Xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy are rare ARCAs characterized by extreme skin photosensitivity in combination with ataxia and possibly other neurological manifestations. Xeroderma pigmentosum is marked by the development of skin cancers, including squamous cell carcinomas and melanoma.12 Cockayne’s syndrome is associated with ataxia, skin manifestations, growth

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retardation, microcephaly and facial malformations, retinal and cochlear degeneration, and neuropathy.12 Trichothiodystrophy is associated with a mutation that produces a phenotype that overlaps with both xeroderma pigmentosum and trichothiodystrophy. Metabolic derangements of many types cause neurodegenerative syndromes and ataxia (see Table 68–2). A complete review of these disorders is beyond the scope of this chapter.

T A B L E 68–3. Select Noncerebellar Clinical Findings in ARCA Neurological Signs (Other than Ataxia) Retinopathy Optic atrophy Ophthalmoplegia Ocular apraxia Hyporeflexia Hypotonia Spasticity Peripheral neuropathy Proprioceptive loss Muscle atrophy Pyramidal signs Head titubation Deafness Choreoathetosis Mental retardation Seizure

Disease Abetalipoproteinemia, Refsum’s disease, ARSACS, AVED Friedreich’s ataxia, IOSCA IOSCA, AVED Ataxia telangiectasia, AOA Friedreich’s ataxia, AVED, abetalipoproteinemia Cayman’s ataxia ARSACS Friedreich’s ataxia, AVED, ARSACS, SCAN Friedreich’s ataxia, AVED, abetalipoproteinemia, PCRP Friedreich’s ataxia, AVED, abetalipoproteinemia Friedreich’s ataxia, AVED AVED Friedreich’s ataxia, Refsum’s disease, IOSCA Ataxia telangiectasia, AOA, IOSCA Marinesco-Sjögren syndrome, AOA, coenzyme Q10 deficiency Coenzyme Q10 deficiency

AOA, ataxia with ocular motor apraxia; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; AVED, ataxia with vitamin E deficiency; IOSCA, infantile spinocerebellar ataxia; PCRP, posterior column ataxia with retinitis pigmentosa; SCAN, spinocerebellar ataxia with axonal neuropathy.

Refsum’s disease is one that is of importance because early diagnosis and intervention can prevent neurological manifestations. A rare disorder caused by accumulation of phytanic acid in body tissues, Refsum’s disease is a syndrome of cerebellar ataxia, sensorimotor polyneuropathy, and retinitis pigmentosa. The cerebrospinal fluid has a high protein concentration without pleocytosis.2 Treatment is based on dietary restriction of the fatty acid phytanic acid (Tables 68–3 and 68–4).

The Autosomal Dominant Cerebellar Ataxias The ADCAs are a clinically and genetically heterogeneous group of neurodegenerative disorders. Overlap exists between the ADCAs in manifestation to such a degree that genetic testing is required for definitive diagnosis. The following discussion, along with Table 68–5, highlights the clinical features of the six most common spinocerebellar ataxias, DRPLA, the episodic ataxias, human spastic ataxia, and fibroblast growth factor 14 mutation and are designed to narrow the differential diagnosis and number of tests required for diagnosis.1,14 Patients with spinocerebellar ataxia type 1 present with ataxia along with dysarthria and eventually develop bulbar signs such as atrophy of facial and masticatory muscles, perioral fasciculations, and severe dysphagia, leading to frequent aspiration.15 The mean age at onset of type 1 is 37, but it can occur from ages 4 to 74 years.16,17 Spinocerebellar ataxia type 2 is similar to types 1 and 3; however slowed saccades, postural and action tremors, myoclonus, and hyporeflexia are more commonly seen.1,18 The mean age at onset is 30.16 The most prevalent and perhaps the most variable ADCA is spinocerebellar ataxia type 3, or Machado-Joseph disease. Distinctive features in some patients include parkinsonism, restless legs syndrome and periodic leg movements in sleep, pseudoexophthalmos, faciolingual myokymia, and dystonia. A relatively specific sign in type 3 is the loss of temperature sensation, involving the limbs, trunk, and face. Three clinical

T A B L E 68–4. Nonneurological Manifestations of Select Autosomal Recessive Cerebellar Ataxias Manifestation

Disease

Sign

Cardiovascular Pulmonary Gastrointestinal Immunological/infectious

Friedreich’s ataxia AVED Ataxia telangiectasia Abetalipoproteinemia Ataxia telangiectasia

Hematological/oncological

Ataxia telangiectasia

Cardiomyopathy Rare cardiomyopathy Bronchiectasis secondary to chronic pulmonary infection Steatorrhea Immune deficiency with lymphopenia and low immunoglobulin levels with frequent sinopulmonary and cutaneous infections Lymphoreticular and germ cell malignancy in childhood and adenocarcinoma and solid tumors in adulthood Acanthocytosis Skin cancers

Musculoskeletal Dermatological

Endocrine

Abetalipoproteinemia Xeroderma pigmentosum, trichothiodystrophy, and Cockayne’s syndrome Friedreich’s ataxia Cockayne’s syndrome and trichothiodystrophy Ataxia telangiectasia Xeroderma pigmentosum, trichothiodystrophy, and Cockayne’s syndrome Abetalipoproteinemia and AVED Friedreich’s ataxia Ataxia telangiectasia

AVED, ataxia with vitamin E deficiency.

Pes cavus and scoliosis Short stature, microcephaly, and prognathism Ocular and cutaneous telangiectasias, premature senile keratosis, and premature graying hair Skin photosensitivity and skin cancers Xanthelasmata and tendon xanthomas Diabetes mellitus Hypogonadism

chapter 68 inherited ataxias T A B L E 68–5. Selected Clinical Signs in Autosomal Dominant Cerebellar Ataxias2,17 Clinical Signs (Other Than Ataxia) Retinopathy Slow saccades Downbeat nystagmus Ophthalmoplegia Upper motor neuron signs Extrapyramidal

Cortical

Pontine signs Fasciculations Myokymia Peripheral neuropathy Vertigo

Disease Spinocerebellar ataxia type 7 Spinocerebellar ataxia types 1, 2, 3, and 7 (rarely type 6) Spinocerebellar ataxia type 6 and episodic ataxia type 2 Spinocerebellar ataxia types 1, 2, and 3 Spinocerebellar ataxia types 1, 3, 7, and 12 (sometimes types 6, 8) Spinocerebellar ataxia types 2, 3, and 12 (parkinsonism) DRPLA (chorea) Spinocerebellar ataxia type 3 (dystonia) Spinocerebellar ataxia types 2 and 14 and occasionally types 1, 3, 6, 7, and 19 (myoclonus) Spinocerebellar ataxia type 20 (dysphonia) FGF14 (dyskinesia) Spinocerebellar ataxia types 12, 16, and 19 and FGF14 (head or hand tremor) Spinocerebellar ataxia type 20 (palatal tremor) Spinocerebellar ataxia types 13 and 21 and FGF14 (mental retardation) Spinocerebellar ataxia types 10 and 7 and DRPLA (seizure) DRPLA and spinocerebellar ataxia type 17 (dementia) DRPLA and spinocerebellar ataxia type 17 (psychosis) Spinocerebellar ataxia types 1, 2, and 3 Spinocerebellar ataxia type 3 Episodic ataxia type 1 Spinocerebellar ataxia types 3, 4, 18, and 25 Episodic ataxia type 2

DRPLA, dentatorubral-pallidoluysian atrophy; FGF14, fibroblast growth factor 14 (mutation causing disease).

forms of type 3 have been described. Type I disease is the most severe and is characterized by a young age at onset, prominent dystonia, rigidity, and bradykinesia. Ataxia is less prominent in type I. The most common form is type II, which is characterized by ataxia and upper motor neuron signs. Spastic paraparesis is a manifestation in some patients. Type III disease is typified by a pronounced peripheral neuropathy; it has a mean later age at onset, 42, and the age at onset is inversely correlated with severity of disease.16 Patients with spinocerebellar ataxia type 3 require walking aids after 10 to 15 years of disease duration. Spinocerebellar ataxia type 6 is typified by “pure” cerebellar ataxia and late onset of disease; 60% of patients present after the age of 50 years.1 Other signs and symptoms can include diplopia, dysarthria, dysphagia, and horizontal and vertical nystagmus. The ataxia is slowly progressive, and life span is not shortened. Episodic ataxia type 2 and familial hemiplegic migraine are genetically related to type 6. Involvement of the eye is the key distinguishing feature of spinocerebellar ataxia type 7; retinal symptoms precede ataxia by as much as 9 years. In cases with a later onset of disease, the opposite is true: The ataxia precedes the eye findings, by 25

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years. Macular degeneration, pigmentary retinopathy, optic atrophy, blue-yellow color blindness, decreased acuity, and blindness are common manifestations. Ophthalmoplegia occurs in 70% of cases. Type 7 is relatively common in Sweden and Finland. Spinocerebellar ataxia type 8 initially manifests with ataxia, dysarthria, and tremor. A key distinguishing feature of type 8 is slow, drawn-out speech and scanning dysarthria. Truncal instability is also an important characteristic. Impaired smooth visual pursuit is almost universal in type 8. Horizontal nystagmus is also commonly seen. The mean age at onset of disease is from 40 to 50 years of age. Ambulation aids are usually needed after 20 years’ duration of disease. The disease is slowly progressive with no apparent effect on life span. DRPLA, or Smith’s disease, is named for its characteristic pathology changes involving the dentate nucleus and external segment of the globus pallidus and their projections to the red and subthalamic nuclei, respectively. It is a rare disorder seen most often in Japan. The clinical features are variable but can include myoclonus, chorea, epilepsy, ataxia, and cognitive impairment.19 Age at onset is from childhood to late adulthood, with a mean age of 30 years. Mutations in fibroblast growth factor 14 produce a rare ADCA with an early onset in childhood. Clinical features include ataxia, nystagmus, dysarthria, head and limb tremor, orofacial dyskinesias, reduced vibration in the legs, psychiatric symptoms of aggression and depression, and cognitive defects.17 Life span is not shortened in this disease. Episodic ataxia types 1 and 2 are rare ADCAs associated with potassium channel and calcium channel dysfunction, respectively. Type 1 is characterized by paroxysmal spells of ataxia lasting seconds to minutes.20 Myokymia around the eyes, lips, or fingers is characteristic during or between episodes.12 Onset is usually in childhood or adolescence. Type 2 is typified by episodes of ataxia, nausea, and vertigo with interictal nystagmus, diplopia, and migraine. The episodes last hours to days and are brought on by stress, exercise, ethanol, phenytoin, and/or caffeine. Episodes can be aborted and prevented with acetazolamide. Type 2 is genetically related to familial hemiplegic migraine and spinocerebellar ataxia type 6. Other episodic ataxias have been recognized. Human spastic ataxia is a syndrome characterized by severe leg spasticity and ataxia that begins in childhood to early adulthood. Other signs such as dysarthria, dysphagia, and oculomotor dysfunction may be present. Human spastic ataxia is similar to ARSACS. Life span is not shortened.

X-Linked Cerebellar Ataxias Cerebellar ataxia has been described in families with an apparent X-linked inheritance (examples are listed in Table 68–1). These syndromes typically have associated clinical features, such as spasticity, mental retardation, deafness, dementia, or sideroblastic anemia.6 For a more complete description of the X-linked cerebellar ataxias, see the review by Evidente and associates.21

Mitochondrial Inherited Cerebellar Ataxias Mitochondrial inherited cerebellar ataxia should be suspected if the ataxia is associated with additional features: neuropathy,

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myopathy, seizures, retinopathy, deafness, diabetes mellitus, cardiomyopathy, myoglobinuria, renal tubular acidosis, and/or short stature. Examples of mitochondrial inherited ataxias are listed in Table 68–1.

in Tables 68–3 and 68–4. Figure 68–1 demonstrates a suggested diagnostic strategy.

EVALUATION, TESTS, AND LABORATORY FINDINGS

DIAGNOSTIC STRATEGY Determining the mode of inheritance is paramount to the diagnosis of an inherited ataxia. Although accurately constructing pedigrees can be difficult and time consuming, this aspect of the history is vital and saves time and money with regard to future genetic testing. The age at symptom onset may add to any conclusions derived from the pedigree. In general, the ARCAs occur in infancy or early childhood, whereas the ADCAs manifest in adulthood. With anticipation, the ADCAs can manifest in childhood, especially if the proband’s parent was affected in early adulthood. For this reason, the pedigree along with the age at symptom onset should be considered. The age at symptom onset can be variable among the Xlinked and mitochondrial inherited ataxias; however, these are rare disorders, and the pedigree may help distinguish these from the more common ADCAs and ARCAs. If known, the ethnicity and geographic background of the patient should also be noted. It is well established that certain spinocerebellar ataxias are more prevalent in particular ethnic groups. Similarly, Friedreich’s ataxia is more common in white persons and has never been identified in sub-Saharan Africans, American Indians, Japanese persons, or Chinese persons. In the next section, Table 68–8 displays the inherited ataxias associated with particular racial groups. Although there is significant overlap between the phenotypes of inherited ataxias, clinical findings can aid in narrowing the differential diagnosis. If an ADCA is considered, the patient’s condition can be grouped into one of Harding’s clinical types represented in Table 68–6. These categories can be used for narrowing the differential diagnosis. Table 68–5 lists neurological signs other than ataxia that are associated with ADCAs, which may aid in genetic testing decisions. The ARCAs likewise have clinical characteristics both neurological and nonneurological that help distinguish them, such as telangiectasia in ataxia telangiectasia or hyporeflexia, cardiomyopathy, and diabetes mellitus in Friedreich’s ataxia. These are displayed

In patients with a clear inheritance pattern suggestive of a genetically derived ataxia, DNA testing should be the first step in establishing the diagnosis. Genetic testing is the most specific and definitive test for an inherited ataxia in which the specific genetic abnormality has been identified. It can also be the most cost-effective test if the direct genetic testing strategy can be directed by a thorough clinical examination, rather than by an expensive comprehensive inherited ataxia screen (several thousand U.S. dollars at most laboratories). Tables 68–7 and 68–8 list the inherited ataxias and their respective available genetic tests. A useful reference for current genetic tests and their availability is www.genetests.org. The ranges for the number of trinucleotide repeats for the ADCAs are listed in Table 68–8. Interpreting test results can be difficult for the inherited ataxias associated with trinucleotide repeats. The presence of expansion repeats is tested by polymerase chain reaction or Southern blot techniques. For example, the test may reveal that only a single repeat length was detected. This usually indicates T A B L E 68–6. Harding’s Classification Harding’s Classification

Disease

ADCA I

Spinocerebellar ataxia types 1, 2, 3, 4, 8, 12, 17, and FGF14 Spinocerebellar ataxia type 7 Spinocerebellar ataxia types 5, 6, 10, 11, 14, 15, and 22 Spinocerebellar ataxia type 13

ADCA II ADCA III Other

From Harding AE: The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of “the Drew family of Walworth.” Brain 1982; 105:1-28. ADCA, autosomal dominant cerebellar ataxia. ADCA I, cerebellar syndrome + other central nervous system signs (pyramidal, extrapyramidal, ophthalmoplegia, and dementia); ADCA II, cerebellar syndrome + pigmentary maculopathy; ADCA III, “pure” cerebellar syndrome ± mild pyramidal signs; FGF14, fibroblast growth factor 14 (mutation causing disease).

T A B L E 68–7. Selected Autosomal Recessive Cerebellar Ataxias and Their Test Availability Disease

Gene

Gene Product

Test Availability

Friedreich’s ataxia Ataxia telangiectasia ARSACS AVED AOA1 AOA2 SCAN IOSCA Abetalipoproteinemia Marinesco-Sjögren syndrome Cayman ataxia

FRDA-1 ATM SACS TTPA APTX SCAR TDP1 IOSCA MTP MSS ATCAY

Frataxin Serine-protein kinase ATM Sacsin Alpha-tocopherol transfer protein Aprataxin Senataxin Tyrosyl-DNA, phosphodiesterase — Microsomal triglyceride transfer protein — Caytaxin

Yes Yes Yes Yes Yes No Research only No Research only No Research only

AOA, ataxia with ocular motor apraxia; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; ATM, ataxia telangiectasia mutation; AVED, ataxia with vitamin E deficiency; IOSCA, infantile-onset spinocerebellar ataxia; SCAN, spinocerebellar ataxia with axonal neuropathy.

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Individual with progressive ataxia

Autosomal recessive or uncertain inheritance

<25 years old

Exclude secondary causes*

ARCAs, X-linked and mitochondrial inherited

>25 years old

Consider ADCAs

Test for: FRDA (GAA); AT (␣-fetoprotein); AVED (vit. E level); Refsum’s (phytanic acid); Wilson’s

Negative

Autosomal dominant inheritance

Negative FH

ADCA I (ataxia + CNS signs) SCA 1, 2, 3, 4, 8, 12, 17, and FGF14

Harding’s classification†

ADCA II (cerebellar syndrome + pigmentary maculopathy) SCA 7

ADCA III (“pure” cerebellar syndrome) SCA 5, 6, 10, 11, 14,15, and 22

Test for other recessive ataxias‡

* See differential diagnosis discussion above. † ‡

See Table 68-5. See Table 68-1.

■

Figure 68–1. Suggested diagnostic strategy. ADCA, autosomal dominant cerebellar ataxia; ARCA, autosomal recessive cerebellar ataxia; AT, ataxia telangiectasia; AVED, ataxia with vitamin E deficiency; CNS, central nervous system; FGF14, fibroblast growth factor 14 (mutation causing disease); FH, family history; FRDA, Friedreich’s ataxia; GAA, guanine-adenine-adenine; SCA, spinocerebellar ataxia.

that the second allele is the same length and therefore cannot be distinguished.22 Another explanation is that the second allele repeat expansion was present but not detected, as can occur with polymerase chain reaction–based testing. The Southern blot should be employed in this instance because of its greater sensitivity. Interpretation of a test is also problematic when the length of the expansion repeat is on the lower border of the pathological range.22 Other than excluding secondary causes of ataxia, few laboratory tests are helpful in the diagnosis. Examples of test results that would aid in diagnosis include low vitamin E levels (in individuals suspected of having AVED or abetalipoproteinemia),

increased α-fetoprotein levels (ataxia telangiectasia), elevated phytanic acid levels (Refsum’s disease), and low ceruloplasmin levels (Wilson’s disease). Magnetic resonance imaging findings such as cerebellar atrophy (Fig. 68–2), spinal atrophy, and olivopontocerebellar atrophy are nonspecific, as are abnormalities found on positron emission tomography studies in inherited ataxia. Similarly, no specific electrophysiological finding is associated with any one inherited ataxia; however, demonstrating a polyneuropathy in a patient may help narrow the differential diagnosis, because this is a finding common to some ataxias and infrequently encountered in others.

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T A B L E 68–8. Genetic Characteristics of Autosomal Dominant Cerebellar Ataxias Trinucleotide Repeat Number Disease Spinocerebellar ataxia Type 1 Type 2 Type 3 Type 4 Type 5 Type 6 Type 7 Type 8 Type 10 Type 11 Type 12

Type 13 Type 14 Type 15 Type 16 Type 17 Type 18 Type 19 Type 21 Type 22 Type 23 Type 25 Type 26 Type 27-FGF14 Type 28 DRPLA Human spastic ataxia Episodic ataxia type 1 Episodic ataxia type 2

Gene/Gene Product

Repeat Type

Normal

Intermediate

Disease

Test

SCA1/ataxin 1 SCA 2/ataxin 2 MJD/ataxin 3 SCA4 SCA5 SCA6/CACNA1A SCA7/ataxin 7 SCA8 SCA10/ataxin 10 SCA11 SCA12 (PPP2R2B)/serine/threonine protein phosphatase 2A, 55-kD regulatory subunit B, β isoform SCA13 SCA14/PKCγ SCA15 SCA16 TBP/TATA-box binding protein — — — — — — — — — DRPLA/atrophin-1 SAX1

CAG CAG CAG — — CAG CAG CTG ATTCT

6-44 <32 <48 — — <19 7-35 15-50 10-22 — 7-31 (45)

36-38 — 48-51 — — 19 28-35 50-70 — — —

39-91 >31 53-86 — — >18-33 >35-300 (71) 80-800 280-4500 — 55-78

Yes Yes Yes — — Yes Yes Yes Yes — Yes

— — — — CAG

— N/A — — 25-42

— N/A — — 42-44

— N/A — — 46-63

— Yes — — Yes

— — — — — — — — — CAG

— — — — — — — — — <36 —

— — — — — — — — — — —

— — — — — — — — — 48-93 —

— — — — — — — — — Yes —

KCNA/voltage-gated potassium channel protein Kv1.1 CACNA1A/voltage-dependent P/Q-type calcium channel α1A subunit CACNB4/dihydropyridinesensitive L-type, calcium channel β4 subunit

—

—

—

—

—

—

—

—

—

—

CAG

*Data from Tan EK, Ashizawa T: Genetic testing in spinocerebellar ataxias: defining a clinical role. Arch Neurol 2001; 58:191-195. ADCA, autosomal dominant cerebellar ataxia; ATTCT, adenine-thymine-thymine-cytosine-thymine; CAG, cytosine-adenine-guanine; CTG, cytosine-guanine-adenine; DRPLA, dentatorubral-pallidoluysian atrophy; FGF14, fibroblast growth factor 14 (mutation causing disease).

DIFFERENTIAL DIAGNOSIS Disorders that can be confused with the inherited ataxias include alcoholic cerebellar ataxia, paraneoplastic cerebellar ataxia (associated most commonly with small cell lung, breast, and ovarian cancers), ataxia with gluten sensitivity, ataxia with antiglutamate decarboxylase antibodies, nutritionally related ataxia (vitamin E deficiency resulting from cystic fibrosis or cholestatic liver disease), drug toxicity (5-fluorouracil, cytosine arabinoside, phenytoin, bismuth [Pepto-Bismol], mercurycontaining fungicides, and lithium), industrial toxin exposure (as in Minamata disease manifesting with ataxia, tremor, and dysarthria resulting from methyl mercurial compounds or cerebellar ataxia secondary to exposures to solvents containing toluene and metals such as lead, manganese, and tin),

endocrinopathy (hypothyroidism and hypopituitarism), infectious causes of ataxia (e.g., human immunodeficiency virus, postinfectious encephalomyelitis, brainstem or Bickerstaff’s encephalitis, or after a viral syndrome such as varicella or Epstein-Barr virus in children), demyelinating diseases, spongiform encephalopathy (kuru, Creutzfeldt-Jakob disease, or other prion diseases), multiple system atrophy, and idiopathic lateonset cerebellar ataxia (probably the most common cerebellar ataxia).

TREATMENT Unfortunately, no specific treatment exists to halt or slow neuronal death in the inherited ataxias except for those secondary

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B Figure 68–2. Typical magnetic resonance imaging (MRI) findings seen in spinocerebellar ataxia type 3 (Machado-Joseph disease). The patient was a 41-year-old woman of Portuguese descent with type 3 (confirmed with genetic testing) who presented at age 18 with ataxia and a family history of ataxia affecting her father, paternal grandmother, and paternal great-grandmother. Cerebellar atrophy is apparent in the T1-weighted sagittal view (A) and the T1-weighted axial view (B), demonstrating prominence of subarachnoid space between the folia of the cerebellum bilaterally. (Images courtesy of H. A. Robles, M.D.)

to vitamin E deficiency and/or other metabolic derangements (if recognized early in the course of illness). However, treatment strategies for certain ataxias are increasingly being studied. For instance, therapeutic strategies have been developed for Friedreich’s ataxia with the use of antioxidants (idebenone, coenzyme Q10, vitamin E, and mitoquinone), iron chelators (desferrioxamine, deferiprone, 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs), glutathione peroxidase mimetics, pharmacological therapy to increase frataxin levels, and gene and cell therapies.10 No double-blind, placebocontrolled trials have demonstrated any benefit for the neurological manifestations of Friedreich’s ataxia. However, because patients may benefit from treatment of other medical problems related to the inherited ataxias (e.g., diabetes mellitus and cardiomyopathy in Friedreich’s ataxia), determining the diagnosis is important. Because spinocerebellar ataxia type 6 is caused by a mutation in the α1A subunit of the voltage-gated neuronal calcium channel, calcium channel blockers and acetazolamide have been suggested as therapies because of their effectiveness in migraine prophylaxis and episodic ataxia type 2, respectively (two diseases with pathophysiology involving neuronal calcium flux). Ataxia was improved in the first open-label trial for spinocerebellar ataxia type 6 with the use of acetazolamide (250 to 500 mg/day) over 88 weeks.23 Parkinsonism associated with the spinocerebellar ataxias has been shown to improve with

levodopa and dopamine agonists.24-26 Spinocerebellar ataxias with symptoms of dystonia and bradykinesia may respond to amantadine.27 Botulinum toxin injections may prove effective in cases with dystonia. Other symptoms, such as restless legs syndrome and periodic leg movements especially common in spinocerebellar ataxia type 3, can be treated with usual dopaminergic treatments.28,29 Table 68–9 lists clinical trials in inherited ataxias completed or ongoing as of January 2005. For a current list of clinical trials for inherited ataxias, refer to www.clinicaltrials.gov.

SUPPORTIVE CARE AND LONG-TERM MANAGEMENT Supportive care remains the mainstay of management. Occupational and physical therapy for gait is imperative, as is the use of mechanical aids such as a cane, walker, or wheelchair for continued safety with ambulation. For patients with dysarthria, speech therapy is warranted. Symptomatic treatment for insomnia, diplopia, spasticity, and urinary urgency or frequency with standard therapies may be necessary for improved quality of life. It is worthwhile to determine vitamin B12, folate, and thyroid status in all patients with ataxia, including those with inherited ataxia, because any patient may have a superimposed

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T A B L E 68–9. Clinical Trials for Inherited Ataxia Study Name

Sponsor

ETE

Type

Design

Location

Start and End Dates

European Integrated Project On Spinocerebellar Ataxias (EUROSCA)

European Commission in the 6th Framework Programme NINDS and Baylor College of Medicine

—

Multiple

Multiple

Europe (22 groups from 9 countries)

—

30

Observational

Screening

11/1999-present

NINDS

300

Observational

Natural history

University of Texas Medical Branch at Galveston NINDS, Bethesda, Maryland

NINDS

750

Observational

Natural history

NINDS

100

Interventional

NINDS

15

Interventional

NINDS

20

NHGRI

NHLBI

Clinical and Molecular Correlations in SCA10 Phenotype/Genotype Correlations in Movement Disorders Study of Inherited Neurological Disorders Safety Study of Idebenone to Treat Friedreich’s Ataxia Phase 1 Trial of Idebenone to Treat Patients with Friedreich’s Ataxia High-Dose IV Immunoglobulin to Treat Cerebellar Degeneration Transitional Life Events in Patients with Friedreich’s Ataxia: Implications for Genetic Counseling Vitamin Replacement in Abetalipoproteinemia

7/2001-present 2/2000-present

Treatment, safety Treatment, safety

NINDS, Bethesda, Maryland NINDS, Bethesda, Maryland NINDS, Bethesda, Maryland

Interventional

Treatment, safety/efficacy

NINDS, Bethesda, Maryland

4/2002-2/2004

40

Observational

Natural history

NHGRI, Bethesda, Maryland

3/2003-1/2004

1

Observational

Natural history

NHLBI, Bethesda, Maryland

2/2000-5/2001

5/2001-present 2/2004-present

ETE, expected total enrollment; NINDS, National Institute of Neurological Disorders and Stroke; NHGRI, National Human Genome Research Institute; NHLBI, National Heart, Lung, and Blood Institute; SCA10, spinocerebellar ataxia type 10.

contribution of a readily treatable secondary cause of ataxia. For similar reasons, it is advisable for patients with ataxia to undergo magnetic resonance imaging and/or computed tomographic scanning of the head on at least one occasion.

PROGNOSIS The prognosis is variable for the inherited ataxias, even between individuals in a single kindred. Inherited ataxias are neurodegenerative, progressive, and currently without any cure or effective treatment to halt progression. A younger age at onset generally portends a poorer prognosis; thus, the ARCAs are especially devastating. The prognosis of an individual patient is difficult to establish; however, predictive determinations can begin with the assessment of the phenotype observed in a single family and the proband’s age at symptomatic onset.

K E Y

P O I N T S

●

Inherited ataxias are neurodegenerative syndromes with variable clinical signs and symptoms, both neurological and systemic.

●

Inherited ataxias are classified by mode of inheritance.

●

ARCAs begin in childhood, the two most common examples being Friedreich’s ataxia and ataxia telangiectasia.

●

ADCAs are typically of adult onset, the most common being spinocerebellar ataxia 3 (Machado-Joseph disease).

●

Diagnosis is based on genetic testing, although pedigrees, ethnicity, age at onset, and clinical features should be assessed to narrow the differential diagnosis.

FUTURE CONSIDERATIONS Therapeutic trials (see Table 68–9) may provide invaluable information concerning disease. Genetic research may also result in the discovery of gene modifiers that can be manipulated to delay the age at symptomatic onset or prevent neuronal destruction altogether. Likewise, delineating the pathophysiology responsible for the neurodegeneration caused by the ataxias may help provide not only therapies for the inherited ataxias but also information on the normal functioning of the cerebellum and its spinal tracts. Searches for biomarkers must be a priority, to determine prognosis before neuronal destruction and strategies for screening to identify asymptomatic individuals in whom definitive genetic testing is appropriate.

Suggested Reading Di Donato S, Gellera C, Mariotti C: The complex and genetic classification of inherited ataxias. II. Autosomal recessive ataxias. Neurol Sci 2001; 22:219-228. Harding AE: The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of “the Drew family of Walworth.” Brain 1982; 105:1-28. Rosa AL, Ashizawa T: Genetic ataxia. Neurol Clin North Am 2002; 20:727-757. Schols L, Bauer P, Schmidt T, et al: Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004; 3:291-304.

chapter 68 inherited ataxias Subramony SH, Currier RD: The classification of familial ataxias. In Vinken PJ, Bruyn GW, Klawans HL, et al, eds: Handbook of Clinical Neurology, vol 60: Hereditary Neuropathies and Spinocerebellar Atrophies. Amsterdam: Elsevier Science, 1991, pp 271-284.

References 1. Schols L, Bauer P, Schmidt T, et al: Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004; 3:291-304. 2. Di Donato S, Gellera C, Mariotti C: The complex and genetic classification of inherited ataxias. II. Autosomal recessive ataxias. Neurol Sci 2001; 22:219-228. 3. Taroni F, Di Donato: Pathways to motor incoordination: the inherited ataxias. Neuroscience 2004; 5:641-655. 4. Van de Warrenburg BPC, Sinke RJ, Verschuuren-Bemelmans CC, et al: Spinocerebellar ataxias in the Netherlands: prevalence and age at onset analysis. Neurology 2002; 58:702-708. 5. Moseley, ML, Benzow KA, Schut LJ, et al: Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998; 51:1666-1671. 6. Bird TD: Hereditary ataxia overview. Available at: http://www.geneclinics.org/servlet/access?db=geneclinics&site -gt&id=8888891&key=U0ECBakjvMZq&gry=&fcn=y&fw=ig9&filename=/profiles/ataxias/index.html (accessed March 28, 2006). 7. Le Ber I, Camuzat A, Castelnovo G, et al: Prevalence of dentatorubral-pallidoluysian atrophy in a large series of white patients with cerebellar ataxia. Arch Neurol 2003; 60:10971099. 8. Chinnery PF: Mitochondrial disorders overview. Available at: http://www.geneclinics.org/servlet/access?id=8888892&key=m WTifFAAeBgi4&gry=INSERTGRY&fcn=y&fw=egAc&filename =/glossary/profiles/mt-overview/index.html (accessed March 28, 2006). 9. Chokravarty A: Friedreich’s ataxia-yesterday, today and tomorrow. Neurol India 2003; 51:176-182. 10. Voncken M, Ioannou P, Delatycki MB: Friedreich ataxia— update on pathogenesis and possible therapies. Neurogenetics 2004; 5:1-8. 11. Klockgether T, Ludtke R, Kramer B, et al: The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998; 121:589-600. 12. Rosa AL, Ashizawa T: Genetic ataxia. Neurol Clin North Am 2002; 20:727-757. 13. Aicarki J, Barbosa C, Andermann E, et al: Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann Neurol 1988; 24:497-502.

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14. Brusco A, Gellara C, Cagnoli C, et al: Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol 2004; 61:727-733. 15. Brandt VL, Zoghbi HY: Spinocerebellar ataxia type 1. Available at: http://www.geneclinics.org/servlet/access?id=8888892&key= 2Jd7dxSHCvTiw&gry=INSERTGRY&fcn=y&fw=XQeU&file name=/glossary/profiles/sca1/index.html (accessed March 28, 2006). 16. Klockgether T, Ludtke R, Kramer B, et al: The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998; 121:589-600. 17. Hereditary ataxias: dominant. Available at: http://www.neuro. wustl.edu/neuromuscular/ataxia/domatax.html#sca1 (accessed March 28, 2006). 18. Pulst S-M: Spinocerebellar ataxia type 2. Available at: http://www.geneclinics.org/servlet/access?id=8888892&key=In WC1vXiLbpgH&gry=INSERTGRY&fcn=y&fw=ikyP&filename =/glossary/profiles/sca2/index.html (accessed March 28, 2006). 19. Warner TT, Williams LD, Walker RWH, et al: A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families. Ann Neurol 1995; 37:452-459. 20. Albin RL: Dominant ataxias and Friedreich ataxia: an update. Curr Opin Neurol 2003; 16:507-514. 21. Evidente VGH, Gwinn-Hardy KA, Caviness JN, et al: Hereditary ataxias. Mayo Clinic Proc 2000; 75:475-490. 22. Margolis RL: The spinocerebellar ataxias: order emerges from chaos. Curr Neurol Neurosci Rep 2002, 2:447-456. 23. Yabe I, Sasaki H, Yamashita I, et al: Clinical trial of acetazolamide in SCA6, with assessment using the Ataxia Rating Scale and body stabilometry. Acta Neurol Scand 2001; 104:4447. 24. Tuite PJ, Rogaeva EA, George-Hyslop PH, et al: Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol 2001; 50:812-815. 25. Buhamann C, Bussopulos A, Oechsner M: Dopaminergic response in parkinsonian phenotype of Machado-Joseph disease. Mov Disord 2003; 18:219-221. 26. Furtado S, Farrer M, Tsuboi Y, et al: SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings. Neurology 2002; 59:1625-1627. 27. Woods BT, Schaumburg HH: Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia: a unique and partially treatable clinico-pathological entity. J Neurol Sci 1972; 17:149-166. 28. Schols L, Haan J, Riess O, et al: Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology 1998; 51:1603-1607. 29. Abele M, Burk K, Laccone F, et al: Restless legs syndrome in spinocerebellar 1,2, and 3. J Neurol 2001; 248:311-314.

CHAPTER

69

HEREDITARY SPASTIC PARAPLEGIAS* ●

●

●

●

John K. Fink

The hereditary spastic paraplegias (HSPs), also known as familial spastic paraplegia and Strümpell-Lorrain disease (per Dorland’s),1 constitute a group of more than 30 inherited neurological disorders in which the predominant symptom is bilateral lower extremity spastic weakness. Previous reviews of HSP are available in articles by Fink and colleagues,2-4 in the Gene Reviews website (http://www.geneclinics.org/profiles/ hsp/), in the University of Michigan’s Hereditary Spastic Paraplegia website (http://www.med.umich.edu/hsp), and in the website for the Spastic Paraplegia Foundation (http://www. sp-foundation.org).

EPIDEMIOLOGY HSP affects individuals of all ethnic groups and ancestries without particular ethnic predilection. The prevalence of HSP has been estimated in Ireland (1.27 per 100,000),5 Italy (2.7 per 100,000),6 and Spain (9.6 per 100,000).5

GENETIC CLASSIFICATION: MODE OF INHERITANCE AND HSP LOCUS There are autosomal dominant, autosomal recessive, and Xlinked forms of HSP, each of which is genetically heterogeneous: Many different, separate gene mutations cause clinically similar, often indistinguishable syndromes of lower extremity spastic weakness). HSP genetic loci are designated SPG (spastic gait) and numbered 1 through 28 in order of their discovery (Table 69–1).

CLINICAL CLASSIFICATION: “UNCOMPLICATED” AND “COMPLICATED” HSP Classifying HSP as complicated or uncomplicated is useful for research purposes because it enables analysis of homogenous cohorts. Uncomplicated HSP (also known as known as “nonsyndromic” or “pure” HSP) refers to the syndrome of insidi*This research is supported by grants from the Veterans Affairs Merit Review and the National Institutes of Health (NINDS R01NS33645, R01NS36177 and R01NS38713) to John K. Fink. The expert secretarial assistance of Ms. Lynette Girbach is gratefully acknowledged.

ously progressive (or, in the case of early childhood onset, essentially nonprogressive) spastic leg weakness, frequently accompanied by urinary urgency and mildly impaired vibration sensation in the distal lower extremities. Complicated forms of HSP are inherited syndromes in which the predominant feature of spastic paraparesis is accompanied by other neurological or systemic abnormalities (such as mental retardation, ataxia, peripheral neuropathy, deafness, cataracts, and muscle atrophy), in addition to lower extremity spastic weakness. Classifying HSP as uncomplicated or complicated is also important for prognosis. Families with “uncomplicated” HSP (e.g., HSP caused by SPG4/spastin gene mutation) are not at risk of having offspring with “complicated” HSP. The converse is not always true, however. Families with some forms of “complicated” HSP (e.g., SPG7 or SPG10 HSP caused by paraplegin or kinesin heavy chain [KIF5A] gene mutations, respectively)7,8 may have offspring affected with either “uncomplicated” or “complicated” HSP. Controversies in HSP classification arise as the knowledge of the HSPs expands. For example, seizures, cognitive impairment, and ataxia9 have been reported in patients with the most common form of dominantly inherited HSP (SPG4, caused by SPG4/spastin gene mutation), generally considered prototypical of uncomplicated HSP.10-14 Further studies to determine the frequency of “extraspinal” features in otherwise uncomplicated HSP are needed.

NEUROPATHOLOGY: DISTAL AXON DEGENERATION INVOLVING LONGEST MOTOR AND SENSORY FIBERS IN THE CENTRAL NERVOUS SYSTEM Postmortem studies of uncomplicated HSP reveal relatively selective axonal degeneration involving terminal portions of corticospinal tracts (maximal in the thoracolumbar region) and dorsal column fibers (maximal in cervicomedullary region).15-20 Spinocerebellar fibers are involved to a lesser extent. Myelin loss is considered secondary to primary axonal degeneration. Decreased numbers of cortical motor neurons and anterior horn cells have been reported.18,19 Peripheral nerves and dorsal root ganglia are normal in uncomplicated HSP.19

899

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T A B L E 69–1. Hereditary Spastic Paraplegia (HSP) Loci Spastic Gait (SPG) Locus

HSP Syndrome

Autosomal Dominant HSP SPG3A (14q11-q21) Uncomplicated HSP: symptoms usually begin in childhood (and may be nonprogressive); symptoms may also begin in adolescence or adulthood and worsen insidiously Genetic nonpenetrance reported De novo mutation reported manifesting as spastic diplegic cerebral palsy SPG4 (2p22) Uncomplicated HSP, symptom onset in infancy through senescence, most common cause of autosomal dominant HSP (≈40%) Some subjects have late-onset cognitive impairment SPG6 (15q11.1) Uncomplicated HSP: prototypical lateadolescent, early-adult onset, slowly progressive uncomplicated HSP

Protein Name and Function

Gene Testing

References

Atlastin: unknown function, appears to be Golgi protein that shares homology with guanylate binding protein 1, a dynamin family GTPase

ADL

Zhao et al35 Hazan et al105 Sauter et al106 Paternotte et al107

Spastin: cytosolic (or possibly nuclear) protein with AAA domain that appears to interact with microtubules and may play a role in microtubule severing

ADL

NIPA1: neuron-specific protein of unknown function, 9 alternating hydrophobic-hydrophilic domains, predictive of integral membrane localization Unknown

ADL

Heinzlef et al10 Roll-Mecak and Vale26 Evans et al33 Hazan et al78,80 Charvin et al108 Hentati et al109 Rainier et al81 Fink et al110,111 Chen et al112

No

Hedera et al113 Reid et al114 Seri et al115

SPG8 (8q23-q24)

Uncomplicated HSP

SPG9 (10q23.3-q24.2)

Complicated HSP: spastic paraplegia associated with cataracts, gastroesophageal reflux, and motor neuronopathy

Unknown

No

SPG10 (12q13)

Uncomplicated HSP or complicated by distal muscle atrophy

Research laboratories only

Reid et al100 Fichera et al116

SPG12 (19q13)

Uncomplicated HSP

Kinesin heavy chain (KIF5A): a molecular motor that participates in axonal transport of organelles and macromolecules Unknown

No

Reid et al114

SPG13 (2q24-34)

Uncomplicated HSP: adolescent and adult onset Complicated HSP: spastic paraplegia associated with amyotrophy of hand muscles (Silver’s syndrome)

Research laboratories only Research laboratories only

Hansen et al41 Fontaine et al117

SPG17 (11q12-q14)

Chaperonin 60 (also known as heat shock protein 60): mitochondrial protein BSCL2/seipin: integral membrane protein in endoplasmic reticulum

Unknown

No

Paraplegin: mitochondrial metalloprotease

Research laboratories only

Wilkinson et al44 Hentati et al121 Muglia et al122 Tang et al123 DeMichele et al7 Garner et al124

Unknown

No

MartinezMurillo et al125 Winner et al126

Unknown

No

Vazza et al92

Autosomal Recessive HSP SPG5 (8p) Uncomplicated HSP

SPG7 (16q)

SPG11 (15q)

SPG14 (3q27-28)

Uncomplicated or complicated HSP: variably associated with mitochondrial abnormalities on skeletal muscle biopsy and dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and evidence of “vascular lesions,” cerebellar atrophy, or cerebral atrophy on cranial MRI Uncomplicated or complicated HSP: spastic paraplegia variably associated with thin corpus callosum, mental retardation, upper extremity weakness, dysarthria, and nystagmus 50% of autosomal recessive HSP cases are considered to be SPG11 Complicated HSP: spastic paraplegia associated with mental retardation and distal motor neuropathy

Patel et al118 Auer-Grumbach et al119 Windpassinger et al120

Continued

chapter 69 hereditary spastic paraplegias

901

T A B L E 69–1. Hereditary Spastic Paraplegia (HSP) Loci—cont’d Spastic Gait (SPG) Locus SPG15 (14q)

SPG20 (13q)

SPG21 (15q22.31)

SPG23 (1q24-q32)

SPG24 (13q14) SPG26 (12p11.1 -12q14)

SPG27 (10q22.1 -q24.1) SPG28 (14q21.3 -q22.3) “SPOAN” syndrome (11q23) X-Linked HSP SPG1 (Xq28)

SPG2 (Xq28)

SPG16 (Xq11.2-q23)

HSP Syndrome

Protein Name and Function

Gene Testing

References

Complicated HSP: spastic paraplegia associated with pigmented maculopathy, distal amyotrophy, dysarthria, mental retardation, and further intellectual deterioration (Kjellin’s syndrome) Complicated HSP: spastic paraplegia associated with distal muscle wasting (Troyer’s syndrome)

Unknown

No

Hughes et al127

Spartin: N-terminal region similar to that of spastin; homologous to proteins involved in the morphology and trafficking of endosomes Maspardin: protein localizes to endosome/trans-Golgi vesicles, may function as protein transport and sorting

Research laboratories only

Patel et al38 Crosby et al40 Cross et al128 Proukakis et al129

Research laboratories only

Simpson et al130

Unknown

No

Blumen et al131

Unknown

No

Hodgkinson et al132

Unknown

No

Wilkinson et al133

Unknown

No

Meijer et al134

Unknown

No

Bouslam et al135

Unknown

No

Macedo-Souza et al136

L1CAM

Research laboratories only

Jouet et al137

Proteolipid protein

Several Hudson48 laboratories* Kobayashi et al138 Saugier-Veber et al139 Cambi et al140 No Steinmuller et al141 Tamagaki et al142

Complicated HSP: spastic paraplegia associated with dementia, cerebellar and extrapyramidal signs, thin corpus callosum, and white matter abnormalities (Mast’s syndrome) Complicated HSP: childhood-onset HSP associated with skin pigment abnormality Complicated HSP: childhood-onset HSP variably complicated by spastic dysarthria and pseudobulbar signs Complicated HSP: childhood-onset progressive spastic paraparesis with dysarthria and distal amyotrophy in both the upper and lower limbs, intellectual impairment Uncomplicated or complicated HSP: adult onset, uncomplicated spastic paraplegia; or spastic paraplegia associated with dysarthria Uncomplicated HSP: childhoodonset progressive spastic gait Complicated HSP: Spastic Paraplegia, Optic Atrophy, Neuropathy (SPOAN) Complicated HSP: associated with mental retardation, and variably, hydrocephalus, aphasia, and adducted thumbs Complicated HSP: variably associated with MRI evidence of CNS white matter abnormality; may have peripheral neuropathy Uncomplicated or complicated HSP: associated with motor aphasia, reduced vision, nystagmus, mild mental retardation, and dysfunction of the bowel and bladder

Unknown

Modified from Fink.2,16,101-104 *Several laboratories, including Dupont Nemours Clinic and Baylor University. AAA, adenine-adenine-adenine; ADL, Athena Diagnostics, Inc. (Boston); CNS, central nervous system; GTPase, guanosine triphosphatase; MRI, magnetic resonance imaging.

Axonal degeneration in uncomplicated HSP thus involves the distal ends of the longest motor (corticospinal tracts) and sensory (dorsal column) fibers in the central nervous system (CNS). In this regard, uncomplicated HSP may be considered a “CNS homologue” of Charcot-Marie-Tooth disease type 2, in which distal motor and sensory axon degeneration is limited to the peripheral nervous system. To extend this analogy, it is noteworthy that one type of HSP (SPG10) is caused by mutation in KIF5A,8 whereas mutations in another kinesin (KIF1B) cause Charcot-Marie-Tooth disease type 2A1.21

EMERGING CONCEPTS OF HSP PATHOGENESIS The molecular mechanisms underlying axon degeneration for most types of HSP are poorly understood. Nonetheless, the discovery of many HSP genes is generating new concepts about the pathophysiology of HSPs.16 Thus far, 28 HSP loci and 11 HSP genes have been discovered (see Table 69–1). The functions of most of these HSP proteins have not been fully elaborated; however, as a group, HSP genes (and their respective proteins) appear highly diverse. This diversity of HSP genes

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(and their proteins) suggests that axonal degeneration in various genetic types of HSP may be caused by diverse, primary biochemical disturbances.22 A tentative biochemical classification of HSP is emerging. It is likely that these disparate biochemical disturbances converge into one or more common pathways.

HSP Caused by Axonal Transport Abnormality There is increasing evidence that disturbance of axonal transport occurs in a variety of motor neuron disorders, including HSP.23,24 The clearest example of axonal transport involvement in HSP is autosomal dominant SPG10 HSP caused by KIF5A mutation. KIF5A is a molecular motor component involved in axonal transport of organelles and macromolecules. SPG4, the most common cause of dominantly inherited HSP, resulting from spastin gene mutation, may be another example of axonal transport or cytoskeletal involvement in HSP. There is accumulating evidence that spastin interacts with microtubules and may be involved in microtubule severing.25-34

HSP Caused by Golgi Abnormalities Atlastin mutations cause approximately 25% of childhoodonset dominantly inherited HSP.35-37 Spartin mutations cause autosomal recessive HSP associated with distal muscle atrophy (Troyer’s syndrome).38 Although the functions of both atlastin and spartin have not been elucidated, it is known that both of these proteins are localized to the Golgi apparatus.39,40

HSP Caused by Mitochondrial Abnormality Two HSP genes encode integral mitochondrial proteins: chaperonin 60/heat shock protein 60, mutations of which cause autosomal dominant uncomplicated SPG13 HSP,41 and paraplegin, mutations of which cause autosomal, complicated recessive SPG7 HSP.42-45 Some but not all patients with paraplegin mutation have evidence of mitochondrial abnormalities in skeletal muscle biopsy.7

HSP Caused by Primary Myelin Disturbance It is important to note that axon degeneration in at least one form of HSP arises not from an intrinsic axon or neuron abnormality but rather from glial abnormality. X-linked SPG2 HSP is caused by proteolipid protein gene mutation. Proteolipid protein is an intrinsic myelin protein, and mutations in the gene cause both Pelizaeus-Merzbacher disease46 (an X-linked infantile-onset dysmyelination disorder) and X-linked HSP (a childhood-onset slowly progressive spastic gait disorder).47,48 Patients and gene-targeted mice lacking proteolipid protein develop length-dependent axon degeneration in the absence of demyelination.49

HSP Caused by Embryonic Development of Corticospinal Tracts Mutations in the neuronal cell adhesion molecule L1 (L1CAM) gene cause a variety of X-linked neurological disorders, includ-

ing X-linked hydrocephalus; the syndrome of mental retardation, aphasia, shuffling gait, and adducted thumbs; and complicated X-linked spastic paraplegia.50-52 L1CAM knockout mice53 exhibit weak hind limbs and reduced size of corticospinal tracts.

SYMPTOMS: SPASTIC GAIT AND URINARY URGENCY Developmental milestones are normal. Prenatal, perinatal, and postnatal periods are uneventful, and developmental milestones are attained normally in uncomplicated HSP. Although the age at which walking begins is not delayed, affected individuals’ persistent toe-walking may be the first sign of earlyonset HSP. The predominant symptom of HSP is abnormal gait caused by bilateral lower extremity spasticity and weakness. This may begin at any age, from infancy through old age. Spastic gait caused by HSP that begins in infancy may be essentially nonprogressive and mimic spastic diplegic cerebral palsy. In contrast, lower extremity spasticity that begins in later childhood through adulthood usually worsens insidiously. It is common for symptoms of lower extremity spasticity to be worse in cold weather, after exertion, and in the evening. Urinary urgency is common and is occasionally an early symptom.

NEUROLOGICAL EXAMINATION: UPPER MOTOR NEURON SIGNS IN THE LEGS; IMPAIRED VIBRATION SENSATION IN THE TOES Examination of individuals with uncomplicated HSP reveals signs of upper motor neuron deficits in the lower extremities: bilateral, approximately symmetrical, lower extremity spasticity and weakness; pathological hyperreflexia; and extensor plantar responses (plantar responses are occasionally flexor in obviously affected patients). Spasticity is noted particularly in the hamstring, Achilles, and adductor tendons. Weakness is noted particularly in the iliopsoas, hamstring, and tibialis anterior muscles. Although all patients with HSP have lower extremity spasticity, the degree of weakness is variable. Some patients have lower extremity spasticity but normal muscle strength. Although Harding19,54 used the variable proportion of weakness and spasticity (along with age at symptom onset) to classify HSP as type I (greater spasticity than weakness) and type II (significant weakness), this classification is not widely used because estimates of the relative contributions of weakness versus spasticity are qualitative and because some genetic types of HSP may manifest as both type I and type II. Vibration sensation in the toes is often mildly impaired in uncomplicated HSP. Distal lower extremity vibratory impairment may not manifest for several years, but when present, this is a helpful diagnostic sign. When not attributed to other disorders (such as peripheral neuropathy or cervical spondylosis), impaired vibration sensation in the toes helps to distinguish HSP’s motor (corticospinal tract) and sensory (dorsal column) patterns of involvement from primary lateral sclerosis (involvement of upper motor neurons with sparing of dorsal columns).55 Although vibratory sense may be mildly impaired

chapter 69 hereditary spastic paraplegias in HSP, severe dorsal column disturbance is not typical of uncomplicated HSP and would prompt a search for other disorders (including Friedreich’s ataxia, subacute combined degeneration, and tertiary syphilis).

Asymptomatic Upper Extremity Involvement in Uncomplicated HSP Whereas corticospinal tract involvement in the legs is obvious and causes functional disability, involvement of corticospinal tracts subserving the upper extremities is not infrequent, always mild, and nearly subclinical. Upper extremity deep tendon reflexes in uncomplicated HSP are often hyperactive (grade 3+ on a 0-4 scale). Nonetheless, upper extremity muscle tone, strength, and dexterity remain normal in uncomplicated HSP. Whereas lower extremity muscle tone and weakness typically worsen, uncomplicated HSP does not involve functional disturbance in the upper extremities.

PES Cavus Individuals with HSP often have pes cavus (high arched feet). Nonetheless, the presence or absence of pes cavus cannot be used reliably to determine the likelihood that an at-risk person will develop HSP.

Spastic Gait Patients with uncomplicated HSP generally exhibit bilaterally symmetrical gait disturbance,56 including short stride length (because of difficulty flexing the thighs and dorsiflexing the feet), circumduction, anterior-foot strike (tendency to walk on the balls of the feet or on the toes), scissoring, hyperlordosis, and sometimes hyperextension at the knee. The ability to walk on the heels is generally compromised. The abnormality of gait varies between individuals. Careful analysis of each affected individual’s gait is necessary to provide specific exercise recommendations, to determine whether the patient would benefit from spasticity-reducing medication, and to determine whether the patient would benefit from ankle-foot orthotic devices.

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ing genetic and possibly environmental factors. One source of modifying genes is polymorphisms in HSP genes themselves. Recently, Svenson and associates analyzed benign SPG4/spastin polymorphisms (S44L and P45Q) and showed that L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the pathogenic mutations in SPG4/spastin’s adenine-adenine-adenine domain.58

Age at Symptom Onset Age at symptom onset may be quite variable between different genetic types of HSP, between patients with one particular genetic type, and even within a family in which affected patients share the same HSP gene mutation. Although the average age at symptom onset is earlier for some types of HSP (SPG10, SPG3A, and SPG12)4 than for other types of HSP (SPG4, SPG13, SPG8, and SPG6), there is significant overlap in the range of ages at which symptoms begin. For SPG4 HSP, meta-analysis of 75 families did not reveal a correlation between spastin mutation class (missense, aberrant splicing, frameshift, premature truncation mutations) and age at symptom onset.59

Genetic Anticipation Genetic anticipation has been reported in SPG4 HSP,60 including patients later shown to have point mutations (not trinucleotide repeat expansions) in the SPG4/spastin gene. The author and colleagues have observed apparent genetic anticipation in SPG3A HSP. For example, they identified the SPG3A mutation V253I in a 70-year-old patient who was asymptomatic and had normal neurological examination findings; his mutation-bearing son developed HSP in his 20s; and his mutationbearing grandson developed HSP before age 7 (J. K. Fink, 2005 unpublished observation).

Relatively Nonprogressive versus Progressive Forms of HSP When HSP begins after adolescence, symptoms usually progress steadily over many years. When symptoms begin in childhood, there may be very little progression even over 10 years.2

SYNDROME VARIABILITY Some genetic forms of HSP represent unique clinical syndromes (e.g., spastic paraplegia associated with distal muscle wasting caused by SPG20/spartin and SPG17/BSCL2 gene mutations that cause autosomal recessive Troyer’s syndrome and autosomal dominant Silver’s syndrome, respectively). Other genetic forms of HSP may be clinically indistinguishable (e.g., uncomplicated SPG4, SPG8, and SPG6 HSP). Within a given genetic type of HSP (such as SPG4 HSP caused by spastin gene mutation), there may be significant clinical variability. Part of this variability may result from the effects of different mutations.57 For example, whereas SPG4 HSP (caused by spastin mutation) is usually uncomplicated, ataxia in addition to spastic paraplegia has been reported in a family with SPG4 mutation GLN490Stop.9 Significant variability between affected patients who share the same HSP gene mutation reflects the influence of modify-

Syndromic Features Although complicated forms of HSP have “syndromic” features (e.g., SPG9, SPG10, and SPG17 have motor neuropathy or distal wasting), such features may be present in only a minority of affected family members (e.g., some with SPG1061 and some with SPG7 45 had complicated HSP, whereas others had uncomplicated HSP).

Subclinical Cognitive Disturbance and Late-Onset Dementia These features have been described in some but not all patients with the most common form of dominantly inherited HSP (caused by SPG4 mutations)10-14 and may be correlated with specific spastin mutations.62 Cognitive impairment is a feature

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of several forms (see Table 69–1) of complicated HSP, particularly SPG11, which appears to be the most common form of autosomal recessive HSP.

Severity The extent to which HSP symptoms are disabling is quite variable both between different genetic types of HSP and within a given family.4

Weakness versus Spasticity As noted previously, some patients with HSP have significant weakness, whereas others have severe spasticity with negligible weakness. Such differences may occur within a given type of HSP.

LABORATORY STUDIES, NEUROIMAGING, AND NEUROPHYSIOLOGICAL EVALUATION These tests are useful for excluding other disorders and for characterizing the pattern of neurological involvement (and thus classifying HSP as uncomplicated or one of the complicated forms). Genetic testing, discussed later, is useful for confirming the clinical diagnosis of HSP. Extensive neurodiagnostic evaluations are not always indicated for every affected patient in large families with definite HSP. The extent of neuroimaging and neurophysiological studies is guided by the certainty of the diagnosis in the patient’s first-degree relatives and the patient’s symptoms, neurological findings, and manner of progression. Extensive neurodiagnostic studies to rule out alternative or coexisting disorders are performed for any individual with atypical signs, symptoms, or clinical course. Neuroimaging is important for ruling out alternative disorders, including multiple sclerosis, leukodystrophies, and structural abnormalities affecting the brain or spinal cord (see “Differential Diagnosis” section). Whereas brain magnetic resonance imaging in uncomplicated HSP is usually normal, those of complicated forms of HSP may reveal syndrome-specific abnormalities, such as thin corpus callosum in autosomal recessive SPG11 HSP (e.g., Casali et al63) and cerebral or cerebellar abnormalities in autosomal recessive SPG7 HSP. Magnetic resonance imaging of the thoracic spinal cord often demonstrates atrophy in uncomplicated HSP.9-11,64 Electromyographic nerve conduction studies usually yield normal results in uncomplicated HSP. Such studies are useful in ruling out other disorders (such as amyotrophic lateral sclerosis, Friedreich’s ataxia, Machado-Joseph disease). Such study results are usually normal in uncomplicated HSP.51,52,65 Exceptions have been reported, however, including peripheral neuropathy in some patients with SPG4 HSP caused by spastin frameshift mutation 906delT53 and axonal neuropathy associated with SPG3A HSP caused by atlastin mutation R495W.66 Subclinical sensory neuropathy in otherwise uncomplicated HSP has been described.67,68 Several types of complicated HSP are associated with peripheral neuropathy (see Table 69–1). Somatosensory evoked potentials may demonstrate dorsal column impairment in uncomplicated HSP. Whereas

somatosensory evoked potentials recorded from lower extremities often show delayed conduction, somatosensory evoked potentials recorded from the upper extremities are usually normal.52,69-72 This finding may help distinguish patients with autosomal recessive, uncomplicated HSP (and those with uncomplicated spastic paraplegia who do not have a family history of the disorder) from patients in an early stage of primary lateral sclerosis (in whom vibration sensation and dorsal column function are normal).55 Cortical evoked potentials provide a useful measurement of corticospinal tract conduction velocity. Studies of patients with uncomplicated HSP often reveal reduced conduction velocity and amplitude when cortical evoked potentials are recorded from the lower extremities.73-76 In contrast, cortical evoked potentials recorded from cervical spinal segments are usually normal or show only mildly reduced conduction velocity.75

Routine Laboratory Evaluations Measurements of vitamin B12, serum long-chain fatty acids, lactate, and pyruvate levels and cerebrospinal fluid examination results are normal in patients with uncomplicated HSP.

Muscle Biopsy Paraplegin, mutations of which cause autosomal recessive SPG7 HSP, is mitochondrial protein. Muscle biopsies from some patients with SPG7 HSP reveal ragged red fibers and cytochrome c oxidase–negative fibers.7 These do not appear to be general phenomena for uncomplicated HSP, however. Muscle biopsies, including analysis of enzymes of oxidationphosphorylation, yielded normal results in patients with autosomal dominant uncomplicated SPG3A, SPG4, SPG6, and SPG8 HSP. Together, these represent the majority of cases of uncomplicated autosomal dominant HSP.77,78 There is some controversy, however, because McDermott and associates79 reported decreases in mitochondrial respiratory chain complexes I and IV in patients with HSP for whom SPG4 HSP (spastin mutation) and SPG7 HSP (paraplegin mutation) were ruled out.

DIAGNOSTIC CRITERIA HSP is diagnosed from (1) symptomatic spastic weakness affecting both legs approximately symmetrically, often accompanied by urinary urgency; (2) neurological findings of bilateral, typically symmetrical, lower extremity spasticity; hyperreflexia; extensor plantar responses (rarely flexor); and often mild impairment of vibration sensation in the toes; (3) family history of the same disorder; and (4) exclusion of other disorders.

Role of Gene Testing in the Diagnosis of HSP Identifying HSP gene mutations (available through Athena Diagnostics, Inc., Boston, for SPG3A/atlastin,35 SPG4/spastin,80 and SPG6/NIPA181 genes, and through DuPont Nemours Clinic for SPG2/proteolipid protein gene) can be used to confirm the clinical diagnosis. When a mutation is identified in an affected

chapter 69 hereditary spastic paraplegias patient, this information can be applied to prenatal genetic testing.82,83 It is important to note that results of HSP gene testing alone do not establish or exclude the diagnosis of HSP. Gene testing is not available for all HSP genes. Among the genes tested, only coding sequences and intron-exon spice junctions are examined. Promoter and other gene regulatory elements are studied. Therefore, the absence of an identified mutation among currently testable genes does not exclude the diagnosis of HSP. Conversely, although identifying an HSP gene mutation indicates that the patient is at risk of developing HSP, this does not indicate that HSP is the correct or sufficient explanation for the patient’s syndrome. Results of HSP gene testing must be interpreted within the clinical context. Whether the patient actually has HSP depends on the patient’s symptoms, disease course, results of clinical and neurodiagnostic evaluations, and exclusion of other disorders. The possibility of alternative or coexisting disorders must be considered for each patient. The author have seen, for example, patients with HSP who also had multiple sclerosis, Charcot-Marie-Tooth disease, diabetic peripheral neuropathy, and Parkinson’s disease.

Differential Diagnosis The differential diagnosis of HSP (reviewed previously2,3) includes treatable disorders (e.g., vitamin B12 deficiency and central folate deficiency84) and conditions whose prognoses differ significantly from those of HSP. Such conditions include structural disorders of the brain and spine (e.g., tethered cord syndrome, spinal cord compression, cervical spondylosis), disorders of central white matter (including vitamin B12 deficiency, multiple sclerosis, adrenomyeloneuropathy85 and other leukodystrophies); infectious diseases (e.g., tropical spastic paraplegia caused by human T cell leukocyte virus type 1 infection86 and tertiary syphilis); and other degenerative disorders (e.g., spinal cord arteriovenous malformation, Machado-Joseph disease [spinocerebellar ataxia type 3], Friedreich’s ataxia,86 primary lateral sclerosis,55 amyotrophic lateral sclerosis, and lathyrism). It is always important to consider the possibility of dopamine-responsive dystonia,87 particularly in children.88

Diagnostic “Red Flags” Uncomplicated HSP progresses insidiously over many years, is usually symmetrical, and is not accompanied by altered superficial sensations. Alternative or coexisting diagnoses should be sought for patients who experience abrupt onset, salutatory progression, or subacute worsening (marked progression over 6 months, for example) of lower extremity spastic weakness; unilateral or markedly asymmetrical symptoms and signs; spinal sensory level; peripheral neuropathy; or functional involvement of upper extremity or bulbar muscles. Muscle bulk is usually preserved in uncomplicated HSP. Although some patients have mildly decreased muscle bulk in their shins, lower motor neuron disturbance is not a feature of uncomplicated HSP. Although distal muscle wasting is a feature of SPG17 complicated autosomal dominant HSP (Silver’s syndrome), SPG20 recessive HSP (Troyer’s syndrome), and HSP syndromes associated with peripheral neuropathy or motor neuronopathy,89,90-92 muscle wasting and fasciculations are not consistent with uncomplicated HSP and should prompt consid-

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eration of an alternative or coexisting diagnosis (such as generalized motor neuron disease or amyotrophic lateral sclerosis).

TREATMENT There is no specific treatment to reverse, retard, or prevent progressive axonal degeneration in HSP. Symptomatic treatment includes efforts to reduce muscle spasticity through musclestretching exercises and medications such as oral or intrathecal baclofen (Lioresal), dantrolene, or tizanidine.93 Oxybutynin is useful in reducing urinary urgency. The author recommend that individuals with HSP participate in daily physical exercise. This recommendation is based not on formal study of the effects of physical therapy in HSP but rather on the consistent reports of individuals with HSP who describe benefits of regular exercise. Exercise, performed in a daily, gradually advancing manner, initially under the guidance of a physical therapist, is advised for stretching and strengthening lower extremity muscles (particularly the tibialis anterior, hamstring, and iliopsoas muscles), for improving cardiovascular fitness, and for improving balance.

PROGNOSIS Patients with HSP symptom onset after early childhood usually show slowly progressive gait disturbance. Nonetheless, a cautious “wait and see” attitude is advised when clinicians give a prognosis, because the extent to which HSP symptoms will be disabling cannot be predicted reliably. Patients may have mild to moderate lower extremity hyperreflexia for many years before gait becomes impaired. The age at which gait disturbance begins, the rate of symptom worsening, the extent of disability, and the benefits of daily physical therapy are highly variable between HSP patients. Within the same family, some individuals may have marked disability and others may have much milder symptoms. Despite the frequent presence of mild hyperreflexia in the upper extremities, a diagnosis of uncomplicated HSP implies that upper extremity strength and dexterity will not be compromised and that speech and swallowing will not be affected.

GENETIC COUNSELING An HSP gene mutation (currently available for SPG3A, SPG4, SPG6, and SPG2 HSP) can be identified in prenatal diagnosis and genetic counseling. The presence of an HSP gene mutation indicates that the patient is at high risk of developing HSP but does not indicate the age at which symptoms will begin or the extent of disability. Genetic counseling in HSP is guided by the mode of inheritance (X-linked, autosomal dominant, autosomal recessive), the frequency of spontaneous mutations, the extent of genetic penetrance, and the degree of phenotypic variability. Spontaneous mutation for autosomal dominant HSP has been reported in SPG3A uncomplicated HSP94 and, although it may occur,95 appears to be uncommon in dominantly inherited SPG3A, SPG4, and SPG6 HSP. Fewer than 10% of patients who have all

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signs and symptoms of HSP but do not have a family history have a mutation in the SPG3A, SPG4, and NIPA1 genes.34,96,97 Genetic penetrance in uncomplicated HSP is age-dependent and, although high (70% to 85% for SPG4 HSP, for example), may be incomplete. Incomplete penetrance implies that some patients may possess an HSP gene mutation, remain asymptomatic with normal neurological examinations, and yet transmit the condition to progeny. Incomplete genetic penetrance has been reported for SPG4,98 SPG8,77 and SPG3A HSP.37,99 Genetic counselors must recognize that the age at symptom onset and extent of disability may vary significantly98 between families with different genetic types of HSP, between families with the same genetic type of HSP, and between individuals from the same family who share the same HSP gene mutation. Often, the extent of clinical variability is a caution against assuming that disability will be similar in all affected relatives. The author have seen families in which some members had progressively disabling spastic paraparesis and others had mild, nondisabling spastic gait. Small families with few affected patients may not enable accurate assessment of the full range of phenotypic variation. As noted previously, a number of families with “complicated” forms of HSP have been described in which the “complicating features” (such as distal muscle atrophy)100 were not present in each patient with spastic paraplegia.7 The author and colleagues have encountered a number of families in which the condition was diagnosed in one or more children before a parent developed symptoms of HSP. Genetic anticipation has been reported in SPG460 and observed in SPG3A HSP (J. K. Fink, 2005 unpublished observation). The mechanism for genetic anticipation in these circumstances presumably involves a tandem repeat expansion in an HSP modifying gene (because the causative HSP gene mutations were missense mutations and not tandem repeat expansions).

K E Y ●

The HSPs constitute a large group of genetic disorders characterized by spastic gait. Whereas adult-onset symptoms typically progress insidiously, individuals with early childhood–onset symptoms may exhibit very little worsening. There may be significant variation in severity and age at symptom onset between different genetic types of HSP, as well as within a family in which affected members share the same HSP gene mutation.

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Complicated forms of HSP are inherited syndromes in which the predominant feature of spastic paraparesis is accompanied by other neurological or systemic abnormalities (such as mental retardation, ataxia, peripheral neuropathy, deafness, cataracts, and muscle atrophy), in addition to lower extremity spastic weakness.

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The neuropathology of uncomplicated HSP involves distal degeneration of long axons (corticospinal tracts and dorsal columns to a lesser extent). Uncomplicated HSP is thus a motor-sensory, distal axonopathy limited to the CNS.

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The molecular basis of selective degeneration of the ends of long CNS axons in HSP is poorly understood. At least some forms of HSP involve disturbance of microtubules and axonal transport (autosomal dominant SPG4 HSP caused by spastin mutation and autosomal dominant SPG10 HSP caused by KIF5A mutation). Two forms of HSP involve mitochondrial proteins (e.g., autosomal recessive SPG7 HSP caused by paraplegin mutation and autosomal dominant SPG13 HSP caused by chaperonin 60/heat shock protein 60 mutation).

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Genetic testing is available for the three most common forms of dominantly inherited HSP (SPG3A/atlastin, SPG4/spastin, and SPG6/NIPA gene analysis). Together, mutations in these genes account for approximately 60% of cases of dominantly inherited HSP. Genetic testing is also available for X-linked HSP caused by proteolipid protein gene mutation. Genetic testing is useful to confirm the clinical diagnosis and can be applied to prenatal diagnosis.

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The differential diagnosis of HSP includes treatable disorders (including vitamin B12 deficiency, dopamineresponsive dystonia, multiple sclerosis, and tethered cord syndrome) and disorders with significantly different prognoses (including amyotrophic lateral sclerosis, primary lateral sclerosis, and adrenomyeloneuropathy).

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Treatment for HSP focuses on physical therapy to reduce spasticity and improve strength, cardiovascular fitness, and endurance; medications to reduce spasticity (such as oral tizanidine, baclofen [Lioresal], or dantrolene or intrathecal baclofen); and medications such as oxybutynin to reduce urinary urgency.

CONCLUSIONS The HSPs constitute a large group of disorders. Twenty-eight different HSP loci have been discovered thus far. Whereas many forms of uncomplicated HSP are clinically very similar (and may be indistinguishable), some complicated forms of HSP may be recognized by specific syndromic features. For most patients, HSP is a diagnosis of exclusion. The differential diagnosis includes treatable disorders and those whose prognoses are quite different from those of HSP. It is essential that alternative disorders be ruled out on the basis of careful history, examination, laboratory studies, neuroimaging, and neurophysiological evaluation findings. Genetic testing is available for SPG3A, SPG4, and SPG6 HSP (collectively representing approximately 60% of cases of dominantly inherited HSP) and for X-linked SPG2 HSP. Genetic test results can be applied for prenatal diagnosis. Uncomplicated HSP involves axonal degeneration at the ends of the longest motor (corticospinal tract) and sensory (dorsal column fibers) nerves in the spinal cord. Studies indicate that different mechanisms may underlie HSP’s distal axonopathy. These include cytoskeletal and axonal transport abnormalities; mitochondrial disturbance; altered Golgi apparatus and endosome function; primary myelin disturbance; and corticospinal tract developmental abnormality. Current treatment for HSP is symptomatic and includes physical therapy and the use of medications to reduce spasticity and urinary urgency.

P O I N T S

chapter 69 hereditary spastic paraplegias Suggested Reading Fink JK: The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 2003; 60:1045-1049. Fink JK: Hereditary spastic paraplegia. In Rimoin DL, Pyeritz RE, Connor JM, et al, eds: Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th ed. London: Churchill Livingston, 2001a, pp 3124-3145. Fink JK: Progressive spastic paraparesis: hereditary spastic paraplegia and its relation to primary and amyotrophic lateral sclerosis. Semin Neurol 2001b; 21:199-208.

References 1. Strümpell A: Die primaere Seitenstrangsklerose (spastischeSpinalparalyse). Dtsch Z Nervenheilk 1904; 27:291339. 2. Fink JK: Hereditary spastic paraplegia. In Rimoin D, Pyeritz RE, Connor J, et al, eds: Emery & Rimoin’s Principles and Practice of Medical Genetics, 4th ed. London: Harcourt, 2002, pp 3124-3145. 3. Fink JK, Heiman-Patterson T, Bird T, et al: Hereditary spastic paraplegia: advances in genetic research. Neurology 1996; 46:1507-1514. 4. Fink JK, Hedera P: Hereditary spastic paraplegia: genetic heterogeneity and genotype-phenotype correlation. Semin Neurol 1999; 19:301-310. 5. Polo AE, Calleja J, Combarros O, et al: Hereditary ataxias and paraplegias in Cantabria, Spain: an epidemiological and clinical study. Brain 1991; 114:855-856. 6. Filla A, DeMichele G, Marconi R, et al: Prevalence of hereditary ataxias and spastic paraplegias in Molise, a region of Italy [Abstract]. J Neurol 1992; 239:351-353. 7. DeMichele G, DeFusco M, Cavalcanti F, et al: A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am J Hum Genet 1998; 63:135-139. 8. Reid E, Kloos M, Ashley-Koch A, et al: A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 2002; 71:1189-1194. 9. Nielsen JE, Johnsen B, Koefoed P, et al: Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. Eur J Neurol 2004; 11:817-824. 10. Heinzlef O, Paternotte C, Mahieux F, et al: Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p. J Med Genet 1998; 35:89-93. 11. McMonagle P, Byrne P, Hutchinson M: Further evidence of dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia. Neurology 2004; 62:407-410. 12. Webb S, Coleman D, Byrne P, et al: Autosomal dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p. Brain 1998; 121:601-609. 13. Byrne PC, Webb S, McSweeney F, et al: Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance. Eur J Hum Genet 1998; 6:275-282. 14. Reid E, Grayson C, Rubinsztein DC, et al: Subclinical cognitive impairment in autosomal dominant “pure” hereditary spastic paraplegia. J Med Genet 1999; 36:797-798. 15. Deluca GC, Ebers GC, Esiri MM: The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol 2004; 30:576-584. 16. Fink JK: Hereditary spastic paraplegia: nine genes and counting. Arch Neurol 2003; 60:1045-1049. 17. Schwarz GA, Liu C-N: Hereditary (familial) spastic paraplegia. Further clinical and pathologic observations. AMA Arch Neurol Psychiatry 1956; 75:144-162.

907

18. Behan W, Maia M: Strümpell’s familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry 1974; 37:8-20. 19. Harding AE: Hereditary spastic paraplegias. Semin Neurol 1993; 13:333-336. 20. Sack GH, Huether CA, Garg N: Familial spastic paraplegia: clinical and pathologic studies in a large kindred. Johns Hopkins Med J 1978; 143:117-121. 21. Zhao C, Takita J, Tanaka Y, et al: Charcot-Marie-Tooth disease type2A caused by mutation in a microtubule motor KIF1Bβ. Cell 2001; 105:587-597. 22. Gould RM, Brady ST: Neuropathology: many paths lead to hereditary spastic paraplegia. Curr Biol 2004; 14:P903-P904. 23. Holzbaur EL: Motor neurons rely on motor proteins. Trends Cell Biol 2004; 14:233-240. 24. Guzik BW, Goldstein LS: Microtubule-dependent transport in neurons; steps towards and understanding of regulation, function and dysfunction. Curr Opin Cell Biol 2004; 16:443450. 25. Sherwood NT, Sun Q, Xue M, et al: Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function. PLoS Biol 2004; 2:e429. 26. Roll-Mecak A, Vale RD: The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules. Curr Biol 2005; 15:650-655. 27. Reid E, Connell J, Edwards TL, et al: The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex–associated endosomal protein CHMP1B. Hum Mol Genet 2005; 14:19-38. 28. McDermott CJ, Grierson AJ, Wood JD, et al: Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation. Ann Neurol 2003; 54:748-759. 29. Wharton SB, McDermott CJ, Grierson AJ, et al: The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol 2003; 62:1166-1177. 30. Molon A, DiGiovanni S, Chen YW, et al: Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle. Neurology 2004; 62:97-104. 31. Trotta N, Orso G, Rossetto MG, et al: The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Curr Biol 2004; 14:1135-1147. 32. Errico A, Claudiani P, D’Addio M, et al: Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody, and the distal axon. Hum Mol Genet 2004; 13:2121-2132. 33. Evans KJ, Gomes ER, Reisenweber SM, et al: Linking axonal degeneration to microtubule remodeling by spastinmediated microtubule severing. J Cell Biol 2005; 168:599-606. 34. Proukakis C, Auer-Grumbach M, Wagner K, et al: Screening of patients with hereditary spatic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. Hum Mutat 2003; 21:170-170. 35. Zhao X, Alvarado D, Rainier S, et al: Mutations in a novel GTPase cause autosomal dominant hereditary spastic paraplegia. Nat Genet 2001; 29:326-331. 36. Alvarado DM, Ming L, Hedera P, et al: Atlastin gene analysis in early onset hereditary spastic paraplegia [Abstract]. Am J Hum Genet 2001; 69:597. 37. Durr A, Camuzat A, Colin E, et al: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. Arch Neurol 2004; 61:1867-1872. 38. Patel H, Cross H, Proukakis C, et al: SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 2002; 31:347-348. 39. Zhu PP, Patterson A, Lavoie B, et al: Cellular localization, oligomerization, and membrane association of the hereditary

908

40.

41.

42.

43.

44. 45.

46.

47. 48. 49.

50.

51. 52. 53. 54. 55. 56. 57.

58.

Section

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spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem 2003; 278:49063-49071. Crosby AH, Patel H, Patton MA, et al: Spartin, the Troyer syndrome gene, suggests defective endosomal trafficking underlies some forms of hereditary spastic paraplegia [Abstract]. Am J Hum Genet 2002; 71:516-516. Hansen JJ, Durr A, Cournu-Rebeix I, et al: Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet 2002; 70:1328-1332. Atorino L, Silvestri L, Koppen M, et al: Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J Cell Biol 2003; 163:777-787. Ferreirinha F, Quattrini A, Pirozzi M, et al: Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J Clin Invest 2004; 113:231-242. Wilkinson PA, Crosby AH, Turner C, et al: A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. Neurology 2003; 61:235-238. Casari G, Fusco M, Ciarmatori S, et al: Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 1998; 93:973-983. Hodes ME, Zimmerman AW, Aydanian A, et al: Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet 1999; 82:132-139. Willard HF, Riordan JR: Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for Xlinked myelin disorders. Science 1985; 230:940-942. Hudson LD: Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol 2003; 18:616-624. Garbern JY, Yool DA, Moore GJ, et al: Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002; 125:551-561. Bateman A, Jouet M, MacFarlane J, et al: Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders. EMBO J 1996; 15:6050-6059. Owens LA, Peterson CR: Familial spastic paraplegia: a clinical and electrodiagnostic evaluation. Arch Phys Med Rehabil 1982; 63:357-361. Dimitrijevic MR, Lenman JAR, Prevec T, et al: A study of posterior column function in familial spastic paraplegia. J Neurol Neurosurg Psychiatry 1982; 45:46-49. Orlacchio A, Kawarai T, Gaudiello F, et al: Clinical and genetic study of a large SPG4 Italian family. Mov Disord 2005; 20:1055-1059. Harding AE: Classification of the hereditary ataxias and paraplegias. Lancet 1983; 1:1151-1155. Fink JK: Progressive spastic paraparesis: hereditary spastic paraplegia and its relation to primary and amyotrophic lateral sclerosis. Semin Neurol 2001; 21:199-208. Klebe S, Stolze H, Kopper F, et al: Gait analysis of sporadic and hereditary spastic paraplegia. J Neurol 2004; 251:571578. Bonsch D, Schwindt A, Navratil P, et al: Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene. J Neurol Neurosurg Psychiatry 2003; 74:1109-1112. Svenson IK, Kloos M, Gaskell PC, et al: Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics 2004; 5:157-164.

59. Yip AG, Durr A, Marchuk DA, et al: Meta-analysis of age at onset in spastin-associated hereditary spastic paraplegia provides no evidence for a correlation with mutational class [Abstract]. J Med Genet 2003; 40:e106-e106. 60. Nielsen JE, Koefoed P, Abell K, et al: CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24. Hum Mol Genet 1997; 6:1811-1816. 61. Pericak-Vance MA, Kloos MT, Reid E, et al: A kinesin heavy chain (K1F5A) mutation in Hereditary Spastic Paraplegia (SPG10) [Abstract]. Am J Hum Genet 2002; 71:165-165. 62. Tallaksen CME, Gomez EG, Verpillat P, et al: Subtle cognitive impairment but no dementia in patients with spastin mutations [Abstract]. Arch Neurol 2003; 60:1113-1118. 63. Stevanin G, Montagna G, Azzedine H, et al: Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity. Neurogenetics 2006; 3:149-156. 64. Hedera P, Eldevik OP, Maly P, et al: Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. Neuroradiology 2005; 47:730-734. 65. Mcleod JG, Morgan JA, Reye C: Electrophysiological studies in familial spastic paraplegia. Neurol Neurosurg Psychiatry 1993; 40:611-615. 66. Scarano V, Mancini P, Criscuolo C, et al: The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy. J Neurol 2005; 252:901-903. 67. Schady W, Scheard A: A qualitative study of sensory functions in hereditary spastic paraplegia. Brain 1990; 113:709-720. 68. Schady W, Smith DI: Sensory neuropathy in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 1994; 57:693-698. 69. Pelosi L, Lanzillo B, Perretti A: Motor and somatosensory evoked potentials in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 1991; 54:1099-1102. 70. Pedersen L, Trojaborg W: Visual, auditory and somatosensory pathway involvement in hereditary cerebellar ataxia, Friedreich’s ataxia and familial spastic paraplegia. Electroencephalogr Clin Neurophys 1981; 52:283-297. 71. Uncini A, Treviso M, Basciani M, et al: Strümpell’s familial spastic paraplegia: an electrophysiological demonstration of selective central distal axonopathy. Electroencephalogr Clin Neurophys 1987; 66:132-136. 72. Battistella PA, Suppiej A, Mandara V: Evoked potentials in familial spastic paraplegia: description of three brothers and review of the literature. Giorn Neuropsi Evol 1997; 17:201212. 73. Schulte T, Miterski B, Bornke C, et al: Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia. Neurology 2003; 60:1529-1532. 74. Nardone R, Tezzon F: Transcranial magnetic stimulation study in hereditary spastic paraparesis. Eur Neurol 2003; 49:234-237. 75. Claus D, Waddy HM, Harding AE: Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study. Ann Neurol 1990; 28:43-49. 76. Claus D, Jaspert A: Central motor conduction in hereditary spastic paraparesis (Strümpell’s disease) and tropical spastic paraparesis. Neurol Croatica 1995; 44:23-31. 77. Hedera P, DiMauro S, Bonilla E, et al: Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to chromosome 8q. Neurology 1999; 53:44-50. 78. Hazan J, Fonknechten N, Mavel D, et al: Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 1999; 23:296-303. 79. McDermott CJ, Taylor RW, Hayes C, et al: Investigation of mitochondrial function in hereditary spastic paraparesis. Genet Nerv Syst Dis 2003; 14:485-488.

chapter 69 hereditary spastic paraplegias 80. Hazan J, Fontaine B, Bruyn RPM, et al: Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p. Hum Mol Genet 1994; 3:1569-1573. 81. Rainier S, Chai J-H, Tokarz D, et al: NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet 2003; 73:967-971. 82. Nielsen JE, Koefoed P, Kjaergaard S, et al: Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection. Prenat Diagn 2004; 24:363366. 83. Hedera P, Williamson J, Alvarado D, et al: Prenatal diagnosis of hereditary spastic paraplegia. Prenat Diagn 2001; 21:202206. 84. Hansen FJ, Blau N: Cerebral folate deficiency: life-changing supplementation with folinic acid. Mol Genet Metab 2005; 84:371-373. 85. Shaw-Smith CJ, Lewis SJ, Reid E: X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis. J Neurol Neurosurg Psychiatry 2004; 75:686-688. 86. Matsumura R, Takayanagi T, Fujimoto Y, et al: The relationship between trinucleotide repeat length and phenotypic variation in Machado-Joseph disease. J Neurol Sci 1996; 139:52-57. 87. Nygaard TG: Dopa-responsive dystonia: clinical, pathological, and genetic distinction from juvenile parkinsonism. In Segawa M, Nomura Y, eds: Age-Related Dopamine-Dependent Disorders: Monographs in Neural Sciences, vol 14. Basel: Karger, 1995, pp 109-119. 88. Fink JK, Filling-Katz M, Barton NW, et al: Treatable dystonia presenting as spastic cerebral palsy. Pediatrics 1988; 82:138. 89. McKusick VA: Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes, 8th ed, Baltimore: Johns Hopkins University Press, 1994. 90. Cavanagh NPC, Eames RA, Galvin RJ, et al: Hereditary sensory neuropathy with spastic paraplegia. Brain 1979; 102:79-84. 91. Stewart RM, Tunell G, Ehle A: Familial spastic paraplegia, peroneal neuropathy, and crural hypopigmentation: a new neurocutaneous syndrome. Neurology 1981; 31:754757. 92. Vazza GZM, Boaretto F, Micaglio GF, et al: A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28. Am J Hum Genet 2000; 67:504-509. 93. Van Schaeybroeck P, Nuttin B, Lagae L, et al: Intrathecal baclofen for intractable cerebral spasticity: a prospective placebo-controlled, double-blind study. Neurosurgery 2000; 46:603-612. 94. Rainier S, Sher C, Reish O, et al: De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch Neurol 2006; 63:445-447. 95. Alber B, Rothmund G, Ludolph AC, et al: Two novel mutations in the spastin gene in a family with hereditary spastic paraparesis and in one patient with apparently sporadic spastic paraplegia [Abstract]. Presented at the 13th Annual International Symposium on ALS/MND, Melbourne, Australia, 2002. 96. Patrono C, Scarano V, Cricchi F, et al: Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations. Hum Mutat 2005; 25:506. 97. Sauter S, Miterski B, Klimpe S, et al: Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat 2002; 20:127-132.

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98. Fonknecten N, Mavel D, Byrne P, et al: Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 2000; 9:637-644. 99. D’Amico A, Tessa A, Sabino A, et al: Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene. Neurology 2004; 62:2138-2139. 100. Reid E, Dearlove AM, Rhodes M, et al: A new locus for autosomal dominant “pure” hereditary spastic paraplegia mapping to chromosome 12q13 and evidence for further genetic heterogeneity. Am J Hum Genet 1999; 65:757-763. 101. Fink JK: Hereditary spastic paraplegia. In Kaminski H, ed: Neuromuscular Disorders in Clinical Practice. London: Butterworth-Heinemann, 2002, pp 1290-1297. 102. Fink JK: Hereditary spastic paraplegia. In Noseworthy J, Rowland LP, eds: Neurological Therapeutics: Principles and Practice. London: Taylor & Francis, 2003, pp 2705-2713. 103. Fink JK: Hereditary spastic paraplegia. In Lynch DR, Farmer JM, eds: Neurogenetics. Philadelphia: WB Saunders, 2002, pp 711-726. 104. Fink JK: Hereditary spastic paraplegia. In Beal F, Lang A, Ludolph A, eds: Neurodegenerative Disease: Neurobiology, Pathogenesis, and Treatment. Cambridge, UK: Cambridge University Press, 2005, pp 794-802. 105. Hazan J, Lamy C, Melki J, et al: Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q. Nat Genet 1993; 5:163-167. 106. Sauter SM, Engel W, Neumann LM, et al: Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. Hum Mutat 2004; 23:98-98. 107. Paternotte C, Rudnicki D, Fizames C, et al: Quality assessment of whole genome mapping data in the refined familial spastic paraplegia interval on chromosome 14q. Genome Res 1998; 8:1216-1227. 108. Charvin D, Fonknechten N, Cifuentes-Diaz C, et al: Mutations in SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized to the nucleus [Abstract]. Am J Hum Genet 2002; 71:516-516. 109. Hentati A, Pericak-Vance MA, Lennon F, et al: Linkage of the late onset autosomal dominant familial spastic paraplegia to chromosome 2p markers. Hum Mol Genet 1994; 3:18671871. 110. Fink JK, Wu C-TB, Jones SM, et al: Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am J Hum Genet 1995; 56:188-192. 111. Fink JK, Sharp G, Lange B, et al: Autosomal dominant hereditary spastic paraparesis, type I: clinical and genetic analysis of a large North American family. Neurology 1995; 45:325331. 112. Chen S, Song C, Guo H, et al: Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. Hum Mutat 2005; 25:135-141. 113. Hedera P, Rainier S, Alvarado D, et al: Novel locus for autosomal dominant hereditary spastic paraplegia on chromosome 8q. Am J Hum Genet 1999; 64:563-569. 114. Reid E, Dearlove AM, Osborn M, et al: A locus for autosomal dominant “pure” hereditary spastic paraplegia maps to chromosome 19q13. Am J Hum Genet 2000; 66:728-732. 115. Seri M, Cusano R, Forabosco P, et al: Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy. Am J Hum Genet 1999; 64:586-593. 116. Fichera M, Lo Giudice M, Falco M, et al: Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 2004; 63:1108-1110.

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117. Fontaine B, Davoine C-S, Durr A, et al: A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am J Hum Genet 2000; 66:702-707. 118. Patel H, Hart PE, Warner TT, et al: The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. Am J Hum Genet 2001; 69:209-215. 119. Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, et al: Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol 2005; 57:415-424. 120. Windpassinger C, Auer-Grumbach M, Irobi J, et al: Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 2004; 36:271-276. 121. Hentati A, Pericack-Vance MA, Hung W-Y, et al: Linkage of the “pure” recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity [Abstract]. Hum Genet 1993; 53:1013-1013. 122. Muglia M, Criscuolo C, Magariello A, et al: Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics 2004; 5:49-54. 123. Tang BS, Chen X, Zhao GH, et al: Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases. Chin Med J (Engl) 2004; 117:1002-1005. 124. Garner CC, Garner A, Huber G, et al: Molecular cloning of microtubule-associated protein 1 (MAP1A) and microtubuleassociated protein 5 (MAP1B): identification of distinct genes and their differential expression in developing brain. J Neurochem 1990; 55:146-154. 125. Martinez-Murillo F, Kobayashi H, Pegoraro E, et al: Genetic localization of a new locus for recessive spastic paraplegia to 15q13-15. Neurology 1999; 53:50-56. 126. Winner B, Uyanik G, Gross C, et al: Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch Neurol 2004; 61:117-121. 127. Hughes CA, Byrne PC, Webb S, et al: SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 2001; 56:1230-1233. 128. Cross HE, McKusick VA: The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol 1967; 16:473-485. 129. Proukakis C, Cross H, Patel H, et al: Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia. J Neurol 2004; 251:1105-1110.

130. Simpson MA, Cross H, Proukakis C, et al: Maspardin is mutated in Mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 2003; 73:1147-1156. 131. Blumen SC, Bevan S, Abu-Mouch S, et al: A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32. Ann Neurol 2004; 54:796-803. 132. Hodgkinson CA, Bohlega S, Abu-Amero SN, et al: A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 2002; 59:19051909. 133. Wilkinson PA, Simpson MA, Bastaki L, et al: A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1*12q14. J Med Genet 2005; 42:80-82. 134. Meijer IA, Cossette P, Roussel J, et al: A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.110q24.1. Ann Neurol 2004; 56:579-582. 135. Bouslam N, Benomar A, Azzedine H, et al: Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann Neurol 2005; 57:567-571. 136. Macedo-Souza LI, Kok F, Santos S, et al: Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13. Ann Neurol 2005; 57:730-737. 137. Jouet M, Rosenthal A, Armstrong G, et al: X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 1994; 7:402-407. 138. Kobayashi H, Hoffman EP, Marks HG: The rumpshaker mutation in spastic paraplegia. Nat Genet 1994; 7:351352. 139. Saugier-Veber P, Munnich A, Bonneau D, et al: X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 1994; 6:257-262. 140. Cambi F, Tang XM, Cordray P, et al: Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. Neurology 1996; 46:11121117. 141. Steinmuller R, Lantingua-Cruz A, Carcia-Garcia R, et al: Evidence of a third locus in X-linked recessive spastic paraplegia [Letter]. Hum Genet 1997; 100:287-289. 142. Tamagaki A, Shima M, Tomita R, et al: Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. Am J Med Genet 2000; 94:5-8.

CHAPTER

70

DEMENTIA WITH LEWY BODIES ●

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●

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Bradley F. Boeve

HISTORICAL PERSPECTIVE Okazaki and colleagues first described Lewy bodies in the cerebral cortex in patients with dementia in 1961.1 Few reports on Lewy body cortical pathology were published over the subsequent several years, perhaps partly because of the challenge of identifying Lewy bodies on standard hematoxylin- and eosinstained cortical regions. In the 1980s, ubiquitin immunocytochemistry allowed easier recognition of Lewy bodies, but structures other than Lewy bodies are stained with ubiquitin.2,3 α-Synuclein immunocytochemistry was developed in the late 1990s, permitting easy identification of Lewy bodies and Lewy neurites (Fig. 70–1).4,5 Investigators from Japan, Europe, and the United States have pioneered much of the clinical and pathological characterization of Lewy body dementia/Lewy body disease since the mid-1980s.2-27 It is now clear that multiple neurotransmitter systems and structures in the brain are dysfunctional in dementia with Lewy bodies (DLB) (Figs. 70–2 and 70–3).

TERMINOLOGY The terminology in the clinical and pathological characterization of Lewy body disease (LBD) has been confusing. Terms have included Lewy body disease, diffuse Lewy body disease, cortical Lewy body disease, Lewy body dementia, the Lewy body variant of Alzheimer’s disease, and senile dementia of the Lewy type. In 1995, the Consortium on Dementia with Lewy Bodies developed the consensus criteria for the clinical and neuropathological diagnoses. The report, published in 1996, suggested that the syndrome be termed dementia with Lewy bodies and that the neuropathological disorder be termed Lewy body disease.6 Therefore, most experts restrict use of the term dementia with Lewy bodies to the clinical syndrome; when characterizing autopsied material, the term Lewy body disease is used instead.

EPIDEMIOLOGY The frequency of a DLB, based primarily on cases in hospitaland referral-based samples, has been approximately 15% to 25% of cases of irreversible dementia.6 More recently, in an autopsy-based study of dementia subjects in Olmsted County,

Minnesota, the frequency of LBD was 10%.28 A populationbased study in Finland suggested that among persons aged 75 years of age and older, the prevalences for dementia and DLB specifically were 22% and 5%, respectively.29 The few published data on frequency or prevalence suggest that DLB and LBD probably account for fewer than 25% of dementia cases and are closer to 5% to 15%. Prevalence may vary among populations, but data are inadequate for concluding whether there are significant differences on the basis of race or ancestral origin. No studies on incidence have been published to date. There does appear to be a male preponderance in DLB.6-8

CLINICAL FEATURES A wide spectrum of symptoms and signs can occur in DLB (Table 70–1).6-8,24,27,30-34 Most symptoms can be categorized into one of five categories: cognitive impairment, neuropsychiatric features, motor dysfunction, sleep disorders, and autonomic dysfunction.

Cognitive Impairment Executive and visuospatial functioning are the domains most consistently impaired in DLB.35 Symptoms of executive dysfunction include changes in problem solving, performance of sequential tasks, multitasking, and complex decision making. Difficulties with navigating in familial surroundings and problems sitting on a sofa or lying in the correct orientation on a bed are commonly voiced symptoms of visuospatial dysfunction. Memory impairment can vary from slight to very severe.35 Verbal blocking, in which a person tends to lose the train of thought in the middle of a sentence, is very common; this phenomenon can be mistaken for dysarthria or aphasia. Apathy and bradyphrenia are also common. Misidentification errors involving people can occur and are particularly upsetting when patients fail to recognize their own spouses or children. Reflections in mirrors may be mistaken for other individuals, and patients may speak to or argue with the perceived person. Most clinicians have regarded these cognitive symptoms as reflecting dysfunction of the frontosubcortical and parieto-occipital neural networks, as well as cholinergic depletion. Fluctuations—periods of time when cognition and arousal are near normal and other periods of more marked confusion

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Figure 70–1. Photomicrograph of Lewy bodies in hematoxylin and eosin (H&E) stain (A) and α-synuclein immunohistochemistry study (B). Note the difficulty identifying Lewy bodies on H&E stain but easy identification of Lewy bodies with α-synuclein. Photomicrograph courtesy of Dennis Dickson, MD.

A

B

A

B

C A

OB

NBM A

H

SN PPN RN LC

B

VLM GCRF Neurotransmitter deficiencies:

■

NBM—acetylcholine SN—dopamine RN—serotonin

■

C

Figure 70–3. Schematic drawing of the key brainstem and subcortical structures, in addition to the limbic cortex and neocortex, affected by Lewy bodies and Lewy neurites in dementia with Lewy bodies. A, amygdala; GCRF, gigantocellular reticular formation; H, hippocampus; LC, locus ceruleus; NBM, nucleus basalis of Meynert; OB, olfactory bulb; PPN, pedunculopontine nucleus, RN, raphe nucleus; SN, substantia nigra; VLM, ventrolateral medulla.

Figure 70–2. Schematic drawing of the key nuclei and neurotransmitter systems that are dysfunctional in dementia with Lewy bodies. NBM, nucleus basalis of Meynert; RN, raphe nucleus; SN, substantia nigra.

or decreased alertness—are considered a defining feature of DLB.6-8 The neural substrate responsible for fluctuations is not clear, but neurochemical alterations31 and sleep/wake dysregulation36 have been proposed.

Neuropsychiatric Features Another defining feature of DLB is the presence of visual hallucinations.6,7,37 Often the hallucinations are first noted in the bedroom when the room is darkened at night; patients often visualize insects, animals, or people in the room, on the bed, or on the ceiling. These hallucinations are often vivid and fully formed, and patients often cannot be convinced that the stimuli are not truly present. In some, visual hallucinations can be frightening or can become the source of delusions (e.g., “That little girl has been stealing my money”). Visual illusions also are common and often coincide with the presence of visual

hallucinations. Delusions are also frequent and typically have a paranoid quality, like the example just noted.37 Capgras’ syndrome—the belief that a relative or friend (usually spouse) has been replaced by an identical-appearing impostor—is also a feature of DLB.38 Depression occurs at some point in the illness in almost all patients with DLB, sometimes years before the onset of dementia.6,37 Anxiety is also common. Auditory, tactile, or olfactory hallucinations can also occur. Agitation and aggressive behavior are more variable; when present, they can be challenging to manage. Hypomania and overt bipolar disorder features can evolve, but they are atypical insofar as the onset usually occurs in patients in their 50s or 60s. The underlying cause of hallucinations, delusions, and agitation probably reflects dopaminergic dysfunction, and serotonin dysfunction is probably involved in depression, anxiety, and bipolar-type features. Rapid eye movement (REM) sleep/wakefulness dysregulation has also been proposed as a mechanism underlying visual hallucinations in Parkinson’s disease and psychosis, in which the dream imagery of REM sleep may invade wakefulness.39 The same mechanism has been proposed to underlie hallucinations associated with DLB.24,33,34 The fact that psychostimulants can sometimes ameliorate

chapter 70 dementia with lewy bodies T A B L E 70–1. Clinical Features Often Present in Dementia with Lewy Bodies

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T A B L E 70–2. Typical Clinical Features of REM Sleep Behavior Disorder

Cognitive Impairment Varying degrees of memory impairment Verbal blocking Executive dysfunction Bradyphrenia Spatial/geographical disorientation Visual misidentification Fluctuations Neuropsychiatric Features Visual hallucinations Illusions Delusions Capgras’ syndrome Depression Anxiety Auditory, tactile, or olfactory hallucinations Agitation or aggressive behavior (usually late in the course if present at all) Motor Dysfunction Tremor (often postural and symmetrical) Bradykinesia Rigidity Shuffling gait Stooped posture Difficulty with fine motor skills Masklike facies Sleep Disorders REM sleep behavior disorder (RBD) Excessive daytime somnolence (EDS) Insomnia Obstructive sleep apnea (OSA) Central sleep apnea (CSA) Restless legs syndrome (RLS) Periodic limb movement in sleep (PLMS) Autonomic Dysfunction Orthostatic hypotension Impotence Urinary incontinence Constipation REM, rapid eye movement. From Boeve B: Dementia with Lewy bodies. In Petersen R, ed: Continuum. Minneapolis: American Academy of Neurology, 2004, pp 81-112.

hallucinations and delusions, which is similar to what occurs in narcolepsy, supports this hypothesis.24,33

Motor Dysfunction Parkinsonism unrelated to dopamine antagonist exposure is another defining characteristic of DLB.6-8 Signs and symptoms include masklike facies, stooped posture, shuffling gait, difficulty with fine motor skills, sialorrhea, tremor, and bradykinesia.40 Tremor tends to be more symmetrical and related to postural/action, rather than the unilateral and predominantly at-rest tremor that is typical of Parkinson’s disease. Myoclonus can also occur, and when the clinical course is rapid, differentiation from Creutzfeldt-Jakob disease can be difficult. Many of these symptoms and signs result from reduced dopaminergic activity.

From Boeve B, Silber M, Ferman T, et al: REM sleep behavior disorder in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In Bedard M, Agid Y, Chouinard S, et al, eds: Mental and Behavioral Dysfunction in Movement Disorders. Totowa, NJ: Humana Press, 2003, pp 383-397.

Sleep Disorders REM sleep behavior disorder (RBD) is common in DLB (as well as in Parkinson’s disease with or without dementia and in multiple-system atrophy).22-27,33,34,41,42 Patients appear to be acting out their dreams by screaming, swearing, punching, and kicking (Table 70–2).23,24,34 The theme of the dream is remarkably consistent across patients, almost always involving chasing or attacking, and the patient is usually protecting himself or herself against aggressors rather than being the attacker. When the patient is awakened and able to recall the dream content, the description of the dream tends to match the behaviors that were exhibited. Injuries such as pulled hair, bruises, lacerations, and broken bones have been described in patients and their bed partners. RBD often begins years or even decades before any cognitive or motor symptoms develop, and therefore RBD may be the first sign of an evolving neurodegenerative disorder in many individuals. Excessive daytime somnolence, in which patients struggle to stay awake through the day, is also common.43,44 Other sleep disorders in DLB include insomnia, obstructive sleep apnea, central sleep apnea, restless legs syndrome, and periodic limb movement during sleep.42 In one polysomnographic series of DLB patients, at least one sleep disorder was present in almost every case.45 These sleep disorders are important to recognize because treatments exist for each one, and clinical improvement can be dramatic in some instances when all sleep disorders are effectively treated. Dysfunction in brainstem neuronal networks are believed to underlie RBD, particularly the pedunculopontine nucleus, locus ceruleus, and gigantocellularis reticular formation (see Fig. 70–3), although the specific networks have not been fully defined.23,24 α-Synuclein–positive pathology is often present in the lateral hypothalamus, which could explain the hypersomnolence and narcolepsy-like features. Central sleep apnea syndrome is also probably caused by brainstem dysfunction. The specificity of these sleep disorders to LBD is still being studied, but at least for RBD, it occurs almost exclusively in the synucleinopathies and rarely in other neurodegenerative disorders.23,24

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Autonomic Dysfunction Orthostatic hypotension, impotence, urinary incontinence, and constipation are common in DLB,46-48 although the frequency of each feature in DLB has not been systematically studied. Lewy bodies have been found in the intermediolateral column of the spinal cord and in the sympathetic nerves in the thoracic and abdominal structures, which reflects the rather widespread nature of Lewy body pathology in the central and peripheral nervous systems.47,49

T A B L E 70–3. Revised Criteria for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB)

DIAGNOSTIC CRITERIA The criteria for the clinical diagnosis of DLB as per the Consortium on Dementia with Lewy Bodies (“McKeith criteria”), originally published in 1996,6 were refined in 1999.7 However, clinicopathological analyses have shown that the accuracy of the clinical criteria has varied widely among groups of investigators50-55; the specificity for the Consortium on Dementia with Lewy Bodies criteria is adequate, but sensitivity is relatively low. Further refinements of the criteria have been suggested through 2004 after several consensus meetings. The 2004 proposed criteria for the clinical diagnosis of DLB, the Third Report of the DLB Consortium55a, are shown in Table 70–3. Attempts continue to be made to operationally define criteria for fluctuations and better characterize the cognitive aspects, visual hallucinations, parkinsonism, sleep aspects, and autonomic aspects of DLB. For the neuropathological criteria, the First and Second Reports of the DLB Consortium suggested that ubiquitin immunohistochemistry be used and required counting Lewy bodies to characterize LBD as being predominantly brainstem, limbic, or neocortical. The recommendations from the Third Report of the DLB Consortium are to use α-synuclein immunohistochemistry and a semiquantitative grading of lesion density (Table 70–4) rather than the counting methods previously proposed, inasmuch as it was agreed that the pattern of regional involvement is more important than total Lewy body count. The grading involves categorizing Lewy body densities as mild, moderate, severe, and very severe and then assessing the regional pattern of Lewy-related pathology by grading it on a template similar to that used in the Consortium to Establish a Registry of Alzheimer’s Disease for neuritic plaques. Finally, the probability that the neuropathological findings are associated with a DLB clinical syndrome will be determined, taking accounts of both Alzheimer’s and Lewy body–type pathologies (Table 70–5). This schema requires validation studies but clearly is a solid refinement of the originally proposed neuropathological characterization of DLB and LBD.

DIAGNOSTIC EVALUATION The primary diagnostic considerations in any patient with cognitive-behavioral changes include mild cognitive impairment, Alzheimer’s disease, DLB, frontotemporal dementia, and vascular dementia (reviewed in detail by Knopman et al56). The American Academy of Neurology practice parameter on the evaluation of individuals with dementia suggests that laboratory testing, neuropsychological testing, and structural neuroimaging be performed.57 Other diagnostic procedures that can aid in the evaluation of patients with possible DLB, partic-

From McKeith IG, Dickson DW, Lowe J, et al: Diagnosis and management of dementia with Lewy bodies: Third report of the DLB consortium. Neurology 2005; 65:1863-1872.

ularly for differentiating DLB from Alzheimer’s disease, include electroencephalography, single photon emission computed tomography, positron emission tomography, polysomnography, autonomic studies, and smell testing. These tests are reviewed in more detail in the following sections.

Blood/Urine The role of laboratory testing is most helpful in identifying treatable causes of cognitive impairment.57 No specific findings on laboratory testing of blood or urine that are characteristic of DLB have been identified as yet.

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T A B L E 70–4. Assignment of Lewy Body Type Based on Pattern of Lewy-Related Pathology in Brainstem, Limbic, and Neocortical Regions

From McKeith IG, Dickson DW, Lowe J, et al: Dementia with Lewy bodies: diagnosis and management: Third report of the DLB Consortium. Neurology 2005; 65:1863-1872.

Cerebrospinal Fluid Analysis On cerebrospinal fluid testing, low Aβ42 and normal tau levels58 have been reported in DLB, but this profile is also consistent with the diagnosis of Alzheimer’s disease. Hence, no specific findings on cerebrospinal fluid analysis that are diagnostic of DLB have been identified as yet.

Neuropsychological Testing Neuropsychological testing typically reveals impairment on measures of attention/concentration and visuospatial functioning in DLB.13,35,59-61 Visuoconstructive abilities can be tested by having a patient draw a clock or copy the Necker cube, intersecting pentagons, and the Rey-Osterreith complex figure (Fig. 70–4). A similar pattern of deficits—impaired visual perceptualorganizational skills, constructional praxis, and verbal fluency—have been demonstrated in patients with dementia plus RBD.41 In a subsequent analysis in which the pattern of neuropsychological impairment was compared between one group of patients with RBD and dementia and another group of patients with autopsy-proved Alzheimer’s disease, a double dissociation was identified, in which the patients with RBD and dementia had worse impairment on measures of attention, visual perceptual-organizational skills, and letter fluency, whereas the patients with Alzheimer’s disease had had significantly worse performance on confrontation naming and verbal memory.25 The same pattern was then found in a group of patients who had dementia and RBD but did not have parkinsonism or visual hallucinations.26 These findings suggest that in the absence of visual hallucinations or parkinsonism, the presence of dementia and RBD may indicate underlying Lewy body disease. More recent neuropathological studies have corroborated this hypothesis.23,24 These studies strongly support

the role of neuropsychological testing in the differential diagnosis in patients with dementia. The most nebulous of the diagnostic features in DLB is fluctuations. Tools have been developed to differentiate fluctuations associated with DLB from those associated with other disorders,62-66 but these are currently being used by a small number of research investigators. An interview-based measure has been shown to reliably differentiate fluctuations by assessing the presence of four features: (1) drowsiness and lethargy, (2) hypersomnolence, (3) staring into space for long periods, and (4) disorganized speech in which the flow of ideas is unclear or not logical.27 The presence of three or four of these features occurred in 63% of patients with DLB, in comparison with 12% of patients with Alzheimer’s disease and only 0.5% of normal elderly persons. A score of 3 or 4 yielded a positive predictive value of 83% for the clinical diagnosis of DLB against an alternative diagnosis of Alzheimer’s disease. A score of less than 3 had a negative predictive value of 70% for the absence of a clinical diagnosis of DLB in favor of Alzheimer’s disease. Therefore, assessing these four features may aid in the diagnosis of DLB even in the office practice setting.

Electroencephalography More background slowing on electroencephalography has been shown in patients with DLB than in those with Alzheimer’s disease,67 but no electroencephalographic findings are specific for DLB. Normal electroencephalographic findings may argue against DLB.

Structural Neuroimaging Structural neuroimaging with computed tomography or magnetic resonance imaging has classically been used to rule out a

T A B L E 70–5. Assessment of the Likelihood That the Pathological Findings Are Associated with a DLB Clinical Syndrome

From McKeith IG, Dickson DW, Lowe J, et al: Dementia with Lewy bodies: diagnosis and management: Third report of the DLB Consortium. Neurology 2005; 65:1863-1872.

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Figure 70–4. Examples of visuoconstructive impairment in patients who have dementia with Lewy bodies: the Necker cube (A is correct template, B and C are abnormal), a clock (D to F are all abnormal), and a Rey-Osterreith complex figure (G is correct template, H and I are abnormal).

tumor, abscess, and hydrocephalus in evaluating patients with dementia. Attention is now turning to the presence and topography of atrophy. Hippocampal atrophy is well established in patients with mild cognitive impairment and Alzheimer’s disease,68-70 and patients with DLB appear to have less hippocampal atrophy on computed tomography and magnetic resonance imaging scans than do those with Alzheimer’s disease and vascular dementia.71-73 Hence, the finding of no significant hippocampal atrophy in a patient with mild to moderate dementia may suggest that the underlying histopathology is more likely to be LBD than Alzheimer’s disease (Fig. 70–5).

Functional Neuroimaging Parietal and particularly occipital hypoperfusion on single photon emission computed tomography and hypometabolism positron emission tomography have been common in patients with DLB (Fig. 70–6). In two studies comparing the occipital hypoperfusion/hypometabolism of DLB to findings in Alzheimer’s disease, the sensitivity was approximately 64% to 90%, whereas the specificity was approximately 80% to 86%.74,75 Therefore, the presence of occipital abnormalities on functional

imaging studies in patients with dementia is suggestive of DLB, although this is not specific to DLB.76

Polysomnography The important polysomnographic finding in RBD involves the loss of the normal electromyographic atonia during REM sleep (Fig. 70–7), also known as REM sleep without atonia (RSWA). RSWA therefore represents the electrophysiological substrate for RBD, but the diagnosis of RBD requires (1) RSWA plus (2) either a history of dream enactment behavior or dream enactment behavior during REM sleep captured on the polysomnography.77 Complicating matters is the fact that some individuals have the polysomnographic finding of RSWA but do not exhibit abnormal behaviors during polysomnography and do not have a history of nightmares and dream enactment behavior. Although the presence of RSWA may be a predictor for subsequent development of RBD, this issue has never been formally studied. Therefore, it is difficult to justify performing polysomnography if the only question is whether the patient has the electrophysiological finding of RSWA. If a patient is exhibiting dream enactment behavior that is potentially injuri-

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Figure 70–5. Coronal T1weighted magnetic resonance imaging (MRI) scans of a 71year-old man who has dementia with Lewy bodies (DLB) (A) and a 76-year-old woman with Alzheimer’s disease (B). Note the more obvious generalized cerebral cortical atrophy and particularly hippocampal atrophy (arrows) in the patient with Alzheimer’s disease than in the patient with DLB.

A

B

ous to himself or herself and the bed partner, polysomnography can be easily justified, because clonazepam, the drug of choice for RBD, would not be desirable for a cognitively impaired patient unless the clinician is certain about the presence of RBD. Also, if a patient has features suggestive of another primary sleep disorder (e.g., loud disruptive snoring and apneic pauses, suggestive of obstructive sleep apnea; hypersomnia associated with nocturnal leg jerks, suggestive of symptomatic periodic limb movement during sleep), then a polysomnogram would be reasonable. If there is sufficient REM sleep on the polysomnogram, the clinician can then scrutinize the record, thereby providing a means of determining whether RSWA and RBD are present. Consensus has not yet been achieved on what defines the minimum amount of electromyographic activity during REM sleep that would warrant a diagnosis of RSWA. Physicians should also be aware that unless a sleep clinician has a particular interest in scrutinizing electromyographic tone during REM sleep, it will probably not be assessed, and the question of RSWA and RBD will remain unanswered.

Autonomic Testing It is now well established that autonomic dysfunction occurs in many patients with DLB (Fig. 70–8).46,47,78 In a comparative analysis involving subjects with DLB, Parkinson’s disease, and multiple-system atrophy, the degree of autonomic dysfunction for DLB was more severe than in Parkinson’s disease but less than in multiple-system atrophy.48 Furthermore, marked degeneration of the ventrolateral medulla—a structure important in the central control of autonomic functioning—was identified in pathologically proved multiple-system atrophy, in comparison with much milder degeneration in the ventrolateral medulla in pathologically proved LBD; this suggests that dysfunction in the peripheral autonomic system but not in the ventrolateral medulla is inherent in LBD.49 In patients with dementia in whom diagnosis is challenging, the presence of significant abnormalities on thermoregulatory sweat testing and autonomic reflex screening may favor underlying LBD rather than either Alzheimer’s disease or a disorder within the frontotemporal lobar degeneration spectrum.

■

Figure 70–6. Left (A) and right (B) lateral technetium Tc 99m bicisate single photon emission computed tomographic scans of a 66year-old man with clinically probable dementia with Lewy bodies. Note the prominent hypoperfusion in the parietooccipital neocortical regions (arrows).

A

B

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A ■

Figure 70–7. Thirty-second polysomnogram fragments showing normal rapid eye movement (REM) sleep (A) and REM sleep without atonia—the electrophysiological substrate for REM sleep behavior disorder (B). The characteristic polysomnographic features of REM sleep are reflected by the rapid eye movements on the “LOC-Fpz” and “ROC-Fpz” derivations; by mixed alpha-theta frequency activity on the “FzCz,” “Cz-Oz,” and “C3-A2” derivations; and by electromyographic (EMG) atonia on the “LLg-RLg” derivations (A). A low-amplitude and highfrequency artifact can be seen on the “CHN-CH3” derivation, and a few muscle twitches (small arrows) can be seen in part A, which is a normal finding, particularly during phasic REM sleep.

Smell Testing 79,80

Anosmia has been studied extensively in Parkinson’s disease, as well as in Alzheimer’s disease.81 Reports have suggested that anosmia in the setting of mild cognitive impairment may be predictive of subsequent conversion to Alzheimer’s disease,82 and anosmia in the setting of RBD may be predictive of an underlying synucleinopathy such as LBD.83 According to Braak and associates’ neuropathological staging system of Parkinson’s disease,9 α-synuclein–positive pathology in the olfactory structures, as well as in the medulla, occurs very early (stage 1) in Parkinson’s disease (see Fig. 70–3); such pathology gradually ascends up the brainstem and eventually to limbic and neocortical structures. Hence, at least in Parkinson’s disease, the progression of anosmia to RBD to parkinsonism to dementia fits well into Braak and associates’ paradigm. Whether

the quantitative and qualitative features of anosmia in patients with dementia have predictive value in determining the underlying neurodegenerative disorder remains to be tested.

MANAGEMENT No therapy that significantly alters synuclein pathophysiology, which is presumed to be central to Lewy body disease, has yet been identified. Management must therefore be directed toward target symptoms (Table 70–6). Although only a few doubleblind, placebo-controlled clinical trials have been carried out specifically in DLB patients, there is sufficient experience to provide some suggestions for therapy. The tenet “start low and go slow” is particularly important in DLB patients.

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B ■

Figure 70–7, cont’d. Note the markedly increased EMG tone on the “LLg-RLg” derivation in part B (large arrows), reflecting REM sleep without atonia.

Although limbic and neocortical neuronal loss clearly occurs in DLB, the severity appears to be less than that in Alzheimer’s disease and other dementias (as exemplified in Fig. 70–5).4,5,11,84 Furthermore, depletion of the cholinergic basal forebrain, classically viewed as part of Alzheimer’s disease, is often even more profound in LBD.4,5 Decreases in dopamine and serotonin are also inherent in LBD. Thus, the marked neurotransmitter deficiencies but better preservation of viable neurons suggests that medical therapy may be as effective in DLB as in other dementing disorders or more so. The following approach addresses strategies for the five categories of symptoms described previously.

Cognitive Impairment The cholinergic deficit in DLB is now well established, and the cholinesterase inhibitors have been shown in open-label and double-blind, placebo-controlled studies to modestly improve

cognition and functional abilities (reviewed in detail by Simard and van Reekum85). The currently available cholinesterase inhibitors include tacrine, donepezil, rivastigmine, and galantamine. Because frequent dosing and laboratory monitoring are necessary with tacrine, this agent is rarely used. Despite the concern that cholinergic stimulation might worsen parkinsonism, this has not been a serious problem in clinical experience and controlled studies.86 Thus, clinicians should consider prescribing one of these agents for patients with DLB in whom there is no contraindication to its use. Studies with relatively few patients have shown improvement with memantine in parkinsonism in patients with Parkinson’s disease,87 but there are no published data on this drug in DLB patients. Clinical experience has shown that some patients with DLB do benefit from memantine, but visual hallucinations, gait impairment, and worsened cognition can occur; these typically resolve on discontinuation of the drug. Psychostimulants, carbidopa/levodopa, and the dopamine agonists can theoretically improve cognition, apathy, and

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B

A

C ■

Figure 70–8. Results of autonomic testing in an 81-year-old man with rapid-eye-movement sleep behavior disorder and classic features of dementia with Lewy bodies, who died at age 84 and in whom neocortical Lewy body disease was found at autopsy. Thermoregulatory sweat testing (A) revealed mild patchy anhidrosis in the limbs. The Quantitative Sudomotor Axon Reflex Test (QSART) revealed relatively preserved sudomotor function (B). The mildly reduced heart rate responses to deep breathing and the Valsalva maneuver (C) are consistent with mild cardiovagal impairment. The marked drop in blood pressure (>70/20 mm Hg) on tilt-table monitoring and dampened responses to the Valsalva maneuver indicate severe orthostatic hypotension with severe adrenergic failure.

psychomotor slowing, but no controlled studies demonstrating efficacy of these agents have been published to date.

Neuropsychiatric Features Visual hallucination is one of the most frequent and pervasive features of DLB, but drug therapy is not required if the hallucinations are not frightening. When they are frightening, or when paranoia develops in concert with hallucinations, drug therapy is often necessary. Conventional neuroleptic agents, which have been classically used to manage hallucinations, can cause striking and irreversible parkinsonism (a phenomenon termed neuroleptic sensitivity), and use of these agents is now strongly discouraged in the management of DLB,88 which underscores the importance of accurate diagnosis in this condition. The cholinesterase inhibitors have been shown to ameliorate hallucinations, as well as apathy.86,89-91 There are reports of neuroleptic sensitivity even among the newer atypical neuroleptic agents, and some of these have been minimally effective for psychotic features.63 The following agents have been reported to improve hallucinations, delusions, or agitation: clozapine,92-94 risperidone,95,96 olanzapine,97,98 quetiapine,94,99 and the cholinesterase inhibitors. Therefore, if problematic

hallucinations, delusions, or agitation occurs in patients with DLB who do not respond to the cholinesterase inhibitors, clinicians should consider quetiapine, clozapine, or olanzapine. There is insufficient evidence on the efficacy of ziprasidone and aripiprazole. Orthostatism can occur with any of the atypical neuroleptic agents. Valproic acid and carbamazepine have mood-stabilizing properties and may be appropriate for some patients. The raphe nucleus is compromised in DLB, which is the likely substrate for depression. The selective serotonin reuptake inhibitors are usually effective and well tolerated. Tricyclic antidepressants, because of their anticholinergic properties, should generally be avoided in DLB. Paroxetine also has anticholinergic effects and should be used cautiously in DLB. Electroconvulsive therapy can be effective in some patients without significantly worsening cognition.100 The selective serotonin reuptake inhibitors and buspirone can improve anxiety.

Motor Dysfunction When significant parkinsonism is present in patients with DLB, the challenge for the clinician is to ameliorate this feature without exacerbating psychotic symptoms, hypersomnolence,

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T A B L E 70–6. Symptoms, Behaviors, and Disorders in Dementia with Lewy Bodies: Select Medications with Suggested Dosing Schedules* Symptom/Behavior/Disorder Cognitive Impairment Forgetfulness

Apathy, psychomotor slowing, or subcortical dementia

Medication

Starting Dose

Donepezil Rivastigmine

5 mg/q.a.m. 1.5 mg/b.i.d.

Galantamine

4 mg/b.i.d.

Memantine

5 mg/q.d.

Methylphenidate

2.5 mg/q.a.m.

Amphetamine/ dextroamphetamine

5 mg/q.a.m.

Modafinil

100 mg/q.a.m.

Carbidopa/levodopa

Neuropsychiatric Features Hallucinations, delusions, behavioral dyscontrol, agitation/aggression, nocturnal wandering, or disinhibition

Donepezil Rivastigmine

5 mg/q.a.m. 1.5 mg/b.i.d.

Galantamine

4 mg/b.i.d.

Memantine

5 mg/q.d.

Donepezil Rivastigmine

5 mg/q.a.m. 1.5 mg/b.i.d.

Galantamine

4 mg/b.i.d.

Risperidone

0.5 mg/q.h.s.

Olanzapine

5 mg/q.h.s.

Clozapine†

12.5 mg/q.h.s.

Quetiapine

25 mg/q.h.s.

Valproic acid†

125 mg/q.h.s. †

Carbamazepine Depression or emotional lability/pseudobulbar affect

Anxiety or obsessions/ compulsions

25/100 1/2 tab/ t.i.d.

100 mg/q.h.s.

Fluoxetine Sertraline

10 mg/q.d. 25 mg/q.d.

Paroxetine

10 mg/q.d.

Citalopram

10 mg/q.d.

Sertraline

25 mg/q.d.

Paroxetine

10 mg/q.d.

Suggested Titrating Schedule

Typical Therapeutic Range

Increase to 10 mg/q.a.m. 4 weeks later Increase in 1.5-mg increments for both doses every 2-4 weeks; maximum, 6 mg/b.i.d. Increase in 4-mg increments for both doses every 4 weeks; maximum, 12 mg/b.i.d. Increase as per titration pack up to 10 mg/b.i.d. Increase in 2.5- to 5-mg increments every 3-5 days in b.i.d. dosing (A.M. and noon) Increase in 5-mg increments every 7 days in q.d.-b.i.d. (A.M. and noon) dosing; maximum, 25 mg/b.i.d. Increase to 200 mg PO q.a.m. 1 week later if necessary; maximum, 400 mg/qam Increase in 1/2-tab increments over all 3 daily doses each week (take 1 hr before or after meals) Increase to 10 mg/q.a.m. 4 weeks later Increase in 1.5-mg increments for both doses every 2-4 weeks, maximum 6 mg/b.i.d. Increase in 4-mg increments for both doses every 4 weeks; maximum, 12 mg/b.i.d. Increase as per titration pack up to 10 mg/b.i.d.

5-10 mg/q.a.m. 1.5-6.0 mg/b.i.d.

Increase to 10 mg/q.a.m. 4 weeks later Increase in 1.5 mg increments for both doses every 4 weeks; maximum, 6 mg/b.i.d. Increase in 4 mg increments for both doses every 4 weeks; maximum, 12 mg/b.i.d. Increase in 0.5-mg increments every 7 days in b.i.d. dosing (A.M. and h.s.) Increase in 5-mg increments every 7 days in b.i.d. dosing (A.M. and h.s.) Increase in 12.5-mg increments every 2-3 days Increase in 25-mg increments every 3 days Increase in 125-mg increments every 3-7 days in b.i.d. to t.i.d. dosing Increase in 100-mg increments every 3-7 days in b.i.d. to t.i.d. dosing Increase to 20 mg 2-4 weeks later Increase to 50 mg 2 weeks later; titrate gradually up to maximum of 200 mg/q.d. Increase to 20 mg 2 weeks later; titrate gradually up to maximum of 50 mg/day Increase to 20 mg 2 weeks later; titrate gradually up to maximum of 60 mg/day Increase to 50 mg 2 weeks later; titrate gradually up to maximum of 200 mg/q.d. Increase to 20 mg 2 weeks later; titrate gradually up to maximum of 50 mg/day

4-12 mg/b.i.d. 5-10 mg/b.i.d. 5 mg/q.a.m.–30 mg/b.i.d. 5 mg/q.a.m.–20 mg/b.i.d. 100-400 mg/q.a.m. 1-3 tabs/t.i.d. 5-10 mg/q.a.m. 1.5-6.0 mg/b.i.d. 4-12 mg/b.i.d. 5 mg/b.i.d.–10 mg/b.i.d.

5-10 mg/q.a.m. 1.5-6.0 mg/b.i.d. 4-12 mg/b.i.d. 0.5 mg/q.h.s.–1.5 mg/b.i.d. 5 mg/q.h.s.–10 mg/b.i.d. 25 mg/q.h.s.–50 mg/t.i.d. 25 mg/q.h.s. –100 mg/ q.a.m. and 400 mg/ q.p.m. 250 mg/q.h.s.–500 mg/t.i.d. 200 mg/q.h.s.–200 mg/t.i.d. 10-40 mg/q.d. 50-100 mg/q.d. 10-40 mg/q.d. 10-60 mg/q.d. 50-100 mg/q.d. 10-40 mg/q.d.

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T A B L E 70–6. Symptoms, Behaviors, and Disorders in Dementia with Lewy Bodies: Select Medications with Suggested Dosing Schedules—cont’d Symptom/Behavior/Disorder

Motor Dysfunction Parkinsonism‡

Medication

Starting Dose

Buspirone

Carbidopa/levodopa Pramipexole

Sleep Disorders REM sleep behavior disorder

Insomnia

Restless legs syndrome/ periodic limb movement disorder§

5 mg/b.i.d.

Increase in 5-mg increments in b.i.d.t.i.d. dosing every 3-5 days; maximum, 60 mg/day

5-10 mg/t.i.d.

25/100 1/2 tab/ t.i.d.

Increase in 1/2-tab increments for all 3 daily doses each week (take 1 hr before or after meals) Increase in 0.125-mg increments for both daily doses every 2-3 days Increase in 0.25-mg increments for both daily doses every 2-3 days

1-3 tabs/t.i.d.

Ropinirole

Clonazepam

0.25 mg/q.h.s.

Melatonin

3 mg

Quetiapine

12.5 mg/q.h.s.

Trazodone

25 mg/q.h.s.

Zolpidem Quetiapine

5 mg/q.h.s. 12.5 mg/q.h.s.

Chloral hydrate

500 mg/q.h.s.

Melatonin Carbidopa/levodopa

3 mg 25/100 or CR 25/100 0.125 mg/ q.h.s. 0.25 mg / q.h.s. 100 mg/q.h.s.

Pramipexole

Gabapentin Methylphenidate

2.5 mg/q.a.m.

Amphetamine/ dextroamphetamine

5 mg/q.a.m.

Modafinil

Autonomic Dysfunction Orthostatic hypotension

Typical Therapeutic Range

0.125 mg / b.i.d. 0.25 mg/b.i.d.

Ropinirole

Excessive daytime somnolence

Suggested Titrating Schedule

100 mg/q.a.m.

Fludrocortisone

0.1 mg/q.d.

Midorine

5 mg/t.i.d.

Increase in 0.25-mg increments every 7 days Increase in 3-mg increments every 3-5 days, up to 12 mg if necessary Increase in 12.5-mg increments every 3-5 days Increase in 25-mg increments every 3-5 days Increase up to 10 mg/q.h.s. Increase in 12.5 mg increments every 3-5 days Increase in 500 mg increments every 5-7 days Increase up to 6 mg if necessary 1 tab/q.h.s.; increase to 2 tabs 1 week later if necessary Increase in 0.125-mg increments every 2-3 days Increase in 0.25-mg increments every 2-3 days Increase in 100-mg increments every 2-3 days Increase in 2.5- to 5-mg increments every 3-5 days in b.i.d. dosing (A.M. and noon) Increase in 5-mg increments every 7 days in q.d.-b.i.d. (A.M. and noon) dosing; maximum, 25 mg/b.i.d. Increase to 200 mg PO q.a.m. 1 week later if necessary; can increase up to a maximum of 400 mg/day, either all in A.M. or 200 mg in A.M. and 200 mg at noon Increase in 0.1-mg increments every 5-7 days; maximum, 0.3 mg/day Increase up to 10 mg/t.i.d. if necessary

0.25-1.0 mg/b.i.d. 0.25-1.5 mg/b.i.d.

0.25-1.0 mg/night 3-12 mg/night 12.5-100 mg/night 50-200 mg/night 5-10 mg/night 12.5-100 mg/night 500-1500 mg/night 3-6 mg/night 1-2 tabs/q.h.s. 0.25-0.75 mg/night 0.25-1.5 mg/night 300-1200 mg/night 5 mg/q.a.m.–30 mg/b.i.d. 5 mg/q.a.m.–20 mg/b.i.d. 100 mg/q.a.m.–400 mg/day

0.1-0.3 mg/q.d. 5-10 mg/t.i.d.

*Disclaimer: The choice of which agents to use and which dosing schedules to recommend must be individualized. It is the responsibility of the clinician to consider potential side effects, drug interactions, allergic responses, life-threatening reactions (e.g., leukopenia with clozapine), dosing changes resulting from renal or hepatic dysfunction, and so forth, before administering any drug to any patient, including those listed. Drs. Boeve and Wszolek, the Mayo Foundation, and Elsevier, Inc., are not responsible for any adverse reactions of any kind in any patient with regard to the content of this information. † Periodic laboratory monitoring necessary; refer to guidelines provided by manufacturer. ‡ Carbidopa/levodopa is the preferred agent for management of parkinsonism in dementia with Lewy bodies; dopamine agonists are generally poorly tolerated and hence should be used cautiously. Pergolide is generally not used at present because of the rare association with cardiac valve abnormalities. § Although pergolide is quite effective for treating restless legs syndrome and periodic limb movement disorder, this agent is generally not used at present because of the rare association with cardiac valve abnormalities. CR, controlled release; PO, orally; REM, rapid eye movement. Adapted from Boeve BF: Diagnosis and management of the non-Alzheimer dementias. In Noseworthy JW, ed: Neurological Therapeutics: Principles and Practice. London: Martin Dunitz, 2003, pp 2826-2854; and Boeve B: Dementia with Lewy bodies. In Petersen R, ed: Continuum. Minneapolis: American Academy of Neurology, 2004, pp 81-112.

chapter 70 dementia with lewy bodies and orthostatism. Experience has shown that many of the parkinsonian signs and symptoms of DLB can respond to carbidopa/levodopa and the dopamine agonists, but these agents must be used cautiously. In one open-label study, levodopa was generally well tolerated, but only one third of the patients experienced significant improvement in motor functioning.101 In those with refractory depression warranting electroconvulsive therapy, parkinsonism can be ameliorated through unknown mechanisms. Invasive strategies for managing parkinsonism, such as pallidotomy and deep brain stimulation, are not appropriate for patients with DLB.

Autonomic Dysfunction Orthostatic hypotension can occur in DLB; it is probably a result of degenerative changes in the intermediolateral cell column of the spinal cord and peripheral autonomic system.48,49 Liberal amounts of salt in the diet, salt tablets, thigh-high compression stockings, fludrocortisone, and midodrine are additional considerations. Although certainly not a first-line agent for the management of orthostatic hypotension, the cholinesterase inhibitors have been shown to ameliorate orthostatic hypotension102; whether this occurs consistently in patients with DLB remains to be seen.

Sleep Disorders REM Sleep Behavior Disorder RBD is manifested as violent dreams or nightmares and potentially injurious dream reenactment behavior, and the diagnosis is usually not difficult if the features listed in Table 70–2 are present. However, patients with moderate to severe obstructive sleep apnea can have features identical to those of RBD; the nightmares and behaviors are typically eliminated with nasal continuous positive airway pressure. Hence, patients should be considered for polysomnography with or without a trial of nasal continuous positive airway pressure if there is a history suggestive of RBD and/or obstructive sleep apnea. The goals of therapy for RBD are to minimize the nightmares and abnormal behavior, and because injuries to patients and their bed partners can occur, treatment should be commenced in patients with the potential for injury.24,42 Simple measures to minimize the potential for injury involve counseling patients and their bed partners to move lamps and furniture away from the bed and to place a mattress or cushion on the floor beside the bed. Clonazepam, the drug of choice for most patients who have RBD without dementia, is usually effective at 0.25 to 0.5 mg per night; dosages higher than 1 mg are sometimes necessary.24,42-44 Clonazepam is not an ideal agent in patients with dementia, but experience has shown that most patients tolerate the drug well at low dosages.24,42 Melatonin can also be effective at 3 to 12 mg per night either as monotherapy or in conjunction with clonazepam.103 Experience suggests that quetiapine can also be effective in managing RBD.24,42

Insomnia Insomnia can be caused by one or more primary sleep disorders (e.g., restless legs syndrome, periodic limb movement during sleep, obstructive sleep apnea, or central sleep apnea

923

syndrome), by depression, and by medications.42 Frequent arousals for no apparent reason may be an intrinsic part of the disease, presumably caused by degenerative changes in the sleep/wake circuits in the brainstem and hypothalamus. A carefully documented sleep history can lead to the correct diagnoses, but polysomnography is often necessary because the cardinal features of obstructive sleep apnea, central sleep apnea, and periodic limb movement during sleep may not be apparent to the patient or bed partner. Contrary to popular belief among clinicians and the lay public, nasal continuous positive airway pressure therapy or bilevel positive airway pressure is tolerated by many patients with dementia.42 Although certainly not universal among DLB patients with one or more sleep disorders, marked clinical improvements in alertness and cognition can occur with effective management of the sleep issues.42 Insomnia can also be caused by medications, particularly the cholinesterase inhibitors, and patients can minimize insomnia by taking donepezil in the morning or taking rivastigmine or galantamine no later than the evening meal. Other drugs effective for primary insomnia include trazodone, chloral hydrate, zolpidem, zaleplon, and the atypical neuroleptic agents (e.g., quetiapine, olanzapine, clozapine, or risperidone). Melatonin was evaluated as part of the Melatonin for Sleep Disturbance in Alzheimer’s Disease clinical trial, but there were no group differences between those treated with low-dose melatonin, highdose melatonin, and placebo.104 However, as pointed out in the report by the investigators, melatonin may be effective in rare instances. Fluoxetine, venlafaxine, and bupropion may precipitate or aggravate insomnia, whereas mirtazapine may ameliorate insomnia. Numerous nonpharmacological strategies are also available for managing insomnia.105

Excessive Daytime Somnolence Excessive daytime somnolence can be caused by primary sleep disorders, depression, and medications as noted previously; adequate evaluation may necessitate polysomnography with or without multiple sleep latency tests.42 Interestingly, there is evidence that some patients with Parkinson’s disease and psychosis have narcolepsy-like features,39 and the same may be true of patients with DLB.24,34 Although psychostimulants would be expected to exacerbate hallucinations and delusions in patients with DLB, experience has shown that excessive daytime somnolence, as well as hallucinations and delusions, can be well managed with agents such as modafinil and methylphenidate.24 This is a controversial aspect in the management of DLB, and clearly controlled trials are necessary to justify use of psychostimulants in this population.

CONCLUSIONS AND FUTURE DIRECTIONS Parkinson’s disease/Lewy body disease has classically been considered a dopamine deficiency disorder. Technical developments and considerable attention directed to the study of dementia and parkinsonism since the mid-1980s have revealed that the syndrome of DLB and the disorder of LBD are clearly far more complex, with motor, cognitive, neuropsychiatric, sleep, and autonomic manifestations, as well as multiple neurotransmitter systems involved. As a more comprehensive approach evolves in the characterization and management of DLB patients, the quality of life for patients and their families

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can be optimized. Further research on α-synuclein and other protein aggregation abnormalities in LBD offer hope that disease-altering and preventive therapies may some day be developed.

K E Y

P O I N T S

●

DLB is a syndrome usually associated with LBD, affecting limbic structures and the neocortex.

●

LBD is a disorder that involves multiple neurotransmitter systems, thereby contributing to the cognitive, neuropsychiatric, motor, and sleep manifestations of DLB.

●

The central and peripheral autonomic systems are also often affected by LBD, which leads to orthostatic hypotension, impotence, and constipation.

●

The Third Consensus Conference on DLB suggested changes in the clinical and pathological classifications of DLB, although the core clinical features of spontaneous parkinsonism, recurrent and fully formed visual hallucinations, and fluctuations in cognition and arousal are maintained.

●

A comprehensive approach toward managing the various features of DLB offers the highest likelihood of ameliorating symptoms and improving quality of life in patients with DLB.

Suggested Reading Barber R, McKeith I, Ballard C, et al: A comparison of medial and lateral temporal lobe atrophy in dementia with Lewy bodies and Alzheimer’s disease: magnetic resonance imaging volumetric study. Dementia Geriatr Cogn Disord 2001; 12:198-205. Boeve B: Dementia with Lewy bodies. In Petersen R, ed: Continuum. Minneapolis: American Academy of Neurology, 2004, pp 81-112. Ferman T, Smith G, Boeve B, et al: Neuropsychological differentiation of dementia with Lewy bodies from normal aging and Alzheimer’s disease. Clin Neuropsychol (in press). McKeith I, Del Ser T, Spano P, et al: Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356:20312036. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1113-1124. McKeith I, Mintzer J, Aarsland D, al: Dementia with Lewy bodies. Lancet Neurology 2004; 3:19-28. Thaisetthawatkul P, Boeve B, Benarroch E, et al: Autonomic dysfunction in dementia with Lewy bodies. Neurology 2004; 62:1804-1809.

References 1. Okazaki H, Lipkin L, Aronson S: Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion. J Neuropathol Exp Neurol 1961; 20:237-244.

2. Kosaka K: Dementia and neuropathology in Lewy body disease. Adv Neurol 1993; 60:456-463. 3. Kosaka K: Diffuse Lewy body disease. Neuropathology 2000; 20(Suppl):S73-S78. 4. Dickson DW: Tau and synuclein and their role in neuropathology. Brain Pathol 1999; 9:657-661. 5. Dickson D: Dementia with Lewy bodies: neuropathology. J Geriatr Psychiatr Neurol 2002; 15:210-216. 6. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:11131124. 7. McKeith IG, Perry EK, Perry RH: Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999; 53:902-905. 8. McKeith I, Mintzer J, Aarsland D, et al: Dementia with Lewy bodies. Lancet Neurology 2004; 3:19-28. 9. Braak H, Del Tredici K, Rub U, et al: Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24:197-211. 10. Braak H, Ghebremedhin E, Rub U, et al: Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318:121-134. 11. Dickson DW, Crystal H, Mattiace LA, et al: Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. Acta Neuropathol 1989; 78:572584. 12. Dickson DW, Ruan D, Crystal H, et al: Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer’s disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology 1991; 41:1402-1409. 13. Salmon D, Galasko D, Hansen L, et al: Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn 1996; 31:148-164. 14. Hansen L, Salmon D, Galasko D, et al: The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 1990; 40:1-8. 15. Hansen L, Samuel W: Criteria for Alzheimer’s disease and the nosology of dementia with Lewy bodies. Neurology 1997; 48:126-132. 16. Lippa CF, Pulaski-Salo D, Dickson DW, et al: Alzheimer’s disease, Lewy body disease and aging: a comparative study of the perforant pathway. J Neurol Sci 1997; 147:161-166. 17. Lippa C, Smith T, Perry E: Dementia with Lewy bodies: choline acetyltransferase parallels nucleus basalis pathology. J Neural Transm 1999; 105:525-535. 18. Lippa CF, McKeith I: Dementia with Lewy bodies: improving diagnostic criteria [Comment]. Neurology 2003; 60:15711572. 19. Duda J, Lee V, Trojanowski J: Neuropathology of synuclein aggregates. J Neurosci Res 2000; 61:121-127. 20. Trojanowski J, Lee V: Parkinson’s disease and related neurodegenerative synucleinopathies linked to progressive accumulations of synuclein aggregates in brain. Parkinsonism Relat Disord 2001; 7:247-251. 21. Duda J, Giasson B, Mabon M, et al: Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 2002; 52:205-210. 22. Boeve B, Silber M, Ferman T, et al: Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001; 16:622630. 23. Boeve B, Silber M, Parisi J, et al: Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003; 61:40-45.

chapter 70 dementia with lewy bodies 24. Boeve B, Silber M, Ferman T: REM sleep behavior disorder in Parkinson’s disease and dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2004; 17:146-157. 25. Ferman TJ, Boeve B, Smith GE, et al: REM sleep behavior disorder and dementia: cognitive differences when compared with AD. Neurology 1999; 52:951-957. 26. Ferman T, Boeve B, Smith G, et al: Dementia with Lewy bodies may present as dementia with REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc 2002; 8:907-914. 27. Ferman T, Smith G, Boeve B: DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology 2004; 62:181-187. 28. Knopman D, Parisi J, Boeve B, et al: Vascular dementia in a population-based autopsy study. Arch Neurol 2003; 60:569575. 29. Rahkonen T, Eloniemi-Sulkava U, Rissanen S, et al: Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry 2003; 74:720-724. 30. Ballard C, Holmes C, McKeith I, et al: Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 1999; 156:1039-1045. 31. Ballard C, O’Brien J, Gray A, et al: Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease. Arch Neurol 2001; 58:977-982. 32. Galasko D: Lewy bodies and dementia. Curr Neurol Neurosci Rep 2001; 1:435-441. 33. Boeve B, Silber M, Ferman T, et al: REM sleep behavior disorder in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In Bedard M, Agid Y, Chouinard S, et al, eds: Mental and Behavioral Dysfunction in Movement Disorders. Totowa, NJ: Humana Press, 2003, pp 383-397. 34. Boeve B: Dementia with Lewy bodies. In Petersen R, ed: Continuum. Minneapolis: American Academy of Neurology, 2004, pp 81-112. 35. Simard M, van Reekum R, Cohen T: A review of the cognitive and behavioral symptoms in dementia with Lewy bodies. J Neuropsychiatr Clin Neurosci 2000; 12:425-450. 36. Ferman T, Boeve B, Silber M, et al: Is fluctuating cognition in dementia with Lewy bodies attributable to an underlying sleep disorder? Sleep 2001; 24:A374. 37. Aarsland D, Ballard C, Larsen J, et al: A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int J Geriatr Psychiatry 2001; 16:528-536. 38. Marantz A, Verghese J: Capgras’ syndrome in dementia with Lewy bodies. J Geriatr Psychiatr Neurol 2002; 15:239241. 39. Arnulf I, Bonnet AM, Damier P, et al: Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 2000; 55:281-288. 40. Burn DJ, Rowan EN, Minett T, et al: Extrapyramidal features in Parkinson’s disease with and without dementia and dementia with Lewy bodies: a cross-sectional comparative study. Mov Disord 2003; 18:884-889. 41. Boeve BF, Silber MH, Ferman TJ, et al: REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 1998; 51:363-370. 42. Boeve B, Silber M, Ferman T: Current management of sleep disturbances in dementia. Curr Neurol Neurosci Rep 2001; 2:169-177. 43. Olson E, Boeve B, Silber M: Rapid eye movement sleep behavior disorder: demographic, clinical, and laboratory findings in 93 cases. Brain 2000; 123:331-339. 44. Schenck C, Mahowald M: REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years

925

after its formal identification in SLEEP. Sleep 2002; 25:120138. 45. Boeve B, Ferman T, Silber M, et al: Sleep disturbances in dementia with Lewy bodies involve more than REM sleep behavior disorder. Neurology 2003; 60:A79. 46. Ballard C, Shaw F, McKeith I, et al: High prevalence of neurovascular instability in neurodegenerative dementias. Neurology 1998; 51:1760-1762. 47. Hishikawa N, Hashizume Y, Yoshida M, et al: Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol (Berl) 2003; 105:341-350. 48. Thaisetthawatkul P, Boeve B, Benarroch E, et al: Autonomic dysfunction in dementia with Lewy bodies. Neurology 2004; 62:1804-1809. 49. Benarroch E, Schmeichel A, Low P, et al: Involvement of medullary regions controlling sympathetic output in Lewy body disease. Brain 2005; 128:338-344. 50. Hohl U, Tiraboschi P, Hansen L, et al: Diagnostic accuracy of dementia with Lewy bodies. Arch Neurol 2000; 57:347-351. 51. Lopez O, Litvan I, Catt K, et al: Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 1999; 53:1292-1299. 52. Lopez O, Hamilton R, Becker J, et al: Severity of cognitive impairment and the clinical diagnosis of AD with Lewy bodies. Neurology 2000; 54:1780-1787. 53. McKeith IG, Ballard CG, Perry RH, et al: Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology 2000; 54:1050-1058. 54. Mega M, Masterman D, Benson D, et al: Dementia with Lewy bodies: reliability and validity of clinical and pathologic criteria. Neurology 1996; 47:1403-1409. 55. Verghese J, Crystal HA, Dickson DW, et al: Validity of clinical criteria for the diagnosis of dementia with Lewy bodies. Neurology 1999; 53:1974-1982. 55a. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: Third report of the DLB consortium. Neurology 2005; 65:1863-1872. 56. Knopman D, Boeve B, Petersen R: Essentials of the proper diagnosis of mild cognitive impairment, dementia, and major subtypes of dementia. Mayo Clin Proc 2003; 78:1290-1308. 57. Knopman D, DeKosky S, Cummings J, et al: Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143-1153. 58. Kanemaru K, Kameda N, Yamanouchi H: Decreased CSF amyloid β42 and normal tau levels in dementia with Lewy bodies. Neurology 2000; 54:1875-1876. 59. Mori E, Shimomura T, Fujimori M, et al: Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol 2000; 57:489-493. 60. Simard M, van Reekum R, Myran D: Visuospatial impairment in dementia with Lewy bodies and Alzheimer’s disease: a process analysis approach. Int J Geriatr Psychiatry 2003; 18:387-391. 61. Ferman T, Smith G, Boeve B, et al: Neuropsychological differentiation of dementia with Lewy bodies from normal aging and Alzheimer’s disease. Clin Neuropsychol (in press). 62. Doubleday E, Snowden J, Varma A, et al: Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002; 72:602-607. 63. Walker Z, Grace J, Overshot R, et al: Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychiatry 1999; 14:459-466. 64. Walker M, Ayre G, Cummings J, et al: The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia. Br J Psychiatry 2000; 177:252-256.

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65. Walker M, Ayre G, Cummings J, et al: Quantifying fluctuation in dementia with Lewy bodies, Alzheimer’s disease, and vascular dementia. Neurology 2000; 54:1616-1625. 66. Walker M, Ayre G, Perry E, et al: Quantification and characterization of fluctuating cognition in dementia with Lewy bodies and Alzheimer’s disease. Dementia Geriatr Cogn Disord 2000; 11:327-335. 67. Briel RC, McKeith IG, Barker WA, et al: EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1999; 66:401-403. 68. Jack CR Jr, Petersen RC, Xu YC, et al: Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Ann Neurol 1998; 43:303-310. 69. Jack CR Jr, Petersen RC, Xu Y, et al: Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology 2000; 55:484-489. 70. Jack CR Jr, Petersen RC, Xu YC, et al: Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 1999; 52:1397-1403. 71. Barber R, McKeith I, Ballard C, et al: A comparison of medial and lateral temporal lobe atrophy in dementia with Lewy bodies and Alzheimer’s disease: magnetic resonance imaging volumetric study. Dementia Geriatr Cogn Disord 2001; 12:198-205. 72. Barber R, Gholkar A, Scheltens P, et al: Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology 1999; 52:1153-8. 73. Barber R, Ballard C, McKeith IG, et al: MRI volumetric study of dementia with Lewy bodies: a comparison with AD and vascular dementia. Neurology 2000; 54:1304-1309. 74. Lobotesis K, Fenwick J, Phipps A, et al: Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001; 56:643-649. 75. Minoshima S, Foster N, Sima A, et al: Alzheimer’s disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann Neurol 2001; 50:358-365. 76. Tang-Wai D, Graff-Radford N, Boeve B, et al: Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology 2004; 63:1168-1174. 77. Mahowald M, Schenck C: REM sleep behavior disorder. In Kryger M, Roth T, Dement W, eds: Principles and Practice of Sleep Medicine, 3rd ed. Philadelphia: WB Saunders, 2000, pp 724-741. 78. Pakiam AS, Bergeron C, Lang AE: Diffuse Lewy body disease presenting as multiple system atrophy. Can J Neurol Sci 1999; 26:127-131. 79. Tissingh G, Berendse H, Bergmans P, et al: Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord 2001; 16:41-46. 80. Ponsen M, Stoffers D, Booij J, et al: Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 2004; 56:173-181. 81. Peters J, Hummel T, Kratzsch T, et al: Olfactory function in mild cognitive impairment and Alzheimer’s disease: an investigation using psychophysical and electrophysiological techniques. Am J Psychiatry 2003; 160:1995-2002. 82. Wang Q, Tian L, Huang Y, et al: Olfactory identification and apolipoprotein E epsilon 4 allele in mild cognitive impairment. Brain Res 2002; 951:77-81. 83. Stiasny-Kolster K, Doerr Y, Möller J, et al: Combination of “idiopathic” REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005; 128:126-137. 84. Dickson DW, Davies P, Mayeux R, et al: Diffuse Lewy body disease. Neuropathological and biochemical studies of six patients. Acta Neuropathol 1987; 75:8-15.

85. Simard M, van Reekum R: The acetylcholinesterase inhibitors for treatment of cognitive and behavioral symptoms in dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci 2004; 16:409-425. 86. McKeith I, Del Ser T, Spano P, et al: Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031-2036. 87. Merello M, Nouzeilles M, Cammarota A, et al: Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin Neuropharmacol 1999; 22:273-276. 88. McKeith I, Fairbairn A, Perry R, et al: Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992; 305:673-678. 89. Shea C, MacKnight C, Rockwood K: Donepezil for treatment of dementia with Lewy bodies: a case series of nine patients. Int Psychogeriatr 1998; 10:229-238. 90. Fergusson E, Howard R: Donepezil for the treatment of psychosis in dementia with Lewy bodies. Int J Geriatr Psychiatry 2000; 15:280-281. 91. Lanctot KL, Herrmann N: Donepezil for behavioural disorders associated with Lewy bodies: a case series. Int J Geriatr Psychiatry 2000; 15:338-345. 92. Chacko RC, Hurley RA, Harper RG, et al: Clozapine for acute and maintenance treatment of psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:471-475. 93. Valldeoriola F, Nobbe FA, Tolosa E: Treatment of behavioural disturbances in Parkinson’s disease. J Neural Transm Suppl 1997; 51:175-204. 94. Dewey RJ, O’Suilleabhain P: Treatment of drug-induced psychosis with quetiapine and clozapine in Parkinson’s disease. Neurology 2000; 55:1753-1754. 95. Workman RH Jr, Orengo CA, Bakey AA, et al: The use of risperidone for psychosis and agitation in demented patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1997; 9:594-597. 96. Leopold NA: Risperidone treatment of drug-related psychosis in patients with parkinsonism. Mov Disord 2000; 15:301304. 97. Aarsland D, Larsen JP, Lim NG, et al: Olanzapine for psychosis in patients with Parkinson’s disease with and without dementia. J Neuropsychiatry Clin Neurosci 1999; 11:392-394. 98. Cummings J, Street J, Masterman D, et al: Efficacy of olanzapine in the treatment of psychosis in dementia with Lewy bodies. Dementia Geriatr Cogn Disord 2002; 13:67-73. 99. Takahashi H, Yoshida K, Sugita T, et al: Quetiapine treatment of psychotic symptoms and aggressive behavior in patients with dementia with Lewy bodies: a case series. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:549-553. 100. Rasmussen K Jr, Russell J, Kung S, et al: Electroconvulsive therapy for patients with major depression and probable Lewy body dementia. J ECT 2003; 19:103-109. 101. Molloy S, McKeith I, O’Brien J, et al: The role of levodopa in the management of dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2005; 76:1200-1203. 102. Singer W, Opfer-Gehrking T, McPhee B, et al: Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension. J Neurol Neurosurg Psychiatry 2003; 74:1294-1298. 103. Boeve B, Silber M, Ferman T: Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4:281-284. 104. Singer C, Tractenberg R, Kaye J, et al: A multicenter, placebocontrolled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 2003; 26:893-901. 105. Hauri P, Linde S: No More Sleepless Nights, 2nd ed. New York: John Wiley & Sons, 1996.

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PARKINSON’S DISEASE ●

●

●

●

Anthony H. V. Schapira

Parkinson’s disease (PD) is a neurodegenerative disease with initial clinical features that are predominantly the result of loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the midbrain. As the disease progresses, the involvement of additional brain areas in the degenerative process produces mainly nondopaminergic, nonmotor features. The discovery of dopamine deficiency in PD and the introduction of levodopa have provided patients with a significant improvement in both quality of life and life expectancy, but the treatment of nonmotor features and slowing of disease progression remain important unmet needs for patients.

HISTORICAL PERSPECTIVE James Parkinson is credited with providing the first and definitive clinical description of a disease, paralysis agitans, that was subsequently to bear his name. Parkinson was born in 1755 in what was then the village of Hoxton near London. His Essay on the Shaking Palsy was published in 1817 and was based on six patients, three of whom were only observed and not examined by Parkinson. His description remains one of the mostpublished detailed analyses of the clinical effects of PD and also makes comment on the etiology and pathogenesis of the disease. His observations on pathology were naturally limited; he did suggest that the disease had its origins in the medulla, “although that part contained within the cervical vertebrae” (sic). Suggestions for the relief of symptoms included the letting of blood from the upper cervical area and the production of a purulent discharge with the use of the Sabine Liniment. Several physicians published case reports based on Parkinson’s description. However, it was Charcot who made significant advances in the clinical classification and differential diagnosis of PD and was the first to propose its eponymous label. The motor and nonmotor features of PD are well described in these early works. The pathological definition of PD evolved rather slowly, perhaps reflecting the complex nature of the type and distribution of degenerative changes. Lewy described the intracytoplasmic inclusions that are a hallmark of the disease in 1912, and Trétiakoff is attributed with locating the cell degeneration in the substantia nigra. Various descriptions of pathological changes followed, including the presence of tangles and the distribution of degeneration, although many cases may not have been “idiopathic” PD.

In 1960, Ehringer and Hornykiewicz identified the dopamine deficiency in PD striatum.1 Studies on the replacement of dopamine with DL-dopa produced equivocal results until used in sufficient quantity.2 This began the era of symptomatic treatment for PD, which has remained focused on the dopaminergic system for almost 40 years.

EPIDEMIOLOGY Defining the epidemiology of PD is confounded by several variables that include the difficulty in diagnosis and the age dependence of the disease. Several studies have sought to define incidence. In the United States, the age-adjusted figure is 13.5 to 13.9 per 100,000 person-years.3,4 The age-adjusted prevalence is approximately 115 per 100,000 and is estimated as 1.3 per 100,000 under age 45 years and 1192.9 per 100,000 in those aged 75 to 85 years.3 A prevalence study in Holland found 3100 cases per 100,000 aged 75 to 85 years and 4300 per 100,000 for those over age 85 years.6 The geographical distribution of the disease appears similar across the United States and Japan, but failure to adjust population figures for age can lead to widely discrepant results, such as the prevalence of 10 per 100,000 in Nigeria.7

PATHOLOGY Macroscopic examination of the sectioned PD brain shows depigmentation of the substantia nigra and locus ceruleus. The characteristic pathological change of PD is the loss of pigmented dopaminergic neurons, particularly in the ventral tier of the SNc with intracytoplasmic eosinophilic inclusions (Lewy bodies) in a proportion of the surviving neurons (Fig. 71–1). The SNc also contains activated microglia and extracellular neuromelanin. There is also cell loss in the locus ceruleus; the nucleus basalis of Meynert; the dorsal motor nucleus of the vagus; the Edinger-Westphal, raphe, and pedunculopontine nuclei; and the pons, midbrain, spinal cord, and peripheral sympathetic ganglia. Lewy bodies may be found in these areas and in the cortex. Thus, in addition to the dopaminergic system, the cholinergic, serotonergic, γ-amino butyric acid, and adrenergic transmitter systems are involved in PD. Lewy bodies have attracted considerable attention over the years, as they may hold important clues to pathogenesis of the disease. They are 5 to 30 μm in diameter with a hyaline

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eosinophilic core, which may be dense and composed of concentric lamellae; a pale halo may be seen around the core. Electron microscopy demonstrates 7- to 20-nm intermediate filaments. The Lewy body is composed of a number of different proteins, staining for ubiquitin, α-synuclein, and proteasomal components. It is not known whether these inclusions represent a protective response to aggregate abnormal or toxic proteins, or whether their formation is part of a toxic process that damages the cell. Studies suggest that the earliest pathological changes are seen in the dorsal motor nucleus and in the olfactory bulbs and nucleus—Braak stages 1 and 28 (Fig. 71–2). In this context, it is noteworthy that loss of olfactory function can occur at a time prior to the onset of dopaminergic symptoms or signs and may serve to define an “at-risk” population.9 Lewy bodies then develop in the locus ceruleus and progress in the medulla and pons.10 The appearance of inclusions in the SNc defines the onset of Braak stage 3 with progression to stage 4. At this stage there is also degeneration in the pedunculopontine nucleus, the dorsal raphe nuclei, and the hypothalamus. Stages 5 and 6 involve progressive involvement of the cerebral cortex and neurodegeneration in those regions already affected. However, it is important to note that Braak’s staging was based on Lewy body formation and distribution and not on neuronal degeneration. In this context, the SNc remains the first location of degeneration in PD.

■

Figure 71–1. A Lewy body (arrow).

ETIOLOGY The etiology of PD is believed to involve both genetic and environmental factors. Several gene mutations have been described in monogenic forms of familial PD, and some of these are also found in apparently sporadic late-onset PD. Nevertheless, these account for only a small proportion of PD patients. Epidemiological studies have discovered certain lifestyle associations with PD, and some specific toxins have been identified that can induce a parkinson-like state in humans or animals.

Genetic Factors Sir William Gowers recognized that there was an increased prevalence of PD among the relatives of sufferers and proposed a genetic cause.11 Epidemiological studies evaluating the genetic contribution of PD are complicated by ensuring an accurate clinical diagnosis, inability to identify presymptomatic cases and the need for an appropriate control population. Casecontrol studies have confirmed Gowers’ observation that PD is more common in relatives of PD cases compared with matched controls.12-16 The relative risk of developing PD in family members has varied widely between different studies, but in many, incomplete family information was obtained and only one study has been population based.16 Overall, the relative risk in first-degree relatives of PD cases is increased approximately two- to threefold.17 A large PD twin study showed no significant concordance for PD among monozygotic twins, suggesting that there was no significant genetic contribution to PD.18 However, there was significant concordance for those with onset before age 50 years, implying that young-onset PD is more likely genetically determined. Another smaller twin study using fluorodopa positron emission tomography (PET) to image dopaminergic function in both affected and unaffected monozygotic and dizygotic twin pairs demonstrated an increased concordance for PD among identical twins.19 At follow-up, the combined concordance levels for subclinical dopaminergic dysfunction and clinical PD were 75% in the 12 monozygotic twins and 22% in the 9 dizygotic twins evaluated twice. Table 71–1 shows the current list of genes known to cause PD. PARK1 through PARK9 have been discovered using large single or combined pedigrees, whereas PARK10 and PARK11 have been identified using association techniques.

T A B L E 71–1. Park Genes

Park Park Park Park Park Park Park Park Park Park Park

1 2 3 4 5 6 7 8 9 10 11

Inheritance

Locus

Onset (y)

Lewy Bodies

Gene

Autosomal dominant Autosomal recessive Autosomal dominant Autosomal dominant Autosomal dominant Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive ?

4q21 6q25 2p13 4q21 4p15 1p35 1p36 12p — 1p32 2q36-37

40s 20s 60s 30s 50s 30s 30s — — —

+ − + + + ? ? ± ? ? ?

α-synuclein parkin ? α-synuclein UCH-L1 Pink-1 DJ1 LRRK2 ? ? ?

chapter 71 parkinson’s disease Presymptomatic phase

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Symptomatic phase

Locus ceruleus Dorsal IX/X nucleus 1

A

2

B Presymptomatic phase

Symptomatic phase

Presymptomatic phase

Symptomatic phase

Neocortex sec. + prim. Neocortex association

Mesocortex

Mesocortex

Substantia nigra

Substantia nigra

Locus coeruleus

Locus ceruleus

Dorsal IX/X nucleus 1

2

3

C ■

Dorsal IX/X nucleus 1

4

2

3

4

5

6

D Figure 71–2. Braak staging of Parkinson’s disease. (From Del Tredici K, Rub U, De Vos RA, et al: Where does Parkinson’s disease pathology begin in the brain? J Neuropathol Exp Neurol 2002; 61:413-426; and Braak H, Del Tredici K, Rub U, et al: Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24:197-211.)

a-Synuclein (PARK1) PARK1 involves mutations in the a-synuclein gene.20,21 The first families with an a-synuclein mutation originated from southern Italy and Greece, and with the description of several additional families with the same A53T mutation, it is believed that they have a common founder. Age at onset was young (mean, 46 years) with a low frequency of tremor and relatively rapid disease progression, although symptoms were levodopa responsive.22 Pathological analysis of the few brains available revealed the presence of Lewy bodies in the substantia nigra and locus ceruleus.23 Linkage to markers on chromosome 4q21-q23 was demonstrated and the locus designated PARK1.24 Further analyses identified a mutation in exon 4 of the gene encoding αsynuclein resulting in an alanine-to-threonine substitution at codon 53 (A53T), which was also found in affected members of

three Greek families with early-onset autosomal dominant PD.20 A second mutation (A30P) was later found in a small German family with PD,21 but extensive study in large groups of PD families and sporadic cases has not identified other patients or families with this mutation.25-28 α-Synuclein is a protein of 140 amino acids that is predominantly expressed in neurons and is one of the most common brain proteins. Its normal function remains unclear, although it plays a role in synaptic plasticity based on song-learning studies in the zebra finch29 and vesicular regulation of dopamine release from knockout mice.30 A key observation linking α-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies.31 Lewy bodies are intracytoplasmic aggregates comprising several proteins, including ubiquitin and α-synuclein, and have supported the notion that abnormal protein handling might be important in

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PD pathogenesis. Furthermore, mutant isoforms of αsynuclein more readily oligomerize and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. Indeed, overexpression of wild-type or mutant protein in transgenic mice or Drosophila reproduces many of the behavioral and pathological features of PD.32,33 Multiplications of the wild-type a-synuclein gene have been described in PD families. A triplication of the gene was identified in a large autosomal dominant kindred with PD and tremor,34 and duplication of the gene was found in one of 42 familial probands of early onset PD.35 A third α-synuclein point mutation (E46K) has been reported in an autosomal dominant family with parkinsonism and Lewy body dementia.36 Several models of abnormal α-synuclein expression have been developed. Knockout of the gene in mice resulted in no detectable abnormality other than an alteration of dopamine release in response to rapid stimulation, although this has no clear functional correlate.30 Overexpression of wild-type human α-synuclein in mice resulted in loss of dopaminergic terminals, intranuclear and cytoplasmic ubiquitin-rich nonfibrillar αsynuclein inclusions in the substantia nigra, hippocampus, cortex, and a rotor-rod motor deficit at 1 year.32 Overexpression of human wild-type and mutant α-synuclein in flies caused a loss of dopaminergic neurons, Lewy body–like inclusions with fibrillar α-synuclein, and a motor deficit with no significant difference between wild-type and mutant α-synuclein.33 Additional mouse models of α-synuclein expression have demonstrated inclusion formation and spinal cord pathology but no dopaminergic cell loss, and motor deficit at late stage.37 Virus-mediated overexpression of α-synuclein induces nigral degeneration in rodents.38 The a-synuclein mutations result in the protofibrillar form, which is considered the more toxic form of the protein. The A53T and A30P a-synuclein mutations promote protofibril formation and A30P inhibits conversion to fibrils.39 Catecholamines, including dopamine and levodopa, inhibit fibril formation in vitro, and this is reversed by antioxidants; that is, catechol oxidation promotes protofibril formation.40 This observation would support a protective role for Lewy bodies in PD. An important observation revealing a potential toxic mechanism for α-synuclein is that the mutant A30P form increases toxicity to dopamine, increasing cell death and free radical–mediated damage.41 The authors proposed that the mutation impaired vesicular uptake of dopamine, resulting in higher cytoplasmic or extravesicular synaptic concentrations of dopamine that would in turn cause free radical–mediated damage. Phosphorylation at the Ser129 residue is required to mediate the toxicity of α-synuclein and increased the formation of inclusions in SHSY-5Y cells.42 This phosphorylated form of α-synuclein is present in Lewy bodies.43 Prevention of this phosphorylation by substitution of an alanine residue reduced inclusion formation in the SHSY-5Y model, and in the Drosophila model this same mutation at 129 that prevents phosphorylation protected against dopaminergic neuronal loss.44

Parkin (PARK2) PARK2 gene mutations were first identified in autosomal recessive juvenile-onset parkinsonism (ARJPD).45 ARJPD has been most commonly seen in the Japanese population and is

characterized by onset before age 40 years, symptomatic improvement following sleep, mild dystonia, and a good response to levodopa.46 Resting tremor is seen less frequently than in idiopathic PD, and patients may have brisk tendon reflexes but no other pyramidal, cerebellar, or autonomic features. The disease is often symmetrical and dyskinesias develop early but progression is usually slow. Pathologically, there is dopaminergic cell loss in the SNc and locus ceruleus but no Lewy bodies are seen.47 The gene responsible for ARJPD was mapped to 6q25.2-q27,48 and in 1998 the gene was discovered and named parkin.45 Affected patients carry deletions or point mutations in various parts of the parkin gene.49,50 The absence of Lewy bodies in ARJPD may simply reflect the limited time over which the pathology has evolved. However, the relationship of parkin mutations to idiopathic PD has been highlighted by the identification of parkin mutations in apparently sporadic cases of PD and by the description of Lewy bodies in parkin positive patients with later-onset disease than ARJPD.51,52 Parkin mutations are a common cause of PD under age 25 years but rare over age 40 years.53,54 Parkin-related PD has been reported in multiple generations in families without consanguinity, suggesting a pseudo-autosomal dominant mode of inheritance for some mutations.55,56 Fluorodopa positron emission tomography (PET) in parkin patients demonstrates reduced uptake in the striatum, although there is some discordance regarding the symmetry and pattern of this reduction57,58 However, the rate of loss of fluorodopa PET signal was slower in the parkin patients than in sporadic PD.59 Asymptomatic heterozygous parkin mutation carriers had intermediate levels of striatal fluorodopa PET uptake compared with normal controls and homozygous symptomatic patients.58 This suggests an intermediate stage of nigrostriatal dysfunction that may interact with other genetic or environmental factors to induce PD. The frequency of heterozygous parkin mutation carriers is not known. PARK2 encodes parkin, which functions as an E3 ligase, ubiquinating proteins for destruction by the proteosome.60,61 Several substrates for parkin have been identified, including a 22-kDa glycosylated form of α-synuclein, parkin-associated endothelin receptor-like receptor (Pael-R), and CDCrel-1. Overexpression of Pael-R causes it to become ubiquinated, insoluble, and unfolded and leads to endoplasmic reticulum stress and cell death.62 It has been demonstrated to accumulate in its insoluble form in the brains of patients with parkin mutations, suggesting a possible toxic mechanism. CDCrel-1 is a protein involved in cytokinesis and may influence synaptic vesicle function.61 Overexpression of parkin protected against dopaminergic loss in rodents coexpressing α-synuclein, suggesting a protective role for parkin.63 A parkin knockout mouse model has been described.64 This showed an increase in striatal extracellular dopamine, a reduction in synaptic excitability, and a mild nonprogressive motor deficit at 2 to 4 months. There was no loss of dopaminergic neurons and no inclusion formation. Dopamine receptor binding affinities and parkin E3 ligase substrate levels were normal. Interestingly, these mice had decreased striatal mitochondrial respiratory chain function and reductions in specific respiratory chain and antioxidant proteins.65 Parkin knockout flies developed muscle pathology, mitochondrial abnormalities and apoptotic cell death.66 Overexpression of parkin in PC12 cells indicated that it is associated with the mitochondrial outer membrane.67 Parkin-positive patients have decreased lymphocyte

chapter 71 parkinson’s disease complex I activity.68 The ability of parkin to ubiquinate proteins may be impaired by S-nitrosylation, which in turn may be a consequence of excitotoxicity-mediated damage.69

UCH-L1 (PARK5) A further mutation in the gene encoding ubiquitin carboxyhydrolase (UCH)-L1 again supported the relevance of the ubiquitin-proteosomal system (UPS) in PD pathogenesis.70 UCH-LI is an enzyme that hydrolyzes the C-terminus of ubiquitin to generate ubiquitin monomers that can be recycled to clear other proteins. A missense mutation was identified in two siblings with typical PD in a German family demonstrating apparent autosomal dominant inheritance.70 Age at onset was 49 years in one and 51 years in the other. The mutant form of UCH-L1 was shown to have reduced enzyme activity resulting in impaired protein clearance through the ubiquitin-proteasome pathway. However, no other mutations in this gene have been identified in other families, suggesting it is a rare cause of PD.71,72 Given that no further cases of PD have been described with mutations in this gene, some doubt has been cast on the relevance of UCH-L1 to PD.

PINK1 (PARK6) The PARK6 locus (chromosome 1p3673) was first identified in a large consanguineous Italian family and subsequently in an additional three Italian families and others from Europe and elsewhere, including Asia.74-78 The mean age at onset ranges from 21 to 57 years. Progression is usually slow and patients exhibit a good response to levodopa. PARK6 mutations appear to be a rare cause of PD. The PINK1 (PTEN-induced kinase 1) gene is ubiquitously transcribed and is believed to encode a mitochondrial kinase.74,79 It is believed that PINK1 may play a role in protecting cells against stress conditions that affect mitochondrial membrane potential, but the downstream targets through which PINK1 mediates its protection have not been identified. As 11 of the 14 reported mutations fall into the kinase domain of PINK1,74,76,77 altered phosphorylation of target proteins probably represents a key pathogenic mechanism, leading to abnormal stress response and neurodegeneration. The reversible phosphorylation of proteins is an important method of regulating cellular activities.80 Up to 30% of eukaryotic proteins are phosphorylated,81 and there are more than 500 human genes encoding protein kinases.82 The phosphorylation of mitochondrial proteins is considered pivotal to the regulation of respiratory activity in the cell and to signaling pathways leading to apoptosis, as well as for other vital mitochondrial processes. For instance the phosphorylation of α-synuclein is an important step in mediating its toxicity (see earlier), and Lewy bodies do contain the phosphorylated form of this protein.

DJ-1 (PARK7) The PARK7 locus on chromosome 1p36, only about 25 cM from the PARK6 locus, was first identified in a small group of youngonset PD patients in a remote region of Holland.83 Average age at onset is 32 years, with a currently reported range of 25 to 40 years. Onset is asymmetrical, progress is slow, and there is a good response to levodopa. Tremor is infrequent, and psychiatric disturbances have been described in some. Fluorodopa

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PET scans demonstrate a symmetrical reduction in uptake. No pathological studies of PARK7 patients have been undertaken at the time of writing. PARK7 encodes DJ-1; mutations are autosomal recessive and comprise both deletions and point mutations that result in a loss or inactivation of the protein. Its function is unknown, but it is widely distributed and conserved. It can protect against toxicity mediated by free radicals and transfers to the outer mitochondrial membrane under conditions of oxidative stress.84,85 Wild-type DJ-1 is also located in the mitochondrial matrix and intermembraneous space, and this distribution is not altered by mutations in the protein.86

LRRK2 (PARK8) Mutations in the LRRK2 gene are the most common cause of either familial or “sporadic” PD identified to date. The LRRK2 G2019S mutation alone has been reported in 2.8% to 6.6% of autosomal dominant PD families87-89 and in 2% to 8% of sporadic cases.90-92 The G2019S mutation has variable penetrance, with 17% at 50 years and 85% at 70 years, a profile that mimics idiopathic, sporadic PD. Although other LRRK2 mutations are described, the G2019S mutation remains the most common cause of either sporadic or familial PD. This mutation has not been seen in Alzheimer’s disease or in parkinsonian syndromes other than idiopathic PD.93,94 Many of the reported cases of LRRK2 mutations have typical features of PD with asymmetrical onset of tremor, bradykinesia, and rigidity. As noted, the age at onset is variable with occasional very late onset cases89 and a report of one carrier male reaching 89 years with only subtle neurological changes.95 Patients have a good response to levodopa but develop motor complications including dyskinesias. Fluorodopa PET and imaging using ligands for the dopamine transporter with single-photon emission computed tomography (SPECT) demonstrate changes typical of those seen in idiopathic PD.96 Although all LRRK2 mutant brains examined to date demonstrate loss of dopaminergic neurons in the SNc, one of the morphological hallmarks of idiopathic PD, additional pathology may also be seen. Pure nigral neuronal degeneration was found in the first family linked to this locus97; neurofibrillary tangles, abnormal tau deposits, and widespread Lewy body synucleinopathy have been described in others, including one family with anterior horn cell loss.98,99 Three brains of “sporadic” PD with G2019S LRRK2 mutations have had pathological examination and all have demonstrated nigral neuronal loss and Lewy body formation typical of PD.90 All of these subjects had PD based on clinical criteria. The LRRK2 gene encodes a 286-kDa cytoplasmic protein that is widely expressed in the brain.100 LRRK2 is a member of the ROCO protein family and appears to have multiple functions, at least by virtue of its predicted structure. These include a Ras/GTPase domain involved in cytoskeletal responses to external stimuli, vesicular trafficking and the stimulation of stress-activated kinase.101 The leucine-rich motif may have numerous functions, including protein-protein interactions and substrate binding for ubiquitination. The LRRK2 kinase domain belongs to the MAPKKK family of kinases with catalytic activity for both serine/threonine and tyrosine residues. The G2019S mutation changes a highly conserved glycine at the start of the kinase activation segment, and it has been postulated that this has an activating effect causing a “gain of

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function” compatible with its autosomal dominant inheritance pattern.89 LRRK2 also has a WD40 domain, which again may be involved in cytoskeletal assembly and signal transduction.

PARK9, PARK10, and PARK11 The PARK9 locus on chromosome 1p36 was described in an autosomal recessive, juvenile-onset parkinsonian disorder with pyramidal features, ophthalmoplegia, and dementia.102,103 PARK10 on chromosome 1p32 was identified in the families of Icelandic PD patients with late-onset disease.104 PARK11 was obtained by association studies, and little information is available on phenotype.

Genetic Associations Only a minority of cases of PD are part of a clear familial pedigree. Some of the single-gene mutations described above may account for a proportion of the remaining patients. However, our current understanding is that such single-gene causes of PD will remain in the minority. Thus, the large proportion of PD patients may develop their disease as a result of environmental factors, polygenic influences, or a combination of the two. There have been several genetic association studies attempting to determine significant polymorphisms that may increase or decrease the risk for PD. Further evidence for the role of genes in PD comes from genome-wide screens.105,106 The first found 174 families with a minimum of two clinically affected individuals with PD per family and identified a marker from the intronic region of parkin in an early-onset group and a region on 9q in a dopa-resistant group. In the total sample, areas of interest were found on chromosomes 5q, 8p, and 17q. Data from the second genome-wide linkage study used a sample of 113 affected sibling pairs with PD and identified suggestive linkage on chromosomes 1, 9, 10, and 16, with no evidence implicating the regions containing parkin, a-synuclein, or tau genes. However, additional studies have shown that asynuclein promoter region variants can influence the risk for PD.107,108 Those alleles that increase α-synuclein expression lead to an increased risk for developing PD, an observation in line with the multiplications of the gene causing familial PD (see earlier). Similarly, variants that influence parkin expression can also modulate the risk for PD: in this case, those alleles that lower parkin expression enhance the risk for PD.109 Mutations in the gene for glucocerebrosidase have been associated with an increased risk for PD among Ashkenazi Jews.110 Glucocerebrosidase deficiency causes type 1 Gaucher’s disease. Thirty-one of 99 Ashkenazi PD patients had one or two mutant alleles of the glucocerebrosidase gene (GBA), and 95 of 1543 controls (Ashkenazi) were carriers. Those with GBA mutations had onset of their PD around age 60 years and clinical features typical of idiopathic disease.

Genetic Causes of Parkinsonism Several disorders that include parkinsonism in their phenotype have been characterized at the genetic level (Table 71–2). The frontotemporal dementias are discussed in detail in Chapter 73, the dystonias in Chapter 35, Huntington’s disease in Chapter 67, Wilson’s disease in Chapter 108 and the inherited ataxias in Chapter 68, so these will be discussed only briefly here.

T A B L E 71–2. Secondary Familial Parkinsonism • • • • • • • • • •

PSP, CBD—tau H1 haplotype FTDP-17 complex—tau mutation X-linked parkinsonism-dystonia (Lubag) Spinocerebellar ataxia (SCA 2) in Chinese—ataxin 2 SCA 3/MJD—ataxin 3 Fragile X mental retardation—CGG repeat in FMR-1 gene NB premutations Wilson’s disease—P-type ATPase Hallevorden-Spatz syndrome—PANK2 Dopa responsive dystonia—GTP cyclohydrolase 1 Dystonia-parkinsonism—Na-K pump mutation

The frontotemporal dementias and parkinsonism linked to chromosome 17 (FTDP-17) usually have onset in the fifth decade, although the age range is wide (25 to 75 years). Symptoms are of gradual onset and include motor dysfunction in the forms of parkinsonism, behavioral, and personality disorders and cognitive decline.111 Patients may exhibit apathy, depression, aggression, disinhibition, obsessive-compulsive disorder, executive dysfunction, and nonfluent aphasia. Patients and families tend to fall into either the predominantly parkinsonian or dementia types. Pathological examination shows severe frontotemporal atrophy and degeneration that includes the substantia nigra and the basal ganglia. There are tau accumulations in the remaining neurons and glia. FTDP-17 is autosomal dominant and is due to mutations in the tau gene. Although the genotype-phenotype relationship is relatively loose, those with the parkinsonism predominant form more commonly have exon 10′ or 5′ mutations. Certain of the spinocerebellar ataxias (SCAs) are associated with parkinsonism and indeed may even manifest with this feature. SCA2 dopa-responsive parkinsonism is most often observed in the Chinese Asian population.112,113 Patients may have asymmetrical disease; a resting tremor and the presence of ataxia and abnormal eye movements may make differentiation from other parkinsonian disorders difficult if genetic testing is not performed. Imaging with fluorodopa PET has produced variable results from changes typical of those seen in PD114 to severe involvement of the caudate.115 The demonstration of an abnormally expanded CAG repeat in the ataxin-2 gene confirms SCA2. SCA3 (Machado-Joseph disease) mutations in conjunction with parkinsonism have been found most often in Caribbean populations. Fragile X mental retardation complex is a common cause of mental retardation. It is an X-linked disease caused by an abnormal CGG expansion in the FMRI gene, which results in reduced gene expression. Intermediate length repeats can be a cause of tremor-ataxia parkinsonism in men. About 60% of these patients have a postural tremor, ataxia, autonomic dysfunction, impaired cognition, and symmetrical parkinsonism.116,117 Patients with very large expansions of CAG repeats in the huntingtin gene can present with juvenile-onset Huntington’s disease, known as the Westphal variant. The predominant features are those of bradykinesia and rigidity with little, if any, response to levodopa. Dystonia in association with parkinsonism is seen in a number of genetic diseases. X-linked dystonia parkinsonism was first reported in men from an island in the Philippines who

chapter 71 parkinson’s disease had early onset of action tremor, dystonia, blepharospasm, and parkinsonism in 40% (Lubag) with poor response to levodopa. This disease is referred to as DYT3.118 Rapid-onset dystonia parkinsonism (DYT12) is an autosomal dominant disorder associated with bulbar features including dysarthria and dysphagia, dystonia, postural instability, and bradykinesia. Symptoms progress rapidly over hours and may be precipitated by physical or emotional stress. There is usually a poor response to levodopa. Mutations in the ATP1A3 gene that encodes a subunit of the sodium-potassium channel have been described in this disorder.119 Mitochondria have their own DNA, and the mitochondrial genome encodes 13 proteins of the oxidative phosphorylation system in addition to 2 ribosomal and 22 transfer RNAs. The discovery of complex I deficiency in PD substantia nigra (see later) raised the possibility that the mutation of genes (nuclear or mitochondrial) encoding complex I subunits might be involved in determining the enzyme’s defective activity. As mitochondrial DNA (mtDNA) is inherited in a strictly maternal pattern, if there were full penetrance of such a mtDNA gene defect, mitochondrial inheritance should be identifiable in pedigrees with parkinsonism. Such maternal inheritance has been described in PD120 but appears rare. However, it is known that 40% of patients with proven mitochondrial diseases and mtDNA mutations present as sporadic cases. Thus maternal inheritance is not a sine qua non of mtDNA gene defects. However, molecular genetic investigations of mtDNA have so far been unable to identify any specific mutation that clearly co-segregates with PD. Studies using age-matched controls found no increase in the 5-kilobase mitochondrial deletion mutation in PD substantia nigra.121 Several studies have sequenced mtDNA in PD, but these have all used unselected patients in terms of their complex I activity.122,123 Although some reports have suggested an increased frequency of certain mtDNA polymorphisms in PD, this has not been replicated in all studies.124-128 Two studies have demonstrated a relationship between mtDNA haplotypes and the risk for developing PD. The first showed a reduced risk for PD in individuals with haplotypes J and K,129 and the second, a 22% decrease in PD in those with the UKJT haplotype cluster.130 In contrast, a smaller study reported an increased risk for PD with haplotypes J and T.131 Mutations in the gene for mtDNA polymerase gamma (POLG) have been demonstrated in patients with progressive external ophthalmoplegia and parkinsonism. Autosomal dominant or recessive inheritance of progressive external ophthalmoplegia with age at onset ranging from 10 to 54 years was followed some years later (range, 6 to 40 years) by the development of an asymmetrical, levodopa-responsive bradykinetic rigid syndrome together with resting tremor in some patients. Additional features included variable limb, pharyngeal or facial weakness, cataracts, ataxia, peripheral neuropathy, and premature ovarian failure.132 Muscle biopsy demonstrated ragged red, cytochrome oxidase–negative fibers in all patients with multiple mtDNA deletions on Southern blotting. Symmetrically reduced striatal 18-fluorodopa PET was seen in two patients. Brain histology was available on an additional two patients; both showed severe loss of substantia nigral dopaminergic neurons but without the development of Lewy bodies or other synuclein aggregates. Four families had the same A2864G mutation inherited in autosomal fashion in three and with a founder effect in the fourth. Mutations in the exonuclease or

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polymerase portions of the gene were identified in the autosomal recessive families. Another patient with autosomal dominant progressive external ophthalmoplegia parkinsonism and an A2492G mutation has been reported.133

Environmental Factors Several studies have sought to define the environmental contributions to the etiology of PD. A rural residency appears to increase the risk of the development of PD and, in particular, young-onset PD.134-136 However, this finding has not been confirmed in all studies.137 Rural living is associated with farming and pesticide use, and an association with the agricultural industry has been found with increased incidence in PD patients.138-140 In addition, another lifestyle study showed increased herbicide exposure in patients with PD.141 Organochloride pesticides were identified as risk factors in a German case-control study142 with the offending agent being identified as the organochloride dieldrin, which was found in 6 of 20 PD brains and none of 14 control brains.143 Another study identified dithiocarbamates as a risk factor for PD,137 a compound that has also been shown to enhance 1-methyl 4-phenyl-1,2,3,6tetrahydropyridine (MPTP) toxicity.144 Some studies have found that the significant association of PD with farming as an occupation cannot be accounted for by pesticide exposure alone.139 Another rural factor that has been linked to PD is the consumption of well water,145 although this may simply be further evidence in support of herbicides or pesticides as etiological factors for PD. Carbon monoxide is a common environmental pollutant that may also play an important role in cell signaling. Acute carbon monoxide poisoning results in the complexing of carbon monoxide with the ferrous iron, protophorphyrin IX, and this prevents the carriage of oxygen. In addition, carbon monoxide is a potent inhibitor of cytochrome oxidase (complex IV) of the mitochondrial respiratory chain. Survivors of carbon monoxide poisoning have developed parkinsonism within a few days or weeks of exposure.146 The affected patients show necrosis of the globus pallidus on computed tomography scanning and magnetic resonance scanning. Pyrethroid pesticides, when administered parenterally to rodents, cause a reduction in tyrosine hydroxylase–positive dopaminergic neurons in the nigrostriatum and an increase in dopamine transporter and brain-derived neurotrophic factor expression.147-150 These results indicate that commonly used pesticides can cross the blood-brain barrier and induce damage to the basal ganglia. Rotenone, a pesticide commonly used in the United States, when infused into rodents, can result in degeneration of nigrostriatal neurons and the formation of αsynuclein–rich Lewy-like inclusions.151 Paraquat, a widely used herbicide, has been shown to increase α-synuclein fibril formation in vitro in a dose-dependent fashion and to increase α-synuclein protein expression in mice with the reversible development of aggregates in substantia nigra dopaminergic neurons.152 Anonnacin, a component of sour-sop in the Caribbean, has been shown to produce a PD-like phenotype in humans and nigrostriatal loss in animals.153 MPTP, a meperidine analog designer drug, is known to produce parkinsonism in humans, other primates, and rodents through uptake and conversion mechanisms that target the nigrostriatal pathway,154 It is noteworthy that these agents result in inhibition of

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mitochondrial NADH CoQ reductase (complex 1) and are free radical generators, features of direct relevance to idiopathic PD. Manganese is a constituent of several pesticides and herbicides as well as being an anti-knock additive to lead-free petrol. Manganese is neurotoxic to the basal ganglia and produces a parkinsonian syndrome with damage predominantly to the globus pallidum. There have been numerous reports of manganism developing among individuals exposed to manganese dioxide ore, usually by inhalation of manganese dust. Exposure is typically chronic over 6 months to 16 years, and the onset of manganism is slow, beginning with apathy, muscle weakness and cramps, and general irritability. Progression occurs and is characterized by dysarthria and psychosis followed by severe rigidity, anarthria, and dystonia.155 Manganese predominantly appears to affect the globus pallidus with sparing of the substantia nigra.156 There has been interest in the potential for manganese containing steel to induce parkinsonian features in welders,157 although this association is controversial. At present, it is not known if manganese-containing pesticides can induce PD. Between 1917 and 1919, there was an epidemic of an influenza-like illness starting in Austria and France and spreading throughout Europe and North America. The illness was characterized by fever, headache, lethargy, and paralysis, particularly of the extraocular muscles. Following this, stupor, coma, sleep disturbance, and seizures could occur. Ocular gyric crises were seen in a high proportion of patients. Mortality was 30% to 40%, and parkinsonism developed in the majority of survivors over the next 10 years.158,159 The specific agent causing encephalitis lethargica was never identified. Although there has been no outbreak of encephalitis lethargica since the 1920s, infection as a cause for PD has still attracted some attention. There are numerous anecdotal reports of infections, particularly encephalitis, being associated with parkinsonism. These include a wide variety of viruses, bacteria (including Borrelia burgdorferii [Lyme disease]), and even fungi, such as Cryptococcus or Aspergillus. However, there is no evidence to suggest that any of these are relevant to the vast majority of patients with idiopathic PD. For instance, patients who develop PD before the age of 40 have no greater history of central nervous system infection than do patients who develop the disease over the age of 60. Intrauterine exposure to, for instance, the influenza viruses pandemic from 1890 to 1930 has not been supported by any association with year of birth.160 Searches for viral particles of antigens within the brains of patients with PD have not proved rewarding.161 Two environmental factors are recognized to lower the risk for PD: cigarette smoking162 and coffee drinking.163 The mechanisms through which they can reduce risk are not known. Coffee drinking appears more protective for men, so it is possible that there is an interaction with endocrine factors. There is evidence of active inflammatory change in the substantia nigra at the time of death in PD, with microglial activation, and expression of proinflammatory cytokines.164-166 The role of this inflammatory change is unknown but has been believed to be relevant to pathogenesis and neuronal damage. Similar changes have been seen in AD brain and prompted retrospective analyses that subsequently demonstrated the potential for anti-inflammatory agents to reduce the risk for AD, although this effect remains controversial.167,168 A similar study in PD has also shown that use of a nonsteroidal anti-inflammatory drug

two or more times per week can produce a 45% lower risk for PD.169

PATHOGENESIS Several biochemical abnormalities have now been identified in PD substantia nigra. These include abnormal iron accumulation, alteration in the concentration of iron binding proteins, evidence for increased oxidative stress and oxidative damage, and mitochondrial complex I deficiency. There is also evidence of increased nitric oxide formation and the generation of nitrotyrosine residues within PD substantia nigra. Each of these factors may form part of the pathogenesis of nigral cell death as well as potentially being etiological factors in themselves. Several of these mechanisms have already been discussed in the section on genetic causes of PD above, given that the monogenic forms of PD appear to involve identical pathogenetic pathways that are seen in idiopathic PD.

Iron High iron concentrations are found in control substantia nigra, globus pallidus and striatum. In PD, there is a 35% increase in substantia nigra iron levels.170,171 Other degenerative diseases involving cell loss in the basal ganglia also showed increased iron in these areas, such as progressive supranuclear palsy and multiple system atrophy. These studies suggested that increased iron concentrations were a reflection of neuronal cell loss rather than any specific pathogenetic factor. High concentrations of iron were also found in macrophages, astrocytes, and reactive microglia in the PD substantia nigra.172 One study, however, using x-ray microanalysis, found increased levels of iron in neuromelanin. In this respect, neuromelanin could again act as a toxic sink.173 In contrast, another study found no difference in iron concentrations between melanized and nonmelanized cells in controls but a significant increase in the cytoplasm of dopaminergic neurons.174 However, there was no apparent correlation between the high concentrations of iron and morphological alterations in the neurons that might suggest degeneration. Iron is capable of catalyzing oxidative reactions that may generate hydrogen peroxide and the hydroxyl ion. O2 + Fe2+ ↔ O2•− + Fe3+ H2O2 + Fe2+ ↔ OH• + OH− + Fe3+

Thus, if iron is available in a free and reactive form, it has the potential for exacerbating oxidative stress and damage. Iron is normally bound to ferritin, which exists in two forms, H and L. Most brain ferritin is in the H form. Three studies have now been undertaken on ferritin concentrations in PD brain. One used a polyclonal antibody predominantly against L-ferritin and found a significant decrease in the concentration of this protein in PD substantia nigra and other areas.175 This decrease was not seen in other parkinsonian syndromes such as progressive supranuclear palsy or multiple system atrophy. Another study,176 again using an antibody against mainly L-ferritin, found an increase in the number of ferritin-positive microglia in substantia nigra. This latter work used immunohistochemistry and therefore is not directly quantifiable. In addition, this study incorporated parkinsonian syndromes as well as idiopathic PD into the disease group (M. Youdim, personal

chapter 71 parkinson’s disease T A B L E 71–3. Oxidative Damage in Parkinson’s Disease • • • • • • • • •

Decreased PUFA Increased malondialdehyde Increased superoxide dismutase Increased lipid hydroperoxide Decreased reduced glutathione Increased OH8dG levels Increased free iron Increased protein carbonyls Increased nitrotyrosine

communication). A third and more comprehensive study involved monoclonal antibodies against both L and H ferritin together with a double capture technique incorporated into an enzyme-linked immunosorbent assay study together with Western blotting studies of PD substantia nigra protein.177 The results did not identify any significant difference in ferritin levels between control and PD substantia nigra. Thus, there are no hard data that ferritin levels are abnormal in PD. Indeed, ferritin has such a high iron binding capacity that the increase of iron noticed in PD brain may not require any increased buffering capacity from ferritin.

Oxidative Stress and Damage There are several lines of evidence that suggest increased oxidative stress and oxidative damage to biomolecules in PD substantia nigra (Table 71–3). 1. Glutathione (GSH) in its reduced form is an important compound in antioxidant defense and in the repair of oxidized proteins. It is oxidized to its disulfide, GSSG. High GSH/GSSG ratios are maintained by glutathione (GSSG) reductase, which converts GSSG to GSH. There is evidence that GSH levels are decreased in PD substantia nigra.178,179 Total GSH levels appear to be slightly lower in PD substantia nigra. This combination suggests enhanced free radical generation in the PD nigra. 2. Superoxide dismutase (SOD) exists in cytosolic (copper/zinc [Cu/Zn]) SOD and mitochondrial manganese (Mn) SOD forms and is important in dismutating superoxide ions. Thus, levels of this enzyme are indicative of superoxide generation. Both copper/zinc and manganese SOD appear to be increased in PD substantia nigra.180,181 High levels of copper/zinc SOD are expressed at the mRNA level in control and PD nigral pigmented neurons.182,183 Taken together, these observations suggest that PD nigral neurons in particular are exposed to increased superoxide generation. 3. Levels of polyunsaturated fatty acids,184 malondialdehyde, and hydroperoxides are increased in PD substantia nigra. These are the products of free radical damage to lipid membranes and imply oxidative damage in PD. Free radical damage to DNA produces intracellular 8-hydroxydeoxyguanosine. Elevated concentrations of this product are seen in PD in the nuclear DNA and particularly in the mtDNA fractions from patients with PD.185 Levels of these products are also particularly high in control brains in the substantia nigra and striatum, confirming that, even in controls, this area of the brain is a site of high oxidative stress.

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The free radical gas nitric oxide (NO•) is present in many tissues, including the central nervous system. NO• is generated by the conversion of L-arginine to L-citrulline by nitric oxide synthase (NOS). At least three NOS isoforms are recognized and are all expressed within the brain. NO• acts as an atypical molecular messenger but at higher concentrations may have a toxic role and be implicated in the neurodegeneration that occurs in PD. As a free radical, NO• could potentially contribute to dopaminergic neuronal death by mechanisms such as increased lipid peroxidation, release of iron(II), and damage to DNA. It can also inhibit a number of enzymes such as cytochrome c oxidase and superoxide dismutase and affects mitochondrial function by inhibiting complexes II, III, and IV. Animal studies have implicated NO• in nigrostriatal neuronal loss. In addition to its possible neuroprotective effect with regard to 1-methyl-4 phenylpyridinium (MPP+) toxicity, 7nitroindazole (7-NI) also protects in the methamphetamine animal model of PD.186 NOS activity is at its highest in the nigrostriatal system in nonhuman primates and humans. Attempts to demonstrate altered levels of NO• in the brains of PD patients have been inconclusive with both decreased and increased levels of cerebrospinal fluid nitrate, a marker of NOS activity, being seen.187-189

Mitochondrial Dysfunction The first link between mitochondria and PD was made in 1989 when a defect in the activity of respiratory chain protein complex I was identified in substantia nigra from patients with PD.190,191 This study has been expanded over the years, and results to date show that there is a specific defect of approximately 35% complex I deficiency in PD nigra.177 This defect in complex I activity in PD brain does not affect any other part of the respiratory chain. In addition, no defect in mitochondrial activity has been identifiable in any other part of PD brain, including the caudate putamen, globus pallidus, tegmentum, cortex, cerebellum, and substantia innominata.192 Following the report of complex I deficiency in PD substantia nigra, respiratory chain abnormalities were described in skeletal muscle mitochondria from PD patients. This particular area has proved very contentious, with several groups either describing similar defects or no abnormality whatsoever (see Schapira193 for review). Two magnetic resonance spectroscopy studies on skeletal muscle mitochondrial function in PD have shown conflicting results.194,195 Finally, mitochondrial complex I deficiency was also identified in platelet mitochondria of PD patients.196-198 In contrast to skeletal muscle, there is a consensus among several laboratories that complex I deficiency does exist in PD platelet mitochondria. The majority of studies, however, suggest that this deficiency, as least based on a groupto-group analysis, is modest (about 20% to 25%) (see Schapira193 for review). The complex I deficiency in PD lacks the sensitivity to allow its use as a biomarker of PD. The discovery of complex I deficiency in PD and the role of mitochondria in PD has been enhanced by the subsequent identification of mutations in genes encoding mitochondrial proteins, such as PINK1 and DJ1, as causes of autosomal recessive PD, and by the mitochondrial abnormalities associated with a-synuclein and parkin expression (see earlier). Furthermore, the environmental toxins causing parkinsonism identified so far are all mitochondrial inhibitors of complex I, such as MPTP, rotenone, and annonacin.

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CLINICAL FEATURES Presymptomatic Epidemiological studies have been able to identify a number of clinical features that may predate the clinical diagnosis of PD by several years. In some part, these represent “risk” factors, but they also reflect known pathological changes that are believed to represent early PD. Olfactory dysfunction is common in PD and eventually affects up to 90% of patients.199 It has been suggested that hyposmia may be a preclinical marker for PD,200,201 and olfactory deficits have been reported in asymptomatic relatives of patients with PD, some of whom subsequently developed PD.202,203 A prospective study involving 361 asymptomatic relatives of PD patients identified 40 with hyposmia.9 Within 2 years of follow-up, 10% of this subgroup had developed PD and another 12% had detectable presynaptic abnormalities on their dopamine transporter SPECT scan. No relative with normal smell had an abnormal SPECT scan or developed PD. It is tempting to relate these findings to Braak’s findings of Lewy body distribution in the olfactory nucleus in stage 1. Olfactory dysfunction has also been reported in diffuse Lewy body disease and multiple system atrophy. Vascular parkinsonism, cortocobasal degeneration, progressive supranuclear palsy, and parkin-associated PD usually have intact olfactory function.204-206 Rapid eye movement (REM) behavior disorder (RBD) is a common sleep disorder in PD. It is characterized by loss of the normal skeletal muscle atonia during REM sleep, thus enabling patients to physically enact their dreams, which are often vivid or unpleasant.207-210 Vocalizations (talking, shouting, vocal threats) and abnormal movements (arm/leg jerks, falling out of bed, violent assaults) are commonly reported by bed partners. In PD, up to one third of patients meet the diagnostic criteria of RBD.207,208 RBD appears to frequently precede the development of motor signs of PD and longitudinal data that suggest that RBD heralds the onset of motor symptoms in up to 40% of PD patients.211,212 In patients with isolated RBD, imaging studies have indicated a small but significant reduction in striatal dopaminergic uptake that may suggest preclinical PD.213,214 The anatomical basis of RBD is believed to involve the pontomedullary area resulting from degeneration of lower brainstem nuclei like the pedunculopontine and subceruleal nucleus; this area is consistent with Braak stages 1 and 2. Constipation often precedes the diagnosis of PD.215-218 A prospective study of 7000 men for 24 years assessed inter alia for bowel habits found that those with constipation (less than one bowel movement per day) had a threefold risk of subsequently developing PD.219 The mean interval between the administration of the bowel questionnaire and the development of PD was 10 years. Colonic dopaminergic neurons degenerate with Lewy body formation in PD, although constipation does not respond well to dopaminergic treatment.220-222

Motor Features The typical early motor features of PD are bradykinesia, rigidity, and tremor. Postural instability, along with several additional motor and nonmotor symptoms, generally develop later in the disease.

Bradykinesia manifests in many ways, including a difficulty or delay in initiating voluntary movement, multitasking, or undertaking rapid motor tasks in sequence. A poverty of movement becomes evident, especially to family and friends. This may be represented by a reduction in spontaneous gestures, decreased facial movement, and blinking. Involvement of the limbs may be seen with impaired fine movements of a hand and in the dominant hand leads to progressive micrographia. There are problems with fastening buttons or a brassiere, tying laces, or using a screwdriver. The patient’s gait becomes slow, small stepped, and shuffling, with the patient sometimes “chasing his own center of gravity.” The arm on the affected side does not swing as much as the contralateral arm. The patient may complain of difficulty turning over in bed or rising from a chair. Freezing usually occurs later in the course of PD, but some patients experience “gait ignition failure,” especially when approaching a doorway. Observation of the patient’s gait can reveal important features that raise the clinician’s suspicion of a diagnosis of PD. Physical examination for bradykinesia will evaluate rapid alternating movements and, in idiopathic PD, show asymmetry of speed, amplitude, and rhythm in the early stages. Examples of helpful maneuvers include finger or heel tapping, pronation-supination of the outstretched arms, and rapid flexion-extension of the extended fingers at the metacarpophalangeal joints. Rigidity represents an increase in tone that is present throughout the range of movement and is independent of the speed at which the limb is moved. The tremor of PD may superimpose on rigidity to produce cog-wheeling, and this phenomenon may be absent if there is no tremor. Examination of the wrist with gentle flexion-extension movements is the best means to elicit cog-wheeling, and this can be repeated at the elbow. Rigidity affects the patient’s posture, producing a flexion at most joints including the spine, and this produces the simian posture typical of PD. An extreme form of this is known as camptocormia.223 Postural abnormalities also affect the distal limbs with extension of the fingers and flexion of the metacarpophalangeal joints or dorsiflexion of the great toe (striatal hand or toe). The development of an asymmetrical intermittent resting tremor at 4 to 6 Hz is estimated to be a manifesting feature in 70% of PD patients. In addition, there is often a higher frequency (about 12 Hz) small-amplitude postural tremor.224 The resting hand tremor is referred to as “pill-rolling” in the style of the pharmacists of the nineteenth century, who would prepare their tablets by hand. A tremor may affect other parts including the foot or leg (in which it may first manifest), lips, jaw, and tongue.225 A head tremor, titubation, is more suggestive of essential tremor. The resting tremor is exacerbated by physical or emotional stress and can in the early stages be voluntarily inhibited for short periods. The tremor usually becomes bilateral after about 5 to 6 years, although the first affected side most often remains the more severe.226

Nonmotor Features The widespread and progressive neurodegeneration in the PD brain leads to the emergence of a variety of features that are collectively grouped under the title of nonmotor symptoms. These are predominantly, but not exclusively, the consequence of loss of nondopaminergic pathways (Table 71–4). The

chapter 71 parkinson’s disease nonmotor symptoms of PD range from cognitive problems such as apathy, depression, anxiety disorders, and hallucinations to fatigue, gait and balance disturbances, hypophonia, sleep disorders, sexual dysfunction, bowel problems, drenching sweats, sialorrhea, and pain. These symptoms are often the most troubling for patients and contribute significantly to morbidity and impaired quality of life.227 Diplopia is a frequent symptom even in early PD, although the neurological basis is not known. Abnormalities of sleep are common in PD and are the result of a combination of the natural consequences of aging, the underlying disease pathology,228 motor and nonmotor complications,229,230 and drugs.231 Disordered sleep often results in excessive daytime sleepiness, and this in turn may be compounded by the sedative effect of dopaminergic drugs.232 Excessive daytime sleepiness and involuntary dozing affects up to 50% of PD patients and may be preclinical markers.233 In some, excessive daytime sleepiness has been linked to the development of sudden onset of sleep and a pattern reminiscent of narcolepsy with abnormal sleep latency period (<5 minutes) in 30% of PD patients. Polysomnographic studies have showed transition from wakefulness to sleep stage 2 within seconds without the sudden onset of REM sleep.234,235 Following reports of road traffic accidents caused by “sudden irresistible attacks of sleep” in eight PD patients, a large body of research focused on the possible effects of dopaminergic drugs and disease progression and the occurrence of sudden onset of sleep.232,236-238 The

T A B L E 71–4. Symptoms Less Responsive to Dopaminergic Therapy Motor Mental changes

Autonomic nervous system dysfunction

Sensory phenomenon Sleep disturbances

Postural instability Gait disorders Speech problems Dementia Depression Anxiety Apathy Orthostatic hypotension Constipation Sexual dysfunction Urinary problems Sweating Pain Dysesthesias Sleep fragmentation Sleep apnea REM behavioral disorder

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issue remains unclear, although is now regarded as part of the nonmotor complex of the disease progression in PD.239 Sexual and bladder dysfunction is common and occurs in both sexes. The dopaminergic treatment of PD may lead to increased sex drive, but the effects of the disease often result in impaired sexual performance.240 Bladder abnormalities particularly cause problems at night with nocturia, which when associated with bradykinesia during nocturnal “off” causes considerable discomfort. Pain is a frequent symptom in PD, and some patients present especially with shoulder pain. Pain, anxiety, akathisia, respiratory distress, depressive mood swings, and slowed and impaired thought are symptoms that may be experienced during “off” periods and that will respond, at least in part, to dopaminergic therapy.241-243

DIFFERENTIAL DIAGNOSIS The diagnosis of PD is best predicted by the presence of an asymmetrical bradykinetic rigid syndrome with a resting tremor and a good response to levodopa.244 The diagnostic specificity of these criteria is estimated at 98.6%, and sensitivity, at 91.1%.245 However, many patients still present a diagnostic challenge, especially those who have no tremor or those with marked asymmetrical tremor but limited bradykinesia or rigidity246 (Tables 71–5 and 71–6). Imaging studies on early PD patients recruited into neuroprotection trials indicate that approximately 10% have normal PET or SPECT scans.247,248 The Parkinson-plus disorders, dementia with Lewy bodies, Wilson’s disease, and tremor are covered in Chapters 72, 70, 108, and 33, respectively, and some of the additional diseases that may mimic PD have been discussed earlier. The clinical features of the main disorders that require differentiation from PD are covered only briefly in the context of diagnosis (see Table 71–4).

T A B L E 71–5. Differential Diagnosis of Parkinson’s Disease • • • • • • • • • •

Drug-induced parkinsonism Essential tremor Multiple system atrophy Progressive supranuclear Corticobasal degeneration Vascular parkinsonism Diffuse Lewy body dementia Post-encephalitic parkinsonism Wilson’s disease Toxins, such as carbon monoxide, manganese

T A B L E 71–6. Clinical Features of Parkinsonian Disorders Multiple System Atrophy

Corticobasal Degeneration

Progressive Supranuclear Palsy

Cerebellar, pyramidal signs Anterocollis Early falls Autonomic failure Bulbar features Myoclonus

Asymmetrical onset Apraxia Aphasia Cortical sensory loss Alien limb Dystonia Focal myoclonus

Down gaze palsy Staring appearance Pseudobulbar features Axial rigidity Early falls

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Drug-Induced Parkinsonism Any dopamine receptor blocker has the potential to induce parkinsonism. In practice, the most common causes are the major neuroleptics, but drugs such as metoclopramide can also induce symptoms that may be confused with PD. A drug history is essential when considering PD. Clinical clues for druginduced parkinsonism include symmetry and the absence of a resting tremor, although their presence does not exclude a drug cause. The presence of akathisia and orofacial dyskinesias supports a drug cause.249 Withdrawal of the drug may result in remission, although this can take months or years, and in some patients, the parkinsonism and related movement disorders are permanent.

Essential Tremor Typical essential tremor comprises a bilateral usually symmetrical, visible, and persistent upper limb postural or kinetic tremor.250 Bradykinesia, rigidity, and postural abnormalities are not present. The tremor of essential tremor is present at rest in only 10% of cases251 but, when present or when asymmetrical, can cause difficulty with a distinction from PD, although such patients usually evolve to PD.252 The presence of a head or voice tremor, a strong and usually autosomal dominant family history, and improvement with alcohol all favor a diagnosis of essential tremor. In contrast, clear asymmetry, the presence of bradykinesia or rigidity, and leg tremor support a diagnosis of PD.

limb), dystonic upper limb posturing with irregular jerks, cortical sensory deficits, primary progressive aphasia, apraxia, and parkinsonism. Tremor is uncommon; cognitive disturbance, particularly involving frontal lobe function, is often seen and frequently is the manifesting sign.258 The disease is rapidly progressive, and there is no or only a very poor response to levodopa.

Vascular Parkinsonism This is a diagnosis that can only be made with confidence in the clinic when there is evidence of widespread vascular disease and usually a history of stepwise progression. The clinical features are usually bilateral if not symmetrical; tremor is rare and gait abnormality is common. The latter manifests as a type of apraxia with a wide-based small stepping gait and freezing, socalled lower body parkinsonism.259 There may be a mild to moderate response to levodopa.

Dementia With Lewy Bodies Dementia will develop in approximately 30% to 40% of PD patients, although it occurs at least 12 months (and usually longer) after the appearance of the motor features.260,161 The clinical diagnosis of dementia with Lewy bodies will be based on the presence of a progressive dementia with fluctuating attentional and visuospatial components, hallucinations, and parkinsonism that usually develops within 1 year of the dementia.

Multiple System Atrophy Multiple system atrophy is a multicentric neurodegenerative disease that includes degeneration of the SNc and hence clinical features that can mimic PD. However, multiple system atrophy patients exhibit additional symptoms that may be predominantly cerebellar or parkinsonian with autonomic failure.253 Onset is similar in age to PD. The diagnosis of multiple system atrophy is supported by the presence of early cerebellar signs, autonomic failure such as bladder dysfunction or postural hypotension, early falls, pyramidal signs, myoclonus, bulbar features, pronounced anterocollis, and a rapid course. The response to levodopa is usually limited in degree and time,254 although some patients can develop dyskinesias, particularly of the orofacial and cervical musculature; they are rare.255

Progressive Supranuclear Palsy Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) typically manifests with gaze palsy, particularly of the vertical downward plane, a staring appearance, symmetrical parkinsonism, and pseudobulbar palsy.256 Axial greater than limb rigidity and falls within the first year are suggestive of progressive supranuclear palsy.257 Response to dopaminergic therapy is poor.

Corticobasal Degeneration Corticobasal degeneration usually manifests as an asymmetrical disorder that may include abnormal limb posturing (alien

INVESTIGATION The diagnosis of PD remains essentially a clinical one with investigations mainly being used to exclude other diagnoses. Imaging by computed tomography is normal in idiopathic PD. There may be superimposed changes of atrophy or cerebrovascular disease, although in the case of the latter this should not be so severe as to raise the diagnosis of vascular PD. CT is helpful in excluding normal pressure hydrocephalus or the rare case of tumor (usually benign) causing parkinsonian features. Magnetic resonance imaging in routine clinical practice has greater definition than CT but does not reveal any specific features for PD. However, magnetic resonance imaging may be useful in helping to differentiate PD from other parkinsonian syndromes. Patients with multiple system atrophy may demonstrate brainstem, cerebellar, and dentate atrophy with hyperintensity of the middle cerebellar peduncle, cerebellum, inferior olives, and pontine fibers producing the “hot cross bun” sign.262,263 There may be putaminal atrophy or lateral putaminal hyperintensity (slit sign). Magnetic resonance volumetry is the most sensitive in distinguishing PD, multiple system atrophy, and progressive supranuclear palsy but is not widely available.264 Imaging with SPECT for the dopamine transporter has become increasingly available and can be used to differentiate PD from essential tremors or drug-induced PD, even in early disease. The signal in PD shows an asymmetrical reduction in transporter binding, particularly affecting the putamen (Fig. 71–3). It cannot distinguish PD from multiple system atrophy or progressive supranuclear palsy unless performed using voxel-based statistical parametric mapping.265 SPECT can be

chapter 71 parkinson’s disease

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Progressive Loss of Striatal ␤-CIT Uptake: Longitudinal DAT Imaging in PD

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Figure 71–3. Sequential β-CIT uptake in Parkinson’s disease. (From the Parkinson Study Group: Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287:1653-1661. Copyright © 2002 American Medical Association. All rights reserved.)

used to follow progression in PD, and it has been calculated that there is an annual loss of 8% to 11% of transporter signal in the early stages of PD.266,267 However, as mentioned, approximately 10% of patients believed by neurologists to have PD have normal imaging on PET or SPECT. It remains unclear whether these patients could have been distinguished by more accurate clinical assessment. SPECT can also be used to image sympathetic cardiac innervation in PD with iodine-123–labeled metaiodobenzylguanidine. This shows postganglionic sympathetic denervation in PD patients, in contrast to retained innervation in multiple system atrophy or progressive supranuclear palsy, with 90% specificity and sensitivity, although the metaiodobenzylguanidine scan may be normal in early PD.268,269 PET scanning has provided valuable insights into the etiology and progression of PD and may emerge as an imaging marker for the latter together with SPECT. However, PET remains relatively limited in its availability and is unlikely to become used in routine practice in the near future. PET in PD has mainly used fluorodopa to demonstrate the integrity of the nigrostriatal system and, like SPECT for the dopamine transporter, shows asymmetrical loss affecting predominantly the putamen and less so the caudate. Transcranial ultrasound has attracted increasing attention.270 This technique may demonstrate hyperechogenicity of the substantia nigra in over 90% of PD patients.271 Additional studies are required to assess its reproducibility in other centers and its application to diagnosis and the differentiation of PD from other parkinsonian diseases. Routine neurophysiological studies are not helpful in the evaluation of PD patients. Autonomic function testing is useful

in identifying patients with multiple system atrophy. For instance, 50% of multiple system atrophy patients have a 30 mm Hg systolic or greater than 15 mm Hg diastolic fall in blood pressure with head-up tilt compared with 20% of PD patients.246 Such drops in blood pressure occur earlier in the course of multiple system atrophy than in PD. The presence of sphincter denervation early in the course of disease favors multiple system atrophy, but none of the autonomic function studies accurately distinguishes PD from the parkinsonian syndromes, except progressive supranuclear palsy, in which autonomic function usually remains intact.272 A good response to dopaminergic therapy is considered an integral part of the confirmation of the diagnosis of PD. It has been suggested that a challenge with levodopa or apomorphine might be a useful aid when there is uncertainty regarding diagnosis.273,274 However, there are problems with interpretation, with 20% of parkinsonian multiple system atrophy patients having a positive response and positive responses may also be seen in progressive supranuclear palsy or vascular parkinsonism.275 In assessing a patient’s potential clinical response to levodopa, it is best to build up gradually to a dose of not less than 1000 mg for a duration of at least 2 months before an accurate view of responsiveness is obtained in the parkinsonian syndromes.

TREATMENT The treatment of PD comprises several stages determined by the natural progression of the disease and by the complications that can develop as a consequence of drug use. Dopaminergic agents are the drugs that are most effective in

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Neurodegenerative Diseases 5-HT1A agonists Adrenergic antagonists Adenosine antagonists Cannabinoid agonists Glutamate antagonists k-Opioid agonists Muscarinic antagonists Nicotinic agonists Stem cells Other cell-based therapies New formulations 2000–

Anticholinergics 1900–1950

1850–1900 Belladonna Arsenic Indian hemp (with opium)

■

Figure 71–4. Evolution of the treatment of Parkinson’s disease.

1950–2000 Levodopa Dopamine agonists MAOIs Amantadine COMT inhibitors Deep-brain stimulation Stereotactic surgery Transplantation

■

Parkinson’s disease Non-pharmacological treatment

Figure 71–5. An algorithm for the treatment of Parkinson’s disease.

Pharmacological Rx Neuroprotective agent(s)? Decision to initiate Rx Cognitively normal

DA agonists or MAO-B

Yes

No

Cognitively impaired or > 70–75 y Anticholinergics Amantadine

L-DOPA COMT inhibitors

Combination therapy

Medication adjustments to optimize efficacy and reduce side effects

improving the motor deficits of PD and include levodopa, dopamine agonists, and the monoamine oxidase B (MAO-B) inhibitors. Several new drugs will shortly be released and reflect the rapid increase in treatment options for PD (Fig. 71–4). An algorithm for the use of drugs in PD is suggested in Figure 71–5.

Levodopa Levodopa was the first drug to be used to replace the dopamine deficiency of PD and remains the “gold standard” against which the efficacy of others are judged. Only 1% of an oral dose of levodopa is absorbed into the blood because of extensive metabolism in the gut and so it is routinely combined with a dopa-decarboxylase inhibitor to reduce peripheral metabolism that in turn both increases absorption to 10% and decreases side effects. Levodopa and other dopaminergic agents improve

Surgery

both the quality of life and life expectancy of PD patients.276-278 It provides rapid and effective relief of bradykinesia, rigidity, and associated pain and improves tremor in many patients. Levodopa improves symptoms in early PD patients by 12 or 13 Unified Parkinson’s Disease Rating Scale (UPDRS) points after 3 months. Side effects are mainly gastrointestinal and consist of nausea, vomiting, and anorexia. These usually disappear over 2 to 3 weeks but may persist in some patients. They can be prevented or treated with domperidone 10 to 20 mg t.i.d., taken usually for a period of 2 to 4 weeks. Constipation, orthostatic hypotension, akathisia, hallucinosis, and daytime sleepiness are less common and are seen more often in the elderly population. Constipation, which can also be a consequence of PD itself, usually responds to standard treatments, including increased fluid, bowel training, timing of evacuation to the patient being “on,” and increased fiber intake. Symptomatic orthostatic hypotension may respond to simple advice regard-

chapter 71 parkinson’s disease Early PD

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Figure 71–6. Treatment complications with levodopa. Early use of levodopa produces a long-duration response. With disease progression this shortens, and in clinical terms, patients begin to oscillate between being “on” with dyskinesias and being “off” (A). The pharmacokinetics of levodopa do not change with disease progression (B), but the progress of the disease and the changes induced by levodopa produce downstream changes that are believed to induce the dyskinesias.

ing postural change, maintaining hydration, the use of pressure stockings, antidiuretic hormone, midodrine, or fludrocortisone. Akathisia, hallucinosis, and daytime sleepiness can all occur as a consequence of PD itself and dopaminergic treatments in general. If due to the latter, they may respond to a reduction in dose. Hallucinations in particular are recognized as a consequence of PD pathology that develop in the mid to advanced stages of the disease.279 Some patients experience additional psychiatric effects from dopaminergic therapy, including obsessive traits, punding, and pathological gambling.280-282 These problems usually respond to a reduction in dopaminergic therapy but sometimes require the use of antipsychotic medication of the type less likely to exacerbate PD. Levodopa has a long-duration response in early disease that enables adequate symptomatic control with dosage schedules of three times daily (Fig. 71–6). Disease progression, however, erodes the usefulness of levodopa as 70% of patients develop motor complications within 6 years of initiation of the drug.283,284 Wearing off effects frequently require modification of dosage and/or dose frequency or the introduction of additional or alternative therapies. Interestingly, so long as the plasma levodopa concentration is maintained, the clinical response will persist285,287 and “wearing off” does not occur if the drug is given by continuous infusion.288,289 A significant long-term complication of levodopa use is the development of dyskinesias. Dyskinesias develop at a rate of approximately 10% per annum, although this rate is much greater in young onset PD patients, of whom 70% will have dyskinesias within 3 years of levodopa

initiation.290 The mechanisms by which these motor complications develop are not completely understood, but pulsatile stimulation of dopamine receptors by short-acting agents, including levodopa, and the degree of striatal denervation have been implicated.291 Dyskinesias may occur at the time of maximal clinical benefit and peak concentration of levodopa (peak dose dyskinesias) or appear at the onset and wearing off of the levodopa effect (diphasic dyskinesias). Motor complications can be an important source of disability for some patients who cycle between “on” periods, which are complicated by dyskinesias, and “off” periods, in which they suffer severe parkinsonism. Thus, levodopa offers a rapidly effective means to treat the motor symptoms of PD with a tolerable early side effect profile but more serious long-term complications.

Catechol-O-methyl Transferase Inhibitors The routine combination of levodopa with a dopa decarboxylase (DDC) inhibitor improves absorption but the majority of levodopa is still metabolized in the gut by catechol-O-methyl transferase (COMT), which produces 3-O-methyldopa. COMT inhibition therefore offers a strategy to increase levodopa absorption and improve kinetics (Fig. 71–7). Two selective COMT inhibitors are available for clinical use for the treatment of PD. These drugs exert profound influences on levodopa kinetics by increasing its bioavailability and elimination half-

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Levodopa alone

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Figure 71–7. The strategy of COMT inhibition.

life. This allows more stable levodopa plasma levels to be obtained via the oral route and, conceivably, more sustained brain dopaminergic stimulation to be attained. Entacapone is a selective, reversible inhibitor of COMT. It does not cross the blood-brain barrier and acts primarily in the gut. Entacapone essentially increases both the peripheral and central availability of levodopa. The plasma elimination of a 200-mg oral dose of entacapone is 1 to 2 hours. The pharmacokinetics of entacapone, particularly its elimination characteristics, are similar to those of levodopa, allowing coadministration of these agents. The recommended dose of entacapone is a 200-mg tablet administered with each dose of levodopa/carbidopa, up to a maximum of 10 times daily (in Europe) and 8 times daily (in the United States). It should be noted that only the dose of levodopa should be titrated; the dose of entacapone administered with each dose of levodopa should remain the same (200 mg). Entacapone is effective in patients with wearing-off–type motor fluctuations and can produce an increase in “on” time and a reduction in “off” time by an average of 60 minutes per day.292 The most common adverse effect seen with entacapone is dyskinesia, which reflects increased central dopaminergic activity. Reducing the daily levodopa dosage by about 25% may be necessary to minimize possible dopaminergic adverse effects. This reduction may be made at the time of entacapone introduction in those patients on more than 800 mg of levodopa daily or in those already with dyskinesias, but generally it is better to delay changing the levodopa dose until the patient’s response can be evaluated. Physicians should be aware that dopaminergic adverse events generally occur within 24 hours of initiating entacapone and may require an immediate adjustment of the levodopa dosage. Entacapone may be combined with both standard and controlled-release formulations of levodopa/carbidopa and may be administered with or without food.

The introduction in 2003 of Stalevo, a combination of levodopa, dopadecarboxylase inhibitor, and entacapone, offered an opportunity to simplify the dosage regimen for patients on entacapone. Patients stable on levodopa and entacapone given separately can be converted straight over to the equivalent dose of Stalevo. Stalevo tablets should not be cut or crushed; only one should be taken at each dose time, and they must not be combined with additional entacapone. Tolcapone (unlike entacapone) can cross the blood-brain barrier293 and may produce some central COMT inhibition, although its clinical effect is likely to be minimal. A study in newly diagnosed, levodopa-naïve patients with PD failed to show any clinical efficacy with the introduction of tolcapone either alone or with selegiline.294 Tolcapone has a similar halflife to entacapone; however, due to a greater bioavailability and smaller volume of distribution, tolcapone produces a greater inhibition of COMT and is required only on a three-times-daily regimen.295 Although tolcapone is available now in both Europe and North America, its use is restricted by its potential to cause severe hepatic toxicity.296 It should not be given to patients with impaired liver function, and those PD patients taking tolcapone require regular monitoring of hepatic enzymes. This effect on liver function is not seen with entacapone and probably reflects their differing potency in inducing mitochondrial permeabilization.297 The use of tolcapone is generally limited to those patients who have failed to derive significant benefit from entacapone. Both entacapone and tolcapone can induce diarrhea, which is more common and may be severe and explosive with the latter drug.298

Dopamine Agonists Several dopamine agonists are available for use in PD and fall broadly into two groups: ergot and non-ergot. Ergot agonists

chapter 71 parkinson’s disease 50 Patients with dyskinesia (%)

include bromocriptine, cabergoline, lisuride, and pergolide, and non-ergot agonists include apomorphine, piribedil, ropinirole, and pramipexole. Bromocriptine, cabergoline, pergolide, pramipexole, and ropinirole have all been studied for monotherapy use in early PD,299-308 as well as for adjunctive treatment in more advanced PD.309-316 They have all demonstrated a significant beneficial effect on motor function and activities of daily living. Their side effect profile is similar to that of levodopa in terms of inducing dopaminergic related symptoms such as nausea, vomiting, and postural hypotension but are associated with a higher rate of peripheral edema, somnolence, and hallucinosis, particularly in the elderly. Somnolence with dopamine agonists is mainly seen during the early dose escalation phase, and patients should be warned of this and the rare but important side effect of sudden onset of sleep.317 In patients with early PD (mean age, 61 years), hallucinosis also occurred more frequently during dose escalation but, like sedation, settled to a rate no higher than levodopa during maintenance. The use of dopamine agonists is rarely associated with the development of pleural, pericardial, or peritoneal fibrosis.318 A report has linked pergolide with fibrotic cardiac valvular disease319 in a pattern similar to that seen with other agents that also stimulate the 5-hydroxytryptamine2 receptor, including methysergide and fenfluramine. There are insufficient data at present to know whether this complication is associated with ergot agonists alone, all dopamine agonists, or all dopaminergic drugs and whether the effect is dose or time related or both. Until such time as additional information becomes available, vigilance is recommended and, when necessary, appropriate investigations (echocardiogram, chest radiography, and erythrocyte sedimentation rate) and referral to a cardiologist. Dopamine agonist monotherapy can effectively control dopaminergic symptoms for a period of time. Long-term follow-up indicates that approximately 85%, 68%, 55%, 43%, and 34% of PD patients initiated on pramipexole or ropinirole are still controlled on monotherapy at 1, 2, 3, 4, and 5 years, respectively.317,320,321 However, this is dependent on the agonist being used at an appropriate dose. Nevertheless, patients will require levodopa supplementation at some point during their disease. If used correctly, agonists can produce symptom control comparable with levodopa. Although the two monotherapy studies quoted earlier showed superiority for levodopa in UPDRS scores by up to 5 points, patients in the agonist arms had comparable quality of life scores and could have taken supplemental levodopa if the physician or patient believed it was required. The explanation for this discrepancy might be because the UPDRS score does not capture all the benefit that a patient might derive from a dopamine agonist, including possible nonmotor effects such as an antidepressive action. Several trials have now confirmed that bromocriptine, cabergoline, pergolide, pramipexole, and ropinirole are associated with a significantly reduced risk for the development of motor complications in comparison with levodopa303,307,320-322 (Fig. 71–8). In the pramipexole study, quality of life scores were also equivalent for the 4-year period.317 This implies that the patients were equally well controlled on agonist (with levodopa supplementation when required) or levodopa alone. Of course the levodopa group had more dyskinesias, but at 4 years these did not intrude significantly into patient quality of life or start to limit treatment options for motor control.

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Figure 71–8. Dopamine agonists delay the development of dyskinesias. (Results are from Rinne UK, Bracco F, Chouza C, et al: Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009. Study Group. Drugs 1998; 55[Suppl 1]:23-30; Rascol O, Brooks DJ, Korczyn AD, et al: A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342:1484-1491; and Parkinson Study Group: Pramipexole vs levodopa as initial treatment for Parkinson disease. A randomized controlled trial. JAMA 2000; 284:19311938.)

In conclusion, dopamine agonists provide effective control of PD-related motor symptoms, delay the onset of motor complications, delay the introduction of levodopa, enable a lower dose of levodopa to be used, and, in the case of pramipexole and ropinirole in particular, offer the possibility for some diseasemodifying effect.

Monoamine Oxidase-B inhibitors Two compounds of the propargylamine group, selegiline (deprenyl) and rasagiline, both of which are irreversible MAOB inhibitors, have demonstrated symptomatic effect in PD patients and neuroprotective efficacy in the laboratory. Selegiline has been available for several years and showed benefit as adjunctive treatment for PD. The DATATOP study was a prospective double-blind, placebo-controlled trial that investigated the effect of selegiline 5 mg twice daily or 2000 IU vitamin E, or both, as putative neuroprotective therapies.324 The time until PD patients required levodopa was used as the primary endpoint. No beneficial effect of vitamin E was detected at the dose given. In contrast, selegiline significantly delayed the need for levodopa compared with placebo, an effect consistent with slowing of disease progression (Fig. 71–9). However, selegiline was also found to exert a mild symptomatic effect that confounded interpretation of the study. In an attempt to avoid this confound, selegiline was compared with placebo using as the primary endpoint, the change in motor score between an untreated baseline visit and an untreated final visit performed after 12 months of treatment and 2 months of study drug withdrawal.325 In this study, PD patients treated with selegiline had less deterioration from baseline than those receiving placebo, again suggesting that selegiline might be neuroprotective. In a long-term follow-up study of the DATATOP cohort, levodopa

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patients who had been taking selegiline for 7 years, compared with those who were changed to placebo after 5 years, had a significantly slower decline and less wearing off, on-off, and freezing but more dyskinesias than in those on deprenyl.326 Although one study did suggest that selegiline use might be associated with excess mortality, a large meta-analysis indicates that no such effect is evident and confirms the clinical efficacy of this drug in PD with the total UPDRS score being improved by 2.7 points at 3 months.327 There is no evidence at present that MAO-B inhibition itself delays the development of motor fluctuations other than through the delay in introduction of levodopa and an ability to use a lower dose. Rasagiline (N-propargyl-1-R-aminoindan) is a relatively selective irreversible MAO-B inhibitor. This selectivity is important in avoiding the “cheese effect” of MAO-A inhibitors. However, higher doses (greater than 2 mg/day) of rasagiline will begin to inhibit MAO-A and so should be avoided. Rasagiline is a propargylamine and so is structurally related to selegiline but is approximately 10 to 15 times more potent. It has good central nervous system penetration and a long half-life that allows a once-daily dosage schedule. Rasagiline is metabolized to aminoindan in contrast to selegiline, which is metabolized to metamphetamine. This difference may have clinical relevance in terms of side effect profile and the potential for disease modification (see later). Rasagiline has been studied in patients with early PD328 (Fig. 71–10). Patients with early PD were randomized to

Probability of reaching the endpoint

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Figure 71–9. The results of the DATATOP study. (From the Parkinson Study Group: Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328:176-183. Copyright 1993 Massachusetts Medical Society. All rights reserved.)

placebo or rasagiline (1 or 2 mg/day). In the placebo and rasagiline 1-mg and 2-mg groups, 81%, 83%, and 80%, respectively, were still on “monotherapy” at 6 months, and there were no statistical differences in the rates for either levodopa supplementation or patient withdrawal. At the end of the 6-month period, the 1-mg rasagiline group had an improved UPDRS score compared with a placebo of 4.2 units, and this was 3.56 for the 2-mg group. The degree of motor improvement over the 6-month period was comparable with that seen for selegiline in the DATATOP study324 but not as great as that seen for dopamine agonists. There were no significant differences in the adverse event profile between the treatment arms and placebo. At 6 months, the two treatment arms were almost back to their respective baseline UPDRS scores. The initial 6-month period was extended by an additional 6 months.328 Patients were continued on their original dose of rasagiline or, if on placebo, were given rasagiline 2 mg/day. Patients requiring additional dopaminergic therapy were prescribed either levodopa or a dopamine agonist. For the entire 12-month period, deterioration from baseline scores was 3.01, 1.97, and 4.17 UPDRS units for the 1-mg, 2-mg, and delayed 2-mg cohorts, respectively. Those given rasagiline 1 mg/day for 12 months compared with those on the 2-mg dose for only the last 6 months maintained a total UPDRS improvement of 1.82 UPDRS units. The 12month rasagiline 2-mg group had a 2.29-unit improvement over the 2-mg 6-month group. There was no significant excess of adverse events in the rasagiline arms compared with the placebo arm. Two studies have been published on the efficacy of rasagiline in PD patients already taking levodopa. The PRESTO trial investigated PD patients on stable levodopa with at least 2.5 hours of “off” (i.e., poor motor state).329 Placebo decreased “off” time by 0.9 hour (15% of “off” time) and rasagiline 1 mg/day by 1.9 hours, equating to a 29% reduction in “off” time. Benefits were seen within 6 weeks of randomization and maintained throughout the 26-week study period. The improvement in “off” time was accompanied by a corresponding increase in “on” time, but 32% of the extra “on” time in the 1-mg group was troublesome with dyskinesia although this did not lead to any early terminations. The 1-mg rasagiline dose also resulted in significant improvements in the UPDRS score. The LARGO study investigated the effect of 1 mg/day rasagiline compared with entacapone or placebo in PD patients on stable levodopa but with at least 1 hour of motor fluctuations per day.330 Placebo reduced “off” time by 0.4 hour, both rasagiline and entacapone decreased “off” time by 1.2 hours. There was a comparable and

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Figure 71–10. Results of the TEMPO study. (From the Parkinson Study Group: A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61:561-566. Copyright © 2004 American Medical Association. All rights reserved.)

chapter 71 parkinson’s disease

Other Drugs Anticholinergics were used to treat the symptoms of PD prior to the introduction of levodopa. Relatively little data are available on their potency and tolerance. Clinical trials have shown a modest benefit for anticholinergics in improving bradykinesia and rigidity,331-333 but this was at the expense of impaired cognitive function. Benztropine was equivalent to clozapine in producing a mild improvement in tremor.334 Amantadine produces mild and transitory improvements in PD symptoms, with benefits usually lasting 6 to 9 months.335 Although some have suggested that in pure PD patients the effects are more long lasting.336 It is generally considered unsuitable for monotherapy in PD and is mostly used as an adjunct. Improvements in bradykinesia and rigidity are generally of the same order of magnitude as anticholinergics, but their combination is additive.337,338 Amantadine use is also limited by its potential to induce cognitive defects.

Initiation of Treatment Treatment for PD is always tailored to the specific needs and circumstances of the patient. Traditionally, drug treatment has been initiated only when the patient’s symptoms interfered significantly with their employment or social activities. The rationale for this was very reasonable: the treatments available were considered symptomatic only and incapable of modifying the course of the disease. Advances in our understanding of the pathophysiology and pharmacology of PD and the availability of new treatments for the disease have required reevaluation of this strategy.340 The clinical onset of PD motor features is directly associated with a series of functional changes in basal ganglia circuits and their target projections.341 Basal ganglia output becomes abnormal and clinical features appear, when dopamine levels fall to less than 7% in MPTP-treated nonhuman primates.342,343 The corresponding figure in humans is not known but may be around 20% to 30%. The estimated asymptomatic latent period of approximately 6 years344 in idiopathic PD (and longer in familial PD) indicates the remarkable capacity for the basal ganglia to cope with progressively lower levels of dopamine, the compensatory mechanisms maintaining apparently normal motor function over the intervening years to diagnosis. These compensatory mechanisms include increased striatal dopamine turnover and receptor sensitivity, upregulation of striatopallidal enkephalin levels, increased subthalamic excitation of the globus pallidum pars externa, and maintenance of cortical motor area activation.345,346 These observations, although neither completely defined nor understood, support the notion that declining dopamine levels during the early phase of PD put the basal ganglia level under stress. The onset of clinical symptoms denotes the point of failure to deal adequately with dopamine depletion. It might be that early correction of the basal ganglia functional abnormalities caused by dopaminergic

12 10 8 6 4 2 0 –2 –4 –6 –8 –10

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significant increase in “on” time without dyskinesias of 0.8 hour with both drugs. These two studies demonstrate that once-a-day rasagiline (1 mg) significantly improves PD control in patients optimized on levodopa with or without additional therapy. Its efficacy is comparable with entacapone but probably less than that of dopamine agonists, which induce a 1- to 2-hour improvement in PD control.314,315

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Figure 71–11. Results of the ELLDOPA study. (From Fahn S, Oakes D, Shoulson I, et al: Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004; 351:2498-2508. Copyright 2004 Massachusetts Medical Society. All rights reserved.)

cell loss and dopamine deficiency is a means to support the intrinsic physiological compensatory mechanisms and both limit and delay the circuitry changes that evolve as PD progresses. Review of the outcomes of the DATATOP, ELLDOPA (Fig. 71–11), and TEMPO studies may support such a proposition.340 In these studies, those patients who received effective symptomatic treatment earlier in the course of their PD fared significantly better clinically than those initiated on placebo even when, as in the case of TEMPO, they were switched to the active drug after only 6 months. Given this, consideration of treatment initiation at the diagnosis of PD appears to be an increasingly viable and indeed attractive option for patients. Early restoration of basal ganglia physiology will support the compensatory events and delay the irreversible modification of circuitry that characterizes the clinical progression of PD. Such an effect may lead to lasting clinical benefit for the patient. However, dopaminergic treatment can be associated with unwanted side effects that may include gastrointestinal disturbances, cognitive problems, and sedation (see earlier). These need to be weighed against the symptomatic improvement that the patient will experience and the hypothetical long-term benefit outlined here. Once an agreement has been reached between the physician and patient on the introduction of drug therapy, consideration needs to be given to the choice of drug to start. As emphasized earlier, this needs to be individualized to the patient. The following therefore represents a general view of initiation options. Those aged 70 to 75 years or younger, with no cognitive impairment and no significant comorbidity, should be considered for introduction of a dopamine agonist or a MAO-B inhibitor. The agonist will improve motor dysfunction more than an MAO-B inhibitor, but the latter is probably better tolerated and the choice between these will depend on the patient’s degree of symptomatic dysfunction. For those patients over age 70 to 75 years, or alternatively, those with cognitive dysfunction or significant comorbidity, levodopa would be the drug of choice for the initiation of therapy.

Maintenance of Treatment Most PD patients respond well to the initiation of dopaminergic therapy in small doses. However, some require regular uptitration of their dose before an adequate control of motor function is reached. This is particularly true of the dopamine

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agonists that may need to be increased to, for example, 3 mg of pramipexole or 12 to 15 mg of ropinirole before there is a good response. Some patients will need these doses to be increased as their disease progresses. As indicated earlier, regardless of what drug is first used, PD patients will eventually require levodopa. This is most often introduced as a three-times-daily regimen, although the short half-life of the drug means that this falls well short of providing continuous dopaminergic stimulation. A higher frequency of administration would provide better symptom control and possibly less risk of the development of motor complications but needs to be balanced against a likely lower rate of compliance.

Motor Complications The majority of PD patients will develop wearing off or dyskinesias at some point in the course of their disease. Although the use of dopamine agonists will delay the onset, once levodopa is introduced the risk for their appearance increases. It is possible that the initiation of levodopa with a COMT inhibitor might delay the onset of motor complications, but evidence for this is lacking at present. The development of dyskinesias is probably related to dose of levodopa347,348 as well as duration,349,350 so the continuation of the dopamine agonist or MAO-B inhibitor to limit the levodopa dose is beneficial. Wearing off equates to the loss of effectiveness of a given dose of dopaminergic therapy and the emergence of the primary motor features of PD (i.e., bradykinesia and rigidity) that remain responsive to dopaminergic treatment. Patients recognize this as a return of symptoms prior to their next dose (“end-of-dose failure”), although some mistakenly associate it with the administration of the next dose given the medication’s latency of effect. As noted, wearing off is eliminated by continuous administration of either levodopa or a dopamine agonist.288,289,351 Although these methods are effective, they are not practical for the majority of patients. The simplest strategy is to increase the frequency of administration of levodopa, although this too may become difficult as dosage regimens increase to six or more times per day. Controlled-release formulations have proved disappointing with often little improvement in duration of response and problems with unpredictability of absorption and motor response. One open-label study demonstrated that the addition of cabergoline, a longacting ergot dopamine agonist, to patients taking pramipexole or ropinirole, both non-ergots, resulted in improved motor control.352 The addition of a COMT or MAO-B inhibitor to levodopa significantly improves “off” time (see earlier) and is an easy and effective strategy for managing wearing off.329,330,353 Dyskinesias are typically choreiform, occasionally dystonic involuntary movements induced predominantly by exposure to levodopa or other short-acting dopaminergic drugs. At first, patients may be unaware of the movements, but they may be noticed by relatives or friends who are frequently more troubled by them than the patient. However, they progress with time and not only cause difficulty and embarrassment but also begin to restrict options for improving motor control. The impact of dyskinesias on quality of life is limited in the beginning. However, this changes as dyskinesias become more severe and options for motor control become limited.

The practical management of dyskinesias depends on the severity of the involuntary movements and their relationship to medication dosage schedule. They may be peak dose, biphasic, or random. Peak dose dyskinesias are related to high plasma concentrations of levodopa and can be managed by fractionating levodopa doses to avoid such peaks. This may or may not require an increase in the total daily dose. Alternative strategies include the introduction of a dopamine agonist if the patient is not already taking such an agent and if he or she remains a suitable candidate. Long-acting agonists are particularly useful in the management of dyskinesias, presumably due to their ability to provide more continuous dopaminergic stimulation while avoiding rapid fluctuations in receptor stimulation.298 Biphasic dyskinesias occur when plasma levodopa concentration is rising or falling and are associated with generally lower plasma levodopa concentrations. They tend to be more stereotypical and repetitive and to involve the lower extremities. They are more troublesome to manage but may respond to higher levodopa doses designed to keep the plasma concentrations above a critical level.354 Amantadine has demonstrated efficacy in improving peak dose dyskinesias.355-357 The effective dose is 200 to 400 mg/day in two divided doses. The severity of dyskinesias may be reduced by 24% to 56% and the effect sustained at 1 year. The potential for the continuous parenteral administration of dopamine agonists or levodopa to improve or abolish motor fluctuations including dyskinesias has been discussed. Apomorphine infusions or duodenal infusion of levodopa offer significant benefits for select patients and can be considered an option prior to surgery.

Management of Nonmotor Complications Depression and, to some extent, apathy (anhedonia) may respond to tricyclics such as amitriptyline or to selective serotonin reuptake inhibitors. Pramipexole may be useful as an antidepressant, separate from its action to improve the motor features of PD.358-360 Anxiety and panic attacks can be prominent in PD, and these may sometimes relate to “wearing off” and so respond to strategies outlined for this complication. However, additional anxiolytic therapy may be needed in some patients. Hallucinations, if due to drugs, usually respond to a reduction in dose. However, in some patients, this is difficult due to re-emergence of motor features, and they may respond to clozapine or quetiapine.361-363 Hallucinations are, of course, an important symptom of diffuse Lewy body disease, and their emergence early in the course of PD is a risk factor for dementia. PD patients who demonstrated dementia after the 2 years diagnosis of PD showed a modest but significant improvement in cognitive function with rivastigmine, to a degree similar to that seen with this drug in Alzheimer’s disease.364 Several strategies are available to improve both nighttime sleep and daytime alertness in PD and include improving sleep hygiene, treating nocturnal motor problems, better managing nocturia, modifying medication,317 and using modafinil in patients with refractory daytime drowsiness.365 Viagra or apomorphine can, in select cases, usefully manage the sexual dysfunction associated with PD.366,367 Bladder abnormalities particularly cause problems at night but can be improved by a range of options that include nonpharmacological and pharmacological strategies. The latter include the use

chapter 71 parkinson’s disease of oxybutinin, detrusitol, or amitriptyline in patients with concomitant depression. Sialorrhea and drooling are often the result of reduced frequency of swallowing and may be helped by simple things such as chewing gum or sucking sweets. Anticholinergic drugs may help but often cause unwanted side effects. Botulinum toxin can be used for refractory cases.368 Constipation may respond to dopaminergic drugs and bowel training. Aperients often need to be added.

Surgery Surgical approaches to the management of PD have been practiced since the mid-twentieth century. The discovery of dopamine depletion and the subsequent introduction of oral levodopa made surgery less attractive. The recognition of motor complications and the development of severe dyskinesias in some patients led to a resurgence of interest in lesioning the brain to control these features. Advances in surgical technique in neurophysiology and in molecular cell biology have provided the stimulus for the generation of a wide range of nonmedical options for PD (Table 71–7).

Destructive Lesions Thalamotomy may produce a reduction in tremor and bradykinesia; the best results have been achieved with lesion in the ventrointermediate nucleus.369 However, thalamotomy is not particularly helpful for bradykinesia or rigidity, and the procedure can be associated with significant morbidity related to the placement of the lesion.370 Thalamotomy has largely been replaced by medical therapies or deep brain stimulation. Posteroventral pallidotomy can provide long-lasting improvement in contralateral dyskinesia and some improvement in bradykinesia and rigidity in PD patients.371-374 Like thalamotomy, pallidotomy has become less common as deep brain stimulation has become more available. However, both destructive lesions may still be offered when symptoms significantly affect one side (bilateral destructive lesions cause increased complications including bulbar dysfunction) and when the opportunity for regular and expensive follow-up is limited. Subthalamotomy has been shown to improve parkinsonian motor abnormalities including dyskinesias in animal

T A B L E 71–7. Surgical Treatments for Parkinson’s Disease Ablative procedures Thalamotomy Pallidotomy Subthalamotomy Deep brain stimulation VIM nucleus of thalamus Globus pallidus pars interna Subthalamic nucleus Restorative procedures Cell-based therapies Fetal human nigral cells Fetal porcine nigral cells Retinal pigmented epithelial cells Stem cells Trophic factors Gene therapies

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models375-377 and in PD patients.378-380 However, dyskinesia and hemiballismus have also been reported, following subthalamotomy, which in a few cases have been permanent.381,382

Stimulation Deep brain stimulation was first proposed as a treatment in PD by Benabid based on his experience with high-frequency stimulation as a means of confirming the target site for an ablative lesion.383 Deep brain stimulation can be used for bilateral procedures with relative safety. Also, the stimulator can be adjusted to maximize benefits and reduce side effects. Deep brain stimulation simulates the effect of a lesion but avoids the need to create a destructive brain lesion. The precise mechanism of action is unknown, but possibilities include depolarization blockade, release of inhibitory neurotransmitters, backfiring, and inhibition of aberrant neuronal signals.384 Deep brain stimulation of the ventral intermediate nucleus significantly improves contralateral tremor and is comparable in effect with destructive lesions but is superior in terms of side effects.385-387 Benefits are long-lasting and have been shown to persist for more than 10 years. However, only tremor is improved and there is no effect on bradykinesia, rigidity, or dyskinesias. Thus deep brain stimulation of the ventral intermediate nucleus is not as attractive as deep brain stimulation of other targets. Deep brain stimulation of the subthalamic nucleus388,389 or globus pallidum interna390-394 improves all of the cardinal features of PD as well as dyskinesias. Patients who could not be further improved with medical therapies (typically because of motor complications) experienced a substantial reduction in disability following deep brain stimulation of the subthalamic nucleus or globus pallidum interna. Long-term studies demonstrate that benefits of deep brain stimulation persist over more than 5 years of follow-up, although disability still progresses from year to year, reflecting degeneration in nondopaminergic sites.395 Adverse events with deep brain stimulation can be related to the intracranial procedure, the electrode system, and stimulation. The surgical procedure can be associated with hemorrhage, tissue damage, and infection. In a multicenter study, 7 of 143 patients experienced hemorrhage and neurological deficits persisted in 4.394 Problems can also occur in relation to the device including lead breaks, lead migration, infection, and skin erosion.397 These occur in about 2% to 3% of cases and occasionally require replacement of the electrode. Severe depression and suicidal ideations or riotous laughing have been observed with stimulation of the subthalamic nucleus,398 suggesting that basal ganglia circuits are involved with higher cortical and/or limbic as well as motor functions. The use of diathermy during surgical procedures should be avoided in patients with deep brain stimulation as excess heat might be conducted to the brain by the electrode wire and cause necrosis. Deep brain stimulation, particularly of the subthalamic nucleus or globus pallidum interna, offers a significant benefit to those patients who have severe dyskinesias not controlled by standard means. Parkinsonian features are also improved but no more than can be achieved by dopaminergic medication. Deep brain stimulation is relatively safe if performed by an experienced surgeon but still carries some small risk of permanent neurological deficit (often quoted as less than 1%).

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Patients should be carefully selected; those with cognitive impairment are excluded because of the risk of exacerbating this with surgery. Continuous follow-up is required, and the procedure is expensive. Fetal nigral transplantation has been evaluated in two double-blind, placebo-controlled trials. The first randomized 40 patients to receive a transplantation or placebo procedure and followed them for 1 year.399 Modest benefits of transplantation were observed in UPDRS scores of activities of daily living and motor function in patients younger than 60 years. There was a significant increase in striatal fluorodopa uptake on PET, and there was modest survival of implanted cells at postmortem. The procedure was well tolerated, but approximately 15% of transplanted patients developed dyskinesias that persisted for days or weeks after levodopa was discontinued and this was a source of major disability in some patients.400 Quality of life, the primary endpoint, was not improved. The second trial was a 2year double-blind placebo-controlled study that used a slightly different implantation protocol.401 Transplanted patients were not significantly improved in comparison with placebo patients, despite having significant increases in striatal fluorodopa uptake on PET and survival of implanted dopaminergic neurons at postmortem. Over one half (56%) of the transplanted patients in this study developed dyskinesia during the practically defined off state when they had been held off levodopa for more than 12 hours (“off-medication dyskinesia”). This phenomenon was not observed in nontransplanted patients. The precise mechanism responsible for off-medication dyskinesia remains unknown. Glial-derived neurotrophic factor has attracted attention as a potential treatment for PD because of its capacity to protect or rescue dopaminergic neurons in tissue culture402 and in MPTP-treated monkeys.403 Intraventricular administration of GDNF to PD patients did not produce benefit.404 One open-label study used an infusion pump to directly administer glialderived neurotrophic factor into the striatum in five PD patients.405 There was an improvement in UPDRS motor scores during practically defined off as well as a small increase in striatal fluorodopa uptake around the catheter tip. However, a double-blind trial comparing glial-derived neurotrophic factor with placebo was negative.406 Gene and stem cell therapies are the subject of intense research effort but have yet to lead to clinically applicable treatments superior to those currently available.

NEUROPROTECTION The limitations of symptomatic dopaminergic treatment have led to the search for agents to slow the progression of neurodegeneration in PD and thereby help prevent or slow clinical progression or even reverse deficits by restoring normal function to defective neurons. It is accepted that such a strategy will be successful only if degeneration is ameliorated in multiple neurotransmitter systems, preventing the progression of both motor and nonmotor features. The drugs that have received most attention in relation to neuroprotection include the MAOB inhibitors and dopamine agonists, although others, including coenzyme Q10, growth factors, antiapoptotic agents, and glutamate inhibitors, have also been the subjects of clinical trials in PD.

MAO-B Inhibitors Selegiline can protect cultured dopaminergic neurons against the toxicity of MPP+ and, in animal models, can reduce dopaminergic cell loss in response to MPTP.407-410 Selegiline also protects against apoptotic cell death induced by serum and growth factor withdrawal,411,412 possibly via an increased production of Bcl2. Selegiline, by virtue of its MAO-B activity, will reduce the turnover of dopamine and so reduce free radical generation. The production of reactive oxygen species and free radical–mediated damage to lipids and proteins have been implicated in PD pathogenesis. Thus, this property, together with the ability for selegiline to protect against MPTP toxicity, led to the evaluation of this drug in the first clinical trial for neuroprotection in PD. The results of the DATATOP and other studies using selegiline and the TEMPO study investigating rasagiline were discussed earlier. There appeared to be some benefit for selegiline, but interpretation is difficult in view of trial design and the compound’s inherent symptomatic action. The results of the delayed start design for TEMPO rasagiline were positive and support a neuroprotective action of the drug, but additional confirmatory trials are required before this drug can be accepted as neuroprotective.

Dopamine Agonists Dopamine agonists have antioxidant activity as a result of their hydroxylated benzyl ring structure, and numerous laboratory studies have demonstrated neuronal protection against free radical–generating systems. These include attenuation of the effects of MPP+, dopamine, 6-hydroxydopamine, and nitric oxide and upregulation of protective scavenging enzymes such as catalase and superoxide dismutase.413-421 However, these benefits are predominantly seen at relatively high concentrations, which may not be relevant in clinical practice. Dopamine agonists have demonstrated antiapoptotic activity in laboratory studies. For instance, pramipexole reduces cell death, prevents the release of cytochrome c and caspase activation in dopaminergic cells treated with MPP+ or rotenone, and prevents a fall in mitochondrial membrane potential.422,423 Importantly, this dopamine agonist has also shown protective effects in the MPTP primate model of PD.424 Several studies suggest that dopamine agonists exert their protective effects not through stimulation of either D2 or D3 receptors, but rather via some alternative mechanism. The potential for dopamine agonists to protect nondopaminergic cells, if translated to the clinic, would have profound implications for disease modification and in particular for preventing the development of nonmotor features in PD. Two studies have sought to determine whether the neuroprotective benefits of dopamine agonists seen in the laboratory can be transferred to patients to modify the course of PD (Fig. 71–12). The CALM-PD study used 2β-carboxymethoxy-3β(4iodophenyl)tropane (β-CIT) SPECT to follow the rate of loss of dopamine transporter as a marker of dopaminergic nigrostriatal cell density.247 Patients with early PD were randomized to pramipexole or levodopa and followed for a total of 4 years; levodopa supplementation was allowed in both arms. At 2, 3, and 4 years, there was a significant reduction in the rate of transporter loss in the pramipexole group, averaging at approximately 40%, consistent with the drug having a relatively

chapter 71 parkinson’s disease % Change in putamen ␤-CIT

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Figure 71–12. Results of SPECT and PET data from dopamine agonist neuroprotection studies. (From the Parkinson Study Group: Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287:1653-1661; and Whone AL, Watts RL, Stoessl AJ, et al: Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REALPET study. Ann Neurol 2003; 54:93101. Copyright © 2002 American Medical Association. All rights reserved.)

Scan interval (months)

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(From Shults CW, Oakes D, Kieburtz K, et al: Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59:1541-1550. Copyright © 2002 American Medical Association. All rights reserved.)

Mean total UPDRS score

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Figure 71–13. Results of the coenzyme Q10 study.

34 32 30 28 26 24 22 20 0

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protective effect in comparison with levodopa. A similar result was seen in the REAL-PET ropinirole study that used a similar trial design but used PET to follow loss of nigrostriatal cell density with fluorodopa.248 This demonstrated an approximately 34% reduction over 2 years in the ropinirole group compared with those on levodopa. These studies have generated considerable interest and debate.425,426 Both studies demonstrate that dopamine agonists are associated with a significant delay in the rate of decline of a surrogate imaging marker of nigrostriatal function. One interpretation of these findings is that these two dopamine agonists slow the rate of cell loss in the substantia nigra of PD patients, and this is consistent with the laboratory findings outlined above. However, neither showed a corresponding clinical benefit, but it can be argued that the time course of the trials was too short to permit such an effect to be detected in the context of viable compensatory mechanisms and powerful symptomatic effects, and this will only become apparent with longer follow-up. Another interpretation of these studies is that levodopa is toxic to nigral neurons. There is concern that levodopa might be toxic as it undergoes oxidative metabolism and has the potential to generate cytotoxic free radicals.427 Levodopa has

16

been shown to be toxic to cultured dopamine neurons, but there is no convincing evidence that levodopa is toxic in in vivo models or in PD patients.428 The ELLDOPA trial investigated the possibility that levodopa may be toxic in PD patients but produced conflicting results. In this study, untreated PD patients were randomized to a total daily dose of 150, 300, or 600 mg of levodopa or placebo. β-CIT SPECT was used as an endpoint for integrity of the nigrostriatal system. Levodopa was associated with a significant increase in the rate of decline of imaging marker over 9 months compared with placebo, consistent with a toxic effect.429 Clinical evaluation, however, showed that those patients on levodopa had better UPDRS scores compared with placebo after 2 weeks of washout (see Fig. 71–9). This would, in contrast, be indicative of a protective effect of levodopa. However, intellectual parsimony would dictate that the simplest explanation for this clinical effect was that the washout period was too brief to eliminate the symptomatic benefits of levodopa. Finally, it has been proposed that the differences between the effects of levodopa and dopamine agonists seen in the CALM-PD and REAL-PET studies are not related to any direct effect of the drugs on dopamine neuron survival or degeneration but rather to a pharmacologic difference in the capacity of

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these drugs to regulate the dopamine transporter or fluorodopa metabolism.426,430,431 However, a review of studies testing the effects of levodopa and dopamine agonists on transporter and fluorodopa metabolism reveals that the data are conflicting and that at present there is insufficient information for or against such an effect.425 In conclusion, the results of the two clinical trials of dopamine agonists using imaging endpoints support, but do not prove, a disease-modifying effect in patients.

Coenzyme Q

10

Coenzyme Q10 has been evaluated in a pilot study of early PD patients to determine whether it might have disease-modifying capabilities.432 The rationale for the use of coenzyme Q10 in PD was based on the observation that mitochondrial complex I activity is decreased in the PD substantia nigra, PD patients have reduced levels of coenzyme Q10, and this compound protects against MPTP toxicity. Coenzyme Q10 is both an antioxidant and an integral component of oxidative phosphorylation that has been shown to enhance electron transport. It is presumed not to have any symptomatic effect. Patients were randomized to either a placebo arm or one of three doses of coenzyme Q10 (300, 600, or 1200 mg) and followed for 16 months. There was a significant benefit for coenzyme Q10 1200 mg in terms of change from baseline in total UPDRS compared with placebo at 16 months and a nonsignificant trend to benefit for lower doses (Fig. 71–13). This interesting and important result is sufficient to support further study of coenzyme Q10 but insufficient at present to advocate that PD patients should use this compound.

K E Y

P O I N T S

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PD is an etiologically heterogeneous disorder.

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Several genetic causes have been characterized and appear to result in downstream effects that include abnormal free radical metabolism, defective mitochondrial function, and dysfunction of the ubiquitin proteasomal system.

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The diagnosis of PD is clinical but can be helped in certain circumstances by imaging with SPECT.

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The differential diagnosis includes a range of bradykinetic diseases such as multiple system atrophy and a number of genetic parkinsonian disorders.

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Treatments are available for the dopaminergic related motor features of PD but the nonmotor symptoms dominate the advanced disease state and require specific attention.

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Treatment options for PD should be discussed early with the newly diagnosed patient, although initiation may be delayed.

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The drug used to begin treatment depends on the patient’s characteristics, but consideration should be given to the balance between effective control and long-term complications of drug therapy.

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Surgery is an important option, although it is usually reserved for the more advanced patient. Most surgery for PD is undertaken to control dyskinesias.

Suggested Reading Ebadi M, Pfeiffer RF, eds: Parkinson’s Disease. Boca Raton: CRC Press, 2005. Nutt JG, Wooten GF: Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005; 353:10211027. Olanow CW, Schapira AHV, Agid Y: Neurodegeneration and prospects for neuroprotection and rescue in Parkinson’s disease. Ann Neurol 2003; 53(Suppl 3):S1-S170. Samii A, Nutt JG, Ransom BR: Parkinson’s disease. Lancet 2004; 363:1783-1793. Schapira AHV, Olanow CW, eds: Principles of Treatment in Parkinson’s Disease. Philadelphia: Butterworth Heinemann, 2005.

References 1. Ehringer H, Hornykiewicz O: Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin Wochenschr 1960; 38:1236-1239. 2. Cotzias GC, Van Woert MH, Schiffer LM: Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967; 276:374-379. 3. Mayeux R, Marder K, Cote LJ, et al: The frequency of idiopathic Parkinson’s disease by age, ethnic group, and sex in northern Manhattan, 1988-1993. Am J Epidemiol 1995; 142:820-827. 4. Bower JH, Maraganore DM, McDonnell SK, et al: Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990. Neurology 1999; 52:1214-1220. 5. Van Den Eeden SK, Tanner CM, Bernstein AL, et al: Incidence of Parkinson’s disease: variation by age, gender, and race/ ethnicity. Am J Epidemiol 2003; 157:1015-1022. 6. de Rijk MC, Breteler MM, Graveland GA, et al: Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology 1995; 45:2143-2146. 7. Zhang ZX, Roman GC: Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology 1993; 12:195208. 8. Del Tredici K, Rub U, De Vos RA, et al: Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 2002; 61:413-426. 9. Ponsen MM, Stoffers D, Booij J, et al: Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 2004; 56:173-181. 10. Braak H, Del Tredici K, Rub U, et al: Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24:197-211. 11. Gowers WR: A Manual of Diseases of the Nervous System. London: Churchill, 1888, p 996. 12. Payami H, Larsen K, Bernard S, et al: Increased risk of Parkinson’s disease in parents and siblings of patients. Ann Neurol 1994; 36:659-661. 13. Bonifati V, Fabrizio E, Vanacore N, et al: Familial Parkinson’s disease: a clinical genetic analysis. Can J Neurol Sci 1995; 22:272-279. 14. Vieregge P, Heberlein I: Increased risk of Parkinson’s disease in relatives of patients. Ann Neurol 1995; 37:685. 15. De Michele G, Filla A, Volpe G, et al: Environmental and genetic risk factors in Parkinson’s disease: a case-control study in southern Italy. Mov Disord 1996; 11:17-23. 16. Marder K, Tang MX, Mejia H, et al: Risk of Parkinson’s disease among first-degree relatives: A community-based study. Neurology 1996; 47:155-160. 17. Gasser T: Genetics of Parkinson’s disease. Ann Neurol 1998; 44(3 Suppl 1):S53-S57.

chapter 71 parkinson’s disease 18. Tanner CM, Ottman R, Goldman SM, et al: Parkinson disease in twins: an etiologic study. JAMA 1999; 281:341-346. 19. Piccini P, Burn DJ, Ceravolo R, et al: The role of inheritance in sporadic Parkinson’s disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999; 45:577-582. 20. Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276:2045-2047. 21. Kruger R, Kuhn W, Muller T, et al: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 1998; 18:106-108. 22. Golbe LI, Di Iorio G, Sanges G, et al: Clinical genetic analysis of Parkinson’s disease in the Contursi kindred. Ann Neurol 1996; 40:767-775. 23. Golbe LI, Di Iorio G, Bonavita V, et al: A large kindred with autosomal dominant Parkinson’s disease. Ann Neurol 1990; 27:276-282. 24. Polymeropoulos MH, Higgins JJ, Golbe LI, et al: Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 1996; 274:1197-1199. 25. Chan P, Tanner CM, Jiang X, et al: Failure to find the alphasynuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson’s disease. Neurology 1998; 50:513-514. 26. Vaughan JR, Farrer MJ, Wszolek ZK, et al: Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson’s disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson’s Disease (GSPD). Hum Mol Genet 1998; 7:751-753. 27. Warner TT, Schapira AH: The role of the alpha-synuclein gene mutation in patients with sporadic Parkinson’s disease in the United Kingdom. J Neurol Neurosurg Psychiatry 1998; 65:378-379. 28. Parsian A, Racette B, Zhang ZH, et al: Mutation, sequence analysis, and association studies of alpha-synuclein in Parkinson’s disease. Neurology 1998; 51:1757-1759. 29. George JM, Jin H, Woods WS, et al: Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 1995; 15:361-372. 30. Abeliovich A, Schmitz Y, Farinas I, et al: Mice lacking alphasynuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000; 25:239-252. 31. Spillantini MG, Schmidt ML, Lee VM, et al: Alpha-synuclein in Lewy bodies. Nature 1997; 388:839-840. 32. Masliah E, Rockenstein E, Veinbergs I, et al: Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000; 287:1265-1269. 33. Feany MB, Bender WW: A Drosophila model of Parkinson’s disease. Nature 2000; 404:394-398. 34. Singleton AB, Farrer M, Johnson J, et al: Alpha-synuclein locus triplication causes Parkinson’s disease. Science 2003; 302:841. 35. Farrer M, Kachergus J, Forno L, et al: Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004; 55:174-179. 36. Zarranz JJ, Alegre J, Gomez-Esteban JC, et al: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004; 55:164-173. 37. Giasson BI, Duda JE, Quinn SM, et al: Neuronal alphasynucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002; 34:521-533. 38. Kirik D, Rosenblad C, Burger C, et al: Parkinson-like neurodegeneration induced by targeted overexpression of alphasynuclein in the nigrostriatal system. J Neurosci 2002; 22:2780-2791.

951

39. Conway KA, Lee SJ, Rochet JC, et al: Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci U S A 2000; 97:571-576. 40. Conway KA, Rochet JC, Bieganski RM, et al: Kinetic stabilization of the alpha-synuclein protofibril by a dopaminealpha-synuclein adduct. Science 2001; 294:1346-1349. 41. Tabrizi SJ, Orth M, Wilkinson JM, et al: Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. Hum Mol Genet 2000; 9:2683-2689. 42. Smith WW, Margolis RL, Li X, et al: Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 2005; 25:55445552. 43. Hasegawa M, Fujiwara H, Nonaka T, et al: Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem 2002; 277:49071-49076. 44. Chen L, Feany MB: Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 2005; 8:657-663. 45. Kitada T, Asakawa S, Hattori N, et al: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392:605-608. 46. Yamamura Y, Sobue I, Ando K, et al: Paralysis agitans of early onset with marked diurnal fluctuation of symptoms. Neurology 1973; 23:239-244. 47. Takahashi H, Ohama E, Suzuki S, et al: Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 1994; 44(3 Pt 1):437-441. 48. Matsumine H, Saito M, Shimoda-Matsubayashi S, et al: Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. Am J Hum Genet 1997; 60:588-596. 49. Hattori N, Kitada T, Matsumine H, et al: Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals. Ann Neurol 1998; 44:935-941. 50. Abbas N, Lucking CB, Ricard S, et al: A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson’s Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Hum Mol Genet 1999; 8:567-574. 51. Farrer M, Chan P, Chen R, et al: Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 2001; 50:293-300. 52. West A, Periquet M, Lincoln S, et al: Complex relationship between parkin mutations and Parkinson disease. Am J Med Genet 2002; 114:584-591. 53. Lucking CB, Durr A, Bonifati V, et al: Association between early-onset Parkinson’s disease and mutations in the parkin gene. French Parkinson’s Disease Genetics Study Group. N Engl J Med 2000; 342:1560-1567. 54. Kann M, Jacobs H, Mohrmann K, et al: Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol 2002; 51:621-625. 55. Klein C, Pramstaller PP, Kis B, et al: Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol 2000; 48:65-71. 56. Lucking CB, Bonifati V, Periquet M, et al: Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology 2001; 57:924-927. 57. Thobois S, Ribeiro MJ, Lohmann E, et al: Young-onset Parkinson disease with and without parkin gene mutations: a fluorodopa F 18 positron emission tomography study. Arch Neurol 2003; 60:713-718.

952

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Neurodegenerative Diseases

58. Hilker R, Klein C, Ghaemi M, et al: Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001; 49:367-376. 59. Khan NL, Brooks DJ, Pavese N, et al: Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 2002; 125:2248-2256. 60. Shimura H, Hattori N, Kubo S, et al: Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000; 25:302-305. 61. Zhang Y, Gao J, Chung KK, et al: Parkin functions as an E2dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A 2000; 97:13354-13359. 62. Imai Y, Soda M, Inoue H, et al: An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of parkin. Cell 2001; 105:891-902. 63. Lo BC, Schneider BL, Bauer M, et al: Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci U S A 2004; 101:17510-17515. 64. Goldberg MS, Fleming SM, Palacino JJ, et al: Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003; 278:43628-43635. 65. Palacino JJ, Sagi D, Goldberg MS, et al: Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 2004; 279:18614-18622. 66. Greene JC, Whitworth AJ, Kuo I, et al: Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A 2003; 100:4078-4083. 67. Darios F, Corti O, Lucking CB, et al: Parkin prevents mitochondrial swelling and cytochrome c release in mitochondriadependent cell death. Hum Mol Genet 2003; 12:517-526. 68. Muftuoglu M, Elibol B, Dalmizrak O, et al: Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov Disord 2004; 19:544-548. 69. Chung KK, Thomas B, Li X, et al: S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 2004; 304:1328-1331. 70. Leroy E, Boyer R, Auburger G, et al: The ubiquitin pathway in Parkinson’s disease. Nature 1998; 395:451-452. 71. Harhangi BS, Farrer MJ, Lincoln S, et al: The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson’s disease. Neurosci Lett 1999; 270:1-4. 72. Lincoln S, Vaughan J, Wood N, et al: Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson’s disease. Neuroreport 1999; 10:427-429. 73. Valente EM, Bentivoglio AR, Dixon PH, et al: Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet 2001; 68:895-900. 74. Valente EM, Abou-Sleiman PM, Caputo V, et al: Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004; 304:1158-1160. 75. Bentivoglio AR, Cortelli P, Valente EM, et al: Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov Disord 2001; 16:999-1006. 76. Rohe CF, Montagna P, Breedveld G, et al: Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism. Ann Neurol 2004; 56:427-431. 77. Hatano Y, Li Y, Sato K, et al: Novel PINK1 mutations in earlyonset parkinsonism. Ann Neurol 2004; 56:424-427. 78. Valente EM, Salvi S, Ialongo T, et al: PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 2004; 56:336-341.

79. Unoki M, Nakamura Y: Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 2001; 20:4457-4465. 80. Hunter T: Signaling: 2000 and beyond. Cell 2000; 100:113127. 81. Cohen P: The origins of protein phosphorylation. Nat Cell Biol 2002; 4:E127-E130. 82. Manning G, Whyte DB, Martinez R, et al: The protein kinase complement of the human genome. Science 2002; 298:19121934. 83. van Duijn CM, Dekker MC, Bonifati V, et al: Park7: a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet 2001; 69:629634. 84. Bonifati V, Rizzu P, van Baren MJ, et al: Mutations in the DJ1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003; 299:256-259. 85. Canet-Aviles RM, Wilson MA, Miller DW, et al: The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteinesulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A 2004; 101:9103-9108. 86. Zhang L, Shimoji M, Thomas B, et al: Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 2005; 14: 2063-2073. 87. Di Fonzo A, Rohe CF, Ferreira J, et al: A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet 2005; 365:412-415. 88. Nichols WC, Pankratz N, Hernandez D, et al: Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005; 365:410-412. 89. Kachergus J, Mata IF, Hulihan M, et al: Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005; 76:672-680. 90. Gilks WP, Abou-Sleiman PM, Gandhi S, et al: A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005; 365:415-416. 91. Deng H, Le W, Guo Y, et al: Genetic and clinical identification of Parkinson’s disease patients with LRRK2 G2019S mutation. Ann Neurol 2005; 57:933-934. 92. Zabetian CP, Samii A, Mosley AD, et al: A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005; 65:741-744. 93. Hernandez D, Paisan RC, Crawley A, et al: The dardarin G 2019 S mutation is a common cause of Parkinson’s disease but not other neurodegenerative diseases. Neurosci Lett 2005; 389:137-139. 94. Toft M, Sando SB, Melquist S, et al: LRRK2 mutations are not common in Alzheimer’s disease. Mech Ageing Dev 2005; 126:1201-1205. 95. Kay DM, Kramer P, Higgins D, et al: Escaping Parkinson’s disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005; 20:10771078. 96. Adams JR, van Netten H, Schulzer M, et al: PET in LRRK2 mutations: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain 2005; 128: 2777-2785. 97. Funayama M, Hasegawa K, Kowa H, et al: A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2q13.1. Ann Neurol 2002; 51:296-301. 98. Wszolek ZK, Pfeiffer RF, Tsuboi Y, et al: Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004; 62:1619-1622. 99. Zimprich A, Biskup S, Leitner P, et al: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004; 44:601-607.

chapter 71 parkinson’s disease 100. Ross OA, Farrer MJ: Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson’s disease. Biochem Soc Trans 2005; 33:586-590. 101. Ridley AJ: Rho family proteins: coordinating cell responses. Trends Cell Biol 2001; 11:471-477. 102. Hampshire DJ, Roberts E, Crow Y, et al: Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. J Med Genet 2001; 38:680-682. 103. Najim al-Din AS, Wriekat A, Mubaidin A, et al: Pallidopyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol Scand 1994; 89:347-352. 104. Hicks AA, Petursson H, Jonsson T, et al: A susceptibility gene for late-onset idiopathic Parkinson’s disease. Ann Neurol 2002; 52:549-555. 105. Scott WK, Nance MA, Watts RL, et al: Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA 2001; 286:2239-2244. 106. DeStefano AL, Golbe LI, Mark MH, et al: Genome-wide scan for Parkinson’s disease: the GenePD Study. Neurology 2001; 57:1124-1126. 107. Farrer M, Maraganore DM, Lockhart P, et al: alpha-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 2001; 10:1847-1851. 108. Tan EK, Tan C, Shen H, et al: Alpha synuclein promoter and risk of Parkinson’s disease: microsatellite and allelic size variability. Neurosci Lett 2003; 336:70-72. 109. West AB, Maraganore D, Crook J, et al: Functional association of the parkin gene promoter with idiopathic Parkinson’s disease. Hum Mol Genet 2002; 11:2787-2792. 110. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R: Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2004; 351:1972-1977. 111. Foster NL, Wilhelmsen K, Sima AA, et al: Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 1997; 41:706-715. 112. Hulette CM, Pericak-Vance MA, Roses AD, et al: Neuropathological features of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke Family 1684. J Neuropathol Exp Neurol 1999; 58:859866. 113. Gwinn-Hardy K, Chen JY, Liu HC, et al: Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese. Neurology 2000; 55:800-805. 114. Lu CS, Wu Chou YH, Yen TC, et al: Dopa-responsive parkinsonism phenotype of spinocerebellar ataxia type 2. Mov Disord 2002; 17:1046-1051. 115. Shan DE, Soong BW, Sun CM, et al: Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism. Ann Neurol 2001; 50:812-815. 116. Hagerman RJ, Leehey M, Heinrichs W, et al: Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X: Neurology 2001; 57:127-130. 117. Jacquemont S, Hagerman RJ, Leehey M, et al: Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003; 72:869-878. 118. Haberhausen G, Schmitt I, Kohler A, et al: Assignment of the dystonia-parkinsonism syndrome locus, DYT3, to a small region within a 1.8-Mb YAC contig of Xq13.1. Am J Hum Genet 1995; 57:644-650. 119. de Carvalho AP, Sweadner KJ, Penniston JT, et al: Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 2004; 43:169175. 120. Wooten GF, Currie LJ, Bennett JP, et al: Maternal inheritance in Parkinson’s disease. Ann Neurol 1997; 41:265-268.

953

121. Schapira AH, Holt IJ, Sweeney M, et al: Mitochondrial DNA analysis in Parkinson’s disease. Mov Disord 1990; 5:294-297. 122. Ozawa T, Tanaka M, Ino H, et al: Distinct clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and with Parkinson’s disease. Biochem Biophys Res Commun 1991; 176:938-946. 123. Ikebe S, Tanaka M, Ozawa T: Point mutations of mitochondrial genome in Parkinson’s disease. Brain Res Mol Brain Res 1995; 28:281-295. 124. Shoffner JM, Brown MD, Torroni A, et al: Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 1993; 17:171-184. 125. Lucking CB, Kosel S, Mehraein P, et al: Absence of the mitochondrial A7237T mutation in Parkinson’s disease. Biochem Biophys Res Commun 1995; 211:700-704. 126. Kosel S, Grasbon-Frodl EM, Hagenah JM, et al: Parkinson disease: analysis of mitochondrial DNA in monozygotic twins. Neurogenetics 2000; 2:227-230. 127. Richter G, Sonnenschein A, Grunewald T, et al: Novel mitochondrial DNA mutations in Parkinson’s disease. J Neural Transm 2002; 109:721-729. 128. Vives-Bauza C, Andreu AL, Manfredi G, et al: Sequence analysis of the entire mitochondrial genome in Parkinson’s disease. Biochem Biophys Res Commun 2002; 290:15931601. 129. van der Walt JM, Nicodemus KK, Martin ER, et al: Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 2003; 72:804-811. 130. Pyle A, Foltynie T, Tiangyou W, et al: Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD. Ann Neurol 2005; 57:564-567. 131. Ross OA, McCormack R, Maxwell LD, et al: mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson’s disease in the Irish. Exp Gerontol 2003; 38:397-405. 132. Luoma P, Melberg A, Rinne JO, et al: Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004; 364:875-882. 133. Mancuso M, Filosto M, Oh SJ, et al: A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and parkinsonism. Arch Neurol 2004; 61:1777-1779. 134. Rajput AH, Uitti RJ, Stern W, et al: Early onset Parkinson’s disease in Saskatchewan-environmental considerations for etiology. Can J Neurol Sci 1986; 13:312-316. 135. Rajput AH, Uitti RJ, Rajput AH: Neurological disorders and services in Saskatchewan: a report based on provincial health care records. Neuroepidemiology 1988; 7:145-151. 136. Behari M, Srivastava AK, Das RR, et al: Risk factors of Parkinson’s disease in Indian patients. J Neurol Sci 2001; 190:49-55. 137. Semchuk KM, Love EJ, Lee RG: Parkinson’s disease and exposure to rural environmental factors: a population based casecontrol study. Can J Neurol Sci 1991; 18:279-286. 138. Barbeau A, Roy M, Bernier G, et al: Ecogenetics of Parkinson’s disease: prevalence and environmental aspects in rural areas. Can J Neurol Sci 1987; 14:36-41. 139. Gorrell JM, DiMonte D, Graham D: The role of the environment in Parkinson’s disease. Environ Health Perspect 1996; 104:652-654. 140. Fall PA, Fredrikson M, Axelson O, et al: Nutritional and occupational factors influencing the risk of Parkinson’s disease: a case-control study in southeastern Sweden. Mov Disord 1999; 14:28-37. 141. Semchuk KM, Love EJ, Lee RG: Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 1992; 42:1328-1335.

954

Section

XII

Neurodegenerative Diseases

142. Seidler A, Hellenbrand W, Robra BP, et al: Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 1996; 46:1275-1284. 143. Fleming L, Mann JB, Bean J, et al: Parkinson’s disease and brain levels of organochlorine pesticides. Ann Neurol 1994; 36:100-103. 144. Corsini GU, Pintus S, Chiueh CC, et al: 1-Methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice is enhanced by pretreatment with diethyldithiocarbamate. Eur J Pharmacol 1985; 119:127-128. 145. Tanner CM, Goldman SM: Epidemiology of Parkinson’s disease. Neurol Clin 1996; 14:317-335. 146. Klawans HL, Stein RW, Tanner CM, et al: A pure parkinsonian syndrome following acute carbon monoxide intoxication. Arch Neurol 1982; 39:302-304. 147. Elwan MA, Richardson JR, Guillot TS, et al: Pyrethroid pesticide-induced alterations in dopamine transporter function. Toxicol Appl Pharmacol 2005. 148. Pittman JT, Dodd CA, Klein BG: Immunohistochemical changes in the mouse striatum induced by the pyrethroid insecticide permethrin. Int J Toxicol 2003; 22:359-370. 149. Bloomquist JR, Barlow RL, Gillette JS, et al: Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways. Neurotoxicology 2002; 23(4-5):537-544. 150. Imamura L, Yasuda M, Kuramitsu K, et al: Deltamethrin, a pyrethroid insecticide, is a potent inducer for the activitydependent gene expression of brain-derived neurotrophic factor in neurons. J Pharmacol Exp Ther 2006; 316:136-143. 151. Betarbet R, Sherer TB, MacKenzie G, et al: Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000; 3:1301-1306. 152. Manning-Bog AB, McCormack AL, Li J, et al: The herbicide paraquat causes up-regulation and aggregation of alphasynuclein in mice: paraquat and alpha-synuclein. J Biol Chem 2002; 277:1641-1644. 153. Champy P, Hoglinger GU, Feger J, et al: Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe. J Neurochem 2004; 88:63-69. 154. Tipton KF, Singer TP: Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem 1993; 61:1191-1206. 155. Hochberg F, Lilienfeld D, Olanow W, et al: Progression after chronic manganese exposure. Neurology 1993; 43:14791483. 156. Mena I: Manganese poisoning. In: Vinken PJ, Bruyn GW, editors. Handbook of Clinical Neurology. Amsterdam: North Holland Publishing Company, 1979, pp 217-237. 157. Jankovic J: Searching for a relationship between manganese and welding and Parkinson’s disease. Neurology 2005; 64: 2021-2028. 158. Ziegler L: Follow-up studies in persons who have had epidemic encephalitis. JAMA 1928; 21:138-141. 159. Von Economo C: The Sequelae of Encephalitis Lethargica. New York: Oxford University Press, 1931, pp 105-106. 160. Ebmeier KP, Mutch WJ, Calder SA, et al: Does idiopathic parkinsonism in Aberdeen follow intrauterine influenza? J Neurol Neurosurg Psychiatry 1989; 52:911-913. 161. Schwartz J, Elizan TS: Search for viral particles and virusspecific products in idiopathic Parkinson disease brain material. Ann Neurol 1979; 6:261-263. 162. Baron JA: Cigarette smoking and Parkinson’s disease. Neurology 1986; 36:1490-1496. 163. Ascherio A, Zhang SM, Hernan MA, et al: Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol 2001; 50:56-63.

164. McGeer PL, Itagaki S, Boyes BE, et al: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988; 38:12851291. 165. Boka G, Anglade P, Wallach D, et al: Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neurosci Lett 1994; 172:151-154. 166. Hunot S, Dugas N, Faucheux B, et al: FcepsilonRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J Neurosci 1999; 19:3440-3447. 167. McGeer PL, Schulzer M, McGeer EG: Arthritis and antiinflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 1996; 47:425-432. 168. In t’ Veld BA, Ruitenberg A, Hofman A, et al: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345:1515-1521. 169. Chen H, Zhang SM, Hernan MA, et al: Nonsteroidal antiinflammatory drugs and the risk of Parkinson disease. Arch Neurol 2003; 60:1059-1064. 170. Dexter DT, Wells FR, Agid F, et al: Increased nigral iron content in postmortem parkinsonian brain. Lancet 1987; 2:1219-1220. 171. Sofic E, Paulus W, Jellinger K, et al: Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 1991; 56:978-982. 172. Jellinger K, Paulus W, Grundke-Iqbal I, et al: Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J Neural Transm Park Dis Dement Sect 1990; 2:327-340. 173. Jellinger K, Kienzl E, Rumpelmair G, et al: Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J Neurochem 1992; 59:1168-1171. 174. Hirsch EC, Brandel JP, Galle P, et al: Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 1991; 56:446451. 175. Dexter DT, Carayon A, Vidailhet M, et al: Decreased ferritin levels in brain in Parkinson’s disease. J Neurochem 1990; 55:16-20. 176. Riederer P, Sofic E, Rausch WD, et al: Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 1989; 52:515-520. 177. Mann VM, Cooper JM, Daniel SE, et al: Complex I, iron, and ferritin in Parkinson’s disease substantia nigra. Ann Neurol. 1994. Dec;36:876-81. 178. Perry TL, Godin DV, Hansen S: Parkinson’s disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 1982; 33:305-310. 179. Sian J, Dexter DT, Lees AJ, et al: Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 1994; 36:348355. 180. Marttila RJ, Lorentz H, Rinne UK: Oxygen toxicity protecting enzymes in Parkinson’s disease. Increase of superoxide dismutase-like activity in the substantia nigra and basal nucleus. J Neurol Sci 1988; 86:321-331. 181. Saggu H, Cooksey J, Dexter D, et al: A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra. J Neurochem 1989; 53:692-697. 182. Hirsch EC, Graybiel AM, Agid Y: Selective vulnerability of pigmented dopaminergic neurons in Parkinson’s disease. Acta Neurol Scand Suppl 1989; 126:19-22. 183. Ceballos I, Lafon M, Javoy-Agid F, et al: Superoxide dismutase and Parkinson’s disease. Lancet 1990; 335:1035-1036. 184. Dexter D, Carter C, Agid F, et al: Lipid peroxidation as cause of nigral cell death in Parkinson’s disease. Lancet 1986; 2:639640.

chapter 71 parkinson’s disease 185. Sanchez-Ramos J, Ocervik E, Ames BN: A marker of oxyradical-mediated DNA damage (8-hydroxy-2′-deoxyguanosine) is increased in nigro-striatum of Parkinson’s disease brain. Neurodegeneration 3. 1994;197-204. 186. Itzhak Y, Ali SF: The neuronal nitric oxide synthase inhibitor, 7-nitroindazole, protects against methamphetamine-induced neurotoxicity in vivo. J Neurochem 1996; 67:1770-1773. 187. Kuiper MA, Visser JJ, Bergmans PL, et al: Decreased cerebrospinal fluid nitrate levels in Parkinson’s disease, Alzheimer’s disease and multiple system atrophy patients. J Neurol Sci 1994; 121:46-49. 188. Molina JA, Jimenez-Jimenez FJ, Navarro JA, et al: Cerebrospinal fluid nitrate levels in patients with Parkinson’s disease. Acta Neurol Scand 1996; 93(2-3):123-126. 189. Qureshi GA, Baig S, Bednar I, et al: Increased cerebrospinal fluid concentration of nitrite in Parkinson’s disease. Neuroreport 1995; 6:1642-1644. 190. Schapira AH, Cooper JM, Dexter D: Mitochondrial complex 1 deficienty in Parkinson’s disease. Annals of neurology 1989; 26:122-123. 191. Schapira AH, Cooper JM, Dexter D, et al: Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1989; 1:1269. 192. Schapira AH, Mann VM, Cooper JM, et al: Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 1990; 55:21422145. 193. Schapira AH: Evidence for mitochondrial dysfunction in Parkinson’s disease—a critical appraisal. Mov Disord 1994; 9:125-138. 194. Taylor DJ, Krige D, Barnes PR, et al: A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson’s disease. J Neurol Sci 1994; 125:77-81. 195. Penn AM, Roberts T, Hodder J, et al: Generalized mitochondrial dysfunction in Parkinson’s disease detected by magnetic resonance spectroscopy of muscle. Neurology 1995; 45:20972099. 196. Parker WD Jr, Boyson SJ, Parks JK: Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989; 26:719-723. 197. Krige D, Carroll MT, Cooper JM, et al: Platelet mitochondrial function in Parkinson’s disease. The Royal Kings and Queens Parkinson Disease Research Group. Ann Neurol 1992; 32:782788. 198. Haas RH, Nasirian F, Nakano K, et al: Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson’s disease. Ann Neurol 1995; 37:714-722. 199. Ansari KA, Johnson A; Olfactory function in patients with Parkinson’s disease. J Chronic Dis 1975; 28:493-497. 200. Doty RL, Deems DA, Stellar S: Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 1988; 38:12371244. 201. Doty RL, Stern MB, Pfeiffer C, et al: Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992; 55:138-142. 202. Montgomery EB Jr, Baker KB, Lyons K, et al: Abnormal performance on the PD test battery by asymptomatic first-degree relatives. Neurology 1999; 52:757-762. 203. Markopoulou K, Larsen KW, Wszolek EK, et al: Olfactory dysfunction in familial parkinsonism. Neurology 1997; 49:12621267. 204. Hawkes C: Olfaction in neurodegenerative disorder. Mov Disord 2003; 18:364-372. 205. Boeve BF, Silber MH, Ferman TJ, et al: Association of REM sleep behavior disorder and neurodegenerative disease may

206. 207. 208.

209. 210. 211.

212. 213. 214.

215. 216.

217. 218. 219. 220.

221.

222. 223.

224. 225.

955

reflect an underlying synucleinopathy. Mov Disord 2001; 16:622-630. Khan NL, Katzenschlager R, Watt H, et al: Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 2004; 62:1224-1226. Gagnon JF, Bedard MA, Fantini ML, et al: REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 2002; 59:585-589. Comella CL, Tanner CM, Ristanovic RK: Polysomnographic sleep measures in Parkinson’s disease patients with treatment-induced hallucinations. Ann Neurol 1993; 34:710714. Ohayon MM, Caulet M, Priest RG: Violent behavior during sleep. J Clin Psychiatry 1997; 58:369-376. Fantini ML, Ferini-Strambi L, Montplaisir J: Idiopathic REM sleep behavior disorder: toward a better nosologic definition. Neurology 2005; 64:780-786. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 1996; 46:388-393. Olson EJ, Boeve BF, Silber MH: Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000; 123:331-339. Albin RL, Koeppe RA, Chervin RD, et al: Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 2000; 55:1410-1412. Eisensehr I, Linke R, Noachtar S, et al: Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain 2000; 123:1155-1160. Byrne KG, Pfeiffer R, Quigley EM: Gastrointestinal dysfunction in Parkinson’s disease. A report of clinical experience at a single center. J Clin Gastroenterol 1994; 19:11-16. Korczyn AD: Autonomic nervous system screening in patients with early Parkinson’s disease. In Przuntek H, Riederer P, eds: Early Diagnosis and Preventive Therapy in Parkinson’s Disease. Vienna: Springer-Velag, 1989, pp 4148. Ashraf W, Pfeiffer RF, Park F, et al: Constipation in Parkinson’s disease: objective assessment and response to psyllium. Mov Disord 1997; 12:946-951. Astarloa R, Mena MA, Sanchez V, et al: Clinical and pharmacokinetic effects of a diet rich in insoluble fiber on Parkinson disease. Clin Neuropharmacol 1992; 15:375-380. Abbott RD, Petrovitch H, White LR, et al: Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 2001; 57:456-462. Singaram C, Ashraf W, Gaumnitz EA, et al: Dopaminergic defect of enteric nervous system in Parkinson’s disease patients with chronic constipation. Lancet 1995; 346:861864. Mathers SE, Kempster PA, Swash M, et al: Constipation and paradoxical puborectalis contraction in anismus and Parkinson’s disease: a dystonic phenomenon? J Neurol Neurosurg Psychiatry 1988; 51:1503-1507. Edwards LL, Quigley EM, Harned RK, et al: Defecatory function in Parkinson’s disease: response to apomorphine. Ann Neurol 1993; 33:490-493. Djaldetti R, Mosberg-Galili R, Sroka H, et al: Camptocormia (bent spine) in patients with Parkinson’s disease— characterization and possible pathogenesis of an unusual phenomenon. Mov Disord 1999; 14:443-447. Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology 1967; 17:427-442. Hunker CJ, Abbs JH: Uniform frequency of parkinsonian resting tremor in the lips, jaw, tongue, and index finger. Mov Disord 1990; 5:71-77.

956

Section

XII

Neurodegenerative Diseases

226. Scott RM, Brody JA, Schwab RS, et al: Progression of unilateral tremor and rigidity in Parkinson’s disease. Neurology 1970; 20:710-714. 227. Hely MA, Morris JG, Reid WG, et al: Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2004; 20:190-199. 228. Jellinger KA: Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991; 14:153-197. 229. Lees AJ, Blackburn NA, Campbell VL: The nighttime problems of Parkinson’s disease. Clin Neuropharmacol 1988; 11:512-519. 230. van Hilten B, Hoff JI, Middelkoop HA, et al: Sleep disruption in Parkinson’s disease. Assessment by continuous activity monitoring. Arch Neurol 1994; 51:922-928. 231. Paus S, Brecht HM, Koster J, et al: Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord 2003; 18:659-667. 232. Hobson DE, Lang AE, Martin WR, et al: Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA 2002; 287:455-463. 233. Garcia-Borreguero D, Larosa O, Bravo M: Parkinson’s disease and sleep. Sleep Med Rev 2003; 7:115-129. 234. Tracik F, Ebersbach G: Sudden daytime sleep onset in Parkinson’s disease: polysomnographic recordings. Mov Disord 2001; 16:500-506. 235. Ulivelli M, Rossi S, Lombardi C, et al: Polysomnographic characterization of pergolide-induced sleep attacks in idiopathic PD: Neurology 2002; 58:462-465. 236. Frucht S, Rogers JD, Greene PE, et al: Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52:1908-1910. 237. Schapira AH: Sleep attacks (sleep episodes) with pergolide. Lancet 2000; 355:1332-1333. 238. Olanow CW, Schapira AH, Roth T: Waking up to sleep episodes in Parkinson’s disease. Mov Disord 2000; 15:212215. 239. Rye DB, Bliwise DL, Dihenia B, et al: FAST TRACK: daytime sleepiness in Parkinson’s disease. J Sleep Res 2000; 9:6369. 240. Basson R: Sex and idiopathic Parkinson’s disease. Adv Neurol 2001; 86:295-300. 241. Marsden CD: Problems with long-term levodopa therapy for Parkinson’s disease. Clin Neuropharmacol 1994; 17(Suppl 2):S32-S44. 242. Hillen ME, Sage JI: Nonmotor fluctuations in patients with Parkinson’s disease. Neurology 1996; 47:1180-1183. 243. Goetz CG, Tanner CM, Levy M, et al: Pain in Parkinson’s disease. Mov Disord 1986; 1:45-49. 244. Hughes AJ, Daniel SE, Kilford L, et al: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55:181-184. 245. Hughes AJ, Daniel SE, Ben Shlomo Y, et al: The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125(Pt 4):861-870. 246. Tolosa E, Wenning G, Poewe W: The diagnosis of Parkinson’s disease. Lancet Neurol 2006; 5:75-86. 247. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287:1653-1661. 248. Whone AL, Watts RL, Stoessl AJ, et al: Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54:93-101. 249. Hardie RJ, Lees AJ: Neuroleptic-induced Parkinson’s syndrome: clinical features and results of treatment with levodopa. J Neurol Neurosurg Psychiatry 1988; 51:850-854.

250. Deuschl G, Bain P, Brin M: Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998; 13(Suppl) 3:2-23. 251. Cohen O, Pullman S, Jurewicz E, et al: Rest tremor in patients with essential tremor: prevalence, clinical correlates, and electrophysiologic characteristics. Arch Neurol 2003; 60:405410. 252. Chaudhuri KR, Buxton-Thomas M, Dhawan V, et al: Long duration asymmetrical postural tremor is likely to predict development of Parkinson’s disease and not essential tremor: clinical follow up study of 13 cases. J Neurol Neurosurg Psychiatry 2005; 76:115-117. 253. Wenning GK, Ben Shlomo Y, Magalhaes M, et al: Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994; 117:835-845. 254. Colosimo C, Albanese A, Hughes AJ, et al: Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson’s disease. Arch Neurol 1995; 52:294-298. 255. Hughes AJ, Colosimo C, Kleedorfer B, et al: The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry 1992; 55:1009-1013. 256. Litvan I, Agid Y, Calne D, et al: Clinical research criteria for the diagnosis of progressive supranuclear palsy (SteeleRichardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47:1-9. 257. Collins SJ, Ahlskog JE, Parisi JE, et al: Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psychiatry 1995; 58:167-173. 258. Grimes DA, Lang AE, Bergeron CB: Dementia as the most common presentation of cortical-basal ganglionic degeneration. Neurology 1999; 53:1969-1974. 259. Winikates J, Jankovic J: Clinical correlates of vascular parkinsonism. Arch Neurol 1999; 56:98-102. 260. Marder K, Tang MX, Cote L, et al: The frequency and associated risk factors for dementia in patients with Parkinson’s disease. Arch Neurol 1995; 52:695-701. 261. McKeith I, Mintzer J, Aarsland D, et al: Dementia with Lewy bodies. Lancet Neurol 2004; 3:19-28. 262. Schrag A, Good CD, Miszkiel K, et al: Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 2000; 54:697-702. 263. Kraft E, Trenkwalder C, Auer DP: T2*-weighted MRI differentiates multiple system atrophy from Parkinson’s disease. Neurology 2002; 59:1265-1267. 264. Schulz JB, Skalej M, Wedekind D, et al: Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson’s syndrome from multiple system atrophy and progressive supranuclear palsy. Ann Neurol 1999; 45:65-74. 265. Scherfler C, Seppi K, Donnemiller E, et al: Voxel-wise analysis of [123I]beta-CIT SPECT differentiates the Parkinson variant of multiple system atrophy from idiopathic Parkinson’s disease. Brain 2005; 128:1605-1612. 266. Marek KL, Seibyl JP, Zoghbi SS, et al: [123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology 1996; 46:231-237. 267. Poewe W, Scherfler C: Role of dopamine transporter imaging in investigation of parkinsonian syndromes in routine clinical practice. Mov Disord 2003; 18(Suppl 7):S16-S21. 268. Braune S, Reinhardt M, Schnitzer R, et al: Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999; 53:1020-1025. 269. Courbon F, Brefel-Courbon C, Thalamas C, et al: Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson’s disease. Mov Disord 2003; 18:890-897. 270. Becker G, Seufert J, Bogdahn U, et al: Degeneration of substantia nigra in chronic Parkinson’s disease visualized by

chapter 71 parkinson’s disease

271. 272.

273. 274.

275.

276. 277. 278. 279. 280. 281. 282. 283. 284. 285.

286. 287.

288. 289.

290.

transcranial color-coded real-time sonography. Neurology 1995; 45:182-184. Berg D, Siefker C, Becker G: Echogenicity of the substantia nigra in Parkinson’s disease and its relation to clinical findings. J Neurol 2001; 248:684-689. Kimber J, Mathias CJ, Lees AJ, et al: Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy. Brain 2000; 123:1422-1430. Barker R, Duncan J, Lees A; Subcutaneous apomorphine as a diagnostic test for dopaminergic responsiveness in parkinsonian syndromes. Lancet 1989; 1:675. Merello M, Nouzeilles MI, Arce GP, et al: Accuracy of acute levodopa challenge for clinical prediction of sustained longterm levodopa response as a major criterion for idiopathic Parkinson’s disease diagnosis. Mov Disord 2002; 17:795-798. Clarke CE, Davies P: Systematic review of acute levodopa and apomorphine challenge tests in the diagnosis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 2000; 69:590-594. Rajput AH: Levodopa prolongs life expectancy and is nontoxic to substantia nigra. Parkinsonism Relat Disord 2001; 8:95100. Karlsen KH, Tandberg E, Arsland D, et al: Health related quality of life in Parkinson’s disease: a prospective longitudinal study. J Neurol Neurosurg Psychiatry 2000; 69:584-589. Clarke CE, Zobkiw RM, Gullaksen E: Quality of life and care in Parkinson’s disease. Br J Clin Pract 1995; 49:288-293. Williams DR, Lees AJ: Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol 2005; 4:605-610. Evans AH, Katzenschlager R, Paviour D, et al: Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004; 19:397-405. Molina JA, Sainz-Artiga MJ, Fraile A, et al: Pathologic gambling in Parkinson’s disease: a behavioral manifestation of pharmacologic treatment? Mov Disord 2000; 15:869-872. Dodd ML, Klos KJ, Bower JH, et al: Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005; 62:1377-1381. Fahn S: Adverse effects of levodopa. In Olanow CW, ed: The Scientific Basis for the Treatment of Parkinson’s Disease. Carnforth: Parthenon Publishing Group, 1992, pp 89-112. Contin M, Riva R, Martinelli P, et al: A levodopa kineticdynamic study of the rate of progression in Parkinson’s disease. Neurology 1998; 51:1075-1080. Shoulson I, Glaubiger GA, Chase TN: On-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975; 25:1144-1148. Hardie RJ, Lees AJ, Stern GM: On-off fluctuations in Parkinson’s disease. A clinical and neuropharmacological study. Brain 1984; 107:487-506. Mouradian MM, Heuser IJ, Baronti F, et al: Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 1990; 27:18-23. Nutt JG: On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol 1987; 22:535540. Kurth MC, Tetrud JW, Tanner CM, et al: Double-blind, placebo-controlled, crossover study of duodenal infusion of levodopa/carbidopa in Parkinson’s disease patients with “onoff” fluctuations. Neurology 1993; 43:1698-1703. Kostic V, Przedborski S, Flaster E, et al: Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 1991; 41:202205.

957

291. Obeso JA, Rodriguez-Oroz C, Chana P, et al: The evolution and origin of motor complications in Parkinson’s disease. Neuroogy 2000; 55(Suppl 4):S13-S20. 292. Parkinson Study Group: Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42:747-755. 293. Russ H, Muller T, Woitalla D, Rahbar A, Hahn J, Kuhn W: Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects. Naunyn Schmiedebergs Arch Pharmacol 1999; 360:719-720. 294. Hauser RA, Molho E, Shale H, et al: A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson’s disease patients. Tolcapone De Novo Study Group. Mov Disord 1998; 13:643-647. 295. Jorga KM: COMT inhibitors: pharmacokinetic and pharmacodynamic comparisons. Clin Neuropharmacol 1998; 21:S9S16. 296. Assal F, Spahr L, Hadengue A, et al: Tolcapone and fulminant hepatitis. Lancet 1998; 352:958. 297. Korlipara LV, Cooper JM, Schapira AH: Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells. Neuropharmacology 2004; 46:562-569. 298. Marco AD, Appiah-Kubi LS, Chaudhuri KR: Use of the dopamine agonist cabergoline in the treatment of movement disorders. Exp Opin Pharmacother 2002; 3:1481-1487. 299. Olanow CW: Single blind double observer-controlled study of carbidopa/levodopa vs bromocriptine in untreated Parkinson patients. Arch Neurol 1988; 45:205. 300. Staal-Schreinemachers AL, Wesseling H, Kamphuis DJ, et al: Low-dose bromocriptine therapy in Parkinson’s disease: double-blind, placebo-controlled study. Neurology 1986; 36:291-293. 301. Rinne UK, Bracco F, Chouza C, et al: Cabergoline in the treatment of early Parkinson’s disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group. Neurology 1997; 48:363-368. 302. Rinne UK, Bracco F, Chouza C, et al: Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs 1998; 55. Suppl 1:23-30. 303. Barone P, Bravi D, Bermejo-Pareja F, et al: Pergolide monotherapy in the treatment of early PD: a randomized, controlled study. Pergolide Monotherapy Study Group. Neurology 1999; 53:573-579. 304. Parkinson Study Group: Safety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study. JAMA 1997; 278:125-130. 305. Shannon KM, Bennett JP Jr, Friedman JH: Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s disease. The Pramipexole Study Group. Neurology 1997; 49:724-728. 306. Korczyn AD, Brunt ER, Larsen JP, et al: A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson’s disease. The 053 Study Group. Neurology 1999; 53:364370. 307. Adler CH, Sethi KD, Hauser RA, et al: Ropinirole for the treatment of early Parkinson’s disease. The Ropinirole Study Group. Neurology 1997; 49:393-399. 308. Hoehn MM, Elton RL: Low dosages of bromocriptine added to levodopa in Parkinson’s disease. Neurology 1985; 35:199206. 309. Toyokura Y, Mizuno Y, Kase M, et al: Effects of bromocriptine on parkinsonism. A nation-wide collaborative double-blind study. Acta Neurol Scand 1985; 72:157-170.

958

Section

XII

Neurodegenerative Diseases

310. Inzelberg R, Nisipeanu P, Rabey JM, et al: Double-blind comparison of cabergoline and bromocriptine in Parkinson’s disease patients with motor fluctuations. Neurology 1996; 47:785-788. 311. Olanow CW, Fahn S, Muenter M, et al: A multicenter doubleblind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson’s disease. Mov Disord 1994; 9:40-47. 312. Diamond SG, Markham CH, Treciokas LJ: Double-blind trial of pergolide for Parkinson’s disease. Neurology 1985; 35:291295. 313. Guttman M: Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson’s disease. International Pramipexole-Bromocriptine Study Group. Neurology 1997; 49:1060-1065. 314. Lieberman A, Ranhosky A, Korts D: Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 1997; 49:162-168. 315. Lieberman A, Olanow CW, Sethi K, et al: A multicenter trial of ropinirole as adjunct treatment for Parkinson’s disease. Ropinirole Study Group. Neurology 1998; 51:1057-1062. 316. Schapira AH: Excessive daytime sleepiness in Parkinson’s disease. Neurology 2004; 63(Suppl 3):S24-S27. 317. Holloway RG, Shoulson I, Fahn S, et al: Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004; 61:1044-1053. 318. Muller T, Fritze J: Fibrosis associated with dopamine agonist therapy in Parkinson’s disease. Clin Neuropharmacol 2003; 26:109-111. 319. Van Camp G, Flamez A, Cosyns B, et al: Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004; 363:1179-1183. 320. Rascol O, Brooks DJ, Korczyn AD, et al: A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342:1484-1491. 321. Parkinson Study Group: Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. JAMA 2000; 284:1931-1938. 322. Oertel WH: Pergolide versus levodopa (PELMOPET). Mov Disord 2000; 15(Suppl 3):4. 323. Schapira AH: Disease modification in Parkinson’s disease. Lancet Neurol 2004; 3:362-368. 324. Parkinson Study Group: Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328:176-183. 325. Olanow CW, Hauser RA, Gauger L, et al: The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 1995; 38:771-777. 326. Shoulson I, Oakes D, Fahn S, et al: Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 2002; 51:604-612. 327. Ives NJ, Stowe RL, Marro J, et al: Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525. patients. BMJ 2004; 11:329. 328. Parkinson Study Group: A controlled, randomized, delayedstart study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61:561-566. 329. Parkinson Study Group: A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62:241-248. 330. Rascol O, Brooks DJ, Melamed E, et al: Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy

331. 332.

333.

334. 335. 336. 337.

338. 339. 340. 341. 342.

343.

344.

345. 346.

347. 348. 349.

with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365:947-954. Cantello R, Riccio A, Gilli M, et al: Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30. patients. Ital J Neurol Sci 1986; 7:139-143. Martin WE, Loewenson RB, Resch JA, et al: A controlled study comparing trihexyphenidyl hydrochloride plus levodopa with placebo plus levodopa in patients with Parkinson’s disease. Neurology 1974; 24:912-919. Cooper JA, Sagar HJ, Doherty SM, et al: Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson’s disease. A follow-up study of untreated patients. Brain 1992; 115:1701-1725. Friedman JH, Koller WC, Lannon MC, et al: Benztropine versus clozapine for the treatment of tremor in Parkinson’s disease. Neurology 1997; 48:1077-1081. Schwab RS, England AC Jr, Poskanzer DC, Young RR: Amantadine in the treatment of Parkinson’s disease. JAMA 1969; 208:1168-1170. Factor SA, Molho ES: Transient benefit of amantadine in Parkinson’s disease: the facts about the myth. Mov Disord 1999; 14:515-517. Parkes JD, Baxter RC, Marsden CD, Rees JE: Comparative trial of benzhexol, amantadine, and levodopa in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1974; 37:422-426. Walker JE, Albers JW, Tourtellotte WW, et al: A qualitative and quantitative evaluation of amantadine in the treatment of Parkinson’s disease. J Chronic Dis 1972; 25:149-182. Shulman LM, Minagar A, Rabinstein A, et al: The use of dopamine agonists in very elderly patients with Parkinson’s disease. Mov Disord 2000; 15:664-668. Schapira AH, Obeso JA; Timing of treatment initiation in Parkinson’s disease: a need for re-appraisal? Ann Neurol 2006; 59:559-562. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al: Pathophysiology of the basal ganglia in Parkinson’s disease. Trends Neurosci 2000; 23(Suppl):S8-S19. Pifl C, Schingnitz G, Hornykiewicz O: Striatal and nonstriatal neurotransmitter changes in MPTP-parkinsonism in rhesus monkey: the symptomatic versus the asymptomatic condition. Neurochem Int 1992; 20(Suppl):295S-297S. Sossi V, Fuente-Fernandez R, Holden JE, et al: Changes of dopamine turnover in the progression of Parkinson’s disease as measured by positron emission tomography: their relation to disease-compensatory mechanisms. J Cereb Blood Flow Metab 2004; 24:869-876. Hilker R, Schweitzer K, Coburger S, et al: Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity. Arch Neurol 2005; 62:378-382. Bezard E, Boraud T, Bioulac B, et al: Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms. Eur J Neurosci 1999; 11:2167-2170. Bezard E, Dovero S, Prunier C, et al: Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 2001; 21:6853-6861. Fabbrini G, Mouradian MM, Juncos JL, et al: Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, Part I: Ann Neurol 1988; 24:366-371. Horstink MW, Zijlmans JC, Pasman JW, et al: Which risk factors predict the levodopa response in fluctuating Parkinson’s disease? Ann Neurol 1990; 27:537-543. Roos RA, Vredevoogd CB, van der Velde EA: Response fluctuations in Parkinson’s disease. Neurology 1990; 40:13441346.

chapter 71 parkinson’s disease 350. Koller WC, Hutton JT, Tolosa E, et al: Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology 1999; 53:1012-1019. 351. Stocchi F, Ruggieri S, Vacca L, et al: Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson’s disease. Brain 2002; 125(Pt 9):2058-2066. 352. Stocchi F, Vacca L, Berardelli A, et al: Dual dopamine agonist treatment in Parkinson’s disease. J Neurol 2003; 250:822-826. 353. Rinne UK, Larsen JP, Siden A, et al: Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998; 51:1309-1314. 354. Lhermitte F, Agid Y, Signoret JL: Onset and end-of-dose levodopa-induced dyskinesias. Possible treatment by increasing the daily doses of levodopa. Arch Neurol 1978; 35:261263. 355. Verhagen ML, Del Dotto P, van den MP, et al: Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 1998; 50:1323-1326. 356. Metman LV, Del Dotto P, LePoole K, et al: Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56:1383-1386. 357. Snow BJ, Macdonald L, Mcauley D, et al: The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000; 23:82-85. 358. Corrigan MH, Denahan AQ, Wright CE, et al: Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 2000; 11:58-65. 359. Lemke MR, Brecht HM, Koester J, et al: Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci 2005; 17:214-220. 360. Rektorova I, Rektor I, Bares M, et al: Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 2003; 10:399-406. 361. Pollak P, Tison F, Rascol O, et al: Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry 2004; 75:689-695. 362. Fernandez HH, Trieschmann ME, Burke MA, et al: Long-term outcome of quetiapine use for psychosis among Parkinsonian patients. Mov Disord 2003; 18:510-514. 363. Mancini F, Tassorelli C, Martignoni E, et al: Long-term evaluation of the effect of quetiapine on hallucinations, delusions and motor function in advanced Parkinson disease. Clin Neuropharmacol 2004; 27:33-37. 364. Emre M, Aarsland D, Albanese A, et al: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509-2518. 365. Happe S, Pirker W, Sauter C, et al: Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol 2001; 248:632-634. 366. Raffaele R, Vecchio I, Giammusso B, et al: Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson’s disease. Eur Urol 2002; 41:382-386. 367. O’Sullivan JD: Apomorphine as an alternative to sildenafil in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002; 72:681. 368. Mancini F, Zangaglia R, Cristina S, et al: Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism. Mov Disord 2003; 18:685-688. 369. Narabayashi H: Stereotaxic Vim thalamotomy for treatment of tremor. Eur Neurol 1989; 29(Suppl 1):29-32.

959

370. Tasker RR: Thalamotomy. Neurosurg Clin N Am 1990; 1:841864. 371. Dogali M, Fazzini E, Kolodny E, et al: Stereotactic ventral pallidotomy for Parkinson’s disease. Neurology 1995; 45:753761. 372. Baron MS, Vitek JL, Bakay RA, et al: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol 1996; 40:355-366. 373. Lang AE, Lozano AM, Montgomery E, et al: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997; 337:1036-1042. 374. Fine J, Duff J, Chen R, et al: Long-term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. N Engl J Med 2000; 342:1708-1714. 375. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990; 249:1436-1438. 376. Aziz TZ, Peggs D, Sambrook MA, et al: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 1991; 6:288-292. 377. Guridi J, Herrero MT, Luquin MR, et al: Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. Brain 1996; 119:1717-1727. 378. Alvarez L, Macias R, Guridi J, et al: Dorsal subthalamotomy for Parkinson’s disease. Mov Disord 2001; 16:72-78. 379. Su PC, Tseng HM, Liu HM, et al: Treatment of advanced Parkinson’s disease by subthalamotomy: one-year results. Mov Disord 2003; 18:531-538. 380. Alvarez L, Macias R, Lopez G, et al: Bilateral subthalamotomy in Parkinson’s disease: initial and long-term response. Brain 2005; 128:570-583. 381. Chen CC, Lee ST, Wu T, et al: Hemiballism after subthalamotomy in patients with Parkinson’s disease: report of 2 cases. Mov Disord 2002; 17:1367-1371. 382. Tseng HM, Su PC, Liu HM: Persistent hemiballism after subthalamotomy: the size of the lesion matters more than the location. Mov Disord 2003; 18:1209-1211. 383. Benabid AL, Pollak P, Louveau A, et al: Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987; 50:344-346. 384. Benazzouz A, Hallett M: Mechanism of action of deep brain stimulation. Neurology 2000; 55(Suppl 6):S13-S16. 385. Blond S, Caparros-Lefebvre D, Parker F, et al: Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg 1992; 77:62-68. 386. Benabid AL, Pollak P, Gao D, et al: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996; 84:203-214. 387. Koller W, Pahwa R, Busenbark K, et al: High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997; 42:292299. 388. Limousin P, Pollak P, Benazzouz A, et al: Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995; 345:91-95. 389. Limousin P, Krack P, Pollak P, et al: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998; 339:1105-1111. 390. Kumar R, Lozano AM, Kim YJ, et al: Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998; 51:850-855. 391. Bejjani B, Damier P, Arnulf I, et al: Pallidal stimulation for Parkinson’s disease. Two targets? Neurology 1997; 49:15641569.

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392. Pahwa R, Wilkinson S, Smith D, et al: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997; 49:249-253. 393. Siegfried J, Lippitz B: Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994; 35:1126-1129. 394. Volkmann J, Sturm V, Weiss P, et al: Bilateral high-frequency stimulation of the internal globus pallidus in advanced Parkinson’s disease. Ann Neurol 1998; 44:953-961. 395. Krack P, Batir A, Van Blercom N, et al: Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349:1925-1934. 396. The Deep-Brain Stimulation for Parkinson’s Disease Study Group: Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001; 345:956-963. 397. Oh MY, Abosch A, Kim SH, et al: Long-term hardware-related complications of deep brain stimulation. Neurosurgery 2002; 50:1268-1274 398. Krack P, Pollak P, Limousin P, et al: Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998; 43:180-192. 399. Freed CR, Greene PE, Breeze RE, et al: Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Eng J Med 2001; 344:710-719. 400. Greene PE, Fahn S, Tsai WY, et al: Severe spontaneous dyskinesias: a disabling complication of embryonic dopaminergic tissue implants in a subset of transplanted patients with advanced parkinson’s disease. Mov Disor 1999; 14:904. 401. Olanow CW, Goetz CG, Kordower JH, et al: A double blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003; 54:403-414. 402. Bjorklund LM, Sanchez-Pernaute R, Chung S, et al: Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 2002; 99:2344-2349. 403. Gash DM, Zhang Z, Cass WA, et al: Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys. J Comp Neurol 1995; 363:345-358. 404. Nutt JG, Burchiel KJ, Comella CL, et al: Randomized, doubleblind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003; 60:69-73. 405. Gill SS, Patel NK, Hotton GR, et al: Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003; 9:589-595. 406. Lang AE, Gill S, Patel NK, et al: Randomized control trial of intraputaminal glial cell line-derived neurotrophic factor infusion in Parkinson’s disease. Ann Neurol 2006; 59:459466. 407. Mytilineou C, Cohen G: Deprenyl protects dopamine neurons from the neurotoxic effect of 1-methyl-4-phenylpyridinium ion. J Neurochem 1985; 45:1951-1953. 408. Tatton WG, Greenwood CE: Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 1991; 30:666-672. 409. Wu RM, Chiueh CC, Pert A, et al: Apparent antioxidant effect of l-deprenyl on hydroxyl radical formation and nigral injury elicited by MPP+ in vivo. Eur J Pharmacol 1993; 243:241247. 410. Wu RM, Chen RC, Chiueh CC: Effect of MAO-B inhibitors on MPP+ toxicity in Vivo. Ann N Y Acad Sci 2000; 899:255-261. 411. Tatton WG, Ju WY, Holland DP, et al: (-)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis. J Neurochem 1994; 63:1572-1575.

412. Wadia JS, Chalmers-Redman RM, Ju WJ, et al: Mitochondrial membrane potential and nuclear changes in apoptosis caused by serum and nerve growth factor withdrawal: time course and modification by (-)-deprenyl. J Neurosci 1998; 18:932947. 413. Ogawa N, Tanaka K, Asanuma M, et al: Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro. Brain Res 1994; 657(1-2):207-213. 414. Muralikrishnan D, Mohanakumar KP: Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J 1998; 12:905-912. 415. Kondo T, Ito T, Sugita Y: Bromocriptine scavenges methamphetamine-induced hydroxyl radicals and attenuates dopamine depletion in mouse striatum. Ann N Y Acad Sci 1994; 738:222-229. 416. Finotti N, Castagna L, Moretti A, et al: Reduction of lipid peroxidation in different rat brain areas after cabergoline treatment. Pharmacol Res 2000; 42:287-291. 417. Yoshioka M, Tanaka K, Miyazaki I, et al: The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals. Neurosci Res 2002; 43:259-267. 418. Nishibayashi S, Asanuma M, Kohno M, et al: Scavenging effects of dopamine agonists on nitric oxide radicals. J Neurochem 1996; 67:2208-2211. 419. Gomez-Vargas M, Nishibayashi-Asanuma S, Asanuma M, et al: Pergolide scavenges both hydroxyl and nitric oxide free radicals in vitro and inhibits lipid peroxidation in different regions of the rat brain. Brain Res 1998; 790:202-208. 420. Iida M, Miyazaki I, Tanaka K, et al: Dopamine D2. receptormediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. Brain Res 1999; 838:51-59. 421. Clow A, Freestone C, Lewis E, et al: The effect of pergolide and MDL 72974 on rat brain CuZn superoxide dismutase. Neurosci Lett 1993; 164:41-43. 422. Kakimura J, Kitamura Y, Takata K, et al: Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole. Eur J Pharmacol 2001; 417:59-67. 423. Gu M, Iravani MM, Cooper JM, King D, et al: Pramipexole protects against apoptotic cell death by nondopaminergic mechanisms. J Neurochem 2004; 91:1075-1081. 424. Iravani MM, Haddon CO, Cooper JM, et al: Pramipexole protects against MPTP toxicity in nonhuman primates. J Neurochem 2006; 96:1315-1321. 425. Schapira AH, Olanow CW: Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004; 291:358-364. 426. Ahlskog JE: Slowing Parkinson’s disease progression: recent dopamine agonist trials. Neurology 2003; 60:381-389. 427. Olanow CW: A radical hypothesis for neurodegeneration. Trends Neurosci 1993; 16:439-444. 428. Agid Y, Olanow CW, Mizuno Y: Levodopa: why the controversy? Lancet 2002; 360:575. 429. Fahn S, Oakes D, Shoulson I, et al: Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004; 351:24982508. 430. Albin RL, Frey KA; Initial agonist treatment of Parkinson disease: a critique. Neurology 2003; 60:390-394. 431. Wooten GF: Agonists vs levodopa in PD: the thrilla of whitha. Neurology 2003; 60:360-362. 432. Shults CW, Oakes D, Kieburtz K, et al: Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59:1541-1550.

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PARKINSON PLUS DISORDERS ●

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Werner Poewe and Gregor K. Wenning

The term parkinson plus disorders has been coined to embrace a heterogeneous group of movement disorders with prominent signs of parkinsonism plus additional features that allow clinical separation of these entities from classic idiopathic Parkinson disease (IPD). A synonymous designation is “atypical parkinsonian disorders” where the prefix “atypical” again refers to features that either are not part of the clinical spectrum of IPD—such as cerebellar ataxia, pyramidal tract signs, myoclonus, supranuclear gaze palsy, or apraxia—or are more pronounced and/or occur earlier in the disease course compared with IPD—such as autonomic failure or dementia. Poor or absent responses to L-dopa is another criterion of “atypical” parkinsonian disorders (APDs). As a group, these disorders have never been strictly defined, but by common understanding, they include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB).

Epidemiology There are only few descriptive epidemiological studies on MSA. Bower and colleagues reported the incidence of MSA over a 14year period in Olmsted County, Minnesota. Nine incident cases of MSA were identified, none of which had an onset before the age of 50 years. The reported crude incidence rate was 0.6 case per 100,000 population per year; when the age band of greater than 50 years was examined, the estimate rose to 3 cases per 100,000 population. Estimates of the prevalence of MSA (per 100,000 in the population) in four studies ranged from 1.9 to 4.9.11-14 These prevalence figures are similar to those of other well-known neurodegenerative disorders such as Huntington disease and motor neuron disease. Although many studies report a possible role of environmental toxins in Parkinson disease, such a role is even more likely in MSA, as this is a sporadic disease. However, to date only three studies have addressed environmental risk factors in MSA.15-17 So far, no single environmental factor has been clearly established as conferring increased or reduced risks to develop MSA.

MULTIPLE SYSTEM ATROPHY MSA is a sporadic neurodegenerative disorder characterized clinically by any combination of parkinsonian, autonomic, cerebellar, or pyramidal symptoms and signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions (GCIs) in several brain and spinal cord structures. The term multiple system atrophy was introduced in 19691; however, cases of MSA were previously reported under the rubrics of striatonigral degeneration (SND),2-4 olivopontocerebellar atrophy (OPCA),5,6 Shy-Drager syndrome (SDS),7 and idiopathic orthostatic hypotension (OH). In 1989, GCIs were first described in the brains of patients with MSA regardless of clinical presentation.8 GCIs were not present in a large series of patients with other neurodegenerative disorders. The abundant presence of GCIs in all clinical subtypes of MSA led to the recognition of SDS, SND, and sporadic OPCA as one disease entity characterized by neuronal multisystem degeneration with unique oligodendroglial inclusion pathology. In the late 1990s, α-synuclein immunostaining was recognized as a sensitive marker of inclusion pathology in MSA,9,10 and MSA is now classified among the “synucleinopathies” along with Parkinson disease and dementia with Lewy bodies (DLBs).

Clinical Presentation, Course, and Prognosis The disease affects both men and women, it usually starts in the sixth decade, and it relentlessly progresses with a mean survival of 6 to 9 years.18-21 There is considerable variation of disease progression, with survival of longer than 15 years in some instances. Clinically, cardinal features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Previous studies suggest that 29% to 33% of patients with isolated late-onset cerebellar ataxia and 8% of patients presenting with parkinsonism eventually develop MSA.22-24 Two major motor presentations can be distinguished clinically. Parkinsonian features predominate in 80% of patients (MSA-P subtype), and cerebellar ataxia is the major motor feature in 20% of patients (MSA-C subtype).21,25 Importantly, both motor presentations of MSA are associated with similar survival times.20 However, MSA-P patients have a more rapid functional deterioration than MSA-C patients.18 MSA-P–associated parkinsonism is characterized by progressive akinesia and rigidity. Jerky postural tremor and, less

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Neurodegenerative Diseases a more severe degree than in Parkinson disease. In contrast, constipation occurs equally in Parkinson disease and MSA. Symptomatic OH is present in 68% of clinically diagnosed patients, but recurrent syncopes emerge in only 15%.21 Levodopa or dopamine agonists may provoke or worsen OH.

Diagnostic Criteria

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Figure 72–1. Orofacial dystonia in MSA. (From Wenning GK, Geser F, Poewe W. The ‘risus sardonicus’ of multiple system atrophy. Mov Disord 2003; 18:1211.)

commonly, tremor at rest may be superimposed. Frequently, patients exhibit orofacial or craniocervical dystonia (Fig. 72–1)26 associated with a characteristic quivering high-pitched dysarthria. Postural stability is compromised early on; however, recurrent falls at disease onset are unusual, in contrast to progressive supranuclear palsy (PSP). Differential diagnosis of MSA-P and Parkinson disease may be exceedingly difficult in the early stages due to a number of overlapping features such as rest tremor or asymmetrical akinesia and rigidity. Furthermore, L-dopa–induced improvement of parkinsonism may be seen in 30% of MSA-P patients. However, the benefit is transient in most of these subjects, leaving 90% of the MSA-P patients unresponsive to L-dopa in the long term. LDopa–induced dyskinesia affecting orofacial and neck muscles occurs in 50% of MSA-P patients, sometimes in the absence of motor benefit.27 In most instances, a fully developed clinical picture of MSA-P evolves within 5 years of disease onset, allowing a clinical diagnosis during follow-up.28 The cerebellar disorder of MSA-C comprises gait ataxia, limb kinetic ataxia, and scanning dysarthria as well as cerebellar oculomotor disturbances. Patients with MSA-C usually develop additional noncerebellar symptoms and signs but before doing so may be indistinguishable from other patients with idiopathic late-onset cerebellar ataxia, many of whom have a disease restricted clinically to cerebellar signs and pathologically to degeneration of the cerebellum and olives.22 Dysautonomia is characteristic of both MSA motor presentations, primarily comprising urogenital and orthostatic dysfunction. Early impotence (erectile dysfunction) is virtually universal in men with MSA, and urinary incontinence or retention, often early in the course or as presenting symptoms, is frequent.21 Disorders of micturition in MSA are due to changes in the complex peripheral and central innervation of the bladder29 and generally occur more commonly, earlier, and to

Clinical diagnostic criteria for MSA were first proposed by Quinn,30,31 who classified cases as either SND or OPCA type MSA depending on the predominance of parkinsonism or cerebellar ataxia. More recently, operationalized criteria have been proposed by an International Consensus Conference.25 The consensus criteria have since been widely established in the research community as well as movement disorders clinics. They define three diagnostic categories of increasing certainty: possible, probable, and definite. The diagnosis of possible and probable MSA is based on the presence of specific clinical features (Table 72–1). In addition, exclusion criteria have to be considered. A definite diagnosis requires a typical neuropathological lesion pattern with α-synuclein–positive GCIs. A recent retrospective evaluation of the Consensus criteria on pathologically proven cases showed excellent positive predictive values for both possible and probable MSA; however, sensitivity for probable MSA was poor.32 While such formal diagnostic criteria are important for certain types of clinical research, they add little to the problem of detecting early cases, and improved screening instruments are certainly needed. Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs or autonomic failure as major diagnostic clues, certain other features (“red flags”) such as orofacial dystonia, stridor, or REM sleep behavior disorder (RBD) may raise suspicion of MSA.30,33 MSA patients may present with isolated RBD.34-36 RBD and other sleep disorders are more common in patients with MSA than in those with Parkinson disease matched for disease duration, reflecting both a profound striatal monoaminergic deficit37 and diffuse subcortical and brainstem disease in MSA.38

Genetics MSA, as reflected in its current definition, is regarded as a sporadic disease,39 and no confirmed familial cases of MSA have been described; notwithstanding, it is conceivable that genetic factors may play a role in the etiology of the disease. This has, for example, been convincingly demonstrated for PSP,40 another disease that, in the vast majority of cases, is a sporadic disease. However, initial screening studies for candidate genes revealed no risk factors.41,42 Other studies have looked for polymorphisms or mutations in candidate genes, which may predispose an individual toward developing MSA. The apolipoprotein ε4 allele is not overrepresented in MSA when compared with controls, and there have been conflicting reports of the association of a cytochrome P450-2D6 polymorphism with MSA.43,44,45 Furthermore, there is no evidence to support an association between MSA and polymorphisms in the H5 pore region of the human homolog of the weaver mouse gene hiGIRK2, the insulin-like growth factor 1 receptor gene, or the ciliary neurotrophic factor gene.41 Genotyping of a functional polymorphism in the dopamine beta-hydroxylase (DBH) gene showed

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T A B L E 72–1. Multiple System Atrophy Consensus Criteria Domain

Criterion

Feature

Autonomic and urinary dysfunction

Orthostatic fall in blood pressure (by 30 mm Hg systolic or 15 mm Hg diastolic) or persistent urinary incontinence with erectile dysfunction in men or both Bradykinesia plus rigidity

Orthostatic hypotension (by 20 mm Hg systolic or 10 mm Hg diastolic) Urinary incontinence or incomplete bladder emptying

Parkinsonism

Cerebellar dysfunction

Corticospinal tract dysfunction

or postural instability or tremor Gait ataxia plus ataxic dysarthria or limb ataxia or sustained gaze-evoked nystagmus No defining features

Bradykinesia (progressive reduction in speed and amplitude of voluntary movements during repetitive actions) Rigidity Postural instability (loss of primary postural reflexes) Tremor (postural, resting, or both) Gait ataxia (wide-based stance with irregular steps) Ataxic dysarthria Limb ataxia Sustained gaze-evoked nystagmus Extensor plantar responses with hyperreflexia

Nomenclature of clinical domains, features (disease characteristics), and criteria (defining features or composite of features) used in the diagnosis of multiple system atrophy. Modified from Gilman S, Sima AA, Junck L, et al: Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996; 39: 241-255.

no association between the DBH–1021 C→T polymorphism and MSA.46 Increased expression of a brain specific protein called ZNF231 in cerebellar neurons has been reported to occur in patients with MSA.47 The gene is located on chromosome 3p21 and encodes a neuronal double zinc finger protein with a nuclear targeting sequence, suggesting that it might function as a transcription regulator. The importance of this finding is as yet uncertain, but it is possible that patients with MSA differ from unaffected individuals by sequence polymorphisms within, and flanking, the putative functional motifs of the ZNF231 gene. Gilman and colleagues48 reported an MSA-like phenotype including GCIs in one SCA-1 (spinocerebellar ataxia type 1) family. Other SCA mutations, except for SCA-2,27 have not been reported to present with MSA-like features.49-54 Conversely, the majority of MSA-C patients do not appear to have expanded SCA1 and SCA3 alleles.41 Indeed, MSA-C appears to be a frequent form of sporadic cerebellar ataxia of late onset; 29% of sporadic adult-onset ataxia patients suffer from MSA.22 This finding corresponds well with data of a study of sporadic OPCA patients who were followed 3 months to 10 years.23 Within this period, 17 of 51 patients developed autonomic failure or parkinsonism indicating a diagnosis of MSA. There is significant overlap in clinical and radiological features between the fragile X–associated tremor/ataxia syndrome (FXTAS) and atypical parkinsonism, in particular, MSA-C. A considerable number of cases with FXTAS have already been described in male carriers of the fragile X premutation.55,56 Kamm and colleagues found an elevated frequency of fragile X mental retardation 1 gene (FMR1) “gray zone” alleles (40 to 54 repeats) in both male MSA and PSP patients compared with controls, suggesting that small repeat expansion in this gene may possibly act as a susceptibility factor for certain types of neurodegenerative diseases in apparently sporadic male patients, probably in combination

with other genetic and environmental factors.57 In contrast, there was no significant difference in allele frequency for either FMR1 “gray zone” alleles for female patients or for FMR1 premutation alleles (55 to 200 repeats) in both male and female patients compared with healthy controls, indicating that FXTAS due to a premutation in the FMR1 gene represents only a rare cause of apparently sporadic atypical parkinsonism.57

Ancillary Investigations The diagnosis of MSA still rests on the clinical history and neurological examination. According to the Consensus Conference on the diagnosis of MSA,25 additional investigations such as autonomic function tests, sphincter electromyography, and neuroimaging may be used to support the diagnosis or to exclude other conditions. The abnormalities reviewed below have been observed in patients with advanced rather than early disease. In the early stages the investigations may give equivocal results. Therefore, the Consensus Conference on MSA considered it premature to incorporate the results of laboratory investigations into the diagnostic guidelines that were established.

Autonomic Function Tests Findings of severe autonomic failure early in the course of the disease make the diagnosis of MSA more likely, although the specificity in comparison with other neurodegenerative disorders is unknown in a single patient. Pathological results of autonomic function tests may account for a considerable number of symptoms in MSA patients and should prompt specific therapeutic steps to improve quality of life and prevent secondary complications like injuries due to hypotensioninduced falls or ascending urinary infections.

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Cardiovascular Function A history of postural faintness or other evidence of OH, such as neck ache on rising in the morning or posturally related changes of visual perception, should be sought in all patients in whom MSA is suspected. After taking a comprehensive history, testing of cardiovascular function should be performed. According the consensus statement of the American Autonomic Society and the American Academy of Neurology on the definition of OH, pure autonomic failure, and MSA, a drop in systolic blood pressure of 20 mm Hg or more, or in diastolic blood pressure of 10 mm Hg or more, compared with baseline is defined as OH and must lead to more specific assessment.58 This is based on continuous noninvasive measurement of blood pressure and heart rate during tilt-table testing.59 In MSA, cardiovascular dysregulation appears to be caused by central rather than peripheral autonomic failure. During supine rest, norepinephrine levels (representing postganglionic sympathetic efferent activity) are normal,60 and there is no denervation hypersensitivity.61 In contrast, mainly postganglionic sympathetic dysfunction is thought to account for autonomic failure associated with Parkinson disease. However, a study demonstrated that abnormal cardiovascular autonomic function tests failed to differentiate autonomic failure associated with Parkinson disease versus MSA.62 Although such abnormalities may be nonspecific, their presence within the first 3 to 5 years of disease onset make a diagnosis of MSA more likely than Parkinson disease.

Bladder Function Assessment of bladder function is mandatory in MSA and usually provides evidence of involvement of the autonomic nervous system at an early stage of the disease (when bladder function is still normal in most Parkinson disease patients). Following a careful history regarding frequency of voiding, difficulties in initiating or suppressing voiding, and the presence of urinary incontinence, a standard urine analysis should exclude an infection. Postvoid residual volume needs to be determined sonographically or via catheterization to initiate intermittent self-catheterization in due course. In some patients, only cystometry can discriminate between hypocontractile detrusor function and a hyperreflexic sphincter-detrusor dyssynergy. The nature of bladder dysfunction is different in MSA and Parkinson disease. Although frequency and urgency are common in both disorders, marked urge or stress incontinence with continuous leakage is not a feature of Parkinson disease apart from very advanced cases. Urodynamic studies show a characteristic pattern of abnormality in MSA patients.63 In the early stages there is often detrusor hyperreflexia, often with bladder neck incompetence due to abnormal urethral sphincter function, which results in early frequency and urgency followed by urge incontinence. Later on, the ability to initiate a voluntary micturition reflex and the strength of the hyperreflexic detrusor contractions diminish, and the bladder may become atonic, accounting for increasing postmicturition residual urine volumes.

Sphincter Electromyography An abnormal sphincter electromyogram (EMG) may be found in many patients with clinically definitive MSA, including those who, as yet, have no urological or anorectal problems. In at

least 80% of patients with MSA, an EMG of the external anal sphincter reveals signs of neuronal degeneration in Onuf’s nucleus with spontaneous activity and increased polyphasia.29,64,65 The prevalence of abnormalities in early stages of MSA remains unclear. These findings do not reliably differentiate between MSA and other forms of APD such as PSP.66 Furthermore, neurogenic changes of external anal sphincter muscle have also been demonstrated in advanced stages of Parkinson disease.67 Also, chronic constipation, previous pelvic surgery, or vaginal deliveries can be confounding factors to induce nonspecific abnormalities.68 However, anal sphincter EMG abnormalities appear to distinguish MSA from Parkinson disease in the first 5 years after disease onset, and from pure autonomic failure, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out.69

Imaging Magnetic Resonance Imaging Routine 1.5-T magnetic resonance imaging (MRI) including diffusion weighted imaging (DWI) should be performed in all patients with suspected MSA because basal ganglia and/or brainstem abnormalities suggestive of MSA may be observed even during early disease stages. These changes include an OPCA-like atrophy pattern indistinguishable from autosomal dominant cerebellar ataxia.70 MRI measures of basal ganglia pathology in MSA are less well established, and naked eye assessments are often unreliable. In advanced cases, putaminal atrophy may be detectable and may correlate with severity of extrapyramidal symptoms (Fig. 72–2A, B). Abnormalities on MRI may include not only OPCA70 or putaminal atrophy71 but also signal abnormalities on T2-weighted images. Signal hyperintensities within the pons and middle cerebellar peduncles are thought to reflect degeneration of pontocerebellar fibers; these changes occasionally resemble a hot cross bun.71 Nonspecific putaminal hypointensities in patients with atypical parkinsonism including MSA were first reported in 1986 by two groups using a 1.5-T T2-weighted images.72,73 This change has subsequently been confirmed by others in cases with pathologically proven MSA.74-76 Similar MRI abnormalities may occur in patients with classic Parkinson disease.77 However, a study demonstrated that hypointense putaminal signal changes were more frequent in MSA than in Parkinson disease patients using T2*-weighted gradient echo (GE) instead of T2-weighted fast spin echo images, indicating that T2*weighted GE sequences are of better diagnostic value for patients with parkinsonism.78 Increased putaminal hypointensities may be associated with a slit-like hyperintense band lateral to the putamen79,80 (Fig. 72–2C). The latter appears to be more specific for MSA than putaminal hypointensity71,79,80; however, further studies in larger cohorts of patients are needed to confirm this. The hyperintense slit-signal correlated with reactive microgliosis and astrogliosis in a case with pathologically proven MSA.76 DWI may represent a useful diagnostic tool that can provide additional support for a diagnosis of MSA-P. DWI is able to discriminate MSA-P and both patients with Parkinson disease and healthy volunteers on the basis of putaminal rADC (regional apparent diffusion coefficient) values81 (Fig. 72–3A, B). The increased putaminal rADC values in MSA-P are likely to reflect ongoing striatal degeneration, whereas most neuropathological

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A

B

■

C

Figure 72–2. (A) Putaminal atrophy (arrow) on T2-weighted routine MRI in MSA. (B) Atrophy of the pons and middle cerebellar peduncles in MSA. Pontine fiber degeneration causes “hot cross bun sign”. (C) Putaminal lateral hyperintensity (putaminal rim, arrow) in MSA.

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A ■

B Figure 72–3. Axial trace maps at the level of mid-striatum in multiple system atrophy-P subtype (MSA-P) (B) and Parkinson disease (A). Note the diffuse hyperintensity—corresponding to increased trace of diffusion tensor [trace (D)] values—in the putamen (arrows) in MSA-P.

studies reveal intact striatum in Parkinson disease. But, since in PSP compared with Parkinson disease rADCs were also significantly increased in both putamen and globus pallidus,82 increased putaminal rADC values do not discriminate MSA-P from PSP. Schulz et al.83 found significant reductions in mean striatal and brainstem volumes in patients with MSA-P, MSA-C, and PSP, whereas patients with MSA-C and MSA-P also showed a reduction in cerebellar volume. More recently, voxel-based morphometry confirmed previous region of interest (ROI)– based volumetric studies83 showing basal ganglia and infratentorial volume loss in MSA-P patients.81 These data also revealed prominent cortical volume loss in MSA-P mainly comprising the cortical targets of striatal projections such as the primary sensorimotor, lateral premotor cortices, and the prefrontal cortex. MR-based volumetry is a helpful tool to investigate the progression of cortical and subcortical atrophy patterns in MSA compared with other disorders; however, it cannot be applied for routine diagnostic workup of individual patients.

Functional Imaging (Single-Photon Emission Computed Tomography and Positron Emission Tomography) Studies of receptor binding in disorders with parkinsonism examine the presynaptic nigrostriatal neurons by evaluating

the dopa decarboxylase activity and the dopamine transporter (DAT), and the postsynaptic dopaminergic function evaluating the dopamine D2 receptor. Single-photon emission computed tomography and positron emission tomography (SPECT and PET) ligands have become available to study cardiac sympathetic innervation as well. Overall presynaptic and postsynaptic dopaminergic markers have yielded disappointing results regarding the differentiation between Parkinson disease, MSA, and PSP.85 PET studies using other ligands such as [11C]diprenorphine (nonselective opioid receptor antagonist)86 and 18F-fluorodeoxyglucose ([18F]FDG)87-89 have proved more consistent in detecting striatal degeneration and in distinguishing patients with MSA-P from those with Parkinson disease, particularly when combined with a dopamine D2 receptor scan.90 Widespread functional abnormalities in MSA-C have been demonstrated using [18F]FDG and PET.91 Reduced metabolism was most marked in the brainstem and cerebellum, but other areas such as the basal ganglia and cerebral cortex were also involved, supporting its nosological status as the cerebellar subtype of MSA. SPECT evaluation of the dopamine transporter (DAT) using [123]β-CIT [2β-carboxymethoxy-3β-(4-iodophenyl)tropane] reflects the disruption of the nigrostriatal pathway, and therefore MSA and PSP cannot be separated from Parkinson disease with this method alone.92 However, a study using voxelwise SPM

chapter 72 parkinson plus disorders analysis of DAT-binding found significant differences between Parkinson disease and MSA patients in an area including the mesopontine junction, and this type of analysis may enhance the differential diagnostic potential DAT-SPECT in MSA versus Parkinson disease.93 SPECT studies using [123I]iodobenzamide ([123] IBZM) as D2 receptor ligand have revealed significant reductions of striatal IBZM binding in clinically probable MSA subjects compared with Parkinson disease patients or controls.94-96 However, striatal IBZM binding is also reduced in other APDs such as PSP95 limiting its predictive value for an early diagnosis of MSA. Scintigraphic visualization of sympathetic cardiac neurons using scintigraphy with [123I]metaiodobenzylguanadine ([123I] MIBG) has been shown to reveal loss of binding in patients with Parkinson disease regardless of disease severity, reflecting postganglionic sympathetic denervation compared with preserved cardiac binding in MSA97,98 and PSP.95 Considering all reports published so far, MIBG scintigraphy was able to accurately discriminate a total of 246 Parkinson disease patients from 45 MSA patients with high sensitivity (90%) and specificity (95%).98 Similarly, 18F-dopa PET is able to demonstrate cardiac sympathetic denervation in pure autonomic failure and Parkinson disease in contrast with intact cardiac sympathetic innervation in MSA.99

Principles of Management Symptomatic Therapy There is virtually no effective treatment for the cerebellar features of the disease.100,101 Therefore, medical treatment is largely aimed at alleviating parkinsonism and dysautonomia.

Parkinsonism The commonly held belief that patients with MSA are non– or poorly L-dopa–responsive is misleading. Clinical series have documented levodopa efficacy in up to 40% of patients with possible or probable MSA.21,102-104 Data obtained from series with pathological confirmation are more variable, with rates of beneficial L-dopa response ranging between 30% and 80%.105-108 L-Dopa responsiveness should be tested by administering escalating doses (with a peripheral decarboxylase inhibitor) over a 3-month period up to a least 1000 mg/day (if necessary and if tolerated).25 However, whatever response there is it usually declines after a few years of treatment.31 Dyskinesias emerge in half of the patients treated with L-dopa and they are often dystonic, predominantly affecting the orofacial district.27,105 Results with dopamine agonists are also variable, but these compounds are no more effective than levodopa and often poorly tolerated. Goetz and colleagues,100 using doses of 10 to 80 mg/day of bromocriptine, reported a benefit in five patients who had previously responded to L-dopa and one patient who had failed to respond to levodopa. In a controlled trial with lisuride in seven patients, only one, who had already responded to levodopa, showed improvement.109 No formal trials looking at the efficacy of pergolide, cabergoline, ropinirole, or pramipexole are available. Despite anecdotal benefit in single cases, a short-term open trial with amantadine at high doses (400 to 600 mg/day) in five patients with MSA unresponsive to L-dopa was negative.110

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Anticholinergics usually do not improve motor symptoms, but they may be helpful when sialorrhea is severe and disturbing. Ablative neurosurgical procedures such as medial pallidotomy fail to improve parkinsonian motor disturbance in MSA.111 However, beneficial short-term and long-term effects of bilateral subthalamic nucleus high-frequency stimulation have been reported in four patients with MSA-P.112 Further studies are needed to establish the scope of deep brain stimulation in MSA. Alternative therapeutic neurosurgical strategies such as trophic factors local delivery and neurotransplantation are currently being explored experimentally in animal models of MSA.113

Autonomic Dysfunction Treatment of OH is often fraught with difficulties, but it is crucial to improve the quality of life in patients with MSA and autonomic dysfunction.114 The treating physician should not to be excessively concerned about a low standing blood pressure if the patient is asymptomatic. Patients with MSA can sometimes tolerate a decreased standing systolic blood pressure without symptoms, probably because their cerebral blood flow is kept at an adequate level thanks to a functioning autoregulation.115 The latter appears to be preserved down to a systolic blood pressure of 60 mm Hg, well below the 80 mm Hg at which autoregulation fails in normal subjects.116 When OH becomes disabling, it can often be alleviated by progressively avoiding aggravating factors, such as the effects of large meals, alcohol intake, drugs, straining during micturition and defecation, and exposure to a warm environment. Other nonpharmacological strategies that are also recommended include elastic stockings and head-up tilt of the bed at night, increasing salt intake, and, in selected cases, cardiac pacing.117 A variety of pharmacological agents with different mechanisms of action have been used to reduce OH; fludrocortisone and desmopressin act through plasma volume expansion and by reducing natriuresis; clonidine and yohimbine both induce release of norepinephrine. Midodrine (adrenergic agonist activating alpha 1-receptors on arterioles and veins) increases peripheral resistance, thereby significantly reducing OH, as shown by three randomized, controlled trials.118-120 DL-Threodihydroxyphenylserine increases endogenous production of norepinephrine,121 whereas ergot derivatives are venoconstrictor agents with direct action on β2-receptors. Most specialists now consider fludrocortisone and midodrine as the first-choice drugs for this condition, the option between the two being made according to the individual characteristics of the patient. Controlled trials comparing the different symptomatic drugs used for OH are not available, and therefore the ultimate choice among them should be made according to the experience and judgment of the treating physician. Supine hypertension (SH) may occasionally be associated with severe OH. SH does not require drug treatment if systolic blood pressure is below 200 mm Hg; if treatment is required, short-acting calcium antagonists given at nighttime are commonly used. Urinary symptoms in MSA are due to a complex mixture of central and peripheral nervous problems, sometimes superimposed on local pathology such as prostatic hypertrophy and perineal laxity.122 Peripherally acting anticholinergic drugs may help incontinence, but often at the expense of inducing

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retention; the administration of desmopressin at night may reverse nocturia. Intermittent self-catheterization or even an indwelling catheter may be needed in the presence of incomplete bladder emptying. Male impotence can be partially circumvented by the use of intracavernosal papaverine, prostaglandin E1 or penile implants. A double-blind, placebo-controlled study showed that sildenafil is efficacious in the treatment of erectile dysfunction in parkinsonism due to MSA, but it may unmask or exacerbate orthostatic hypotension.123 Therefore, measurement of lying and standing blood pressure before prescribing sildenafil to men with parkinsonism is recommended. Inspiratory stridor develops in about 30% of patients, possibly due to progressive degeneration of the nucleus ambiguus124 and consequent bilateral laryngeal abductor weakness. Continuous positive airway pressure may be helpful in some of these patients but in about 4% a tracheostomy is needed, after having considered all the ethical issues related to this procedure.125,126 Sleep apnea may also occur and should be managed appropriately.

Other Therapies Because the results of drug treatment for MSA are generally poor, other therapies are all the more important. Physiotherapy helps maintain mobility and prevent contractures, and speech therapy can improve speech and swallowing and provide communication aids. Dysphagia may require feeding via a nasogastric tube or even percutaneous endoscopic gastrostomy. Tracheostomy is only rarely needed in mobile patients with severe inspiratory stridor; it should be avoided in preterminal stages of the disease. These palliative management decisions should be based on careful clinical judgement, taking into account the expectations of both patient and caregivers. Occupational therapy helps to limit the handicap resulting from the patient’s disabilities and should include a home visit. Provision of a wheelchair is usually dictated by the liability to falls because of postural instability and gait ataxia but not by akinesia and rigidity per se. Psychological support for patients and partners needs to be stressed.

PROGRESSIVE SUPRANUCLEAR PALSY Progressive supranuclear palsy (PSP) is a chronic progressive neurodegenerative disorder characterized by continuation of clinical features including akineto-rigid parkinsonism, postural instability supranuclear vertical gaze palsy, axial dyskinesia, and frontolimbic dementia.127-129 It was originally delineated as a novel heterogeneous system disorder by Richardson and colleagues130 and later termed PSP by Steele, Richardson, and Olszewski in their seminal report of 1964.131 Its unique neuropathology involves neurodegeneration with neuronal and oligodendroglial deposition of abnormally phosphorylated tau protein forming abundant neurofibrillary tangles (NFTs) in distinct basal ganglia and brainstem regions but also in the frontal cortex and dentate nucleus of the cerebellum.131-133 Subcortical NFT formation with granulovacuolar neuronal degeneration and gliosis are especially marked in the globus pallidus, subthalamic nucleus, substantia nigra, as well as in the midbrain and pontine reticular formation including the midbrain oculomotor complex and superior colliculi, periaqueductal gray, and basis pontis.

T A B L E 72–2. Neurodegenerative Diseases with Intraneuronal Accumulation of Abnormal Tau Protein (“Tauopathies”) Presenting with parkinsonism Progressive supranuclear palsy (PSP) or other movement disorder Corticobasal degeneration (CBD) Postencephalitic parkinsonism Guadeloupean parkinsonism Presenting with dementia Alzheimer disease Dementia pugilistica Down syndrome Pick disease Parkinsonism dementia FTDP-17 syndromes Parkinsonism-dementia-complex of Guam Niemann-Pick disease type C

Abnormal intraneuronal deposits of tau protein are the pathological hallmark of PSP and a group of neurodegenerative disease that may either present with dementia or a parkinsonian movement disorder or combinations thereof and have accordingly been collectively grouped as “tauopathies” (Table 72–2). At the ultrastructural and molecular levels, however, there are differences between the types of tau aggregates and tau composition in these various disorders.134,135 While in Alzheimer disease hyperphosphorylated tau protein deposits appear as paired helical filaments at the ultrastructural level, NFTs in PSP appear as 15- to 18-nm straight filaments. In addition, tau aggregates in PSP predominantly consist of the four repeat tau isoforms whereas all six protein isoforms of the alternatively spliced tau gene are present in NFTs of Alzheimer disease.

Epidemiology There are no data on incidence and prevalence of PSP from population-based studies. Some hospital-based studies have found low prevalence rates of 1 to 2 cases per 100,000136,137 and an age-dependent rise in the incidence rate from 1.7 cases per 100,000 at age 50 to 59 to 14.7/100,000 at age above 80.137 Using a hospital linkage system of general practitioners in an area of London serving a population of more than 120,000, Schrag and colleagues138 arrived at an age-adjusted prevalence rate of 6.4/100,000, which is similar to the value of 5.0 calculated from a nationwide ascertainment study performed in the United Kingdom.139 Given the considerable rate of misdiagnosis and underdiagnosis of PSP shown in a number of clinical and neuropathological studies,139,140 it appears likely that the true prevalence is above these estimates. Neuropathological series from specialized centers suggest that PSP may be the second most common type of degenerative parkinsonism after idiopathic Parkinson disease, accounting for around 6% of cases diagnosed with a parkinsonian syndrome in life.141

Clinical Presentation, Course, and Prognosis The classic clinical syndrome of PSP is characterized by symmetrical rigid-bradykinetic parkinsonism with prominent extensor rigidity and dystonia of neck muscles producing an

chapter 72 parkinson plus disorders erect posture with neck hyperextension. Facial immobility with markedly reduced blink rates and elevated eyebrows with frontalis muscle overactivity cause a characteristic staring and astonished facial expression, and further clinical hallmarks include pronounced postural instability with recurrent falls, typically backward. Rest tremor is distinctly uncommon in PSP and most patients lack a meaningful response of their parkinsonism to trials of L-dopa. Abnormalities of eye movement are considered pathognomic and include slowing of vertical and horizontal saccades, hypometric saccades, and the development of a highly distinctive supranuclear vertical gaze palsy with complete loss of vertical eye movements and fully preserved excursions of vestibulo-ocular reflex movements. As the disease progresses, pseudobulbar symptoms of slurred dysarthria and dysphagia evolve, and there may also be palilalia or episodes of pathological laughter or crying. The movement disorder of PSP is complemented by neuropsychological dysfunction of a “subcortical dementia” or “frontal lobe” type with cognitive slowing, a dysexecutive syndrome, and other frontal lobe deficits including utilization behavior. The mean age at disease onset is around 60 years and mean survival is 6 years.142 The disease is progressive despite any therapy. In the late stage, PSP patients are wheelchair or bed bound. Their speech shows a characteristic growling and groaning. Dressing and feeding themselves is impossible. Marked difficulty in swallowing bears the danger of aspiration and consequent pneumonia. Goetz and colleagues have studied the progression of global disability in PSP by defining median latencies from disease onset to certain milestones of key disabilities. The median delay to any key motor disability was as short as 48 months in their study of 50 patients with PSP; loss of ambulation, inability to stand, and a wheelchair-bound state were reached after a median of 5 years; speech had become unintelligible after a median of 6 years; and tube feeding was required after a mean of 87 months.143 By definition, classic PSP is poorly levodopa responsive, and overall drug treatment has little impact on the natural history of this relentlessly progressive disorder. In some instances it can be difficult to distinguish PSP from Parkinson disease patients during the first 2 to 3 years from symptom onset if the former do not yet clearly exhibit postural instability or ophthalmoplegia, and when they may still show a response to levodopa. Lees and co-workers140 presented evidence that the syndrome of PSP is probably heterogeneous. In a careful clinicopathological study of 103 consecutive cases of pathologically confirmed PSP, they assessed early clinical features occurring within the first 2 years after disease onset. Supranuclear gaze palsy was present in less than half of all cases, and falls only occurred in some 60% (Table 72–3). Taken together, about 50% of cases were characterized by early postural instability and falls associated with supranuclear vertical gaze palsy and cognitive dysfunction, corresponding to the classic pattern captured in current diagnostic criteria (Table 72–4). A second group of almost one third of their cases, however, had a parkinsonian phenotype with asymmetrical onset, rest tremor, and a moderate therapeutic response to levodopa, therefore providing greater room for diagnostic error regarding the differentiation from Parkinson disease. These authors propose to subdivide PSP into at least two clinically distinct subtypes termed “Richardson’s syndrome”, corresponding

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T A B L E 72–3. Early Clinical Features (First 2 Years) in Progressive Supranuclear Palsy Clinical Feature

%

Falls Impaired postural reflexes Bradykinesia Rigidity Cognitive decline Speech disturbance Supranuclear gaze palsy Abnormal pursuit or saccades Nonspecific visual symptoms Asymmetrical onset

60 62 75 42 29 39 38 44 21 28

N = 103. From Williams DR, de Silva R, Paviour DC, et al: Charcteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain 2005; 128:1247-1258.

to the classic syndrome and “PSP-parkinsonism” with greater similarity to Parkinson disease (Table 72–5). The isoform composition of insoluble tangle-tau isolated from the brains of these patients also differed between the two major subtypes of PSP: in classic PSP the mean ratio of fourrepeat to three-repeat tau was 2.8 while in the parkinsonian variant it was 1.6. The authors interpreted this as evidence that the parkinsonian PSP variant may be a distinct nosological entity.

Diagnostic Criteria The NINDS diagnostic criteria for PSP have been established as the gold standard during the last 5 years144 (see Table 72–4). These criteria have been developed primarily as clinical research criteria and have been shown to have rather low sensitivity at first presentation in a recent clinicopathological study.145 PPPV at first visit, however, was 100% while sensitivity remained low at 34% even at the last visit before death. As Williams and colleagues have pointed out in their series of 103 pathologically confirmed cases of PSP, misdiagnosis as Parkinson disease is common and accounted for 23% of cases even in the hands of hospital specialists. As outlined earlier, this is probably due to the existence of at least one major clinical subtype of PSP that is not captured by the current NINDS criteria.

Genetics In PSP (and CBD) pathological tau, composed of aggregated four-repeat (E10+) tau isoforms, accumulates in cells and glia in subcortical and cortical areas. Interestingly, recent genetic studies have indicated that a specific haplotype of the tau gene is overrepresented in PSP and CBD indicating a common genetic background of these tauopathies.146

Ancillary Investigations The diagnosis of PSP is primarily clinical and relies on the NINDS criteria specified above. However, ancillary investiga-

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T A B L E 72–4. NINDS-SPSP Clinical Criteria for the Diagnosis of Progressive Supranuclear Palsy (PSP)

From Litvan I, Agid Y, Calne D, et al: Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47:1-9.

T A B L E 72–5. Classification of Progressive Supranuclear Palsy (PSP) Richardson’s Syndrome

PSP-Parkinsonism

Falls, dementia Supranuclear gaze palsy Poorer prognosis Overrepresentation of men 4R predominant tau tangles

Asymmetrical onset tremor Mild/moderate L-dopa response Better prognosis Equal sex distribution 3R and 4R tau tangles

From Williams DR, de Silva R, Paviour DC, et al: Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain 2005; 128:1247-1258.

tions have been explored in an attempt to improve the diagnostic accuracy. These include analysis of cerebrospinal fluid and protein biomarkers and structural and functional imaging as well as neurophysiological techniques.

Cerebrospinal Fluid Studies Several investigators have attempted to identify biomarkers in the cerebrospinal fluid to achieve early and accurate diagnosis of PSP. Cerebrospinal fluid concentrations of tau appear to be

higher in corticobasal degeneration than in PSP, with sensitivity and specificity of 100% and 87.5%.147 High cerebrospinal fluid concentrations of neurofilament have been observed in atypical parkinsonian disorders; however, PSP could not be differentiated from other atypical disorders such as MSA. Furthermore, sensitivity was suboptimal due to overlapping ranges of neurofilament concentrations.148 It has been suggested that the concomitant use of a levodopa test and the neurofilament protein assay could improve diagnostic accuracy for atypical parkinsonism to 90%.149

Magnetic Resonance Imaging A number of findings suggestive of PSP, such as midbrain atrophy with enlargement of the third ventricle and tegmental atrophy, signal increase in the midbrain and in the inferior olives, as well frontal cortex and temporal lobe atrophy, have been described.71 Indirect parameters of midbrain atrophy comprising reduced anteroposterior midbrain diameter and abnormal superior profile of the midbrain (flat or concave versus convex aspect in PSP patients) may assist in the differential diagnosis of PSP (Fig. 72–4).150 Visual assessment of atrophy of the superior peduncle has been shown to differentiate PSP patients from controls and patients with other parkin-

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B Figure 72–4. Midbrain atrophy (arrow) in PSP (A) compared with no brainstem atrophy in Parkinson disease (B) on midsagittal T1weighted images.

sonian disorders including Parkinson disease and MSA, with a sensitivity of 74% and a specificity of 94%.151 Using MRI-based volumetry (MRV) with semiautomatic segmentation techniques, patients with PSP showed significant reductions in whole brain, striatal, brainstem (especially midbrain), and frontal volumes compared with Parkinson disease patients.152,153 Groschel and colleagues154 used a mathematical model derived from a discriminant analysis using only postmortem confirmed cases of PSP and CBD as well as controls. The volumes of midbrain, parietal white matter, temporal gray matter, brainstem, frontal white matter, and pons were identified to separate best between groups, predicting correctly the diagnosis in 95% of controls as well as in 76% of all PSP and 83% of all CBD patients. Voxel-based morphometry (VBM) has been used to study neurodegenerative parkinsonian disorders including PSP, MSA, and Parkinson disease. VBM permits operator-independent and semiautomated detection of significant differences in different tissue types of the whole brain, avoiding a priori rangeof-interest (ROI) selection. Two studies reported the use of VBM in PSP patients.155,156 Brenneis and colleagues155 showed gray matter loss in frontotemporal, insular, supplementary motor, and mediotemporal areas compared with healthy controls. Further, white matter loss was observed in the midbrain and frontotemporal areas. The second study confirmed these findings comparing PSP patients not only with healthy controls but also Parkinson disease patients.156 Interestingly, this study tested the clinical utility of the VBM results as a guide for the differential diagnosis of PSP from Parkinson disease and healthy controls. On neuroradiological review of the T1-weighted MR images, the study participants were allocated to either PSP or non-PSP based on the presence or absence of the midbrain

tissue loss in the PSP group highlighted using VBM. With these regional differences on VBM as a guide, neuroradiological diagnosis achieved a sensitivity of 83% and a specificity of 79%. Using magnetization transfer imaging (MTI), abnormalities of the basal ganglia and substantia nigra have been reported in patients with parkinsonism.157 Although this technique may be useful to separate Parkinson disease from atypical parkinsonian disorders, discrimination of PSP and MSA is suboptimal. More recently, DWI has been applied to patients with various parkinsonian disorders including PSP. Pathological DWI findings in Parkinson disease are very rare. In contrast, abnormal putaminal diffusivity appears to be common in clinically established atypical parkinsonian disorders.81,82 Therefore, DWI seems useful to discriminate Parkinson disease from atypical parkinsonism; however, DWI fails to separate MSA from PSP on the basis of elevated putaminal diffusivity. Proton magnetic resonance spectroscopy can provide an indirect measure of neuronal loss in vivo. Several investigators have reported spectral changes in the lentiform nucleus of PSP patients.158,159 The discriminatory value of this technique on an individual basis remains questionable.160

Functional Imaging Several studies of blood flow and oxygen or glucose metabolism on PET in patients with PSP have demonstrated frontal lobe hypometabolism.161 Investigation of the nigrostriatal dopaminergic system with cocaine analogs and PET or SPECT imaging can reliably show presynaptic dopaminergic degeneration in PSP and also progression of this degeneration.162 However, the pattern of abnormality is nonspecific and cannot differentiate

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PSP from other parkinsonian syndromes, even when used in combination with a dopamine D2 receptor ligand.163 Ligands for the cholinergic system may offer more hope in improving diagnostic accuracy for PSP. Use of carbon-11–labeled N-methyl-4piperidyl acetate and PET to measure acetylcholinesterase activity showed a preferential loss of cholinergic innervation to the thalamus in PSP compared with Parkinson disease and controls.164 More recently, imaging of activated microglia with carbon11–labeled PK11195 and PET in four PSP patients revealed increased binding in the lentiform nucleus and pons in particular, although dorsolateral prefrontal cortex, caudate, substantia nigra, and thalamus were also involved.165 These findings raise the possibility that disease activity could be monitored.

Neurophysiology Various neurophysiological techniques have been used to study PSP, aiming to improve diagnostic accuracy and to understand the underlying pathophysiological disease process.166 Electrooculography has shown a distinct and progressive profile of deficits characterized by decreased saccadic velocity, frequent square-wave jerks, and increased error rates on antisaccade tasks.167 Autonomic function testing is usually normal in PSP compared with MSA.168 Sphincter EMG can differentiate Parkinson disease from atypical parkinsonism but fails to reliably discriminate PSP from MSA.69 The auditory startle response is delayed or absent in PSP in contrast to frequent hyperexcitability in MSA.169 The clinical usefulness and pathophysiological basis of evoked potential abnormalities in PSP remain to be elucidated in further studies.

Principles of Management Parkinsonism To date, there have been no randomized double-blind controlled trials of dopaminergic replacement therapies (L-dopa and dopamine agonists) in PSP patients except for one shortterm trial of pergolide limited by small sample size.170 The literature evidence is based on anecdotal case reports, small-scale open-label trials or retrospective chart reviews using clinical, at times not validated, criteria for diagnosing PSP. Taken together, the results suggest that dopaminergic agents are usually ineffective in PSP, reflecting striatal dopamine receptor loss as well as lesions in nondopaminergic neurotransmitter systems including cholinergic brainstem and basal forebrain nuclei. Overall, only around 20% to 40% of the patients show transient mild benefit to L-dopa.171-173 L-Dopa–induced motor or psychiatric complications appear to be rare. In a review of 82 consecutive patients treated with open-label L-dopa (mean maximum daily dose, 1.015 mg) only three had mild dyskinesias, and one had an acute psychotic reaction when amitriptyline was added to the L-dopa regimen.171 In theory, postsynaptic dopamine receptor agonists should be more effective in ameliorating PSP symptoms than L-dopa, as the former agents do not require metabolic conversion by degenerating dopaminergic neurons in order to become pharmacologically effective. In practice, however, dopamine agonists have proved no less ineffective. Williams and colleagues174 failed to demonstrate any significant improvement in most of nine PSP patients treated

with bromocriptine in a double-blind placebo-controlled trial. However, transient antiparkinsonian efficacy has been observed in a retrospective chart review of 12 autopsy-proved PSP patients treated with bromocriptine.172 Modest 20% improvement of motor disability has also been reported in a doubleblind controlled trial of pergolide conducted in 3 PSP patients.170 In contrast, lack of antiparkinsonian efficacy was reported for lisuride175 and pramipexole176 in two small-scale open-label studies. Nevertheless, in the absence of more effective antiparkinsonian treatment these therapies should be tried when parkinsonism is present in PSP because of the possibility of a sometimes moderate, but useful effect, and because the lack of a sustained or marked benefit from L-dopa effectively rules out Parkinson disease, and may therefore support the diagnosis of PSP or other atypical parkinsonian disorders. A mild (rarely dramatic) symptomatic improvement of parkinsonism may also be seen with tricyclic antidepressants in a minority of patients.177-179 Amitriptyline and desipramine were both shown to ameliorate parkinsonian features in a small-scale double-blind crossover trial of four PSP patients.177 In addition, gaze palsy was improved in one patient and apraxia of eyelid opening in two patients. Side effects were mild and included reversible urinary retention and a dry mouth. A recent open-label trial in two patients with PSP reported antiparkinsonian efficacy and improved tolerability of low-dose amitriptyline.178 Nortriptiline may also be used in patients with PSP; however, future multicenter controlled trials are necessary to definitively establish the role of antidepressants. Idazoxan is a potent and selective alpha-2 presynaptic inhibitor drug whose overall effect is to increase norepinephrine neurotransmission. A double-blind crossover trial in nine PSP patients revealed significant improvement of mobility, balance, gait, and finger dexterity.180 In contrast, efaroxan, a more potent enhancer of norepinephrine neurotransmission compared with idaxozan, failed to confer any benefit to 14 PSP patients in a double-blind crossover trial.181 Methysergide, a serotonin antagonist, has been reported to improve swallowing, speech, parkinsonian features, and oculomotor disturbances in an open-label study of 12 patients,182 but this observation could not be confirmed by others.183 Serotonin antagonists such as methysergide may cause severe side effects such as retroperitoneal fibrosis or pleuropulmonary fibrosis. Aniracetam, a metabolic activator with acetylcholine-like properties, was reported to improve motor and cognitive function in two PSP patients; however, there is no further evidence to substantiate these findings.184 Other drugs with minimal or absent efficacy in PSP include amantadine, baclofen, bupropion, fluoxetine, selegeline, and valproate.185,186,171 Electroconvulsive therapy was reported to ameliorate motor dysfunction in some PSP patients; however, hospitalization was prolonged and patients experienced treatment-induced confusion, thus limiting the usefulness of this technique.187,188 Implantation of adrenal medullary tissue into the caudate nucleus has been performed in a few PSP patients; however, the procedure proved to be ineffective as well as hazardous with substantial perioperative morbidity and mortality.189,190

Oculomotor and Related Disturbances Zolpidem, a short-acting hypnotic drug and selective agonist of the benzodiazepine receptor subtype BZ1, was shown to improve saccadic eye movements and parkinsonism in a

chapter 72 parkinson plus disorders double-blind crossover study of 10 patients with probable PSP; however, the benefit was limited by drowsiness, particularly at dosages higher than 5 mg/day.191 Involuntary eye closure may be treated with botulinum toxin injections.192-195 Visual prisms are rarely of help; patients may instead resort to books on tape. Artificial tears are useful to avoid exposure keratitis secondary to decreased eye blink rate.

Cognitive Disturbance Administration of cholinergic agents is not beneficial, indeed, mental status and gait of patients may worsen with these drugs.196-198 To date, only three cholinergic agents have been used to treat PSP. Foster et al.196 evaluated the effects of RS-86, an M1-M2 muscarinic agonist, on motor and cognitive function in 10 PSP patients during a 9-week double-blind randomized controlled trial. No effects were found with regard to either cognitive tasks or motor functions. Litvan and colleagues reported lack of therapeutic efficacy for physostigmine and scopalamine in a double-blind placebo-controlled study of nine PSP patients.197 Fabbrini and colleagues198 demonstrated lack of efficacy for donezepil, a centrally acting cholinesterase inhibitor, in an open-label trial of six PSP patients.

Other Features Because gait instability shows only minimal or no response to drug therapy, weighted walkers should be considered. Swallowing disturbances should be regularly evaluated by speech therapists to avoid aspiration pneumonia. Dysphagia can be managed by the use of straws, food thickeners, or soft processed food. The question of whether a nasogastric tube or percutaneous endoscopic gastrostomy could reduce the chances of aspiration pneumonia needs further assessment. Patients can also be helped by a variety of communication aids. Although drooling can be managed with anticholinergics, these drugs should be used cautiously because they can worsen patient symptomatology. Emotional incontinence has been reported to improve with amitriptyline.199

Practical Management Due to the small number of randomized controlled trials, the practical management of PSP is largely based on empirical evidence (level C) or a single randomized study (level B). Although improvement is rarely seen, L-dopa (up to 1000 mg/day, if tolerated) should be administered as first-line therapy. Secondline drugs include amitriptyline (orally up to 25 mg t.i.d.) and zolpidem (5 to 10 mg o.d.), both of which may improve motor impairment transiently for weeks or months. At present, there is no role for cholinergic, serotonergic, or noradrenergic drug therapy in PSP. In view of the limited pharmacological options, physiotherapy, occupational therapy, and speech therapy are recommended. Dysphagia may require feeding via a nasogastric tube or percutaneous endoscopic gastrostomy. Tarsal and pretarsal blepharospasm as well as limb dystonia can respond well to local injections of botulinum toxin A.

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CORTICOBASAL DEGENERATION Corticobasal degeneration (CBD) is a multisystem disorder affecting the nigrostriatal motor system plus a variety of other subcortical structures, including variable cell loss in the thalamus, subthalamic nucleus, the pallidum, red nucleus, and dentate nucleus, and scattered changes in other brainstem nuclei. In addition there is prominent and usually asymmetrical cortical degeneration involving frontoparietal areas. The resulting clinical picture is one of a strikingly asymmetrical akinetorigid parkinsonian syndrome associated with other movement disorders—most often dystonia and myoclonus.

Epidemiology The incidence and prevalence of CBD are largely unknown. Schrag and coworkers138 failed to identify a single case in a community-based prevalence study of parkinsonism covering more than 120,000 persons, and the series by Hughes and colleagues covering 143 cases of postmortem confirmed parkinsonian syndromes in a highly specialized movement disorder unit only included four CBD cases.200 This would suggest that CBD might count for only some 3% of patients with degenerative parkinsonism.

Clinical Presentation, Course, and Prognosis Similar to the other conditions discussed in this chapter, CBD is a multisystem disorder affecting the nigrostriatal motor system plus a variety of other subcortical structures, including variable cell loss in the thalamus, subthalamic nucleus, pallidum, red nucleus, and dentate nucleus, and scattered changes in other brainstem nuclei. In addition, there is prominent and usually asymmetrical cortical degeneration involving frontoparietal areas. The resulting clinical picture is one of a strikingly asymmetrical akinetorigid parkinsonian syndrome associated with other movement disorders—most often dystonia and myoclonus—in combination with cortical signs including apraxia and “alien limb” phenomena, cortical sensory loss, and variable degrees of dysphasia. Between 30% and 50% of patients eventually show signs of depression and frontal-lobe type behavioral changes including apathy or disinhibition, impulsiveness, and irritability,201-203 and some series suggest that 25% may become demented.172 The clinical picture of CBD in its full expression including limb apraxia, alien limb behavior, and strictly asymmetrical parkinsonism, and jerky dystonia of the limbs is so characteristic that there is little room for clinical diagnostic error. On the other hand, early CBD with unilateral limb rigidity and clumsiness can be confused with idiopathic Parkinson disease; patients with significant postural instability and falls may be confused with PSP patients when there is some additional limited vertical gaze or frontal executive dysfunction. However, the supranuclear gaze palsy in CBD usually affects horizontal and vertical gaze equally, whereas vertical gaze is more severely affected in PSP. CBD presenting with cognitive impairment is also difficult to diagnose, and there is some controversy that frontotemporal dementia and CBD may represent different ends of a single disease spectrum.204 Overall, diagnostic sensitivity to CBD is suboptimal even among expert neurologists who only detected 30% of postmortem confirmed CBD cases on the basis

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T A B L E 72–6. Corticobasal Degeneration Presenting Symptom Limb, clumsiness (arm) Gait disorder Tremor Speech disturbance Behavioral disturbance

T A B L E 72–7. % ≈50 ≈30 ≈20 Rare Rare

Data from Rinne JO, Lee MS, Thompson PD, et al: Corticobasal degeneration: a clinical study of 36 cases. Brain 1994;117:1183-1196; and Wenning GK, Litvan I, Jankovic J, et al: Natural history and survival of 14 patients with corticobasal degeneration confirmed at post-mortem examination. J Neurol Neurosurg Psychiatry 1998; 64:184-189.

Clinical Diagnostic Criteria for CBD

• Marked asymmetry at onset (includes motor and cortical sensory signs, apraxia and dysphasia) • Progressive course • Presence of a. Movement disorder Akinetic-rigid parkinsonism Limb dystonia Focal myoclonus PLUS b. Cortical dysfunction

Exclusion of

of clinical presentation at first visit.205 Table 72–6 summarizes the most common presenting symptoms of CBD as described in two clinicopathological series.

Clinical Course Although publications on CBD have multiplied since the late 1980s, there are still no available data on its incidence and prevalence. There appears to be no sex predominance.201 Classically, patients with CBD present in the sixth or seventh decade of life with a unilateral jerky tremulous akinetorigid and apraxic extremity held in a fixed posture and displaying the alien limb syndrome.202 However, presentations can vary widely; they may relate to difficulty in walking, speech, or, less commonly, limb sensation. Symptoms usually remain clearly asymmetrical, eventually spreading from the affected arm to the ipsilateral leg, and progress steadily until death which usually occurs 4 to 8 years after disease onset. Bilateral parkinsonian features at first neurological evaluation predict shorter survival, particularly in the presence of frontal lobe dysfunction.201 The etiology and pathogenesis of CBD remain to be resolved. There is abnormal aggregation of tau affecting both basal ganglia and motor cortex. Recent evidence suggests that there may be a genetic predisposition toward tau accumulation that is shared by PSP patients.146

Diagnostic Criteria Several schemes for diagnostic criteria for CBD have been proposed and most focus on the presence of a markedly asymmetrical parkinsonian syndrome with relentless progression and various combinations of movement disorders and cortical dysfunction. Table 72–7 summarizes the key components of clinical diagnostic criteria proposed by Kumar and colleagues.206

Genetics CBD is usually a sporadic disorder but there have been rare reports of familial occurrence of a CBD like syndrome, with autopsy-proved CBD in one family member.207 Although there have been no documented tau mutations in cases of CBD, some studies found higher prevalences of the H1/H1-genotype in CBD, indicating that tau gene polymorphisms may play a role in this condition.146,208

Cortical sensory loss Alien limb phenomena (levitation only excluded) Apraxia Early dementia Levodopa responsiveness Downgaze palsy Typical rest tremor Severe dysautonomia Alternative pathology accounting for clinical features on appropriate imaging studies

Adapted from Kumar R, Bergeron C, Lang AE. Corticobasal degeneration. In Jankovic J, Tolosa E, eds: Parkinson’s Disease and Movement Disorders, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 185-198.

Ancillary Investigations While routine laboratory studies or cerebrospinal fluid studies are normal in patients with CBD, classic patients usually show asymmetrical frontoparietal cortical atrophy, which was present in 88% of cases on MR imaging in one series.209 Functional imaging using SPECT and dopamine transporter ligands show nigrostriatal terminal dopaminergic dysfunction which is similar to Parkinson disease or other degenerative forms of parkinsonism including PSP but may be helpful in differentiating CBD from Pick disease. PET studies have shown asymmetrical reductions in glucose metabolism and blood flow predominantly in the frontoparietal area but also subcortical nuclei like the thalamus or striatum,210 and PET studies using PK11195 have shown asymmetrical basal ganglia and cortical microglial activation in CBD.211 Neurophysiological studies are of limited usefulness in CBD, but electroencephalograms may show asymmetrical cortical slowing over the hemisphere contralateral to the most effected extremities in full-blown cases.

Principles of Management Overall, CBD is often considered an untreatable condition due to its relentless progression and the at-best modest response to various symptomatic interventions. Nonetheless, at least temporary improvement can be achieved for several of the clinical problems highlighted in up to two thirds of patients depending on the target symptom (Table 72–8).172 It has to be pointed out, however, that due to the rarity of CBD (even tertiary referral centers usually follow less than 20 patients),172 to date there has been no single controlled or even uncontrolled prospective clinical trial of any intervention, and all recommendations given below are based on retrospective uncontrolled case series.

chapter 72 parkinson plus disorders T A B L E 72–8. Drug Treatment Responses in CBD Medication

Exposed, n (%)

Dopaminergic agents Levodopa/carbidopa Agonist Selegiline Amantadine Benzodiazepines Anticholinergics Baclofen Antidepressants Anticonvulsants Propanolol Neuroleptics Botulinum toxin

135 (92) 128 (87) 33 (25) 30 (20) 24 (16) 47 (32) 38 (27) 28 (19) 16 (11) 13 (9) 11 (8) 6 (4) 9 (6)

Clinical Improvement, n (%) 33 (24) 33 (26) 2 (6) 3 (10) 3 (13) 19 (40) 8 (21) 2 (7) 1 (6) 3 (23) 2 (18) 4 (67) 6 (67)

Values are number of patients of a total possible of 147. From Kompoliti K, Goetz CG, Litvan I, et al: Pharmacological therapy in progressive supranuclear palsy. Arch Neurol 1998; 55:1099-1102.

Treatment of Parkinsonism in Corticobasal Degeneration Parkinsonism in CBD is dominated by rigidity and bradykinesia while tremor is present in only 30% to 50% of cases and is often irregular and jerky.172,201 In addition parkinsonism contributes to the gait disorder of CBD, which becomes a major source of disability in the course of disease with marked postural instability and falls. Due to the impact of cerebellar dysfunction and apraxia, antiparkinsonian medications have a variable effect on the gait problems of CBD patients. The drugs that have been used to improve parkinsonian features in CBD include levodopa, dopamine agonists, selegiline, amantadine, and anticholinergics. The largest case series with uncontrolled retrospective data on drug responses was published by Kompoliti and colleagues (1998)211a who had included 147 patients followed at eight movement disorder centers.

L-Dopa In the series by Kompoliti and coworkers211a, 87% of cases had been exposed to therapeutic trials of L-dopa with a mean daily dose of 300 mg (range, 100 to 2000 mg). Some clinical improvement of parkinsonism was noted in 26% of patients, and bradykinesia and rigidity responded the most, but there are no data on the magnitude or duration of this response. One patient each of a total of 33 responding to L-dopa was noted to improve regarding dystonic or alien limb features while 5% had some degree of worsening either of parkinsonism or gait dysfunction or dystonia and myoclonus. L-Dopa–induced dyskinesias were not observed in this series even with high-dose treatment, and there are also no other reports in the literature noting the occurrence of dyskinesias in response to L-dopa in CBD.212 Gastrointestinal complaints were present in 15%, followed by confusion, dizziness and somnolence (4% each), and hallucinosis (2%).

Dopamine Agonists Dopamine agonists are less commonly used than L-dopa to treat parkinsonian features of CBD; 25% of the 147 patients collected by Kompoliti and associates (1998) had been treated with either

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pergolide or bromocriptine, and doses were analyzed as “pergolide equivalents” with a conversion ratio of 1 : 10. Mean agonist dose was thus reported as 0.82 mg of pergolide equivalent (range, 0.15 to 3.0 mg), but it is not clear from the report if this was in monotherapy or as adjunct to L-dopa. Not surprisingly, given the low mean doses, only 6% of patients showed some improvement—again no further details on the type and magnitude or duration of response are given. Agonist-induced confusion was relatively common, affecting 14% of patients, whereas gastrointestinal side effects or dizziness was noted in 11% each.

Other Antiparkinsonian Drugs Data on the efficacy and safety of other antiparkinsonian agents in CBD are even more fragmentary and unsystematic as for Ldopa and dopamine agonists. Selegiline was used in 20% of cases of the above series, improving parkinsonism in 3 of 30 patients, and amantadine was given to 24 patients (16% of that series), producing some benefit in three cases (13%). Other than tremor and rigidity, gait was reported to improve following amantadine. Thirty-eight patients (27%) had been exposed to anticholinergics—either trihexiphenidyl or benztropine— and four of these (10%) had improvements in rigidity or tremor. Side effects of such treatment, specifically cognitive dysfunction, are not commented upon in this report or indeed any report in the literature.

Treatment of Dystonia in Corticobasal Degeneration Dystonia is one of the cardinal motor features of CBD, affecting between 50% and 80% of patients,213 most often as asymmetrical limb dystonia producing jerky or fixed postural deformities that may the render the affected extremity functionally useless and may also be painful. It is therefore an area of great therapeutic need, but again there are no controlled prospective or controlled trials of antidystonic interventions on which to base treatment decisions. Retrospective uncontrolled observations point to the possible efficacy of drugs like anticholinergics, benzodiazepines, baclofen and—most strongly— of local botulinum toxin injections.

Systemic Drug Therapy Anticholinergics as well as baclofen were reported to have improved dystonia in individual cases of the series of Goetz and coworkers214 and Kompoliti and colleagues212 and these authors as well as Vanek and Jankovic213 remark on the efficacy of clonazepam to improve myoclonic dystonia. Details on doses employed, effect size, or side effects are absent from all these reports.

Botulinum Toxin Injections Because asymmetrical focal limb dystonia is a typical presentation of dystonia in CBD,201,202,213 localized injections of botulinum toxin have been tried in this situation—in analogy to their successful use in adult-onset focal idiopathic dystonia. Again no systematic or controlled trials of this form of treatment for dystonia in CBD are available. Of nine patients in the large series reported by Kompoliti and coworkers (1998), who received local botulinum toxin injections to treat focal limb

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dystonia, six (67%) reportedly showed some improvement. All 6 patients in the series of 66 cases reported by Jankovic and colleagues213 had some response of their focal dystonic symptoms to botulinum toxin injections—two of these experienced marked degrees of improvement of both dystonia and pain with this form of therapy. Unfortunately, none of these reports gives any detailed dose of botulinum toxin or muscle selection, so that it is difficult to derive practical treatment recommendations from them. Müller and colleagues195 recently reported on two patients with CBD who received successful treatment with botulinum toxin injections for focal limb dystonia. Dosages used were 40 to 120 units Dysport for finger flexor muscles, 80 to 120 units Dysport for wrist flexor and extensor muscles, and 160 to 240 units Dysport for elbow flexor muscles.

of time to physiotherapy, and occupational therapy may increase functional hand use, particularly when combined with antiparkinsonian and antidystonic pharmacotherapy.

K E Y ●

The term Parkinson plus disorders has been coined to embrace a heterogeneous group of movement disorders with prominent signs of parkinsonism plus additional features that allow clinical separation of these entities from classic idiopathic parkinson disease.

●

MSA is characterized clinically by combinations of poorly L-dopa–responsive parkinsonism, dysautonomia and cerebellar ataxia, and its parkinsonian variant (MSA-P) is the one parkinson plus disorder most commonly confused with IPD early in the disease. Neuropathological hallmarks of MSA are synuclein-positive oligodendroglial inclusions in many brain areas, with the substantia nigra, striatum, pons, inferior olives, and cerebellar Purkinje cells bearing the brunt of neuronal pathology together with cell loss in the ncl intermediolateralis and Onuf’s nucleus of the spinal cord. Clinical dignosis may be aided by changes on routine MRI, and sensitivity may be enhanced by applying DWI techniques. MSA is fast and relentlessly progressive, and treatment is multimodal and palliative

●

PSP is a chronic progressive neurodegenerative disorder characterized by continuation of clinical features including akinetorigid parkinsonism, postural instability supranuclear vertical gaze palsy, axial dyskinesia, and frontolimbic dementia. Standard clinical diagnostic criteria focus on early supranuclear gaze palsy and falls but fail to capture atypical presentations. Recent work has identified a “parkinsonian” subtype of PSP present in about one third of cases in which gaze palsy and falls may be missing; a partial L-dopa response may occur and progression is less rapid compared with the classic syndrome’

●

CBD is a multisystem disorder affecting the nigrostriatal motor system plus a variety of other subcortical structures, including variable cell loss in the thalamus, subthalamic nucleus, the pallidum, red nucleus, and dentate nucleus, and scattered changes in other brainstem nuclei. There is prominent and usually asymmetrical cortical degeneration involving frontoparietal areas. The result is asymmetrical akinetorigid parkinsonian syndrome associated with other movement disorders in combination with cortical signs. CBD is often considered an untreatable condition due to its relentless progression and the at-best modest response to various symptomatic interventions.

Treatment of Myoclonus in Corticobasal Degeneration The use of benzodiazepines—most often clonazepam—as well as of valproate, mysoline, and piracetam to treat myoclonic jerking in CBD has been reported in a number of studies in anecdotal fashion.172,205,213 Results are inconsistent and the drug most often reported as beneficial is clonazepam ameliorating myoclonic jerking in 23% of patients in the series of Kompoliti and co-workers in 1998. Sedation is the most common side effect, affecting 26% of patients exposed to clonazepam in that report.

Treatment of Cortical Dysfunction in Corticobasal Degeneration Apraxia, dysphasia, cortical sensory loss, and alien limb behavior are hallmarks of the cortical pathology in this condition. There is no evidence available that various methods of physiotherapy, occupational therapy, or speech therapy significantly reduce the disability caused by the symptoms or indeed affect their progression.

Practical Management Intervention should be based on the relative impact of various clinical features found in a given patient on his or her global disability. For the treatment of parkinsonism, L-dopa given in maximum tolerated doses in order to achieve the best possible motor response (300 to 2000 mg) is the drug of first choice. Dopamine agonists are of no added value and definitely less well tolerated and also more expensive. The expected response rate to L-dopa is in the order of 25% of patients. Anticholinergics can be useful in cases were both rigidity and dystonia cause limb postural deformities. Local botulinum toxin injections are an option for focal limb dystonia and may also reduce associated pain and jerking. Depending on target muscles, doses between 40 and 300 units of Dysport or 10 and 100 units of Botox per muscle may be used. Alternatively, myoclonus can be treated with clonazepam in doses between 0.5 and 2 mg/day. Speech and swallowing problems are common as CBD progresses and should be treated with speech therapy; nasogastric or gastrostomy tube feeding for severe dysphagia is rarely necessary but should be considered in case of silent aspirations. Limb apraxia may show a limited response for a limited period

P O I N T S

Suggested Reading Mahapatra RK, Edwards MJ, Schott JM, et al: Corticobasal degeneration. Lancet Neurol 2004; 3:736-743. Steele JC, Richardson JC, Olszewski J: Progressive supranuclear palsy. A heterogeneous degeneration involving the brainstem, basal ganglia and cerebellum with vertical gaze and pseudo-

chapter 72 parkinson plus disorders bulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10:333-359. Wenning GK, Ben Shloma Y, Magalhaes M, et al: Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994; 117:835-845. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:93-103. Williams DR, de Silva R, Paviour DC, et al: Charcteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy. Richardson’s syndrome and PSPparkinsonism. Brain 2005; 128:1247-1258.

References 1. Graham J, Oppenheimer DR: Orthostatic-hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 1969; 32:28-34. 2. van der Eecken H, Adams RD, van Bogaert L: Striopallidalnigral degeneration. A hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 1960; 19:159-161. 3. Adams R, Van Bogaert L, Van der Eecken H: Degenerescenes nigro-striees et cerebello-nigro-striees. Psychiat Neurol (Basel) 1961; 142:219-259. 4. Adams R, Van Bogaert L, Van der Eecken H: Striato-nigral degeneration. J Neuropathol Exp Neurosci 1964; 23:584-698. 5. Dejerine J, Thomas A: L’atrophie olivo-ponto-cerebelleuse. Nouvelle iconographie de la Salpetriere: Clinique des Malacies du Systeme Nerveux 1900; 13:330-370. 6. Stauffenberg: Zur Kenntnis des extrapyramidalen motorischen Systems und Mitteilung eines Falles von sog. “Atrophie olivo-pontocérébelleuse.” Z Gesamte Neurol Psychiatrie 1918; 39:1-55. 7. Shy G, Drager GA: A neurological syndrome associated with orthostatic hypotension. A clinicopathological study. Arch Neurol 1960; 2:511-527. 8. Papp M, Kahn JE, Lantos PL: Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and ShyDrager syndrome). J Neurol Sci 1989; 94:79-100. 9. Wakabayashi K, Yoshimoto M, Tsuji S, et al: Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 1998; 249:180-182. 10. Spillantini MG, Crowther RA, Jakes R, et al: Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson disease and dementia with Lewy bodies. Neurosci Lett 1998; 251:205-208. 11. Tison F, Yekhlef F, Chrysostome V, et al: Prevalence of multiple system atrophy. Lancet 2000; 355:495-496. 12. Schrag A, Ben-Shlomo Y, Quinn NP: Prevalence of progressive supranuclear palsy and multiple system atrophy: a crosssectional study. Lancet 1999; 354:1771-1775. 13. Wermuth L, Joensen P, Bunger N, et al: High prevalence of Parkinson disease in the Faroe Islands. Neurology 1997; 49:426-432. 14. Chio A, Magnani C, Schiffer D: Prevalence of Parkinson disease in Northwestern Italy: comparison of tracer methodology and clinical ascertainment of cases. Mov Disord 1998; 13:400-405. 15. Nee LE, Gomez MR, Dambrosia J, et al: Environmentaloccupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991; 1:9-13. 16. Vanacore N, Bonifati V, Fabbrini G, et al: Smoking habits in multiple system atrophy and progressive supranuclear palsy. Neurology 2000; 54:114-119. 17. Hanna P, Jankovic J, Kirkpatrick JB: Multiple system atrophy. The putative causative role of environmental toxins. Arch Neurol 1999; 56:90-94.

977

18. Watanabe H, Saito Y, Terao S, et al: Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 2002; 125:1070-1083. 19. Testa D, Monza D, Ferrarini M, et al: Comparison of natural histories of progressive supranuclear palsy and multiple system atrophy. Neurol Sci 2001; 22:247-251. 20. Ben-Shlomo Y, Wenning G, Tison F, et al: Survival of patients with pathologically proven multiple system atrophy: a metaanalysis. Neurology 1997; 48:384-393. 21. Wenning GK, Ben Shlomo Y, Magalhaes M, et al: Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994; 117:835-845. 22. Abele M, Burk K, Schols L, et al: The aetiology of sporadic adult-onset ataxia. Brain 2002; 125:961-998. 23. Gilman S, Little R, Johanns J, et al: Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy. Neurology 2000; 55:527-532. 24. Schwarz J, Tatsch K, Gasser T, et al: 123I-IBZM binding compared with long-term clinical follow up in patients with de novo parkinsonism. Mov Disord 1998; 13:16-19. 25. Gilman S, Low P, Quinn N, et al: Consensus statement on the diagnosis of multiple system atrophy. Clin Auton Res 1998; 8:359-362. 26. Wenning GK, Geser F, Poewe W: The ‘risus sardonicus’ of multiple system atrophy. Mov Disord 2003; 18:1211. 27. Boesch SM, Wenning GK, Ransmayr G, et al: Dystonia in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 72:300-303. 28. Wenning GK, Ben Shlomo Y, Hughes A, et al: What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson disease? J Neurol Neurosurg.Psychiatry 2000; 68:434-440. 29. Beck R, Betts C, Fowler C: Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol1994; 151:1336-1341. 30. Quinn N: Multiple system atrophy—the nature of the beast. J Neurol Neurosurg Psychiatry 1989; 52 (suppl):78-89. 31. Quinn N: Multiple system atrophy. In Marsden CD, Fahn S, eds: Movement Disorders 3. London: ButterworthHeinemann, 1994, pp 262-281. 32. Osaki Y, Wenning GK, Daniel SE, et al: Do published criteria improve clinical diagnostic accuracy in multiple system atrophy? Neurology 2002; 59:1486-1491. 33. Gouider-Khouja N, Vidailhet M, Bonnet AM, et al: “Pure” striatonigral degeneration and Parkinson disease: a comparative clinical study. Mov Disord 1995; 10:288-294. 34. Tison F, Wenning GK, Quinn NP, et al: REM sleep behaviour disorder as the presenting symptom of multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:379-389. 35. Plazzi G, Corsini R, Provini F: REM sleep behavior disorders in multiple system atrophy. Neurology 1997; 48:1094-1097. 36. Olson EJ, Boeve BF, Silber MH: Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000; 123:331-339. 37. Gilman S, Koeppe RA, Chervin RD, et al: REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003; 61:29-34. 38. Ghorayeb I, Yekhlef F, Chrysostome V, et al: Sleep disorders and their determinants in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 72:798-800. 39. Wenning GK, Wagner S, Daniel S, et al: Multiple system atrophy: sporadic or familial? Lancet 1993; 342:681. 40. Baker M, Litvan I, Houlden H, et al: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999; 8:711-715. 41. Bandmann O, Sweeney MG, Daniel SE, et al: Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration. Neurology 1997; 49:1598-1604.

978

Section

XII

Neurodegenerative Diseases

42. Nicholl DJ, Bennett P, Hiller L, et al: A study of five candidate genes in Parkinson disease and related neurodegenerative disorders. European Study Group on atypical parkinsonism. Neurology 1999; 53:1415-1421. 43. Iwahashi K, Miyatake R, Tsuneoka Y, et al: A novel cytochrome P-450IID6 (CYPIID6) mutant gene associated with multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:263-264. 44. Bandmann O, Wenning GK, Quinn NP, et al: Arg296 to Cys296 polymorphism in exon 6 of cytochrome P-450-2D6 (CYP2D6) is not associated with multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 59:557. 45. Cairns NJ, Atkinson PF, Kovacs T, et al: Apolipoprotein E e4 allele frequency in patients with multiple system atrophy. Neurosci Lett 1997; 221:161-164. 46. Healy DG, Abou-Sleiman PM, Jain S, et al: Assessment of a DJ-1 (PARK7) polymorphism in Finnish Parkinson disease. Neurology 2003; 61:1000-1002. 47. Hashida H, Goto J, Zhao N, et al: Cloning and mapping of ZNF231, a novel brain-specific gene encoding neuronal double zinc finger protein whose expression is enhanced in a neurodegenerative disorder, multiple system atrophy (MSA). Genomics 1998; 54:50-58. 48. Gilman S, Sima AA, Junck L, et al: Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996; 39:241-255. 49. Schols L, Peters S, Szymanski S, et al: Extrapyramidal motor signs in degenerative ataxias. Arch Neurol 2000; 57:14951500. 50. Ranum LP, Lundgren JK, Schut LJ, et al: Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 1995; 57:603-608. 51. Silveira I, Lopes-Cendes I, Kish S, et al: Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology 1996; 46:4-8. 52. Leggo J, Dalton A, Morrison PJ, et al: Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich’s ataxia genes in spinocerebellar ataxia patients in the UK. J Med Genet 1997; 34:982-985. 53. Futamura N, Matsumura R, Fujimoto Y, et al: CAG repeat expansions in patients with sporadic cerebellar ataxia. Acta Neurol Scand 1998; 98:55-59. 54. Moseley ML, Benzow KA, Schut LJ, et al: Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998; 51:1666-1671. 55. Hagermann RJ, Leehey M, Heinrichs W, et al: Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2002; 58:987. 56. Jacquemont S, Hagerman RJ, Leehey M, et al: Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003; 72:869878. 57. Kamm C, Leung J, Joseph S, et al: Refinded linkage to the RDP/DYT12 locus on 19q13.2 and evaluation of GRIK5 as a candidate gene. Mov Disord 2004; 19:845-847. 58. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. J Neurol Sci 1996; 144:218-219. 59. Bannister R, Mathias C: Investigation of autonomic disorders. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford: Oxford University Press, 1999, pp 169-195. 60. Ziegler M, Lake C, Kopin I: The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med 1977; 296:293-297.

61. Polinsky R, Kopin I, Ebert M, et al: Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981; 31:1-7. 62. Riley DE, Chelimsky TC: Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson disease. J Neurol Neurosurg Psychiatry 2003; 74:56-60. 63. Kirby R, Fowler CJ, Gosling J, et al: Urethro-vesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986; 49:554-562. 64. Pramstaller PP, Wenning GK, Smith SJ, et al: Nerve conduction studies, skeletal muscle EMG, and sphincter EMG in multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:618-621. 65. Palace J, Chandiramani VA, Fowler CJ: Value of sphincter electromyography in the diagnosis of multiple system atrophy. Muscle Nerve 1997; 20:1396-1403. 66. Valldeoriola F, Valls-Sole J, Tolosa ES, et al: Striated anal sphincter denervation in patients with progressive supranuclear palsy. Mov Disord 1995; 10:550-555. 67. Giladi N, Simon ES, Korczyn Alzheimer diseaseet al: Anal sphincter EMG does not distinguish between multiple system atrophy and Parkinson disease. Muscle Nerve 2000; 23:731734. 68. Colosimo C, Inghilleri M, Chaudhuri KR: Parkinson disease misdiagnosed as multiple system atrophy by sphincter electromyography. J Neurol 2000; 247:559-561. 69. Vodusek B: Sphincter EMG and differential diagnosis of multiple system atrophy. Mov Disord 2001; 16:600-607. 70. Wüllner U, Klockgether T, Petersen D, et al: Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology 1993; 43:318-325. 71. Schrag A, Good CD, Miszkiel K, et al: Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 2000; 54:697-702. 72. Drayer B, Olanow W, Burger P, et al: Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 1986; 159:493-498. 73. Pastakia B, Polinsky R, Di Chiro G, et al: Multiple system atrophy (Shy-Drager syndrome): MR imaging. Radiology 1986; 159:499-502. 74. O’Brien C, Sung JH, McGeachie RE, et al: Striatonigral degeneration: clinical, MRI, and pathologic correlation. Neurology 1990; 40:710-711. 75. Lang A, Curran T, Provias J, et al: Striatonigral degeneration: iron deposition in putamen correlated with the slit-like void signal of magnetic resonance imaging. Can J Neurol Sci 1994; 21:311-318. 76. Schwarz J, Weis S, Kraft E: Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60:98-101. 77. Schrag A, Kingsley D, Phatouros C, et al: Clinical usefulness of magnetic resonance imaging in multiple system atrophy. J Neurol Neurosurg Psychiatry 1998; 65:65-71. 78. Kraft E, Trenkwalder C, Auer DP: T2*-weighted MRI differentiates multiple system atrophy from Parkinson disease. Neurology 2002; 59:1265-1267. 79. Konagaya M, Konagaya Y, Iida M: Clinical and magnetic resonance imaging study of extrapyramidal symptoms in multiple system atrophy. J Neurol Neurosurg Psychiatry 1994; 57:1528-1531. 80. Kraft E, Schwarz J, Trenkwalder C, et al: The combination of hypointense and hyperintense signal changes on T2weighted magnetic resonance imaging sequences: a specific marker of multiple system atrophy? Arch.Neurol 1999; 56: 225-228. 81. Schocke M, Seppi K, Esterhammer R, et al: Diffusionweighted MRI differentiates the Parinson variant of multiple

chapter 72 parkinson plus disorders

82.

83.

84. 85.

86.

87. 88.

89. 90.

91.

92. 93.

94.

95.

96. 97. 98. 99.

system atrophy from Parkinson disease. Neurology 2002; 58:575-580. Seppi K, Schocke MF, Esterhammer R, et al: Diffusionweighted imaging discriminates progressive supranuclear palsy from Parkinson disease, but not from the parkinson variant of multiple system atrophy. Neurology 2003; 60:922927. Schulz J, Skalej M, Wedekind D, et al: Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson syndrome from multiple system atrophy and progressive supranuclear palsy. Ann Neurol 1999; 45:65-74. Brenneis C, Seppi K, Schocke M, et al: Voxel-based morphometry detects cortical atrophy in the Parkinson variant of multiple system atrophy. Mov Disord 2003; 18:1132-1138. Brooks D, Ibanez V, Sawle GV, et al: Differing patterns of striatal 18F-dopa uptake in Parkinson disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28:547-555. Burn DJ, Rinne JO, Quinn NP, et al: Striatal opioid receptor binding in Parkinson disease, striatonigral degeneration and Steele-Richardson-Olszewski syndrome, A [11C]diprenorphine PET study. Brain 1995; 118:951-958. De Volder A, Francart J, Laterre C, et al: Decreased glucose utilization in the striatum and frontal lobe in probable striatonigral degeneration. Ann Neurol 1989; 26:239-247. Perani D, Bressi S, Testa D, et al: Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18 positron emission tomographic study. Arch Neurol 1995; 52:179-185. Antonini A, Kazamuta K, Feigin A, et al: Differential diagnosis of parkinsonism with 18F-fluorodeoxyglucose and PET. Mov Disord 1998; 13:268-274. Ghaemi M, Hilker R, Rudolf J, et al: Differentiating multiple system atrophy from Parkinson disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging. J Neurol Neurosurg Psychiatry 2002; 73:517-523. Gilman S, Koeppe RA, Junck L, et al: Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol 1994; 36:166-175. Brücke T, Djamshidian S, Bencsits G, et al: SPECT and PET imaging of the dopaminergic system in Parkinson disease. J Neurol 2000; 247(Suppl 4):2-7. Scherfler C, Seppi K, Donnemiller E, et al: Voxel-wise analysis of [123I]beta-CIT SPECT differentiates the Parkinson variant of multiple system atrophy from idiopathic Parkinson disease. Brain 2005; 128:1605-1612. Schulz J, Klockgether T, Petersen D, et al: Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 57:1047-1056. van Royen E, Verhoeff NFLG, Speelman JD, et al: Multiple system atrophy and progressive supranuclear palsy: diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM sigle photon emission computed tomography. Arch Neurol 1993; 50:13-16. Brücke T, Wenger S, Asenbaum S: Dopamine D2 receptor imaging and measurement with SPECT. Adv Neurol 1993; 60:494-500. Braune S, Reinhardt M, Schnitzer R, et al: Cardiac uptake of (123I)MIBG separates Parkinson disease from multiple system atrophy. Neurology 1999; 53:1020-1025. Braune S: The role of cardiac metaiodobenzylguanidine uptake in the differential diagnosis of parkinsonian syndromes. Clin Auton Res 2001; 11:351-355. Goldstein DS, Holmes C, Cannon RO III, et al: Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 1997; 336:696-702.

979

100. Goetz CG, Tanner CM, Klawans HL: The pharmacology of olivopontocerebellar atrophy. Adv Neurol 1984; 41:143-148. 101. Botez MI, Botez-Marquard T, Elie R, et al: Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study. J Neurol Neurosurg Psychiatry 1996; 61:259-264. 102. Albanese A, Colosimo C, Bentivoglio A, et al: Multiple system astrophy presenting as parkinsonism: clinical features and diagnostic criteria. J Neurol Neurosurg Psychiatry 1995; 59:144-151. 103. Parati E, Fetoni V, Geminiani C, et al: Response to L-DOPA in multiple system atrophy. Clin Neuropharmacol 1993; 16:139-144. 104. Lees A: The treatment of the motor disorder of multiple system atrophy. In Mathias C, Bannister R, eds: Autonomic Failure. Oxford: Oxford University Press, 1999, pp 357-363. 105. Hughes A, Colosimo C, Kleedorfer B, et al: The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry 1992; 55:1009-1013. 106. Colosimo C, Albanese A, Hughes A: Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson disease. Arch Neurol 1995; 52:294298. 107. Wenning GK, Ben Shlomo Y, Magalhaes M, et al: Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:160-166. 108. Rajput AH, Rozdilsky B, Rajput A, et al: Levodopa efficacy and pathological basis of Parkinson syndrome. Clin Neuropharmacol 1990; 13:553-558. 109. Lees A, Bannister R: The use of lisuride in the treatment of multiple system atrophy with autonomic failure (Shy Drager syndrome). J Neurol Neurosurg Psychiatry 1981; 44: 347-351. 110. Colosimo C, Merello M, Pontieri FE: Amantadine in parkinsonian patients unresponsive to levodopa: a pilot study. J Neurol 1996; 243:422-425. 111. Lang AE, Lozano A, Duff J, et al: Medial pallidotomy in latestage Parkinson disease and striatonigral degeneration. Adv Neurol 1997; 74:199-211. 112. Visser-Vandewalle V, Temel Y, Colle H, et al: Bilateral highfrequency stimulation of the subthalamic nucleus in patients with multiple system atrophy–parkinsonism. Report of four cases. J Neurosurg 2003; 98:882-887. 113. Wenning G, Tison F, Scherfler C, et al: Towards neurotransplantation in multiple system atrophy: clinical rationale, pathophysiological basis, and preliminary experimental evidence. Cell Transpl 2000; 9:279-288. 114. Mathias CJ: Autonomic disorders and their recognition. N Engl J Med 1997; 336:721-724. 115. Mathias C, Mallipeddi R, Bleasdale-Barr KM: Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. J Neurol 1999; 246:893-898. 116. Thomas DJ, Bannister R: Preservation of autoregulation of cerebral blood flow in autonomic failure. J Neurol Sci 1980; 44:205-212. 117. Chaudhuri K, Hu M: Central autonomic dysfunction. In Appenzeller O, ed: Handbook of Clinical Neurology. Part II. Amsterdam: Elsevier Science, 2000, pp 161-202. 118. Low PA, Gilden JL, Freeman R, et al: Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997; 277:1046-1051. 119. Wright RA, Kaufmann HC, Perera R, et al: A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124. 120. Jankovic J, Gilden JL, Hiner BC, et al: Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993; 95:38-48.

980

Section

XII

Neurodegenerative Diseases

121. Freeman R, Landsberg L, Young J: The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine: a randomized, placebo-controlled, crossover trial. Neurology 1999; 53:2151-2157. 122. Bonnet AM, Pichon J, Vidailhet M, et al: Urinary disturbances in striatonigral degeneration and Parkinson disease: clinical and urodynamic aspects. Mov Disord 1997; 12:509-513. 123. Hussain IF, Brady CM, Swinn MJ, et al: Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71:371-374. 124. Hayashi M, Isozaki E, Oda M, et al: Loss of large myelinated nerve fibers of the recurrent laryngeal nerve in patients with multiple system atrophy and vocal cord palsy. J Neurol Neurosurg Psychiatry 1997; 62:234-238. 125. Silber M, Levine S: Stridor and death in multiple system atrophy. Mov Disord 2000; 15:699-704. 126. Iranzo A, Santamaria J, Tolosa E, Barcelona Multiple System Atrophy Study Group: Continuous positive air pressure eliminates nocturnal stridor in multiple system atrophy. Lancet 2000; 356:1329-1330. 127. Maher ER, Lees AJ: The clinical features and natural history of the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 1986; 36:1005-1008. 128. Litvan I: Diagnosis and management of progressive supranuclear palsy. Semin Neurol 2001; 21:41-48. 129. Nath U, Ben-Shlomo Y, Thomson RG, et al: Clinical features and natural history of progressive supranuclear palsy: a clinical cohort study. Neurology 2003; 60:910-916. 130. Richardson JC, Steele J, Olszewski J: Supranuclear opthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia. A clinical report on eight cases of “heterogeneous system degeneration.” Trans Am Neurol Assoc 1963; 88:25-29. 131. Steele JC, Richardson JC, Olszewski J: Progressive supranuclear palsy. A heterogeneous degeneration involving the brainstem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10:333-359. 132. Hauw JJ, Daniel SE, Dickson D, et al: Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Review Neurology 1994; 44:2015-2019. 133. Morris HR, Gibb G, Katzenschlager R: Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy. Brain 2002; 125:969-975. 134. Spillantini MG, Goedert M: Tau protein pathology in neurodegenerative diseases. Trends Neurosci 1998; 21:428-433. 135. Arvanitakis Z, Wszolek ZK: Recent advances in the understanding of tau protein and movement disorders. Curr Opin Neurol 2001; 14:491-497. 136. Golbe LI, Davis PH, Schoenberg BS, et al: Prevalence and natural history of progressive supranuclear palsy. Neurology 1988; 38:1031-1034. 137. Bower JH, Maraganore DM, McDonnell SK, et al: Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997; 49:1284-1288. 138. Schrag A, Ben-Shlomo Y, Quinn NP: Prevalence of progressive supranuclear palsy and multiple system atrophy: a crosssectional study. Lancet 1999; 354:1771-1775. 139. Nath U, Ben-Shlomo Y, Thomson RG, et al: The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK. Brain 2001; 124:1438-1449. 140. Williams DR, de Silva R, Paviour DC, et al: Charcteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSPparkinsonism. Brain 2005; 128:1247-1258.

141. Hughes AJ, Ben-Shlomo Y, Daniel SE, et al: What features improve the accuracy of linical diagnosis in Parkinson disease: a clinicopathologic study 1992. Neurology 2001; 57(Suppl3):34-38. 142. Litvan I, Agid Y, Jankovic J, et al: Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy. (Steele-Richardson-Olszewski syndrome). Neurology 1996; 46:922-930. 143. Goetz CG, Leurgans S, Lang AE, et al: Progression of gait, speech and swallowing deficits in progressive supranuclear palsy. Neurology 2003; 60:917-922. 144. Litvan I, Agid Y, Calne D, et al: Clinical research criteria for the diagnosos of progressive supranuclear palsy (SteeleRichardson-Olszewski syndrome): report of the NINDS-SPSP internation workshop. Neurology 1996: 47:1-9. 145. Osaki Y, Ben-Shlomo Y, Lees AJ, et al: Accuracy of clinical diagnosis of progressive supranuclear palsy. Mov Disord 2004; 19:181-189. 146. Di Maria E, Tabaton M, Vigo T, et al: Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 2000; 47:374-377. 147. Urakami K, Wada K, Arai H, et al: Diagnostic significance of Tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J Neurol Sci 2001; 183:95-98. 148. Holmberg B, Rosengren L, Karlsson JE, et al: Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple-system atrophy compared with Parkinson disease. Mov Disord 1998; 13:70-77. 149. Holmberg B, Johnels B, Ingvarsson P, et al: cerebrospinal fluid-neurofilament and levodopa tests combined with discriminant analysis may contribute to the differential diagnosis of Parkinsonian syndromes. Parkinsonism Relat Disord 2001; 8:23-31. 150. Warmuth-Metz M, Neumann M, Csoti I, et al: Measurement of the midbrain diameter on routine magnetic resonance imaging: a simple and accurate method of differentiating between Parkinson disease and progressive supranuclear palsy. Arch Neurol 2001; 58:1076-1079. 151. Paviour DC, Price SL, Stevens JM, et al: Quantitative MRI measurement of superior cerebellar peduncle in progressive supranuclear palsy. Neurology 2005; 64:675-679. 152. Schulz JB, Skalej M, Wedekind D, et al: Magnetic resonance imaging–based volumetry differentiates idiopathic Parkinson syndrome from multiple system atrophy and progressive supranuclear palsy. Ann Neurol 1999; 45:65-74. 153. Cordato NJ, Pantelis C, Halliday GM, et al: Frontal atrophy correlates with behavioural changes in progressive supranuclear palsy. Brain 2002; 125:789-800. 154. Groschel K, Hauser TK, Luft A, et al: Magnetic resonance imaging–based volumetry differentiates progressive supranuclear palsy from corticobasal degeneration. Neuroimage 2004; 21:714-724. 155. Brenneis C, Seppi K, Schocke M, et al: Voxel based morphometry reveals a distinct pattern of frontal atrophy in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2004; 75:246-249. 156. Price S, Paviour D, Scahill R, et al: Voxel-based morphometry detects patterns of atrophy that help differentiate progressive supranuclear palsy and Parkinson disease. Neuroimage 2004; 23:663-669. 157. Eckert T, Sailer M, Kaufmann J, et al: Differntiation of idiopathic Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls using magnetization transfer imaging. Neuroimage 2004; 21:229-235. 158. Davie CA, Barker GJ, Machado C, et al: Proton magnetic resonance spectroscopy in Steele-Richardson-Olszewski syndrome. Mov Disord 1997; 12:767-771.

chapter 72 parkinson plus disorders 159. Tedeschi G, Litvan I, Bonavita S, et al: Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson disease and corticobasal degeneration. Brain 1997; 120:1541-1552. 160. Clarke CE, Lowry M: Systematic review of proton magnetic resonance spectroscopy of the striatum in parkinsonian syndromes. Eur J Neurol 2001; 8:573. 161. Brooks DJ: Functional imaging in relation to parkinsonian syndromes. J Neurol Sci 1993; 115:1-17. 162. Pirker W, Djamshidian S, Assenbaum S, et al: Progression of dopaminergic degeneration in Parkinson disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study. Mov Disord 2002; 17:45-53. 163. Kim YJ, Ichise M, Ballinger JR, et al: Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of Parkinson disease, MSA, and PSP. Mov Disord 2002; 17:303-312. 164. Shinotoh H, Namba H, Yamaguchi M, et al: Positron emission tomographic measurement of acetylcholinesterase activity reeals differential loss of ascending cholinergic systems in Parkinson disease and progressive supranuclear palsy. Ann Neurol 1999; 46:62-69. 165. Gerhard A, Trender-Gerhard I, Turkheimer F, et al: In vivo imaging of miroglial activation with [C]®-PK11195 PET in progressive supranuclear palsy. Mov Disord 2006; 21:89-93. 166. Valls-Sole J. Neurophysiological characterization of parkinsonian syndromes. Neurophysiol Clin 2000; 30:352-367. 167. Rivaud-Pechoux S, Vidailhet M, Gallouedec G, et al: Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 2000; 54:10291032. 168. Kimber J, Mathias CJ, Lees AJ, et al: Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy. Brain 2000; 123:1422-1430. 169. Vodusek DB: Sphincter EMG and differential diagnosis of multiple system atrophy. Mov Disord 2001; 16:600-607. 170. Kofler M, Wenning GK, Poewe W, et al: Cortical and brainstem hyperexcitability in a pathologically confirmed case of multiple system atrophy. Mov Disord 2000; 15:362-363. 171. Nieforth KA, Golbe LI: Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol 1993; 16:338-346. 172. Kompoliti K, Goetz CG, Litvan I, et al: Pharmacological therapy in progressive supranuclear palsy. Arch Neurol 1998; 55:1099-1102. 173. Litvan I, Agid Y, Calne D, et al: Clinical research criteria for the diagnosis of progressive supranuclear palsy (SteeleRichardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47:1-9. 174. Williams AC, Nutt J, Lakes CR, et al: Actions of bromocriptine in the Shy-Drager and Steele-Richardson-Olszewski syndrome. In Fixe K, Calne DB, eds: Dopaminergic Ergots and Motor Control. Oxford: Pergamon Press, 1979, pp 271-283. 175. Neophytides A, Lieberman AN, Goldstein M, et al: The use of lisuride, a potent dopamine and serotonin agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1982; 45:261-263. 176. Weiner WJ, Minagar A, Shulman LM: Pramipexole in progressive supranuclear palsy. Neurology 1999; 52:873-874. 177. Newman GC: Treatment of progressive supranuclear palsy with tricyclic antidepressants. Neurology 1985; 35:1189-1193. 178. Engel PA: Treatment of progressive supranuclear palsy with amitriptyline: therapeutic and toxic effects. J Am Geriatr Soc 1996; 44:1072-1074. 179. Tamai S, Almeida OP: Nortriptyline for the treatment of depression in progressive supranuclear palsy. J Am Geriatr Soc 1997; 45:1033-1034.

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180. Ghika J, Tennis M, Hoffman E, et al: Idazoxan treatment in progressive supranuclear palsy. Neurology 1991; 41:986-991. 181. Rascol O, Sieradzan K, Peyro-Saint-Paul H, et al: Efaroxan, an alpha-2 antagonist, in the treatment of progressive supranuclear palsy. Mov Disord 1998; 13:673-676. 182. Rafal RD, Grimm RJ: Progressive supranuclear palsy: functional analysis of the response to methysergide and antiparkinsonian agents. Neurology 1981; 31:1507-1518. 183. Paulson GW, Lowery HW, Taylor GC: Progressive supranuclear palsy: pneumoencephalography, electronystagmography and treatment with methysergide. Eur Neurol 1981; 20:13-16. 184. Nagasaka T, Togashi S, Amino A, et al: Aniracetam for treatment of patients with progressive supranuclear palsy. Eur Neurol 1997; 37:195-198. 185. Colosimo C, Merello M, Pontieri FE: Amantadine in parkinsonian patients unresponsive to levodopa: a pilot study. J Neurol 1996; 243:422-425. 186. Golbe LI, Langston JW, Shoulson I: Selegiline and Parkinson disease. Protective and symptomatic considerations. Drugs 1990; 39:646-651. 187. Barclay CL, Duff J, Sandor P, et al: Limited usefulness of electroconvulsive therapy in progressive supranuclear palsy. Neurology 1996; 46:1284-1286. 188. Hauser RA, Trehan R: Initial experience with electroconvulsive therapy for progressive supranuclear palsy. Mov Disord 1994; 9:467-469. 189. Koller WC, Morantz R, Vetere-Overfield B, et al: Autologous adrenal medullary transplant in progressive supranuclear palsy. Neurology 1989; 39:1066-1068. 190. Waxman MJ, Morantz RA, Koller WC, et al: High incidence of cardiopulmonary complications associated with implantation of adrenal medullary tissue into the caudate nucleus in patients with advanced neurologic disease. Crit Care Med 1991; 19:181-186. 191. Daniele A, Moro E, Bentivoglio AR: Zolpidem in progressive supranuclear palsy. N Engl J Med 1999:341:543-544. 192. Polo KB, Jabbari B: Botulinum toxin-A improves the rigidity of progressive supranuclear palsy. Ann Neurol 1994; 35:237239. 193. Piccione F, Mancini E, Tonin P, et al: Botulinum toxin treatment of apraxia of eyelid opening in progressive supranuclear palsy: report of two cases. Arch Phys Med Rehabil 1997; 78:525-529. 194. Barclay CL, Lang AE: Dystonia in progressive supranuclear palsy. J Neurol Neurosurg. Psychiat 1997; 62:352-356. 195. Müller J, Wenning GK, Wissel J, et al: Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia. J Neurol 2002; 249:300-304. 196. Foster NL, Aldrich MS, Bluemlein L, et al: Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep. Neurology 1989; 39:257-261. 197. Litvan I, Blesa R, Clark K, et al: Pharmacological evaluation of the cholinergic system in progressive supranuclear palsy. Ann Neurol 1994; 36:55-61. 198. Fabbrini G, Barbanti P, Bonifati V, et al: Donepezil in the treatment of progressive supranuclear palsy. Acta Neurol Scand 2001; 103:123-125. 199. Newman GC: Treatment of progressive supranuclear palsy with tricyclic antidepressants. Neurology 1985; 35:11891193. 200. Hughes AJ, Daniel SE, Ben Shlomo Y, et al: The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125:861-870. 201. Wenning GK, Litvan I, Jankovic J, et al: Natural history and survival of 14 patients with corticobasal degeneration confirmed at post-mortem examination. J Neurol Neurosurg Psychiatry 1998; 64:184-189.

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202. Rinne JO, Lee MS, Thompson PD, Marsden CD: Corticobasal degeneration: a clinical study of 36 cases. Brain 1994; 117:1183-1196. 203. Cummings JL, Litvan I: Neuropsychiatric aspects of corticobasal degeneration. Adv Neurol 2000; 82:147-152. 204. Kertesz A, Martinez-Lage P, Davidson W, et al: The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 2000; 55:13681375. 205. Litvan I: Progressive supranuclear palsy and corticobasal degeneration. Bailliere’s Clin Neurol 1997; 6:167-185. 206. Kumar R, Bergeron C, Lang AE: Corticobasal degeneration. In Jankovic J, Tolosa E, eds: Parkinson Disease and Movement Disorders, 4th ed. Philadelphia: Lippincott, Williams & Wilkins, 2002, pp 185-198. 207. Brown J, Lantos PL, Roques P, et al: Familial dementia with swollen achromatic neurons and corticobasal inclusion bodies: a clinical and pathological study. J Neurol Sci 1996; 135:21-30.

208. Houlden H, Baker M, Morris HR, et al: Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 2001; 56:1702-1706. 209. Soliveri P, Monza P, Paridi D, et al: Cognitive and magnetic resonance imaging aspects of corticobasal degeneration and progressive supranuclear palsy. Neurology 2000; 54: 1878. 210. Brooks DJ: Functional imaging studies in corticobasal degeneration. Adv Neurol 2000; 82:209-215. 211. Gerhard A, Watts J, Trender-Gerhard I, et al: In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord 2004; 19:1221-1226. 211a. Kompoliti K, Goetz CG, Boeve BF, Maraganore DM, et al: Clinical presentation and pharmacological therapy in corticobasal degeneration. Arch Neurol 1998; 55(7):957-961. 212. Kompoliti K, Goetz CG: Therapeutic approaches. Adv Neurol 2000; 82:217-221. 213. Vanek ZF, Jankovic J: Dystonia in corticobasal degeneration. Adv Neurol 2000; 82:61-67.

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FRONTOTEMPORAL DEMENTIA ●

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●

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Bryan Woodruff and Neill Graff-Radford

After Alzheimer’s disease, Lewy body disease, and vascular dementia, frontotemporal dementias (FTDs) as a group constitute a significant percentage of the degenerative dementias, accounting for 5% to 7% of some autopsy series. FTD is overrepresented among the early-onset dementias (manifesting before the age of 70), accounting for 8% to 17% of patients in such cases. Arnold Pick provided the first clinical and pathological description of an aphasic dementia in 1892.1 The term Pick’s disease was subsequently used to describe patients with behavioral changes and circumscribed atrophy affecting frontal and temporal lobes of the brain. Mesulam (2001) later described the progressive aphasias in relation to preferential left hemisphere degeneration.2 Advances in the study of dementia have improved genetic and biochemical characterization of this group of disorders and are discussed in this chapter. Case examples are provided in order to familiarize the reader with approaches to evaluation of these disorders. Future directions of research are also discussed.

CLINICAL FEATURES Varied terminology makes the literature on FTD somewhat confusing. This ultimately resulted in a consensus among experts in the field on preferred terminology (Table 73–1). Neary and associates (1998) outlined the clinical features commonly encountered in frontotemporal lobar degeneration (so-called Neary criteria).3 Pick’s complex of diseases is another term proposed for this group of disorders by Kertesz and colleagues (1998),4 but at present, frontotemporal dementia is the preferred term. The Neary classification describes three major clinical syndromes (Tables 73–2 to 73–4). The progressive aphasias include nonfluent primary progressive aphasia (PPA) and semantic dementia, which involve degeneration affecting the left frontal and temporal lobes respectively. The behavioral manifestation of FTD involves degeneration of both frontal lobes, although asymmetrical degeneration can occur. Although uncommon, cases of primarily right temporal degeneration exist with clinical features of prosopagnosia and/or associative agnosia. Unfortunately, clinical manifestations of FTD that do not strictly conform to the proposed criteria also occur. For example, aphasic dementias that do not meet criteria for PPA or semantic dementia exist, and some patients otherwise meeting criteria for an FTD syndrome may exhibit

symptoms implicating parietal lobe involvement. The aphasic and behavioral manifestations of FTD can also overlap. Other clinical features can occur in the setting of FTD and include parkinsonism, motor neuron disease, corticobasal degeneration, and progressive supranuclear palsy (PSP). All the various FTD subtypes share certain features: namely, insidious onset with gradual progression and onset often before age 65. Clinical features atypical of FTD include abrupt onset, severe amnesia early in the disease course, myoclonus, ataxia, and choreoathetosis. Nondegenerative causes of cognitive or behavioral disturbance such as recent head trauma, alcoholism, significant metabolic derangement, infection, and other neurological disorders are not features of FTD. Atypical imaging findings such as multifocal abnormalities or significant cerebrovascular disease also would not suggest FTD.

Primary Progressive Aphasia Clinical features of the PPAs involve predominantly language difficulty with a combination of some or all of the following: word-finding difficulties, abnormal speech patterns, decreased comprehension, and impaired spelling. Deficits of orientation, visuospatial skills, or inability to perform activities of daily living early in the course of disease precludes the diagnosis. Isolated language difficulty for at least 2 years before development of more generalized deficits is necessary for the diagnosis of PPA. As the diseases progresses, development of clinical features implicating parietal lobe dysfunction (dysarthria, ideomotor apraxia, dyscalculia, and constructional deficits) can occur. The concept of PPA therefore has a broader scope, because it does not require that clinical symptoms be restricted to functions of the frontal and temporal lobes. Other clinical features such as dysarthria or apraxia may also be encountered.

Frontotemporal Dementia with Parkinsonism FTD with parkinsonism linked to chromosome 17 (FTDP-17) is a rare clinical syndrome with autosomal dominant inheritance and characterized by progressive cognitive and behavioral disturbance and parkinsonism. Genetic analysis of affected families localized the mutations to 17q21-22, in the gene coding for the microtubule-associated protein tau.5 Clinical and pathological variabilities exist even among affected family members

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T A B L E 73–1. Frontotemporal Dementia Terminology*

T A B L E 73–3. Progressive Nonfluent Aphasia

Overall Clinical Syndrome Frontotemporal dementia (FTD) Alternative terms Pick’s complex Pick’s disease Behavioral presentation of FTD Frontotemporal dementia (FTD) Alternative term Frontal lobe dementia Language presentation of FTD Primary progressive aphasia (PPA) Alternative term Progressive nonfluent aphasia Progressive semantic deficit Semantic dementia Alternative term Semantic aphasia

Core Features: Nonfluent Spontaneous Speech with at Least One of the Following: Agrammatism Phonemic paraphasias Anomia

Overall Pathological Syndrome Frontotemporal degeneration (FTD) Alternative terms Frontotemporal lobar degeneration (FTLD) Focal atrophy (FA) Pick’s complex *A problem with this preferred terminology is the persistent use of overlapping abbreviations for both clinical and pathologic aspects of these disorders, such as “FTD.”

T A B L E 73–2. Frontal Lobe Dementia Core Features Impaired interpersonal conduct Impaired regulation of personal conduct Emotional blunting Limited insight Supportive Features Behavioral disorder Poor hygiene Mental rigidity and inflexibility Distractibility and impersistence Hyperorality and dietary changes Perseverative and stereotyped behavior Utilization behavior Speech and language Altered speech output Stereotypy of speech Echolalia Perseveration Mutism Adapted from Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:15461554.

with the same mutation, presumably in relation to other differing genetic or environmental factors.

Frontotemporal Dementia with Motor Neuron Disease Clinical features of FTD and motor neuron disease can coexist in the same individual.6 There is no predictable temporal rela-

Supportive Features Stuttering or oral apraxia Impaired repetition Alexia, agraphia Early preservation of word meaning Late mutism Early preservation of social skills Adapted from Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-1554.

T A B L E 73–4. Semantic Dementia/Progressive Fluent Aphasia Core Features: Language Disorder Characterized by: Progressive, fluent, empty spontaneous speech Loss of word meaning, manifested by impaired naming and comprehension Semantic paraphasias Supportive Features Press of speech Idiosyncratic word usage Surface dyslexia and dysgraphia Adapted from Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-1554.

tionship between the cognitive and motor features of the syndrome. Also of interest are cases of clinically diagnosed FTD lacking motor symptoms in which pathological findings of motor neuron disease are encountered. Just as in classic amyotrophic lateral sclerosis, motor symptoms of dysphagia or respiratory failure adversely affect prognosis in patients with FTD.

Corticobasal Degeneration Corticobasal degeneration is a pathological diagnosis and is clinically characterized by asymmetrical rigidity, apraxia, and alien limb phenomena. However, many patients with corticobasal degeneration do not have asymmetrical rigidity and apraxia.7 Relevant to this discussion is that pathological corticobasal degeneration may manifest clinically as FTD. This furthers the concept that both clinical and pathological findings implicating involvement of regions other than the frontal and temporal lobes should not prevent the diagnosis of FTD.

PATHOLOGY Nearly a century after Pick first described the pathological features of frontotemporal degeneration, different pathological subtypes were described as well.8 Three major pathological

chapter 73 frontotemporal dementia divisions were identified: Pick’s disease type A, with neuronal loss, astrocytic gliosis, Pick bodies, and swollen neurons; Pick’s disease type B, with neuronal loss, astrocytic gliosis, and swollen neurons; and Pick’s disease type C, with neuronal loss and gliosis. Additional advances in the field of pathology have allowed further characterization of the FTDs through immunohistochemical and biochemical techniques. Typical gross pathological findings include decreased whole brain weight (mild to severe) and sometimes striking atrophy of the frontal and temporal lobes. The regional atrophy may be asymmetrical, especially in cases with progressive aphasia. In grossly atrophic regions, there is thinning of the cortical ribbon with associated discoloration of the underlying white matter. Atrophy of the hippocampus and basal ganglia may be seen. Enlargement of the ventricular system is correlated with the degree of regional atrophy. For example, asymmetrical enlargement of the left lateral ventricle is often observed in cases of progressive aphasia. In certain cases, pallor of the substantia nigra and atrophy of the anterior nerve roots with discoloration of the lateral funiculus in the spinal cord may be seen. Further classification of FTD is achieved through the use of microscopy. Affected cortical regions typically show neuronal loss, microvacuolation, astrocytic gliosis centered on cortical layer II, and, in some cases, ballooned neurons. A major biochemical subdivision of degenerative dementias, including FTD, involves the presence or absence of tau protein–related pathology. There are more than 20 recognized “tauopathies,” as shown in Table 73–5,9 with Pick’s disease, corticobasal degeneration, FTDP-17, PSP, and Alzheimer’s disease most commonly identified in cases with a clinical manifestation of FTD. Assays for ubiquitin-positive inclusions are required when no tau, synuclein, or amyloid pathology is identified. Intranuclear or cytoplasmic ubiquitin inclusions, as well as ubiquitinated neurites (axons and dendrites), may be noted. Such inclusions may also be found in motor neurons in amyotrophic lateral sclerosis, which furthers the overlap between motor neuron disease and FTD. Intraneuronal ubiquitin inclusions have been reported in familial cases of FTD, and a comprehensive review of the neuropathology of FTD is presented by Munoz and col-

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leagues (2003).10 Neuronal intranuclear ubiquitin inclusions appear to be the distinction between familial and sporadic cases of FTD with ubiquitin immunoreactivity.11 Presence of neuronal loss, gliosis, and microvacuolation in the absence of any recognizable inclusions defines dementia lacking distinctive histological features.12 This entity less commonly identified as careful immunohistochemical analysis often reveals ubiquitin pathology. In addition to the identification of ubiquitinimmunoreactive inclusions, in many cases initially characterized as dementia lacking distinctive histological features, there also appears to be a high prevalence of hippocampal sclerosis.13 It is possible to further classify the tau protein–based forms of FTD. Six isoforms of the tau protein exist, one half referred to as “three-repeat forms” and the remainder as “four-repeat forms.” This terminology refers to the presence of three or four repeated sequences in the tau protein, representing microtubule binding sites. The fourth repeated sequence is coded for by exon 10 of the tau gene; alternate splicing of exon 10 generates three-repeat or four-repeat isoforms. Tauopathies characterized by four-repeat isoforms include corticobasal degeneration, PSP, and argyrophilic grain disease, whereas Pick’s disease is characterized by four-repeat isoforms, shown in Figure 73–1.

GENETICS Although estimates among research groups vary, a family history of FTD is uncommon in most cases. Tau gene mutations account for most of the familial forms of FTD. Just as characterization of the genetics of familial forms of AD has revolutionized its treatment approaches, better understanding of the genetic forms of FTD is hoped to enable development of therapies targeting its underlying pathophysiology. Whether therapies effective for genetic forms of these diseases will apply to the more sporadic cases remains to be seen. The more heterogeneous pathology encountered in FTD also makes development of effective therapies challenging. The following section outlines the currently known genetic aspects of FTD.

Tau Gene T A B L E 73–5. Diseases in Which Filamentous Tau Protein Deposits Have Been Described Alzheimer’s disease Amyotrophic lateral sclerosis/parkinsonism-dementia complex Argyrophilic grain disease Autosomal-recessive juvenile parkinsonism Corticobasal degeneration Dementia pugilistica Diffuse neurofibrillary tangles with calcification Down syndrome Familial British dementia Frontotemporal dementia and parkinsonism linked to chromosome 17 Gerstmann-Sträussler-Scheinker disease Hallervorden-Spatz disease Myotonic dystrophy Niemann-Pick disease, type C Pick’s disease Postencephalitic parkinsonism Progressive supranuclear palsy Subacute sclerosing panencephalitis Tangle-only dementia

Tau mutations account for only a small percentage of FTD in general, although they constitute the most recognized genetic cause of FTD. FTDP-17 is inherited in an autosomal dominant manner; multiple kindreds have been recognized in many countries. Three mutations account for more than one half of the known cases of FTDP-17, despite there being more than 30 known mutations. These are the P301L mutation, the mutation of the 5′ splice site of exon 10 at position +16, and the N279K mutation, depicted in Figure 73–2. Each mutation can be associated with a classic FTD phenotype, although the +16 mutation and N279K mutation typically produce features of parkinsonism, the latter with features resembling PSP. Other features encountered in FTDP-17 include paranoid delusions, antisocial behavior, seizures, and, on occasion, amyotrophy. Most mutations affecting the splicing of exon 10 are associated with parkinsonism. Clinical differences among individuals harboring the same mutation suggest that other genetic or environmental factors influence phenotype. Knowledge of tau protein biochemistry facilitates recognition of the effects of tau gene mutations, with an excellent

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Figure 73–1. Cases of frontotemporal dementia with parkinsonism linked to chromosome 17 may exhibit either three-repeat or four-repeat isoforms or a combination of the two. Plus signs denote the presence and minus signs the absence of exon 2, 3, or 10, which generate different tau protein isoforms. (From Munoz DG, Dickson DW, Bergeron C, et al: The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol 2003; 54(Suppl 5):S24-S28.

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Figure 73–2. Distribution of mutations within the Tau gene, grouped by exon. Number of mutations are in italics. Locations of the three most common tau mutations (N279K, P301L, and position +16) are shown.

review by Hutton (2000). The tau protein is soluble in the normal human brain. Microtubule binding is mediated by specific domains in the carboxy-terminal portion of the protein, coded for by exons 9, 10, 11, and 12 of the tau gene. These domains are composed of tandem repeat sequences of 31 amino acids with either three or four microtubule-binding domains present on the protein. Alternative splicing of exon 10 dictates the number of microtubule binding domains, and an approximate 1 : 1 ratio of three-repeat and four-repeat tau isoforms exists in the normal human brain. Disruption of this balance between three-repeat and four-repeat isoforms is associated with the pathological inclusions of FTDP-17. Nearly all mutations that have been identified in families with FTDP-17 are located from exons 9 to 13, or in the 5′ splice site of the intron after exon 10. Mutations in exon 10 and the intronic 5′ splice site after exon 10 (see Fig. 73–2) appear to increase the amount of four-repeat tau isoforms produced. The abnormal ratio of tau isoforms appears to decrease tau microtubule binding and to increase tau aggregation into insoluble filaments. Despite increased knowledge of the biochemical effects of these mutations, clinical heterogeneity remains largely unexplained. For example, phenotypes resembling the behavioral manifestations of FTD, corticobasal degeneration, and PSP have all been reported with the P301L mutation.

PSP and corticobasal degeneration; it accounts for 90% of the haplotypes in affected patients, in comparison with 78% in the normal population.14 The tau H2 haplotype appears more common in the SD subtype of FTD when compared to other FTD subtypes (Short, Graff-Radford, et al, 2002).15

Apolipoprotein E Genotype Although the apolipoprotein E (apoE) genotype is a known genetic risk factor for Alzheimer’s disease, its effect on FTD remains controversial. This largely stems from the same problem of FTD classification: Different studies involved different clinical and pathological criteria. For example, the apoE4 allele has been reported to be overrepresented in both Pick’s disease with Pick bodies16 and in patients with semantic dementia.15

Other Loci Familial forms of FTD have also been reported with linkage to chromosomes 3 and 9. The former involves a kindred with clinical FTD and pathology that is consistent with dementia lacking distinctive histology,17 whereas the latter is characterized by affected individuals expressing clinical features of motor neuron disease.18 In several kindreds with familial FTD, the disease has been linked to chromosome 17q21-22 with no mutation in the tau gene identified.19

Tau Haplotype There are two extended tau haplotypes (H1 and H2), consisting of a series of polymorphisms throughout the tau gene in linkage disequilibrium. The tau H1 haplotype is associated with

Genetic Testing Clinical genetic testing for known tau gene mutations is available (Table 73–6). As with other untreatable genetic disorders

chapter 73 frontotemporal dementia T A B L E 73–6. Centers Providing Clinical Screening for Tau Gene Mutations Chapman Institute/Center for Genetic Testing at St. Francis Genetics Laboratory, Tulsa, Oklahoma Nancy J. Carpenter, PhD, FACMG; Frederick V. Schaefer, PhD, FACMG University of California, San Francisco, Molecular Diagnostics Laboratory, San Francisco, California Farid F. Chehab, PhD

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(MRI) of her brain showed prominent atrophy affecting primarily the frontal lobes bilaterally, with associated increased T2 signal in the frontal lobe white matter. This case demonstrates typical clinical features of frontal lobe dementia in which prominent behavioral changes dominate the initial symptom complex. The family history is suggestive of a hereditary basis for her particular syndrome. Figure 73–3 demonstrates typical imaging findings in frontal lobe dementia.

Case 2: Progressive Nonfluent Aphasia such as Huntington’s disease, caution should be used when arranging for genetic testing. Referral for genetic counseling would be appropriate before testing.

CLINICAL VIGNETTES Cases 1 through 4 illustrate the clinical features outlined in the Neary criteria (see Table 73–1).

Case 1: Frontal Lobe Dementia A 55-year-old right-handed attorney presented with a 2-year history of progressive cognitive and behavioral changes. Problems were first noted at work, in which she became excessively argumentative and confrontational with coworkers. This escalated until she lost her job. Her spouse noted that she did not seem to have significant problems with forgetfulness but rather seemed unable to remain focused on any task. For this reason, she stopped cooking and participating in essentially all complex activities of daily living. She exhibited some problems with personal hygiene, such as neglecting to remove her clothing before showering. She also had a tendency to wander, thus requiring constant supervision. In addition to her irritability, there were also times when she seemed overly giddy and disinhibited. She made inappropriate comments about strangers in public. She developed a predilection for sweets, and her intake had to be monitored. Her actions also became repetitive; for example, repeatedly asking her spouse when it was time to leave and pacing when an outing was planned. She often echoed what others said and developed an unusual tendency to speak in a high-pitched, childlike voice at times. The patient’s mother, maternal uncle, and maternal grandmother all had a history of cognitive decline in their 60s. No details regarding their clinical manifestations were available. On examination, she scored 19 of 38 on a Short Test of Mental Status, missing points for orientation, digit span, learning, calculation, and construction. She recalled three of four items after a delay. Many of her difficulties stemmed from inattentiveness during testing, which necessitated frequent redirection. She would often perseverate, answering new questions with prior responses. No focal findings were noted on neurological examination. She did exhibit psychomotor agitation, getting up frequently during the history and examination and pacing around the room. Her laboratory studies were unrevealing, including spinal fluid analysis. An electroencephalogram was also unremarkable. Magnetic resonance imaging

An 87-year-old right-handed retired teacher presented for evaluation of progressive language difficulties. She noted that over approximately the prior 18 months, she had experienced progressive difficulties “getting her words out.” She denied problems comprehending what others were saying but found that she could not keep up with the pace of most conversations. For this reason, she became somewhat withdrawn socially. There was no history of significant forgetfulness or decline in ability to keep up with her personal affairs. She also denied any difficulties with disorientation. Family members corroborated her history. There was no known family history of any similar symptoms or other cognitive disorder. On examination, she scored 34 of 38 on a Short Test of Mental Status, missing a point each for digit span, learning, construction, and delayed verbal recall. She did exhibit nonfluent speech, with paraphasic errors such as “sinced” for “since” and “kepiz me” for “keeps me.” She did not exhibit anomia and could comprehend simple and complex commands. She had mild difficulties with repetition. The remainder of the neurological examination findings were unremarkable. Laboratory study findings were within normal limits. MRI of her brain showed mild asymmetrical atrophy affecting primarily the left perisylvian region. This case is illustrative of progressive nonfluent aphasia, a subtype of PPA. The preservation of general cognitive function despite the language disturbance is typical, as is the early absence of any significant behavioral disturbance (Fig. 73–4).

Case 3: Semantic Dementia A 60-year-old right-handed owner of a flooring business presented with a 3-year history of difficulties “coming up with words.” He began noticing these problems when he would give presentations, in which he would be at a loss for words that he had previously known but would not use regularly, with relative preservation of words common to his profession. For example, he could not come up with the words “helicopter” and “scissors,” although he could readily and accurately describe them and their functions. He could still function fairly well at work but found he would often have to resort to simpler, related terms for words he could not recall or use gestures to describe what he meant. He denied any problems keeping up with work or household responsibilities, which was confirmed by his spouse. She had noted that he had become somewhat irritable but believed that this was secondary to his frustration with his word-finding difficulties. No socially inappropriate behavior had been observed.

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Figure 73–3. Frontal lobe dementia. Axial magnetic resonance images (A and B) and positron emission tomographic images (C and D) demonstrate focal atrophy and hypometabolism affecting primarily the frontal lobes.

There was a family history of memory difficulties in the patient’s mother in her 80s but no clear language disturbance. On examination, he scored 31 of 38 on the Short Test of Mental Status, missing points for calculation, verbal abstract thinking, general fund of knowledge, and delayed verbal recall. He exhibited prominent anomia on the Boston Naming Test

during neuropsychological assessment. He frequently used general descriptors for names of items he could not recall, such as “whatchamacallit.” The general neurological examination revealed no additional findings. Laboratory study findings were unremarkable. MRI of his brain showed asymmetrical atrophy affecting the left anterior and superior temporal lobes.

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D Figure 73–4. Progressive nonfluent aphasia. Axial magnetic resonance images (A and B) and positron emission tomographic images (C and D) demonstrate focal atrophy and hypometabolism affecting primarily the left frontal lobe and perisylvian region.

This case demonstrates typical history and examination findings for semantic dementia, a subtype of PPA. Patients generally exhibit prominent anomia and progressively lose the meaning of words, initially less common ones but then even common words as the disease progresses. Figure 73–5 shows typical imaging findings in a case of semantic dementia.

Case 4: Progressive Prosopagnosia A 73-year-old right-handed mechanic related a 5-year history of progressive difficulties recognizing people. These difficulties first involved acquaintances he encountered while at the store or church, but over time they progressed to include even family

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Figure 73–5. Semantic dementia. Left parasagittal (A) and axial (B) magnetic resonance images and axial positron emission tomographic images (C and D) demonstrate focal atrophy and glucose hypometabolism affecting primarily the left temporal lobe.

members. He often would greet people when addressed and would be able to recognize them only by the sound of their voice. This difficulty extended beyond recognizing people: He also found that he had developed problems recognizing different makes and models of vehicles, which he found quite frustrating in light of his prior occupation. He denied any other difficulties from a cognitive or perceptual standpoint. He continued to keep up with his household affairs and hobbies without significant problems. His family

noted that he seemed to be at a loss for words at times but not excessively. He admitted that he no longer enjoyed watching television, because he did not recognize any of the people in the news or other programs. On examination, he scored 28 of 38 on a Short Test of Mental Status, missing points for digit span, learning, calculation, construction, and delayed recall. He could not recognize pictures of celebrities from a magazine, although he knew they were “famous people.” When shown a picture of a grizzly bear

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T A B L E 73–7. Internet Resources for Frontotemporal Dementia The Association for Frontotemporal Dementias Pick’s Disease Support Group Northwestern Alzheimer’s Disease Center Primary Progressive Aphasia (PPA) Program University of California, San Francisco, Memory and Aging Center Alzheimer’s Association National Institute of Neurological Disorders and Stroke (NINDS) GeneTests Web Site Online Mendelian Inheritance in Man (OMIM)

http://www.ftd-picks.org/ http://www.pdsg.org.uk http://www.brain.northwestern.edu/ppa/ppa.html http://memory.ucsf.edu/Education/Disease/ftd.html http://www.alz.org/ www.ninds.nih.gov http://www.geneclinics.org/ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

standing in a mountain stream and was asked what was depicted, he stated, “an animal.” When asked to elaborate, he speculated, “It might be a dog.” He exhibited moderate anomia on the Boston Naming Test during neuropsychological assessment. His general neurological examination findings were unremarkable. Laboratory studies were unrevealing. MRI of his brain showed bitemporal atrophy, greater on the right side than on the left. This case demonstrates a case of progressive prosopagnosia with prominent difficulties recognizing familiar faces and even objects. The ability to recognize categories of items such as “vehicles” or “animals” with inability to subcategorize them can be seen and was evident in this particular patient. Figure 73–6 demonstrates typical imaging findings in a case of prosopagnosia related to prominent right temporal lobe degeneration.

IMAGING In all patients presenting with progressive impairment of cognitive or behavioral functions, an imaging study of the brain is warranted, to rule out mass lesions or other structural abnormalities. For example, a tumor involving the frontal lobes could produce manifestations mimicking the clinical features of FTD. In FTD, the frontal and temporal lobe atrophy is often evident on standard computed tomography and MRI of the brain. Asymmetrical atrophy may be evident in the setting of PPA and semantic dementia. Longitudinal volumetric MRI demonstrates predictable patterns of regional change among the subtypes of FTD; semantic dementia exhibits the most dramatic longitudinal change in the temporal lobe.20 White matter abnormalities, best appreciated on fluid-attenuated inversion recovery MRI sequences, may also be evident in the underlying affected cortical regions. Functional neuroimaging may be helpful, especially in cases lacking obvious regional atrophy. Regional hypoperfusion on single photon emission computed tomography or hypometabolism on positron emission tomography may be evident in the frontal and temporal lobes, but further clinicopathological data are necessary to determine the diagnostic utility of these two imaging modalities.

THERAPY There are no approved pharmacological therapies for FTD. Offlabel use of cholinesterase inhibitors and memantine for the

cognitive symptoms of FTD occurs, but their efficacy is not established. A randomized controlled trial of trazodone also demonstrated promising results for behavioral symptoms.21 Atypical neuroleptic agents and anticonvulsants with moodstabilizing properties can also be considered. As with other dementia syndromes that progressively impair judgment, the environment must be optimized for safety. Safeguarding or removing dangerous tools or other items is recommended. If patients have sufficient cognitive impairment to warrant a diagnosis of mild dementia, they should not drive. Patients with isolated language disturbance may be able to drive safely, but driving safety should periodically be reassessed. Patients with PPA or semantic dementia may benefit from formal speech therapy. Caregiver burden is an important issue for all dementing illnesses, but because of the relatively younger age at onset in patients with FTD, this problem can be particularly difficult. Educational material about available community resources such as the Alzheimer’s Association should be made available. Social workers or geriatric counselors can provide invaluable information to patients and their families regarding care options. Internet resources for FTD are listed in Table 73–7.

FUTURE DIRECTIONS In summary, the term frontotemporal dementia encompasses a group of disorders that have diverse clinical, pathological, biochemical, and genetic features. Better understanding of these disorders will be achieved only through collaboration of specialists in both the clinical and basic science disciplines. A multicenter initiative to monitor patients with FTD longitudinally is already under way and is hoped to enable additional therapeutic trials in the future. Powerful research tools such as transgenic animal models will expedite development of therapies specifically targeting the underlying pathophysiology of FTD and other degenerative disorders affecting the nervous system.22 Development of assays for biomarkers such as phosphorylated tau species may allow more accurate differentiation between FTD and other neurodegenerative disorders, especially early in the disease course.23 Although research focusing on FTD may appear daunting in light of the heterogeneity of the condition, any advances made will potentially affect patients with a host of other related disorders and should therefore be avidly pursued.

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D Figure 73–6. Progressive prosopagnosia. Axial computed tomographic scans (A and B) and positron emission tomographic images (C and D) demonstrate focal atrophy and hypometabolism affecting primarily the right temporal lobe.

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ACKNOWLEDGMENTS

Suggested Reading

This paper was supported in part by a National Institute on Aging grant AG16574 and a grant from Clarice and Robert Smith.

Hutton M: Molecular genetics of chromosome 17 tauopathies. Ann N Y Acad Sci 2000; 920:63-73. Kertesz A, Munoz D: Pick’s disease, frontotemporal dementia, and Pick complex: emerging concepts. Arch Neurol 1998; 55:302304. Mesulam MM: Primary progressive aphasia. Ann Neurol 2001; 49:425-432. Munoz DG, Dickson DW, Bergeron C, et al: The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol 2003; 54(Suppl 5):S24-S28. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554.

K E Y

P O I N T S

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Nonfluent PPA is typically associated with prominent degeneration in the left frontal lobe and the perisylvian region.

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Semantic dementia is characterized by progressive loss of word meaning, with prominent degeneration in the left temporal lobe.

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Prominent degeneration of the right temporal lobe can be associated with the clinical syndrome prosopagnosia, or the inability to recognize familiar faces.

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The behavioral manifestations of FTD may be characterized by disinhibition, lack of insight, and apathy.

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Clinical overlap exists between the various subtypes of FTD, especially later in the course of the disease.

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Clinical overlap between FTD and other clinical entities such as corticobasal degeneration and PSP also occurs.

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Parkinsonism and motor neuron disease may be encountered in patients with FTD.

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Typically, prominent gross atrophy of the frontal and temporal lobes is seen in FTD.

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Characteristic histological features of FTD include neuronal loss, microvacuolization, and astrocytic gliosis centered on cortical layer 2.

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The presence or absence of tau protein pathology is one major distinguishing feature among the various FTD syndromes.

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The presence or absence of ubiquitin inclusions helps to differentiate the non-tau forms of FTD.

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Cytoplasmic versus intranuclear location of ubiquitin inclusions appears to differentiate sporadic from familial forms of FTD with ubiquitin inclusions.

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Mutations in the gene coding for the microtubule-associated protein tau account for a significant percentage of cases of familial FTD and FTDP-17.

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Most tau mutations are located in the region of the gene coding for the microtubule-binding domains of the tau protein.

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Alternative splicing of exon 10 of the tau gene results in formation of either three-repeat or four-repeat tau isoforms.

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Tau mutations typically disrupt the normal ratio of threerepeat and four-repeat tau isoforms, which may promote the development of abnormal tau inclusions.

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Linkage to loci on chromosomes other than chromosome 17 and other genetic risk factors may be present in some cases of FTD.

References 1. Pick A: Uber die Beziehungen der senilen Hirnantropie zur aphasie. Prager Medizinishe Wochenscrift 1892; 17:165-167. 2. Mesulam MM: Primary progressive aphasia. Ann Neurol 2001; 49:425-432. 3. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554. 4. Kertesz A, Munoz D: Pick’s disease, frontotemporal dementia, and Pick complex: emerging concepts. Arch Neurol 1998; 55:302-304. 5. Hutton M: Molecular genetics of chromosome 17 tauopathies [Review]. Ann N Y Acad Sci 2000; 920:63-73. 6. Strong MJ, Lomen-Hoerth C, Caselli RJ, et al: Cognitive impairment, frontotemporal dementia, and the motor neuron diseases. Ann Neurol 2003; 54(Suppl 5):S20-S23. 7. Boeve BF, Maraganore DM, Parisi JE, et al: Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999; 53:795-800. 8. Constantinidis J, Richard J, Tissot R: Pick’s disease. Histological and clinical correlations. Eur Neurol 1974; 11:208-217. 9. Goedert M: Introduction to the tauopathies. In Dickson D, ed: Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Basel, Switzerland: ISN Neuropath Press, 2003, pp 82-85. 10. Munoz DG, Dickson DW, Bergeron C, et al: The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol 2003; 54(Suppl 5):S24-S28. 11. Mackenzie IR, Feldman H: Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases. Dement Geriatr Cogn Disord 2004; 17:333-336. 12. Knopman DS, Mastri AR, Frey WH 2nd, et al: Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 1990; 40:251-256. 13. Josephs KA, Jones AG, Dickson DW: Hippocampal sclerosis and ubiquitin-positive inclusions in dementia lacking distinctive histopathology. Dement Geriatr Cogn Disord 2004; 17:342345. 14. Baker M, Litvan I, Houlden H, et al: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999; 8:711-715. 15. Short R, Graff-Radford N, Adamson J, et al: Differences in tau and apolipoprotein E polymorphism frequencies in sporadic frontotemporal lobar degeneration syndromes. Arch Neurol 2002; 59:611-615. 16. Kalman J, Juhasz A, Majtenyi K, et al: Apolipoprotein E polymorphism in Pick’s disease and in Huntington’s disease. Neurobiol Aging 2000; 21:555-558. 17. Brown J: Chromosome 3-linked frontotemporal dementia [Review]. Cell Mol Life Sci 1998; 54:925-927.

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18. Hosler BA, Siddique T, Sapp PC, et al: Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 2000; 284:1664-1669. 19. Ghetti B, Hutton M, et al: Frontotemporal dementia and parkinsonism linked to chromosome 17 associated with tau gene mutations (FTDP-17T). In Dickson D, ed: Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, vol 1. Basel, Switzerland: ISN Neuropath Press, 2003, pp 86-102. 20. Whitwell JL, Anderson VM, Scahill RI, et al: Longitudinal patterns of regional change on volumetric MRI in frontotempo-

ral lobar degeneration. Dement Geriatr Cogn Disord 2004; 17:307-310. 21. Lebert F, Stekke W, Hasenbroekx C, et al: Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004; 17:355-359. 22. Hutton M, Lewis J, Dickson D, et al: Analysis of tauopathies with transgenic mice [Review]. Trends Mol Med 2001; 7:467470. 23. Hampel H, Teipel SJ: Total and phosphorylated tau proteins: evaluation as core biomarker candidates in frontotemporal dementia. Dement Geriatr Cogn Disord 2004; 17:350-354.

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EPIDEMIOLOGY AND GENETICS MULTIPLE SCLEROSIS ●

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Jan D. Lünemann and Roland Martin

Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) that usually begins in early adulthood and is characterized by demyelination, gliosis, a varying degree of axonal pathology, and episodic or progressive neurological disability. More than 1 million people worldwide and at least 350,000 individuals in the United States alone are affected with multiple sclerosis, which is second only to trauma as a cause of acquired disability in young adults in most white populations.1,2

DISEASE HETEROGENEITY The heterogeneous nature of multiple sclerosis is reflected by its variable clinical phenotype, its nonuniform neuropathology, and its heterogeneous molecular pathogenesis. Both genetic and environmental factors are believed to have an effect either in modulating susceptibility or influencing the development of the disease. Autoreactive T cells are considered to play a key role in mediating the disease process. Evidence for a role of autoreactive T cells stems from the composition of inflammatory infiltrates in the CNS, which consist mainly of lymphocytes and monocytes, and from data from its animal model, experimental allergic (autoimmune) encephalomyelitis. The injection of myelin components into susceptible animals leads to a CD4+ T cell–mediated autoimmune disease resembling multiple sclerosis and can be adoptively transferred from sick to healthy animals via encephalitogenic CD4+ T cells. A role of autoaggressive T cells in multiple sclerosis is further supported by the therapeutic, although limited, efficacy of immunosuppressive and immunomodulatory agents and by the fact that certain major histocompatibility complex (MHC) class II alleles represent the strongest genetic risk factor, presumably because of their role as antigen-presenting molecules to pathogenic CD4+ T cells. Inflammatory events are considered to initiate and drive the disease process during early stages. The myelin damage and axonal injury that account for the permanent neurological deficit seen during later phases of multiple sclerosis probably result from a complex sequence of events, including processes intrinsic to the CNS, such as increased vulnerability to tissue injury and/or poor repair, which might progress independently of immune factors. Multiple sclerosis is therefore not solely a disease of the immune system; CNS-specific components,

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although largely overlooked in their potential pathogenetic role, are presumably equally important for its pathogenesis.3 The clinical pattern of multiple sclerosis is generally divided into two major forms. The first, most frequent (85% to 90%) subtype follows a relapsing-remitting course and is characterized by separate episodes of neurological deficits involving different sites of the CNS, each lasting for at least 24 hours and separated by intervals of at least 1 month. Relapsing-remitting multiple sclerosis usually evolves over decades and in most cases transforms into a secondary progressive course. About 10% to 15% of patients present with insidious disease onset and steady progression, termed primary progressive multiple sclerosis. There is heterogeneity in morphological alterations of the brain, as visualized by either magnetic resonance imaging (MRI) or histopathological evaluation, but also in clinical presentation, such as which CNS system and areas are primarily affected and whether a patient responds to treatment. The factors underlying the different disease courses and the disease heterogeneity are incompletely understood but presumably include a complex genetic trait that translates into different immune abnormalities and/or increased vulnerability of CNS tissue to inflammatory insult or reduced ability to repair damage. Current knowledge about how certain genes confer risk for multiple sclerosis or any other autoimmune disease at the molecular level is incomplete. However, numerous studies on the genetic epidemiology of multiple sclerosis, which are described in the following sections, provide compelling evidence that the susceptibility to the disease is inherited, although additional environmental triggers might be necessary to translate disease susceptibility into the clinical phenotype.

POPULATION PREVALENCE The disease prevalence varies between 60 and 200 per 100,000 in North America and northern Europe and generally follows a north-to-south decreasing gradient on the northern hemisphere and the opposite on the southern hemisphere, with very low rates or virtual absence of the disease near the equator (Fig. 74–1). This geographical distribution can be attributed to both environmental factors and genetic effects. For many years, an infectious etiology of multiple sclerosis has been suspected,

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Figure 74–1. Worldwide distribution of multiple sclerosis. Multiple sclerosis is most common in parts of the world with cooler climates. Europe, North America, and parts of Australia and New Zealand have multiple sclerosis prevalence rates (60 to 200 per 100,000) that are much higher than rates in countries clustered around the equator. (Adapted from Marrie RA: Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 2004; 12:709-718.)

because it is consistent with a number of epidemiological observations and with immunopathological characteristics of the disease. Migration studies showed that individuals who migrate from high-risk to low-risk areas after the age of 15 tend to retain their risk of multiple sclerosis, whereas individuals who migrate from high-risk to low-risk areas before the age of 15 acquire a lower risk; this indicates that childhood exposure to an environmental factor increases disease susceptibility. Supportive data for an infectious agent also come from reports of endemic clusters of multiple sclerosis. After the British occupation of the Faroe Islands, off the coast of Denmark, where no cases of multiple sclerosis had been reported before, several islanders developed the disease between 1940 and the end of World War II, and the affected areas were found to be locations of British troop encampments after 1940. Other examples of multiple sclerosis epidemics have been described in northern America and Europe. These observations suggest that an environmental factor is relevant for the initiation of the disease process, and in the established disease, infections are additionally known to be capable of triggering exacerbations. No specific transmissible agent has so far been linked convincingly to multiple sclerosis. The most consistent evidence of a potential role in the disease exists for Epstein-Barr virus and human herpesvirus 6, as a result of the detection of viral DNA in brain specimens derived from multiple sclerosis lesions (in the case of human herpesvirus 6) and by convincing seroepidemiological studies. Both are ubiquitous viruses that act at the population level and produce latent, recurrent infections. Generally conceptualized as a trigger for the manifestation of the

disease in genetically susceptible individuals, the mechanisms by which these viruses and other potential candidates initiate, exacerbate, and perpetuate the disease are, however, far from understood. Arguing for a genetic basis of multiple sclerosis is the fact that the disease prevalence differs strikingly between geographically close but genetically distinct populations. Ethnic groups such as the Lapps in Scandinavia, Gypsies in Hungary, Maoris in New Zealand, or Aborigines in Australia are rarely if ever affected by multiple sclerosis, although the disease is otherwise common in these latitudes. Furthermore, multiple sclerosis is rare among Japanese and Chinese populations, African Blacks, North and South Amerindians, and the native populations in southern countries of the former Soviet Union (Turkmen, Uzbeks, Kazakhs, Kyrgyzis), but it occurs notably more frequently among Whites living in the same area. Further examples are the different prevalence rates in genetically distant populations living on the same island, as reported for Sardinia, Cyprus, and Ireland. The idea that genetic factors may have a role in multiple sclerosis was first raised in the 1890s with the identification of familial aggregation. Further milestones in establishing the concept of genetic susceptibility to multiple sclerosis were the appreciation of ethnic risks in the 1920s, comprehensive studies on the geographical distribution of the disease in the 1950s, and the description of the MHC associations in the 1970s. It took, however, a century until the first systematic genetic epidemiological analyses on familial aggregation were initiated. These studies formed the groundwork for the

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T A B L E 74–1. Familial Risks for Multiple Sclerosis

Degree of Relatedness General population First-degree relative Dizygotic twin Monozygotic twin Adoptive “first-degree” relative Half-sibling Offspring of two parents with multiple sclerosis

Age-Adjusted Lifetime Risk (%)

Relative Risk in Comparison to General Population

% Identity Descendant

0.2 3-5 3-5 38 0.2 1.3 29.5

1 15-25 15-25 190 1 6.5 147.5

0 50 50 100 0 25 50*

*Fifty percent of genetic material is shared with the affected mother and father, respectively. Adapted from Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol 2004; 3:104-110.

understanding of multiple sclerosis as a genetically determined disease.

FAMILIAL AGGREGATION Familial aggregation studies, including research with twins, siblings, and adoptees, demonstrated that the risk of developing multiple sclerosis increases with the degree of relatedness between individuals.4 For example, monozygotic twins of patients with multiple sclerosis have a risk more than 100 times higher than that of the general population of developing the disease, and full siblings have a lifetime risk approximately 20 times higher than that of the general population (Table 74–1). Although these recurrence risk values are considerably lower than the ones for mendelian-dominant disorders such as Huntington’s disease (approximately 5000-fold increased risk for siblings), they are similar to the risks that have been reported for other complex polygenic diseases, such as systemic lupus erythematosus or type I diabetes mellitus (approximately 20- to 30-fold increased risk for siblings).

genetic sharing) and half-siblings in comparison with full siblings (25% and 50% genetic sharing, respectively). Adopted relatives, although raised from infancy with the patients who have multiple sclerosis, do not develop multiple sclerosis more frequently than would be expected for the general population.4 Half-siblings raised apart (different environments) or together (same environment) with patients who have multiple sclerosis have similar risks of developing the disease, and the recurrence risk for half-siblings is significantly lower than that for full siblings raised in the same family (1.32% versus 3.46%). Studies of familial aggregation made clear that the excess of the disease in biological relatives results from the sharing of genetic material, but the disease does not follow a simple mendelian mode of inheritance. There is no evidence for transmission of the disease within affected families. Any nongenetic, environmental factor is therefore more likely to be ubiquitous in nature and to act on a large population basis rather than being specifically relevant within the family microenvironment.

SUSCEPTIBILITY GENES Twin Studies Twin studies consistently showed that the concordance rate (whereby both twins develop the disease) is approximately 25% to 30% for monozygotic twins and 2% to 5% for dizygotic twins.5 The 10-fold increased risk for monozygotic twins indicates a strong genetic component, whereas the fact that the concordance rate is not nearly 100% is usually taken as an argument for the impact of nongenetic, environmental factors. Studies on animal models of systemic lupus erythematosus, however, demonstrated that the rate of disease expression can be influenced by the number of disease-associated genes under identical environmental influences.6 A simple concordance rate in monozygotic twins might therefore not optimally reflect, and might underestimate, the contribution of genetic factors to a complex genetic trait disease such as multiple sclerosis.

Adoption and Half-Sibling Studies An elegant approach to dissecting the effect of genetic sharing versus a shared family environment for the development of multiple sclerosis are epidemiological studies of adoptees (no

Numerous searches have been performed and are currently ongoing in order to identify single candidate genes or a set of genes that are relevant for the disease. The strongest and most consistent evidence exists for the area of the MHC, the human leukocyte antigen (HLA), on chromosome 6p21. The total genetic susceptibility attributed to the HLA locus in multiple sclerosis is estimated to be between 15% and 50%.7 Other candidate genes selected for their potential involvement in the pathogenesis of multiple sclerosis—such as T cell receptor genes, genes encoding myelin components, interferons, various chemokines, cytokines, and complement factors, to name a few—have been studied extensively. The results of these studies, however, were inconclusive and most of the initial positive reports could not be confirmed in subsequent analyses. In an alternative approach to a traditional case-control design that has been applied to investigate allelic variants of single candidate genes, whole-genome screens of affected relatives have been used to assess linkage of polymorphic markers spread throughout the genome. Linkage studies have been successfully applied in genetic diseases that follow a mendelian single-gene trait with a high penetrance of the allelic variant

chapter 74 epidemiology and genetics of multiple sclerosis Class II

DP

␤ ␣ ■

DN DM

LMP/TAP

␣ ␣ ␤

Class III

DO

␤

DQ

DR

␤ ␣ ␤ ␤

999

Class I

B C

A

␣

Figure 74–2. The major histocompatibility complex (MHC) region on chromosome 6p21. To date, the MHC-class II region containing genes for the α and β chains of the antigen-presenting MHC class II molecules human leukocyte antigen (HLA)-DR, HLA-D P, and HLA-DQ remains the only area of the whole genome clearly associated with multiple sclerosis. The most consistent association was found for HLA-DR and HLA-DQ genes. (Adapted from Janeway CA, et al, eds: Immunobiology. New York: Garland Publishing.)

and a clear clinical phenotype, such as those in Huntington’s disease or in muscular dystrophy. Linkage studies in multiple sclerosis, mainly performed in North America and northern Europe, did not provide strong evidence for a single major contributing locus, but, in accordance with the previously mentioned surveys on single candidate genes, they consistently identified an increased sharing of the MHC region (6p21) in affected individuals. No consensus could be reached for other susceptibility loci. The ambiguity of gene searches in a complex and heterogenous disease such as multiple sclerosis is presumably at least partially a consequence of methodological problems such as an insufficient stratification of the population investigated with regard to their HLA haplotypes, clinical-pathological features, or ethnic background. In addition, the classic genetic epidemiological methods that have been applied so far are probably of limited power to identify and localize small genetic effects for complex traits with unknown modes of inheritance. Furthermore, even though whole-genome screens employed 6000 microsatellites, these are still too far apart and unevenly spread out through the genome. Because no major single risk locus could be identified by whole-genome linkage studies, a large number of common allelic variants, each with only subtle but important variations, might synergistically lead to the major genetic risk that is associated with the occurrence of the disease. For example, the overall number of susceptibility loci that have been identified in the most comprehensive genomic screen so far is 411.8 Because of the low resolution and the weak signals that can be achieved by traditional linkage studies in polygenic diseases, the identification of such common variants requires different approaches. To date, the MHC class II region remains the only area of the whole genome clearly associated with multiple sclerosis, although the precise genes within this area that confer disease susceptibility are not yet known.

THE HUMAN LEUKOCYTE ANTIGEN GENE COMPLEX The MHC region on chromosome 6p21 encompasses 4.5 megabases and encodes approximately 200 genes. Aside from genes for histones and transfer RNA, most of the encoded molecules play an important role in the development, maturation, and regulation of the T cell repertoire and other immunological processes. The MHC regions harbors separate clusters of

MHC class I, class II, and class III genes (Fig. 74–2). The classic class I genes are HLA-A, HLA-B, and HLA-C. These genes encode the heavy (α) chain of MHC class I molecules. The class II region contains genes for the α and β chains of the antigenpresenting MHC class II molecules HLA-DR, HLA-DP, and HLADQ. The class III region encodes structurally and functionally diverse proteins such as complement components, tumor necrosis factors α and β, and heat shock proteins (HSP70). Other interesting candidates within this region include the gene for myelin oligodendrocyte glycoprotein, a minor structural but immunogenic component of the CNS myelin and so called class I–like genes such as the MHC class I polypeptiderelated sequence gene family that regulates the activation and inhibition of natural killer cells. The most consistent association of multiple sclerosis was found for HLA-DR and HLA-DQ genes. In particular, the HLADR15 haplotype (DRB1*1501, DRB5*0101, DQA1*0102, DQB1*0602) showed a strong association with the disease among white persons in northern and central Europe, North America, and Australia, and even a dose effect of HLA-DR15 could be identified in homozygous patients with multiple sclerosis. Because DRB1 and DQB1 genes are in strong linkage disequilibrium, it has been difficult to distinguish the relative contribution from each allelic variant to the susceptibility haplotype. Both additive and independent effects have been reported for the DQA1*0102/DQB1*0602 locus. More recent investigations, however, indicated a primary role of the DRB1*1501 locus independent of DQB1*0602 at least in a white population.9 The HLA-DR15 association was comparably weak or lacking in other ethnic groups. Mediterranean populations with a distinct genetic background, such as Sardinians, showed a stronger association with HLA-DR4, and no apparent association with any HLA haplotype could be identified in a southern Chinese population. Much less information is available for risks conferred by class I alleles, although HLA-A3 and HLA-B7 are the first MHC genes that were found to be associated with multiple sclerosis.10 Their association with multiple sclerosis, however, appears to be much lower than that of the HLA-DR and HLA-DQ alleles. In addition to these risk genes, certain MHC class I and class II allelic variants have been identified as exerting protective properties. Table 74–2 summarizes the reports on risk/protective alleles for multiple sclerosis within the MHC region. Only limited data are available for the association of clinical features with the HLA-DR/HLA-DQ risk alleles in multiple

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T A B L E 74–2. Selected Studies on the Associations of MHC Class I and Class II Alleles with Multiple Sclerosis MHC Class I or II Allele DRB1*1501

Ethnicity/Geographical Location

Multiple Sclerosis Subtype Association

Remark

White persons; many countries and backgrounds, including Japanese and Tasmanians India

All subtypes

Sardinia Turkey/Canary Island Sweden Russia Canada

None None Progressive multiple sclerosis Higher T2 MRI load None

DQB1*0602

Many multiple sclerosis populations

All subtypes

DPB1*0301 DPB1*0501 A*0301 B*07/B*12 A*02 A*0201

Japan Japan Whites, Russia, Sweden Whites, Russia Russia Sweden

Classic multiple sclerosis Opticospinal (Asian) multiple sclerosis Poor outcome, none Poor outcome, none More benign outcome More benign outcome

DRB1*1506, DRB1*1508 DRB1*0301 DRB1*04 DRB1*04 DRB1*04 DR in general

None

Independent and joint with DQ; dose effect Joint with DRB1*1501 — — — — In DR15-negative families Independent contribution Independent and joint with DRB1*1501 — — No association — — Protective

Adapted from Sospedra M, Martin R: Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23:683-747. HLA, human leukocyte antigen; MHC, major histocompatibility complex; MRI, magnetic resonance imaging.

sclerosis patients. It has been reported that patients expressing the DR15 haplotype have an earlier disease onset, more often have relapsing-remitting multiple sclerosis, are female, and have optic neuritis or spinal involvement as an initial event. DR4-positive patients are described to have a worse clinical outcome or progressive course. However, as mentioned previously, the HLA association studies are heterogeneous with regard to sample size, methodology, ethnic background, and clinical findings. In older studies, the exact MHC class II gene has not even been determined by molecular typing techniques. HLA-DR and HLA-DQ molecules are by far the strongest genetic risk factors in multiple sclerosis. The mechanisms that are responsible for the genetic association of HLA alleles with multiple sclerosis are, however, incompletely understood. The MHC molecules (1) may fail in contributing to the deletion of autoreactive T cells within the thymus, (2) may preferentially process and present CNS antigens and activate encephalitogenic T cells, or (3) may show an organ- or tissue-dependent expression pattern with a selective detrimental induction in the CNS environment. MHC class I genes may additionally act independently of class II genes in some patients, either through similar mechanisms or by modulation of natural killer cell activity.

are evolutionarily stable, not changing much from generation to generation, which makes them easier to monitor in population studies. Because of their frequency and stability, SNPs are believed to be more informative than are conventional methods in identifying risk-conferring genes in complex diseases such as multiple sclerosis. Commercial platforms with ever increasing numbers of SNPs become rapidly available, and it has been shown that retyping existing patient cohorts with these tools yields valuable information. Furthermore, it is hoped that additional discovery-oriented techniques such as gene expression profiling by oligonucleotide or complementary DNA microarrays and, at some point, also proteomics will enable clinicians to discern the functional role of susceptibility loci. However, as promising as these approaches may be, they should be combined with better phenotypic characterization of multiple sclerosis patients by neuroimaging, careful clinical characterization, and individual treatment responsiveness. Only the integration of all these observations will eventually allow clinicians to understand the etiology and pathogenesis of multiple sclerosis.

K E Y FUTURE DIRECTIONS With the exception of the MHC region on chromosome 6p21, traditional genetic study designs and analytical methods have obviously not been very successful in identifying multiple sclerosis–associated alleles. In future studies, investigators not only must employ more patients but also, of more importance, must use more densely distributed markers throughout the genome such as single nucleotide polymorphisms (SNPs). SNPs are DNA sequence variations that occur when a single nucleotide in the genome sequence is altered. These polymorphisms make up about 90% of all human genetic variation and occur every 100 to 300 bases along the 3 billion–base human genome. SNPs

P O I N T S

●

Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS. It develops in young adults with a complex predisposing genetic trait, and an inciting environmental insult such as a viral infection is believed to be necessary to initiate the disease. Multiple sclerosis is most common in temperate areas, with population prevalences of 60 to 200 per 100,000.

●

The susceptibility to multiple sclerosis is inherited, and the risk of developing the disease increases with the degree of relatedness in a nonmendelian mode of inheritance. The strongest and most consistent association with the disease

chapter 74 epidemiology and genetics of multiple sclerosis exists for the area of the MHC on chromosome 6, and the HLA-DR15 haplotype appears to be of particular importance in white populations. ●

Aside from the MHC class II region, no major single risk locus for multiple sclerosis has yet been identified. It can therefore be assumed that a large number of common allelic variants, each with only subtle but important variations, synergistically lead to the major genetic risk that is associated with the occurrence of the disease.

Suggested Reading Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol 2004; 3:104-110. Hafler DA, De Jager PL: Applying a new generation of genetic maps to understand human inflammatory disease. Natl Rev Immunol 2005; 5:83-91. Sospedra M, Martin R: Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23:683-747.

References 1. McFarlin DE, McFarland HF: Multiple sclerosis (first of two parts). N Engl J Med 1982; 307:1183-1188.

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2. McFarlin DE, McFarland HF: Multiple sclerosis (second of two parts). N Engl J Med 1982; 307:1246-1251. 3. Sospedra M, Martin R: Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23:683-747. 4. Ebers GC, Sadovnick AD, Risch NJ: A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995; 377:150-151. 5. Sadovnick AD, Armstrong H, Rice GP, et al: A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33:281-285. 6. Wakeland EK, Liu K, Graham RR, et al: Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001; 15: 397-408. 7. Haines JL, Terwedow HA, Burgess K, et al: Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet 1998; 7:1229-1234. 8. GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative: A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol 2003; 143:39-46. 9. Oksenberg JR, Barcellos LF, Cree BA, et al: Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004; 74:160-167. 10. Jersild C, Ammitzboll T, Clausen J, et al: Association between HL-A antigens and measles antibody in multiple sclerosis. Lancet 1973; 1:151-152.

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75

PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS: DEMYELINATION AND AXONAL INJURY ●

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Raju Kapoor and Kenneth J. Smith

The inflammatory demyelinating lesions of multiple sclerosis cause a range of axonal conduction abnormalities that, in turn, produce the major clinical features of the illness. The clinical effects of these lesions were previously thought to arise directly from the consequences of the demyelination alone, but more recent findings have substantially broadened this understanding. It is now recognized that (1) conduction abnormalities reflect a reorganization of axonal membrane currents after demyelination, (2) inflammation may have direct effects on axonal function, and (3) neuroaxonal degeneration plays a significant role in disease progression.

DEMYELINATION Action potentials generated by inward sodium currents at the nodes of Ranvier propagate successfully along normal myelinated axons because of the insulating layer of myelin covering the internode. The thickness of the myelin reduces the leakage of current between the nodes by increasing the resistance of the membrane and, of more importance, by reducing its capacitance. These properties have the effect of reducing the leakage of current between nodes and thus reducing the current that needs to be generated at the node for secure conduction to occur. In normal myelinated axons, the action potential at an individual node generates three to seven times more current than required to discharge the next node along the axon; this is referred to as a safety factor of three to seven.1 It is now clear that the membrane of the adult myelinated axon has a complicated molecular structure (Fig. 75–1).2,3 Apart from sodium channels, which are clustered at the nodes and expressed at a much lower density in the internodal membrane, there are also a number of potassium channels, including socalled slow channels, located mainly at the nodes, and faster channels, located in the juxtaparanodal region. These serve to limit the excitability of the fiber.4 There are a number of other potassium channels, of which some are inhibited by adenosine triphosphate (ATP) and others are activated by intracellular calcium ions. The axonal membrane is also known to contain calcium channels, but these do not appear to contribute significantly to action potential generation or propagation, at least under normal conditions. The ionic balance across the axonal membrane is maintained by a number of ATP-dependent

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pumps, including the sodium and calcium pumps, and calcium homeostasis also depends on the sodium/calcium exchanger. Demyelination reduces the safety factor for conduction, and conduction fails, at least initially, if an internode or more of myelin is removed (Fig. 75–2). The failure occurs partly because the local excitatory sodium current generated by the last node of Ranvier before the demyelinated segment is now dispersed across a much wider area of naked axonal membrane than just the nodal membrane. Even partial-thickness demyelination increases the effective capacitance of the axolemma as the thickness of the myelin is reduced, increasing the amount of local current necessary to depolarize the nodal membrane to its firing threshold and perhaps resulting in conduction block. Conduction is also likely to be blocked, or severely impaired, if the myelin loss occurs preferentially at the paranodes, which causes nodal widening and increases the capacitance of the “nodal” axolemma. Although conduction may later be restored (see later discussion), the density of sodium channels in the newly exposed axolemma is initially too low to support conduction along the demyelinated axolemma.5,6 Conduction block in clinically eloquent areas is thought to cause all the major negative features of relapse in multiple sclerosis, including sensory and motor deficits and visual failure. The restoration of conduction by adaptive mechanisms is associated with remission, although conduction may remain insecure, and the recovery may be incomplete. Of course, conduction block occurring in clinically silent areas may have no detectable clinical consequences, although the total volume of deep white matter lesions is correlated with the extent of neuropsychological dysfunction.

Effects of Temperature Small changes in temperature can have dramatic effects on conduction in demyelinated axons7-10 (Fig. 75–3), because the safety factor in demyelinated axons is typically reduced near to unity. The success of conduction in many demyelinated axons is therefore finely balanced, inasmuch as small changes can tip the safety factor either to just below unity, in which case conduction is blocked, or to just above unity, in which case conduction will succeed. Temperature changes affect the safety factor by altering the kinetics of the sodium channels.11

chapter 75 pathophysiology of multiple sclerosis Excluding Lesion

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⫺40 ⫺19 ⫺6 3 ■

Figure 75–1. Immunohistochemical labeling of sodium channels

Demyelination

7

(red) and potassium channels (Kv1.2; green) at a node of Ranvier located on a rat sciatic nerve fiber. The sodium channels are restricted to the nodal gap (double arrowheads), whereas the potassium channels are segregated beneath the juxtaparanodal myelin (V-shaped arrowheads) and apposed to Schmidt-Lanterman incisures (triangular arrowhead). (Reproduced from Arroyo EJ, Scherer SS: On the molecular architecture of myelinated fibers. Histochemistry 2000; 113:1-18.)

14

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22 29 36

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48 67

Warming shortens the action potential,12 thereby reducing the time that current is able to flow to depolarize the demyelinated region to its firing threshold, and cooling has the opposite effect. Even subtle changes in body temperature can profoundly alter the expression of symptoms, such as in the visual system (Uhthoff’s phenomenon).13 Thus, vision can improve simply by drinking a glass of cold water,14 whereas a hot shower or bath, or sunbathing, can aggravate disability significantly.15 Indeed, in earlier years, the deleterious effects of body warming underpinned the “hot bath test” for multiple sclerosis. The therapeutic benefits both of body cooling11,16 and of prolonging the action potential17,18 have been considered. Thus, the potassium channel–blocking drugs 4-aminopyridine and 3,4-diaminopyridine can prolong the action potential, favoring successful conduction in demyelinated axons.19 These drugs have been found to improve disability in clinical trials in multiple sclerosis,20 although it has also been suggested that this effect could arise from the potentiation of synaptic transmission.21 The widespread use of aminopyridines has been inhibited by the fact that they are markedly proconvulsant at doses that are not much higher than the therapeutic dose.22

Activity-Dependent Conduction Block Apart from fixed conduction block, demyelinated axons with a safety factor just above unity have a prolonged refractory period for conduction through the lesion23 (Fig. 75–4) and can also exhibit intermittent conduction failure as a result of periods of sustained electrical activity. The rise in the intra-axonal sodium concentration with repetitive firing stimulates the activity of the electrogenic Na+/K+-ATPase (sodium pump) and leads to axonal hyperpolarization.24 Even a small hyperpolarization can effectively, and abruptly, block conduction in such demyelinated axons for periods of approximately 0.2 to 2 seconds.25 Conduction resumes as the intra-axonal sodium concentration recovers and pump activity falls, and this cycle may then be repeated, causing a continuous train of impulses to be divided into short bursts separated by silent periods. The intermittent failure of impulse transmission on sustained activation may

81 97

cal 30 ␮V ■

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2 ms

Figure 75–2. Records showing the slowing changes in conduction occurring over a 5-month period as a result of the induction and spontaneous repair of an experimental central demyelinating lesion in the dorsal columns. Records obtained when the conduction pathway excluded the lesion (left) were quite stable throughout, as were those obtained when the site of the lesion was included but before the lesion was induced (right, top three records). The intraspinal injection of lysolecithin resulted in axonal demyelination and conduction block, but conduction was restored progressively during the period of repair by remyelination. Remyelination also restored the ability of the axons to conduct closely spaced impulses (not shown). (Reproduced from Smith KJ, Blakemore WF, McDonald WI: Central remyelination restores secure conduction. Nature 1979; 280:395-396. Reprinted by permission from Macmillan Publishers Ltd. Copyright 1979. http://www.nature.com/index.html.)

contribute significantly to the fatigability experienced by many patients with multiple sclerosis: for example, those with spinal cord lesions whose gait becomes impaired on walking short distances, or those whose vision “fades” or becomes blurred on fixated gaze, particularly in bright surroundings.26,27 There is therefore a potential therapeutic role for partial blockade of Na+/K+-ATPase, and indeed some benefit with such a therapy has been demonstrated in a small number of patients.28

REMYELINATION There is ample evidence that demyelinated axons can undergo repair by remyelination in multiple sclerosis29,30 and that remyelination is likely to play a major role in restoring conduction and in the remission of neurological deficits after relapses.31 New internodes are thinner and shorter than normal, but remyelinated axons can nonetheless conduct, even when invested with only thin new myelin sheaths composed of

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Control

Lesioned

Cool

Cool

37°C

20 ␮V 37°C

2 ␮V 2 ms

Heat/cool

REC

STIM

Lesion ■

Figure 75–3. Records showing the sensitivity of conduction in demyelinated axons to changes in temperature. Two families of superimposed records are shown, obtained from two excised dorsal columns examined in vitro, with the recording arrangement shown. The records on the left show conduction along normal tissue, whereas those on the right show conduction along a pathway that includes an experimental demyelinating lesion. Temperature changes (from 25° to 37° C in 1° C intervals) applied selectively to the tissue in the central recording lane had little effect on conduction in the normal tissue but profoundly affected conduction in the tissue with lesions. Here, the compound action potential included a second, delayed peak resulting from conduction in demyelinated axons. Conduction in these axons was markedly temperature sensitive, so that very few were able to conduct at normal body temperature, but many were able to conduct when cooled. STIM, stimulation; REC, recording. (Reproduced from Smith KJ: Conduction properties of central demyelinated and remyelinated axons, and their relation to symptom production in demyelinating disorders. Eye 1994; 8:224-237. Reprinted by permission from Macmillan Publishers Ltd. Copyright 1979. http://www.nature.com/eye/index.html.)

as few as five myelin lamellae.32 New nodes formed by remyelination show aggregations of sodium channel immunoreactivity,33 and, at least in the peripheral nervous system, the new nodes are excitable.34 Not only do axons repaired by remyelination conduct (see Fig. 75–2) but also remyelination restores the security5,35 and velocity of conduction to near-normal values regardless of whether the repair is effected primarily by oligodendrocytes,35 Schwann cells (even within the central nervous system),36,37 or transplanted olfactory ensheathing cells.38 Although the role of axonal impulse activity in promoting myelination and remyelination remains controversial, it is possible that because demyelinated axons often exhibit conduction block, the absence of electrical activity could contribute to the failure of remyelination in some multiple sclerosis lesions.39,40 Remyelination is likely to confer not only secure conduction to repaired axons but also protection from degeneration, and developing strategies to promote remyelination is an active area of research.

ADAPTIVE CHANGES IN THE EXPRESSION OF ION CHANNELS IN DEMYELINATION The clustering of voltage-sensitive ion channels and other axolemmal proteins, such as the L1 cell adhesion molecule family members neurofascin and NrCAM, and 480/270kD ankyrin at nodes of Ranvier,41 requires contact with, or at least close proximity to, myelinating Schwann cells in the peripheral nervous system and with oligodendrocytes in the central nervous system.42-46 Because maintenance of ion channel distribution also seems to depend, at least in part, on the presence of compact myelin and the formation of normal, tight paranodal axoglial junctions,47-50 demyelination can produce changes in the patterns of expression of these ion channels. In fact, the restoration of conduction in demyelinated axons involves substantial remodeling of the axonal membrane at a molecular level. Immunocytochemical studies have revealed an increased expression of two different isoforms of voltage-gated

chapter 75 pathophysiology of multiple sclerosis

S1 410 Hz

S2 1000 Hz

R

■

0.5 msec

Figure 75–4. Records showing activity in a single unit isolated from a dorsal root caudal to a demyelinating lesion (hatched area) induced by the injection of diphtheria toxin into the cat dorsal column. The stimulus artifacts appear as dotted lines, and the action potentials as solid lines. Stimulation at S1 includes the lesion in the conduction pathway, whereas the lesion is excluded by stimulation at S2. The axon can conduct faithfully at 1000 Hz when the lesion is excluded from stimulation, but when it is included, and even when the stimulation frequency is reduced to 410 Hz, only three impulses are successfully propagated through the lesion before alternate impulses fail. (Reproduced from McDonald WI, Sears TA: The effects of experimental demyelination on conduction in the central nervous system. Brain 1970; 93:583598. Reprinted by permission of Oxford University Press.)

sodium channels, Nav 1.6 and Nav 1.2, along demyelinated axons.47,48,51 Both of these sodium channels, particularly Nav 1.6, can generate persistent sodium currents, which may be important in axonal degeneration (see later discussion). The Nav 1.8 channel, which is normally expressed only in adult spinal sensory and trigeminal neurons, has also been shown to occur aberrantly in Purkinje cells in multiple sclerosis and in experimental autoimmune encephalomyelitis and potentially to contribute to cerebellar dysfunction.52-55 On physiological examination, both a seemingly continuous distribution of sodium channels56 and, in contrast, an aggregation of sodium channels into “φ-nodes,”34 have been described. φ-Nodes appear to be the precursors of the new nodes of Ranvier formed during remyelination, and it may be significant that the initial observation of a continuous distribution of sodium channels was made in a lesion (diphtheria toxin) in which repair by remyelination is only slowly achieved. It is still not clear how sodium channels aggregate during remyelination to form the new nodes of Ranvier. The formation of the channel aggregations may be driven by the axon and may also depend on the adjacent myelinating cells.33,44,46,50,57,58 These adaptive changes can, in some axons, lead to the restoration of conduction, even in the absence of repair by remyelination. Factors favoring the restoration of conduction in a particular axon include a small diameter59,60 and either a short internode59,61,62 or a widened node before the demyelinated region. The first two of these factors characterize axons in the optic nerve, and they may contribute to the excellent recovery of vision that can follow optic neuritis. However, axons as large as 5.5 μm in diameter have been shown to conduct in the absence of remyelination, which raises the possibility that

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most central axons might be able to conduct under ideal conditions. This possibility may help explain the presence in some patients of clinically silent demyelinating lesions in pathways that usually manifest in symptom production.63-67 The restoration of conduction in segmentally demyelinated axons was first demonstrated by a sophisticated examination of conduction in spinal root axons demyelinated by the intrathecal injection of diphtheria toxin56; nearly 20 years were to pass before there was proof that conduction could also occur in demyelinated central axons,32 although circumstantial evidence had accumulated.68-71 In the peripheral nervous system, conduction can resume as soon as 6 days after the induction of a demyelinating lesion, but in the central nervous system, longer intervals (e.g., 2 to 3 weeks) appear to be required. Once restored, conduction is continuous, or microsaltatory, rather than saltatory, and it is therefore much slower than normal and also less secure. The velocity of conduction along a demyelinated segment of rat ventral root axons is reduced from normal, to the range of 0.7 to 2.3 m/second34,56 and similar values are likely to apply in the central nervous system. Even though this degree of slowing occurs across only the demyelinated portion of an axon, it is still sufficient to disperse and delay the compound action potential and, perhaps coupled with a reduction in the total number of axons conducting, to result in diagnostically valuable delays in the visual,72 somatosensory, and brainstem auditory evoked potentials. Slowing of conduction (as opposed to conduction block) generally causes few symptoms, although sensations dependent on the precise timing of impulses in different axons may be affected. For example, patients with unilateral optic neuritis may perceive the Pulfrich phenomenon (the tendency of a pendulum to appear to trace a circle when a neutral density filter is placed over one eye, because of delayed transmission of information in the filtered pathway) without the normal need of the filter,73 and auditory functions dependent on precisely coordinated information may be distorted by a unilateral lesion in the auditory pathway. The reversal of neurological deficit during remissions in multiple sclerosis can be attributed to the restoration of conduction to demyelinated axons by a combination of remyelination and adaptive changes in the axonal membrane. It seems likely that the relative importance of each mechanism varies between patients and in individual patients at different times.

PLASTIC CHANGES Recovery from a relapse of multiple sclerosis is also likely to involve “plastic” cortical changes; functional magnetic resonance imaging and other evidence support this view.74-81 Thus, to accomplish even minor tasks, patients with multiple sclerosis activate a larger part of the cortex than normal, including cortical areas not normally associated with the particular activity. Whether this increased cortical activation contributes to the sense of fatigue experienced by many patients remains unresolved.

POSITIVE SYMPTOMS: AXONAL HYPEREXCITABILITY The recovery processes in demyelinated axons can lead not only to the restoration of conduction but also to axonal hyperexcitability.82,83 Ectopic impulses can be generated in regular or bursting discharges, and they conduct away from

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their site of initiation in both directions along the axon.84,85 Discharges in sensory pathways may give rise to tingling sensations referred to the body parts normally innervated by those axons. Similar discharges are likely to underlie other paroxysmal phenomena, including trigeminal neuralgia, tonic spasms, hemifacial spasm, and possibly episodic dysarthria and limb ataxia. Positive phenomena can be enhanced in patients by measures that increase axonal excitability, such as hyperventilation, and treatment with bicarbonate or calcium chelators.83,86-88 It appears that spontaneous discharges can arise from the excitatory effects of inward sodium currents that can develop in the demyelinated axolemma,83,89 and sodium channel blockers such as carbamazepine and phenytoin are effective treatments for positive symptoms. Spontaneous discharges could also arise from inward potassium currents that can result from the accumulation of potassium ions in limited extracellular compartments around axons.90 Finally, it has been proposed that impulses can sometimes be “reflected” from sites of demyelination91-93; that is, an impulse propagating through a demyelinated site can induce the formation of a second impulse that travels back along the same axon in the opposite direction. A pair of reflecting sites could generate a train of apparently spontaneous impulses. Single, normally evoked impulses propagating through generator sites where any of these mechanisms of hyperexcitability have arisen could also trigger episodes of ectopic activity.25,91,94,95 Sensory axons are more prone to develop ectopic discharges than are motor axons, and, accordingly, positive sensory phenomena are more common in demyelinating disease than are their motor counterparts.96,97 These differences may occur partly because of the greater expression of persistent sodium currents along sensory axons.98 The application of tumor necrosis factor directly to the sciatic nerve has been found to evoke ectopic discharges in nociceptive axons, including unmyelinated axons.99 It is therefore possible that in inflammatory demyelinating diseases such as multiple sclerosis, tumor necrosis factor is involved in promoting the generation of ectopic discharges along demyelinated axons within inflammatory foci. Other inflammatory mediators may also favor ectopic activity. For example, exposure to nitric oxide is known to be conducive to persistent opening of sodium channels.100,101

Ephaptic Transmission between Axons Ephaptic interactions involving electrical crosstalk between demyelinated axons can explain a number of clinical observations in which paroxysmal, positive phenomena affect anatomically adjacent axonal pathways.102-104 For example, tonic spasms may involve sensory symptoms along with contralateral limb contraction, as expected from a lateral spread of excitation from the spinothalamic to the corticospinal tract within the spinal cord. Hartmann102 described a patient in whom trigeminal neuralgia could be triggered by auditory stimuli and who had a pontine lesion involving the adjacent lateral lemniscus and trigeminal sensory pathway on magnetic resonance imaging. That said, ephaptic transmission has rarely been demonstrated electrophysiologically. Indeed, the best documented interaction occurs between normal and amyelinated (i.e., never myelinated, rather than demyelinated) axons in the spinal roots of the dystrophic mouse.105,106 The authors have occasionally observed massed synchronous discharges arising from the spinal cord in animals with

experimental demyelinating lesions in the dorsal columns.107 The discharges take the form of repeated bouts of highfrequency bursts of compound action potentials, but their relevance to multiple sclerosis remains uncertain.

Mechanosensitivity Demyelinated axons can become markedly mechanosensitive, so that even mild deformation can result in the generation of bursts of impulses or change the firing frequency of axons that are already spontaneously active.108 Stretch-sensitive ion channels, if they appear in the demyelinated membrane, might underlie mechanosensitivity, but this possibility remains speculative. It is reasonable to suppose that the mechanosensitivity of demyelinated axons in the cervical dorsal columns is responsible for Lhermitte’s phenomenon109-111 and for the perception of flashes of light (phosphenes) upon eye movements in patients with demyelinating lesions of the optic nerve.

THE ROLE OF INFLAMMATION It is now accepted that the inflammatory response in multiple sclerosis plays a significant role in symptom production and clinical relapse.112 Clinical and magnetic resonance imaging studies have shown a correlation between inflammation in the optic nerve and visual loss in patients with acute optic neuritis,113 and administration of the antilymphocyte antibody alemtuzumab (Campath-1H) to patients with multiple sclerosis provokes acute exacerbations of previously expressed symptoms, presumably because conduction in damaged axons had been blocked.114 Inflammation may impair conduction indirectly by opening the blood-brain barrier, thereby exposing axons to potentially deleterious factors in the vasculature, or directly, as a result of the local action of soluble agents such as nitric oxide, cytokines, peptides, and antibodies produced during the immune response. Demyelinated axons have an inherently low safety factor for conduction and are therefore likely to be particularly susceptible to factors impairing conduction, even when the factors may exert only subtle effects on normal axons. Clinically, the time course of relapse and remission in multiple sclerosis tends to coincide with the onset and resolution of inflammatory activity within plaques, which supports the beliefs that inflammation contributes to the deficit and that recovery is associated with the restoration of conduction as inflammation subsides.113

Cytokines Cytokines have been implicated as a cause of conduction block in some clinical studies, particularly in axons already compromised by disease processes. For example, the symptoms that occur after the administration of alemtuzumab are associated with a transient elevation of circulating proinflammatory cytokines,115 and they can be prevented by pretreatment with steroids. These neurological effects could be mediated by direct effects of cytokines on axonal ion channels and/or indirectly, because cytokines such as interleukin-1β and interferon γ are potent inducers of the inducible form of nitric oxide synthase (iNOS) in human astrocytes and also probably in microglia. It may therefore be clinically significant that interferon β inhibits

chapter 75 pathophysiology of multiple sclerosis both the expression of iNOS116 by astrocytes and the production of reactive oxygen species by monocytes from patients with relapsing-remitting multiple sclerosis.

Nitric Oxide Levels of nitric oxide metabolites and of iNOS are increased in multiple sclerosis,117,118 and low micromolar concentrations of nitric oxide can block axonal conduction,119,120 particularly in demyelinated axons.119 The blockade is reversible, which raises the possibility that nitric oxide may be an important contributor to the reversible clinical deficits in the relapses and remissions of multiple sclerosis. The mechanisms underlying conduction block have not been established but may include direct effects of nitric oxide on ion channels,100,121-123 inhibition of mitochondrial respiration by nitric oxide,124,125 and effects on the levels of axonal cyclic guanosine monophosphate.126 If nitric oxide does impair conduction in inflammatory demyelinating disease, then agents that inhibit its production should ameliorate symptoms. However, this rationale may have unpredictable consequences in the context of an autoimmune demyelinating disease, in which nitric oxide may have protective as well as damaging effects. There have been more than 40 studies of the role of nitric oxide and its related compounds in experimental autoimmune encephalomyelitis, but there is little consensus regarding its effects or the mechanisms through which they are mediated.127

Antibodies Antiganglioside antibodies have been identified in patients with progressive forms of multiple sclerosis.128,129 These antibodies may contribute to the neurological deficit because some (but not all) studies have revealed that they can have electrophysiological effects on peripheral axons.130

DISABILITY AND AXONAL DEGENERATION It has long been believed that the persistence and progression of disability in multiple sclerosis can be explained by persistent conduction block in demyelinated axons caused by a failure of the repair mechanisms discussed earlier. However, it is now clear that axonal degeneration also plays an important and perhaps primary role.131-136 In pathological studies, there is prominent axonal degeneration at an early stage of multiple sclerosis,137,138 and in magnetic resonance studies, there is atrophy of the whole brain and regions that include the cerebellum, spinal cord and thalamus, as well as a reduction of the neuronal marker N-acetyl aspartate.131,133,139 Axonal injury is correlated with disability in both the pathological and magnetic resonance studies. There are probably numerous mechanisms of axonal degeneration. However, the magnitude of axonal degeneration in pathological studies is correlated with the intensity of the inflammatory response, which raises the possibility that some mediators of inflammation may have a damaging effect on adjacent axons. Experimentally sustained impulse activity at physiological frequencies has been shown to result in axonal degeneration, even in normal axons, if the activity occurs in conjunction with exposure to nitric oxide (Fig. 75–5).140 The combination of impulse activity and nitric oxide exposure may

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be expected to occur within inflammatory lesions; therefore, this mechanism could contribute to axonal degeneration in multiple sclerosis. In this respect, it is interesting that the smallest axons are the most susceptible to degeneration caused by impulse activity during nitric oxide exposure and that they are also the axons that are preferentially lost in multiple sclerosis lesions.141,142 The mechanisms responsible for the effects of nitric oxide are not yet certain, but because nitric oxide is known to inhibit mitochondrial energy production, and because demyelinated axons express more sodium channels, it seems reasonable to hypothesize that axonal degeneration might result from the combination of a reduced capacity for energy production as a result of nitric oxide exposure and an increased energy demand from sodium loading of the axon as a result of impulse activity.143 The consequent failure of Na+/K+-ATPase to maintain ionic homeostasis would result in an elevation of the intraaxonal sodium ion concentration, perhaps to a level capable of driving the sodium-calcium exchanger into reverse activity.144 This sequence of events could culminate in a pathological accumulation of calcium ions within the axon and the activation of intra-axonal degrading enzymes. Demyelinated axons in multiple sclerosis or experimental autoimmune encephalomyelitis can also express immunoreactivity for subunits of the N-type calcium channel:145 If such channels are functional, they could add to an influx of calcium ions during impulse activity. Furthermore, there is increasing evidence of mitochondrial genetic dysfunction in multiple sclerosis,145a which might render subgroups of patients more vulnerable to axonal injury that depends on energy failure. This hypothesis, which links inflammation, increased expression of sodium channels, metabolic failure, and ultimately calcium overloading of the axon, has received support from studies showing that sodium channel blockade with drugs such as phenytoin,146 flecainide (Fig. 75–6),147-150 and lamotrigine (unpublished observations) can indeed protect axons from degeneration, both on exposure to nitric oxide and in animals with experimental autoimmune encephalomyelitis and experimental autoimmune neuritis.

Glutamate Excitotoxicity Glutamate is likely to be present in active multiple sclerosis lesions after its liberation by activated microglia and leukocytes151 and perhaps by axons,144 and its levels may be amplified still further within inflammatory foci by the action of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor α, which have been reported to inhibit the glutamate uptake activity of astrocytes in vitro by a mechanism that involves nitric oxide. Glutamate-mediated excitotoxicity acting through Ca2+-permeable α-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA)/kainate receptors may contribute to the death of oligodendrocytes (and neurons) in multiple sclerosis, and indeed the blockade of AMPA/kainate receptors has been found to reduce both axon and oligodendrocyte loss in experimental allergic encephalomyelitis, with a corresponding amelioration of clinical outcome.152,153 Furthermore, excitotoxic damage to oligodendrocyte-like cells is prevented by agents that elevate cyclic adenosine monophosphate levels, such as rolipram, which has been shown to be protective in experimental allergic encephalomyelitis.154,155 The

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Figure 75–5. Records showing the vulnerability of nerve fibers to degeneration as a result of sustained impulse activity during exposure to nitric oxide (NO). Two series of averaged compound action potentials can be seen, recorded in parallel from two dorsal roots in an anesthetized rat, in the arrangement indicated (see inset). The data are shown in three-dimensional perspective, with the earliest records at the front and with a 2-minute interval between adjacent records; each plot therefore shows approximately 12 hours of recorded data. The left plot shows records obtained at continuous 1-Hz stimulation, whereas in the right plot, the nerve fibers were stimulated at 100 Hz for the first 6 hours of recording. On the left, the records were stable for the first 2.5 hours, but conduction block was imposed on nearly all the axons by a 2-hour exposure to nitric oxide. Such block has been described by Redford and colleagues,119 and it might help explain how inflammation can cause negative symptoms in multiple sclerosis (see text). The block was released on removal of nitric oxide, and the axons continued to conduct for the remaining 7.5 hours of the experiment. On the right, conduction was also blocked during exposure to nitric oxide, but recovery after washing was inconsistent and only temporary, so that within 2 hours, conduction had ceased in all axons. Histological examination of the roots at the end of the experiment revealed that all the axons exposed to nitric oxide in conjunction with stimulation at 100 Hz had undergone degeneration, whereas the root stimulated at only 1 Hz during the period of nitric oxide exposure was quite normal in appearance. (Redrawn from Smith KJ, Kapoor R, Hall SM, et al: Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001; 49:470-476.)

precise mechanisms of injury to neurons and to oligodendrocytes may differ, inasmuch as oligodendrocytes appear to possess only AMPA/kainate receptors, whereas neurons possess N-methyl-D-aspartate receptors as well. The situation is less clear for axons, although there is emerging evidence that they do express novel glutamate receptors after demyelination. Finally, research suggests that axonal degeneration in experimental allergic encephalomyelitis may be influenced by the activity of cannabinoid receptors, acting in part through their effects on glutaminergic systems.156

Cortical Lesions and Neuronal Loss in Gray Matter The lesions of multiple sclerosis are not restricted to the white matter, and different forms of cortical lesions are known to

occur.157,158 Their contribution to the clinical features of multiple sclerosis is a subject of increasing interest. Magnetic resonance imaging and spectroscopy have demonstrated that atrophy and lowered N-acetyl aspartate levels are present in cortical and deep gray matter areas.159-163 This work, which is in keeping with the results of histopathological studies, indicates that there is a significant component of degeneration of neuronal cell bodies in multiple sclerosis, not only in advanced secondary progressive disease but also in early relapsing disease. Gray matter neuroaxonal pathology may therefore be an important factor in the development of disability. The mechanisms of damage to neuronal cell bodies probably differ to some extent from those causing axonal degeneration, and it may be relevant that cortical lesions in multiple sclerosis contain a smaller leukocytic infiltrate and more microglial activity than do white matter lesions.

chapter 75 pathophysiology of multiple sclerosis

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Figure 75–6. Representative photomicrographs of the dorsal columns of rats with chronic relapsing experimental allergic encephalomyelitis. The axons have been labeled immunohistochemically for neurofilaments. Control animals show substantial axonal loss (left; seen at higher magnification, bottom), whereas in animals treated with the sodium channel–blocking agent flecainide, most of the axons have survived (right). (Modified from Bechtold DA, Kapoor R, Smith KJ: Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 2004; 55:607-616.)

K E Y ●

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P O I N T S

The pathological hallmarks of multiple sclerosis are demyelination, inflammation, and neuroaxonal degeneration. The pathophysiological consequences of these events account for the key clinical features of the disorder, including the phenomena of relapse, remission, and the progressive accumulation of disability. Demyelination can lead to axonal conduction block, the main cause of neurological dysfunction in relapse, and can also be associated with temperature-dependent symptoms and fatigability of function. A significant cause of the conduction block and disability during relapse is believed to be associated with the inflammation that can be a prominent component of lesions, rather than with demyelination alone.

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Recovery from relapse involves remyelination and adaptive changes in the axonal membrane, including an increased expression of sodium channels. “Plastic” changes also contribute.

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Residual and progressive disability is related to the failure of these adaptive mechanisms and to neuroaxonal degeneration, which occurs at an early stage of the illness.

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The mechanisms of neurodegeneration are being clarified, and some research suggests that it is realistic to believe that a neuroprotective treatment may be achievable within the foreseeable future.

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Suggested Reading Bechtold DA, Smith KJ: Sodium-mediated axonal degeneration in inflammatory demyelinating disease. J Neurol Sci 2005; 233:2735. Burke D, Kiernan MC, Bostock H: Excitability of human axons. Clin Neurophysiol 2001; 112:1575-1585. Craner MJ, Newcombe J, Black JA, et al: Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci U S A 2004; 101:8168-8173. Smith KJ, Felts PA, Kapoor R: Axonal hyperexcitability: mechanisms and role in symptom production in demyelinating diseases. Neuroscientist 1997; 3:237-246. Smith KJ, McDonald I, Miller D, et al: The pathophysiology of multiple sclerosis. In Compston A, Confavreux C, Lassman H, et al, eds: McAlpine’s Multiple Sclerosis. London: Churchill Livingstone, 2005, pp 601-659.

References 1. Tasaki I: Nervous Transmission. Springfield, IL: Charles C Thomas, 1953. 2. Arroyo EJ, Scherer SS: On the molecular architecture of myelinated fibers. Histochemistry 2000; 113:1-18. 3. Kazarinova-Noyes K, Shrager P: Molecular constituents of the node of Ranvier. Mol Neurobiol 2002; 26:167-182. 4. Reid G, Scholz A, Bostock H, et al: Human axons contain at least five types of voltage-dependent potassium channel. J Physiol (Lond) 1999; 518:681-696. 5. Smith KJ, Hall SM: Nerve conduction during peripheral demyelination and remyelination. J Neurol Sci 1980; 48:201219. 6. Waxman SG, Ritchie JM: Molecular dissection of the myelinated axon. Ann Neurol 1993; 33:121-136. 7. Davis FA, Schauf CL, Reed BJ, et al: Experimental studies of the effects of extrinsic factors on conduction in normal and demyelinated nerve. J Neurol Neurosurg Psychiatry 1975; 39:442-448. 8. Rasminsky M: The effects of temperature on conduction in demyelinated single nerve fibers. Arch Neurol 1973; 28:287292. 9. Sears TA, Bostock H, Sheratt M: The pathophysiology of demyelination and its implications for the symptomatic treatment of multiple sclerosis. Neurology 1978; 28:21-26. 10. Smith KJ: Conduction properties of central demyelinated and remyelinated axons, and their relation to symptom production in demyelinating disorders. Eye 1994; 8:224-237. 11. Davis FA, Schauf CL: Approaches to the development of pharmacological interventions in multiple sclerosis. Adv Neurol 1981; 31:505-510. 12. Paintal AS: The influence of diameter of medullated nerve fibres of cats on the rising and falling phases of the spike and its recovery. J Physiol (Lond) 1966; 184:791-811. 13. Uhthoff W: Untersuchungen über die bei der multiplen Herdsklerose vorkommenden Augenstörungen. Arch Psychiatr Nervenkr 1890; 21:55-116. 14. McDonald WI: The pathophysiology of multiple sclerosis. In McDonald WI, Silberberg DH, eds: Multiple Sclerosis. London: Butterworth, 1986, pp 112-133. 15. Waxman SG, Geschwind N: Major morbidity related to hyperthermia in multiple sclerosis. Ann Neurol 1983; 13:348. 16. Waxman SG, Utzschneider DA, Kocsis JD: Enhancement of action potential conduction following demyelination: experimental approaches to restoration of function in multiple sclerosis and spinal cord injury. Prog Brain Res 1994; 100:233-243.

17. Sherratt RM, Bostock H, Sears TA: Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres. Nature 1980; 283:570-572. 18. Targ EF, Kocsis JD: 4-Aminopyridine leads to restoration of conduction in demyelinated rat sciatic nerve. Brain Res 1985; 328:358-361. 19. Bowe CM, Kocsis JD, Targ EF, et al: Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers. Ann Neurol 1987; 22:264-268. 20. Bever CT Jr: 4-Aminopyridine: use in multiple sclerosis. CNS Drug Rev 1995; 1:261-279. 21. Smith KJ, Felts PA, John GR: Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain 2000; 123(Pt 1):171-184. 22. Blight AR, Toombs JP, Bauer MS, et al: The effects of 4aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial. J Neurotrauma 1991; 8:103-119. 23. McDonald WI, Sears TA: The effects of experimental demyelination on conduction in the central nervous system. Brain 1970; 93:583-598. 24. Bostock H, Grafe P: Activity-dependent excitability changes in normal and demyelinated rat spinal root axons. J Physiol (Lond) 1985; 365:239-257. 25. Felts PA, Kapoor R, Smith KJ: A mechanism for ectopic firing in central demyelinated axons. Brain 1995; 118(Pt 5):12251231. 26. Smith KJ, McDonald I, Miller D, et al: The pathophysiology of multiple sclerosis. In Compston A, Confavreux C, Lassman H, et al, eds: McAlpine’s Multiple Sclerosis. London: Churchill Livingstone, 2005, pp 601-659. 27. Waxman SG: Clinicopathological correlations in multiple sclerosis and related diseases. Adv Neurol 1981; 31:169-182. 28. Kaji R, Happel L, Sumner AJ: Effect of digitalis on clinical symptoms and conduction variables in patients with multiple sclerosis. Ann Neurol 1990; 28:582-584. 29. Prineas JW, Barnard RO, Kwon EE, et al: Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 1993; 33:137151. 30. Prineas JW, Kwon EE, Sharer LR, et al: Massive early remyelination in acute multiple sclerosis [Abstract]. Neurology 1987; 37(Suppl):109. 31. Jeffery ND, Blakemore WF: Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 1997; 120(Pt 1):27-37. 32. Felts PA, Baker TA, Smith KJ: Conduction in segmentally demyelinated mammalian central axons. J Neurosci 1997; 17:7267-7277. 33. Novakovic SD, Deerinck TJ, Levinson SR, et al: Clusters of axonal Na+ channels adjacent to remyelinating Schwann cells. J Neurocytol 1996; 25:403-412. 34. Smith KJ, Bostock H, Hall SM: Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline. J Neurol Sci 1982; 54:13-31. 35. Smith KJ, Blakemore WF, McDonald WI: The restoration of conduction by central remyelination. Brain 1981; 104:383404. 36. Felts PA, Smith KJ: Schwann cell remyelination of demyelinated central fibres restores secure conduction. Neuropathol Appl Neurobiol 1987; 13:494. 37. Honmou O, Felts PA, Waxman SG, et al: Restoration of normal conduction properties in demyelinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells. J Neurosci 1996; 16:3199-3208. 38. Imaizumi T, Lankford KL, Kocsis JD: Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord. Brain Res 2000; 854:70-78.

chapter 75 pathophysiology of multiple sclerosis 39. Colello RJ, Pott U: Signals that initiate myelination in the developing mammalian nervous system. Mol Neurobiol 1997; 15:83-100. 40. Stevens B, Fields RD: Response of Schwann cells to action potentials in development. Science 2000; 287:2267-2271. 41. Bennett V, Lambert S: Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltagegated sodium channels. J Neurocytol 1999; 28:303-318. 42. Boiko T, Rasband MN, Levinson SR, et al: Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 2001; 30:91-104. 43. Kaplan MR, Cho MH, Ullian EM, et al: Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron 2001; 30:105-119. 44. Kaplan MR, Meyer-Franke A, Lambert S, et al: Induction of sodium channel clustering by oligodendrocytes. Nature 1997; 386:724-728. 45. Rasband MN, Peles E, Trimmer JS, et al: Dependence of nodal sodium channel clustering on paranodal axoglial contact in the developing CNS. J Neurosci 1999; 19:7516-7528. 46. Rasband MN, Taylor CM, Bansal R: Paranodal transverse bands are required for maintenance but not initiation of Nav1.6 sodium channel clustering in CNS optic nerve axons. Glia 2003; 44:173-182. 47. Craner MJ, Lo AC, Black JA, et al: Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 2003; 126(Pt 7):1552-1561. 48. Craner MJ, Newcombe J, Black JA, et al: Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci U S A 2004; 101:8168-8173. 49. Novakovic SD, Levinson SR, Schachner M, et al: Disruption and reorganization of sodium channels in experimental allergic neuritis. Muscle Nerve 1998; 21:1019-1032. 50. Rasband MN, Trimmer JS, Peles E, et al: K+ channel distribution and clustering in developing and hypomyelinated axons of the optic nerve. J Neurocytol 1999; 28:319-331. 51. Craner MJ, Hains BC, Lo AC, et al: Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 2004; 127(Pt 2):294-303. 52. Black JA, Dib-Hajj S, Baker D, et al: Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proc Natl Acad Sci U S A 2000; 97:11598-11602. 53. Craner MJ, Kataoka Y, Lo AC, et al: Temporal course of upregulation of Na(v)1.8 in Purkinje neurons parallels the progression of clinical deficit in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol 2003; 62:968-975. 54. Renganathan M, Gelderblom M, Black JA, et al: Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar Purkinje cells. Brain Res 2003; 959:235-242. 55. Waxman SG: Cerebellar dysfunction in multiple sclerosis: evidence for an acquired channelopathy. Prog Brain Res 2005; 148:353-365. 56. Bostock H, Sears TA: Continuous conduction in demyelinated mammalian nerve fibers. Nature 1976; 263:786-787. 57. Deerinck TJ, Levinson SR, Bennett GV, et al: Clustering of voltage-sensitive sodium channels on axons is independent of direct Schwann cell contact in the dystrophic mouse. J Neurosci 1997; 17:5080-5088. 58. Novakovic SD, Eglen RM, Hunter JC: Regulation of Na+ channel distribution in the nervous system. Trends Neurosci 2001; 24:473-478. 59. Bostock H, Sears TA: The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J Physiol (Lond) 1978; 280:273-301.

1011

60. Waxman SG: Demyelination in spinal cord injury. J Neurol Sci 1989; 91:1-14. 61. Shrager P, Rubinstein CT: Optical measurement of conduction in single demyelinated axons. J Gen Physiol 1990; 95:867-890. 62. Waxman SG, Brill MH: Conduction through demyelinated plaques in multiple sclerosis: computer simulations of facilitation by short internodes. J Neurol Neurosurg Psychiatry 1978; 41:408-416. 63. Ghatak NR, Hirano A, Lijtmaer H, et al: Asymptomatic demyelinated plaque in the spinal cord. Arch Neurol 1974; 30:484-486. 64. Namerow NS: The pathophysiology of multiple sclerosis. In Wolfgram F, Ellison GW, Stevens JG, et al, eds: Multiple Sclerosis: Immunology, Virology and Ultrastructure. New York: Academic Press, 1972, pp 143-172. 65. O’Riordan JI, Losseff NA, Phatouros C, et al: Asymptomatic spinal cord lesions in clinically isolated optic nerve, brain stem, and spinal cord syndromes suggestive of demyelination. J Neurol Neurosurg Psychiatry 1998; 64:353-357. 66. Phadke JG, Best PV: Atypical and clinically silent multiple sclerosis: a report of 12 cases discovered unexpectedly at necropsy. J Neurol Neurosurg Psychiatry 1983; 46:414-420. 67. Ulrich J, Groebke-Lorenz W: The optic nerve in multiple sclerosis: a morphological study with retrospective clinicopathological correlations. Neuroophthalmology 1983; 3:149159. 68. Chalk JB, McCombe PA, Pender MP: Conduction abnormalities are restricted to the central nervous system in experimental autoimmune encephalomyelitis induced by inoculation with proteolipid protein but not with myelin basic protein. Brain 1994; 117:975-986. 69. Kaji R, Suzumura A, Sumner AJ: Physiological consequences of antiserum-mediated experimental demyelination in CNS. Brain 1988; 111:675-694. 70. Pender MP: The pathophysiology of acute experimental allergic encephalomyelitis induced by whole spinal cord in the Lewis rat. J Neurol Sci 1988; 84:209-222. 71. Smith KJ, Blakemore WF, McDonald WI: Central remyelination restores secure conduction. Nature 1979; 280:395-396. 72. Halliday AM, McDonald WI, Mushin J: Visual evoked response in diagnosis of multiple sclerosis. BMJ 1973; 4:661-664. 73. Frisen L, Hoyt WF, Bird AC, et al: Diagnostic uses of the Pulfrich phenomenon. Lancet 1973; 2:385-386. 74. Kerschensteiner M, Bareyre FM, Buddeberg BS, et al: Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J Exp Med 2004; 200:1027-1038. 75. Pantano P, Iannetti GD, Caramia F, et al: Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain 2002; 125(Pt 7):1607-1615. 76. Reddy H, Narayanan S, Woolrich M, et al: Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain 2002; 125(Pt 12):2646-2657. 77. Rocca MA, Mezzapesa DM, Falini A, et al: Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Neuroimage 2003; 18:847-855. 78. Rocca MA, Pagani E, Ghezzi A, et al: Functional cortical changes in patients with multiple sclerosis and nonspecific findings on conventional magnetic resonance imaging scans of the brain. Neuroimage 2003; 19:826-836. 79. Toosy AT, Hickman SJ, Miszkiel KA, et al: Adaptive cortical plasticity in higher visual areas after acute optic neuritis. Ann Neurol 2005; 57:622-633. 80. Toosy AT, Werring DJ, Bullmore ET, et al: Functional magnetic resonance imaging of the cortical response to photic

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92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102.

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stimulation in humans following optic neuritis recovery. Neurosci Lett 2002; 330:255-259. Werring DJ, Bullmore ET, Toosy AT, et al: Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: a functional magnetic resonance imaging study. J Neurol Neurosurg Psychiatry 2000; 68:441-449. Burke D: Microneurography, impulse conduction, and paresthesias. Muscle Nerve 1993; 16:1025-1032. Smith KJ, Felts PA, Kapoor R: Axonal hyperexcitability: mechanisms and role in symptom production in demyelinating diseases. Neuroscientist 1997; 3:237-246. Baker M, Bostock H: Ectopic activity in demyelinated spinal root axons of the rat. J Physiol (Lond) 1992; 451:539-552. Smith KJ, McDonald WI: Spontaneous and evoked electrical discharges from a central demyelinating lesion. J Neurol Sci 1982; 55:39-47. Baker MD: Axonal flip-flops and oscillators. Trends Neurosci 2000; 23:514-519. Burchiel KJ: Ectopic impulse generation in demyelinated axons: effects of PaCO2, pH, and disodium edetate. Ann Neurol 1981; 9:378-383. Davis FA, Becker FO, Michael JA, et al: Effect of intravenous sodium bicarbonate, disodium edetate (Na2EDTA), and hyperventilation on visual and oculomotor signs in multiple sclerosis. J Neurol Neurosurg Psychiatry 1970; 33:723-732. Kapoor R, Li YG, Smith KJ: Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons. Brain 1997; 120(Pt 4):647-652. Kapoor R, Smith KJ, Felts PA, et al: Internodal potassium currents can generate ectopic impulses in mammalian myelinated axons. Brain Res 1993; 611:165-169. Calvin WH, Devor M, Howe JF: Can neuralgias arise from minor demyelination? Spontaneous firing, mechanosensitivity, and afterdischarge from conducting axons. Exp Neurol 1982; 75:755-763. Calvin WH, Loeser JD, Howe JF: A neurophysiological theory for the pain mechanism of tic douloureux. Pain 1977; 3:147154. Howe JF, Calvin WH, Loeser JD: Impulses reflected from dorsal root ganglia and from focal nerve injuries. Brain Res 1976; 116:139-144. Burchiel KJ: Abnormal impulse generation in focally demyelinated trigeminal roots. J Neurosurg 1980; 53:674683. Huizar P, Kuno M, Miyata Y: Electrophysiological properties of spinal motoneurones of normal and dystrophic mice. J Physiol (Lond) 1975; 248:231-246. Chen Y, Devor M: Ectopic mechanosensitivity in injured sensory axons arises from the site of spontaneous electrogenesis. Eur J Pain 1998; 2:165-178. Sedano MJ, Trejo JM, Macarron JL, et al: Continuous facial myokymia in multiple sclerosis: treatment with botulinum toxin. Eur Neurol 2000; 43:137-140. Mogyoros I, Bostock H, Burke D: Mechanisms of paresthesias arising from healthy axons. Muscle Nerve 2000; 23:310-320. Sorkin LS, Xiao WH, Wagner R, et al: Tumour necrosis factoralpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 1997; 81:255-262. Ahern GP, Hsu S-F, Klyachko VA, et al: Induction of persistent sodium current by exogenous and endogenous nitric oxide. J Biol Chem 2000; 275:28810-28815. Hammarstrom AKM, Gage PW: Nitric oxide increases persistent sodium current in rat hippocampal neurons. J Physiol (Lond) 1999; 520:451-461. Hartmann M, Rottach KG, Wohlgemuth WA, et al: Trigeminal neuralgia triggered by auditory stimuli in multiple sclerosis. Arch Neurol 1999; 56:731-733.

103. Matthews B: Symptoms and signs of multiple sclerosis. In Compston A, Ebers G, Lassmann H, et al, eds: McAlpine’s Multiple Sclerosis. London: Churchill Livingstone, 1998, pp 145-190. 104. Matthews WB: Paroxysmal symptoms in multiple sclerosis. J Neurol Neurosurg Psychiatry 1975; 38:619-623. 105. Rasminsky M: Ephaptic transmission between single nerve fibres in the spinal nerve roots of dystrophic mice. J Physiol (Lond) 1980; 305:151-169. 106. Rasminsky M: Ectopic generation of impulses and cross-talk in spinal nerve roots of “dystrophic” mice. Ann Neurol 1978; 3:351-357. 107. Smith KJ, McDonald WI: The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Phil Trans R Soc Lond B 1999; 354:1649-1673. 108. Smith KJ, McDonald WI: Spontaneous and mechanically evoked activity due to central demyelinating lesion. Nature 1980; 286:154-155. 109. Kanchandani R, Howe JG: Lhermitte’s sign in multiple sclerosis: a clinical survey and review of the literature. J Neurol Neurosurg Psychiatry 1982; 45:308-312. 110. Lhermitte J, Bollack J, Nicholas M: Les douleurs à type de décharge électrique consécutives à la flexion céphalique dans la sclérose en plaques. Rev Neurol 1924; 2:56-62. 111. Nordin M, Nystrom B, Wallin U, et al: Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns. Pain 1984; 20:231-245. 112. Bitsch A, Wegener C, Da Costa C, et al: Lesion development in Marburg’s type of acute multiple sclerosis: from inflammation to demyelination. Mult Scler 1999; 5:138-146. 113. Youl BD, Turano G, Miller DH, et al: The pathophysiology of acute optic neuritis. An association of gadolinium leakage with clinical and electrophysiological deficits. Brain 1991; 114:2437-2450. 114. Moreau T, Coles A, Wing M, et al: Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 1996; 119(Pt 1):225-237. 115. Coles AJ, Wing MG, Molyneux P, et al: Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999; 46:296-304. 116. Hua LL, Liu JSH, Brosnan CF, et al: Selective inhibition of human glial inducible nitric oxide synthase by interferonbeta: implications for multiple sclerosis. Ann Neurol 1998; 43:384-387. 117. Giovannoni G, Miller RF, Heales SJR, et al: Elevated cerebrospinal fluid and serum nitrate and nitrite levels in patients with central nervous system complications of HIV-1 infection: a correlation with blood-brain-barrier dysfunction. J Neurol Sci 1998; 156:53-58. 118. Smith KJ, Lassmann H: The role of nitric oxide in multiple sclerosis. Lancet Neurol 2002; 1:232-241. 119. Redford EJ, Kapoor R, Smith KJ: Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 1997; 120(Pt 12):2149-2157. 120. Shrager P, Custer AW, Kazarinova K, et al: Nerve conduction block by nitric oxide that is mediated by the axonal environment. J Neurophysiol 1998; 79:529-536. 121. Ahern GP, Hsu S-F, Jackson MB: Direct actions of nitric oxide on rat neurohypophysial K+ channels. J Physiol (Lond) 1999; 520:165-176. 122. Li Z, Chapleau MW, Bates JN, et al: Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons. Neuron 1998; 20:1039-1049. 123. Renganathan M, Cummins TR, Hormuzdiar WN, et al: Nitric oxide is an autocrine regulator of Na+ currents in axotomized C-type DRG neurons. J Neurophysiol 2000; 83:2431-2442.

chapter 75 pathophysiology of multiple sclerosis 124. Bolanos JP, Almeida A, Stewart V, et al: Nitric oxide–mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 1997; 68:2227-2240. 125. Brown GC, Bolanos JP, Heales SJ, et al: Nitric oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration. Neurosci Lett 1995; 193:201-204. 126. Garthwaite G, Goodwin DA, Garthwaite J: Nitric oxide stimulates cGMP formation in rat optic nerve axons, providing a specific marker of axon viability. Eur J Neurosci 1999; 11:4367-4372. 127. Willenborg DO, Staykova MA, Cowden WB: Our shifting understanding of the role of nitric oxide in autoimmune encephalomyelitis: a review. J Neuroimmunol 1999; 100:2135. 128. Acarin N, Rio J, Fernandez AL, et al: Different antiganglioside antibody pattern between relapsing-remitting and progressive multiple sclerosis. Acta Neurol Scand 1996; 93:99-103. 129. Sadatipour BT, Greer JM, Pender MP: Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann Neurol 1998; 44:980983. 130. Willison HJ, Yuki N: Peripheral neuropathies and antiglycolipid antibodies. Brain 2002; 125(Pt 12):2591-2625. 131. Davie CA, Barker GJ, Webb S, et al: Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 1995; 118(Pt 6):1583-1592. 132. De Stefano N, Matthews PM, Fu L, et al: Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998; 121:1469-1477. 133. Losseff NA, Webb SL, O’Riordan JI, et al: Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 1996; 119(Pt 3):701-708. 134. Matthews PM, De Stefano N, Narayanan S, et al: Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Semin Neurol 1998; 18:327-336. 135. Stevenson VL, Leary SM, Losseff NA, et al: Spinal cord atrophy and disability in MS: a longitudinal study. Neurology 1998; 51:234-238. 136. Truyen L, Van Waesberghe JHTM, Van Walderveen MAA, et al: Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996; 47:1469-1476. 137. Bjartmar C, Trapp BD: Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 2001; 14:271-278. 138. Ferguson B, Matyszak MK, Esiri MM, et al: Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120(Pt 3):393399. 139. Bjartmar C, Kidd G, Mork S, et al: Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 2000; 48:893-901. 140. Smith KJ, Kapoor R, Hall SM, et al: Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001; 49:470-476. 141. Lovas G, Szilagyi N, Majtenyi K, et al: Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 2000; 123:308-317. 142. McGavern DB, Murray PD, Rivera-Quinones C, et al: Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain 2000; 123:519-531.

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143. Bechtold DA, Smith KJ: Sodium-mediated axonal degeneration in inflammatory demyelinating disease. J Neurol Sci 2005; 233:27-35. 144. Stys PK: White matter injury mechanisms. Curr Mol Med 2004; 4:113-130. 145. Kornek B, Storch MK, Bauer J, et al: Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 2001; 124(Pt 6):1114-1124. 145a. Dutta R, McDonough J, Yin X, et al: Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006; 59:478-489. 146. Lo AC, Black JA, Waxman SG: Neuroprotection of axons with phenytoin in experimental allergic encephalomyelitis. Neuroreport 2002; 13:1909-1912. 147. Bechtold DA, Kapoor R, Smith KJ: Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 2004; 55:607-616. 148. Bechtold DA, Yue X, Evans RM, et al: Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide. Brain 2005; 128(Pt 1):18-28. 149. Kapoor R, Davies M, Blaker PA, et al: Blockers of sodium and calcium entry protect axons from nitric oxide–mediated degeneration. Ann Neurol 2003; 53:174-180. 150. Smith KJ, Blaker PA, Kapoor R, et al: Protection of axons from degeneration resulting from exposure to nitric oxide. J Neurol Neurosurg Psychiatry 2001; 70:282. 151. Piani D, Frei K, Do KQ, et al: Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 1991; 133:159-162. 152. Pitt D, Werner P, Raine CS: Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000; 6:67-70. 153. Smith T, Groom A, Zhu B, et al: Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 2000; 6:62-66. 154. Jung S, Zielasek J, Kollner G, et al: Preventive but not therapeutic application of rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol 1996; 68:1-11. 155. Martinez I, Puerta C, Redondo C, et al: Type IV phosphodiesterase inhibition in experimental allergic encephalomyelitis of Lewis rats: sequential gene expression analysis of cytokines, adhesion molecules and the inducible nitric oxide synthase. J Neurol Sci 1999; 164:13-23. 156. Baker D, Pryce G: The therapeutic potential of cannabis in multiple sclerosis. Expert Opin Investig Drugs 2003; 12:561567. 157. Kidd D, Barkhof F, McConnell R, et al: Cortical lesions in multiple sclerosis. Brain 1999; 122:17-26. 158. Peterson JW, Bo L, Mork S, et al: Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50:389-400. 159. Cifelli A, Matthews PM: Cerebral plasticity in multiple sclerosis: insights from fMRI. Mult Scler 2002; 8:193-199. 160. Dalton CM, Chard DT, Davies GR, et al: Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 2004; 127:1101-1107. 161. Chard DT, Griffin CM, McLean MA, et al: Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 2002; 125:2342-2352. 162. Chard DT, Griffin CM, Parker GJ, et al: Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain 2002; 125:327-337. 163. De Stefano N, Matthews PM, Filippi M, et al: Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurol 2003; 60:1157-1162.

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76

CLINICAL SPECTRUM: DEFINITION AND NATURAL PROGRESSION ●

●

●

●

Rajas Deshpande, Marcelo Kremenchutzky, and George P. A. Rice

Once a neurological illness common in the Western and developed world, multiple sclerosis (MS) is now being increasingly reported from most parts of the world, including tropical countries. Marked by ambulatory disabilities caused at a relatively early age, MS is complicated by unpredictability of attacks and progression. We discuss the definition, clinical features, and natural progression of MS in this chapter. The major inputs for natural progression in this chapter are courtesy of the natural history database at the London Multiple Sclerosis Clinic, London Health Sciences Center, University of Western Ontario, London Ontario, Canada, with over 26,000 patient-years of studies.

DEFINITION MS is a disease characterized by demyelination in the central nervous system at different loci and at different times and axonal degeneration either primarily or secondary to demyelination.

CLINICAL PHENOTYPES OF MULTIPLE SCLEROSIS There are no specific clinical or paraclinical markers for MS. Among the many classifications that have been proposed, we chose for the purpose of this chapter the phenomenological classification initially suggested by McAlpine,1 later reviewed by an international survey,2 although there was no unanimity of opinion: Relapsing remitting MS Secondary progressive MS Primary progressive MS The following phenotypes represent circumstantial variations in the clinical presentation of phenotypes mentioned above: Acute malignant MS Benign MS Childhood MS Spinal/progressive spinal MS Opticospinal MS or neuromyelitis optica Cerebral MS Chronic cerebellar MS

The terms relapsing progressive or progressive relapsing are self-explanatory, but are unnecessary additions to the phenotypes, and hence are best avoided.3-5 Relapsing remitting MS (RRMS) is the most common initial clinical phenotype, accounting for up to about 85% of the total MS population at the onset of the disease. RRMS is characterized by episodes of acute or subacute onset of neurological dysfunction (referred to as a relapse, attack, flare-up, or exacerbation), which last for more than 24 hours, usually resolve within weeks, and remit to complete or partial recovery. Following a period of this “relapsing-remitting” course, the majority of these patients (over 80% in 25 years) gradually develop progressive worsening, evolving into the secondary progressive MS (SPMS) category. An acute attack or exacerbation or relapse, as defined by Schumacher and colleagues,6 is a focal disturbance of function, affecting a white matter tract, and lasting for more than 24 hours. Typically, an acute exacerbation tends to progress over a period of a few days, reaching a maximum in less than 1 week, and then slowly resolving. Complete recovery from an attack is common early in the disease. The mean annual frequency of relapses has been shown to be between 0.4 and 1.1 relapses per patient per year.7-12 The average attack rate in the first year was found to be 1.5 to 2.3 relapses per patient per year, falling with age and duration13 of disease. The relapse frequency starts to decrease by the second year of the disease.14 The interval between two relapses can be a minimum of 1 month (as defined by Schumacher6) to more than 35 years. A typical relapse lasts for about 6 weeks. Recovery starts by the second week in most patients. The earlier a relapse starts to recover, the better is the total recovery.14 A pseudo-relapse is acute-onset worsening of preexisting symptoms or signs or reappearance of symptoms or signs in the same location as a prior attack, with lesser or equal severity. The usual causes are physiological, primarily fever, urinary tract infection, or vaccination. Table 76–1 compares true and pseudo-relapses. Relapses and their associations or precipitating factors have been studied by many. Relapses have been claimed15 but unproved to be more common in warmer months. Large studies have not documented significant reduction in the relapse rates during pregnancy, but the overall relapse rate is higher in the first 6 months postpartum, especially during

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T A B L E 76–1. True Relapses Versus Pseudo-relapses Parameter

True Relapses

Pseudo-relapses

Onset Duration Previous deficit Fever associated

Acute/subacute Weeks likely Not necessary Not likely

Acute more likely Days rather than weeks Likely Usually

Courtesy of Paty DW, Ebers GC: Multiple Sclerosis. Contemporary Neurology Series (50). Philadelphia: FA Davis, 1997.

the first 3 months.16-21 Relapse rates are not influenced by breastfeeding.19 In some instances, relapses have been associated temporally with immunization.22 Large studies failed to confirm increased relapse risk after immunization in the MS population.23 However, in clinical practice, postimmunization relapses have been documented. On the other hand, infections have been found in most studies to be temporally associated with increased relapse rates in the postinfectious phase,24-26 and it is a common observation that MS patients present typically 3 to 4 weeks after an infection, with a true or pseudo-relapse. Relapse rates were not increased postsurgically or postanesthesia in most studies.27,28 Stress and life adversities have been claimed to be associated with increased relapse risk, but this is difficult to assess objectively.29-31 There are no data to support the notion that physical trauma can precipitate relapses or “unmask” dormant MS that otherwise would have remained silent.15,27,28,32 A small number of patients complain of deterioration in functional capacity in the luteal phase of the menstrual cycle. Slight temperature elevation during this phase may be responsible,33 and tiredness and fatigue may worsen preexisting deficits. Following a period of this “relapsing-remitting” course, the majority of these patients (over 80% in 25 years) relentlessly develop gradual worsening with progressive accumulation of disability. Accordingly, these patients, formerly in the RRMS category, merge to conform the SPMS category. Primary progressive MS (PPMS) is characterized by a subacute or chronic onset of unremitting neurological dysfunction with gradual worsening (i.e., progression) over years, with cumulative fixed disability and hardly any reversal of acquired neurological dysfunction. Overlapping exacerbations may occur in PPMS at any time in the early years or even decades after clinical onset, but tend to be uncommon. Although the above categories encompass most clinical presentations of MS, individual variations are very common. There may be attacks in PPMS, and sometimes SPMS may begin after one single attack, labeled single attack progressive MS.34 There may be relapses with very little recovery, accumulating rapid neurological disability. It is also not uncommon to encounter patients who have had one or two relapses followed by a disease silence and minimal or no disability for many years. Benign MS: This subcategory of RRMS tends to be common in women with a younger age of onset who had sensory symptoms as the presenting feature. An Expanded Disability Scale Score (EDSS) score of less than 3 for more than 10 years of MS diagnosis was considered as benign in a study by Redekop and Paty,35 and they found 24% of the 536 patients studied in British

Columbia belonged to this category. Freedom from either attacks or progression for decades can be considered to be typical of benign MS. It is most easily recognized in hindsight. Acute malignant MS:14 Some patients often have a polysymptomatic onset and progress rapidly to severe disability, death, or both within months (very rare) or a few years (uncommon). Even this most malignant clinical course cannot be reliably predicted at onset. The distinction between acute malignant MS and acute disseminated encephalomyelitis can be difficult. New lesions manifest clinically or on MRI and progression beyond 2 months are features more consistent with a diagnosis of MS than acute disseminated encephalomyelitis. In addition, in the adult, acute disseminated encephalomyelitis is much less common than MS, so that most patients with the acute malignant progression will turn out to have MS. Opticospinal MS (Devic’s disease, neuromyelitis optica):14 Reported very frequently from the orient, opticospinal MS predominantly involves attacks and progressive worsening in the optic and spinal systems. This variant is characterized by an earlier age of onset, early progression, minimal or no recovery of neurodeficit after an attack, and poor prognosis. Pure motor, motor–cerebellar, motor–sensory, or combinations therein are seen as clinical presentation, with unilateral or bilateral optic neuritis or even gradual deterioration of vision. This variant is often debated to be a separate disease entity unrelated to MS. Lennon and associates36 from the Mayo Clinic, Rochester, Minnesota, studied 102 North American and 12 Japanese patients with neuromyelitis optica against controls, including MS, optic neuritis, myelopathies, and other conditions, for the presence of neuromyelitis optica IgG antibodies. They claim that this is a specific marker autoantibody for neuromyelitis optica, distinguishing the latter from MS. Based on the prevalence of this marker, the group also comments that Asian opticospinal MS is the same entity as neuromyelitis optica. Progressive and chronic cerebellar MS have both been believed to be variants of PPMS. Progressive spinal MS: This is commoner in older men and is characterized by either pure motor or motor and sensory deficits. It usually typifies itself as Laboratory-Supported Definite MS (LSDMS), as it is difficult to document dissemination clinically. Chronic cerebellar MS: This presentation is most disabling in MS, especially if truncal ataxia accompanies it. These patients have a poor prognosis. There may be wide, sometimes self-injurious tremors, or violent shakes of the whole body, which makes it difficult to take care of such a patient in nursing homes or even hospitals. Cerebral MS: Some of the patients develop predominantly cerebral lesions, which clinically manifest as dementia, personality changes, impaired judgment, and/or amnesic states. These may be early symptoms and have a severe impact on a person’s work environment and hence should be actively dealt with. Childhood MS is rare (less than 4% of cases). Youngest cases reported include 10-month-old, 24-month-old, and 4-year-old children. This variant is further more frequent in females (3 : 1). Vertigo is a frequent presenting feature. Most patients will have a remitting sensory onset. Deterioration is slower, and the youngest patients have the best prognosis for disability. About 82% of childhood MS patients have positive oligoclonal banding in the cerebrospinal fluid. In an excellent review of childhood

chapter 76 clinical spectrum: definition and natural progression T A B L E 76–2. Common Presenting Multiple Sclerosis Symptoms Sensory deficits in limbs Visual loss (usually unilateral optic neuritis) Motor, slowly developing Diplopia Gait disturbance Motor, acute-onset deficits Sensory symptoms in the face Balance problems Vertigo Lhermitte’s symptom Bladder symptoms Acute transverse or diffuse myelopathy Limb ataxia Pain Other nonspecific symptoms, mostly sensory Polysymptomatic onset

MS, Banwell37 writes that the onset of progression in MS beginning before the age of 16 years is later as compared to adultonset MS, by an average of 15 years.

CLINICAL FEATURES OF MULTIPLE SCLEROSIS The common presenting symptoms in MS are summarized in Table 76–2.

Consciousness and Cognition Although uncommon, acute major brainstem relapse or acute widespread cerebral demyelination has been associated with stupor or coma. This usually keeps the company of severe neurological deficits like paraparesis, quadriparesis, or brainstem abnormalities. The rarity of depressed consciousness as a presentation demands a thorough search for other etiologies. Cognitive and psychiatric changes in MS have traditionally been underemphasized. Studies have demonstrated that minor deficits in cognition are quite common (up to 70%), even in early MS (up to 50%).38-40 Dementia can be an accompaniment of severe disabling MS of long-term duration. Lesions seen in the corpus callosum on the MRI scan are also well correlated with cognitive defects. Periventricular lesions and the width of the third ventricle are described to be the most frequent MRI correlates with cognitive deficits.41 Euphoria is commonly a manifestation of subtle or obvious cognitive change.42 Focal cortical deficits such as aphasia, apraxia, and agnosias have been reported uncommonly. The most frequent cognitive abnormalities in MS are subtle defects in abstraction and memory,43-46 attention, and word finding.47 These are usually associated with emotional lability and decreased speed of information processing.45,46 Traditional tests for dementia designed for use in neuronal degenerative diseases such as Alzheimer’s disease are not sensitive to the changes seen in MS.47 The most sensitive bedside measures for cognitive defects in MS have been tests such as the repetition of seven numbers forward or backward, serial 7s or 3s, and visual recognition tests.48,49 Verbal working memory is specially susceptible to impairment in MS.50 Mood disorders are frequent in patients with MS. An association may exist between MS and bipolar disorder.51-53 A survey

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in the University of British Columbia Multiple Sclerosis clinic shows that 38% of patients with MS have been depressed or could have bipolar disorder.52 Other forms of psychosis are rare but can be seen. Some patients develop hypomanic behavior with steroid therapy, commonly used to treat relapses.

Sleep Disturbances Studies have shown that patients with MS are more likely than control subjects to have sleep disturbances.54 The sleep problems may be due to nocturnal spasms. They may also be a major contributor to fatigue that is so common in MS. Overall, patients with MS have poor sleep efficiency with frequent awakening. Periodic leg movements are also frequent and may contribute to the sleep disturbances.55 Incontinence and other bladder symptoms like nocturia may further deteriorate sleep quality and duration. Narcotic symptoms are common.56

Fatigue Fatigue, a frequent and disabling feature of MS,57,58 is considered a state of exhaustion distinct from depressed mood or physical weakness.59 It could be one of two types: 1. Fatigability: A single muscle or group of muscles becomes weaker after repetitive use and recovers after rest. This type of muscle fatigue resembles that of myasthenia gravis. It is like Uhthoff’s phenomenon, which occurs with increased body temperature. 2. Lassitude: This is a persistent sense of tiredness. Sleep usually helps, but extensive sleep may also not restore wellbeing. It may occur without any neurological change but with new large MRI lesions. This is one of the most challenging symptoms to both evaluate and treat in MS patients. Fatigue may or may not accompany an attack. It may also be a transient phenomenon, with sudden appearance, often “knocking down” the patient mid-day. Severe fatigue appearing de novo and persisting beyond 24 hours could be considered as an attack and may improve with steroids.

Seizures Convulsive seizures occur in about 2% of MS patients. One half of the seizures are probably due to the MS lesion itself, and the other one half are due to chance association. Seizures in MS are usually easily controlled with anticonvulsants. Patients with seizures tend to have more subcortical or temporal lobe lesions or both than do control MS patients without seizures.60

Headache Headache is a frequent complaint in MS.61 Occasionally, acute headache occurs in the pseudotumor, acute-onset type of relapse. One type of headache seen sometimes in MS is hemicranial and may be associated with an acute pontine lesion.62 Most patients with MS who have headache probably have tension headache due to muscle spasm in the neck and the scalp muscles or have migraine or are depressed.14 Pain on eye

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movement due to optic neuritis may also be responsible for headache.63

RIGHT

LEFT

Cranial Nerve Involvement in Multiple Sclerosis AMBIENT LIGHT: Equal pupils

Pupillary Defects Most of these defects are related to the afferent pupillary defect (or Marcus Gunn pupil) (Fig. 76–1). Fixed dilated pupils associated with or independent of other elements of a third nerve palsy are extremely rare. Central Horner’s syndrome is occasionally seen.64

RT. EYE ILLUMINATION: Modest bilateral constriction

Loss of Vision Acute loss of vision due to optic neuritis is a common feature of MS and is mostly unilateral. This is also a common clinical presenting feature. About 50% to 70% patients with optic neuritis proceed to develop MS in future; Table 76–3 shows major trials documenting this. Optic neuritis may be retrobulbar, chiasmal, or even retrochiasmal. Many patients recover functionally normal vision after optic neuritis, even in the face of severe residual optic atrophy.78,79 Visual field deficits in MS tend to be central, but occasionally a clinician can encounter paracentral or peripheral scotomata or quadrantanopic or hemianopic defects. Homonymous hemianopias can occur in MS but are unusual; when seen, they should raise the possibility of coexistent tumor or vascular disease. Fortunately, legal blindness in MS is unusual (less than 5%).80 Many patients experience a dimming, blurring, or obscuring of vision associated with exercise and heat. Uhthoff first described this symptom.81 The transient appearance or worsening of neurodeficits (most typically, visual impairment, but any functional system can be involved) on exposure to any form of heat (atmospheric, hot shower, exercise, fever, or even hot food or drinks) is known as Uhthoff’s phenomenon, and is a very common accompaniment to relapses. Pain is usually seen as an accompaniment to acute optic neuritis82 and may be due to traction of the origins of the superior and medial recti on the optic nerve sheath. Besides the blurring

LT. EYE ILLUMINATION: Brisk, more extensive bilateral constriction

RT. EYE ILLUMINATION: Bilateral dilatation

LT. EYE ILLUMINATION: Brisk, more extensive constriction (consensual in the right eye) ■

Figure 76–1. Afferent pupillary defect (Marcus Gunn pupil).

T A B L E 76–3. Risk of Multiple Sclerosis in Follow-up Studies of Patients With Isolated Optic Neuritis Year

Senior Author

1974 1978 1979 1983 1986 1987 1988 1989 1990 1991 1993 1994 2003

Nikoskelainen65 Compston66 Landy67 Kinnunen68 Hely69 Francis70 Riikonen71 Sanders72 Sandberg-Wollheim73 Scholl74 Morrissey76 Rodriguez156 ONTT77

No. of Patients With Optic Neuritis

Duration of Follow-up (yr)

No. (%) Who Developed Multiple Sclerosis

116 146 105 296 82 101 14 48 86 81 44 156 388

10 4 9 9 4.7 11.6 4.6 0.5–3.5 13 3.5 5 14.4 12

58 (50) 58 (40) 58 (55) 56 (19) 26 (32) 58 (57) 7 (50) 29 (60) 33 (38) 35 (43) 24 (55) 64% after 40-year follow-up. 40%

Modified from Paty DW, Ebers GC: Multiple Sclerosis. Contemporary Neurology Series (50). Philadelphia: FA Davis, 1997.

chapter 76 clinical spectrum: definition and natural progression of vision and central scotoma, relative afferent pupillary defect (RAPD), color blindness, and sometimes Pulfrich phenomenon are clinical signs found in most MS patients. The Pulfrich phenomenon83 is a subjective correlate of conduction delay in one optic nerve. A pendulum oscillating in front of a normal individual will appear to traverse an ellipse if a neutral density filter or a piece of dark glass is placed over one eye. A patient with unilateral optic neuritis may see this illusion without a filter: the disease delays conduction just as does the filter. Anosmia may be found on examination in many MS patients,84 although this may not be voluntarily reported by the patient. Unilateral or bilateral loss of taste is infrequent. Paty and Ebers have observed this in several patients, and this was the presenting complaint in one patient. This symptom always remitted,14 in their observation.

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I.N.O. (RT.) RIGHT EYE

LEFT EYE

Primary gaze

(No adduction)

Left gaze (Abduction + nystagmus)

Right gaze Normal

Normal

Ocular Motility Disorders in Multiple Sclerosis The most common in this group is nystagmus.85-88 The frequency of occurrence of nystagmus in MS has been reported to be between 28.3% and 63%. Nystagmus in MS may be acquired pendular, gaze evoked, rebound, torsional, periodic alternating, or another type. Optokinetic nystagmus is never impaired in isolation.14 The most common is the nystagmus that accompanies internuclear ophthalmoplegias. In many MS patients, inappropriate initiation of saccadic eye movements during fixation or change in gaze position results in saccadic intrusions (square wave jerks, saccadic pulse, and double saccadic pulses) and saccadic oscillations (macro-square wave jerks, macrosaccadic oscillations, and ocular flutter).89 A square wave jerk consists of a small amplitude conjugate saccade away from fixation followed by a saccade back to fixation after a latency delay of about 200 milliseconds. One of the most common ocular paresis in MS is sixth cranial nerve paresis. This may even be a presenting feature and mostly resolves completely. Oculomotor nerve pareses are uncommon presentations of MS but are known, and Paty and Ebers14 reported it as an initial presentation in two cases. Paresis of fourth cranial nerve as an isolated feature is rare.14 Another common abnormality of eye movements in MS is internuclear ophthalmoplegia, bilateral (most frequent) or unilateral.14 Internuclear ophthalmoplegia manifests as partial or complete paresis of adduction on the side of lesion, with ataxic nystagmus in the other (abducting) eye (Fig. 76–2). Skew deviation and vertical nystagmus (upbeat on gaze up or downbeat on gaze down) may also occur. Bilateral internuclear ophthalmoplegias are associated with vertical nystagmus in one or both directions. One-and-a-half syndrome (Fig. 76–3) and wall eyed bilateral internuclear ophthalmoplegia (Fig. 76–4) have been reported often in the MS literature. Lateral gaze pareses are also a common manifestation of MS. Visual suppression of the vestibulo-ocular reflex is often abnormal.

Trigeminal Motor and Sensory Symptoms Facial sensory loss can occur in as many as 10% of MS patients.14 This can be a presenting feature as in a relapse or a lingering transient symptom. Trismus has also been reported.90 Trigeminal neuralgia is discussed later in the section on pain.

Convergence normal in posterior type L

R III

III

Lesion

Lesion in the right M.L.F. Note right eye adduction paresis on left gaze.

MLF

■

P P R F

P P R F

VI

VI

Figure 76–2. Internuclear ophthalmoplegia.

Facial Palsy The acute development of a peripheral facial nerve paresis is an uncommon but recognized feature of MS.14 It occurs in less than 4% of patients and almost always recovers spontaneously and completely. Recovery from an MS-associated facial palsy is usually not associated with autonomic abnormalities such as crocodile tears; however, aberrant reinnervation, myokymia, and the phenomenon of intrafacial synkinesis are all commonly seen. Acute facial palsies are accompanied by other brainstem findings such as a sixth nerve palsy, lateral gaze palsy, or deafness. Paty and Ebers have seen one case with remitting bilateral facial myokymia that was disabling because the patient could not open his eyes. The symptom responded to carbamazepine therapy.

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Acute 11/2 syndrome RIGHT EYE

Dysphagia

LEFT EYE

Mild dysphagia is common.14 It usually coexists with dysarthria, often in the setting of pseudobulbar palsy. Dysphagia is usually due to desynchronization of the swallowing mechanism.

Primary gaze

Dysarthria Cerebellar dysarthria is a common component of relapses but is usually late to occur in the progressive phase.14 There is intention tremor of the voice, which can be demonstrated by having the patient sustain a vowel sound for 10 to 15 seconds. The variation in the intensity and sometimes pitch of the sound is easily heard; the frequency is usually 5 to 7 Hz, similar to other cerebellar tremors. Patients may show elements of combined cerebellar and pseudobulbar (spastic) dysarthria. Some patients have only spastic speech. Pseudobulbar dysarthria is caused by spastic vocal cords, which result in a high-pitch, lowvolume speech, in which consonants are slurred. These patients do not have the oscillating tremor or the explosive variability associated with cerebellar speech. Some patients with MS develop dysarthria after several minutes of sustained speech. This effort-induced symptom tends to recover after a few minutes of rest.

Left gaze

Right gaze L

R III

III

MLF

P P R F

P P R F

VI

VI

Breathing Disturbance Lesion

Rarely, MS patients have a peculiar air hunger, usually associated with severe fatigue. Serious respiratory problems other than pneumonia and bronchitis are uncommon. Howard and colleagues92 described 19 patients who developed respiratory complications an average of 5.9 years after onset. Of these, 12 required mechanical ventilatory support, and 5 recovered. Six patients died after an average of 17.7 months.

Motor and Sensory Findings ■

Figure 76-3. One-and-a-half syndrome.

Deafness Central lesions resulting in impaired hearing commonly occur, but persistent complete deafness is unusual in the absence of another etiology.91

Vertigo This is a relatively common symptom. As many as 50% of patients have intermittent episodes of vertigo. In a review of initial symptoms in MS by Paty and Ebers,14 it was found that onset with vertigo as a symptom favored a long-term, more benign outcome.

Primary gaze ■

Figure 76–4. Wall eyed bilateral internuclear ophthalmoplegia.

Sensory loss is the most frequent of all neurological findings in MS.14 It is present in 90% of patients at some time during the clinical course. The distribution of sensory loss between upper and lower extremities can vary. Isolated transient facial numbness is frequently seen. Unremitting unilateral facial numbness is more likely due to isolated trigeminal neuropathy. It is also unusual for a sensory segmental level of pain or temperature loss to persist, even in advanced cases. However, during acute exacerbations, a sensory level can be seen in 10% to 15% of patients. When persistent abnormalities in touch, pain, and temperature sensation do occur, the pattern of loss is likely to be a patchy one. In contrast, posterior column or discriminatory sensation testing can be very useful. From 85% to 95% of patients with MS have an abnormality in posterior column sensation at some time during their clinical course. The sensation loss is often prominent in the lower extremities, but bilateral predominant upper extremity impairment is common. The useless hand syndrome (Table 76–4) is a particularly interesting sensory manifestation that is usually seen in patients with predominant upper extremity proprioceptive loss.93 Even though the useless hand syndrome can occur in other disorders, it is highly characteristic of MS. It is common to see young adults with MS develop lack of discriminatory sensation in one upper extremity to the extent that the extremity

chapter 76 clinical spectrum: definition and natural progression T A B L E 76–4. Useless Hand Syndrome Characteristics

T A B L E 76–5. Types of Pain in Multiple Sclerosis

Loss of dexterity presenting symptom Vibration and proprioception loss usually profound Usually unilateral but can be bilateral Acute in onset (80%) Strength usually normal (must be examined with visual control of movement) Cerebellar function usually normal (again, with eyes open) Usually recovers completely

Paroxysmal or phasic pain Trigeminal neuralgia Radicular Pelvic Itchiness Painful tonic spasms Pain on eye movement Chronic neurogenic pain Dysesthetic leg pain Radicular Phantom limb

becomes functionally useless despite normal crude sensation, motor, and cerebellar function. The useless hand syndrome in MS usually resolves spontaneously, although it can be extremely disabling while present. It usually begins with either tingling or lack of fine sensory discrimination in the fingers. The patient notices an inability to recognize objects in the pocket or purse. The patient can then develop impairment of hand function because of the inability to distinguish various subtleties in tactile sensation and lack of feedback control of movement. The useless hand syndrome is typically accompanied by pseudo-athetosis, a situation in which the hand cannot be maintained in a steady position with the eyes closed. The lack of proprioceptive sense, even to a subtle degree, results in or exacerbates spontaneous movement of the hands when visual feedback is removed.

Lhermitte’s Symptom This is the occurrence of tingling and “electric current–like” sensation in the arms, down the back, into the legs, or in all the three areas, associated with forward flexion of the neck.14,94,95 This symptom occurs in 3% of patients at the onset of the disease and probably occurs in 30% to 40% of patients overall at some time during the clinical course. It is most frequently associated with MS, although it is not specific to this disease. Symptoms are usually precipitated by forward flexion of the neck but can also be brought on by forward flexion of the spine or even other minor movements. This symptom may sometimes occur spontaneously. In unusual circumstances, Lhermitte’s symptom can be disabling in the absence of other significant neurological deficits, usually because of its frequency, duration, or intensity. Such disabling symptoms usually respond somewhat to gabapentin, carbamazepine, or benzodiazepine therapy.

Paroxysmal Symptoms Many patients have brief symptoms of a paroxysmal nature. Transient symptoms such as hemiparesis, positive or negative sensory phenomena, or dysarthria are not well recognized by non-neurologists as features of MS. Other paroxysmal symptoms in MS include ataxias, vertigo, painful and disturbing paresthesias, dysesthesias, monocular blurring or blindness, pain, and weakness. Paroxysmal motor phenomena include not only weakness but also spasticity and spasms, tonic seizures, akinesia, diplopia, dysarthria, and chorea in addition to focal and generalized seizures.96,97 Paroxysmal symptoms in MS characteristically have an abrupt onset, short duration, and a tendency to stop sponta-

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neously. They can recur up to 50 times per day or more. In some patients, paroxysmal symptoms can be very frightening, disabling, or both. Disabling paroxysmal symptoms usually involve an overwhelming sensation of tingling, numbness, or generalized weakness. The episode can climax in a brief period of akinesia. Fortunately, paroxysmal symptoms in MS respond well to benzodiazepines or anticonvulsants. As they tend to be self-limited, prolonged therapy is usually unnecessary. The best known of these paroxysmal disturbances is the painful tonic spasm. This is usually manifested by tonic flexion or extension of a limb with a writhing movement reminiscent of paroxysmal athetosis.98 The muscular tension in the limb is so high that it becomes quite painful. A particularly difficult situation can be due to the paroxysmal loss of neurological function, as in paroxysmal monoparesis or hemiparesis or paroxysmal blindness. Paroxysmal itching has also been described.99

Pain in Multiple Sclerosis There are two major categories of pain (Table 76–5): paroxysmal (such as trigeminal neuralgia) and chronic.14,100 Less than one half of the patients have musculoskeletal pain of various types. It makes sense that patients with weak muscles and poor support of the spine would have such pains (e.g., low backache, neckache, joint pains). Pain can be seen at the onset of MS.101 Pain as a chronic symptom is more frequently seen in patients with MS of longer duration and is usually associated with spasticity. The most common form of this neurogenic pain is usually described as “persistent extremity pain.” The pain is usually greatest in the lower extremities, although occasionally a painful radicular syndrome in the upper extremity can be present. Pain of trigeminal neuralgia has been well discussed in MS. The trigeminal neuralgia features in MS are essentially the same as in idiopathic trigeminal neuralgia.100 Interestingly, trigeminal neuralgia in MS is more frequently bilateral (32%) than idiopathic trigeminal neuralgia (4%).14

Weakness and Spasticity Weakness in MS is usually pyramidal in distribution but can be remarkably focal.14 For example, marked interosseous weakness can occur with preservation of thenar muscle strength. The weakness is usually more distal than proximal. Foot drop may be seen in the presence of normal proximal strength.

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Spasticity is one of the more frequent features encountered in MS. As many as 90% of patients will develop some signs of spasticity during the clinical course. In some patients with severely weak legs, spasticity is actually useful for walking or standing. Weak legs may be able to support considerable weight because of involuntary contraction of the antigravity muscles; attempts to treat spasticity may be counterproductive in such patients. Occasional patients have a syndrome of severe increase in muscle tone with a paradoxical reduction in deep tendon reflexes. This is due to a combination of extrapyramidal and pyramidal lesions.

Cerebellar Features in Multiple Sclerosis As mentioned earlier, cerebellar involvement may produce one of the most disabling forms of the disease.14 Cerebellar intention tremor is usually related to lesions in the cerebellar outflow pathways. Cerebellar manifestations include intention tremor, titubation, gait ataxia, and dysarthria. Action tremor may be superimposed on intention tremor. The intention tremor may be severe enough to appear even with an intention to move, thus manifesting practically at rest. The characteristic tremor in MS is the oscillating tremor at 5 to 7 Hz perpendicular to the direction of the movement. Besides this, clumsiness, dyssynergia, and dysmetria are present.

Basal Ganglionic Features Basal ganglionic features are very rare and late to appear, if at all, in MS. Tremor is the most common symptom, although hypokinesia, dyskinesias, dystonias, and speech abnormalities may occur. Rigidity is uncommon.

Amyotrophy (Muscle Wasting) in Multiple Sclerosis Amyotrophy is considered an uncommon clinical finding in MS.103 However, autopsy studies have shown that it is quite common. The three most common causes described are: 1. Disuse occurs due to corticospinal or basal ganglionic involvement. 2. Pressure palsies occur due to posture in weak or wheelchairbound patients. Bilateral ulnar palsies are common. Patients with paraplegia or distal hand weakness commonly use elbows to turn in bed or to transfer. 3. Syringomyelia has often been reported in MS patients,104,105 and this contributes to the third cause. Also, MS lesions may involve the lower motor neuron pathways in the spinal cord. This phenomenon explains the amyotrophic lateral sclerosis–like syndromes in MS patients. Very few cases of MS and amyotrophic lateral sclerosis (some with even Parkinson’s disease) have been reported. Gray matter plaques, now being increasingly recognized in MS, may also explain myoatrophy.

Peripheral Neuropathy This is very uncommon, and many researchers have described subtle electrophysiological findings suggesting peripheral

neuropathy in MS patients.106-109 Chance occurrences of clinical peripheral neuropathy and acute and chronic inflammatory demyelinating polyradiculoneuropathy have been described.

Autonomic Disturbances in Multiple Sclerosis Nearly 3% of patients of MS present with isolated bladder symptoms.110 Urgency, frequency, and hesitancy are the most common features. Different combinations of detrusor-sphincteric dyssynergia manifestations are seen. Urinary tract infections worsen the symptoms significantly and are a great concern in MS patients with bladder problems. Incontinence is also common. Forty-three percent of MS patients have been shown to have constipation.111 Fecal incontinence occurred at least once in 51% of patients and once per week or more frequently in about 25% of patients. The overall prevalence of bowel dysfunction was 68%. In a small number of patients, malabsorption,112 incontinence, and frequent diarrheal episodes113 are also reported. Sexual dysfunction is another major concern in MS and can also be a presenting symptom.114-118 There is a high degree of correlation between sexual dysfunction and urinary dysfunction in MS. The reported prevalence is 80% in males and 33% in females.119 Male sexual dysfunction in MS is usually organic, but psychosocial factors are important, too. Female patients may have decreased arousal, decreased libido, lesser frequency of orgasm, fatigue, and decreased sensation.120 Males complain of erectile dysfunction, decreased sensation, fatigue, decreased libido, and orgasmic dysfunction. The prognosis of neurogenic erectile dysfunction is poor. Other treatable causes should always be excluded.

Nonsphincteric Autonomic Problems These can be quite troublesome in some patients. Postural hypotension is common. A cyanotic hue or bluish-red mottling in paretic limbs, especially legs, with some edema may also be commonly seen. Other less common symptoms in this category include hypothermia, paroxysmal atrial fibrillation,121-123 orthostatic hypotension,124 exercise-induced tachycardia, and breathlessness.125 These symptoms are believed to be contributed by lesions in the ascending autonomic pathways in the brainstem or spinal cord.126 Yokota and colleagues127 reported abnormal sympathetic skin responses in 75% of MS patients studied. Chronic hypothermia is sometimes seen.128 Paty and Ebers14 described six cases, some of which were severe enough to produce obtundation or coma. It may be precipitated by urinary or other infection. Patients usually respond to warming measures and antibiotics. Hypothalamic MRI lesions may be seen. Electrolyte disturbances and syndrome of inappropriate antidiuretic hormone secretion have also been reported. As MS can affect white matter anywhere in the brain and spine, many unusual presentations are possible and have been reported in the literature (Table 76–6).

chapter 76 clinical spectrum: definition and natural progression

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T A B L E 76–6. Unusual (but Not Rare) Presentations of Multiple Sclerosis

T A B L E 76–7. Baseline Annual Relapse Rates Reported in Different Multiple Sclerosis Studies

Pain Paroxysmal symptoms Visual loss Generalized sensory disturbances Positive motor phenomena Weakness Brainstem dysfunction: dysarthria, diplopia, trigeminal neuralgia, etc. Dementia and affective disorders Fatigue Others (movement disorders, seizures, aphasia, hemianopsia, autonomic disturbance)

Year

Natural Progression Relapsing-Remitting Multiple Sclerosis In the RRMS category, the mean age at symptomatic onset is 29 years, with the majority of patients in the age group between 20 and 39 years. This compares well with reports from other researchers such as the Lyon, France, group, where the mean age at onset was 31 years (SD, 10 years; range, 5 to 67 years).129,130 In a study at the Mayo Clinic, the median age at onset was reported to be 37.2 years (range, 16.7 to 65.3 years) for men, 35.4 years (range, 17.3 to 59.6 years) for women, and 36.2 years (range, 16.7 to 65.3 years) overall.131 In approximately 10% to 15% of our patients, onset is before the age of 20 (mostly in their late teens, although pediatric MS is more often recognized), whereas about 5% of patients have MS onset after the age of 49 years. A selective gender predilection is commonly seen in MS, as it is often reported in other autoimmune conditions. The maleto-female ratio is 1 : 2, and there is a much more conspicuous female preponderance among younger RRMS patients compared with persons with older progressive MS cases. In a study from the Mayo Clinic, newly diagnosed MS cases over a period of 15 years from 1985 through 2000 included 38 men and 94 women, with the male-to-female ratio being 1 : 2.4.131 Another study from Lyon, France, reported a male-to-female ratio of 1 : 1.7.129,130 The attack rate in the early years of MS is an important predictor of long-term outcome. In London, Ontario studies, the mean annual attack rate in the first year after onset was 1.5 in the total population. However, attack rates vary greatly in different studies, particularly when patients are specifically selected (e.g., for participation in clinical trials) or represent selected subgroups (e.g., hospitalized, and so on). Several studies serve to illustrate such variation. Of course, the relapse rates reported differ for treated and untreated patients. Table 76–7 compares the reported relapse rates in some relevant trials. Interestingly, although there may be variation when surveying untreated populations as well, figures tend to be more closely grouped. However, it is typical for there to be a remarkable drop in the relapse rate after the second year. In 1952, McAlpine12 described attack rates of 1.23 in the first year and 0.42 in the second year. Now, early studies from our London, Ontario geographically based cohort demonstrated attack rates of 1.57 in the first year and 0.35 in the second year for the

1971 1982 1989 1994 1995 1996 2003 2004

Senior Author Gudmundsson Patzold7 Goodkin132 Durelli133 Johnson134 Jacobs135 Russo136 Kalanie137

Annual Relapse Rate Reported 157

0.14 1.1 0.64 0.94 2.90 1.20 0.87 1.0

natural history cohort.138 Most studies report a reduced attack rate with time. It is therefore difficult to assess the true worth and efficacy of disease-modifying agents like interferons and other drugs with respect to reduction in attack rates. The subsequent disease course is less unpredictable for populations compared with any given individual patient. Relapses occur varying frequency in various patients. The frequency of relapses varies even in a given patient at different times. However, there is a clear tendency for the frequency of relapses to be greater in the initial years, and the recovery more complete.13,138-141 With the passage of time, relapses may leave behind more neurological and functional deficits. The contribution of attacks to progression is unclear. After this early relapsing phase, most patients enter the progressive phase of the disease. After the first decade from onset, over 50% of patients whose disease was initially relapsing-remitting enter a progressive phase of MS. Approximately a cumulative 90% develop progressive disease after 25 years of follow-up.142 It has been commented that if followed up long enough, eventually nearly all RRMS patients will be found to have developed the progressive form of the disease. Our personal observations have shown a mean duration of conversion from the time of the first attack to the onset of the progressive form of the disease is approximately 11 years, although it has been reported to be up to 19 years.143,144 After entering this phase, progression appears to be independent of, although worsened by, the accumulated neurodeficits due to, relapses. Gradual, relentless worsening of predominantly the pyramidal and cerebellar systems ensues, often complicated by sphincter and sexual dysfunction. Additionally, cortical types of deficits as described earlier may occur. Disturbances of brainstem functions, including deglutition, set in, and aspiration becomes common. This phase is discussed in detail in the following text.

PROGRESSIVE MULTIPLE SCLEROSIS Curiously enough, but consistently over many study years, the progressive profile of both the phenotypes of MS has been demonstrated to have remarkable similarities in its clinical features. It makes sense to discuss the natural history of progression of MS, whether primary or secondary, under one heading—that of progressive MS. However, certain distinctions between the primary and secondary progressive MS classes and certain facts about them are of particular interest and are worth separate discussion.

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T A B L E 76–8. Time in Years From Onset of MS to Reach Selected Levels of Disability Level of Disability DSS 3 DSS 4 DSS 6 DSS 7 DSS 8

Weinshenker et al., London Ontario13

Confavreux et al., Lyons, France 130

7.69 14.97

Pittock et al., Mayo Clinic, Rochester151

Runmarker et al., Sweden155

17 11.4 23.1 33.1

24

>20

46.39

DSS, Disability Status Scale (Kurtzke) (comparable with Expanded Disability Scale Score).

Clinically, PPMS begins at a relatively later age compared with RRMS. Its onset peaks in the late fourth decade in contrast to early fourth decade in RRMS. The female preponderance in RRMS is not as prominent as in PPMS, with a female-to-male ratio of 1.3 : 1. Progression appears to worsen at a faster pace, but this may be apparent only in the early years. The progression rates in both groups are similar once progression begins.34,129 Relapses in the preprogressive phase of SPMS do not seem to significantly impact the later speed or severity of the progressive phase. Of course, the preexisting neurodeficits (relapse remnants) may exaggerate the disability on initial assessment. Worth noticing, though, is the fact that in individuals with one single attack predating the progressive phase of MS, the severity of the inaugural attack may be negatively associated with the onset of secondary progression (involvement of more than three neurological systems due to attack is associated with earlier onset of progression).34,145 Progressive MS presents most commonly as subtle pyramidal-cerebellar dysfunction gradually evolving over months or years in a frank myelopathy. The diffuse involvement of these two systems, added with the transient sensory phenomena, make it very difficult to localize the lesions. This in fact aids the physician by alerting the presence of a myelopathy, which should raise the possibility of a diagnosis of MS even when there is no prior history of relapses. In all classes of MS, progression predominantly involves the pyramidal system, followed by the cerebellar system. This “chronic progressive myelopathy” is a characteristic presentation of most PPMS patients. Posterior columns are next in frequency of initial presentation, and cranial nerves are commonly only involved in very late stages. In progressive MS, cortical and bulbar functions and, to a greater extent, basal ganglionic functions appear preserved until very late in the disease course in most cases. Progression does not seem to begin specifically at the sites affected by earlier relapses. The site of the original attack has been suspected of becoming a locus minoris resistentiae where progression begins.146 However, most researchers agree that there appears to be no demonstrable relationship between the site of the initial clinically evident expression of disease and the location of the progressive deficit. In our samples, patients with optic neuritis, brainstem, and spinal sensory MS onset are all characterized by an overwhelming predominance of distal central motor dysfunction at outset of the progressive phase of the disease. Progression is seldom joined by overlapping relapses in its march, but when relapses occur, they tend to behave like RRMS relapses, with typical temporal profile and partial or complete recovery.

On the pyramidal-cerebellar background of progressive MS, sphincter and sexual dysfunction, as well as posterior column sensory deficits, add to the patient’s misery. Severe visual deficits are usually rare. Over the years, disability accumulates and patients reach for a cane. This happens on an average of about 8 to 12 years after the beginning of the progressive phase. At this stage, the progression seems to relatively stabilize for some time, but this appearance of stability probably represents the limitations of the present disability scale used.14,139 Table 76–8 shows the median time in years from onset of MS to reach selected levels of disability. Although the time interval for PPMS patients to reach an EDSS score of 3 is less, they have comparable time intervals (with RRMS patients) to reach an EDSS score of 8. The next hallmark of progression is wheelchair dependence, which usually comes approximately 10 and 20 years from the onset of progression.139 Around this period, many things can happen simultaneously. The patient may develop many medical conditions that usually accompany this age group. Lack of mobility, stress of disability, need for catheterization, and resultant infections increase a patient’s morbidity for lifethreatening consequences. Falls, aspirations due to bulbar weakness, depression, memory retrieval deficits, and emotional lability occur more frequently. Coexisting morbidity for strokes and cardiac, pulmonary, or renal disease may further complicate the scene. An EDSS score of 10 means death due to MS, and this is usually reached after an average of 18 to 30 years from onset of progression.

DISABILITY IN MULTIPLE SCLEROSIS The EDSS has been designed to objectively evaluate MS patients.147,148 This is necessary when longitudinally evaluating patients in clinical trials for comparable outcome measures. The EDSS is based on assessment of clinical deficits in various functional systems of the central nervous system, rating them according to severity, rating the ambulation capacity and in its absence the use of upper limbs, and scoring the total not by addition but by overall review of the individual system scores and deficits in ambulation and effective use of hands. The functional systems included are visual, sensory, pyramidal, cerebellar, brainstem, bowel-bladder, cerebral, and others. EDSS has 20 scoring points from 0 to 10; each point after 1 is divided in two. The key milestones in EDSS are as follows:

chapter 76 clinical spectrum: definition and natural progression Score 1 represents objective evidence of minimal involvement of only one functional system, with only signs and no functional disability. Score 3 represents moderate involvement of one functional system with or without mild involvement of others. This is associated with minimal disability. Score 6 means that a cane or unilateral support is required for walking, this represents ambulation disability. Score 8 represents wheelchair dependency, with a relatively good use of hands still maintained. An EDSS score of 10 represents death due to MS. The EDSS is not linear in its function. Also, with lack of comparability of neurodeficits in various neurological systems, the scale has to depend mainly on the disability in ambulation as a comparable criterion. After the score of 5, the scale mainly depends on ambulation, with progression in other systems being sidelined.139 On the other hand, the scale still is the best available tool for comparable longitudinal evaluation of MS patients, as it offers hard outcome parameters eventually reached by most MS patients over the course of their disease progression. However, there is tendency to (1) progress relatively slowly from scores 1 through 3 and (2) linger on for relatively longer time periods over two grades, scores 6 and 7. Obviously, these facts do not mean that the progression pace retards at these stages; they only convey a desperate need for better quantification of progression in the absence of pyramidal and cerebellar parameters. In RRMS, the initial deficit, as mentioned, is quite variable due to diverse neurological system involvements of different degrees; hence, the score of 3 on the EDSS grossly represents a disability level signifying moderate compromise in at least one functional system, with or without mild deficits in others. This level forms a good comparable level for natural history evaluation. The mean duration taken by the patients to reach this level is discrepant in RRMS and PPMS, quite understandably, given the late onset and probably faster early progression of PPMS.14,139,149 The mean time for an RRMS patient to reach an EDSS score of 3 is 6 to 8 years, whereas that for a PPMS patient is 1 to 2 years. This observation may differ depending on whether the patient was observed retrospectively or prospectively.14,139,149,150 The next level generally used for comparison is EDSS score 6, and the score is reached by most RRMS patients in 9 to 15 years, whereas most PPMS patients reach this score in 3 to 5 years.139 Most RRMS patients achieve wheelchair dependency or an EDSS score of 8 in their progressive (SPMS) phase, and the time required for this varies from 18 to 30 years. PPMS patients reach this score in an average 20 years from onset of progression.139 The Mayo Clinic group reported recently that the median time from diagnosis to EDSS score of 3 and 6 was 17 and 24 years, respectively. Only 25% of patients with RRMS were expected to reach an EDSS score of 3 within 20 years based on Kaplan-Meier plots of time. The median time expected for SPMS patients to reach EDSS scores of 3, 6, and 8 was about 3, 10, and 38 years, respectively. The median time from diagnosis to EDSS scores of 6 and 8 for patients with PPMS was 3 and 25 years, respectively.151 In a study from Lyon, France, it was reported that the median time from onset of MS to the assignment of a score of 4, 6, and 7 was 8.4 years (range, 7.8 to

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9.6 years), 20.1 years (range, 18.1 to 22.5 years), and 29.9 years (range, 25.1 to 34.5 years), respectively. Runmarker and associates155 reported comparable results (see Table 76–8). These observations are analogous to the data published by our group, with minor variations. The median interval from onset of disease to reach each of these scores was significantly longer in females than in males and in patients with a younger age at onset of MS. The interval was also longer in those with an initial relapsing remitting course of MS, in those with complete recovery from the first relapse, and those with longer first interattack intervals. Interestingly, the median intervals to reach these target scores were significantly longer for cases with isolated optic neuritis at onset compared with those with isolated long tract dysfunction.127 A series of studies drew a very useful conclusion: Approximately 50% of patients with MS are still able to ambulate independently after 15 years of disease.137

PREDICTORS OF PROGNOSIS, LONG-TERM OUTCOME Given the fact that in their later course both RRMS and PPMS have similar paces of progression and the disabilities are comparable, many predictors have been evaluated in the early course138,139,145,152 (Table 76–9). Relapsing remitting course, early age, and complete recovery from first attack; optic neuritis at onset; sensory onset; and female sex are predictors of favorable long-term outcome in MS. The most important and reliable predictors of unfavorable long-term outcome in MS were found, in some studies, to be (1) attack rate in the first year of MS, (2) shortness of first interattack interval, and (3) rate of development of early disability (EDSS score of 3). Late age at onset, male gender, polysymptomatic onset, incomplete recovery from first attack, and brainstem, cerebral, and/or cerebellar involvement are predictive factors for an adverse outcome. In the PPMS patients, it has been shown that an involvement of three or more neurological systems at onset and the rapidity of early progression are adverse prognostic factors, shortening the time span to an EDSS score of 8. A shorter time of achievement of an EDSS score of 3 from the onset denotes faster early accumulation of disability. This has been associated in many studies with an earlier achievement of further milestones of disability (i.e., EDSS scores of 6

T A B L E 76–9. Prognostic Factors in Multiple Sclerosis Better

Worse

Female Onset: RRMS; optic neuritis, sensory; complete recovery Younger age at onset Longer interattack intervals in early course Long time to DSS 3

Male Onset: polysymptomatic, motor, incomplete recovery Late onset More frequent attacks in early course Short time to DSS 3

DSS, Disability Status Scale (Kurtzke) (comparable with Expanded Disability Scale Score).

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and 8) compared with those who had slower early accumulation of disability. A positive oligoclonal banding, although a very important aid for diagnosis, was not a significant predictor of long-term outcome. MRI is increasingly changing the way we evaluate MS patients in recent years, and new techniques are widening our understanding of MS in multiple dimensions. The typical MRI lesions seen with demyelination aid in documenting time and space dissemination so vital in the diagnosis of RRMS. Although correlations are so far relatively and disappointingly poor, measures such as T2 hypointensities in gray matter, white matter atrophy, residual brain volume, spinal cord atrophy, early lesion load, and magnetization transfer ratio analysis of normal appearing brain tissue have all been directly associated with increased disability in MS.153 Comorbidity with other diseases definitely negatively affects long-term outcome.

direct complications of MS, and the other one third die from various other causes. A greater propensity of MS patients to succumb to depression, fatigue, and other medical conditions, combined with multisystem neurological deficits, may be responsible for a minor shortening (≈5 years) of total life span compared with the normal population. There does not seem to be any difference in the causes of mortality when RRMS (and subsequent SPMS) patients are compared with PPMS patients154 (Table 76–10). We are not yet able to pinpoint the exact etiopathogenesis of MS, and there is presently no cure for this condition, which is devastating for many. However, the natural history data reliably provide us with good insights into the general behavior of this disease, uncertainty inclusive. The availability of some disease-modifying molecules and some very reliable, timetested and effective drugs for most of the symptoms come to the rescue of a neurologist in the practical management of MS patients.

MORTALITY IN MULTIPLE SCLEROSIS Mortality in MS is not significantly different from the agematched general population in the early, low disability years of MS. As the disease ages, MS-specific complications set in. The cause of death in about 50% patients of MS is due to some complication of MS, most commonly, pneumonia and urosepsis. In the other one half of patients, the common causes of death are the same as in the general population and include acute myocardial infarction, stroke, and malignancy. A significant minority of MS patients commit suicide, and this could be due to increased incidences of depression and disability.139 A study of the mean time to death in MS patients revealed that the mean time to death in PPMS patients was shorter (22.3 years) compared with non-PPMS patients. It was also stated that approximately two thirds of patients of PPMS die due to

T A B L E 76–10. Primary Causes of Death in Multiple Sclerosis Patients Listed on 312 Death Certificates in the London, Ontario, Natural History Cohort152 Cause of Death Pneumonia Multiple sclerosis Cancer Heart disease Septicemia Respiratory failure Stroke Cardiac arrest Suicide Pulmonary embolism Aspiration Cachexia Gastrointestinal bleeding Accident Dehydration Respiratory arrest Other* (1 case each)

K E Y ●

MS is a disease characterized by demyelination in the central nervous system at different loci and at different times, and axonal degeneration either primarily or secondary to demyelination. The two most common types are RRMS, where repeated demyelinating episodes (attacks) occur earlier and progressive deficits follow at a later stage, and PPMS, where there are no distinct “demyelinating” attacks but a steady progression of neurological deficits.

●

Typical age at onset of MS is the third or fourth decade, with female preponderance more marked in the RRMS type. Caucasian extraction, growing in the developed world away from equator, and incidence of MS in family are associated with increased risk of developing MS. A combination of genetic and environmental factors is implicated.

●

The most common presentations in RRMS are sensory deficits, optic neuritis, transverse myelitis, internuclear ophthalmoplegias, sphincteric disturbances, ataxia, and the useless hand syndrome. Common presentations of PPMS are varieties of gradually progressive predominantly motor myelopathies, usually with posterior column involvement. Attacks are uncommon but known in PPMS. Cognitive deficits are late to appear in both types of MS. Basal ganglionic signs are very rare.

●

A typical attack in RRMS lasts for 6 weeks. Attacks become rarer in time as secondary progression sets in. A short first interattack interval and multisystem central nervous system involvement are predictors of early or severe disability in future course. Nearly one half of the patients need a walking aid after 15 years of clinical onset. PPMS progresses to this disability level within 8 to 10 years.

●

The EDSS is the best available quantitative measure for recording objective disability in MS patients but is limited by overemphasis on motor deficits and ambulation and a relative neglect of disability due to involvement of other central nervous system systems.

No. of Deaths (N = 312) 99 43 43 28 19 15 15 13 6 4 3 3 3 2 2 2 12

*Other causes of death (1 case each): acute renal failure, assisted suicide, encephalopathy, bowel infarction, cardiac arrhythmia, cardiac failure, chronic bronchitis, chronic renal failure, pyelonephritis, intestinal obstruction, head injury, pulmonary edema.

P O I N T S

chapter 76 clinical spectrum: definition and natural progression ●

Pregnancy appears to confer some protection against attacks, and attack risk increases in the first 3 months after delivery. MS does not affect pregnancy itself or lactation; however, some disease-modifying agents may need to be stopped during pregnancy for safety concerns.

●

Overall life span in MS patients is about 3 to 5 years shorter than for a healthy individual and is affected by comorbidity with other chronic diseases. Aspiration, deep venous thrombosis, and pneumonias are common complications.

●

Opticospinal MS, Balo’s concentric sclerosis, and malignant MS are considered clinical phenotypes of MS.

Suggested Reading Cook SD (ed): Handbook of Multiple Sclerosis, 3rd ed. New York: Marcel Dekker, 2001. Filippi M, Comi G: Primary Progressive Multiple Sclerosis. Top Neurosci Springer, Milan, Italy, 2002. Glaser JS: Neuro-ophthalmology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Paty DW, Ebers GC: Multiple Sclerosis. Contemporary Neurology Series (50). Philadelphia: FA Davis, 1997. Scheinberg L, Raine CS: Multiple sclerosis: experimental and clinical aspects. Ann N Y Acad Sci 1984; 436.

References 1. McAlpine D, Lumsden CE, Acheson ED: Multiple Sclerosis— A Reappraisal. Edinburgh: Livingstone, 1965. 2. Lublin FD, Reingold SC: Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46:907-911. 3. Kremenchutzky M, Cottrell D, Rice G, et al: The natural history of multiple sclerosis: a geographically based study. VII. Progressive-relapsing and relapsing-progressive multiple sclerosis: a re-evaluation. Brain 1999; 122:1941-1949. 4. Weinshenker BG: Progressive forms of multiple sclerosis: classification streamlined or consensus overturned? Lancet 2000; 355:162-163. 5. Andersson PB, Waubant E, Gee L, et al: Multiple sclerosis that is progressive from the time of onset: clinical characteristics and progression of disability. Arch Neurol 1999; 56:11381142. 6. Schumacher GA, Beebe GW, Kibler RF, et al: Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965; 122:552-568. 7. Patzold U, Pocklington PR: Course of multiple sclerosis. First results of a prospective study out of 102 MS patients from 1976-1980. Acta Neurol Scand 1982; 65:248-266. 8. Goodkin DE, Hertsgaard D, Rudick RA: Exacerbation rates and adherence to disease type in a prospectively followed-up population with multiple sclerosis. Implication for clinical trials. Arch Neurol 1989; 46:1107-1112. 9. Fog T, Linnemann F: The course of multiple sclerosis in 73 cases with computer designed curves. Acta Neurol Scand 1970; (Suppl)47: 3-175.

1027

10. Leibowitz U, Alter M: Clinical factors associated with increased disability in multiple sclerosis. Acta Neurol Scand 1970; 46:53-70. 11. Panelius M: Studies on epidemiological, clinical and etiological aspects of multiple sclerosis. Acta Neurol Scand 1969; 45(suppl 39):1-82. 12. McAlpine D, Compston N: Some aspects of the natural history of disseminated sclerosis. Q J Med 1952; 21:135-167. 13. Weinshenker BG, Ebers GC: The natural history of multiple sclerosis. Can J Neurol Sci 1987; 14:255-261. 14. Paty DW, Ebers GC: Multiple Sclerosis. Contemporary Neurology Series (50). Philadelphia: FA Davis, 1997. 15. Bamford CR, Sibley WA, Thies C: Seasonal variation of multiple sclerosis exacerbations in Arizona. Neurology 1983; 33:697-701. 16. Birk K, Ford C, Smeltzer S, et al: The clinical course of multiple sclerosis during pregnancy and the puerperium. Arch. Neurol 1990; 47:738-742. 17. Birk K, Rudick RA: Pregnancy and multiple sclerosis. Arch Neurol 1986; 43:719-726. 18. Frith JA, McLeod JG: Pregnancy and multiple sclerosis. J Neurol Neurosurg Psychiatry 1988; 51:495-498. 19. Nelson LM, Franklin GM, Jones MC; the Multiple Sclerosis Study Group: Risk of multiple sclerosis exacerbation during pregnancy and breastfeeding. JAMA 1988; 359:3441-3443. 20. Schapira K, Poskanzer DC, Newell DJ, et al: Marriage, pregnancy, and multiple sclerosis. Brain 1966; 89:419-428. 21. Sadovnick AD, Eisen K, Hashimoto SA, et al: Pregnancy and multiple sclerosis: a prospective study. Arch Neurol 1994; 51:1120-1124. 22. Miller H, Cendrowski W, Schapira K: Multiple sclerosis and vaccination. BMJ 1967; 2:210-213. 23. Andersen E, Isager H, Hyllested K: Risk factors in multiple sclerosis: tuberculin reactivity, age at measles infection, tonsillectomy and appendectomy. Acta Neurol Scand 1981; 63:131-135. 24. Martyn CN, Colquhoun I: Radiological evidence of sinus infection in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 1991; 54:925-926. 25. Sibley WA: Therapeutic Claims in Multiple Sclerosis. New York: Demos Publications, 1988. 26. Sibley WA, Bamford CR, Clark K: Clinical viral infections and multiple sclerosis. Lancet 1985; 1:1313-1315. 27. Bamford CR, Sibley WA, Thies C, et al: Trauma as an etiologic and aggravating factor in multiple sclerosis. Neurology 1981; 31:1229-1234. 28. Sibley WA, Bamford CR, Clark K, et al: A prospective study of physical trauma and multiple sclerosis. J Neurol Neurosurg Psychiatry 1991; 54:584-589. 29. Warren S, Greenhill S, Warren KG: Emotional stress and the development of multiple sclerosis: case control evidence of a relationship. J Chronic Dis 1982; 35:821-831. 30. Warren S, Warren KG, Cockerill R: Emotional stress and coping in multiple sclerosis. Exacerbations. J Psychosom Res 1991; 35:37-47. 31. Buljevac D, Hop WCJ, Reedeker W, et al: Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003; 327:646-653. 32. Mohr DC, Hart SL, Julian L, et al: Association between stressful life events and exacerbation in multiple sclerosis: a metaanalysis. BMJ 2004; 328:731. 33. Rice GPA, Ebers GC: Management of multiple sclerosis in women. Female Patient 1995; 20:19-32. 34. Kremenchutzky M, Rice GPA, Baskerville J, et al: The natural history of multiple sclerosis: a geographically based study. IX. Observations on the progressive phase of the disease (unpublished article).

1028

Section

XIII

M u lt i p l e S c l e ro s i s a n d D e m y e l i nat i n g D i s o r d e rs

35. Redekop K, Paty D: PhD thesis. University of British Columbia, Vancouver, 1995. 36. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364:2106-2112. 37. Banwell B: Pediatric multiple sclerosis. Curr Neurol Neurosci Rep 2004; 4:245-252. 38. Klonoff H, Clark C, Oger JJF, et al: Neuropsychological performance in patients with mild multiple sclerosis. J Nerv Ment Dis 1991; 179:127-131. 39. Rao SM: Neuropsychology of multiple sclerosis: a critical review. J Clin Exp Neuropsychol 1986; 8:503-542. 40. Ron MA, Feinstein A: Multiple sclerosis and the mind [Editorial]. J Neurol Neurosurg Psychiatry 1992; 55:1-3. 41. Pozzilli C, Bastianello S, Padovani A, et al: Anterior corpus callosum atrophy and verbal fluency in multiple sclerosis. Cortex 1991; 27:441-445. 42. Peyser JM, Edwards KR, Poser CM, et al: Cognitive function in patients with multiple sclerosis. Arch Neurol 1980; 137:577-579. 43. Carroll M, Gates R, Roldan F: Memory impairment in multiple sclerosis. Neuropsychologia 1984; 22:297-302. 44. Boyle EA, Clark CM, Klonoff H, et al: Empirical support for psychological? profiles observed in multiple sclerosis. Arch Neurol 1991; 48:1150-1154. 45. Litvan I, Grafman J, Vendrell P: Multiple memory deficits in patients with multiple sclerosis: exploring the working memory system. Arch Neurol 1988; 45:607-610. 46. Litvan I, Grafman J, Vendrell P, et al: Slowed information processing in multiple sclerosis. Arch Neurol 1988; 45:281-285. 47. Mahler ME: Behavioral manifestations associated with multiple sclerosis. Psychiatr Clin North Am 1992; 15:425-438. 48. Peyser JM, Rao SM, LaRocca NG, et al: Guidelines for neuropsychological research in multiple sclerosis. Arch Neurol 1990; 47:94-97. 49. Rao SM, Leo GJ, Ellington L et al: Cognitive dysfunction in multiple sclerosis. 2. Impact impact on employment and social functioning. Neurology 1991; 41:692-696. 50. Ruchkin DS, Grafman J, Krauss GL, et al: Event-related brain potential evidence for a verbal working memory deficit in multiple sclerosis. Brain 1994; 117(pt 2):289-305. 51. Joffe RT, Lippert GP, Gray TA, et al: Mood disorder and multiple sclerosis. Arch Neurol 1987; 44:376-378. 52. Remick RA, Sadovnick AD, Allen JM, et al: Mood disorders and multiple sclerosis [Abstract]. Canadian Psychiatric Association annual meeting, Ottawa, 1994. 53. Schiffer RB, Rudick RA, Herndon RM: Psychological aspects of multiple sclerosis. N Y State J Med 1983; 83:312-316. 54. Clark Cm, Fleming JA, Li DKB, et al: Sleep disturbance, depression, and lesion site in patients with multiple sclerosis. Arch Neurol 1992; 49:641-643. 55. Ferini-Strambi L, Fillipi M, Martinelli V, et al: Nocturnal sleep in multiple sclerosis: correlations with clinical and brain magnetic resonance imaging findings. J Neurol Sci 1994; 125:194-197. 56. Poirier G, Montplaisir J, Dumont M, et al: Clinical and sleep laboratory study of narcoleptic symptoms in multiple sclerosis. Neurology 1987; 37:693-695. 57. Fisk JD, Pontefract A, Rivto PG, et al: The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994; 21:9-14. 58. Sandroni P, Walker C, Starr A: “Fatigue” in multiple sclerosis: motor pathway conduction and event related potentials. Arch Neurol 1992; 49:517-524. 59. Krupp LB: Fatigue in multiple sclerosis: definition, pathophysiology and treatment. CNS Drugs 2003; 17:225-234. 60. Truyen L, Barkhof F, Frequin STF, et al: A case-control study of epilepsy in multiple sclerosis using magnetic resonance

61. 62. 63. 64. 65. 66. 67.

68. 69. 70.

71.

72.

73. 74.

75. 76.

77.

78. 79.

imaging: implications for treatment trials with 4-aminopyridine. 10th Congress of the European Committee for Treatment and Research in multiple sclerosis, Book of Abstracts, Athens, Greece, 1994, p 38. Rolak LA, Brown S: Headaches and multiple sclerosis: a clinical study and review of the literature. J Neurol 1990; 237:300-302. Paty DW, Ebers GC: Multiple Sclerosis. Contemporary Neurology Series (50). Philadelphia: FA Davis, 1997, Chapter 5. McDonald WI: Pain around the eye: inflammatory and neoplastic causes. Trans Ophthalmol Soc UK 1980; pt 2:260262. Bamford CR, Smith MS, Sibley WA: Horner’s syndrome, an unusual manifestation of multiple sclerosis. Can J Neurol Sci 1980; 7:65-66. Nikoskelainen E, Riekkinen P: Optic neuritis: a sign of multiple sclerosis or other diseases of the central nervous system. Acta Neurol Scand 1974; 50:690-718. Compston DAS, Batchelor JR, Earl CJ, et al: Factors influencing the risk of multiple sclerosis developing in patients with optic neuritis. Brain 1978; 101:495-511. Landy PJ, Innis M, Boyle R: Factors likely to affect the development of multiple sclerosis in patients presenting with optic neuritis in a tropical and subtropical area. Clin Exp Neurol Proc Assoc Neurol 1979; 16:175-182. Kinnunen E: The incidence of optic neuritis and its prognosis for multiple sclerosis. Acta Neurol Scand 1983; 68:371377. Hely MA, McManis PG, Doran TJ, et al: Acute optic neuritis: a prospective study of the risk factors for multiple sclerosis. J Neurol Neurosurg Psychiatry 1986; 49:1125-1130. Francis DA, Compston DAS, Batchelor JR, et al: A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up. J Neurol Neurosurg Psychiatry 1987; 50:758-765. Riikonen R, Ketonen L, Sipponen J: Magnetic resonance imaging, evoked responses and cerebrospinal fluid findings in a follow-up study of children with optic neuritis. Acta Neurol Scand 1988; 77:44-49. Sanders EACM, Van Lith GHM: Optic neuritis, confirmed by visual evoked response, and the risk of multiple sclerosis: a prospective survey. J Neurol Neurosurg Psychiatry 1989; 52:799-810. Sandberg-Wollheim M, Bynke H, Conqvist S, et al: A longterm prospective study of optic neuritis: evaluation of risk factors. Ann Neurol 1990; 27:386-393. Scholl GB, Song HS, Wray SH: Uhthoff’s symptom in optic neuritis: relationship to magnetic resonance imaging and development of multiple sclerosis. Ann Neurol 1991; 30:180184. Rolak LA, Beck RW, Paty DW, et al: Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial. Neurology 1996; 46:368-372. Morrissey SP, Miller DH, Kendall BE, et al: The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Brain 1993; 116:135-146. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 2003; 121:944-949. Sharpe JA, Sanders MD: Atrophy of myelinated nerve fibers in the retina in optic neuritis. Br J Ophthalmol 1975; 59:229232. Slamovitis TL, Rosen CE, Cheng KP, et al: Visual recovery in patients with optic neuritis and visual loss to no light perception. Am J Ophthalmol 1991; 111:209-214.

chapter 76 clinical spectrum: definition and natural progression 80. Gasperini C, Pozzilli C, Bernardi S: Irreversible total blindness in multiple sclerosis [Letter]. Ital J Neurol Sci 1991; 12:329. 81. Uhthoff W: Untersuchungen uber bei multiplen Herdsklerose vorkommenden Augenstorugen. Arch Fur Psychiatr Nervenkrankheiten 1890; 21:55-116, 303-410. 82. Lepore FE: The origin of pain in optic neuritis. Determinants of pain in 101 eyes with optic neuritis. Arch Neurol 1991; 48:748-749. 83. Pulfrich C: Die Stereoskopie im dienste der isochromen und heterochromen photometrie. Naturwissenschaften 1922; 10:533-564. 84. Ansari KA: Olfaction in multiple sclerosis, with a note on the discrepancy between optic and olfactory involvement. Eur Neurol 1976; 14:138-145. 85. Christ T, Pillunat LE, Stodtmeister R: The ‘flicker test’ according to Aulhorn in the diagnosis of acute optic neuritis. Ophthalmologica 1986; 192:220-227. 86. Savitsky N, Rangell L: The ocular findings in multiple sclerosis. Res Publ Assoc Res Nerv Ment Dis 1950; 28:403-413. 87. Wybar KC: The ocular manifestations of disseminated sclerosis. Proc R Soc Med 1952; 45:315-320. 88. Marshall D: Ocular manifestation of multiple sclerosis and relationship to retrobulbar neuritis. Trans Am Ophthalmol Soc 1950; 48:487-525. 89. Brown P: Pathophysiology of spasticity [Editorial and Review]. J Neurol Neurosurg Psychiatry 1994; 57:773-777. 90. D’Costa DF, Vania AK, Millac PA: Multiple sclerosis associated with trismus. Postgrad Med J 1990; 66:853-854. 91. Noffsinger D, Olen WO, Carhart R, et al: Auditory and vestibular aberrations in multiple sclerosis. Acta Otolaryngol Suppl 1972; 303:1-63. 92. Howard RS, Wiles CM, Hirsch NP, et al: Respiratory involvement in multiple sclerosis. Brain 1992; 115:479-494. 93. Oppenheim H: Textbook of Nervous Diseases for Physicians and Students. Edinburgh: O Schulze and Co, 1991. 94. Babinski J, Dubois R: Douleurs a forme de decharge electrique, consecutive aux tramatismes de la nuque. Presse Med 1998; 26:64. 95. L’hermitte J, Bollak, Nicholas M: Les douleurs a type de decharge electrique consecutives a la flexion cephalique dans la sclerose en plaques. Rev Neurol 1924; 42:56-62. 96. Hess DC, Sethi KD: Elipepsia partialis continua in multiple sclerosis. Int J Neurosci 1990; 50:109-111. 97. Hong LS, Wasserstein PH, Adornato BT: Tonic spasms in multiple sclerosis. Anatomic basis and treatment. West J Med 1991; 154:723-726. 98. Shibasaki H, Kuroiwa Y: Painful tonic seizure in multiple sclerosis. Arch Neurol 1974; 30:47-51. 99. Osterman PO: Paroxysmal itching in multiple sclerosis. Int J Dermatol 1979; 18:626-627. 100. Moulin DE: Pain in multiple sclerosis. Neurol Clin 1989; 7:321-331. 101. Portenoy RK, Yang K, Thorton D: Chronic intractable pain: an atypical presentation of multiple sclerosis. J Neurol 1988; 325:226-228. 102. Rushton JG, Olafson RA: Trigeminal neuralgia associated with multiple sclerosis. Arch Neurol 1965; 13:383-384. 103. Fisher M, Long RR, Drachman DA: Hand muscle atrophy in multiple sclerosis. Arch Neurol 1983; 40:811-815. 104. Masur H, Oberwittler C: MS and syringomyelia [Letter to the Editor]. Neurology 1992; 42:464-592. 105. Ransohoff RM, Whitman GJ, Weinstein MA: Noncommunication syringomyelia in multiple sclerosis: detection by magnetic resonance imaging. Neurology 1990; 40:718-721. 106. Miglietta O, Lowenthal M: A study of peripheral nerve involvement in fifty-four patients with multiple sclerosis. Arch Phys Med Rehabil 1961; 42:573-578.

1029

107. Zee PC, Cohen BA, Walczak T, et al: Peripheral nervous system involvement in multiple sclerosis. Neurology 1991; 41:457-460. 108. Eisen AA, Odusote K: Central and peripheral conduction times in multiple sclerosis. Electroencephalogr Clin Neurophysiol 1980; 48:253-265. 109. Waxman SG: Peripheral nerve abnormalities in multiple sclerosis [Editorial]. Muscle Nerve 1993; 16:1-5. 110. Bemelmans BL, Hommes OR, Van Kerrebroeck PE, et al: Evidence for early lower urinary tract dysfunction in clinically silent multiple sclerosis. J Urol 1991; 145:1219-1224. 111. Hinds JP, Eidelman BH, Wald A: Prevalence of bowel dysfunction on multiple sclerosis: a population survey. Gastroenterology 1990; 98:1538-1542. 112. Fantelli FJ, Mitsumoto H, Sebek BA: Multiple sclerosis and malabsorption. Lancet 1978; 1:1039-1040. 113. Sorensen M, Lorentzen M, Petersen J, et al: Anorectal dysfunction in patients with urologic disturbance due to multiple sclerosis. Dis Colon Rectum 1991; 34:136-139. 114. Lilius HG, Valtonen EJ, Wirkstrom J: Sexual problems in patients suffering from multiple sclerosis. J Chronic Dis 1976; 29:643-647. 115. Stenager E, Stenager EN, Jensen K: Sexual aspects of multiple sclerosis. Semin Neurol 1992; 12:120-124. 116. Szasz G, Paty DW, Lawton-Speert S, et al: A sexual functioning scale in multiple sclerosis. Acta Neurol Scand 1984; 70(Suppl 101): 37-43. 117. Szasz G, Paty DW, Maurice WL: Sexual dysfunctions in multiple sclerosis. Ann NY Acad Sci 1984; 436:443-452. 118. Vas CJ: Sexual Impotence and some autonomic disturbances in men with multiple sclerosis. Acta Neurol Scand 1969; 45:166-182. 119. Ivers RR, Goldstein NP: Multiple sclerosis: a current appraisal of symptoms and signs. Proc Mayo Clin 1963; 38:457. 120. Valleroy ML, Kraft GH: Sexual dysfunction in multiple sclerosis. Arch Phys Med Rehab 1984; 65:125-128. 121. Pentland B, Ewing DJ: Cardiovascular reflexes in multiple sclerosis. Eur Neurol 1987; 26:46-50. 122. Senaratne MPJ, Carroll D, Warren KG, et al: Evidence for cardiovascular autonomic nerve dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry 1984; 47:947-952. 123. Schroth WS, Tenner SM, Rappaport BA, et al: Multiple sclerosis as a cause of atrial fibrillation and electrocardiographic changes. Arch Neurol 1992; 49:422-424. 124. Anema JR, Heijenbrok MW, Faes TJ, et al: Cardiovascular autonomic function in multiple sclerosis. J Neurol Sci 1991; 104:129-134. 125. Cartlidge NE: Autonomic function in multiple sclerosis. Brain 1972; 95:661-664. 126. Vita G, Fazio MC, Milone S, et al: Cardiovascular autonomic dysfunction in multiple sclerosis is likely related to brainstem lesions. J Neurol Sci 1993; 120:82-86. 127. Yokota T, Matsunaga T, Okiyama R, et al: Sympathetic skin response in patients with multiple sclerosis compared with patients with spinal cord transection and normal controls. Brain 1991; 114:1381-1394. 128. Sullivan F, Hutchinson M, Bahandeka S, et al: Chronic hypothermia in multiple sclerosis. J Neurol Neurosurg Psychiatry 1987; 50:813-815. 129. Confavreux C, Vukusic S, Adeleine P: Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process: Brain 2003; 126:770-782. 130. Confavreux C, Aimard G, Devic M: Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980; 103:281-300. 131. Mayr WT, Pittock SJ, McClelland RL, et al: Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985-2000. Neurology 2003; 61:1373-1377.

1030

Section

XIII

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132. Goodkin DE, Hertsgaard D, Rudick RA: Exacerbation rates and adherence to disease type in a prospectively followed-up population with multiple sclerosis. Implications for clinical trials. Arch Neurol 1989; 46:1107-1112. 133. Durelli L, Bongioanni MR, Cavallo R, et al: Chronic systemic high-dose recombinant interferon alfa-2a reduces exacerbation rate, MRI signs of disease activity, and lymphocyte interferon gamma production in relapsing-remitting multiple sclerosis. Neurology 1994; 44:406-413. 134. Johnson KP, Brooks BR, Cohen JA, et al: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, doubleblind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45:1245-1247. 135. Jacobs LD, Cookfair DL, Rudick RA, et al: Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39:285-294. 136. Russo P, Paolillo A, Caprino L, et al: Effectiveness of interferon beta treatment in relapsing remitting multiple sclerosis: an Italian cohort study. J Eval Clin Pract 2004; 10:511-518. 137. Kalanie H, Gharagozle K, Hemmatie A, et al: Interferon beta 1a and intravenous immunoglobulin treatment for multiple sclerosis in Iran. Eur Neurol 2004; 52:202-206. 138. Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis: a geographically based study. II. Predictive value of the early clinical course. Brain 1989; 112:1419-1428. 139. Ebers GC, Paty DW: Natural history studies and applications to clinical trials. In Paty DW, Ebers GC, eds: Multiple Sclerosis. Philadelphia: FA Davis, 1998, pp 192-228. 140. Ebers GC, Paty DW: Natural history studies and applications to clinical trials. In Paty DW, Ebers GC, eds: Multiple Sclerosis. Philadelphia: FA Davis, 1998, pp 192-228. 141. Poser C: The course of multiple sclerosis. Arch Neurol 1985; 42:1035. 142. Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989; 112:133-146. 143. Vukusic S, Confavreux C: Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci 2003; 206:135-137.

144. Minderhoud JM, Van der Hooven JH, Prange AJ: Course and prognosis of chronic progressive multiple sclerosis: results of an epidemiological study. Acta Neurol Scand 1988; 78:10-15. 145. Poser S, Poser W, Schlaf G, et al: Prognostic indicators in multiple sclerosis. Acta Neurol Scand 1986; 74:387-392. 146. Fog T: Topographic distribution of plaques in the spinal cord in multiple sclerosis. Arch Neurol 1950; 63:382-414. 147. Kurtzke JF: International symposium on MS—Goteberg 1972. Ann NY Acad Sci 1974; (Suppl 58):14. 148. Kurtzke JF: On the evaluation of disability in multiple sclerosis. Neurology 1961; 11:686-694. 149. Kurtzke JF: Clinical manifestations of multiple sclerosis. In Vinken PJ, Bruyn GW, eds: Handbook of Clinical Neurology. Amsterdam: Elsevier North-Holland, 1970, pp 161-216. 150. Rice GP, Kremenchutzky M, Cottrell D, et al: Observations from the natural history cohort of London, Ontario. In: Filippi M, Comi G, eds: Primary Progressive Multiple Sclerosis Series—Topics in Neuroscience. Springer-Verlag, Milan, Italy, 2001, Chapter 2. 151. Pittock SJ, Mayr WT, McClelland RL, et al: Rodriguez: Disability profile of multiple sclerosis did not change over 10 years in a population based prevalence cohort: Neurology 2004; 62:601-606. 152. Weinshenker BG, Rice GPA, Noseworthy JH, et al: The natural history of multiple sclerosis: a geographically based study. III. Multivariate analysis of predictive factors and models of outcome. Brain 1991; 114:1045-1056. 153. Traboulsee A, Dehmeshki J, Peters KR, et al: Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities. Mult Scler 2003; 9:566573. 154. Kremenchutzky M, Sim D, Baskerville J, et al: A study of the causes of death in multiple sclerosis patients. Neurology 2000; 54(Suppl 3A):350. 155. Runmarker B, Andersen O: Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116:117-134. 156. Rodriguez M, Siva A, Cross S, O’Brien P, Kurland L: Optic neuritis: A population based study in Olmsted county, Minnesota. Neurology 1994; 44(Suppl. 2):A374. 157. Gudmundsson KR: Clinical Studies of MS in Iceland. Acta Neurol Scand 1971; 47(Suppl. 48):1-78.

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INVESTIGATIONS IN MULTIPLE SCLEROSIS ●

●

●

●

Robert Brenner

Investigations in the setting of multiple sclerosis have three main roles: to help support or refute the diagnosis, to provide insights into the mechanisms underlying pathogenesis of the illness and to provide a means of monitoring progression and thus assessing the effect of treatment.

BLOOD INVESTIGATIONS In the absence of a diagnostic blood test, these are used broadly to exclude alternative conditions that are generally infective or inflammatory (Table 77-1).

LUMBAR PUNCTURE Examination of the cerebrospinal fluid in patients with multiple sclerosis has become much less frequent since the widespread availability of magnetic resonance imaging (MRI). It remains useful in the atypical case and in older patients whose changes on MRI may be due to vascular disease. It is also one of the criteria (no longer essential) for the diagnosis of primary progressive disease. Two main abnormalities are found: a leukocytosis and abnormalities of immunoglobulin production.

Cell Count A cerebrospinal fluid pleocytosis is found in approximately two thirds of patients at the time of relapse, generally between 10 and 25 cells/mm3, and is rarely greater than 50. Counts of greater than 100 should raise suspicions of alternative diagnoses, such as acute disseminated encephalomyelitis or Devic’s disease.

Abnormalities of Cerebrospinal Fluid Immunoglobulin Production These abnormalities have been known for some 40 years.1 Detection of cerebrospinal fluid immunoglobulins remain one of the most sensitive, but not specific, tests for the disease. If isoelectric focusing is used, then evidence of intrathecal synthesis of oligoclonal immunoglobulin is found in approximately 95% of definite cases2 compared with 75% for quantitative techniques. These oligoclonal bands are indicative of the plasma cell expansion within the central nervous system. If the

initial result is negative and clinical suspicion is high or there is only a single band, it is worth repeating the lumbar puncture. It is essential that paired serum and cerebrospinal fluid samples are analyzed in order to exclude the possibility of a systemic polyclonal response diffusing across the blood-brain barrier. Oligoclonal bands may be found in acute disseminated encephalomyelitis but tend to disappear, whereas in multiple sclerosis they persist.3 The investigation is nonspecific, and oligoclonal bands may be found in a wide range of other conditions such as infective and inflammatory processes as well as paraneoplastic phenomena. Therefore, although their presence may merely be supportive, their absence should strongly encourage the search for an alternative diagnosis.4 A committee brought together to support the McDonald (2001) guidance (see later) concluded that the most informative analysis is qualitative assessment, best performed using immunoelectrophoresis, together with some form of immunodetection (blotting or fixation).5 This should be performed using unconcentrated cerebrospinal fluid and must be compared directly with a serum sample run simultaneously. They highlight that the result should be interpreted with values from all other tests, including cell count protein, glucose, etc. In certain cases, evaluation using light chains for immunodetection can help resolve equivocal oligoclonal immunoglobulin G patterns. They emphasize that consideration should be given to repeating the lumbar puncture if clinical suspicion is high and the results are equivocal or show only a single band. It is, of course, important to emphasize that the procedure is moderately invasive and must be analyzed in the most effective manner. Five main patterns are found6 (Fig. 77–1): Type 1: No bands in cerebrospinal fluid or serum Type 2: Oligoclonal bands in cerebrospinal fluid but not in serum Type 3: Oligoclonal bands in cerebrospinal fluid with additional, identical paired bands in cerebrospinal fluid and serum Type 4: Identical (paired) bands in cerebrospinal fluid and serum Type 5: Monoclonal bands in cerebrospinal fluid and serum Types 2 and 3 are supportive of a diagnosis of multiple sclerosis. Type 4 reflects systemic generation of immunoglobulin G with transfer of the bands into the cerebrospinal fluid. In primary progressive multiple sclerosis, in which the likelihood of a false-positive diagnosis is highest, the 2001 McDonald criteria required the presence of oligoclonal bands. This has

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been revised in the most recent guidance7 in view of the large study by Wolinsky in which one third of patients were negative.8 It was also suggested that this group had a less inflammatory illness. It is important to appreciate, however, that the cerebrospinal fluid analysis in this study was based on a quantitative technique and thus may have underestimated an isoelectrically focused result.

EVOKED POTENTIALS The development of averaging techniques allows the recording of the arrival of an action potential by a scalp electrode placed over the appropriate cortical region. Its use in multiple sclerosis is in identifying clinically silent regions of the central nervous system. Furthermore, it is the only way in which the pathological process of the central nervous system demyelination may be demonstrated in vivo. Initially, somatosensory potentials were studied in a range of neurological diseases, including multiple sclerosis.9 It was not until the development of the technique of pattern reversal visual evoked potentials that the method was applied to diagnosis in multiple sclerosis. A prolonged latency was found in over 90% of patients with a history of optic neuritis.10 This done, attention was turned to multiple sclerosis patients without such a history, where a finding of a conduction delay within the visual pathways would demonstrate evidence of lesions that had not been clinically apparent.11 In clinical practice, potentials are recorded over the scalp after visual, somatosensory, and auditory stimuli or may be recorded peripherally after central magnetic stimulation of the motor cortex.

T A B L E 77–1. Blood Tests to Consider in Investigations Workup Blood Test

Differential Diagnosis

Vitamin B12/folate Autoantibodies Immunoglobulins/ferritin Lupus anticoagulant status Extractable nuclear antigens Lyme serology HTLV-1 antibodies HIV Leber’s mutation NMO-IgG

Subacute combined degeneration Autoimmune diseases Inflammatory diseases Antiphospholipid antibody syndrome Sjögren’s syndrome Lyme borreliosis Tropical spastic paraplegia HIV Harding’s disease Devic’s disease

Visual Evoked Potentials

■

The visual evoked potential (V.E.P.) is an averaged response recorded from three occipital electrodes with a mid-frontal voltage reference. The main component is a wave of electropositivity at 100 milliseconds (P100). This is preceded by a smaller negative response at 75 milliseconds (Fig. 77–2). The stimulus takes the form of a high-contrast checkerboard, which reverses its pattern and occupies the central 40º of the visual field. Half-field stimulation is used as an adjunct to anatomical localization of a detected delay. The response is dependent on a level of visual acuity to the extent that, if this is worse than 6/24, the potential will be absent. This is of use in patients whom one suspects may have a nonorganic visual loss. The latency is shorter in women and increases with age over 60.

Figure 77–1. Patterns of cerebrospinal fluid immunoelectrophoresis. (Courtesy of Dr. G. Giovanonni, Institute of Neurology, London, England.)

A ■

B Figure 77–2. Normal (A) and abnormal (B) visual evoked potentials, showing delayed waveform of normal amplitude. (Courtesy of the Department of Neurophysiology, Royal Free Hospital.)

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B Figure 77–3. Normal (A) and abnormal (B) somatosensory evoked potentials. (Courtesy of the Department of Neurophysiology, Royal Free Hospital.)

The mean delay recorded is approximately 35 m/sec and will persist in the majority of adult patients.12 The prospect for full recovery is much greater in children, perhaps reflecting a viral etiology. In the acute inflammatory phase, there may be conduction block, leading to reduced amplitude response or even its absence, which is then followed by a typical delayed normal amplitude waveform during recovery. From 85% to 95% of patients who eventually receive a diagnosis of clinical definite multiple sclerosis will have a visual evoked potential abnormality. It is important to stress that this is when using the more oldfashioned opticomechanical stimulator. More modern computer monitors, although appearing instantaneous visually, take up to 18 m/sec to draw the checkerboard, resulting in a more dispersed stimulus.13 It is suggested that sensitivity may be as low as 25% in this setting.14 There may be a small increase in detection if central field stimulation (4º of visual field) is used. The asymmetry of the delay may be of diagnostic value. The interocular difference is rarely greater than 5 milliseconds in normal subjects. The asymmetry helps distinguish patchy processes as found in multiple sclerosis from more diffuse causes of optic neuropathy such as Friedreich’s ataxia or vitamin B12 deficiency.

is normal, indicating a discrete lesion within the gracile funiculus. Abnormalities are found in approximately 80% of patients without sensory features in clinically definite multiple sclerosis15 and in 20% of patients with a clinically isolated syndrome.16 There is an expectedly higher yield (approximately 10%) following stimulation of the posterior tibial nerve. It is interesting that abnormalities may be purely unilateral in one third of patients.

Somatosensory Evoked Potentials

The three most prominent peaks, that is, I, III, and V, are measured at their interpeak latency. Thus, I through III represent conduction through the auditory nerve and lower brainstem, and III through V represent the upper brainstem and mid-brain. In multiple sclerosis, asymptomatic lesions are reported in approximately 40%. The usefulness of evoked potentials was assessed by the Quality Standards Sub-Committee of the American Academy of Neurology.17 Following a review of 16 studies that included 715 patients, it was concluded that visual evoked potentials were probably useful in identifying patients with clinically isolated syndromes who are at increased risk of developing multiple sclerosis. Sensory evoked potentials were regarded as possibly useful, and it was believed that there was insufficient evidence to recommend brainstem evoked potentials.

The response is recorded from electrodes placed over the primary somatosensory cortex (Brodmann area 3b) following a suprathreshold electrical stimulation within the territories of the median or posterior tibial nerve (Fig. 77–3). The potentials are characterized by a peak at an average of 20 m/sec for median stimulation and 40 m/sec for posterior tibial. Assuming normal peripheral conduction, delay will indicate an area of demyelination within the central sensory pathways. A normal median response with an abnormal posterior tibial indicates a lesion within the spinal cord. Central conduction time may be calculated by subtracting the recordings made over the cervical and lumber root entry zones. Very occasionally, the median evoked potential is delayed while the posterior tibial response

Brainstem (Auditory) Evoked Potentials These are obtained following a clicking auditory stimulation by electrodes placed over the vertex and ipsilateral mastoid (Fig. 77–4). It is a complex waveform, with five main peaks due to passage via brainstem and mid-brain structures: I: Distal portion of the eighth nerve II: Proximal eighth nerve with contribution from the ipsilateral cochlear nucleus III: Pons IV and V: Lateral meniscus and contra lateral inferior caliculus

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Central Motor Conduction

IMAGING

Magnetic cortical stimulation over the motor cortex will induce a response in the appropriate muscle group,18 allowing, with certain caveats, an assessment of central motor conduction velocity. Delays may be found if there are lesions along the motor pathways.19 However, these invariably occur with clinical evidence of such lesions restricting the usefulness of the investigation. There is a correlation between central motor conduction delay, spinal cord lesion load, and disability. It has been suggested that this is due to axonal loss,20 as it appears to occur independent of demyelination.

Computed Tomography Scanning Although this is essentially a redundant technique in the investigation of multiple sclerosis, there are occasional patients in whom MRI is contraindicated or is unavailable. Computed tomography (CT) scanning was first demonstrated to be of use in multiple sclerosis in 1976.21 The main findings were of atrophy, but approximately one third of patients had periventricular low-density lesions (Fig. 77–5). The detection rate increased with increasing sophistication of imaging techniques and, within a few years, contrast enhancement was reported in acute lesions.22 Furthermore, with serial imaging, it became clear that the enhancement was a temporary phenomenon,23 which would resolve faster after steroid therapy. With optimization by increasing the dose of contrast, delaying imaging, and high-resolution scanners, up to 89% of patients were found to have enhancing lesions within 8 weeks of relapse.24

Magnetic Resonance Imaging

■

In 1981, Young25 demonstrated the exquisite sensitivity that MRI has in revealing the lesions of multiple sclerosis. They examined 10 patients in whom CT scanning had established 19 lesions. An additional 112 lesions were found on MRI. Furthermore, it was now possible to clearly see lesions in the posterior fossa. Virtually all lesions seen on CT are MRI visible.26 Imaging protocols use techniques to optimize tissue contrast. A routine MRI study will generally include proton density, fluid-attenuated inversion recovery (FLAIR), and T1- and T2weighted images, as well as occasionally a postcontrast T1weighted image. Periventricular deep white matter lesions are the most common finding. The corpus callosum and posterior fossa are also commonly affected and help different inflamma-

Figure 77–4. Normal brainstem evoked potential. (Courtesy of the Department of Neurophysiology, Royal Free Hospital.)

A ■

B Figure 77–5. Brain CT scan of a patient with longstanding multiple sclerosis, revealing periventricular low densities and atrophic change.

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tory lesions as occur in multiple sclerosis from the consequences of small vessel disease. Cerebral MRI will reveal abnormalities in 95% of patients with multiple sclerosis.27 Of the remainder, one half tend to have primary progressive disease. In a study of 20 patients with negative cerebral MRI, all were found to have abnormalities on spinal imaging, 87% had cerebrospinal fluid oligoclonal bands, and 56% had abnormal evoked potentials.28 Cord lesions may be seen in up to 75% of clinically definite cases.

Conventional Imaging Protocols T2-Weighted Imaging T2 is prolonged with increasing mobility of bulk water, such as in inflammation, and in gliosis. For this reason, there is a lack of pathological specificity. T2 is so sensitive that subsequent pathological analysis demonstrates only subtle evidence of inflammatory infiltration,29 although it is likely that fixation methods would make the changes less apparent. Radiologists often incorrectly report the widespread periventricular lesions seen in T2-weighted scans as being due to the consequences of demyelination. The nature of multiple sclerosis is such that patho-radiological correlation is only rarely possible. There is a substantial heterogeneity to the pathological features of multiple sclerosis, and it has not been possible to distinguish the subtypes by MRI. T2-weighted imaging reveals multiple sclerosis lesions as high signal foci contrasting against the low signal background. Problems arise if they are periventricular, as they often will merge with the cerebrospinal fluid, which has a similar signal (Fig. 77–6). Further lesions may be visualized in the spinal cord30 (Fig. 77–7). They are aligned longitudinally. Both gray and white matter tracts are involved, and in an acute lesion, there may some associated cord swelling. In multiple sclerosis, cord lesions tend to extend for a short length (one or two vertebral levels) whereas in acute disseminated encephalomyelitis they are substantially longer. The cervical cord is most frequently affected and is an unusual site for vascular disease. It is worthwhile to routinely include a sagittal T2 cervical scan in patients over 50 in whom small vessel changes are likely. There is a striking difference in the amount of T2 activity between the different types of multiple sclerosis. The greatest activity being found in relapsing and remitting compared with benign multiple sclerosis, which in turn exhibits more activity than patients with primary progressive disease.31 In patients who undergo serial imaging, new T2 hyperintensities occur at up to 10 times the rate of onset of new clinical symptoms.32 In clinically isolated syndromes, the number of T2-weighted lesions has prognostic value and correlates with the later likelihood of developing clinically definitive multiple sclerosis33 (Table 77–2). The lesion load over the first 5 years of disease is a predictor of cerebral atrophy 14 years later.34 Fully or semiautomated segmentation techniques allow quantification of the total burden of T2 lesional tissue. The overall volume of T2 lesion load increases with disease duration (by approximately 8% per annum, average volume approximately 20 mL for secondary progressive, 15 mL for primary progressive or relapsing and remitting), but there is no relationship between this and clinical deficit except for cognitive

A

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Figure 77–6. T2-weighted MRI demonstrating (A) periventricular and (B) corpus callosal lesions. (Courtesy of the Department of Neuroradiology, Royal Free Hospital.)

impairment.35 There are a number of possible reasons: (1) pathological heterogeneity of lesions, (2) insensitive methods of assessment such as the heavily motor function–biased Expanded Disability Status Scale (EDSS), and, most important, (3) cerebral lesions predominately occur in regions that are not clinically eloquent. There is an association between spinal cord cross-sectional area and EDSS, although not lesion load.36 Such automated techniques and the fact that T2-weighted MRI demonstrates considerably more evidence of disease activity

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M u lt i p l e S c l e ro s i s a n d D e m y e l i nat i n g D i s o r d e rs have led to its being used in all major treatment trials, allowing fewer patients to be studied. However, despite considerable suppression of most MRI parameters (T2 lesion load, gadolinium-DTPA enhancement, T1 black holes), there is only modest suppression of relapses with most therapies. Occasionally, large T2 lesions contain a peripheral ring of hypointensity; this is believed to be due to the paramagnetic effect of iron within macrophages and is correlated with type 2 pathology. These may respond to plasmapheresis.

Fluid-Attenuated Inversion Recovery The FLAIR sequence was developed in order to overcome the difficulty due to high cerebrospinal fluid signal, which led to problems in differentiating subcortical lesions as well as cerebrospinal fluid from the commonly found periventricular lesions. More lesions are visualized37 (Fig. 77–8), although it is not especially good for detecting cord or posterior fossa lesions. Furthermore, normal brain tissue can give a misleadingly abnormal appearance (Fig. 77–9).

T1-Weighted Imaging A

Gadolinium Enhancement

B ■

Figure 77–7. T2-weighted spinal MRI demonstrating a typical lesion at C6-7. (Courtesy of the Department of Neuroradiology, Royal Free Hospital.)

The paramagnetic and toxic rare earth metal gadolinium is rendered safe if chelated with EDTA. The chelation also serves to exclude from passage across a healthy brain barrier. One of the earliest magnetic resonance signs of new lesion activity is cerebral parenchymal enhancement (Fig. 77–10). This is invariably found at an anatomically appropriate site at the onset of a new clinical symptom.38 Experimental studies have demonstrated vesicular transendothelial passage of the brain barrier marker, as an active process.39 In multiple sclerosis, correlation with pathology has confirmed inflammatory change at the site of enhancement.40 The degree of enhancement in multiple sclerosis usually lasts for 4 to 6 weeks. It may be temporarily impeded by intravenous steroid therapy, possibly implying that restoration of blood-brain barrier function as a mode of action.41 A week after a 3-day course of intravenous methyl prednisolone, the degree of enhancement is at the level one would have predicted without steroids. As lesions age, the pattern of enhancement appears to be more peripheral and, despite the evolution of an area of T1 enhancement expanding, retracting, and then leaving an area of T2 high signal, brain mapping has demonstrated that areas of T1 enhancement tend to lie more deeply within the white matter rather than the periventricular areas favored by T2 lesions. If the lesion lies completely within white matter, an initial ring of enhancement that fills from the periphery is seen. But

T A B L E 77–2. T2-Weighted Imaging Characteristic

Baseline

5.3 yr

9.7 yr

14.1 yr

Patients clinically assessed Abnormal baseline MRI (%) Total clinically definite multiple sclerosis Clinically definite multiple sclerosis: abnormal baseline MRI Clinically definite multiple sclerosis: normal baseline MRI No. undergoing MRI

109 69 (63) 0 0

89 57 (64) 38 (43) 37 (65)

81 54 (67) 48 (59) 45 (83)

71 50 (70) 48 (68) 44 (88)

1 (3)

3 (11)

4 (19)

0 109

89

64

55

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B Figure 77–8. Lesions on T2-weighted MRI (A) are less well defined than FLAIR sequence (B). (Courtesy of the Department of Neurophysiology, Royal Free Hospital.)

if it lies at the gray-white matter interface, then the ring is incomplete and open to the gray matter. The number of lesions detected increases with dose of contrast medium and the timing of imaging following infusion.42

T1 Hypointensities A proportion of T2 lesions appear hypointense (also known as “black holes”) on T1 imaging (Fig. 77–10). These correlate best with hyperintensities seen with FLAIR sequences. The hypointensities related to T2 lesions occur more frequently in progressive rather than relapsing patients. A substantial proportion (approximately 50%)43 of the black holes resolve within 6 months; the remainder tend to persist and represent various degrees of axonal loss.44 Clinical disability is more strongly correlated with the burden of T1 black holes than T2 lesions.45

RESEARCH PROTOCOLS Magnetization Transfer Imaging

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Figure 77–9. FLAIR sequence revealing the normal finding of high signal in the posterior fossa. (Courtesy of the Department of Neurophysiology, Royal Free Hospital.)

This technique facilitates imaging of protons within large molecules. Ordinarily, they would not be visualized as they are rigidly bound and have a very short T2; their signal will have been dissipated before image acquisition. An initial radiofrequency pulse selectively saturates the magnetization within tightly bound protons. This is then exchanged with adjacent relatively mobile protons, that is, those within the cerebrospinal fluid (Fig. 77–11). By comparing the signal obtained

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A ■

B Figure 77–10. T1-weighted MRI demonstrating black holes (A) that enhance with gadolinium (B). (Courtesy of Dr. G. Giovanonni, Institute of Neurology, London, England.)

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B Figure 77–11. Magnetization transfer imaging before (A) and after (B) preexcitation pulse. (Courtesy of the Department of Neuroradiology, Royal Free Hospital.)

chapter 77 investigations in multiple sclerosis with and without the saturating radiofrequency pulse, a magnetization transfer ratio is obtained. A high ratio implies a high degree of exchange of magnetization. Tissue disruption leads to a reduced ratio. Serial studies reveal reduction of magnetization transfer ratio before the appearance of gadolinium-enhancing lesions, which then reduces further at the onset of enhancement.46 The recovery has been shown to be greater in patients on interferon β-1B or steroids. A marked decline at the onset of inflammation is predictive of the subsequent development of a T1 black hole. If there is only a mild reduction, then an increase in the ratio tends to follow over the ensuing months. Reduction of magnetization transfer ratio has also been found within the normal-appearing white matter and gray matter. Reduction tends to be worse in patients with progressive illness. Two large studies have addressed this and revealed that reduction in magnetization transfer ratio at disease onset predicts disability in studies with follow-ups for 4.5 and 5 years.47,48 It has also been found to predict the development of clinically definite multiple sclerosis in patients with clinically isolated syndromes.49

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ness. There is evidence of a genetic predisposition to the development of atrophy in that it is five times more common in carriers of the APOE e4 allele.60 Overall, there is an approximately 1.3% loss of cerebral parenchymal tissue per year with slightly higher rates in primary compared with secondary progressive disease. The highest rates seem to be in relapsing and remitting patients. As measures of atrophy are so readily reproducible and of great clinical relevance, they have been included as secondary outcome measures in trials of disease-modifying therapies. Both glatiramer and the β-interferons have been reported to reduce atrophic change.61

NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY By suppression of the water resonance, other mobile protons that contribute to the MR signal may be visualized. However, due to the vast reduction in concentration (approximately 10,000-fold), either a very low resolution image or a spectrum is produced. In localized spectroscopy, three major peaks are resolved (Fig. 77–12). The first peak is the choline or, alterna-

Diffusion-Weighted Imaging Diffusion-weighted imaging is a technique that measures the free random diffusion of mobile protons. Free diffusion is normally impeded by cellular structure. The usual pattern will be disrupted by disease processes altering the normal cytostructure. Diffusion-weighted imaging scans will show changes due to T2 effects and are distinguished by measuring the apparent diffusion coefficient. The apparent diffusion coefficient is especially high in acutely enhancing inflammatory lesions50 and in regions of axonal loss as evidenced by T1 black holes. Changes are particularly striking in areas where there is an obvious directional propensity, such as a white matter tract. There is close correlation between DTI of the pyramidal tracts and EDSS.51 The apparent diffusion coefficient is increased in normal-appearing white matter compared with healthy controls.52 Apparent diffusion coefficient also increases in normalappearing white matter several weeks before the development of a new lesion, at which time there is a further substantial elevation.53

ATROPHY Quantification techniques have been used to measure brain volumes and reveal evidence of atrophy occurring from very early in the disease course.54 The pathological basis is unclear and is not simply due to shrinkage in regions of T2 change. Atrophy within gray matter55 is a common feature not explained by the one sixth of lesions that are cortical but may perhaps be related to wallerian degeneration.56 The early onset of gray matter atrophy in the absence of similar changes in white matter suggests this is a more sensitive predictor of subsequent disability. The gray matter tends to be affected by a less inflammatory process.57 There seems to be no relationship between the degree of gadolinium-DTPA enhancement but possibly with T1 hypointensities58,59 It seems likely that there will be a contribution from the known but relatively unexplored changes seen in normal-appearing white matter. Patients with secondary progressive disease usually develop increasing paraplegia in the absence of a history of prior relapses leading to limb weak-

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Figure 77–12. Serial NMR spectrum from an acute lesion compared with normal appearing white matter demonstrating lipid peaks. (From Davie CA, Hawkins CP, Barker GJ, et al: Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 1994; 117:49-58. Reprinted by permission of Oxford University Press.)

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tively, the trimethylamine–containing peak, which is derived from compounds required for membrane synthesis and the products of its catabolism. The next peak is derived from creatine and phosphocreatine. These molecules are involved in energy metabolism and exist in equilibrium, the total concentration remaining constant. They are thus often used as an internal standard, semiquantitative results being quoted as ratios to the creatine/phosphocreatine peak. Finally, the Nacetyl–containing compound peak is formed predominantly from N-acetyl aspartate, an amino acid that resides solely within neurons. It has been described in the O2A progenitor cell and is believed to represent a marker for neuronal function. Other resonances may be resolved, attributed to amino acids such as glutamate, glutamine, γ-amino butyric acid, and myo-inositol. It is also possible to resolve peaks due to lactate and the products of myelin degradation.

Trimethylamine Resonance The trimethylamine peak is elevated in new lesions,62 prompting speculation that it was due to demyelination (Fig. 77–13). However, there are similar findings in purely inflammatory experimental lesions. Furthermore, serial studies in multiple sclerosis have revealed an elevation localized to normalappearing white matter several weeks before the onset of a new T2 and gadolinium-DTPA–enhancing lesion.63 The trimethylamine peak then increases further. These findings imply ongoing cellular activity before the onset of inflammatory change or impairment of blood-brain barrier function. We have studied by high-field nuclear magnetic resonance (NMR) spectroscopy the components of the trimethylamine peak and found that the elevation was due to increases in choline, phosphorylcholine, and especially betaine,64 an intracellular osmolyte.65 This may imply an abnormality in water homeostasis.

N-Acetyl Resonance There is a reduction of N-acetyl aspartate in normalappearing white and gray matter when compared with controls. In acute lesions, the N-acetyl aspartate resonance diminishes. It then gradually increases over ensuing weeks and months but may not recover to its previous level66 (Fig. 77–14). The reduction is most marked and persistent in the center of the lesion. Periventricular N-acetyl aspartate/creatine ratios have been found to be related to duration of disease as well as EDSS. As with other attempts at clinicoradiological correlation, the strongest association appears to be with cognition. The partial reversibility of the reduction suggests that it may be metabolic. We have studied N-acetyl aspartate synthesis in intact cerebral mitochondrial preparations isolated from animals with acute EAE. We found a substantial reduction in synthesis rate in the experimental (37.4 ± 3.9 nmol/min/mg protein) compared with controls (64.5 ± 7.5 nmol/min/mg protein) (unpublished results). It has been proposed that Nacetyl aspartate functions as a molecular water pump. A single N-acetyl aspartate molecule has the ability to transport 32 molecules of water against a concentration gradient.67 It is thus

feasible that the increase in trimethylamine at the onset of a new lesion is in response to neuronal mitochondrial dysfunction leading to reduced N-acetyl aspartate production and consequent impairment of osmoregulation. It is of course interesting to speculate on the pathogenic role of the recently described (NMO–Igg) NMO–immunoglobulin G to the water channel protein, aquaporin-4.

MAGNETIC RESONANCE IMAGING DIAGNOSIS OF MULTIPLE SCLEROSIS In 2001, the International Panel on the Diagnosis of Multiple Sclerosis presented what was soon to be known as the “McDonald Criteria.”68 These criteria allowed the incorporation of new MRI activity as evidence of new lesions and thus formalize the diagnosis at an earlier stage. In 2005, following widespread support and after further suggestions, the criteria were revised69 (Table 77–3).

T A B L E 77–3. McDonald Criteria Clinical Features At least two episodes with objective clinical evidence of at least two lesions At least two episodes with objective clinical evidence of one lesion One episode with objective clinical objective evidence of two lesions One episode with clinical objective evidence of one (clinically isolated syndrome) Relentless progression for at least 6 months MRI Requirements Nil MRI evidence of dissemination in space Or Two or more typical MRI lesions and cerebrospinal fluid oligoclonal bands MRI evidence of dissemination in time MRI evidence of dissemination in space Or Two or more typical MRI lesions and cerebrospinal fluid oligoclonal bands And MRI evidence of dissemination in time MRI evidence of dissemination in space and time MRI Evidence of Dissemination in Time 1. Detection of a gadolinium-enhancing lesion at least 3 months after the onset of the initial event 2. Detection of a new T2 lesion at any time compared with a reference scan performed at least 30 days after the onset of the initial event MRI Evidence of Dissemination in Space Three of the following: 1. At least one gadolinium-enhancing or nine T2-hyperintense lesions 2. At least one infratentorial lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions Note: A spinal lesion can be considered as infratentorial and may contribute to the total number of T2 hyperintensities. An enhancing cord lesion is considered equivalent to an enhancing brain lesion.

chapter 77 investigations in multiple sclerosis

A

B ■

Figure 77–13. NMR spectra from regions within an acute lesion demonstrating an elevation in the trimethylamine (Cho) peak. (From Davie CA, Hawkins CP, Barker GJ, et al: Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 1994; 117:49-58.)

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Suggested Reading Bakshi R, Minagar A, Jaisani Z, et al: Imaging of multiple sclerosis: role in neurotherapeutics. NeuroRx 2005; 2:277-303. Freedman multiple sclerosis, Thompson EJ, Deisenhammer F, et al: Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 2005; 62:865-870. McDonald WI, Compston A, Edan G, et al: Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121-127. Polman CH, Reingold SC, Edan G, et al: Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria. Ann Neurol 2005; 58:840-846. Walsh P, Kane N, Butler S: The clinical role of evoked potentials. J Neurol Neurosurg Psychiatry 2005; 76(Suppl 2):16-22.

References

■

Figure 77–14. Serial NMR spectra from an acute lesion demonstrating an initial reduction in N-acetyl aspartate followed by incomplete recovery. (From Davie CA, Hawkins CP, Barker GJ, et al: Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 1994; 117:49-58.)

K E Y

P O I N T S

●

Lumber puncture remains useful, as a negative result should strongly encourage a search for an alternative diagnosis.

●

Evoked potentials provide the only method of demonstrating the presence of a demyelinating process invivo.

●

The changes found on T2-weighted MR imaging are nonspecific and not necessarily due to demyelination.

●

In patients with vascular risk factors (including age over 50), it is worthwhile to include a sagittal cervical view in the MRI protocol.

1. Tourtellotte WW, Parker JA: Multiple sclerosis: correlation between immunoglobulin-G in cerebrospinal fluid and brain. Science 1966; 154:1044-1045. 2. McLean BN, Luxton RW, Thompson EJ: A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications. Brain 1990; 113:1269-1289. 3. Kesselring J, Miller DH, Robb SA, et al: Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis. Brain 1990; 113:291-302. 4. Zeman A, McLean B, Keir G, et al: The significance of serum oligoclonal bands in neurological diseases. J Neurol Neurosurg Psychiatry 1993; 56:32-35. 5. Freedman multiple sclerosis, Thompson EJ, Deisenhammer F, et al: Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 2005; 62:865-870. 6. Andersson M, Alvarez-Cermeño J, Bernardi G, et al: Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994; 57: 897-902. 7. Polman CH, Reingold SC, Edan G, et al: Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria. Ann Neurol 2005; 58:840-846. 8. Wolinsky JS: The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 2003; 206:145-152. 9. Halliday AM, Wakefield GS: Cerebral evoked potentials in patients with dissociated sensory loss. J Neurol Neurosurg Psychiatry 1963; 26:211-219. 10. Halliday AM, McDonald WI, Mushin J: Delayed visual evoked response in optic neuritis. Lancet 1972; 1:982-985. 11. Halliday AM, McDonald WI, Mushin J: Visual evoked response in diagnosis of multiple sclerosis. Br Med J 1973; 4:661664. 12. Matthews WB, Small DG: Serial recording of visual and somatosensory evoked potentials in multiple sclerosis. J Neurol Sci 1979; 40:11-21. 13. Walsh P, Kane N, Butler S: The clinical role of evoked potentials. Journal of neurology neurosurgery and psychiatry. J Neurol Neurosurg Psychiatry 2005; 76(suppl 2):1622. 14. Filippini G, Comi GC, Cosi V, et al: Sensitivities and predictive values of paraclinical tests for diagnosing multiple sclerosis. J Neurol 1994; 241:132-137. 15. Aminoff MJ, Eisen AA : AAEM minimonograph 19: somatosensory evoked potentials. Muscle Nerve 1998; 21:277-290.

chapter 77 investigations in multiple sclerosis 16. Trojaborg W, Petersen E: Visual and somatosensory evoked cortical potentials in multiple sclerosis. J Neurol Neurosurg Psychiatry 1979; 42:323-330. 17. Gronseth GS, Ashman EJ: Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 54:17201725. 18. Barker AT, Jalinous R, Freeston IL: Non-invasive magnetic stimulation of human motor cortex. Lancet 1985; 1:11061107. 19. Hess CW, Mills KR, Murray NM, et al: Magnetic brain stimulation: central motor conduction studies in multiple sclerosis. Ann Neurol 1987; 22:744-752. 20. Kidd D, Thompson PD, Day BL, et al: Central motor conduction time in progressive multiple sclerosis. Correlations with MRI and disease activity. Brain 1998; 121:1109-1116. 21. Cala LA, Mastaglia FL: Computerised axial tomography in multiple sclerosis. Lancet 1976; 1:689. 22. Lidegaard O, Gyldensted C, Juhler M, et al: CT findings in acute multiple sclerosis. Acta Neurol Scand 1983; 68:77-83. 23. Aita JF: Cranial CT and multiple sclerosis: contrast-enhancing lesions. Arch Neurol 1978; 35:183. 24. Drayer BP, Barrett L: Magnetic resonance imaging and CT scanning in multiple sclerosis. Ann N Y Acad Sci 1984; 436:294-314. 25. Young IR, Hall AS, Pallis CA, et al: Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 1981; 2:1063-1066. 26. Poser CM: MRI and CT scan in multiple sclerosis. JAMA 1985; 253:3250. 27. Ormerod IE, Miller DH, McDonald WI, et al: The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions. A quantitative study. Brain 1987; 110:1579-1616. 28. Thorpe JW, Kidd D, Moseley IF, et al: Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. Brain 1996; 119:709-714. 29. Newcombe J, Hawkins CP, Henderson CL, et al: Histopathology of multiple sclerosis lesions detected by magnetic resonance imaging in unfixed postmortem central nervous system tissue. Brain 1991; 114:1013-1023. 30. Lycklama G, Thompson A, Filippi M, et al: Spinal-cord MRI in multiple sclerosis. Lancet Neurol 2003; 2:555-562. 31. Thompson AJ, Kermode AG, MacManus DG, et al: Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ 1990; 300:631-634. 32. Paty DW, Li DK, Oger JJ, et al: Magnetic resonance imaging in the evaluation of clinical trials in multiple sclerosis. Ann Neurol 1994; 36(suppl):S95-S96. 33. Brex PA, Ciccarelli O, O’Riordan JI, et al: A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002; 346:158-164. 34. Chard DT, Brex PA, Ciccarelli O, et al: The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study. J Neurol Neurosurg Psychiatry 2003; 74:1551-1554. 35. Ron MA, Callanan MM, Warrington EK: Cognitive abnormalities in multiple sclerosis: a psychometric and MRI study. Psychol Med 1991; 21:59-68. 36. Kidd D, Thorpe JW, Thompson AJ, et al: Spinal cord MRI using multi-array coils and fast spin echo. II. Findings in multiple sclerosis. Neurology 1993; 43:2632-2637. 37. Filippi M, Yousry T, Baratti C, et al: Quantitative assessment of MRI lesion load in multiple sclerosis. A comparison of conventional spin-echo with fast fluid-attenuated inversion recovery. Brain 1996; 119:1349-1355.

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38. Grossman RI, Gonzalez SF, Atlas SW, et al: Multiple sclerosis: gadolinium enhancement in MR imaging. Radiology 1986; 161:721-725. 39. Hawkins CP, Munro PM, Landon DN, et al: Metabolically dependent blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis. Acta Neuropathol 1992; 83:630-635. 40. Brück W, Bitsch A, Kolenda H, et al: Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 1997; 42:783-793. 41. Miller DH, Thompson AJ, Morrissey SP, et al: High dose steroids in acute relapses of multiple sclerosis: MRI evidence for a possible mechanism of therapeutic effect. J Neurol Neurosurg Psychiatry 1992; 55:450-453. 42. Silver NC, Good CD, Barker GJ, et al: Sensitivity of contrast enhanced MRI in multiple sclerosis. Effects of gadolinium dose, magnetization transfer contrast and delayed imaging. Brain 1997; 120:1149-1161. 43. Bagnato F, Jeffries N, Richert ND, et al: Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years. Brain 2003; 126:1782-1789. 44. van Walderveen MA, Kamphorst W, Scheltens P, et al: Histopathologic correlate of hypointense lesions on T1weighted spin-echo MRI in multiple sclerosis. Neurology 1998; 50:1282-1288. 45. Truyen L, van Waesberghe JH, van Walderveen MA, et al: Accumulation of hypointense lesions (black holes) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996; 47:1469-1476. 46. Filippi M, Rocca MA, Martino G, et al: Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 1998; 43:809-814. 47. Rovaris M, Agosta F, Sormani MP, et al: Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. Brain 2003; 126:2323-2332. 48. Santos AC, Narayanan S, de Stefano N, et al: Magnetization transfer can predict clinical evolution in patients with multiple sclerosis. J Neurol 2002; 249:662-668. 49. Iannucci G, Tortorella C, Rovaris M, et al: Prognostic value of MR and magnetization transfer imaging findings in patients with clinically isolated syndromes suggestive of multiple sclerosis at presentation. AJNR Am J Neuroradiol 2000; 21:10341038. 50. Droogan AG, Clark CA, Werring DJ, et al: Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging. Magn Reson Imaging 1999; 17:653-661. 51. Wilson M, Tench CR, Morgan PS, et al: Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability. J Neurol Neurosurg Psychiatry 2003; 74:203-207. 52. Horsfield MA, Lai M, Webb SL, et al: Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance. Magn Reson Med 1996; 36:393-400. 53. Werring DJ, Brassat D, Droogan AG, et al: The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain 2000; 123: 1667-1676. 54. Brex PA, Jenkins R, Fox NC, et al: Detection of ventricular enlargement in patients at the earliest clinical stage of multiple sclerosis. Neurology 2000; 54:1689-1691. 55. De Stefano N, Matthews PM, Filippi M, et al: Evidence of early cortical atrophy in multiple sclerosis: relevance to white matter changes and disability. Neurology 2003; 60:1157-1162.

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56. Ge Y, Grossman RI, Udupa JK, et al: Brain atrophy in relapsing-remitting multiple sclerosis: fractional volumetric analysis of gray matter and white matter. Radiology 2001; 220: 606-610. 57. Peterson JW, Bö L, Mörk S, et al: Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50:389-400. 58. Rudick RA, Fisher E, Lee JC, et al: Use of the brain parenchymal fraction to measure whole brain atrophy in relapsingremitting multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Neurology 1999; 53:1698-1704. 59. Bakshi R, Benedict RH, Bermel RA, et al: Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings. J Neuroimaging 2001; 11:129-136. 60. Enzinger C, Ropele S, Smith S, et al: Accelerated evolution of brain atrophy and black holes in multiple sclerosis patients with APOE-epsilon 4. Ann Neurol 2004; 55:563569. 61. Bermel RA, Bakshi R: The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006; 5:158-170.

62. Matthews PM, Francis G, Antel J, et al: Proton magnetic resonance spectroscopy for metabolic characterization of plaques in multiple sclerosis. Neurology 1991; 41:1251-1256. 63. Narayana PA, Doyle TJ, Lai D, et al: Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998; 43:56-71. 64. Brenner RE, Munro PM, Williams SC, et al: The proton NMR spectrum in acute EAE: the significance of the change in the Cho : Cr ratio. Magn Reson Med 1993; 29:737-745. 65. Petronini PG, De Angelis EM, Borghetti P, et al: Modulation by betaine of cellular responses to osmotic stress. Biochem J 1992; 282:69-73. 67. Baslow MH: N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 2003; 28:541-553. 68. McDonald WI, Compston A, Edan G, et al: Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121-127. 69. Polman CH, Reingold SC, Edan G, et al: Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria. Ann Neurol 2005; 58:840-846.

CHAPTER

TREATMENT

OF ●

78

MULTIPLE SCLEROSIS ●

●

●

Richard Lango and Steven R. Schwid

The ultimate goals of multiple sclerosis therapy are to stop ongoing inflammatory and degenerative processes that lead to central nervous system damage and to repair the existing damage responsible for impairment, disability, and handicap. Unfortunately, there do not yet exist treatments that fully address these goals. In their absence, however, there are treatments that can reduce disease activity, delay the progression of disability, and ameliorate symptoms that affect quality of life. This chapter describes the benefits of the currently available course-modifying therapies (Table 78–1) and symptomatic treatments as demonstrated by rigorous clinical trials.

TREATMENT FOR ACUTE RELAPSES Since the early 1950s, neurologists have used corticosteroids to treat acute exacerbations.1 Placebo-controlled clinical trials2-5 have demonstrated that short-term corticosteroid treatment hastens recovery from a relapse, but the optimal treatment regimen remains unclear. Results of head-to-head comparisons of intravenous methylprednisolone and subcutaneous adrenocorticotrophic hormone have been mixed. One study of 25 patients with clinically definite multiple sclerosis6 revealed that patients receiving intravenous methylprednisolone had more rapid improvement than patients receiving intramuscular adrenocorticotrophic hormone. But this difference, seen at days 3 and 28, was no longer apparent after 3 months. Other studies were not able to demonstrate any significant difference between the agents.7-9 Typically, patients begin experiencing improvement between the first and third days of steroid treatment, and improvement continues for 15 to 45 days before symptoms stabilize clinically.4 The Optic Neuritis Treatment Trial, assessing recovery of vision in patients with their first episode of acute optic neuritis, provided further insight into the short- and long-term effects of corticosteroids on demyelination. Study patients (N = 457) received (1) intravenous methylprednisolone plus a prednisone taper, (2) prednisone alone, or (3) oral placebo. As in the earlier studies in patients with multiple sclerosis exacerbations, patients receiving steroids recovered faster, especially those receiving intravenous treatment.10 But the differences in visual acuity between the treatment and placebo recipients seen at

days 4 and 15 were no longer apparent by 6 months,10 which, again, indicates that steroids affect the timing of recovery from an attack but not the extent of the recovery.11 In general, for treatment of an acute relapse, higher doses of steroids are more effective. For example, in a study of 32 patients with relapse who were randomly assigned to receive 1000 mg of intravenous methylprednisolone per day for 1 day or 5 days, disability scores at 1 month improved more after the extended treatment.12 In another study, 2 g/day of intravenous methylprednisolone was compared with 0.5 g/day, both for 5 days, in a randomized, double-blind study of 31 patients with relapsing-remitting multiple sclerosis. Although the average improvement in disability scores was comparable between the groups, the higher dose recipients had fewer contrast-enhancing lesions on magnetic resonance imaging (MRI) at 30 and 60 days, respectively, which indicates more thorough reduction in ongoing inflammation.13 The rate of occurrence of side effects was similar in the two groups. The Optic Neuritis Treatment Trial showed that high-dose, intravenous steroid administration is more beneficial than low-dose prednisone.10 The effects of high doses of steroids given orally, however, may be more comparable. A small (N = 35) randomized, double-blind trial in which 500 mg of oral methylprednisolone was compared with 500 mg given intravenously, both for 5 days, revealed no difference in disability score at 5 and 28 days.14 The safety of oral prednisone, 1250 mg/day, has been demonstrated15; the efficacy of this approach is being studied. In rare cases, serious side effects have been reported with high-dose methylprednisolone therapy, including fatal arrhythmias,16,17 anaphylaxis,18 anaphylactoid reactions,19 and seizures.20 Although pulse-administered steroids have also been shown to transiently depress some markers of bone growth,21 a prospective study of the effect of sporadic methylprednisolone pulse treatment on bone density did not demonstrate bone loss 6 months after treatment.22 As with any intervention, these risks must be weighed against the potential benefits of treatment. Despite treatment with corticosteroids, relapses frequently leave patients with permanent deficits,23 a fact that has prompted researchers to seek additional therapies. Intravenous immunoglobulin (IVIg) infusions were shown to improve functional outcome in a small study of patients with acute

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COURSE-MODIFYING TREATMENT

disseminated encephalomyelitis refractory to intravenous steroids.24 However, in a randomized, double-blind, placebocontrolled pilot study of 19 patients with multiple sclerosis relapse, in which IVIg infusions were added to treatment with intravenous methylprednisolone, there was no difference in disability after 4 weeks; this suggests that the benefit of adding IVIg infusions to intravenous methylprednisolone is minimal at best. In two randomized, blind, controlled studies, researchers have examined the value of plasma exchange for acute exacerbations. In the first, 116 patients with an acute multiple sclerosis relapse were treated with intramuscular adrenocorticotrophic hormone plus oral cyclophosphamide, and then randomly assigned to receive 11 plasma exchange treatments or 11 sham treatments, administered over 8 weeks.25 Although patients receiving plasma exchange experienced moderately enhanced improvement after 2 weeks in comparison with the sham-treated patients, and although the median time to recovery of disability status before attack was significantly shorter in the plasma exchange recipients, there was no difference between groups at 12 months. The second controlled plasma exchange study included only patients with severe deficits from a recent demyelinating event that did not improve with intravenous corticosteroids.26 Of the 22 patients studied, 12 had multiple sclerosis; the others had an acute demyelinating syndrome such as acute disseminated encephalomyelitis, neuromyelitis optica, or transverse myelitis. Patients receiving plasma exchange were more likely to have a “moderate or greater” improvement in their primary disability score than were those receiving sham treatment (42% versus 66%), which supports the use of plasma exchange for severe multiple sclerosis exacerbations refractory to steroids.

Relapsing-Remitting Multiple Sclerosis Interferon b Interferons are cytokines normally produced by the immune system in response to viral infection. In 1993, the IFNB Study Group reported the first multicenter, randomized, placebocontrolled, double-blind study to clearly demonstrate that interferon β-1b (IFN β-1b) can modify the course of multiple sclerosis.27 Patients with relapsing-remitting multiple sclerosis (N = 372) received 1.6 MIU or 8 MIU of IFN β-1b (Betaseron) or placebo, by subcutaneous injection, every other day for up to 5 years. The primary outcome measure, annual relapse rate, was reduced by 31% in the high-dose recipients in comparison with the placebo recipients, and there was a consistent dose response for all endpoints. MRI, used innovatively, demonstrated a pathological basis for the observed clinical benefits, confirming that they reflected a persistent, profound effect on the inflammatory process.28 Reduction in the rate of accumulation of disability, however, could not be demonstrated in the post hoc analysis. In 1996, another large (N = 301), randomized, double-blind, multicenter study confirmed and extended these observations by demonstrating that IFN β—in this case, 30 μg of weekly intramuscular IFN β-1a (Avonex)—delayed the time to sustained progression of disability, defined as a one-point worsening of the Expanded Disability Status Scale (EDSS) score.29 Over 2 years, 21.9% of patients receiving interferon experienced progression of disability, in comparison with 34.9% of placebo recipients. Post hoc analysis showed that over the course of 2 years, fewer treated patients progressed to EDSS scores of 4 (moderate disability) or 6 (requiring a cane).30 The largest placebo-controlled study of IFN β in relapsing multiple sclerosis included 560 patients randomly assigned to receive 22 or 44 μg of subcutaneous IFN β-1a (Rebif) or matching placebo three times per week for 2 years. The study demonstrated that IFN β decreased the annual relapse rate by 27% to 33%, in comparison with placebo31; delayed progression of disability, as measured by the EDSS31; and prevented the accumulation of new and enlarging lesions, as demonstrated on T2-weighted MRI.32 After the 2-year placebo-controlled phase of the study, 79% of the participants continued in a 2-year exten-

T A B L E 78–1. U.S. Food and Drug Administration– Approved Course-Modifying Therapy for Multiple Sclerosis Disease Type

Drug

Relapsing

Interferon β-1a (Avonex, Rebif) Interferon β-1b (Betaseron) Glatiramer acetate (Copaxone) Mitoxantrone (Novantrone) None approved

Secondary progressive Primary progressive

(Table 78–2)

T A B L E 78–2. Demonstrated Benefits of Course-Modifying Therapies for Relapsing Multiple Sclerosis Interferon b-1a Medication

Low-Dose Treatment

High-Dose Treatment

Interferon b-1b

Glatiramer acetate

Dose Route Frequency Proten effect on relapse rate disability progression cognitive worsening gadolinium T1 lesion activity T2 lesion activity atrophy

30 μg IM Weekly

44 μg SC Three times a week

250 μg SC Every other day

20 mg SC Daily

x x x x x x

x x

x

x

x x

x x

x x

IM, intramuscular; SC, subcutaneous; x, yes.

chapter 78 treatment of multiple sclerosis sion phase, in which patients originally randomly assigned to receive active treatment continued with their assigned interferon dose, whereas patients originally assigned to receive placebo were randomly reassigned to receive either 22 or 44 μg of IFN β-1a three times weekly.33 The change to active drug decreased the relapse rate and the MRI parameters of disease of those who had initially received placebo, but they continued to have more rapid progression of disability and more MRI lesions over the entire study period than did those who had received IFN β from the start. These observations, combined with studies demonstrating significant benefits in patients treated with low doses of IFN β at the time of their first clinically apparent demyelinating event,34,35 suggest that early treatment is appropriate for preventing as much central nervous system damage and resulting disability as possible. To determine the relative benefits of different interferon formulations and dosing regimens, head-to-head studies are needed. In the largest and most rigorous of these studies to date, 677 patients with relapsing-remitting multiple sclerosis were randomly assigned to receive either subcutaneous IFN β1a (Rebif), 44 μg three times weekly, or intramuscular IFN β1a (Avonex), 30 μg once weekly for a year. The relapse rate in the high-dose, high-frequency recipients was 21% lower than that in the low-dose, weekly recipients.36 Participants on the high-dose high-frequency interferon regimen also had better control of MRI disease activity. The increase in efficacy in the high-dose recipients was associated with more frequent injection site reactions and (asymptomatic) elevations in liver enzyme levels. At the end of this comparative phase of the study, most participants continued into a cross-over phase in which all patients received the high-dose, high-frequency IFN β-1a regimen. Patients who had crossed over from low-dose, weekly IFN β-1a experienced significant reductions in relapse rates and MRI activity, in comparison with those who had continued the high-dose treatment from the start of the study.37 A smaller study in which patients were randomly assigned to receive high-dose, high-frequency IFN β-1b (Betaseron) or low-dose weekly IFNβ-1a (Avonex) yielded similar results.38 Several side effects can occur with interferon therapy. Most patients experience flulike symptoms, including myalgia, arthralgia, headache, malaise, and fever for 12 to 24 hours after each injection. This reaction is most common when treatment is initiated and tends to decrease in intensity with continued therapy. It can be minimized with dose titration and concomitant acetaminophen, nonsteroidal anti-inflammatory medications, or low doses of prednisone.39 Transient injection site reactions, with focal erythema and skin induration, are also common with subcutaneous interferon injections. Pretreatment of the injection site with a topical anesthetic or ice can ameliorate this symptom. In rare cases, injection site reactions can persist or progress into focal areas of necrosis, necessitating surgical treatment.40 There has been concern that interferons may worsen depression,41 which is common in patients with multiple sclerosis. However, a post hoc analysis of data from the large Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial demonstrated no increase in the frequency of depression in patients treated with interferon in comparison with those receiving placebo.42 Most patients develop antibodies against IFN β during treatment, especially those receiving high-dose, high-frequency treatment by subcutaneous injection. Antibodies generally arise

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in the first year of treatment and have variable persistence thereafter.43 A subset of these antibodies interferes with the effects of IFN β in in vitro assays; these have been called neutralizing antibodies. Although the results of clinical studies conflict somewhat, most studies suggest that patients with persistent high titers of neutralizing antibodies have increased signs of disease activity, although this may take years to become clinically apparent. For example, in the initial 2-year PRISMS study, antibodies to IFN β-1a did not affect clinical outcome measures,31 but in the subsequent 2-year extension phase of the study, patients with neutralizing antibodies to IFN β-1a had more relapses and MRI activity than did those without antibodies.33 Because the extension phase had no placebo condition, it was not possible to quantify any partial benefit from treatment despite the antibodies.

Glatiramer Acetate Glatiramer acetate is a mixture of synthetic polypeptides with amino acids in a ratio similar to that in myelin basic protein, a major component of the myelin sheath. In the pivotal trial, 251 patients were treated with glatiramer acetate or placebo for 2 years.44 The primary outcome, relapse rate, was reduced by 29% in those receiving active drug, in comparison to placebo. With regard to disability, those receiving placebo were more likely to experience worsening (by one EDSS point or more) over the course of the study, but the percentages of patients with “sustained disability” (lasting at least 90 days) were comparable in the two groups, as was their ability to ambulate. Most of the initially randomly assigned patients (83%) continued to be monitored in the open-label extension phase of the study,45 in which patients who initially received placebo were offered glatiramer acetate. At 6 years, those remaining in the study had substantially fewer relapses and progression of disability46 than would be predicted by natural history studies.47 At 8 years, 142 (56.6%) of the original patients remained in the study. Those receiving glatiramer acetate from the time of random assignment had a very low rate of relapse, about one every 5 years, and were also about 20% less likely to have worsening of their disability than were those who had initially received placebo.48 A separate MRI study of 239 patients with multiple sclerosis demonstrated that the mean total number of enhancing lesions was 29% lower in patients receiving glatiramer acetate than in those receiving placebo during 9 months of treatment.49 Secondary analysis showed that in patients treated with glatiramer acetate, fewer gadolinium-enhancing lesions became hypointense on T1-weighted MRI, which would indicate the most severe tissue damage.50 Most of these patients were also evaluated for changes in brain volume by MRI, but no difference could be detected between patients receiving glatiramer acetate and those receiving placebo.51 Aside from necessitating a daily injection, glatiramer acetate is generally well tolerated. Common side effects include pain and redness at the injection site, and rarely atrophy of subcutaneous fat. Symptoms resembling panic attack (flushing, palpitations, dyspnea) lasting 15 to 30 minutes occur sporadically in 10% of patients, typically immediately after injection.

Natalizumab Natalizumab is a humanized monoclonal antibody to α4β1 integrin, an adhesion molecule important for the transmigration

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of leukocytes across the blood-brain barrier. The medication was approved for prescription use in the United States in November 2004 on the basis of favorable preliminary results from two large randomized trials. In February 2005, the medication was withdrawn from the market because of the occurrence of progressive multifocal leukoencephalopathy in two patients receiving natalizumab in combination with IFN β for more than 2 years. It is hoped that additional studies will provide more information about the safe use of this medication.

Intravenous Immunoglobulin After it was demonstrated to have efficacy in the treatment of peripheral demyelinating disease,52,53 IVIg treatment was studied for the treatment of relapsing-remitting multiple sclerosis in four randomized, double-blind studies.54-59 Although the dosages of IVIg differed substantially among the studies (0.2 to 2.0 g/kg body weight/month), all four studies revealed significant benefits in the patients who received IVIg, in comparison with those receiving placebo. The largest of these studies (N = 150), the Austrian Immunoglobulin in Multiple Sclerosis Study Group,56 compared disability scores and the proportions of patients whose disability had improved, stabilized, or worsened with IVIg, 0.15 to 0.2 g/kg/month for 2 years, as opposed to placebo. Disability scores improved more among patients receiving active treatment than among placebo recipients (31% versus 14%) and worsened among fewer treated patients (16% versus 23%).56 The other three studies, which were smaller, also demonstrated differences between treatment and placebo with regard to relapse rate55,57 and number of enhancing lesions on brain MRI.59 One study, in which two dosage conditions (0.2 g/kg body weight and 0.4 g/kg body weight monthly) were used, demonstrated no differences in relapse rates between low and high doses, but both yielded better results than did placebo.55 The incidence of side effects was comparable with that of placebo in the studies that included the lower doses. High-dose (2.0 g/kg body weight/month) IVIg infusions led to adverse events more frequently than did placebo (headache, 26% versus 6%; nausea, 9% versus 0%; and urticaria, 7% versus 1%).59

Corticosteroids Corticosteroid pulse treatment clearly shortens the duration of acute relapses, but its long-term effect on disease course is less certain. Treatment of multiple sclerosis with long-term, lowdose corticosteroids has been studied for several decades and has not proved effective.60 In the Optic Neuritis Treatment Trial, patients experiencing their first demyelinating event were less likely to have another attack over the next 2 years if they were treated with intravenous methylprednisolone treatment (7.5%) than if they received oral prednisone (14.7%) or placebo (16.7%).61 The validity of this observation is unclear, however, because group differences were not sustained beyond 2 years,11 and the results have not been replicated in similar studies.62 The benefits of periodic corticosteroid pulse treatment were addressed more directly in a study of 88 patients with relapsing-remitting multiple sclerosis randomly assigned to receive a 5-day course of high-dose intravenous methylprednisolone either every 4 months or only at the time of a relapse. After 5 years, the group receiving scheduled treatments had less progression in brain atrophy and lower hypointense lesion volume

on T1-weighted MRI.63 The clinical significance of these observations remains to be determined.

3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase Inhibitors 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) have been known to have antiinflammatory effects for many years64 and have shown benefit in animal models of multiple sclerosis65,66 and in vitro studies.67 Two preliminary, uncontrolled studies of statins have been published to date. The first study (N = 7) showed that 20 mg of lovastatin per day was well tolerated, although no change in multiple sclerosis parameters could be documented. Another study (N = 30) revealed that simvastatin, 80 mg/day, decreased the average frequency of new gadolinium-enhancing lesions in comparison with patients’ pretreatment baselines.68 These preliminary study results suggest that larger controlled studies are warranted.

Clinically Isolated Syndromes Suggestive of Multiple Sclerosis Patients with a single episode of neurological dysfunction that is probably the result of demyelination, such as optic neuritis, transverse myelitis, or a brainstem syndrome, are at substantial risk for future demyelinating events. If the initial brain MRI shows a clinically silent lesion, the 10-year risk of developing multiple sclerosis is 83%, in comparison with 11% when no such lesion is demonstrated.69 Because of the preventive nature of multiple sclerosis immunotherapy, it is logical to consider treatment in patients as soon as the disease process has been identified. In two randomized, controlled studies, researchers have examined the effect of IFN β-1a on preventing progression to definite multiple sclerosis. Both studies included only patients with one or more asymptomatic brain lesion. The first, a large (N = 383) randomized, double-blind, multicenter study, showed that patients with a first-ever demyelinating event could decrease the 3-year risk of developing a second demyelinating event by 44% by using weekly intramuscular IFN β-1b (Avonex) injections.34 In addition, treated patients demonstrated improvement in several MRI parameters of disease at 18 months, including a substantial decrease in the median growth (in total volume) of T2-weighted lesions (1% versus 16%) and mean number of enhancing T1-weighted lesions (0.4 versus 1.4).34 In the second study (N = 308), a lower dosage of IFN β1a (Rebif, 22 μg) was administered subcutaneously once a week. At 2 years, this treatment decreased the risk of developing a second exacerbation by 48%.70 Treated patients also had significantly less brain atrophy than did those receiving placebo.35 IVIg has also been studied for treatment of a clinically isolated event. A randomized, double-blind study (N = 91) of highdose IVIg (2.0g/kg loading dose, with a 0.4 g/kg booster dose every 6 weeks) found that over 1 year, treated patients had a 64% reduction in the risk of progressing to definite multiple sclerosis.71

Secondary Progressive Multiple Sclerosis Most cases of relapsing multiple sclerosis eventually transition from a course with relapses intermixed with stable deficits to

chapter 78 treatment of multiple sclerosis one with progressive deficits and less prominent relapses.72 The pathophysiology underlying this transition is not completely understood, but the transition is believed to be the result of a change in the multiple sclerosis disease process from primarily inflammatory to primarily neurodegenerative.73 Because the disease-modifying therapies for relapsing-remitting multiple sclerosis are immune modulators, it might be reasonable to expect less benefit from these treatments in the secondary progressive phase.

Interferon b In four large, randomized, double-blind, multicenter trials, investigators assessed the safety and efficacy of IFN β in patients with secondary progressive multiple sclerosis.74-77 All four studies revealed that interferons decrease the annual relapse rate and improve MRI measures of disease activity and cumulative disease burden. Effects on disability progression, on the other hand, were found in the earliest European study74 but not in the other two trials, in which change in EDSS scores was the primary endpoint.75-77 The disparate results may reflect subtle differences between patients enrolled in these studies. Of most importance, more patients in the trial demonstrating IFN β effects still had a relapsing quality to their course; that subgroup appeared to be most likely to respond to treatment.78 Furthermore, the EDSS may not be responsive to change adequately to demonstrate benefits over 2 to 3 years. To address this possibility, the Improving Mood: Promoting Access to Collaborative Treatment (IMPACT) investigators used the Multiple Sclerosis Functional Composite (MSFC)79 as the primary measure of disability progression.76 In that large (N = 436) randomized, double-blind, multicenter study, patients receiving high-dose (60 μg) weekly IFN β (Avonex) had less worsening in MSFC scores at 2 years than did subjects receiving placebo. Neither group showed significant changes in EDSS scores, which confirms that the EDSS was more sensitive to change and therapeutic effects.

Intravenous Immunoglobulin IVIg, which had demonstrated enhanced remyelination in an animal model of multiple sclerosis,80 was of particular interest for patients with long-standing deficits from multiple sclerosis. Unfortunately, in two small studies of patients with secondary progressive multiple sclerosis, IVIg was not able to appreciably change either central motor conduction time81 or stable neurological deficits,82 in comparison with placebo. In the large (N = 318) randomized, placebo-controlled, multicenter European Study on Intravenous Immunoglobulin in Multiple Sclerosis (ESIMS),83 IVIg treatment (1 g/kg body weight/month) did not affect the time to progression of disability (by one EDSS point) over 2 years, its primary outcome measure. The rate of relapse was also no different between the treated patients and the placebo recipients.83 Furthermore, the improvement in MRI parameters of disease observed in earlier studies, which included patients with both relapsing-remitting and secondary progressive multiple sclerosis,59 were not seen in this study of only patients with secondary progressive multiple sclerosis. The ESIMS patients were then studied with the more sensitive magnetization transfer MRI analysis, which is believed to detect multiple sclerosis pathology in areas of white matter that appear normal on standard MRI sequences.84 No significant dif-

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ference between groups was seen with this more sensitive method.85

Mitoxantrone Chemotherapeutic agents, including azathioprine, methotrexate, and cyclophosphamide, have been used in patients in whom multiple sclerosis progresses despite other medications. One such agent, mitoxantrone (Novantrone), was approved by the U.S. Food and Drug Administration in 2000 for worsening multiple sclerosis, on the basis of the results of a large (N = 194) randomized, multicenter study in patients with worsening relapsing-remitting or secondary progressive multiple sclerosis.86 In that study, treatment with mitoxantrone infusions (12mg/m2) every three months for 2 years, in comparison with placebo, led to improvement in a composite endpoint that incorporated change in EDSS, change in ambulation index, number of relapses requiring steroids, length of time to first treated relapse, and change in a standardized neurological rating scale.86 Although mitoxantrone is generally well tolerated, the potential for serious side effects, including cardiotoxicity and leukemia, limits its use.

Primary Progressive Multiple Sclerosis It remains unclear whether primary progressive multiple sclerosis should be considered within the spectrum of inflammatory and degenerative changes seen in relapsing multiple sclerosis, or as a distinct disease.87 Regardless, MRI and pathological studies88 indicate that primary progressive multiple sclerosis has less inflammatory activity, which suggests that immunomodulatory treatments may be less effective than in relapsing multiple sclerosis. Furthermore, the lack of relapses, often the primary endpoint in studies of patients experiencing relapse, makes it difficult to study patients with primary progressive and relapsing disease in the same trial. As a result, few studies have focused on course modification in patients with primary progressive multiple sclerosis. The only treatment subjected to rigorous trials in this setting is IFN β; 50 patients were randomly assigned to receive 30 μg, 60 μg, or placebo once weekly. No effect on length of time to sustained progression of disability was demonstrated, although the study was powered only to detect large effects. MRI evidence of treatment effect was mixed: Subjects receiving 30 μg weekly had a lower rate of accumulation of T2-weighted lesion load than did subjects receiving placebo, but subjects receiving 60 μg weekly had a greater rate of ventricular enlargement than did controls.89 To date, there is no well-established treatment for these patients, although immunomodulators and chemotherapeutic agents with demonstrated efficacy in relapsing and secondary progressive multiple sclerosis are often used when advancing disability forces action.

SYMPTOMATIC THERAPY

(Table 78–3)

Spasticity Spasticity causes stiffness, cramps, spasms, and clonus. Stretching exercises can often reduce mild spasticity, but more significant symptoms necessitate medication. Both baclofen and

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T A B L E 78–3. Treatable Multiple Sclerosis Symptoms Motor Dysfunction Spasticity Tremor Weakness Fatigue Sensory Symptoms Dysesthesias Allodynia Bladder Dysfunction Urgency Retention Dyssynergia Sexual Dysfunction Erectile dysfunction Inadequate lubrication Anorgasmia Affective Symptoms Depression Anxiety Pathological laughter and crying Cognitive Impairment Attention deficits Memory deficits Executive dysfunction

tizanidine have well-established effects on spasticity.90 They have similar antispasticity effects and side effects, although tizanidine may be less likely to cause muscle weakness.91 Gabapentin and benzodiazepines may be useful adjunctive medications.92,93 Use of all of these medications tends to be limited by their tendency to cause sedation. Dantrolene, which acts directly on muscles, does not cause sedation but is more likely to cause weakness.94 In rare cases, it can cause severe liver toxicity.94 Patients with refractory spasticity often respond to intrathecal baclofen, which is infused through an implantable subcutaneous pump.95 Botulinum toxin is helpful for focal spasticity.96

Tremor Tremor can be one of the most disabling symptoms of multiple sclerosis and is generally difficult to treat satisfactorily. Occupational therapy can sometimes help patients partially compensate for tremor, with specialized utensils and positioning training.97 A wide variety of treatments, including benzodiazepines,98 primidone,99 propranolol,100 isoniazid,101 trazodone,102 5hydroxytryptamine-3 antagonists,103 and cannabinoids,104 as well as stereotactic surgery,105 have been tried but frequently prove to be intolerable and/or are only partially effective. None of these treatments has demonstrated reproducible benefits in randomized controlled trials; thus, tremor is one of the most disabling and untreatable symptoms of multiple sclerosis.

Weakness Physical therapy can help strengthen muscles that are weak as a result of disuse and can help patients learn techniques for

moving more safely and efficiently. Assistive devices such as ankle-foot orthoses, canes, and walkers can help maintain mobility despite substantial leg weakness. Individualized comprehensive rehabilitation programs have been demonstrated to improve functional abilities,106 but the duration of this benefit is unknown. Several investigators have examined the effect of 4-aminopyridine and 3,4-diaminopyridine on motor function in patients with multiple sclerosis.107,108 Modest benefits in strength, spasticity, and walking speed have been consistently demonstrated, although the optimal use of this medication remains uncertain because of a dose-dependent risk of seizures.109

Fatigue In general, management of fatigue begins with identification and amelioration of other factors contributing to it, such as depression, pain, sleep disorders, and comorbid medical conditions. Nonpharmacological treatments, including graded exercise training,110 “energy management” strategies,111 and cooling therapy,112-114 have been tried, but evidence supporting their effectiveness is limited. The main treatments demonstrated to have an effect on fatigue in placebo-controlled clinical trials are amantadine, pemoline, and modafinil, but all these studies had limitations. Of five randomized, placebo-controlled trials of amantadine,115-119 all had relatively small sample sizes (10 to 32 patients treated with amantadine) and brief treatment periods (1 to 6 weeks); in four, a cross-over design was used. The investigators used self-report measures of fatigue severity as primary endpoints and generally demonstrated modest but significant benefits of amantadine versus placebo. Pemoline is a central nervous system stimulant with dopaminergic rather than sympathomimetic effects.120 Two randomized, placebo-controlled trials of pemoline for the treatment of fatigue in multiple sclerosis have been published.119,121 Limitations of these studies are similar to those of the amantadine trials, and results conflicted. Moreover, potential liver toxicity122,123 has limited further pemoline use. Modafinil has been studied in one controlled trial, in which patients with multiple sclerosis crossed over from placebo to modafinil and back to placebo over 9 weeks.124 During treatment, scores on two commonly used self-report questionnaires improved significantly. However, the design of this study does not adequately rule out the possibility that temporary placebo effects confounded the results. In a more rigorous randomized, placebo-controlled, double-blind, parallel-group study, modafinil- and placebo-treated patients had equally dramatic improvements in questionnaire scores, which raises serious questions about its true benefits.125

Sensory Dysfunction Multiple sclerosis causes both positive symptoms (dysesthesia/allodynia) and negative symptoms (hypesthesia). Negative symptoms cannot be corrected, but they are not usually major contributors to disability. Positive sensory symptoms, on the other hand, can cause significant distress and can often be minimized with the same medications used for other forms of neuropathic pain, including antidepressants and anticonvulsants.126 Paroxysmal dysesthesias such as trigeminal neuralgia

chapter 78 treatment of multiple sclerosis are especially responsive to anticonvulsants.127 Surgical ablation can be helpful for medically refractory cases.128

Bladder Dysfunction Bladder dysfunction in patients with multiple sclerosis often causes a mixture of symptoms, including urgency, retention, and dyssynergia. Scheduled voiding may be an adequate treatment for milder symptoms. Anticholinergics are helpful when urgency, related to uncontrolled detrusor activity, is the dominant problem. α-Adrenergic antagonists may be helpful when retention is the dominant problem. Significant retention necessitates intermittent catheterization, both for extending the time between voiding episodes and for reducing the incidence of urinary tract infections. More complicated cases necessitate urodynamic monitoring and a combined approach.129

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The next step in helping patients with cognitive impairment is the development of compensatory strategies. A wide variety of approaches have been employed, including external aids (e.g., memory notebooks, calendars, pill cases, personal digital assistants) and internal aids (e.g., instruction in the use of mnemonics and visual associations). These are relatively simple strategies that can be employed by all patients. Pharmacotherapy may also be helpful in ameliorating symptoms. The effect of immunotherapies (interferon, glatiramer acetate) on cognitive function has been assessed in several studies,135,136 but the effects probably represent course modification rather than symptomatic benefit. A small single-center study showed that donepezil can improve verbal memory in mildly impaired patients with multiple sclerosis137; larger studies are under way to examine the effects of cholinesterase inhibitors in a broader group of patients.

Sexual Dysfunction

CONCLUSIONS

The most common symptoms of sexual dysfunction in women with multiple sclerosis are decreased desire, anorgasmia, and decreased lubrication. Counseling and foreplay may be helpful for all of these symptoms130; synthetic lubricants are also beneficial. Men with multiple sclerosis have erectile dysfunction, anorgasmia, and decreased desire. Again, counseling and foreplay may help all of these symptoms. Sildenafil (Viagra) has been shown to be effective for erectile dysfunction in a randomized, placebo-controlled study in patients with multiple sclerosis.131

There are currently four well-established treatments for course modification in patients with relapsing multiple sclerosis. Consensus treatment recommendations indicate that patients with active relapsing multiple sclerosis should be offered such treatments in an effort to prevent relapses and progressive disability. If the initial choice is ineffective or intolerable, an alternative should be tried. Ongoing studies are addressing additional treatment options, including optimizing the use of existing medications, identifying new therapeutic approaches, and combining treatments in safe and beneficial ways. Aside from mitoxantrone, which is generally reserved for patients with very aggressive disease, treatments for secondary and primary progressive multiple sclerosis have not clearly proved to be helpful, and so there is no standard of care for these patients. Regardless of the patient’s course and other treatments, symptomatic therapy should be offered for treatable problems, although evidence supporting the use of specific interventions is often inadequate.

Affective Symptoms Depression and anxiety are extremely common in patients with multiple sclerosis, partly because of situational factors associated with chronic disease and disability and probably also as a result of the underlying brain disease. In general, the same treatments that are helpful for depression and anxiety in the general population are equally successful in patients with multiple sclerosis. As in the general population, combined approaches with psychotherapy and medications are most effective.132 Pathological laughter and crying (pseudobulbar affect) occur in 10% of patients with multiple sclerosis and can be socially debilitating symptoms.133 They can often be treated successfully with low doses of antidepressants.134

Cognitive Impairment As with fatigue, the first step in managing patients with cognitive impairment begins with a search for factors other than multiple sclerosis that might be contributing. Depression, anxiety, and fatigue are very common symptoms in multiple sclerosis, and they can interfere considerably with both cognitive and noncognitive activities, especially those that require substantial effort. Separating the effects of affective disorders and fatigue from primary cognitive impairment is often difficult, however, and so the most logical approach is to treat all of their symptoms simultaneously. Medications may also contribute to cognitive impairment in patients with multiple sclerosis, especially medications that cause sedation or have anticholinergic properties.

K E Y

P O I N T S

●

Corticosteroids help acute relapses resolve more rapidly but not more thoroughly.

●

The optimal corticosteroid regimen remains uncertain.

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Corticosteroids are the only well-established treatment for acute relapses.

●

IFN β and glatiramer acetate have qualitatively similar benefits on clinical measures of disease activity, but interferon has a greater effect on imaging measures.

●

High-dose, high-frequency interferon reduces clinical and imaging measures of disease activity more thoroughly than does low-dose weekly interferon during the first 1 to 2 years of treatment.

●

Although the long-term benefits of IFN β and glatiramer acetate for relapsing multiple sclerosis remain difficult to quantify, there is no evidence that they lose their effects over time unless patients develop neutralizing antibodies.

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The treatments proved effective for relapsing multiple sclerosis appear to be helpful at the time of the first demyelinating event but not after progressive nonrelapsing disease develops.

●

Symptomatic treatments can be useful adjuncts to coursemodifying therapies.

Suggested Reading Beck RW, Cleary PA, Anderson MM Jr, et al: A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 1992; 326:581-588. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon β1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343:898-904. Kappos L, Weinshenker B, Pozzilli C, et al: Interferon β-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004; 63:1779-1787. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352:1498-1504. Weinshenker BG, O’Brien PC, Petterson TM, et al: A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46:878886.

References 1. Fog T: [ACTH therapy of disseminated sclerosis.]. Nord Med 1951; 46:1742-1748. 2. Miller H, Newell DJ, Ridley A: Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet 1961; 2:1120-1122. 3. Milligan NM, Newcombe R, Compston DA: A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry 1987; 50:511-516. 4. Durelli L, Cocito D, Riccio A, et al: High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations. Neurology 1986; 36:238243. 5. Rose AS, Kuzma JW, Kurtzke JF, et al: Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo—final report. Neurology 1970; 20(5):1-59. 6. Barnes MP, Bateman DE, Cleland PG, et al: Intravenous methylprednisolone for multiple sclerosis in relapse. J Neurol Neurosurg Psychiatry 1985; 48:157-159. 7. Abbruzzese G, Gandolfo C, Loeb C. “Bolus” methylprednisolone versus ACTH in the treatment of multiple sclerosis. Ital J Neurol Sci 1983; 4:169-172. 8. Milanese C, La Mantia L, Salmaggi A, et al: Double-blind randomized trial of ACTH versus dexamethasone versus methylprednisolone in multiple sclerosis bouts. Clinical, cerebrospinal fluid and neurophysiological results. Eur Neurol 1989; 29:10-14. 9. Thompson AJ, Kennard C, Swash M, et al: Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology 1989; 39:969-971.

10. Beck RW, Cleary PA, Anderson MM Jr, et al: A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 1992; 326:581-588. 11. Beck RW: The optic neuritis treatment trial: three-year follow-up results. Arch Ophthalmol 1995; 113:136-137. 12. Bindoff L, Lyons PR, Newman PK, et al: Methylprednisolone in multiple sclerosis: a comparative dose study. J Neurol Neurosurg Psychiatry 1988; 51:1108-1109. 13. Oliveri RL, Valentino P, Russo C, et al: Randomized trial comparing two different high doses of methylprednisolone in MS: a clinical and MRI study. Neurology 1998; 50:1833-1836. 14. Alam SM, Kyriakides T, Lawden M, et al: Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry 1993; 56:1219-1220. 15. Metz LM, Sabuda D, Hilsden RJ, et al: Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis. Neurology 1999; 53:2093-2096. 16. Bocanegra TS, Castaneda MO, Espinoza LR, et al: Sudden death after methylprednisolone pulse therapy. Ann Intern Med 1981; 95:122. 17. Moses RE, McCormick A, Nickey W: Fatal arrhythmia after pulse methylprednisolone therapy. Ann Intern Med 1981; 95:781-782. 18. Burgdorff T, Venemalm L, Vogt T, et al: IgE-mediated anaphylactic reaction induced by succinate ester of methylprednisolone. Ann Allergy Asthma Immunol 2002; 89:425428. 19. Pryse-Phillips WE, Chandra RK, Rose B: Anaphylactoid reaction to methylprednisolone pulsed therapy for multiple sclerosis. Neurology 1984; 34:1119-1121. 20. Suchman AL, Condemi JJ, Leddy JP: Seizure after pulse therapy with methyl prednisolone. Arthritis Rheum 1983; 26:117. 21. Cosman F, Nieves J, Herbert J, et al: High-dose glucocorticoids in multiple sclerosis patients exert direct effects on the kidney and skeleton. J Bone Miner Res 1994; 9:1097-1105. 22. Schwid SR, Goodman AD, Puzas JE, et al: Sporadic corticosteroid pulses and osteoporosis in multiple sclerosis. Arch Neurol 1996; 53:753-757. 23. Lublin FD, Baier M, Cutter G: Effect of relapses on development of residual deficit in multiple sclerosis. Neurology 2003; 61:1528-1532. 24. Marchioni E, Marinou-Aktipi K, Uggetti C, et al: Effectiveness of intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis. J Neurol 2002; 249:100104. 25. Weiner HL, Dau PC, Khatri BO, et al: Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology 1989; 39:1143-1149. 26. Weinshenker BG, O’Brien PC, Petterson TM, et al: A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46:878-886. 27. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993; 43:655-661. 28. Paty DW, Li DK: Interferon β-1b is effective in relapsingremitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 1993; 43:662-667. 29. Jacobs LD, Cookfair DL, Rudick RA, et al: Intramuscular interferon β-1a for disease progression in relapsing multiple

chapter 78 treatment of multiple sclerosis

30.

31.

32.

33. 34.

35.

36. 37.

38.

39. 40.

41. 42.

43. 44.

45.

46.

sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39:285-294. Rudick RA, Goodkin DE, Jacobs LD, et al: Impact of interferon β-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1997; 49:358-363. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352:1498-1504. Li DK, Paty DW: Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-β1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-β1a Subcutaneously in Multiple Sclerosis. Ann Neurol 1999; 46:197-206. PRISMS-4: Long-term efficacy of interferon-β-1a in relapsing MS. Neurology 2001; 56:1628-1636. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon β-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343:898-904. Filippi M, Rovaris M, Inglese M, et al: Interferon β-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:1489-1496. Panitch H, Goodin DS, Francis G, et al: Randomized, comparative study of interferon β-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 2002; 59:1496-1506. Schwid SR, Thorpe J, Sharief M, et al: Enhanced benefit of increasing interferon β-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE study. Arch Neurol 2005; 62:785-792. Durelli L, Verdun E, Barbero P, et al: Every-other-day interferon β-1b versus once-weekly interferon β-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002; 359:1453-1460. Rio J, Nos C, Bonaventura I, et al: Corticosteroids, ibuprofen, and acetaminophen for IFNβ-1a flu symptoms in MS: a randomized trial. Neurology 2004; 63:525-528. Frohman EM, Brannon K, Alexander S, et al: Disease modifying agent related skin reactions in multiple sclerosis: prevention, assessment, and management. Mult Scler 2004; 10:302-307. Mohr DC, Likosky W, Dwyer P, et al: Course of depression during the initiation of interferon β-1a treatment for multiple sclerosis. Arch Neurol 1999; 56:1263-1265. Patten SB, Metz LM: Interferon β-1a and depression in relapsing-remitting multiple sclerosis: an analysis of depression data from the PRISMS clinical trial. Mult Scler 2001; 7:243-248. Vartanian TK, Zamvil SS, Fox E, et al: Neutralizing antibodies to disease-modifying agents in the treatment of multiple sclerosis. Neurology 2004; 63(11, Suppl 5):S42-S49. Johnson KP, Brooks BR, Cohen JA, et al: Copolymer 1 reduces relapse rate and improves disability in relapsingremitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45:12681276. Johnson KP, Brooks BR, Cohen JA, et al: Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998; 50:701-708. Johnson KP, Brooks BR, Ford CC, et al: Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis

47.

48. 49.

50. 51.

52.

53.

54. 55.

56.

57. 58. 59. 60. 61.

62.

63. 64.

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patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 2000; 6:255-266. Weinshenker BG, Rice GP, Noseworthy JH, et al: The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome. Brain 1991; 114(Pt 2):1045-1056. Johnson KP, Ford CC, Lisak RP, et al: Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data. Acta Neurol Scand 2005; 111:42-47. Comi G, Filippi M, Wolinsky JS: European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging—measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49:290297. Filippi M, Rovaris M, Rocca MA, et al: Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes.” Neurology 2001; 57:731-733. Rovaris M, Comi G, Rocca MA, et al: Short-term brain volume change in relapsing-remitting multiple sclerosis: effect of glatiramer acetate and implications. Brain 2001; 124(Pt 9):1803-1812. van der Meche FG, Schmitz PI: A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. Dutch Guillain-Barré Study Group. N Engl J Med 1992; 326:1123-1129. Dyck PJ, Litchy WJ, Kratz KM, et al: A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 1994; 36:838-845. Sorensen PS, Wanscher B, Schreiber K, et al: A double-blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: preliminary results. Mult Scler 1997; 3:145-148. Lewanska M, Siger-Zajdel M, Selmaj K: No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 2002; 9:565-572. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al: Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet 1997; 349:589-593. Achiron A, Gabbay U, Gilad R, et al: Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 1998; 50:398-402. Strasser-Fuchs S, Fazekas F, Deisenhammer F, et al: The Austrian Immunoglobulin in MS (AIMS) study: final analysis. Mult Scler 2000; 6(Suppl 2):S9-S13. Sorensen PS, Wanscher B, Jensen CV, et al: Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998; 50:1273-1281. Troiano R, Cook SD, Dowling PC: Steroid therapy in multiple sclerosis. Point of view. Arch Neurol 1987; 44:803-807. Beck RW, Cleary PA, Trobe JD, et al: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med 1993; 329:1764-1769. Sharrack B, Hughes RA, Morris RW, et al: The effect of oral and intravenous methylprednisolone treatment on subsequent relapse rate in multiple sclerosis. J Neurol Sci 2000; 173:73-77. Zivadinov R, Rudick RA, De Masi R, et al: Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001; 57:1239-1247. Kurakata S, Kada M, Shimada Y, et al: Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, pravastatin sodium and simvastatin, on sterol

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72. 73. 74.

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synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacology 1996; 34:51-61. Youssef S, Stuve O, Patarroyo JC, et al: The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002; 420:78-84. Nath N, Giri S, Prasad R, et al: Potential targets of 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol 2004; 172:1273-1286. Kieseier BC, Archelos JJ, Hartung HP: Different effects of simvastatin and interferon β on the proteolytic activity of matrix metalloproteinases. Arch Neurol 2004; 61:929-932. Vollmer T, Key L, Durkalski V, et al: Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363:1607-1608. O’Riordan JI, Thompson AJ, Kingsley DP, et al: The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain 1998; 121(Pt 3):495-503. Comi G, Filippi M, Barkhof F, et al: Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357:1576-1582. Achiron A, Kishner I, Sarova-Pinhas I, et al: Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, doubleblind, placebo-controlled trial. Arch Neurol 2004; 61:15151520. Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989; 112(Pt 1):133-146. Trapp BD, Ransohoff R, Rudick R: Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999; 12:295-302. Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon β-1b in secondary progressive MS. Lancet 1998; 352:1491-1497. Randomized controlled trial of interferon-β-1a in secondary progressive MS: Clinical results. Neurology 2001; 56:14961504. Cohen JA, Cutter GR, Fischer JS, et al: Benefit of interferon β-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59:679-687. Panitch H, Miller A, Paty D, et al: Interferon β-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004; 63:1788-1795. Kappos L, Weinshenker B, Pozzilli C, et al: Interferon β-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004; 63:1779-1787. Cutter GR, Baier ML, Rudick RA, et al: Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999; 122(Pt 5):871-882. Rodriguez M, Lennon VA: Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 1990; 27:12-17. Stangel M, Boegner F, Klatt CH, et al: Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 68:89-92. Noseworthy JH, O’Brien PC, Weinshenker BG, et al: IV immunoglobulin does not reverse established weakness in MS. Neurology 2000; 55:1135-1143. Hommes OR, Sorensen PS, Fazekas F, et al: Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004; 364:11491156. van Waesberghe JH, van Walderveen MA, Castelijns JA, et al: Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and

85.

86.

87. 88.

89. 90.

91. 92.

93. 94. 95.

96.

97. 98. 99. 100. 101. 102. 103.

magnetization transfer MR. AJNR Am J Neuroradiol 1998; 19:675-683. Filippi M, Rocca MA, Pagani E, et al: European study on intravenous immunoglobulin in multiple sclerosis: results of magnetization transfer magnetic resonance imaging analysis. Arch Neurol 2004; 61:1409-1412. Hartung HP, Gonsette R, Konig N, et al: Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, doubleblind, randomised, multicentre trial. Lancet 2002; 360:2018-2025. Bjartmar C, Wujek JR, Trapp BD: Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 2003; 206:165-171. Katz D, Taubenberger JK, Cannella B, et al: Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 1993; 34:661-669. Leary SM, Miller DH, Stevenson VL, et al: Interferon β-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003; 60:44-51. Nance PW, Sheremata WA, Lynch SG, et al: Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis. Arch Neurol 1997; 54:731736. Bass B, Weinshenker B, Rice GP, et al: Tizanidine versus baclofen in the treatment of spasticity in patients with multiple sclerosis. Can J Neurol Sci 1988; 15:15-19. Cutter NC, Scott DD, Johnson JC, et al: Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000; 81:164169. From A, Heltberg A: A double-blind trial with baclofen (Lioresal) and diazepam in spasticity due to multiple sclerosis. Acta Neurol Scand 1975; 51:158-166. Pinder RM, Brogden RN, Speight TM, et al: Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity. Drugs 1977; 13:3-23. Zahavi A, Geertzen JH, Middel B, et al: Long term effect (more than five years) of intrathecal baclofen on impairment, disability, and quality of life in patients with severe spasticity of spinal origin. J Neurol Neurosurg Psychiatry 2004; 75:15531557. Hyman N, Barnes M, Bhakta B, et al: Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study. J Neurol Neurosurg Psychiatry 2000; 68:707-712. Gillen G: Improving mobility and community access in an adult with ataxia. Am J Occup Ther 2002; 56:462466. Orsnes GB, Sorensen PS: Evaluation of electronic equipment for quantitative registration of tremor. Acta Neurol Scand 1998; 97:36-40. Henkin Y, Herishanu YO: Primidone as a treatment for cerebellar tremor in multiple sclerosis—two case reports. Isr J Med Sci 1989; 25:720-721. Koller WC, Biary N: Effect of alcohol on tremors: comparison with propranolol. Neurology 1984; 34:221-222. Bozek CB, Kastrukoff LF, Wright JM, et al: A controlled trial of isoniazid therapy for action tremor in multiple sclerosis. J Neurol 1987; 234:36-39. Sanson F, Schergna E, Semenzato D, et al: [Therapeutic effects of trazodone in the treatment of tremor. Multicentric double-blind study]. Riv Neurol 1986; 56:358-364. Gbadamosi J, Buhmann C, Moench A, et al: Failure of ondansetron in treating cerebellar tremor in MS patients— an open-label pilot study. Acta Neurol Scand 2001; 104:308311.

chapter 78 treatment of multiple sclerosis 104. Fox P, Bain PG, Glickman S, et al: The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004; 62:1105-1109. 105. Schuurman PR, Bosch DA, Bossuyt PM, et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000; 342:461468. 106. Petajan JH, Gappmaier E, White AT, et al: Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol 1996; 39:432-441. 107. Bever CT Jr, Anderson PA, Leslie J, et al: Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebocontrolled, crossover trial. Neurology 1996; 47:1457-1462. 108. Schwid SR, Petrie MD, McDermott MP, et al: Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology 1997; 48:817-821. 109. Bever CT Jr, Young D, Anderson PA, et al: The effects of 4aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentrationcontrolled, crossover trial. Neurology 1994; 44:1054-1059. 110. Di Fabio RP, Soderberg J, Choi T, et al: Extended outpatient rehabilitation: its influence on symptom frequency, fatigue, and functional status for persons with progressive multiple sclerosis. Arch Phys Med Rehabil 1998; 79:141-146. 111. Stuifbergen AK, Rogers S: The experience of fatigue and strategies of self-care among persons with multiple sclerosis. Appl Nurs Res 1997; 10:2-10. 112. Schwid SR, Petrie MD, Murray R, et al: A randomized controlled study of the acute and chronic effects of cooling therapy for MS. Neurology 2003; 60:1955-1960. 113. Beenakker EA, Oparina TI, Hartgring A, et al: Cooling garment treatment in MS: clinical improvement and decrease in leukocyte NO production. Neurology 2001; 57:892-894. 114. Flensner G, Lindencrona C: The cooling-suit: case studies of its influence on fatigue among eight individuals with multiple sclerosis. J Adv Nurs 2002; 37:541-550. 115. Murray TJ: Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci 1985; 12:251-254. 116. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. The Canadian MS Research Group. Can J Neurol Sci 1987; 14:273-278. 117. Rosenberg GA, Appenzeller O: Amantadine, fatigue, and multiple sclerosis. Arch Neurol 1988; 45:1104-1106. 118. Cohen RA, Fisher M: Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol 1989; 46:676-680. 119. Krupp LB, Coyle PK, Doscher C, et al: Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995; 45:1956-1961. 120. Montuori E, Gonzalez HA, Cenal EE: [Pharmacologic study of magnesium pemoline. Mechanism of action]. C R Seances Soc Biol Fil 1974; 168:1152.

1055

121. Weinshenker BG, Penman M, Bass B, et al: A doubleblind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology 1992; 42: 1468-1471. 122. Berkovitch M, Pope E, Phillips J, et al: Pemoline-associated fulminant liver failure: testing the evidence for causation. Clin Pharmacol Ther 1995; 57:696-698. 123. Adcock KG, MacElroy DE, Wolford ET, et al: Pemoline therapy resulting in liver transplantation. Ann Pharmacother 1998; 32:422-425. 124. Rammohan KW, Rosenberg JH, Lynn DJ, et al: Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72:179-183. 125. Stankoff B Waubant E, Confavreux C, et al: Modafinil for fatigue in MS: a randomized placebo-controlled double blind study. Neurology 2005; 64:1139-1143. 126. Ross EL: The evolving role of antiepileptic drugs in treating neuropathic pain. Neurology 2000; 55(5 Suppl 1):S41-S46; discussion, Neurology 2000; 55(5 Suppl 1):S54-S48. 127. Khan OA: Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology 1998; 51:611-614. 128. Tenser RB: Trigeminal neuralgia: mechanisms of treatment. Neurology 1998; 51:17-19. 129. Andrews KL, Husmann DA: Bladder dysfunction and management in multiple sclerosis. Mayo Clin Proc 1997; 72:11761183. 130. Fowler CJ: The cause and management of bladder, sexual and bowel symptoms in multiple sclerosis. Baillieres Clin Neurol 1997; 6:447-466. 131. Miller JF, C; Sharief, M. Effect of sildenafil citrate (Viagra) on quality of life in men with erectile dysfunction and multiple sclerosis. Ann Neurol 1999; 46:496-497. 132. Mohr DC, Boudewyn AC, Goodkin DE, et al: Comparative outcomes for individual cognitive-behavior therapy, supportiveexpressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol 2001; 69:942-949. 133. Smith RA, Berg JE, Pope LE, et al: Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Mult Scler 2004; 10:679-685. 134. Schiffer RB, Herndon RM, Rudick RA: Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med 1985; 312:1480-1482. 135. Fischer JS, Priore RL, Jacobs LD, et al: Neuropsychological effects of interferon β-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol 2000; 48:885-892. 136. Weinstein A, Schwid SR, Schiffer RB, et al: Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Arch Neurol 1999; 56:319-324. 137. Krupp LB, Christodoulou C, Melville P, et al: Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63:1579-1585.

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79

ACUTE DISSEMINATED

ENCEPHALOMYELITIS AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ●

●

●

●

Richard T. Johnson Viral infections lead to a variety of demyelinating diseases of the central and peripheral nervous systems in animals and humans. These diseases may be acute or chronic with progressive or relapsing-remitting courses. The pathology and pathogenesis are varied; inflammation may or may not be prominent; the oligodendrocytes or Schwann cells that maintain the myelin may or may not be altered.1 In natural and experimental animal infections, a number of mechanisms have been studied (Table 79–1). Some involve infections of oligodendrocytes, and such infections can expose myelin membranes of the cell to systemic immune responses or can cause direct lysis of the oligodendrocytes; the latter is the apparent mechanism of demyelination in progressive multifocal leukoencephalopathy (PML) in humans. In lentivirus infections of sheep and goats, the microglia and macrophages in the central nervous system are infected, and the astrocytes and oligodendrocytes are not. Cytokines or viral proteins released by the infected cells appear to lead to myelin disruption.2 Demyelination can also result from immune responses against myelin in the absence of nervous system infection. When myelin proteins are injected in vaccines made from nerve tissues, an acute, autoimmune, demyelinating encephalomyelitis can be evoked.3 Sequence similarity between infectious agents and encephalitogenic neural proteins may lead to an autoimmune response, a phenomenon called molecular mimicry.4,5 Finally, infection can activate T cells, leading to hindered cell-mediated immune responses and inappropriate cell-mediated immune responses at the same time. This disruption of immune responses in combination with autoimmune responses is seen in human immunodeficiency virus (HIV) infections6 and appears to be the cause of acute postmeasles encephalomyelitis.7

ACUTE DISSEMINATED ENCEPHALOMYELITIS Definition Acute disseminated encephalomyelitis (ADEM) is an acute, inflammatory, demyelinating disease of the brain and spinal

cord. In most cases, it follows a viral exanthem or virus-like illness, but the disease is not specific to viral infections and has been reported after several bacterial infections, vaccinations, and drug and serum administration. Terminology is confusing. The disorder is commonly called postinfectious encephalomyelitis, or postmeasles, postvaccinal, or postinfluenzal encephalomyelitis, to describe the clinical setting. Other authors employ terms such as autoimmune or allergic encephalomyelitis, which implies that the mechanism of pathogenesis is known. Perivenular or acute demyelinating encephalomyelitis, as well as ADEM, are descriptive terms for the neuropathological changes. Because the pathology is the defining element for diagnosis, the term acute disseminated encephalomyelitis is most frequently used. Acute hemorrhagic necrotizing leukoencephalitis is regarded as an exaggerated form of ADEM. This rare disease, however, has distinct clinical and pathological features and is associated with a different spectrum of antecedent infections.8

Epidemiology ADEM occurs worldwide and in all seasons. Immunization policies, however, have dramatically altered the frequency of ADEM and the causal agents. The overall frequency has been reduced by the introduction of vaccines for childhood diseases and by the cessation of vaccination against smallpox. Measles, formerly the commonest cause of ADEM (Table 79–2), has now been eliminated in countries with universal immunization programs. Rubella and mumps virus infections have also been greatly reduced, because many countries use the combined measles-mumps-rubella vaccine. Varicella-zoster virus vaccine has also reduced the cases of ADEM. The second commonest cause of ADEM, vaccination with vaccinia virus, was eliminated after the eradication of smallpox. Before these changes, ADEM was thought to represent one third of all cases of encephalitis; now ADEM represents only about 10% of cases of acute encephalitis. The commonest infections preceding ADEM are nonspecific influenza-like illnesses. ADEM occurs after EpsteinBarr virus, Mycoplasma pneumoniae, and influenza virus infections, but the frequency is uncertain.

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T A B L E 79–1. Mechanisms of Virus-Induced CNS Demyelination CNS Infection Infection of oligodendrocytes Direct destruction Pathogenic immune response to viral antigens on cell membranes Introduction of cell membranes into systematic circulation Infection of other CNS cells Release of cytokines or viral proteins toxic to myelin-supporting cells or myelin membranes Extraneural Infection Molecular mimicry (virus proteins and myelin proteins) Disruption of immune responses From Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini R, ed: Myelin Biology and Disorders. San Diego, CA: Academic Press, 2004. CNS, central nervous system.

T A B L E 79–2. ADEM Associated with Exanthematous Viral Infections Disease

Case Rate

Vaccinia Measles Varicella* Rubella*

1 : 63 to 1 : 250,000 1 : 1000 1 : 10,000 1 : 20,000

Fatality Rate 10% 25% 5% 20%

Sequela Rate Rare Frequent 10% Very rare

*Estimates are difficult to determine because of frequency of toxic encephalopathy or Reye’s syndrome (different pathology) and acute cerebellar ataxia (unknown pathology) and the rare documentation of perivenular disease. ADEM, acute disseminated encephalomyelitis. Modified from Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia, Lippincott-Raven, 1998.

■

Figure 79–1. Acute disseminated encephalomyelitis with Epstein-Barr virus infection. The patient, a female college student, developed Monospot-positive infectious mononucleosis. Two weeks after onset, she abruptly developed multifocal neurological signs, followed by coma. The enhanced magnetic resonance image shows numerous white matter lesions with intense enhancement. The patient subsequently recovered with minimal sequelae. (Reprinted from Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 953-983.)

Clinical Features Symptoms and signs of acute encephalitis (fever, nuchal rigidity, depression of consciousness, focal neurological signs, and/or seizures) usually develop 3 days to 3 weeks after the exanthema or respiratory or gastrointestinal illness. Onset of the encephalitis is typically abrupt and reaches maximal intensity within 24 to 48 hours. Signs of the antecedent illness, such as the fading rash of measles or varicella or the persistent lymphadenopathy of Epstein-Barr virus infection, may still be detectable. The spinal fluid usually exhibits lymphocytic pleocytosis and mild elevation of protein content. Increased immunoglobulin G synthesis and oligoclonal bands are usually not found. Myelin basic protein levels may be elevated early in the disease. Virus cultures usually yield negative results. The spinal fluid is entirely normal in some cases.7,9 In the absence of a characteristic exanthema preceding the disease, differentiation from acute viral encephalitis is difficult. Magnetic resonance imaging (MRI) can be helpful; in ADEM, multiple white matter lesions of similar age or degree of enhancement are found (Fig. 79–1). Also, in the absence of an exanthem or fever, differentiation from the first attack of multiple sclerosis may be difficult; the presence of nonenhancing periventricular lesions on MRI or the presence of oligoclonal bands are consistent with the diagnosis of multiple sclerosis. Childhood onset, fever, severe depression of consciousness or coma, and seizures all are more consistent with a diagnosis of ADEM.10

Clinical signs vary with some precipitating agents. After chickenpox, one half of the neurological complications are limited to cerebellar ataxia, which may or may not represent a focal form of ADEM. Neurological disease complicates 1% of cases of infectious mononucleosis caused by the Epstein-Barr virus; some are acute demyelinating neuropathies (GuillainBarré syndrome), some are acute cerebellar ataxia, and others are typical ADEM. Each of these neurological complications characteristically has an onset 1 to 2 weeks after the onset of infectious mononucleosis, which is suggestive of a postinfectious autoimmune process. ADEM and acute demyelinating neuropathy occur as rare complications of HIV infection. These inflammatory, demyelinating complications occur primarily at the time of seroconversion with the initial activation of CD4 cells and are assumed to represent virus-induced autoimmune responses.6 Acute transverse myelitis, in some cases, may also be a localized form of ADEM. It may also occur as a result of vascular disease or tumors or as a first attack of multiple sclerosis.11

Pathophysiology When death occurs during the acute phase, the brain is swollen and congested, and on gross examination, streaks of discoloration are seen along the veins of the white matter. On micro-

chapter 79 adem and pml

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T A B L E 79–3. Comparisons of Experimental Allergic Encephalomyelitis with Encephalomyelitis after Rabies Vaccine and Viral Infections

Inducing event Latent period Clinical forms Acute onset Monophasic disease Occasional chronic or relapsing forms Pathologic findings Perivenular lymphocytes Perivenular demyelination Immunological studies Lymphocytes stimulated in vitro by myelin basic protein In vitro demyelination by lymphocytes Antimyelin protein antibodies

Experimental Allergic Encephalomyelitis

Postrabies Vaccine Encephalomyelitis

Postinfectious Encephalomyelitis

Inoculation with CNS tissue or myelin protein

Inoculation with CNS tissue

Infection with enveloped viruses

10-21 days + + +

7-42 days + + +

10-40 days* + + +

− +

− +

− +

+

+

−

+ +

? +

− −

*From beginning incubation periods. CNS, central nervous system; +, Present; −, absent; ?, unknown. Modified from Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1998.

■

Figure 79–2. Acute disseminated encephalomyelitis after chickenpox (varicella). The patient, a 12-year-old girl, developed acute paraparesis 2 weeks after the onset of uncomplicated chickenpox. Over the next 3 days, arm weakness, blindness, and seizures developed, and she died. Neuropathological examination showed widespread perivenular demyelination, as shown here in the spinal cord. (Courtesy of Carlos Pardo.)

scopic examination, mononuclear cells are found along veins and venules, and myelin loss is evident in this area of inflammation; in the spinal cord, this produces a radial pattern (Fig. 79–2). In patients who die later, the flame-shaped demyelinated lesions are more sharply demarcated and contain lipid-laden macrophages. In the 1930s, the similarity of this pathology to the perivenular demyelinating disease that complicated postexposure rabies prevention was noted. Postexposure rabies vaccine at that time consisted of inactivated virus grown in sheep or rabbit brain

and spinal cord tissue, and it was administrated as a series of daily injections over several weeks. Experimentally monkeys were similarly inoculated repeatedly with rabbit brain homogenates without virus, and this led to a disease resembling ADEM and postrabies vaccine encephalomyelitis—an experimental disease called experimental allergic (or autoimmune) encephalomyelitis.12 The experimental disease was shown to result from a cell-mediated immune response against myelin proteins. Subsequent investigations of patients with ADEM complicating measles and varicella and of patients receiving rabies vaccines prepared in central nervous system tissue have shown abnormal lymphocyte proliferation responses to purified human myelin basic protein (Table 79–3).3,7 How a variety of different viral infections leads to an autoimmune response against myelin is unclear. In the case of measles, the virus infects monocytes, which leads to lymphocyte activation and release of several cytokines. The patient cannot respond normally to new antigens and thus is immunocompromised and vulnerable to opportunistic infections. The commonest causes of death secondary to measles are respiratory and gastrointestinal opportunistic infections. Abnormal immune responses also occur, and in about 15% of patients, a lymphocyte proliferative response against myelin can be detected. In a small percentage of these patients, clinical encephalitis develops, even though no virus is found in the brain or spinal cord.7

ACUTE HEMORRHAGIC NECROTIZING LEUKOENCEPHALITIS This disorder probably represents a hyperacute form of ADEM. However, it rarely follows the exanthems frequently associated in the past with ADEM; it usually follows nonspecific respiratory illnesses. One to 20 days after the prodromal illness, the patient develops fever, severe obtundation, seizures, and neurological signs often suggestive of a mass lesion. Most such patients die within 5 days. The spinal fluid shows polymorphonuclear cells and red blood cells; peripheral leukocytosis and proteinuria are usually present. The pathological specimen

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demonstrates gross swelling with multiple hemorrhages; microscopically, both veins and arterioles exhibit fibrinoid necrosis with extravasations of fibrin and red blood cells; the inflammatory infiltrates are predominantly polymorphonuclear. Despite the large areas of necrosis, the findings are most intense in the white matter, and myelin loss is more prominent than axonal destruction.13 Some authorities regard this as a distinct disease, but most think this disease represents a continuum with ADEM. It occurs in similar postinfectious settings despite a distinct spectrum of precipitating infections; the pathological changes overlap in some cases, and an animal model of hyperacute experimental allergic encephalomyelitis has been developed with all the pathological features of acute hemorrhagic necrotizing leukoencephalitis.

Prevention and Treatment Introduction of vaccines for childhood viral infections and discontinuation of vaccination against smallpox have had a major effect in reducing the incidence of ADEM. The maintenance of vaccination programs is essential for continued prevention. No treatment has been shown to be effective once the disease occurs. Although many anecdotal reports of the efficacy of corticosteroids are in the literature, the limited randomized or retrospective analyses of steroid treatment are suggestive of no significant benefit. Intensive supportive care is often necessary; lowering of fever, management of seizures, artificial ventilation, reducing intracranial pressure, and prevention of pulmonary, urinary, and skin infections are important, because remarkable recoveries are possible from ADEM even after prolonged coma.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

middle age, more than 70% have antibody. No clinical symptoms or signs have been associated with the primary infection.

Clinical Features PML can develop insidiously at any time during the course of the underlying immunodeficiency disorder. It is the AIDSdefining disease in 1% of HIV-infected patients and is usually not manifested until the CD4 count is low. Paralysis, mental deterioration, visual loss, and sensory abnormalities are the common manifestations; symptoms and signs are often indicative of multifocal disease. Hemiparesis and hemianopsia are common early findings. Signs of cerebellar, brainstem, and spinal cord involvement occur but are less frequent. Affected patients are usually afebrile and free of headache. The presenting deficits progressively worsen; new signs indicating new areas of cerebral involvement evolve, and the course is usually unremitting, leading to death in 3 to 6 months. The spinal fluid is generally normal with no pleocytosis, normal protein content, and no abnormalities or increase in immunoglobulins. In patients with HIV infections, however, cell and protein level elevations may result from central nervous system infection coexistent with HIV. The electroencephalogram shows nonspecific findings. Serological tests for JC virus antibody are of no help, inasmuch as antibody is present in most adults, its levels are not unusually elevated in PML patients, and it is not found in spinal fluid. Polymerase chain reaction testing for JC virus in spinal fluid is a useful diagnostic method and has a sensitivity rate of 80% to 90%.17 Computed tomographic imaging or MRI of the brain provides an important clue to the diagnosis of PML. Lucencies on computed tomography or densities on T2-weighted MRI images have a characteristic pattern of multiple nonenhancing lesions of subcortical white matter.

Pathology and Pathogenesis Definition PML is a subacute demyelinating disease caused by a papovavirus, JC virus, in immunocompromised hosts.

Epidemiology PML was originally described in 1958 as “a heretofore unrecognized complication of chronic lymphocytic leukemia and Hodgkin’s disease.”14 It was subsequently reported in patients undergoing aggressive immunosuppression to treat connective tissue diseases and to prevent rejection of transplanted organs. Nevertheless, PML remained a very rare disease. During the first 25 years after its description, only one case was diagnosed at the Johns Hopkins Hospital. With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980s, the disease abruptly became common, representing the cause of death in about 4% of patients with AIDS.15 The disease affects patients with AIDS worldwide. The JC virus is a papovavirus originally isolated in 1971 from the brain of a young man who had PML complicating Hodgkin’s disease.16 The virus is ubiquitous but has not been definitely associated with any other illness. The majority of people develop antibody to JC virus between 1 and 14 years of age; by

The neuropathological findings in PML are unique. On gross examination of the brain, discolored lesions in the white matter are evident, ranging from pinpoint size to large confluent areas of leukomalacia. Lesions are most prominent at the cortical white matter junction (Fig. 79–3). Microscopically, foci show a relative sparing of axons and a loss of both oligodendrocytes and myelin. Many oligodendrocytes surrounding the demyelinated foci are greatly enlarged and contain large intranuclear inclusions with a “ground glass” appearance (Fig. 79–4). Within the demyelinated areas, astrocytes are enlarged and have bizarre mitotic forms, multiple nuclei, and multilobular nuclei. In the original description of PML, the authors stated that “astrocytes of this sort are ordinarily met with only in neoplastic processes.”14 Inflammatory cells are usually absent or in minimal numbers. Immunocytochemical staining for JC virus antigens in glial cells confirms the diagnosis on biopsy or autopsy brain tissue. Speculation that a virus infection might be causative arose from the finding of inclusion bodies and the occurrence of the disease in immunosuppressed patients (Fig. 79–5). In 1965, astonishing electron microscopic findings demonstrating that the inclusion bodies consisted of crystalline arrays of particles corresponding in size to polyomaviruses were published.18 At that time, no human polyomaviruses were known, but through

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Oligodendrocyte

Astrocyte ■

Figure 79–4. Schematic diagram of the selective vulnerability of neural cells in progressive multifocal leukoencephalopathy. Within the demyelinated focus, the oligodendrocytes are depleted; surrounding the focus, they are greatly enlarged and contain large intranuclear inclusion bodies that are packed with virions, often in pseudocrystalline arrays. Within the demyelinated focus, astrocytes are enlarged and many have bizarre forms; some are multinucleated, others contain mitotic figures. The neurons (not shown in the diagram) appear normal, and many intact but demyelinated axons course through the demyelinated focus. (Modified from Johnson RT: Viral Infections of the Nervous System. Philadelphia: Lippincott-Raven, 1998.)

■

Suggested primary routes of infection

Figure 79–3. Progressive multifocal leukoencephalopathy in a middle-aged man with Hodgkin’s disease. Small lesions concentrated along the cortical white matter junction show confluence that will ultimately become large demyelinating lesions undercutting the cortical ribbon. (Photomicrograph of section from Case 3 of Astrom KE, Mancall EL, Richardson EP: Progressive multifocal leukoencephalopathy. Brain 1958; 81:93-127. Reprinted by permission of Oxford University Press.)

the use of human fetal brain cultures, JC virus, the first known human polyomavirus, was isolated.16 Initial infection with JC virus in childhood is probably through the respiratory route. Latent virus has been shown in bone marrow and kidneys, and virus has been found in tonsils and urine. B cells have been implicated in the spread of virus, and these cells are thought to carry the virus to the brain after activation in immunosuppressed patients.19 In the brain, JC virus is unique. Highly productive infection occurs only in oligodendrocytes. Astrocytes in lesions express T antigen, have bizarre forms, and appear to proliferate, which are indications of viral transformation; however, contrary to true transformation, astrocytes contain small numbers of virions. In contrast, except for patches of granular cells in the cerebellum, neurons and other cells appear resistant to infection.20

TREATMENT Both cytarabine (Ara-C), a nucleoside used in cancer therapy, and cidofovir, an antiviral agent effective in the treatment of cytomegalovirus retinitis and genital herpes, have been reported in case reports and small case series to stabilize or to improve PML. Controlled trials of both drugs, however, have

Respiratory inhalation

Gastrointestinal tract Initial infection Asymptomatic Viral dissemination B

Spleen

Tonsil+

Lung

Viral latency and activation

Colon

Liver

Kidney*+

B Blood brain barrier

Periphery Brain Astrocytes ■

Bone* marrow

Oligos

Figure 79–5. Schematic diagram of the pathogenesis of systemic infection with JC virus. Primary infection is by unknown route (probably respiratory or gastrointestinal); during asymptomatic infection, virus latency is established in the kidneys and bone marrow; activation has been demonstrated in the kidneys and tonsils, and B cells are infected. Transit of virus into the brain in plasma or B cells is thought to lead to selective infection of glial cells. Asterisk denotes sites of presumed JC virus latency; plus signs denote Active JC replication has been demonstrated. (Modified from Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 953-983.)

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failed to show differences in survival between treated and untreated patients. In patients with PML complicating immunosuppressive therapy, the reduction of the immunosuppressant medication is thought to stabilize or retard the disease. The institution of highly active antiretroviral therapy (HAART) for HIV infections has shown the validity of this strategy. The immune status often improves with HAART, and clinical symptoms, radiological findings, and survival times of PML can improve with treatment.21 This is not a panacea, however, inasmuch as PML can develop in patients while they are receiving HAART, and the decrease in HIV load and increase in CD4 cell counts provided by HAART are not always correlated with improvement in PML.22

that affects severely immunocompromised patients, predominantly those with AIDS. The disease has an insidious onset and a progressive course of multifocal symptoms and signs. In most cases, the disease leads to death in 3 to 6 months. Selective infection and destruction of oligodendrocytes by a papovavirus, JC virus, causes the disease. No effective treatment is known except the reversal of the immunodeficiency state.

Suggested Reading CONCLUSIONS Both ADEM and PML are demyelinating diseases; that is, the pathology is more prominent in white matter, in which there is myelin loss and a relative preservation of axons. Lesions do occur in the cortex, and axons are interrupted within demyelinated areas of ADEM and PML, just as they are in multiple sclerosis. Both ADEM and PML are clearly related to specific viral infections, but here the similarity ends. ADEM is an acute disease predominantly of previously healthy children, and the pathology and pathogenesis show remarkable parallels to experimental allergic encephalomyelitis. In the case of postmeasles encephalomyelitis, the disease occurs after virus clearance by the immune response, and measles virus in brain cells has not been found at the time of the acute encephalopathy. In contrast, PML is an opportunistic infection of severely immunodeficient patients. The disease is subacute or chronic and noninflammatory. In this case, direct selective vulnerability of oligodendrocytes leads to demyelination. The diseases demonstrate contrasting examples of how viral infections can cause demyelinating diseases.

K E Y

P O I N T S

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Demyelinating diseases can be caused by viral infections. Myelin destruction can occur by direct infection of oligodendrocytes, by toxins or cytokines released by other neural cells, and by immune responses evoked against myelin antigens even without infection of the nervous system.

●

ADEM is an acute, perivenular, demyelinating disease of the brain and spinal cord that occurs after a variety of infections and some vaccinations. The disease generally has an acute onset with fever, multifocal signs, and impaired consciousness days or weeks after the inciting event. Abnormal immune responses to myelin proteins can be found in some cases even when the infection has not involved the nervous system. Treatment should focus on intensive supportive care; corticosteroids are often given, but their efficacy in unproved.

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Progressive multifocal leukoencephalopathy is a subacute or chronic demyelinating disease of the central nervous system

Garg RK: Acute disseminated encephalomyelitis. Postgrad Med J 2003; 79:11-17. Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1998. Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 953-983. Koralnik IJ: New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004; 17:365-370.

References 1. Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 953-983. 2. Kennedy PG, Narayan O, Ghotbi Z, et al: Persistent expression of Ia antigen and viral genome in visna-maedi virus–induced inflammatory cells. Possible role of lentivirus-induced interferon. J Exp Med 1985; 162:1970-1982. 3. Hemachudha T, Phanuphak P, Johnson RT, et al: Neurologic complications of Semple-type rabies vaccine. Neurology 1987; 37:550-556. 4. Fujinami RS, Oldstone MB: Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985; 230:10431045. 5. Wucherpfennig KW: Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 2001; 108:10971104. 6. Jones HR, Ho DD, Forgacs P, et al: Acute fulminating fatal leukoencephalopathy as the only manifestation of human immunodeficiency virus infection. Ann Neurol 1988; 23:519522. 7. Johnson RT, Griffin DE, Hirsch RL, et al: Measles encephalomyelitis—clinical and immunologic studies. N Engl J Med 1984; 310:137-141. 8. Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1998. 9. Tenembaum S, Chamoles N, Fejerman N: Acute disseminated encephalomyelitis. A long-term follow-up study of 84 pediatric patients. Neurology 2002; 59:1224-1231. 10. Dale RC, de Sousa C, Chong WK, et al: Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000; 123:2407-2422. 11. Al Deeb SM, Yaqub BA, Bruyn GW, et al: Acute transverse myelitis. A localized form of postinfectious encephalomyelitis. Brain 1997; 120:1115-1122. 12. Rivers TM, Schwentker FF: Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. J Exp Med 1935; 61:689-702.

chapter 79 adem and pml 13. Sharmeela K, Ostrow P, Landi MK, et al: Acute hemorrhagic leukoencephalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology 2003; 60:721-722. 14. Astrom KE, Mancall EL, Richardson EP: Progressive multifocal leukoencephalopathy. Brain 1958; 81:93-127. 15. Berger JR, Kaszovitz B, Post MJD, et al: Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infections. A review of the literature with a report of sixteen cases. Ann Intern Med 1987; 107:78-87. 16. Padgett BL, Walker DL, ZuRhein GM, et al: Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. Lancet 1971; 1:1257-1260. 17. McGuire NM, Barhite S, Hollander H, et al: JC virus DNA in cerebrospinal fluid of human immunodeficiency virus– infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol 1995; 37:395-399. 18. ZuRhein GM, Chou S-M: Particles resembling papovaviruses in human cerebral demyelinating disease. Science 1965; 148:1477-1479.

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19. Tornatore C, Berger EO, Houff SA, et al: Detection of JC virus DNA in peripheral lymphocytes for patients with and without progressive multifocal leukoencephalopathy. Ann Neurol 1992; 31:454-462. 20. Koralnik IJ, Wuthrich C, Dang X, et al: JC virus granular cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005; 57:576-580. 21. Clifford DB, Yiannoutsos C, Glicksman M, et al.: HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 1999; 52:623-625. 22. Cinque P, Bossolasco S, Brambilla AM, et al: The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003; 9(Suppl 1):73-80.

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Hugo W. Moser and Sakkubai Naidu

The leukodystrophies are now defined as disorders that (1) have a known or presumptive genetic cause; (2) have a progressive clinical course; (3) involve predominantly and usually confluently central nervous system (CNS) white matter; and (4) are characterized by a primary lesion of myelin or myelinating cells. This is the definition recommended by Powers1 and conforms to that proposed by Bielschowsky and Henneberg, who introduced this name in 1928.2 These diseases must be distinguished from abnormalities of myelin caused by infectious or toxic agents, disturbances of blood flow, anoxia or asphyxia, trauma, or genetic disorders in which damage to myelin or myelinating cells is a secondary event. The understanding, definition, and classification have been enhanced greatly by the combined use of neuroimaging and genetic techniques. Magnetic resonance imaging (MRI) is a powerful tool for the definition and categorization of leukoencephalopathies of unknown origin.3,4 For instance, MRI pattern analysis, combined with clinical data, led to the recognition that vanishing white matter disease5 (also referred to as childhood ataxia with diffuse central nervous hypomyelination)6 and megalencephalic leukoencephalopathy with subcortical cysts (MLC)7 are distinct clinical entities. Rapid application of positional cloning led to the identification of the gene defects.8-10 Although conventional MRI techniques have been of great value for the definition and classification of the leukodystrophies, these are now being supplemented by proton magnetic resonance spectroscopy (MRS), diffusion tensor imaging, and magnetization transfer techniques. One review summarized these novel techniques, as well as the current understanding of the alterations of myelin structure and function that underlie the neuroimaging abnormalities.11 Although these techniques represent important advances, van der Knaap cautioned against “diagnostic euphoria,”3 because for up to 50% of children with white matter abnormalities evident on MRI, no specific diagnosis could be established despite repeated MRI and extensive laboratory investigations.11 The 12 leukodystrophies in which the gene defect has been defined are the primary focus of this chapter.

X-LINKED ADRENOLEUKODYSTROPHY Other names12 by which this disease is known include adrenomyeloneuropathy, Schilder’s disease, Addison’s disease with diffuse sclerosis, encephalitis periaxialis diffusa, Bronzekrankheit, and skelosierende encephalomyelitis.

Clinical Features13,14 Phenotypes Male Patients Childhood Cerebral Phenotype This form is characterized by inflammatory demyelination. The onset occurs between ages 3 and 10 years. The initial presentation resembles attention deficit/hyperactivity disorder. Progressive behavioral, cognitive, neurological, and visual deficits often lead to total disability within 3 years of onset. Eighty percent of patients have primary adrenocortical insufficiency. This form affects about 35% of the total male population with adrenoleukodystrophy.

Adolescent Cerebral Phenotype This form has an onset between ages 11 and 21 years. It resembles the childhood cerebral form with somewhat slower progression. It affects about 5% of the total male population with adrenoleukodystrophy.

“Pure” Adrenomyeloneuropathy This form is a noninflammatory distal axonopathy that affects spinal cord long tracts and peripheral nerves. The mean age at onset is 28 ± 9 years. Slowly progressive paraparesis, sphincter disturbances, sexual dysfunction, and impaired vibration and position sense in the legs are characteristics. Some cases progress over decades; some patients survive to the ninth decade. This form affects 30% to 40% of the total male population with adrenoleukodystrophy.

“Adrenomyeloneuropathy Cerebral” Form Pure adrenomyeloneuropathy combined with rapidly progressive inflammatory brain disease manifests with behavioral disturbances, psychiatric symptoms, dementia, and seizures. The brain disease may coincide with or, more commonly, be superimposed on pure adrenomyeloneuropathy. This form affects about 15% of the total population with adrenoleukodystrophy.

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Adult Cerebral Dementia Behavioral disturbances and sometimes focal deficiencies occur without preceding adrenomyeloneuropathy. There is a brain white matter inflammatory response. The progress of this form parallels that of the childhood cerebral form. About 3% of the total male adrenoleukodystrophy population is affected.

Olivopontocerebellar Phenotype15 This form consists mainly of cerebellar and brainstem involvement. It affects 1% to 2% of the total male population with adrenoleukodystrophy.

Addison-Only Phenotype This type is characterized by primary adrenocortical insufficiency (Addison’s disease). The onset is common before 7.5 years. The disease is most common in childhood but also occurs in adolescents and young adults. Virtually all of the patients with the Addison-only phenotype later develop one of the neurological phenotypes.

Female Patients Approximately 50% of women heterozygous for the adrenoleukodystrophy gene develop pure adrenomyeloneuropathy in middle age or later.16 The onset is later, and progression is slower than in male patients, but disability may be severe, necessitating the use of a wheelchair. Inflammatory brain disease17 and clinically or biochemically demonstrable adrenal insufficiency18 are rare in this disorder. They are present in about 1% of women heterozygous for the adrenoleukodystrophy gene.

Pathology Inflammatory Cerebral Phenotype In the inflammatory cerebral forms, there is loss of myelin, which is confluent and usually symmetrical with caudorostral progression.19 The periventricular and central white matter are involved. Cavitation and calcification may be seen. Arcuate fibers are relatively spared. In the most common form with posterior manifestation, the posterior cingulum, corpus callosum, fornix, hippocampal commissure, posterior limb of the internal capsule, and optic systems are typically involved. The cerebellar white matter exhibits similar but milder changes. In about 15% of affected patients, the cerebral pathology begins in the frontal white matter and advances rostrocaudally. Histopathological study reveals marked loss of myelin and, to a lesser degree, axons and a loss of oligodendrocytes in association with hypertrophic reactive astrocytosis. The pathology of the inflammatory cerebral lesions can be subdivided into three zones, which are also demonstrable in imaging studies.20 Zone 1, the advancing active edge of myelin loss, includes areas of intense perivascular inflammation and accumulation of lipidladen macrophages. In Zone 2, there are large perivascular collections of mononuclear cells, particularly lymphocytes and mostly CD8 cytotoxic cells,21 which are highly characteristic in the area of early breakdown. In Zone 3, there are gliosis, loss of myelin, and variable loss of axons. In the inflammatory cerebral forms, there is also secondary corticospinal tract degener-

ation extending down through the peduncles, basis pontis, medullary pyramid, and spinal cord.

Pure Adrenomyeloneuropathy The spinal cord bears the brunt of the disease process in men with pure adrenomyeloneuropathy and also in neurologically symptomatic women heterozygous for the adrenoleukodystrophy gene. Loss of myelinated axons and a milder loss of oligodendrocytes, but with little or no inflammatory response, are observed in the long ascending and descending tracts of the spinal cord.22 The pattern of fiber loss is consistent with a distal axonopathy in that the greatest losses are observed in the distal segments: that is, the cervical region for the ascending fasciculus gracilis and the low thoracic and lumbar segments for the descending corticospinal tract. The number of dorsal root ganglion cells is not reduced. This is indicative of axonal pathology and not neuronal damage as the primary event.23 Mitochondria are abnormal and contain lipid inclusions.24 Peripheral nerve lesions in adrenomyeloneuropathy are variable and mild in comparison with those of the myelopathy. Sural and peroneal nerves have displayed loss of large- and small-diameter myelinated fibers, endoneurial fibrosis, and thin myelin sheaths.25,26 Neurophysiological studies in 18 patients suggest that primary axonal pathology (present in 67%) is the principal abnormality. Only 9% of the patients fulfilled the electrodiagnostic criteria for primary demyelination.27

Adrenal Cortex and Testis Adrenocortical cells become ballooned as a result of the accumulation of lamellae, lamellar lipid-laden cells, and fine lipid clefts. The striated material, which contains cholesterol esters esterified with very-long-chain fatty acids (VLCFAs), appears to lead to cell dysfunction, atrophy, and death.28 In fetuses affected by X-linked adrenoleukodystrophy (X-ALD), the fetal adrenal zone is already severely involved.29 In the testes, lamellae and lamellar lipid-laden cells are present in the interstitial cells of Leydig and their precursors. Degenerative changes in the seminiferous tubules and Sertoli cells are observed in adrenomyeloneuropathy30 and may eventually lead to azoospermia.31

Neuroimaging Inflammatory Cerebral Phenotypes The most common MRI abnormality in the childhood inflammatory phenotype is a pattern that involves the parietooccipital white matter most severely. It is present in about 80% of affected patients.32-34 Arcuate fibers are relatively spared. After administration of gadolinium–diethylenetriamine pentaacetic acid contrast material, a rim enhancement can be seen surrounding the most severely affected area. Three zones can often be identified.32 The outer advancing zone is in the process of active demyelination without inflammation. Inflammation is present in the second zone. The third zone is completely demyelinated and gliotic, and cavitation and calcification may be present. Demyelination advances in the frontal direction. Structures that are affected relatively early are the lateral and medial geniculate bodies and, in some cases, the lateralinferior part of the thalamus, the posterior limb of the internal capsule, and the external capsule. In the brainstem, there is involvement of the occipitoparietotemporopontine and pyram-

chapter 80 the leukodystrophies idal tracts, the brachia of the inferior colliculus and of the superior colliculus, and the lateral lemniscus. In approximately 15% of patients, the process starts in the frontal area with concomitant involvement of the rostrum and genu of the corpus callosum and of the anterior limb of the internal capsule,32,34 and then it spreads caudally. On occasion, the initial lesions are in the pons and cerebellum.35 The initial lesions may be asymmetrical and mistaken for a brain tumor.36 Proton MRS abnormalities precede changes demonstrable by conventional MRI37-39 and can be predictive of outcome; they aid in the selection of patients for hematopoietic cell transplantation (HCT) therapy and in the evaluation of therapies.40 Reduction of N-acetyl aspartate levels is the earliest change; increases in the choline peaks are correlated with the extent of the demyelinative process.

Adrenomyeloneuropathy Conventional brain MRI usually appears normal in patients with “pure” adrenomyeloneuropathy. Abnormalities may be seen in the corticospinal and frontopontine tracts and have been interpreted as centripetal extension of the distal axonopathy.34,41 Brain MRS studies in patients with pure adrenomyeloneuropathy have revealed evidence of diffuse axonal pathology.42 Studies of the spinal cord with conventional MRI have demonstrated diffuse atrophy mainly in the lower thoracic cord.41 The magnetization transfer MRI appears to be a sensitive method for the quantitation of structural abnormalities in adrenomyeloneuropathy.43

Genetics The mode of inheritance is usually classified as X-linked recessive, but the fact that 50% of heterozygous women are neurologically symptomatic indicates that a designation as X-linked is more accurate, as proposed by Dobyns and associates.44 The disease incidence is estimated at 1 per 17,000 and appears to be the same in all ethnic groups.45 The defective gene has been mapped to Xq28.46 The gene codes for a peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP).47 ALDP is a member of the adenosine triphosphate–binding cassette (ABC) transporter superfamily.48 Forty-eight mammalian ABC transporters are estimated to exist. They transport a variety of substrates, including ions, sugars, amino acids, proteins, and lipids.49 Four mammalian peroxisomal ABC transporters have been identified and are designed as subgroup ABCD. The gene deficient in X-ALD has been assigned the name ABCD1. ABCD2 may also be relevant to X-ALD (see section on therapy). ABCD2, which has been mapped to 12q11, codes for the adrenoleukodystrophy-related protein ALDR, which has 66% homology with ALDP50 and can substitute for some of the functions of ALDP.51,52 More than 500 mutations in ALDP have been identified in patients with X-ALD53 and are updated in the X-linked Adrenoleukodystrophy Database website (www.x-ald.nl). Fiftyseven percent of the mutations are nonrecurrent, and many are unique to a kindred. Of all the mutations, 55.9% were found to be missense mutations, 27.1% nonsense mutations, 3.9% small in-frame amino acid insertions or deletions, and another 3.9% large deletions of one or more exons.53 No correlation between phenotype and genotype has been demonstrated. A single mutation may be associated with a wide range of phenotypes.54 It is common for widely varying phenotypes to co-occur in the same family. The action of a modifier gene has been postulated.55,56

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Diagnosis Definitive diagnosis of X-ALD depends on the demonstration of biochemical abnormalities and on results of mutation analysis. Demonstration of characteristic abnormalities in the levels of saturated VLCFAs in plasma is the most frequently used test.57 Statistically significant increases in the levels of hexacosanoic acid (C26 : 0) and in the ratios of C26 : 0 to C24 : 0 and to C22 : 0 are present in more than 99% of male patients with adrenoleukodystrophy and in approximately 85% of women heterozygous for the X-ALD gene.58 Increases in VLCFA levels in patients with other peroxisomal disorders, such as Zellweger’s syndrome, neonatal adrenoleukodystrophy, and infantile Refsum’s disease,59 can usually be distinguished easily on the basis of clinical manifestation and tests of the other peroxisomal functions. Patients on the ketogenic diet may produce false-positive results60; VLCFA levels are also increased in cultured skin fibroblast,61 and study of cultured fibroblasts can be helpful when results of plasma samples are equivocal. VLCFA levels are also increased in red blood cell membranes,16,62 in leukocytes,63 and in cultured amniocytes64 and chorionic villus cells.65 The plasma VLCFA assay57 is highly reliable for the identification of affected male patients. Abnormalities are already present on the day of birth.57 There are two reports of falsenegative test results in a total of three male patients with XALD,66,67 but this has not observed in more than 100 affected male patients.57 In contrast, false-negative results occur in 15% to 20% of women heterozygous for the X-ALD gene. Because of this, mutation analysis is much preferred for the determination of carrier status in women at risk for X-ALD. More than 500 pathogenic mutations in the ABCD2 gene have been identified in patients with X-ALD53 and are updated in the X-linked Adrenoleukodystrophy Database website. Reliable methods for their identification in affected men and in heterozygous women have been published.68 The first step is to define the nature of the mutation in affected male family members or in a family member who is an obligate carrier. Once the mutation is found in a nuclear family member or a more distant relative, it can be determined whether this mutation exists in lymphoblasts or cultured fibroblasts of the at-risk person. VLCFA analysis in cultured amniocytes or chorion villus samples is a valuable technique for the identification of affected fetuses.65 However, false-negative results have been reported,69,70 and confirmation by mutation analysis should be performed when the nature of the mutation has been defined in an affected male patient or obligate heterozygote family member.

Pathogenesis Role and Pathogenesis of Very-Long-Chain Fatty Acid Excess The abnormal accumulation of saturated VLCFAs is the principal biochemical abnormality in X-ALD.14,71 There is considerable evidence that this contributes to pathogenesis, according to studies in model membranes72 and in cultured human adrenal cells73 and correlative studies in postmortem brain74 and adrenal tissue.75 Excess saturated VLCFAs are normally oxidized in the peroxisome.76 This process is impaired in cultured skin fibroblasts, leukocytes, and amniocytes of patients with X-ALD.77 The defect in X-ALD was localized to the first step:

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namely, the formation of the coenzyme ester of VLCFA acids.78,79 This reaction is catalyzed by VLCFA–coenzyme A synthetase (VLCS).80 VLCS structure and levels are normal in patients with X-ALD and in the X-ALD animal model.81-83 ALDP, the protein that is deficient in X-ALD, is required for the oxidation of VLCFA in fibroblasts of patients with X-ALD.51,52,84 ALDP has no homology with VLCS; as already noted, it is a member of the ABC transporter superfamily.48 The mechanism by which ALDP influences VLCFA metabolism is complex and not yet understood.85 Adding to the complexity are findings of several earlier86 and more recent studies87 that suggest that VLCFA synthesis is also increased in X-ALD.

Pathogenesis of Pure Adrenomyeloneuropathy The studies of Powers and associates established that the primary defect in pure adrenomyeloneuropathy is a noninflammatory axonopathy that affects most severely the distal portions of the dorsal columns and corticospinal tracts in the spinal cord.22,23 The demyelination appears to be secondary to the axonal damage. The mechanism responsible for the axonal dysfunction has not been defined. It is postulated that the VLCFA excess destabilizes the axonal membrane or impairs the function of trophic factors.23 Mitochondrial abnormalities23 and oxidative stress88 have been proposed as contributing to pathogenesis. The pathology and clinical features in the mouse model of X-ALD resemble those of adrenomyeloneuropathy,89 and further studies in this model may increase understanding of the pathogenesis of adrenomyeloneuropathy.

Pathogenesis of Inflammatory Cerebral Forms of X-Linked Adrenoleukodystrophy The most generally accepted concept for the pathogenesis of the inflammatory response is that the accumulation of VLCFA has an adverse effect on myelin and oligodendrocyte stability and function, which renders them vulnerable to various other adverse events (a “second hit”), which in turn initiates a destruction cascade that results in the death of oligodendrocytes and rapid destruction of myelin.90 Cytokines, such as tumor necrosis factor α, play an important role.91 Apoptosis of oligodendrocyte has been reported.92 Ito and colleagues21 demonstrated that most of the perivascular cells that accumulate in the active demyelinating lesions are CD8 cytotoxic cells. They concluded that oligodendrocyte death was lytic/cytotoxic rather than apoptotic. There was strong CD1 immunoreactivity in astrocytes and microglia. CD1 molecules are antigenpresenting glycoproteins that, unlike the major histocompatibility complex proteins, can present self-lipid antigens to T-cells.93 This has led to the intriguing hypothesis that VLCFAcontaining complex lipids, which are present in brain tissue from patients with X-ALD but not in normal brain tissue, act as triggers for the autoimmune response in patients with the inflammatory adrenoleukodystrophy phenotype. Asheuer and associates94 demonstrated decreased expressions of an ABCD transporter gene (ABCD4) and a VLCS (BG1) in patients with X-ALD and their susceptibility to the inflammatory phenotype. This is the first demonstration of a possible genotypephenotype correlation in X-ALD.

Therapy Three forms of therapy are in current use: (1) adrenocortical hormone replacement; (2) HCT; and (3) dietary therapy with Lorenzo’s oil.

Steroid Replacement Therapy The importance of evaluating adrenal function and providing appropriate replacement therapy cannot be overemphasized. Steroid replacement therapy in general does not alter neurological progression, except possibly in some patients with adrenomyeloneuropathy,95 but it can improve strength and well-being and may be lifesaving. Most male patients with X-ALD have increased plasma adrenocortical hormone and impairment of cortisol responsiveness to a 0.25-mg intravenous dose96 of cosyntropic (Cotrosyn) after 60 minutes. The authors and colleagues recommend that at least one of these tests be performed yearly. Isolated measurements of plasma cortisol levels are insufficient and may lead to the false conclusion that adrenal insufficiency has been ruled out. Glucocorticoid dose requirements are generally the same as those used for other forms of primary adrenal insufficiency.97 To mimic diurnal rhythms of physiological cortisol secretion, adult patients receive 25 mg of cortisone acetate or 20 mg of hydrocortisone in the early morning and a smaller second dose, 12.5 or 10 mg, respectively, in the late afternoon. The dosage in children is 5 to 10 mg per 24 hours. Not all require mineralocorticoid replacement. When postural hypotension, hyponatremia, or hyperkalemia does persist despite adequate glucocorticoid therapy, fludrocortisone, 0.05 mg to 0.1 mg/day, is prescribed.

Hematopoietic Cell Transplantation HCT is an important therapeutic modality for the cerebral inflammatory forms of X-ALD. Either bone marrow cells or umbilical cord cells are used.98 Aubourg and coauthors99 were the first to report stabilization and reversal of neurological manifestation in an 8-year-old boy who had early evidence of cerebral involvement. This patient was healthy 10 years later (P. Aubourg, personal communication, July 2000). Shapiro and associates100 reported long-term stabilization in patients who had received bone marrow cells. Peters and colleagues98 provided follow-up on 126 patients with X-ALD who received HCT. This study provided important guidelines in regard to the selection of patients for HCT. The overall 5-year survival rate was 56%, compared with an estimated 45% rate among untreated patients. The rate of transplantation-related mortality was 14%. Outcome with respect to mortality, morbidity, and quality of life was unsatisfactory for patients who were already severely ill at the time of HCT, and the procedure is not recommended for them. In contrast, the 5-year survival rate was 92% in a group of patients whose neurological involvement (performance IQ > 80) and neuroradiological involvement (Loes MRI score < 9, range = 0-34)101 were still relatively mild, and the procedure is recommended for them. Peters and colleagues98 provided a more detailed discussion of the indications for HCT. At this time, the procedure is not recommended for asymptomatic patients with normal MRI findings or for those with pure adrenomyeloneuropathy. The mechanism of the beneficial effect of bone marrow cell transplantation is incompletely understood.14

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Dietary Therapy with Lorenzo’s Oil

Juvenile Form

Lorenzo’s oil is a 4 : 1 mixture of glyceryl trioleate and glyceryl trierucate. It has the remarkable biochemical effect of normalizing the plasma levels of VLCFA in patients with X-ALD within 4 weeks, probably by inhibiting endogenous VLCFA synthesis.102 Investigators reported that administration of Lorenzo’s oil to asymptomatic boys who had normal brain MRI findings significantly reduced their risk of developing childhood cerebral XALD.103 It was recommended that asymptomatic patients with normal brain MRI findings who are younger than 8 years be placed on a carefully supervised program of Lorenzo’s oil and dietary therapy. Adrenal function and brain MRI appearance must be monitored at 6-month intervals. Lorenzo’s oil does not alter significantly the neurological progression in patients with X-ALD who already have evidence of inflammatory cerebral involvement104,105 and in adrenomyeloneuropathy.106 However, results of a single cohort study suggested that it may slow the progression of adrenomyeloneuropathy in patients who did not have evidence of cerebral involvement.107 A double-blind placebo-controlled study of Lorenzo’s oil therapy in men and women with pure adrenomyeloneuropathy is now in progress. Other pharmacological therapeutic approaches have shown therapeutic potential in preclinical studies and preliminary clinical trials. These include 4-phenylbutyrate,51 lovastatin,108,109 and lovastatin with arginine butyrate.110 Gene replacement therapy is under active investigation. Preclinical studies have shown encouraging results.111,112

Age at onset ranges from 4 to 16 years. Patients show gradual deterioration in school performance, slurred speech, clumsy gait, and incontinence. There may also be emotional or behavioral disturbances. Within a year, spastic paresis and cerebellar ataxia develop, and patients are no longer able to walk. Deep tendon reflexes are usually brisk, optic atrophy develops, and, in 50%, epileptic seizures occur. The illness progresses to complete tetraplegia and a decerebrate state. Most patients die before the age of 20 years. A distinction can be made between early and late juvenile forms. The early variant has its onset between the ages of 4 and 6 years and resembles the late infantile form in that gait disturbance and other motor dysfunctions are early manifestations. In the late juvenile form (onset between the ages of 6 and 16 years), behavioral abnormalities, poor school performance, and language regression appear first, followed by gait disturbance.

METACHROMATIC LEUKODYSTROPHY Other names for metachromatic leukodystrophy (MLD) include Scholz-Bielschowsky-Henneberg diffuse cerebral sclerosis and sulfatide lipidosis.

Adult Form Onset of adult MLD has been reported at varying ages up to age 63.115 Patients show gradual decline in intellectual abilities. They become emotionally labile and show memory deficits, disorganized thinking, behavioral abnormalities, or psychiatric symptoms such as hallucinations or delusions.116 Clumsiness of movement and urinary and sometimes fecal incontinence are also present. A progressive spastic paresis of the arms and legs develops, with increased tendon reflexes and extensor plantar reflexes. Ataxia and extrapyramidal symptoms and dystonia may be present, as well as optic atrophy and signs of bulbar dysfunction. Peripheral neuropathy is often absent.117

Pathology Clinical Manifestations There are late infantile, juvenile, and adult manifestations. In about 75% of patients, the late infantile and juvenile forms are equally divided in frequency. The other 25% have the adult form.113

Late Infantile Form This form manifests between 6 months and 4 years of age and has been subdivided into four clinical stages.114 In clinical stage I, there is hypotonia of the legs or of all four limbs. If the child is walking, the gait becomes unsteady. Deep tendons are diminished or absent. This stage lasts for a few months to more than a year. In stage II, the child can no longer stand and shows mental regression. Speech deteriorates as a result of dysarthria and aphasia. Nystagmus, ataxia, and truncal signs develop, and muscle tone in the legs is increased. This stage lasts only a few months. In stage III, the flaccid paresis is superseded by spastic tetraplegia with pathological reflexes and extensor plantar reflexes, and the child becomes bedridden. Feeding difficulties and episodes of airway obstruction occur. About 25% of patients develop epileptic seizures. In stage IV, the patients enter a decerebrate state and lose all contact with their surroundings. Death usually occurs about 5 years after onset of clinical symptoms.

The pathology of MLD in the nervous system is characterized primarily by demyelination and deposits of metachromatic granules in the central and peripheral nervous systems. Highresolution electron microscopy of the storage granules revealed that the inclusions are surrounded by a membrane, which suggests that they are located in the lysosome.115 The central white matter is reduced in amount, is firm, and in severely affected regions may show cavitation of spongy degeneration. The subarcuate fibers are usually spared. There is moderate to severe loss of myelin sheaths. The intrafascicular oligodendrocytes are reduced in number. There is a striking accumulation of metachromatic granules in macrophages that are prominent in perivascular spaces and also in oligodendrocytes and in neurons. Immunocytochemical studies have shown that the accumulated material in neurons and glial cells contains sulfatide.118 The cerebellum is atrophic with severe demyelination, prominent gliosis, storage granules, and a reduction of Purkinje cells. The peripheral nervous system shows segmental demyelination. Metachromatic granules are present in Schwann cells and in endoneurial macrophages.

Neuroimaging MRI reveals periventricular white matter abnormalities with a symmetrical distribution.119 In juvenile and adult cases, there

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is preferential frontal lobe involvement. The arcuate fibers are relatively spared. The corpus callosum is invariably affected. The posterior limb of the internal may be involved. Brainstem lesions in the pyramidal tract may be observed, and the cerebellar white matter may be involved. Contrast enhancement is usually absent; this helps differentiate MLD from X-ALD, in which enhancement is often prominent. Diffusion-weighted images vary with the stage of the illness. Oguz and associates reported that diffusion was restricted in the early stage and increased in the later stage.120 MRI in MLD often exhibits radially oriented hypointense stripes in T2-weighted hyperintense areas. Postmortem studies in which neuroimaging patterns were correlated precisely with histopathological findings revealed that the stripes corresponded to perivenular zones in which there was relative preservation of myelin, together with the accumulation of lipid-laden glial cells.121

lation signal. A pseudodeficiency allele is common. It is present in 10% to 20% of Europeans. As a result, 1% to 2% of Europeans display a substantial deficiency of arylsulfatase A activity (5% to 15% of normal values). This degree of reduction of arylsulfatase A activity does not appear to pose health risks, but it complicates the differential diagnosis of MLD.

Saposin B Deficiency A small number of patients with clinical features that resemble those of MLD have a deficiency of saposin B, the sulfatide activator protein. These patients have increased levels of sulfatide in tissues and urine, but arylsulfatase A activity is normal. Nine cases have been reported and include patients with late infantile, juvenile, and adult onset.123 The molecular defects involve homoallelic point mutations that destroy a glycosylation site.

Multiple Sulfatase Deficiency Genetics The mode of inheritance is autosomal recessive. The incidence of late infantile MLD varies in different countries.115 MLD appears to be most common in northern Sweden, where the incidence is estimated to be 1 per 40,000 among some groups, and among Arabs living in Israel. In France and in Germany, the incidence was estimated to be 1 per 130,000 to 1 per 170,000. The defective gene has been mapped to locus 22q13. It codes for arylsulfatase A, which catalyzes the desulfation of 3sulfogalactosyl–containing glycolipids. Four such glycolipids have been identified.115 Of these, galactosylceramide-3-sulfate is present in the highest concentration and most relevant to MLD.

Metachromatic Leukodystrophy–Causing Mutations Sixty-three MLD-causing mutations have been identified. The mutations can be subdivided into two general categories: the null alleles, in which the mutation does not allow synthesis of any function, and the R-alleles, in which there are low amounts of residual enzyme activity. Null alleles tend to be associated with the late infantile phenotype, R-alleles with the adult phenotype, and heterozygosity for null and R-alleles with the juvenile phenotype. However, there is considerable phenotypical variability of severity when patients with the identical genotype are compared.122 Among European patients, three defective alleles occur with high frequency. The most common (15% to 43%) bear a splice donor site mutation of the exon 2/intron 2 border (459+1A→G), a null mutation. The second most frequent (16% to 25%) is an amino acid substitution at proline 426→leucine. The substitution Ile 179→Ser is the third most common (12%). The two latter are R-allele mutations.

Pseudodeficiency Genes The term pseudodeficiency is applied to patients who have about 5% to 15% of normal arylsulfatase A activity but are clinically normal. The arylsulfatase A enzyme in pseudodeficient individuals has two polysaccharide side chains instead of the three that are normally present. This abnormality can be caused by two polymorphisms, one leading to the loss of Nglycolysation sites and the other leading to loss of polyadeny-

In multiple sulfatase deficiency, the catalytic activity of 12 sulfatases, including arylsulfatase A, is impaired. More than 50 cases have been described.124 The clinical manifestation resembles that of classic MLD but with certain additional features such as mildly coarse features, dysostosis multiplex, stiff joints, ichthyosis, hydrocephalus, deafness, and enlarged liver, attributable to defects in one of the other sulfatases. The gene defect leads to reduced activity of a post-translational system that generates an α-formyl glycine residue from a thiol group of an active site cysteine that is conserved in all members of the mammalian sulfatase family.

Diagnosis The laboratory diagnosis of MLD depends on the demonstration of decreased arylsulfatase A activity and increased excretion of sulfatide in urine. The arylsulfatase A assay is performed in peripheral blood leukocytes or cultured fibroblasts.125 The major problems in the enzymatic diagnosis is the frequent occurrence of the clinically benign pseudodeficiency alleles, which reduce arylsulfatase A activity. Measurement of urinary sulfatide excretion is key to the distinction between MLD and pseudodeficiency. This excretion is markedly increased in patients with MLD and normal in patients with pseudodeficiency or in persons heterozygous for the MLD-causing mutation.126 MLD and pseudodeficiency can also be distinguished by the sulfatide loading assay.127 Patients with multiple sulfatase are distinguished by demonstration of deficient activity of arylsulfatase B and C, in addition to the defect of arylsulfatase A. Patients with saposin B deficiency have normal arylsulfatase A activity, but their sulfatide loading value and urinary sulfatide excretion are increased. Mutation analysis is of great value for the identification of persons heterozygous for the MLD-causing mutation. It detects the pseudodeficiency. However, it must be kept in mind that alleles bearing the relatively common pseudodeficiency polymorphism may, in addition, contain an MLD-causing mutation.

Pathogenesis The accumulation of sulfatide, secondary to the deficiency arylsulfatase A, is the principal biochemical abnormality in MLD.

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The sulfatides accumulate mainly within the lysosome. The sulfatide accumulation is noted in several extraneural tissues, such as the gallbladder, liver, kidneys, pancreas, adrenal cortex, and sweat glands, but it leads to pathological changes only in the gallbladder. The demyelination that occurs in MLD appears to be secondary to sulfatide-induced changes within the cells responsible for myelin maintenance: namely, the oligodendrocytes in the CNS and the Schwann cells in the peripheral nervous system.129 Changes in the subcellular organelles of these cells are observed before any morphological abnormalities in the myelin sheaths associated with them are detectable.115 Investigators who used immunocytochemical techniques have demonstrated the accumulation of sulfatides in neurons and glial cells in arylsulfatase A–deficient mice.118 The degeneration of neurons and glia is enhanced and accelerated by the secretion of proinflammatory cytokines by monocytes.130 Other pathogenetic mechanisms that may contribute are impaired myelin stability secondary to its abnormal biochemical composition131 and the abnormal accumulation of sulfogalactosylsphingosine (lysosulfatide).132 Lysosulfatide has been shown to inhibit the activity of protein kinase C and cytochrome oxidase at concentrations far below those found in tissues of patients with MLD.132,133

ness of the limbs. Slight regression of psychomotor development, feeding difficulties, and vomiting may be observed. Early peripheral nervous system manifestations are common.143 In stage II, there is rapid deterioration. There is marked hypertonicity, with extended and crossed legs, flexed arms, and arched back. Optic atrophy and sluggish pupillary reflexes are common. Stage III is the “burnt-out” stage, sometimes reached within few weeks or months. The child is in a decerebrate state, is blind, and has no contact with his or her surroundings. Patients rarely survive for more than 2 years. Juvenile- and adult-onset cases are well documented. The juvenile cases have been subdivided into the late infantile (early childhood)–onset form, which begins at ages 6 months to 3 years, and the late childhood–onset form, which begins at ages 3 to 8 years.144 The early childhood form progresses rapidly, with death approximately 2 years after onset. The late childhood cases manifest with loss of vision and with hemiparesis, ataxia, and psychomotor regression; death occurs 10 months to 7 years after onset. The number of reports of adult-onset cases is increasing. Progressive paraparesis and tetraparesis with demyelination in the spinal cord are often the main abnormalities. One female patient developed slowly progressive paraparesis at 38 years of age.145 Other cases were misdiagnosed as amyotrophic lateral sclerosis.146

Therapy

Pathology

Bone marrow transplantation is under investigation as a therapy for MLD. It has not been effective in symptomatic patients with the late infantile form of the disease and may even accelerate the progression of the disease.134 Several reports suggest that bone marrow transplantation arrests the progression in patients with the juvenile- or adult-onset MLD phenotype.135-137 Evaluation of these results is difficult because of the relatively short follow-up and the variability of progression in untreated patients. Several presymptomatic patients have undergone transplantation.138,139 Longer follow-up is necessary to assess effectiveness. Therapeutic studies in the mouse model of MLD are highly encouraging. Ex vivo administration of genetic modification of hematopoietic stem cells led to a remarkable correction of neuropathological changes.140 Matzner and coauthors reported the unexpected and surprising findings that intravenous administration of purified arylsulfatase A improved nervous system pathology and function.141

The pathology is confined mainly to the nervous system.147 Postmortem examination reveals that the brain is small and atrophic, with shrunken gyri and widened sulci. The major histopathological changes are demyelination, gliosis, and the presence of unique macrophages, the globoid cells in the white matter. The subarcuate fibers tend to be spared. The phylogenetically newer fiber tracts are usually more involved in the demyelinating process. In the spinal cord, the pyramidal tracts are more affected than are the dorsal columns. The oligodendroglial cell population is severely diminished in the areas of demyelination. Globoid cells are clustered around blood vessels and may be multinucleated. They contain tubular inclusions that have morphological similarities to the inclusions of pure galactosylceramide.148 Secondary axonal degeneration is a consistent finding. The peripheral nerves are commonly affected. They show endoneurial fibrosis, proliferation of fibroblasts, and segmental demyelination. Inclusions similar to those in the globoid cells in the brain are found in the cytoplasm of histiocytes, macrophages, and Schwann cells.

GLOBOID LEUKODYSTROPHY Other names by which globoid leukodystrophy (GLD) is known include Krabbe’s disease, galactosylceramide lipidosis, globoid cell leukoencephalopathy, and galactocerebroside (GalC) deficiency.

Clinical Features The infantile form of the disease is most common. Hagberg and associates subdivided the course of the disease into three stages.142 In stage I, the child, apparently normal during the first few months after birth, becomes hyperirritable and hypersensitive to auditory and tactile stimuli, and there is some stiff-

Neuroimaging In the early stages, computed tomographic changes may be more evident than MRI changes. In stage I, computed tomographic scans may be normal or exhibit symmetrical increased density in the thalami, the corona radiata, and the posterior limb of the internal capsule and basal ganglia.149 MRI confirms the presence of white matter abnormalities with relative sparing of arcuate fibers in infantile-onset GLD (Fig. 80–1). The posterior limb of the internal capsule, corpus callosum, cerebellar white matter, and brain tracts are also involved. In cases of adult-onset GLD, both computed tomography and MRI reveal predominant involvement of the occipital periventricular white matter with extension in the parietal and temporal direction

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Figure 80–1. Globoid leukodystrophy. Classic disease is shown, with posterior occipital white matter abnormalities that may be mistaken for adrenoleukodystrophy (A). Adult-onset isolated corticospinal tract involvement (B) can be traced to the lower brainstem (D to F). Corpus callosal involvement can also been seen (C).

and associated involvement of the splenium of the corpus callosum, a pattern that resembles that seen in X-ALD. In adultonset cases, symmetrical high–signal intensity lesions may be evident on T2-weighted MRI in frontoparietal white matter, the centrum semiovale, and the posterior limb of the internal capsule, with sparing of the periventricular white matter (see Fig. 80–1).145 MRS in patients with infantile-onset GLD revealed pronounced elevation of myoinositol- and choline-containing compounds, which reflected gliosis and demyelination. Nacetyl aspartate levels were decreased, which reflected neuroaxonal loss.150

Genetics The mode of inheritance is autosomal recessive. The gene has been mapped to loci 14q24.3-32.1. It codes for galactocerebroside (psychosine) β-galactosidase. The incidence is estimated to be 1 per 100,000 in the United States but appears to be higher in the Scandinavian countries. More than 60 mutations have been identified.147,151 Although there is no consistent correlation between genotype and phenotype,152 some associations have been identified. The 502T/del mutation accounts for 50%

of mutant alleles in The Netherlands and 75% in Scandinavian countries. The mutation probably occurred initially in Sweden and traveled from there throughout Europe, Asia, and the United States. This 30-kilobase deletion eliminates all of the coding region of one of the subunits of the enzyme, and patients who are homozygous for this deletion have the severe infantileonset phenotype. Two other mutations, C1538T and A1652T, account for about 10% to 15% of mutant alleles of infant patients with European ancestry. The G809A mutation is common in patients with adult-onset GLD. One copy of the G809A mutation is probably enough to explain a mild phenotype in heterozygous patients whose other allele has a mutation that usually is associated with a severe phenotype.147 A series of polymorphic changes in the gene that occur on the same allele as disease-causing mutations have been identified; they influence the enzyme activity and clinical manifestations in persons who are heterozygous for GLD-causing mutations.153

Diagnosis Assays of GalC activity in peripheral leukocytes or cultured fibroblasts is the most reliable method for diagnosis.154 Leuko-

chapter 80 the leukodystrophies cyte and cultured fibroblast results are equally reliable. Wenger and colleagues147 listed citations for validated techniques that use natural substrates. The same assay in cultured amniotic cells or in biopsy specimens of chorionic villi is used for prenatal diagnosis, but it is valuable for measuring the GalC enzyme activity in the carrier parents beforehand, because some carriers have enzyme levels that are sufficiently low to characterize them as homozygous affected. When this is the case, special care must be taken in the interpretation of the results of the prenatal study, and the results can be complemented by mutation analysis. The wide range of enzyme activity in normal individuals and in carriers, which results mainly from polymorphic amino acid changes that cause a wide range in the values tested, limits the reliability of the enzyme assay for carrier identification. In families in which the mutations have been defined, carrier status is determined by mutation analysis. An important diagnostic development is the progress that has been made toward mass neonatal screening for lysosomal disorders, including GLD,155-157 Neurophysiological studies, such as motor conduction velocity and visual and auditory evoked responses are abnormal in most patients with GLD,158 but it is important to realize that they may be normal in patients with the adult-onset phenotypes.159

Pathogenesis The globoid cell, the hallmark pathological feature of GLD, is the consequence of the accumulation of galactosylceramide. Galactosylceramide is unique among sphingolipids in its ability to elicit the globoid cell reaction when injected into normal rat brain.160 Even though the galactosylceramide thus plays a role in some aspects of the pathogenesis of GLD, there is increasingly compelling evidence that it is the accumulation of psychosine (sphingosine-galactose) that is the principal pathogenetic factor. This pathogenetic mechanism, now referred to as the psychosine hypothesis, was first proposed by Miyatake and Suzuki161 and reexamined in detail 25 years later by Suzuki.162 GalC, the gene product that is deficient in GLD, catalyzes the degradation of both galactosylceramide and psychosine. Psychosine is present in very low concentration in normal brain tissue, but its concentration in GLD white matter is increased 100-fold.147 Psychosine with its free amino group is highly cytotoxic. Its effect is mediated by caspase activation.163 Psychosine-induced apoptosis is a mouse oligodendrocyte precursor line mediated by caspase activity. Oligodendrocytes are selectively destroyed because psychosine formation occurs primarily in these cells. The molecular mechanisms of psychosine-induced cell death have been clarified.164 Psychosine-induced apoptosis in human oligodendrocyte cell line studies in animal models, particularly the canine model and the twitcher mouse, have been of great value for the studies of pathogenesis of GLD and its therapy.165

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(CSF) diminished.166 The effect of HCT in patients with infantile-onset GLD and in asymptomatic infants with GLD has been evaluated.167 Although the symptomatic boys with infantile GLD experienced no benefit, there was strong evidence of a beneficial effect in 11 asymptomatic newborns who received umbilical cord blood transplants at 12 to 44 days after birth. At the time of follow-up (median age, 3.0 years) they had ageappropriate cognitive function and receptive language skills, and serial MRI studies demonstrated progressive central myelination. There is no doubt the procedure has a profound effect with regard to mortality and early development, but there were mild-to-moderate delays in expressive language and gross motor function. Additional follow-up is needed to assess the long-range outcome. Ethical aspects of this therapeutic approach were discussed in an editorial.168 Another approach, therapy aimed to reduce the concentrations of substrate, is being tested in experimental animals.169 Studies of transplantation of neural cells and direct infection of the brain with viral vector containing GalC, are in progress in experimental animals.

PELIZAEUS-MERZBACHER DISEASE Pelizaeus-Merzbacher disease is known as several entities: classic Pelizaeus-Merzbacher disease,170 connatal PelizaeusMerzbacher disease,171,172 X-linked spastic paraparesis type 2 (SPG2),173,174 proteolipid protein (PLP) null syndrome, and pure spastic paraplegia.

Clinical Features Classic Pelizaeus-Merzbacher Disease This disorder is characterized by abnormal eye movements (horizontal or rotatory) with onset during the first months of life; psychomotor deterioration before 2 years of age; and the appearance of bilateral pyramidal tract signs, dystonia, and often ataxia during the first years of life. Laryngeal stridor and optic atrophy are frequent.170

Connatal Pelizaeus-Merzbacher Disease This disorder is characterized by nystagmus at birth, pharyngeal weakness, stridor, hypotonia, severe spasticity, and seizures.174

Complicated Spastic Paraplegia This disorder is characterized by nystagmus, ataxia, and spastic gait, but little or no cognitive impairment.174

Pure Spastic Paraplegia Therapy HCT and bone marrow transplantation for GLD are under intense investigation. HCT was of benefit in four patients with adult-onset GLD: CNS deterioration was reversed, MRI findings improved in three patients, and levels in cerebrospinal fluid

This disorder is characterized by autonomic dysfunction (spastic urinary bladder) and spastic gait, but cognition is normal. The life span is normal. Women heterozygous for Pelizaeus-Merzbacher disease may develop spastic paraplegia, which resembles pure spastic paraplegia or SPG2 in men.175

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Pathology Features include lack of myelin in all parts of the CNS. Islets of preserved myelin around blood vessels in deeper parts of brain produce the so-called tigroid pattern. Axons are relatively preserved. Oligodendrocytes are reduced in number, as is the number of cytoplasmic processes. A length-dependent axonal degeneration is also present.173

toms of classic Pelizaeus-Merzbacher disease or SPG2. Virtually all patients with Pelizaeus-Merzbacher disease eventually have MRI findings consistent with a leukodystrophy.187,188 A search for proteolipid protein 1 (PLP1) gene duplication is the most efficient initial screening test. Both interphase fluorescent in situ hybridization and quantitative polymerase chain reaction should be used.182 If neither method yields a positive result, direct sequencing of the PLP1 gene should be performed.189 Prenatal diagnosis has been accomplished.190

Neuroimaging MRI reveals an arrest of myelination. In some cases, no myelin appears to be present; in other cases, myelin is present in parts of the brainstem, cerebellar white matter, the posterior limb of the internal capsule, the thalamus, and the globus pallidus. The pattern described is normal for a neonate or an infant in the first few months of life, although not normal at the age of the patient. The white matter may appear speckled, reflecting the tigroid pattern seen pathologically. There also is evidence of neuroaxonal injury, based on the demonstration of significant and widespread reduction in brain N-acetyl aspartate levels.176

Genetics The mode of inheritance is X-linked recessive. Some women heterozygous for Pelizaeus-Merzbacher disease develop neurological progressive paraparesis.175,177,178 The gene maps to locus Xq22 and codes for PLP. This protein makes up approximately 50% of myelin protein weight. It is composed of four helices that span the cell membrane. Portions of the protein chain extend into the extracellular space, where they have a homophilic interaction with PLP molecules in adjacent spirals of the cell membrane.179 This region is visualized as the intraperiod line on electron microscopy.180 Duplication of the region surrounding locus Xq22 accounts for the majority, perhaps up to 70%, of the mutations in PLP.181 These duplications arise from sister chromatid exchange. Striking variations in the breakpoints and in the size of the duplication occur.182,183 Most patients with mutations have the classic phenotype182; some have the connatal form,184 and others have the mild SPG2 phenotype. Deletions of the PLP locus occur only rarely.185,186 Patients in whom no PLP protein product is formed, referred to as null mutations, tend to have a mild phenotype with relatively mild spastic paraparesis, which progressed during adolescence and (unlike that in classic Pelizaeus-Merzbacher disease) was associated with demyelinating peripheral neuropathy.173 About 20% of patients have point mutations at the PLP locus that alter the amino acid sequence of the PLP/DM20 proteins. Approximately 100 distinct mutations have been discovered to date. The majority of abnormal PLP/DM20 proteins result in severe phenotypes through a toxic gain of function, whereas the remainder result in a milder form that is associated with loss of function.

Pathogenesis Because mutations in which no PLP1 protein is synthesized lead to the mildest disease, it has been postulated that toxic effects are caused either by overexpression of the gene in patients with duplications of the normal gene or by the presence of mutant genes. In patients with the gene duplications, excessive amounts of PLP1 have been shown to accumulate in the late endosomal and lysosomal compartments. PLP1 normally is associated with cholesterol and other lipids to form “lipid rafts” that traffic through the Golgi compartment. In rodent models of Pelizaeus-Merzbacher disease in which there is an excess of PLP1, these lipid rafts are shunted to the late endosomal and lysosomal compartments, effectively draining myelin lipids from the Golgi compartment.191 In patients with mutations in the PLP1 coding region, the differences in clinical severity appear to be related to differential effects of the mutation on protein folding and trafficking.192 These unfolded proteins accumulate in the endoplasmic reticulum, and this leads to the unfolded protein response.193,194 This response, which involves the increased expression of unfolded protein response effector genes, protects the cell against metabolic stress to preserve or reestablish homeostasis. In cells in which homeostasis cannot be maintained, there often is apoptosis by activation of caspase cascades.195 This pathogenetic mechanism is presumed to be operative in oligodendrocytes and neurons. The understanding of the pathogenesis of PelizaeusMerzbacher disease has been aided greatly by studies in animal models of the disease.196 These include the “jimpy” mouse and the “jimpy-msd” mouse, in which the disorder resembles classic Pelizaeus-Merzbacher disease; the “jimpy-4j” mouse, in which the disorder resembles connatal Pelizaeus-Merzbacher disease; and the “rumpshaker” mouse, which is a model of SPG2. The myelin-deficient rat also provides a model of connatal Pelizaeus-Merzbacher disease. Because rats are larger animals, this model is well suited for neurophysiological studies of pathogenesis and for the study of therapeutic interventions.197,198

Therapy At this time, there is no specific therapy for PelizaeusMerzbacher disease.

Diagnosis Although the classic phenotype has a relatively distinct clinical manifestation,170 the connatal form can be confused with motor neuron disease or spinal muscular atrophy. The mildest forms merge clinically with the syndromes of SPG2. MRI is essential for the evaluation of individuals with clinical signs and symp-

CANAVAN’S DISEASE Other names by which this condition is known include spongy degeneration of the white matter, infantile CNS spongy degeneration, spongy degeneration of the CNS, van Bogaert– Bertrand disease, and aspartoacylase deficiency.

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Clinical Features

Genetics

Age at onset is most commonly between 3 and 6 months. In the patients with early onset, mental changes are severe, and the clinical phenomena of nervous system maturation are not observed.199-203 Instead, there is increasing difficulty in feeding, progressive lethargy, and increasing stiffness of the limbs. When the disease begins later in infancy, normal development of social, motor, and visual responses is seen at first, but this is lost as the disease advances. Hypotonia is present early in the course of the disease and is followed by increased tone that begins in the legs and produces a posture of extension. Optic atrophy occurs in a large proportion of cases. Macrocephaly (>90th percentile) was documented in 54 of 59 children; 51 of 58 had nystagmus, 38 of 60 had epilepsy, and optic atrophy was present in 17 of 60.202 Although cases with later onset have been reported,204,205 only two cases have been biochemically confirmed,206 and in these patients, onset of symptoms occurred by 2 years of age. Although most patients die during the first decade, 14 of the 60 patients in Traeger and Rapin’s series202 were alive in the second or third decade, albeit all severely disabled.

The mode of inheritance is autosomal recessive. The defective gene maps to chromosome 17pter and has been isolated.210 It codes for aspartyl acylase, which hydrolyzes N-acetyl aspartate to aspartate and acetate. Canavan’s disease occurs most frequently in the Ashkenazi Jewish population, in which carrier frequency is 1 per 38.211 Two mutations are most common among Jewish patients: a missense mutation in codon 285 with substitution of glutamic acid to alanine, which accounted for 86.3% of mutations in 104 alleles, and a nonsense mutation on codon 231, tyrosine to stop codon, which was found in 13.4%. Together, these two mutations accounted for 97% of all the alleles in Jewish patients with Canavan’s disease. In non-Jewish patients, the mutations are different and more diverse: the most common is in codon 305, a missense mutation substituting alanine to glutamic acid. This mutation was observed in 35.7% of 70 alleles from 35 unrelated non-Jewish patients. Fifteen other mutations accounted for 24 mutant alleles.

Pathology The majority of affected infants show an increase in brain size and weight. In formalin-fixed sections, the white matter is soft, gelatinous, and darker than normal; enlargement of ventricles increases as the disease advances. The most striking microscopic change is the widespread vacuolization, which characteristically involves the lower layer of the cerebral cortex and the subcortical white matter; the more central zones are relatively or entirely spared. There is a widespread lack of myelin, which involves the area of spongy degeneration and extends far beyond them. In the areas of spongy degeneration, as well as in the demyelinated zones, oligodendrocytes are preserved. Axis cylinders in the areas of demyelination are diminished but not absent. Throughout the cerebral cortex and basal ganglia, there are conspicuous increases in the number and size of protoplasmic astrocytes.201 Ultrastructural studies have shown that the vacuoles in the subcortical white matter lie within the myelin sheaths, between split lamellae of the myelin spirals. The split was noted between the major dense lines.207 Some of the membranes were focally ruptured. The vacuoles communicated through these ruptured membranes into the widened extracellular spaces. Cell membranes of protoplasmic astrocytes were also disrupted. The mitochondria within the astrocytes displayed enormous elongations and contained distended and distorted cristae.

Neuroimaging In all stages of the disease, MRI shows the most severe abnormalities in the subcortical white matter of the cerebrum and cerebellum. Central white matter structures such as the periventricular rim of white matter, internal capsule, corpus callosum, and brainstem are preserved longer. After several years, cerebral atrophy with enlargement of the ventricles ensues.208 The most characteristic neuroimaging abnormality is the accumulation of N-acetyl aspartic acid, demonstrable by proton spectroscopy.209

Diagnosis Definitive diagnosis is achieved by measurement of levels of N-acetyl aspartic acid in urine. It is essential that the isotope dilution assay procedure be used.212,213 N-acetylneuraminic acid (NANA) levels in Canavan’s disease are 80 to 120 times higher than control levels. NANA assay in amniotic fluid enables prenatal diagnosis.214 Further studies of this assay showed that although significantly increased levels of amniotic fluid NANA were reliable markers, moderate increases should be interpreted with caution and could lead to false-negative results.215 Measurement of aspartoacylase activity is not reliable for postnatal or prenatal diagnosis.214,216 It is recommended strongly that, whenever possible, it be combined with mutation analysis in amniocytes or trophoblasts.217,218 Mutation analysis is a key diagnostic procedure.211 It is particularly so in the Ashkenazi Jewish populations, in which two common mutations account for all the mutations that have been encountered. The American College of Obstetrics and Gynecology has recommended that molecular carrier screening be offered to Ashkenazi Jewish couples.219

Pathogenesis The key defect in Canavan’s disease is the deficiency of N-acyl-L-aspartate aminohydrolase,220 which hydrolyses NANA to L-aspartate and acetate. NANA is found only in the nervous system, in which its normal concentration, 6 to 7 μmol/g, is second only to that of glutamic acid in the free amino acid pool. NANA is synthesized in neuronal mitochondria by the enzyme aspartate N-acyltransferase, whereas the catabolic enzyme N-acyl-L-aspartate is present mainly in oligodendrocytes,221 and its concentration is even higher in Canavan’s disease. Three pathogenetic mechanisms for Canavan’s disease have been proposed: (1) Madhavarao and colleagues221 demonstrated that levels of acetate in the brain and the synthesis of myelin lipids are reduced significantly in the mouse model of Canavan’s disease and also in a patient with Canavan’s disease, and they proposed that this is a consequence of an impaired acetate supply in the oligodendrocyte secondary to the N-acyl-

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L-aspartate deficiency. (2) Levels of N-acetyl aspartate glutamate may be increased in Canavan’s disease and may interfere with the function of the N-methyl-D-aspartate receptor.222 (3) Because of its high concentration, NANA may act as an organic osmolyte that normally removes excess water from neurons by acting as a molecular water pump, and this function may be deficient in Canavan’s disease.223 Two animal models of Canavan’s disease have been developed. Aspartoacylase gene knockout in the mouse leads to reproduction of the clinical, pathological, radiological, and biochemical defects of Canavan’s disease in humans.224,225

Therapy There is no specific therapy for Canavan’s disease. It was the first neurodegenerative disorder to be treated by gene therapy.226 A nonviral lipid-entrapped, polycation-condensed delivery system in conjunction with adeno-associated virus–based plasmid containing recombinant N-acyl-Laspartate was administered by intraventricular injection to two patients with Canavan’s disease. The procedure was well tolerated. Fifteen additional patients were treated.227 There were no definitive changes in clinical course. The availability of animal models of Canavan’s disease has made it possible to test gene transfer therapy in these models. Stereotactic delivery of adeno-associated virus 2–mediated Nacyl-L-aspartate to “tremor rats” reduced brain NANA levels and was associated with some improvement in motor function.228 On the basis of the hypothesis that acetate deficiency in Canavan’s disease limits synthesis of myelin lipids,221 a trial of dietary supplementation with acetate or acetate precursors has been proposed.221

ALEXANDER’S DISEASE Other names by which this condition is known include leukodystrophy with Rosenthal fibers and progressive fibrinoid degeneration of fibrillary astrocytes.

Clinical Features Early infantile-, juvenile-, and adult-onset forms have been described. The early infantile-onset form manifests at approximately 6 months with rapidly progressive neurological and mental retardation, in association with macrocephaly spasticity and seizure, and leads to death in the second or third year.229,230 Among patients with the juvenile-onset form, macrocephaly was present in only 27%, and progressive cognitive defects occurred in 60%. In the adult-onset form, ataxia, eye movement disturbances, and bulbar and pseudobulbar symptoms231 predominate. Palatal myoclonus,232 autonomic disturbances, and sleep disturbances have also been reported.233

Pathology In the early infantile-onset form, the brain is enlarged with a normal convolutional pattern. The white matter is discolored, soft, and swollen in the frontal region. Light microscopy reveals

that the main abnormalities are the abundance of Rosenthal fibers and demyelination of the white matter (Rosenthal fibers are eosinophilic intracytoplasm filamentous cytoplasmic fibers within astrocytes).234 The major chemical components of Rosenthal fibers are glial fibrillary acidic protein, the small heat-shock proteins α-crystalline and hsp27, and ubiquitin.235 Rosenthal fibers have a tendency to accumulate at interfaces with mesodermal tissue that is underneath the pia mater and around the blood vessels. They are most prominent in the frontal and parietal regions and much less so in the occipital lobes. The basal ganglia are also involved. The tracts and nuclei of the brainstem nuclei are involved heavily from the midbrain to lower medulla; the cerebellar hemispheres, only slightly.229,236

Neuroimaging On the basis of the study of 5 patients with the infantile-onset form and 14 with the juvenile-onset form, van der Knaap and colleagues237 proposed five MRI criteria for the diagnosis of Alexander disease: (1) extensive cerebral white matter T2weighted abnormalities with a frontal preponderance; (2) the presence of a periventricular rim of decreased T2-weighted signal intensity but with increased T1-weighted signal intensity in the same region; (3) abnormalities in the basal ganglia and thalami, in the form of either elevated signal intensity or atrophy and either elevated or decreased signal intensity on T2weighted images; (4) brainstem abnormalities, particularly those involving the midbrain and medulla; and (5) contrast enhancement involving one or more of the following structures: ventricular lining, periventricular rim of tissue, white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brainstem structures (Fig. 80–2). The authors concluded that the imaging pattern in infantile- and juvenile-onset cases was sufficiently specific to allow the in vivo MRI diagnosis of Alexander’s disease and that brain biopsy is necessary only in atypical cases. However, in a later study of 10 patients with later onset and atypical features, the same group of investigators reported that this typical pattern was not found.238 In these patients, late-onset disease, ataxia, bulbar symptoms, and eye movement disturbances dominated the clinical findings.231,233 The MRI revealed predominantly posterior lesions, including multiple tumor-like brainstem lesions.

Genetics The mode of inheritance is autosomal dominant. The abnormal gene has been mapped to locus 17q21. It codes for the glial fibrillary acid protein. One hundred and two pathogenic mutations have been identified.239-241 In one study, 72 patients had the infantile-onset phenotype, 22 had the juvenile-onset phenotype, 7 had the adult-onset phenotype, and 1 was asymptomatic. All of the cases of the infantile phenotype, 21 of those with the juvenile phenotype, and 4 of those with the adult phenotype were sporadic. Five pedigrees with more than one affected member have been reported. All of the 16 affected persons in these pedigrees had the adult or the juvenile phenotype.

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Figure 80–2. Alexander’s disease. Frontal preponderance of frontal white matter lesions (A) and abnormality in the basal ganglia that may sometimes be enhanced (B). In juvenile- and adult-onset forms, lesions are more often localized in the brainstem and cerebellum with demarcation of the dentate nucleus (C). Cerebellar pathways and pontine lesions may get mistaken for glial tumors (D).

Diagnosis

Pathogenesis

In the patients with the typical infantile phenotype, the clinical features, combined with brain MRI findings,237 are sufficiently specific to establish the diagnosis. However, in juvenile- and adult-onset cases, mutation analysis239 is required for diagnosis. In these cases, the range of phenotypical expression and MRI abnormalities is wider than had been recognized in the past. It is recommended that mutation analysis be performed not only in the affected persons but also in their parents. This makes it possible to distinguish between sporadic cases (the majority) and familial cases. In familial cases, mutation analysis should be performed in at-risk members. Most of the familial cases have the adult-onset phenotype, and their identification is required for genetic counseling.

Glial fibrillary acidic protein is one of the intermediate filament proteins, which also includes the keratins, vimentin, desmin, peripherin, and nestin.242 Intermediate filament contains αhelical polypeptides that are linked and intertwined to form protofilaments. There is a great deal of evidence that the mutations in Alexander’s disease have a dominant negative effect: namely, that the abnormal glial fibrillary acidic protein allele product in astrocytes causes secondary dysfunction of oligodendrocytes and neurons.243 In support of this is the fact that no null mutations have been identified in patients with Alexander’s disease (which suggests that these would be lethal) and that glial fibrillary acidic protein knockout genes in mice cause only subtle pathological changes.243

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Therapy There is currently no specific therapy. Because the abnormal allele probably acts in a dominant negative manner, techniques such as RNA interference244 may offer hope for the future.

particularly The Netherlands, Italy, Israel, and Japan. The gene maps to locus 2q33ter. It codes for a sterol 27-hydroxylase (CYP27A).250 More than 20 mutations have been defined.251

Diagnosis CEREBROTENDINOUS XANTHOMATOSIS Another name by which this condition is known is forme cérébrale de la cholestérinose généralisée.245

Clinical Features Clinical features develop slowly and may manifest irregularly in varying combinations. The most common features are xanthomas in the Achilles tendon, neurological dysfunction, and cataracts. As patients grow older, they develop progressive coronary arteriosclerosis and osteoporosis that predisposes to bone fractures.246 The CNS manifestations are gradual deterioration of intellectual function, which progresses to dementia; behavior and psychiatric manifestations; pyramidal tract signs; spastic paraplegia; ataxia; dysarthria; and nystagmus. Epileptic seizures occur in half of the symptomatic subjects. Peripheral neuropathy is also present. Chronic diarrhea is a frequent symptom. Some specific clinical points have been highlighted; for example, the spinal phenotype (without xanthomas) may be misdiagnosed as multiple sclerosis.247 In children, cataracts may be the first manifestation of cerebrotendinous xanthomatosis,248 and xanthomata may be absent in patients with severe neurological involvement.249

Pathology In the nervous system, the most conspicuous abnormalities are found in the cerebellum. Xanthomatous tissue, with large amounts of neutral fat, needle-like clefts, and cystic spaces, may replace the white matter. The outflow tracts of the dentate nucleus and the superior cerebellar peduncles are most severely involved. In the brainstem, the pyramidal tracts, transverse pontine fibers, and fiber tracts emanating from the inferior olive are demyelinated. The cerebral cortex and hemispherical white matter usually appear normal. Smaller areas of demyelination are found in the optic tract, the internal capsule, and the periventricular region.

Neuroimaging The most important and earliest MRI abnormalities occur in the cerebellum. On T2-weighted images, there are high-intensity lesions in the dentate nuclei and cerebellar hemispheres.4,214 Atrophy of cerebellar folia and symmetrical lesions in the corticospinal tracts, the medial lemniscus in the brainstem, and the inferior olive may occur. In the supratentorial region, ill-defined slight signal changes are seen in the periventricular region.

Genetics The mode of inheritance is autosomal recessive. Several hundred cases have been reported from many countries,

Although the clinical manifestations and MRI findings of cerebrotendinous xanthomatosis are rather characteristic, laboratory diagnosis is required for definitive diagnosis. Laboratory techniques also enable presymptomatic diagnosis and early initiation of therapy. Demonstration of abnormally increased levels of cholestanol through precise methods such as selected ion monitoring252 is a key diagnostic step.251 A screening method that detects increased levels of 7α-hydroxylated bile acids in urine is a valuable technique.253 Mutation analysis in at-risk relatives250 of known patients is recommended highly for presymptomatic identification of affected persons and for genetic counseling.

Pathogenesis The primary defect in cerebrotendinous xanthomatosis is the deficiency of C27-steroid hydroxylase, which leads to defective bile acid synthesis and the accumulation of a variety of metabolites with the C27-steroid side chains. There are series of complex metabolic and pathological consequences.251 The major clinical manifestations are caused by generalized accumulation of cholestanol and cholesterol in nearly every tissue, including the CNS. Menkes and associates demonstrated the accumulation of cholestanol in the brains of patients with cerebrotendinous xanthomatosis in 1968.254 Cholesterol synthesis is greatly increased, because in the absence of bile acids, the normal bile acid feedback inhibition does not take place. Cholestanol is normally produced from cholesterol in small quantities by a four-step pathway. In cerebrotendinous xanthomatosis, C27-steroids that cannot be converted into bile acids may be shunted into this pathway.251 The C27-steroid hydroxylase that is deficient in cerebrotendinous xanthomatosis normally may also act on the C25-steroid hydroxylase that is involved in vitamin D metabolism, and this may contribute to osteoporosis. C27-steroid hydroxylase also functions to transport steroids out of cells, and a defect in this mechanism may contribute to the premature atherosclerosis in cerebrotendinous xanthomatosis.

Therapy There is compelling evidence that oral administration of chenodeoxycholic acid in a dosage of 750 mg/day benefits patients with cerebrotendinous xanthomatosis. Chenodeoxycholic acid is one of the bile acids produced in normal persons, but it is not produced in patients with cerebrotendinous xanthomatosis because of the enzymatic defect. Chenodeoxycholic acid administration reduces the levels of cholestanol in plasma and CSF255,256 and was shown to reduce the excretion of urinary bile alcohols257 and bile alcohol glucuronides.258 It has been reported to improve somatosensory and motor evoked potentials,259 visual and brainstem auditory evoked responses,260 brain MRI abnormalities,261 and osteoporosis.262,263 There are several reports that it stopped or slowed neurological progression.256,264 Berginer and coauthors255 reported improvements in

chapter 80 the leukodystrophies cerebellar function, behavioral disturbances, and seizure control after 1 year of chenodeoxycholic acid therapy. Beneficial effects are most evident if therapy is started when deficits are slight. Biochemical and DNA screening of at-risk relatives now enables identification of asymptomatic persons with cerebrotendinous xanthomatosis. It is possible that chenodeoxycholic acid therapy will reduce or prevent later disability. Addition of lovastatin or simvastatin to the chenodeoxycholic acid regimen may further decrease cholestanol levels,265-267 but additional clinical benefits have not been demonstrated.268 Reduction of cholestanol levels can also be achieved with low-density lipoprotein apheresis,269 but this relatively invasive therapy, which would need to be administered repeatedly and is the subject of controversy,270,271 should be considered only in patients who have not responded to pharmacological therapy.

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mally high signal intensity in the periventricular high matter on T2-weighted images. The abnormality was present already at 2 years of age and remained relatively stable after that. The subarcuate fibers, cerebellum, and corpus callosum were relatively spared. The gray matter was normal. Mild cerebral atrophy was found in most patients older than 10 years. MRS revealed a prominent and narrow resonance at 1.3 ppm, at which protons of methylene groups resonate. The nature of the lipids that give rise to this peak has not been defined. This peak was present in the white matter but not in the gray matter. The total N-acetyl aspartate level was normal, which was consistent with the relative preservation of neurons; creatine, choline, and inositol levels were increased, which was consistent with the gliosis and myelin damage.

Genetics SJÖGREN-LARSSON SYNDROME Another name by which this condition is known is fatty aldehyde dehydrogenase deficiency.

Clinical Features The three cardinal features are ichthyosis, mental retardation, and spastic diplegia or tetraplegia.272 The ichthyosis is already present at birth or in the neonatal period. It is mild to moderate in severity and generalized in distribution. The face is mildly involved or spared. Neurological symptoms vary considerably but become evident within the first 3 years of life. Spastic diplegia is much more common than tetraplegia. Many patients never gain the ability to walk, and many who do walk require leg braces. The degree of mental retardation tends to be correlated with the severity of spasticity. In a study of Swedish patients, two thirds had an IQ of less than 50. Of enzymatically confirmed cases, 13% showed no mental retardation.273 Most patients have speech deficits of various types, including delayed speech and dysarthria. Two thirds have an associated seizure disorder. Patients with Sjögren-Larsson syndrome generally do not show neurological regression, and most survive well into adulthood. Abnormalities of the retina are frequent. The most consistent findings are glistening white dots in the foveal and perifoveal regions.274

Pathology The nervous system shows a widely distributed loss of myelin, most prominent in the centrum semiovale, pyramidal tracts, and frontal lobes.275 There is considerable variation in the degree of myelin deficiency. Ballooning of myelin sheaths has been noted in the areas of myelin loss and near blood vessels. There is significant gliosis and proliferation of astrocytes. Gray matter is much less affected. The loss of neurons and axons tends to occur in areas where myelin loss has become extensive and appears to be secondary to myelin loss.

Neuroimaging A study of 18 patients with Sjögren-Larsson syndrome demonstrated characteristic changes.276 MRI revealed a zone of abnor-

The mode of inheritance is autosomal recessive. SjögrenLarsson syndrome is a rare disorder, first reported and apparently most common in Sweden, where the frequency is 0.4 per 100,000. By 2001,273 more than 200 patients had been recognized in all parts of the world. The gene maps to locus 17p11.2. It codes for fatty aldehyde dehydrogenase.277 Mutations of the gene were first identified by De Laurenzi and associates.278 Seventy-two mutations in the gene have been defined.279

Diagnosis Diagnosis is suggested by the clinical triad of ichthyosis, mental retardation, and spasticity and is aided by brain MRI and MRS studies276 and the presence of glistening spots in the retina.274 Definitive diagnosis depends on demonstration of fatty aldehyde dehydrogenase deficiency in cultured skin fibroblasts.280,281 This assay also enables prenatal diagnosis.282 Van den Brink and associates reported an alternative enzymatic assay based on demonstration of impaired phytol degradation in cultured fibroblasts of Sjögren-Larsson syndrome patients.283 DNA-based diagnosis is feasible278 and is being applied increasingly for heterozygote identification and prenatal diagnosis.

Pathogenesis The deficiency of fatty aldehyde dehydrogenase leads to a large number of biochemical derangements, but it is not yet clear which contributes to pathogenesis. These derangements include the following: 1. Accumulation of fatty aldehydes and metabolites. Free fatty aldehydes are very reactive. They form aldehyde protein adducts. They react with phosphatidyl ethanolamine to form N-alkyl phosphatidyl ethanolamine. Phosphatidyl ethanolamine is present in high concentration in myelin, and N-alkyl phosphatidyl ethanolamine formation could alter myelin stability. 2. Accumulation of long-chain alcohols. This could impair the skin-water barrier and be the cause of the ichthyosis. 3. Willemsen and coworkers284 demonstrated that patients with Sjögren-Larsson syndrome accumulate the ω-hydroxyoxidation product of leukotriene B-4, a proinflammatory aliphatic lipid mediate.

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The levels of essential polyunsaturated fatty acids in plasma are reduced.285

Treatment Treatment is symptomatic. Topical administration of keratolytic agents and the systemic administration of short-acting retinoids has ameliorated the ichthyosis. A variety of fat-modified diets, such as those in which long-chain fatty acids are replaced by medium-chain fatty acids, and the administration of polyunsaturated fatty acids have been used without definitive favorable effects.273 Haug and Braun-Falco286 reported that adeno-associated virus vectors restored fatty aldehyde dehydrogenase deficiency in fibroblast cell lines from patients with Sjögren-Larsson syndrome, which suggests that gene therapy may eventually become an option.

VANISHING WHITE MATTER DISEASE5 Other names by which this condition is known include childhood ataxia with central hypomyelination6 and myelinopathia centralis diffusa.287 Allelic conditions include Cree eukoencephalopathy288 and leukodystrophy in patients with ovarian dysgenesis.289

Clinical Features Classic Form The onset is in the juvenile period (3 to 10 years of age). Ataxia and spasticity are present, and intellect is relatively preserved. The course is chronic and progressive with episodes of deterioration, which may include coma, precipitated by minor injuries, fever, or fright.290

(2) part or all of the abnormal white matter has a signal intensity close to or the same as CSF in both T2-weighted and either proton density or fluid-attenuated inversion recovery images; and (3) a fine meshwork of remaining tissue strands is visible within the areas of CSF-like white matter.

Genetics The mode of inheritance is autosomal recessive. The distribution is panethnic, possibly more common in white persons from Western Europe and North America. The incidence is 1 per 40,000 in certain parts of The Netherlands. This disease is probably more common than had been recognized. The basic defect involves the eukaryotic translation initiation factor eIF2β. eIF2β is a complex consisting of five subunits, eIF2β1 to eIF2β5, encoded on loci 3q27, 14q24, 1q34.1, 2q23.3, and 12q24.3. Mutations of eIF2β5 (3q27) are most common. In one series, 14 of 16 mutations were missense,8 and most involved nonconserved amino acids. The R113H mutations in eIF2β5 and the E213G mutations in eIF2β2 appear to be associated with milder phenotypes.296,297

Diagnosis The wide range of phenotypical expression is a challenge to clinical diagnosis. The episodic worsening or coma in association with minor injuries, fever, or fright provides a clue. Provisional diagnosis is based on the characteristic brain MRI and MRS findings. Mutation analysis is required for definitive diagnosis.

Pathogenesis

Extensive degeneration of white matter with cystic degeneration is a feature. The cortex is preserved. There is increased density and apoptosis of oligodendrocytes.295 Astrocyte structure is abnormal.288

eIF2β plays a fundamental role in the initiation of translation and was summarized by van der Knaap and colleagues.8 The first step of the translation process is that a complex of eIf2–guanosine triphosphate (GTP) and methionyl-transfer RNA binds to the ribosome; eIf2 leaves the ribosome as eIF–guanosine diphosphate. In order to bind another methionyl-transfer RNA, eIf2 must be reactivated by exchange of guanosine diphosphate for guanosine triphosphate. This reaction is catalyzed by eIF2β. Under a variety of stress conditions, protein synthesis is decreased. This response is a protective mechanism. The down regulation is induced by the rapid expression of a specific set of proteins called heat shock proteins. In the absence or impaired function of eIF2β, these key regulatory mechanisms cannot take place. The processes that lead to the specific defects in vanishing white matter disease are not yet clear. Apoptosis of oligodendrocytes295 and impairment of astrocyte generation288 have been demonstrated. The nearly instantaneous neurological worsening after a frightful event that has been reported by Vermeulen and associates290 provided hints about the speed and complexity of these control mechanisms.

Neuroimaging

Therapy

Three imaging findings are characteristic: (1) Cerebral hemispherical white matter is symmetrically and diffusely abnormal;

There is no specific therapy for vanishing white matter disease. Prompt treatment of fever and reasonable steps to prevent

Severe Infantile Form, Cree Leukoencephalopathy The onset is at ages 3 to 9 months. This form is characterized by hypotonia, seizures, spasticity, hyperventilation, blindness, developmental regression, and death by 21 months.291,292

Adolescent or Adult Forms This form is characterized by progressive ataxia and spasticity and by mildly to moderately impaired mental capacity.293 Age of onset typically is 10 to 21 years. Adult-onset cases may manifest with dementia and psychiatric symptoms.294 The disorder may be associated with ovarian dysgenesis in women.289

Pathology

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Figure 80–3. Megalencephalic leukoencephalopathy in a 45-year-old patient with significant white matter involvement and progressive cortical atrophy. T1-weighted magnetic resonance image (A) shows involvement of diffuse white matter and a temporal lobe cyst. Fluidattenuated inversion recovery image (B and C) show involvement of white matter involved with multiple cysts.

injuries and other forms of stress may help reduce the risk for rapid stepwise neurological progression.

MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS Other names by which MLC is known include leukoencephalopathy with swelling and a discrepantly mild clinical course,7 van der Knaap’s megalencephalic leukoencephalopathy,298 and leukoencephalopathy with megalencephaly and mild clinical course.299

Clinical Features Macrocephaly is present at birth or, more frequently, develops during the first year of life.7,298-301 After the first year of life, the head growth rate normalizes. The first clinical symptom is delay in walking. Walking is often unstable, and the child falls frequently.4 After an interval of several years, there is slow deterioration of motor function, with the development of ataxia. Signs of pyramidal tract dysfunction are late and minor. Most affected children become wheelchair dependent at the end of the first decade or during the second decade of life. Mental deterioration is late and mild. Speech becomes increasingly dysarthric, and dysphagia may develop. Some patients have dystonia and athetosis. Almost all patients have epilepsy from early on; it is usually controlled easily with medication.300 Minor head trauma may induce temporary degeneration.4

Pathology The cerebral white matter exhibits status spongiosus with innumerable vacuoles.301 The white matter shows intense fibrillary astrogliosis. Electron microscopy reveals splitting of the myelin sheaths at the intraperiod line with intramyelinic vacuole formation. There is no evidence of axonal degeneration or loss. The cerebral cortex is normal.

Neuroimaging The cerebral hemispherical white matter is diffusely abnormal and swollen. The swelling is most marked during the first year of life, with obliteration of peripheral CSF spaces and narrowing of ventricles (Fig. 80–3). The external and extreme capsules are prominently involved. The central white matter structures are relatively spared.4 Cysts are present almost invariably in the anterior temporal regions and often also in the frontal and parietal subcortical regions (see Fig. 80–3). They enlarge with age and may become very large. Only a few infants and children with MLC lack cysts. MRS shows reduction of all signals, which is indicative of high water content.

Genetics The mode of inheritance is autosomal recessive. It is a rare disorder but relatively prevalent among Turkish people and in a certain Asian-Indian community, the Agrawal ethnic group. The defective gene has been mapped to locus 22qter.10 It encodes a protein of unknown function with eight transmembrane domains and is now referred to as MLC1. It is highly conserved throughout evolution. MLC1 mutations have been demonstrated in 70% of patients with MLC. Twelve mutations have been defined.8-10

Diagnosis Diagnosis of MLC is based on the characteristic clinical, MRI, and MRS findings. Mutations in the MLC1 gene have been identified in 70% of the patients.4,8-10

Pathogenesis Within the brain, MCL1 protein is expressed in astrocytic endfeet in the perivascular, subependymal, and subpial regions.4,302 This localization suggests a possible role in a transport process across the blood-brain barrier.303 Of interest is that

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water transport proteins such as aquaporin-4 display a similar localization.304

Therapy There is no specific therapy. Anticonvulsants are effective for seizure control. Even minor head trauma should be avoided.

MEMBRANOUS LIPODYSTROPHY Other names by which this condition is known include polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and TYRO protein tyrosine kinase– binding protein (TYRObp) deficiency.

Clinical Features The clinical course is divided into four stages:305 (1) The latent stage extends into adulthood; (2) the osseous stage begins in the third decade and is characterized by fractures after minor injuries, cystic rarefaction, metaphyseal cysts, and replacement of cancellous bone by cysts; (3) The neuropsychiatric stage, which begins in the third or fourth decade, is characterized by progressive dementia with predominately frontal syndrome and by agnosia, apraxia, and loss of social inhibition; and (4) the dementia stage is characterized by cachexia, seizures, and death between 35 and 45 years of age. Palatal myoclonus, dysarthria, nystagmus and ataxic gait have been reported in patients in stage 3.306 One 56-year-old patient had an unusually benign course, with bone lesions for 16 years but no neurological or psychiatric disturbances.307

Pathology In the bone lesion, bone and hematopoietic tissue are replaced by cysts originating from adipocytes. They contain membrane membranes that are autofluorescent and carbohydrate, phospholipids, and fatty acid crystals. Periodic acid–Schiff stain of these cysts yields positive results.305,308 Brain weight is reduced. There is atrophy of the superior frontal gyri. Deep frontal white matter is shrunken with grayish discoloration, and basal ganglia are reduced in size. Neocortical cytoarchitecture is generally preserved; there are no pathological inclusions. There is severe loss of axons and myelin, accompanied by scattered axonal spheroids and widespread activation of microglia. Vascular alterations are present in the deep frontal and white matter. These alterations affect scattered small arterioles and capillaries and consist of concentric thickening of the vascular wall with narrowing or obliteration of lumen.309

Neuroimaging MRI shows bilateral T2-weighted hyperintensity and areas of cavitation in the periventricular region. Subarcuate fibers are spared. There is frontotemporal atrophy. Cerebellum and brainstem are atrophic. Computed tomography revealed calcification in the dentate nucleus and putamen.306,310

Genetics The mode of inheritance is autosomal recessive. The disorder is rare. By 1997, it had been observed in fewer than 150 patients.305 Most cases occur in two widely separated population groups: the Japanese population and the Finnish population in northern Scandinavia. The estimated population frequency in the Finns is 2 × 10−6. The defective gene maps to 19q13.1. It codes for TYRObp,311 a transmembrane protein that is a key activating signal in natural killer cells.312 Loss-of-function mutations have been identified in both Japanese and Finnish patients.

Diagnosis Diagnosis is based on the characteristic combination of clinical findings and radiological skeletal changes and, in the past, brain biopsy findings. It is anticipated that DNA analysis will be of key importance for diagnosis, carrier identification, and prenatal diagnosis.

Pathogenesis The defect of TYRObp is suggestive of a link between the bone and CNS lesions. This gene is expressed in microglial cells313 and may also be expressed in osteoclasts. The detailed pathogenetic mechanisms are still unclear. The glial proliferation in white matter and the TYRObp expression patterns suggest that microglia contribute to the pathogenesis of CNS abnormalities. It is not known whether the abnormalities in small blood vessels in white matter play a primary role in pathogenesis or are a secondary event.309

Therapy There is no specific therapy.

RIBOSE-5-PHOSPHATE ISOMERASE DEFICIENCY Another name by which this condition is known is leukoencephalopathy associated with a disturbance in the metabolism of polyols. So far, this disorder has been reported in only a single 14year-old patient. Early development was slow and walking was delayed until 2.5 years. Seizures began at age 4 to 7 years. There was slow regression, deterioration of vision and speech, and incoordination. At age 14 years, bilateral optic atrophy, nystagmus, mixed cerebellar pseudobulbar dysarthria, and cerebellar ataxia of the arms and legs were present. Deep tendon reflexes were hyperactive, and there were plantar extensor and mild distal leg atrophy. The patient’s mental age is estimated at 2.6 to 4.8 years.314 MRI showed increased T2-weighted signal in cerebral hemispheres involving subarcuate fibers, but there was partial sparing of periventricular white matter. Some vermal atrophy was present. No signal abnormality was detected in the basal ganglia, cerebral cortex, brainstem, or cerebellum. MRS demonstrated several peaks between 3.5 and 4.0 ppm, later identified as arabitol and ribitol. The mode of inheritance is autosomal recessive. The gene maps to locus 2p11.2. It codes

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T A B L E 80–1. Leukodystrophies in Which the Gene Defect Is Not Defined

T A B L E 80–2. Disorders That Resemble Leukodystrophies in Which the Primary Defect Does Not Involve Myelin

Disease

Disease

Leukoencephalopathy with brainstem involvement and high lactate Cystic leukoencephalopathies without megalencephaly Familial orthochromatic leukodystrophy Hereditary leukoencephalopathy with spheroids Other leukodystrophies in children Leukodystrophies in adults Hereditary leukodystrophy and palmoplantar keratoderma: a newly recognized disorder with increased skin collagen content Oculodentodigital dysplasia with cerebral white matter abnormalities in a two-generation family

Reference(s) 317, 318 319, 320 321, 322 323, 324 325, 326 327-332 333 334

for ribose-5-phosphate isomerase (Enzyme Commission number 5.3.1.6), which catalyzes conversion of ribulose-5phosphate to ribose-5-phosphate. A mutation in this isomerase was demonstrated in the proband, and the mother was heterozygous for this mutation. Diagnosis is based on demonstration of increased levels of arabitol and ribitol on brain MRS and in urine, plasma, and CSF315 and on demonstration of defective activity of ribose-5-phosphate isomerase.316 Polyol accumulation is postulated to lead to polyneuropathy, possibly secondary to defective Na+/K+–adenosine triphosphatase regulation as a result of myoinositol depletion.316 There is no specific therapy.

LEUKODYSTROPHIES IN WHICH THE GENETIC DEFECT IS NOT YET DEFINED

Reference(s)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Binswanger’s microangiopathic leukoencephalopathy; leukoaraiosis Leukoencephalopathy associated with mitochondrial disorders Leukodystrophy in disorders of mucopolysaccharide metabolism Leukodystrophy in disorders of amino acid metabolism Leukodystrophy in inborn errors of single carbon transfer pathway Leukodystrophy and muscular dystrophy Posterior leukoencephalopathy

K E Y

335, 336 337 338-340 341 342 343 344-346 347

P O I N T S

●

Molecular and biochemical bases of twelve leukodystrophies are now defined.

●

Novel leukodystrophies are being defined by the combination of MRI pattern analysis and positional cloning.

●

There is a wide range of phenotypical expression.

●

Noninvasive diagnostic techniques are available, reducing the stress of a diagnostic odyssey.

●

Genetic counseling is imperative for disease prevention.

●

Emerging therapies are effective only in presymptomatic or minimally symptomatic stages of illness.

Table 80–1 lists the disorders that are probably distinct leukodystrophies but whose genetic defects are not yet defined.

DISORDERS THAT RESEMBLE LEUKODYSTROPHIES BUT IN WHICH THE PRIMARY DEFECT DOES NOT AFFECT MYELIN OR MYELINATING CELLS These disorders are listed in Table 80–2.

SUMMARY AND CONCLUSIONS The delineation and the understanding of the pathogenesis of leukodystrophies have increased greatly since 2000. The gene defects have been defined in 12 of the leukodystrophies. All can be identified presymptomatically and prenatally. Carrier identification and genetic counseling are available. Therapy with varying degrees of success is available for cerebrotendinous xanthomatosis, GLD, adrenoleukodystrophy, and MLD. The use of neuroimaging and gene analysis is expected to lead to the definition of a large proportion of leukodystrophies that remain unclassified. It is likely that the study of animal models of human leukodystrophies will lead to improved understanding of pathogenesis and more effective therapies.

Suggested Reading Barkovich AJ: Magnetic resonance techniques in the assessment of myelin and myelination. J Inherit Metab Dis 2005; 28:311-343. Di Rocco M, Biancheri R, Rossi A, et al: Genetic disorders affecting white matter in the pediatric age. Am J Med Genet B Neuropsychiatr Genet 2004; 129:85-93. Lazzarini RA: Myelin Biology and Disorders. Amsterdam: Elsevier, 2004. van der Knaap MS, Valk J: Magnetic Resonance of Myelination and Myelin Disorders, 3rd ed. Berlin: Springer, 2005. van der Knaap MS: Magnetic resonance in childhood white-matter disorders. Dev Med Child Neurol 2001; 43:705-712.

References 1. Powers JM: Leukodystrophies: overview and classification. In Lazzarini RA, ed: Myelin Biology and Disorders. London: Elsevier, 2004, pp 663-690. 2. Bielschowsky M, Henneberg R: Ueber familiare diffuse Sklerose (Leukodystrophia cerebri progressive hereditaria). J Psychol Neurol (Lpz) 1928; 36:131-181.

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3. van der Knaap MS, Breiter SN, Naidu S, et al: Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213:121-133. 4. van der Knaap MS, Valk J: Magnetic Resonance of Myelin, Myelination, and Myelin Disorders, 2nd ed. Berlin: SpringerVerlag, 2005. 5. van der Knaap MS, Barth PG, Gabreels FJ, et al: A new leukoencephalopathy with vanishing white matter. Neurology 1997; 48:845-855. 6. Schiffmann R, Moller JR, Trapp BD, et al: Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994; 35:331-340. 7. van der Knaap MS, Barth PG, Stroink H, et al: Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37:324-334. 8. van der Knaap MS, Leegwater PA, Konst AA, et al: Mutations in each of the five subunits of translation initiation factor eIF2β can cause leukoencephalopathy with vanishing white matter. Ann Neurol 2002; 51:264-270. 9. Leegwater PA, Yuan BQ, van der Steen J, et al: Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001; 68:831-838. 10. Topcu M, Gartioux C, Ribierre F, et al: Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet 2000; 66:733739. 11. Barkovich AJ: Magnetic resonance techniques in the assessment of myelin and myelination. J Inherit Metab Dis 2005; 28:311-343. 12. Moser HW: Adrenoleukodystrophies. In Lazzarini R, ed: Myelin Biology and Disorders. New York: Academic Press, 2003, pp 807-839. 13. Moser HW: Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997; 120:1485-1508. 14. Moser HW, Smith KD, Watkins PA, et al: X-linked adrenoleukodystrophy. In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001, pp 3257-3301. 15. Kurihara M, Kumagai K, Yagishita S, et al: Adrenoleukomyeloneuropathy presenting as cerebellar ataxia in a young child: a probable variant of adrenoleukodystrophy. Brain Dev 1993; 15:377-380. 16. Tsuji S, Suzuki M, Ariga T, et al: Abnormality of long-chain fatty acids in erythrocyte membrane sphingomyelin from patients with adrenoleukodystrophy. J Neurochem 1981; 36:1046-1049. 17. Fatemi A, Barker PB, Ulug AM, et al: MRI and proton MRSI in women heterozygous for X-linked adrenoleukodystrophy. Neurology 2003; 60:1301-1307. 18. el-Deiry SS, Naidu S, Blevins LS, et al: Assessment of adrenal function in women heterozygous for adrenoleukodystrophy. J Clin Endocrinol Metab 1997; 82:856-860. 19. Schaumburg HH, Powers JM, Raine CS, et al: Adrenoleukodystrophy. A clinical and pathological study of 17 cases. Arch Neurol 1975; 32:577-591. 20. van der Knaap MS, Valk J: MR of adrenoleukodystrophy: histopathologic correlations. AJNR Am J Neuroradiol 1989; 10:S12-S14. 21. Ito M, Blumberg BM, Mock DJ, et al: Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J Neuropathol Exp Neurol 2001; 60:1004-1019. 22. Powers JM, DeCiero DP, Ito M, et al: Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000; 59:89-102.

23. Powers JM, DeCiero DP, Cox C, et al: The dorsal root ganglia in adrenomyeloneuropathy: neuronal atrophy and abnormal mitochondria. J Neuropathol Exp Neurol 2001; 60:493501. 24. Jansen GA, Wanders RJ, Watkins PA, et al: Phytanoylcoenzyme A hydroxylase deficiency—the enzyme defect in Refsum’s disease. N Engl J Med 1997; 337:133-134. 25. Julien JJ, Vallat JM, Vital C, et al: Adrenomyeloneuropathy: demonstration of inclusions at the level of the peripheral nerve. Eur Neurol 1981; 20:367-373. 26. Martin JJ, Ceuterick C, Libert J: Skin and conjunctival nerve biopsies in adrenoleukodystrophy and its variants. Ann Neurol 1980; 8:291-295. 27. van Geel BM, Koelman JH, Barth PG, et al: Peripheral nerve abnormalities in adrenomyeloneuropathy: a clinical and electrodiagnostic study. Neurology 1996; 46:112-118. 28. Powers JM, Schaumburg HH, Johnson AB, et al: A correlative study of the adrenal cortex in adrenoleukodystrophy—evidence for a fatal intoxication with very long chain saturated fatty acids. Invest Cell Pathol 1980; 3:353-376. 29. Powers JM, Moser HW, Moser AB, et al: Fetal adrenoleukodystrophy: the significance of pathologic lesions in adrenal gland and testis. Hum Pathol 1982; 13:1013-1019. 30. Powers JM, Schaumburg HH: The testis in adrenoleukodystrophy. Am J Pathol 1981; 102:90-98. 31. Brown FR 3rd, Van Duyn MA, Moser AB, et al: Adrenoleukodystrophy: effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids. Johns Hopkins Med J 1982; 151:164-172. 32. van der Knaap MS, Valk J: Magnetic Resonance of Myelination and Myelin Disorders, 3rd ed. Berlin: Springer, 2005. 33. Kumar AJ, Rosenbaum AE, Naidu S, et al: Adrenoleukodystrophy: correlating MR imaging with CT. Radiology 1987; 165:497-504. 34. Loes DJ, Fatemi A, Melhem ER, et al: Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology 2003; 61:369-374. 35. Tateishi J, Sato Y, Suetsugu M, et al: Adrenoleukodystrophy with olivopontocerebellar atrophy-like lesions. Clin Neuropathol 1986; 5:34-39. 36. Afifi AK, Menezes AH, Reed LA, et al: Atypical presentation of X-linked childhood adrenoleukodystrophy with an unusual magnetic resonance imaging pattern. J Child Neurol 1996; 11:497-499. 37. Kruse B, Barker PB, van Zijl PC, et al: Multislice proton magnetic resonance spectroscopic imaging in X-linked adrenoleukodystrophy. Ann Neurol 1994; 36:595-608. 38. Eichler FS, Barker PB, Cox C, et al: Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002; 58:901-907. 39. Oz G, Tkac I, Charnas LR, et al: Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients. Neurology 2005; 64:434-441. 40. Moser HW, Barker PB: Magnetic resonance spectroscopy: a new guide for the therapy of adrenoleukodystrophy. Neurology 2005; 64:406-407. 41. Kumar AJ, Kohler W, Kruse B, et al: MR findings in adultonset adrenoleukodystrophy. AJNR Am J Neuroradiol 1995; 16:1227-1237. 42. Dubey P, Fatemi A, Barker PB, et al: Spectroscopic evidence of cerebral axonopathy in patients with “pure” adrenomyeloneuropathy. Neurology 2005; 64:304-310. 43. Fatemi A, Smith SA, Dubey P, et al: Magnetization transfer MRI demonstrates spinal cord pathology in adrenomyeloneuropathy. Neurology 2005; 64:1739-1745.

chapter 80 the leukodystrophies 44. Dobyns WB, Filauro A, Tomson BN, et al: Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A 2004; 129:136-143. 45. Bezman L, Moser AB, Raymond GV, et al: Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol 2001; 49:512-517. 46. Migeon BR, Moser HW, Moser AB, et al: Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci U S A 1981; 78:5066-5070. 47. Mosser J, Douar AM, Sarde CO, et al: Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993; 361:726-730. 48. Dean M, Hamon Y, Chimini G: The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 2001; 42:1007-1017. 49. Higgins CF: ABC transporters: from microorganisms to man. Annu Rev Cell Biol 1992; 8:67-113. 50. Lombard-Platet G, Savary S, Sarde CO, et al: A close relative of the adrenoleukodystrophy (ALD) gene codes for a peroxisomal protein with a specific expression pattern. Proc Natl Acad Sci U S A 1996; 93:1265-1269. 51. Kemp S, Wei HM, Lu JF, et al: Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy. Nat Med 1998; 4:1261-1268. 52. Braiterman LT, Watkins PA, Moser AB, et al: Peroxisomal very long chain fatty acid beta-oxidation activity is determined by the level of adrenodeukodystrophy protein (ALDP) expression. Mol Genet Metab 1999; 66:91-99. 53. Kemp S, Pujol A, Waterham HR, et al: ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat 2001; 18:499-515. 54. Berger J, Molzer B, Fae I, et al: X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes. Biochem Biophys Res Commun 1994; 205:1638-1643. 55. Maestri NE, Beaty TH: Predictions of a 2-locus model for disease heterogeneity: application to adrenoleukodystrophy. Am J Med Genet 1992; 44:576-582. 56. Smith KD, Kemp S, Braiterman LT, et al: X-linked adrenoleukodystrophy: genes, mutations, and phenotypes. Neurochem Res 1999; 24:521-535. 57. Moser AB, Kreiter N, Bezman L, et al: Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999; 45:100-110. 58. Moser HW, Moser AE, Trojak JE, et al: Identification of female carriers of adrenoleukodystrophy. J Pediatr 1983; 103:54-59. 59. Moser AB, Rasmussen M, Naidu S, et al: Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 1995; 127:13-22. 60. Theda C, Woody RC, Naidu S, et al: Increased very long chain fatty acids in patients on a ketogenic diet: a cause of diagnostic confusion. J Pediatr 1993; 122:724-726. 61. Moser HW, Moser AB, Kawamura N, et al: Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts. Ann Neurol 1980; 7:542-549. 62. Antoku Y, Sakai T, Tsukamoto K, et al: A simple diagnostic method of adrenoleukodystrophy: total fatty acid analysis of erythrocyte membranes. Clin Chim Acta 1987; 169:121125. 63. Molzer B, Bernheimer H, Heller R, et al: Detection of adrenoleukodystrophy by increased C26:0 fatty acid levels in leukocytes. Clin Chim Acta 1982; 125:299-305. 64. Moser HW, Moser AB, Powers JM, et al: The prenatal diagnosis of adrenoleukodystrophy. Demonstration of increased hexacosanoic acid levels in cultured amniocytes and fetal adrenal gland. Pediatr Res 1982; 16:172-175.

1085

65. Moser AB, Moser HW: The prenatal diagnosis of X-linked adrenoleukodystrophy. Prenat Diagn 1999; 19:46-48. 66. Kennedy CR, Allen JT, Fensom AH, et al: X-linked adrenoleukodystrophy with non-diagnostic plasma very long chain fatty acids. J Neurol Neurosurg Psychiatry 1994; 57:759-761. 67. Wanders RJ, van Roermund CW, Lageweg W, et al: X-linked adrenoleukodystrophy: biochemical diagnosis and enzyme defect. J Inherit Metab Dis 1992; 15:634-644. 68. Boehm CD, Cutting GR, Lachtermacher MB, et al: Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Mol Genet Metab 1999; 66:128-136. 69. Gray RG, Green A, Cole T, et al: A misdiagnosis of X-linked adrenoleukodystrophy in cultured chorionic villus cells by the measurement of very long chain fatty acids. Prenat Diagn 1995; 15:486-490. 70. Carey WF, Poulos A, Sharp P, et al: Pitfalls in the prenatal diagnosis of peroxisomal β-oxidation defects by chorionic villus sampling. Prenat Diagn 1994; 14:813-819. 71. Igarashi M, Schaumburg HH, Powers J, et al: Fatty acid abnormality in adrenoleukodystrophy. J Neurochem 1976; 26:851-860. 72. Ho JK, Moser H, Kishimoto Y, et al: Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. J Clin Invest 1995; 96:1455-1463. 73. Whitcomb RW, Linehan WM, Knazek RA: Effects of longchain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J Clin Invest 1988; 81:185-188. 74. Paintlia AS, Gilg AG, Khan M, et al: Correlation of very long chain fatty acids accumulation and inflammatory disease progression in childhood ALD: implications for potential therapies. Neurobiol Dis 2003; 14:425-439. 75. Powers JM, Schaumburg HH, Johnson AB, et al: A correlative study of the adrenal cortex in adreno-leukodystrophy—evidence for a fatal intoxication with very long chain saturated fatty acids. Invest Cell Pathol 1980; 3:353-376. 76. Singh I, Moser AE, Goldfischer S, et al: Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A 1984; 81:4203-4207. 77. Singh I, Moser AE, Moser HW, et al: Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes. Pediatr Res 1984; 18:286-290. 78. Lazo O, Contreras M, Hashmi M, et al: Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy. Proc Natl Acad Sci U S A 1988; 85:7647-7651. 79. Wanders RJ, van Roermund CW, van Wijland MJ, et al: Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids. Biochem Biophys Res Commun 1988; 153:618624. 80. Uchiyama A, Aoyama T, Kamijo K, et al: Molecular cloning of cDNA encoding rat very long-chain acyl–CoA synthetase. J Biol Chem 1996; 271:30360-30365. 81. Heinzer AK, Watkins PA, Lu JF, et al: A very long chain acyl–CoA synthetase–deficient mouse and its relevance to Xlinked adrenoleukodystrophy. Hum Mol Genet 2003; 12:11451154. 82. Heinzer AK, Kemp S, Lu JF, et al: Mouse very long-chain acyl–CoA synthetase in X-linked adrenoleukodystrophy. J Biol Chem 2002; 277:28765-28773. 83. Heinzer AK, McGuinness MC, Lu JF, et al: Mouse models and genetic modifiers in X-linked adrenoleukodystrophy. Adv Exp Med Biol 2003; 544:75-93.

1086

Section

XIII

M u lt i p l e S c l e ro s i s a n d D e m y e l i nat i n g D i s o r d e rs

84. Braiterman LT, Zheng S, Watkins PA, et al: Suppression of peroxisomal membrane protein defects by peroxisomal ATP binding cassette (ABC) proteins. Hum Mol Genet 1998; 7:239247. 85. McGuinness MC, Lu JF, Zhang HP, et al: Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy. Mol Cell Biol 2003; 23:744-753. 86. Tsuji S, Sano T, Ariga T, et al: Increased synthesis of hexacosanoic acid (C23:0) by cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). J Biochem (Tokyo) 1981; 90:12331236. 87. Kemp S, Valianpour F, Denis S, et al: Elongation of very longchain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol Genet Metab 2005; 84:144-151. 88. Di Biase A, Di Benedetto R, Fiorentini C, et al: Free radical release in C6 glial cells enriched in hexacosanoic acid: implication for X-linked adrenoleukodystrophy pathogenesis. Neurochem Int 2004; 44:215-221. 89. Pujol A, Hindelang C, Callizot N, et al: Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum Mol Genet 2002; 11:499-505. 90. Dubois-Dalcq M, Feigenbaum V, Aubourg P: The neurobiology of X-linked adrenoleukodystrophy, a demyelinating peroxisomal disorder. Trends Neurosci 1999; 22:4-12. 91. Powers JM, Liu Y, Moser AB, et al: The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 1992; 51:630-643. 92. Feigenbaum V, Gelot A, Casanova P, et al: Apoptosis in the central nervous system of cerebral adrenoleukodystrophy patients. Neurobiol Dis 2000; 7:600-612. 93. Moody DB, Besra GS, Wilson IA, et al: The molecular basis of CD1-mediated presentation of lipid antigens. Immunol Rev 1999; 172:285-296. 94. Asheuer M, Bieche I, Laurendeau I, et al: Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy. Hum Mol Genet 2005; 14:1293-1303. 95. Zhang LX, Bakshi R, Fine E, et al: Clinical and electrophysiological improvement of adrenomyeloneuropathy with steroid treatment. J Neurol Neurosurg Psychiatry 2003; 74:822-823. 96. Dubey P, Raymond G, Moser AB, et al: Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long chain fatty acid screening. J Pediatr 2005; 146:528532. 97. Moser HW, Bergin A, Naidu S, Ladenson PW: Adrenoleukodystrophy. Endocrinol Metab Clin North Am 1991; 20:297-318. 98. Peters C, Charnas LR, Tan Y, et al: Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 2004; 104:881-888. 99. Aubourg P, Blanche S, Jambaque I, et al: Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 1990; 322:1860-1866. 100. Shapiro E, Krivit W, Lockman L, et al: Long-term effect of bone-marrow transplantation for childhood-onset cerebral Xlinked adrenoleukodystrophy. Lancet 2000; 356:713-718. 101. Loes DJ, Hite S, Moser H, et al: Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 1994; 15:1761-1766. 102. Rizzo WB, Leshner RT, Odone A, et al: Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 1989; 39:1415-1422.

103. Moser HW, Raymond GV, Lu SE, et al: Follow-up of 89 asymptomatic adrenoleukodystrophy patients treated with Lorenzo’s oil. Arch Neurol 2005; 62:1073-1080. 104. van Geel BM, Assies J, Haverkort EB, et al: Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with “Lorenzo’s oil.” J Neurol Neurosurg Psychiatry 1999; 67:290-299. 105. Uziel G, Bertini E, Bardelli P, et al: Experience on therapy of adrenoleukodystrophy and adrenomyeloneuropathy. Dev Neurosci 1991; 13:274-279. 106. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al: A two-year trial of oleic and erucic acids (“Lorenzo’s oil”) as treatment for adrenomyeloneuropathy. N Engl J Med 1993; 329:745-752. 107. Koehler W, Sokolowski P: Clinical phenotypes, diagnosis and treatment of adulthood X-linked adrenoleukodystrophy. In Berger J, Köhler W, Stöckler-Ipsiroglu S, eds: Understanding and Treating Adrenoleukodystrophy: Present State and Future Perspectives. Heilbronn: Verlag, 2005, pp 28-59. 108. Singh I, Pahan K, Khan M: Lovastatin and sodium phenylacetate normalize the levels of very long chain fatty acids in skin fibroblasts of X-adrenoleukodystrophy. FEBS Lett 1998; 426:342-346. 109. Weinhofer I, Forss-Petter S, Zigman M, et al: Cholesterol regulates ABCD2 expression: implications for the therapy of X-linked adrenoleukodystrophy. Hum Mol Genet 2002; 11: 2701-2708. 110. McGovern MM, Wasserstein MP, Aron A, et al: Biochemical effect of intravenous arginine butyrate in X-linked adrenoleukodystrophy. J Pediatr 2003; 142:709-713. 111. Flavigny E, Sanhaj A, Aubourg P, et al: Retroviral-mediated adrenoleukodystrophy-related gene transfer corrects very long chain fatty acid metabolism in adrenoleukodystrophy fibroblasts: implications for therapy. FEBS Lett 1999; 448: 261-264. 112. Benhamida S, Pflumio F, Dubart-Kupperschmitt A, et al: Transduced CD34+ cells from adrenoleukodystrophy patients with HIV-derived vector mediate long-term engraftment of NOD/SCID mice. Mol Ther 2003; 7:317-324. 113. Baumann M, Korenke GC, Weddige-Diedrichs A, et al: Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy. Eur J Pediatr 2003; 162:6-14. 114. Hagberg B: Clinical symptoms, signs, and tests in metachromatic leukodystrophy. In Folch-Pi J, Bauer H, eds: Brain Lipids and Lipoproteins and the Leukodystrophies. Amsterdam: Elsevier, 1963, p 134. 115. von Figura K, Gieselmann V, Jaeken J: Metachromatic leukodystrophy. In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001, pp 3695-3724. 116. Kumperscak HG, Paschke E, Gradisnik P, et al: Adult metachromatic leukodystrophy: disorganized schizophrenialike symptoms and postpartum depression in 2 sisters. J Psychiatry Neurosci 2005; 30:33-36. 117. Marcao AM, Wiest R, Schindler K, et al: Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene. Arch Neurol 2005; 62:309-313. 118. Molander-Melin M, Pernber Z, Franken S, et al: Accumulation of sulfatide in neuronal and glial cells of arylsulfatase A deficient mice. J Neurocytol 2004; 33:417-427. 119. Holtzman NA: Expanding newborn screening: how good is the evidence? JAMA 2003; 290:2606-2608. 120. Oguz KK, Anlar B, Senbil N, et al: Diffusion-weighted imaging findings in juvenile metachromatic leukodystrophy. Neuropediatrics 2004; 35:279-282.

chapter 80 the leukodystrophies 121. van der Voorn JP, Pouwels PJ, Kamphorst W, et al: Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders. AJNR Am J Neuroradiol 2005; 26:442-446. 122. Gieselmann V, Zlotogora J, Harris A, et al: Molecular genetics of metachromatic leukodystrophy. Hum Mutat 1994; 4:233-242. 123. Sandhoff K, Kolter T, Harzer H: Sphingolipid activator proteins. In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001, pp 3371-3388. 124. Hopwood JJ, Ballabio A: Multiple sulfatase deficiency and the nature of the sulfatase family. In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001, pp 37253732. 125. Baum H, Dodgson KS, Spencer B: The assay of arylsulphatases A and B in human urine. Clin Chim Acta 1959; 4:453-455. 126. Strasberg PM, Warren I, Skomorowski MA, et al: HPLC analysis of urinary sulfatide: an aid in the diagnosis of metachromatic leukodystrophy. Clin Biochem 1985; 18:92-97. 127. Kihara H, Ho CK, Fluharty AL, et al: Prenatal diagnosis of metachromatic leukodystrophy in a family with pseudo arylsulfatase A deficiency by the cerebroside sulfate loading test. Pediatr Res 1980; 14:224-227. 128. Gieselmann V, Polten A, Kreysing J, et al: Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and Nglycosylation site. Proc Natl Acad Sci U S A 1989; 86:94369440. 129. Gieselmann V, Franken S, Klein D, et al: Metachromatic leukodystrophy: consequences of sulphatide accumulation. Acta Paediatr Suppl 2003; 92:74-79. 130. Proia RL, Wu YP: Blood to brain to the rescue. J Clin Invest 2004; 113:1108-1110. 131. Ginsberg L, Gershfeld NL: Membrane bilayer instability and the pathogenesis of disorders of myelin. Neurosci Lett 1991; 130:133-136. 132. Toda K, Kobayashi T, Goto I, et al: Lysosulfatide (sulfogalactosylsphingosine) accumulation in tissues from patients with metachromatic leukodystrophy. J Neurochem 1990; 55:15851591. 133. Hannun YA, Bell RM: Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 1987; 235:670-674. 134. Krivit W, Lockman LA, Watkins PA, et al: The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis 1995; 18:398-412. 135. Guffon N, Souillet G, Maire I, et al: Juvenile metachromatic leukodystrophy: neurological outcome two years after bone marrow transplantation. J Inherit Metab Dis 1995; 18:159161. 136. Krivit W, Lipton ME, Lockman LA, et al: Prevention of deterioration in metachromatic leukodystrophy by bone marrow transplantation. Am J Med Sci 1987; 294:80-85. 137. Dhuna A, Toro C, Torres F, et al: Longitudinal neurophysiologic studies in a patient with metachromatic leukodystrophy following bone marrow transplantation. Arch Neurol 1992; 49:1088-1092. 138. Malm G, Ringden O, Winiarski J, et al: Clinical outcome in four children with metachromatic leukodystrophy treated by bone marrow transplantation. Bone Marrow Transplant 1996; 17:1003-1008. 139. Pridjian G, Humbert J, Willis J, et al: Presymptomatic lateinfantile metachromatic leukodystrophy treated with bone marrow transplantation. J Pediatr 1994; 125:755-758.

1087

140. Biffi A, De Palma M, Quattrini A, et al: Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J Clin Invest 2004; 113:1118-1129. 141. Matzner U, Herbst E, Hedayati KK, et al: Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet 2005; 14:1139-1152. 142. Hagberg B, Kollberg H, Sourander P, et al: Infantile globoid cell leucodystrophy (Krabbe’s disease). A clinical and genetic study of 32 Swedish cases 1953-1967. Neuropadiatrie 1969; 1:74-88. 143. Korn-Lubetzki I, Dor-Wollman T, Soffer D, et al: Early peripheral nervous system manifestations of infantile Krabbe disease. Pediatr Neurol 2003; 28:115-118. 144. Loonen MC, Van Diggelen OP, Janse HC, et al: Lateonset globoid cell leucodystrophy (Krabbe’s disease). Clinical and genetic delineation of two forms and their relation to the early-infantile form. Neuropediatrics 1985; 16:137-142. 145. Satoh JI, Tokumoto H, Kurohara K, et al: Adult-onset Krabbe disease with homozygous T1853C mutation in the galactocerebrosidase gene. Unusual MRI findings of corticospinal tract demyelination. Neurology 1997; 49:1392-1399. 146. Henderson RD, MacMillan JC, Bradfield JM: Adult onset Krabbe disease may mimic motor neurone disease. J Clin Neurosci 2003; 10:638-639. 147. Wenger DA, Suzuki K, Suzuki Y, et al: Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGrawHill, 2001, pp 3669-3694. 148. Yunis EJ, Lee RE: Tubules of globoid leukodystrophy: a righthanded helix. Science 1970; 169:64-66. 149. van der Knaap MS, Valk J: Magnetic Resonance of Myelination and Myelin Disorders, 3rd ed. Berlin: Springer, 2005. 150. Brockmann K, Dechent P, Wilken B, et al: Proton MRS profile of cerebral metabolic abnormalities in Krabbe disease. Neurology 2003; 60:819-825. 151. Wenger DA, Rafi MA, Luzi P: Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. Hum Mutat 1997; 10:268-279. 152. Fu L, Inui K, Nishigaki T, et al: Molecular heterogeneity of Krabbe disease. J Inherit Metab Dis 1999; 22:155-162. 153. Harzer K, Knoblich R, Rolfs A, et al: Residual galactosylsphingosine (psychosine) β-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta 2002; 317:77-84. 154. Suzuki Y, Suzuki K: Krabbe’s globoid cell leukodystrophy: deficiency of glactocerebrosidase in serum, leukocytes, and fibroblasts. Science 1971; 171:73-75. 155. Meikle PJ, Ranieri E, Simonsen H, et al: Newborn screening for lysosomal storage disorders: clinical evaluation of a twotier strategy. Pediatrics 2004; 114:909-916. 156. Li Y, Scott CR, Chamoles NA, et al: Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem 2004; 50:1785-1796. 157. Li Y, Brockmann K, Turecek F, et al: Tandem mass spectrometry for the direct assay of enzymes in dried blood spots: application to newborn screening for Krabbe disease. Clin Chem 2004; 50:638-640. 158. Husain AM, Altuwaijri M, Aldosari M: Krabbe disease: neurophysiologic studies and MRI correlations. Neurology 2004; 63:617-620. 159. Grewal RP, Petronas N, Barton NW: Late onset globoid cell leukodystrophy. J Neurol Neurosurg Psychiatry 1991; 54:1011-1012.

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XIII

M u lt i p l e S c l e ro s i s a n d D e m y e l i nat i n g D i s o r d e rs

160. Austin JH, Lehfeldt D: Studies in globoid (Krabbe) leukodystrophy. 3. Significance of experimentally-produced globoidlike elements in rat white matter and spleen. J Neuropathol Exp Neurol 1965; 24:265-289. 161. Miyatake T, Suzuki K: Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. Biochem Biophys Res Commun 1972; 48:539-543. 162. Suzuki K: Twenty five years of the “psychosine hypothesis:” a personal perspective of its history and present status. Neurochem Res 1998; 23:251-259. 163. Zaka M, Wenger DA: Psychosine-induced apoptosis in a mouse oligodendrocyte progenitor cell line is mediated by caspase activation. Neurosci Lett 2004; 358:205-209. 164. Haq E, Giri S, Singh I, et al: Molecular mechanism of psychosine-induced cell death in human oligodendrocyte cell line. J Neurochem 2003; 86:1428-1440. 165. Suzuki K: Models of Krabbe disease. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 1101-1113. 166. Krivit W, Shapiro EG, Peters C, et al: Hematopoietic stemcell transplantation in globoid-cell leukodystrophy. N Engl J Med 1998; 338:1119-1126. 167. Escolar ML, Poe MD, Provenzale JM, et al: Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Engl J Med 2005; 352:2069-2081. 168. Weinberg KI: Early use of drastic therapy. N Engl J Med 2005; 352:2124-2126. 169. Biswas S, Biesiada H, Williams TD, et al: Substrate reduction intervention by L-cycloserine in twitcher mice (globoid cell leukodystrophy) on a B6;CAST/Ei background. Neurosci Lett 2003; 347:33-36. 170. Boulloche J, Aicardi J: Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol 1986; 1:233-239. 171. Kaye EM, Doll RF, Natowicz MR, et al: Pelizaeus-Merzbacher disease presenting as spinal muscular atrophy: clinical and molecular studies. Ann Neurol 1994; 36:916-919. 172. Seitelberger F: [Merzbacher-Pelizaeus disease; clinicoanatomic studies of its position among the diffuse scleroses]. Wien Z Nervenheilkd Grenzgeb 1954; 9:228-289. 173. Garbern JY, Yool DA, Moore GJ, et al: Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002; 125:551-561. 174. Hudson LD, Garbern JY: Pelizaeus-Merzbacher. In Lazzarini RE, ed: Myelin Biology and Disorders. New York: Academic Press, 2003, pp 867-885. 175. Inoue K, Tanaka H, Scaglia F, et al: Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann Neurol 2001; 50:747-754. 176. Bonavita S, Schiffmann R, Moore DF, et al: Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology 2001; 56:785-788. 177. Hodes ME, DeMyer WE, Pratt VM, et al: Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene. Am J Med Genet 1995; 55:397-401. 178. Nance MA, Boyadjiev S, Pratt VM, et al: Adult-onset neurodegenerative disorder due to proteolipid protein gene mutation in the mother of a man with Pelizaeus-Merzbacher disease. Neurology 1996; 47:1333-1335. 179. Weimbs T, Stoffel W: Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioesterlinked cysteine residues and implications for the membrane topology of PLP. Biochemistry 1992; 31:12289-12296. 180. Knapp PE: Proteolipid protein: is it more than just a structural component of myelin? Dev Neurosci 1996; 18:297308.

181. Mimault C, Giraud G, Courtois V, et al: Proteolipoprotein gene analysis in 82 patients with sporadic PelizaeusMerzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease. Am J Hum Genet 1999; 65:360-369. 182. Inoue K, Osaka H, Imaizumi K, et al: Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol 1999; 45:624-632. 183. Woodward K, Kendall E, Vetrie D, et al: Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH. Am J Hum Genet 1998; 63:207-217. 184. Ellis D, Malcolm S: Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease. Nat Genet 1994; 6:333334. 185. Inoue K, Lupski JR: Molecular mechanisms for genomic disorders. Annu Rev Genomics Hum Genet 2002; 3:199-242. 186. Raskind WH, Williams CA, Hudson LD, et al: Complete deletion of the proteolipid protein gene (PLP) in a family with Xlinked Pelizaeus-Merzbacher disease. Am J Hum Genet 1991; 49:1355-1360. 187. Cambi F, Tartaglino L, Lublin F, et al: X-linked pure familial spastic paraparesis. Characterization of a large kindred with magnetic resonance imaging studies. Arch Neurol 1995; 52:665-669. 188. Hodes ME, Zimmerman AW, Aydanian A, et al: Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet 1999; 82:132-139. 189. Hobson GM, Davis AP, Stowell NC, et al: Mutations in noncoding regions of the proteolipid protein gene in PelizaeusMerzbacher disease. Neurology 2000; 55:1089-1096. 190. Inoue K, Kanai M, Tanabe Y, et al: Prenatal interphase FISH diagnosis of PLP1 duplication associated with PelizaeusMerzbacher disease. Prenat Diagn 2001; 21:1133-1136. 191. Simons M, Kramer EM, Macchi P, et al: Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease. J Cell Biol 2002; 157:327-336. 192. Southwood CM, Garbern J, Jiang W, et al: The unfolded protein response modulates disease severity in PelizaeusMerzbacher disease. Neuron 2002; 36:585-596. 193. Kozutsumi Y, Segal M, Normington K, et al: The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 1988; 332: 462-464. 194. Ma Y, Hendershot LM: The unfolding tale of the unfolded protein response. Cell 2001; 107:827-830. 195. Harding HP, Calfon M, Urano F, et al: Transcriptional and translational control in the mammalian unfolded protein response. Annu Rev Cell Dev Biol 2002; 18:575-599. 196. Knave AM, Griffith IR: Models of Pelizaeus-Merzbacher disease. In Lazzarini RAE, ed: Myelin Disorders and Classification. London: Elsevier, 2004, pp 1125-1142. 197. Duncan ID, Nadon NL, Hoffman RL, et al: Oligodendrocyte survival and function in the long-lived strain of the myelin deficient rat. J Neurocytol 1995; 24:745-762. 198. Brustle O, Jones KN, Learish RD, et al: Embryonic stem cell–derived glial precursors: a source of myelinating transplants. Science 1999; 285:754-756. 199. Bogaert L, Bertrand L: Sur une idiotie familiale avec degenescence spongieuse nevraxe—note preliminaire. Acta Neurol Belg 1949; 49:572-587.

chapter 80 the leukodystrophies 200. Bogaert L, Bertrand I: Spongy Degeneration of the Brain in Infancy. Amsterdam: North-Holland, 1967. 201. Banker BQ, Victor ML: Spongy degeneration of the brain in infancy. In Goodman RM, Motulsky AG, eds: Genetic Diseases Among Ashkenazi Jews. New York: Raven Press, 1979, pp 201216. 202. Traeger EC, Rapin I: The clinical course of Canavan disease. Pediatr Neurol 1998; 18:207-212. 203. Hogan GR, Richardson EP Jr: Spongy degeneration of the nervous system (Canavan’s disease). Pediatrics 1965; 35:284294. 204. Jellinger K, Seitelberger F: Juvenile form of spongy degeneration of the CNS. Acta Neuropathol (Berl) 1969; 13:276281. 205. Goodhue WW Jr, Couch RD, Namiki H: Spongy degeneration of the CNS: an instance of the rare juvenile form. Arch Neurol 1979; 36:481-484. 206. Toft PB, Geiss-Holtorff R, Rolland MO, et al: Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr 1993; 152:750-753. 207. Adachi M, Wallace BJ, Schneck L, Volk BW: Fine structure of spongy degeneration of the central nervous system (van Bogaert and Bertrand type). J Neuropathol Exp Neurol 1966; 25:598-616. 208. van der Knaap MS, Valk J, eds: Canavan’s disease. In Magnetic Resonance of Myelin, Myelination, and Myelin Disorders, 2nd ed. Berlin: Springer-Verlag, 1995, pp 216-220. 209. Grodd W, Krageloh-Mann I, Petersen D, et al: In vivo assessment of N-acetylaspartate in brain in spongy degeneration (Canavan’s disease) by proton spectroscopy. Lancet 1990; 336:437-438. 210. Kaul R, Gao GP, Balamurugan K, et al: Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet 1993; 5:118-123. 211. Kaul R, Gao GP, Aloya M, et al: Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet 1994; 55:34-41. 212. Kelley RI, Stamas JN: Quantification of N-acetyl-L-aspartic acid in urine by isotope dilution gas chromatography-mass spectrometry. J Inherit Metab Dis 1992; 15:97-104. 213. Jakobs C, ten Brink HJ, Langelaar SA, et al: Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherit Metab Dis 1991; 14:653-660. 214. Bennett MJ, Gibson KM, Sherwood WG, et al: Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis. J Inherit Metab Dis 1993; 16:831-836. 215. Besley GT, Elpeleg ON, Shaag A, et al: Prenatal diagnosis of Canavan disease—problems and dilemmas. J Inherit Metab Dis 1999; 22:263-266. 216. Rolland MO, Mandon G, Bernard A, et al: Unreliable verification of prenatal diagnosis of Canavan disease: aspartoacylase activity in deficient and normal fetal skin fibroblasts. J Inherit Metab Dis 1994; 17:748. 217. Elpeleg ON, Shaag A, Anikster Y, et al: Prenatal detection of Canavan disease (aspartoacylase deficiency) by DNA analysis. J Inherit Metab Dis 1994; 17:664-666. 218. Matalon R, Michals-Matalon K: Prenatal diagnosis of Canavan disease. Prenat Diagn 1999; 19:669-670. 219. ACOG committee opinion. Screening for Canavan disease. Number 212, November 1998. Committee on Genetics. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1999; 65:91-92. 220. Matalon R, Michals K, Sebesta D, et al: Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 1988; 29:463-471.

1089

221. Madhavarao CN, Arun P, Moffett JR, et al: Defective Nacetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan’s disease. Proc Natl Acad Sci U S A 2005; 102:5221-5226. 222. Burlina AP, Ferrari V, Divry P, et al: N-acetylaspartylglutamate in Canavan disease: an adverse effector? Eur J Pediatr 1999; 158:406-409. 223. Baslow MH: Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci 2003; 21:185-190. 224. Matalon R, Rady PL, Platt KA, et al: Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. J Gene Med 2000; 2:165-175. 225. Kitada K, Akimitsu T, Shigematsu Y, et al: Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J Neurochem 2000; 74:25122519. 226. Leone P, Janson CG, Bilaniuk L, et al: Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 2000; 48:27-38. 227. Fink DJ: Gene therapy for Canavan disease? Ann Neurol 2000; 48:9-10. 228. McPhee SW, Francis J, Janson CG, et al: Effects of AAV2–mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. Brain Res Mol Brain Res 2005; 135:112-121. 229. Alexander WS: Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 1949; 72:373-381. 230. Pridmore CL, Baraitser M, Harding B, et al: Alexander’s disease: clues to diagnosis. J Child Neurol 1993; 8:134-144. 231. Martidis A, Yee RD, Azzarelli B, et al: Neuro-ophthalmic, radiographic, and pathologic manifestations of adult-onset Alexander disease. Arch Ophthalmol 1999; 117:265-267. 232. Thyagarajan D, Chataway T, Li R, et al: Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene. Mov Disord 2004; 19:1244-1248. 233. Stumpf E, Masson H, Duquette A, et al: Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol 2003; 60:1307-1312. 234. Hallervorden J: [The development of the myelin sheath and Rosenthal’s fibers]. Dtsch Z Nervenheilkd 1961; 181:547-580. 235. Goldman JE, Corbin E: Rosenthal fibers contain ubiquitinated αB-crystallin. Am J Pathol 1991; 139:933-938. 236. Friede RL: Alexander’s disease. Arch Neurol 1964; 11:414-422. 237. van der Knaap MS, Naidu S, Breiter SN, et al: Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22:541-552. 238. van der Knaap MS, Salomons GS, Li R, et al: Unusual variants of Alexander disease. Ann Neurol 2005; 57:327-338 [erratum in Ann Neurol 2005; 58:172]. 239. Brenner M, Johnson AB, Boespflug-Tanguy O, et al: Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001; 27:117-120. 240. Rodriguez D, Gauthier F, Bertini E, et al: Infantile Alexander disease: spectrum of GFAP mutations and genotypephenotype correlation. Am J Hum Genet 2001; 69:1134-1140. 241. Li R, Johnson AB, Salomons G, et al: Glial fibrillary acidic protein mutations in infantile, juvenile and adult forms of Alexander disease. Ann Neurol 2005; 57:310-326. 242. Fuchs E: The cytoskeleton and disease: genetic disorders of intermediate filaments. Annu Rev Genet 1996; 30:197-231. 243. Li R, Messing A, Goldman JE, et al: GFAP mutations in Alexander disease. Int J Dev Neurosci 2002; 20:259-268.

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Section

XIII

M u lt i p l e S c l e ro s i s a n d D e m y e l i nat i n g D i s o r d e rs

244. Stevenson M: Therapeutic potential of RNA interference. N Engl J Med 2004; 351:1772-1777. 245. Bogaert L, Scherer H, Epstein E: Une Forme Cerebrale de la Cholesterinose Generalisee. Paris: Masson et Cie, 1937. 246. Berginer VM, Salen G, Patel Y: Cerebrotendinous xanthomatosis. In Rosenberg RN, Prusiner SB, de Mauro S, et al, eds: Molecular and Genetic Basis of Neurologic and Psychiatric Disease. Philadelphia: Elsevier, 2003, pp 575-580. 247. Bartholdi D, Zumsteg D, Verrips A, et al: Spinal phenotype of cerebrotendinous xanthomatosis—a pitfall in the diagnosis of multiple sclerosis. J Neurol 2004; 251:105-107. 248. Wevers RA, Cruysberg JR, Van Heijst AF, et al: Paediatric cerebrotendinous xanthomatosis. J Inherit Metab Dis 1992; 15:374-376. 249. Gilad R, Lampl Y, Lev D, et al: Cerebrotendinous xanthomatosis without xanthomas. Clin Genet 1999; 56:405406. 250. Cali JJ, Hsieh CL, Francke U, et al: Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 1991; 266:77797783. 251. Bjorkhem I, Boberg KM, Lettersdorf Y: Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001, pp 2961-2988. 252. Seyama Y, Ichikawa K, Yamakawa T: Quantitative determination of cholestanol in plasma with mass fragmentography. Biochemical diagnosis of cerebrotendinous xanthomatosis. J Biochem (Tokyo) 1976; 80:223-228. 253. Koopman BJ, van der Molen JC, Wolthers BG, et al: Screening for cerebrotendinous xanthomatosis by using an enzymatic assay for 7α-hydroxylated steroids in urine. Clin Chem 1987; 33:142-143. 254. Menkes JH, Schimschock JR, Swanson PD: Cerebrotendinous xanthomatosis. The storage of cholestanol within the nervous system. Arch Neurol 1968; 19:47-53. 255. Berginer VM, Salen G, Shefer S: Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 1984; 311:1649-1652. 256. Federico A, Dotti MT: Cerebrotendinous xanthomatosis: clinical manifestations, diagnostic criteria, pathogenesis, and therapy. J Child Neurol 2003; 18:633-638. 257. Wolthers BG, van der Molen JC, Walrecht H, et al: Reduction of urinary bile alcohol excretion and serum cholestanol in patients with cerebrotendinous xanthomatosis after oral administration of deoxycholic acid. Clin Chim Acta 1990; 193:113-118. 258. Batta AK, Salen G, Shefer S, et al: Increased plasma bile alcohol glucuronides in patients with cerebrotendinous xanthomatosis: effect of chenodeoxycholic acid. J Lipid Res 1987; 28:1006-1012. 259. Mondelli M, Sicurelli F, Scarpini C, et al: Cerebrotendinous xanthomatosis: 11-year treatment with chenodeoxycholic acid in five patients. An electrophysiological study. J Neurol Sci 2001; 190:29-33. 260. Pedley TA, Emerson RG, Warner CL, et al: Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. Ann Neurol 1985; 18:517-518. 261. Swanson PD, Cromwell LD: Magnetic resonance imaging in cerebrotendinous xanthomatosis. Neurology 1986; 36:124126. 262. Berginer VM, Shany S, Alkalay D, et al: Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Metabolism 1993; 42:69-74. 263. Federico A, Dotti MT, Lore F, et al: Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. J Neurol Sci 1993; 115:67-70.

264. van Heijst AF, Verrips A, Wevers RA, et al: Treatment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr 1998; 157:313-316. 265. Lewis B, Mitchell WD, Marenah CB, et al: Cerebrotendinous xanthomatosis: biochemical response to inhibition of cholesterol synthesis. Br Med J (Clin Res Ed) 1983; 287:21-22. 266. Nakamura T, Matsuzawa Y, Takemura K, et al: Combined treatment with chenodeoxycholic acid and pravastatin improves plasma cholestanol levels associated with marked regression of tendon xanthomas in cerebrotendinous xanthomatosis. Metabolism 1991; 40:741-746. 267. Salen G, Batta AK, Tint GS, et al: Comparative effects of lovastatin and chenodeoxycholic acid on plasma cholestanol levels and abnormal bile acid metabolism in cerebrotendinous xanthomatosis. Metabolism 1994; 43:1018-1022. 268. Dotti MT, Lutjohann D, von Bergmann K, et al: Normalisation of serum cholestanol concentration in a patient with cerebrotendinous xanthomatosis by combined treatment with chenodeoxycholic acid, simvastatin and LDL apheresis. Neurol Sci 2004; 25:185-191. 269. Mimura Y, Kuriyama M, Tokimura Y, et al: Treatment of cerebrotendinous xanthomatosis with low-density lipoprotein (LDL)–apheresis. J Neurol Sci 1993; 114:227-230. 270. Berginer VM, Salen G: LDL-apheresis cannot be recommended for treatment of cerebrotendinous xanthomatosis. J Neurol Sci 1994; 121:229-232. 271. Kuriyama M, Mimura Y: LDL-apheresis in cerebrotendinous xanthomatosis: reply to letter. J Neurol Sci 1994; 121:231232. 272. Sjögren T, Larsson T: Oligophrenia in combination with congenital ichthyosis and spastic disorders; a clinical and genetic study. Acta Psychiatr Neurol Scand 1957; 32:1-112. 273. Rizzo WB: Sjögren-Larsson syndrome: fatty aldehyde dehydrogenase deficiency. In Scriver CR, Beaudet AL, Sly WS, et al, eds: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001, pp 2239-2258. 274. Jagell S, Polland W, Sandgren O: Specific changes in the fundus typical for the Sjögren-Larsson syndrome. An ophthalmological study of 35 patients. Acta Ophthalmol (Copenh) 1980; 58:321-330. 275. McLennan JE, Gilles FH, Robb RM: Neuropathological correlation in Sjögren-Larsson syndrome. Oligophrenia, ichthyosis and spasticity. Brain 1974; 97:693-708. 276. Willemsen MA, van der Graaf M, van der Knaap MS, et al: MR imaging and proton MR spectroscopic studies in Sjögren-Larsson syndrome: characterization of the leukoencephalopathy. AJNR Am J Neuroradiol 2004; 25:649-657. 277. Rizzo WB, Dammann AL, Craft DA: Sjögren-Larsson syndrome. Impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol : nicotinamide adenine dinucleotide oxidoreductase activity. J Clin Invest 1988; 81:738-744. 278. De Laurenzi V, Rogers GR, Hamrock DJ, et al: SjögrenLarsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet 1996; 12:52-57. 279. Rizzo WB, Carney G: Sjögren-Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2). Hum Mutat 2005; 26:1-10. 280. Rizzo WB, Craft DA: Sjögren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol : NAD+ oxidoreductase in cultured fibroblasts. J Clin Invest 1991; 88:1643-1648. 281. Kelson TL, Craft DA, Rizzo WB: Carrier detection for Sjögren-Larsson syndrome. J Inherit Metab Dis 1992; 15:105111. 282. Rizzo WB, Craft DA, Kelson TL, et al: Prenatal diagnosis of Sjögren-Larsson syndrome using enzymatic methods. Prenat Diagn 1994; 14:577-581.

chapter 80 the leukodystrophies 283. van den Brink DM, van Miert JM, Wanders RJ: Assay for Sjögren-Larsson syndrome based on a deficiency of phytol degradation. Clin Chem 2005; 51:240-242. 284. Willemsen MA, de Jong JG, van Domburg PH, et al: Defective inactivation of leukotriene B4 in patients with SjögrenLarsson syndrome. J Pediatr 2000; 136:258-260. 285. Hernell O, Holmgren G, Jagell SF, et al: Suspected faulty essential fatty acid metabolism in Sjögren-Larsson syndrome. Pediatr Res 1982; 16:45-49. 286. Haug S, Braun-Falco M: Adeno-associated virus vectors are able to restore fatty aldehyde dehydrogenase-deficiency. Implications for gene therapy in Sjögren-Larsson syndrome. Arch Dermatol Res 2005; 296:568-572. 287. Hanefeld F, Holzbach U, Kruse B, et al: Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993; 24:244-248. 288. Dietrich J, Lacagnina M, Gass D, et al: EIF2β5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med 2005; 11:277-283. 289. Schiffmann R, Tedeschi G, Kinkel RP, et al: Leukodystrophy in patients with ovarian dysgenesis. Ann Neurol 1997; 41:654661. 290. Vermeulen G, Seidl R, Mercimek-Mahmutoglu S, et al: Fright is a provoking factor in vanishing white matter disease. Ann Neurol 2005; 57:560-563. 291. Fogli A, Wong K, Eymard-Pierre E, et al: Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2β5 locus. Ann Neurol 2002; 52:506-510. 292. Ainsworth C: Molecular medicine: lost in translation. Nature 2005; 435:556-558. 293. van der Knaap MS, Kamphorst W, Barth PG, et al: Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998; 51:540-547. 294. Ohtake H, Shimohata T, Terajima K, et al: Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2β5. Neurology 2004; 62:16011603. 295. Van Haren K, van der Voorn JP, Peterson DR, et al: The life and death of oligodendrocytes in vanishing white matter disease. J Neuropathol Exp Neurol 2004; 63:618-630. 296. Fogli A, Schiffmann R, Bertini E, et al: The effect of genotype on the natural history of eIF2β-related leukodystrophies. Neurology 2004; 62:1509-1517. 297. van der Knaap MS, Leegwater PA, van Berkel CG, et al: Arg113His mutation in eIF2βε as cause of leukoencephalopathy in adults. Neurology 2004; 62:1598-1600. 298. Besenski N, Bosnjak V, Cop S, et al: Neuroimaging and clinically distinctive features in van der Knaap megalencephalic leukoencephalopathy. Int J Neuroradiol 1997; 3:244-249. 299. Goutieres F, Boulloche J, Bourgeois M, et al: Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases. J Child Neurol 1996; 11:439-444. 300. Higuchi Y, Hattori H, Tsuji M, et al: Partial seizures in leukoencephalopathy with swelling and a discrepantly mild clinical course. Brain Dev 2000; 22:387-389. 301. van der Knaap MS, Barth PG, Vrensen GF, et al: Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol (Berl) 1996; 92:206-212. 302. Boor PKI, de Groot K, Waisfisz Q, et al: MCL1: a novel protein in distal astroglial processes. J Neuropathol Exp Neurol 2005; 64:412-419. 303. Schmitt A, Gofferje V, Weber M, et al: The brain-specific protein MLC1 implicated in megalencephalic leukoencephalopathy with subcortical cysts is expressed in glial cells in the murine brain. Glia 2003; 44:283-295.

1091

304. Neely JD, Amiry-Moghaddam M, Ottersen OP, et al: Syntrophin-dependent expression and localization of aquaporin-4 water channel protein. Proc Natl Acad Sci U S A 2001; 98:14108-14113. 305. Verloes A, Maquet P, Sadzot B, et al: Nasu-Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia. J Med Genet 1997; 34:753-757. 306. Malandrini A, Scarpini C, Palmeri S, et al: Palatal myoclonus and unusual MRI findings in a patient with membranous lipodystrophy. Brain Dev 1996; 18:59-63. 307. Haruta K, Matsunaga S, Ito H, et al: Membranous lipodystrophy (Nasu-Hakola disease) presenting an unusually benign clinical course. Oncol Rep 2003; 10:1007-1010. 308. Nasu T, Tsukahara Y, Terayama K: A lipid metabolic disease— ”membranous lipodystrophy”—an autopsy case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues. Acta Pathol Jpn 1973; 23:539-558. 309. Paloneva J, Autti T, Raininko R, et al: CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology 2001; 56:1552-1558. 310. Iivanainen M, Hakola P, Erkinjuntti T, et al: Cerebral MR and CT imaging in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. J Comput Assist Tomogr 1984; 8:940-943. 311. Paloneva J, Kestila M, Wu J, et al: Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 2000; 25:357-361. 312. Colonna M: Immunology. Unmasking the killer’s accomplice. Nature 1998; 391:642-643. 313. Bakker AB, Wu J, Phillips JH, et al: NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals. Hum Immunol 2000; 61:18-27. 314. Verhoeven NM, Huck JH, Roos B, et al: Transaldolase deficiency: liver cirrhosis associated with a new inborn error in the pentose phosphate pathway. Am J Hum Genet 2001; 68:1086-1092. 315. van der Knaap MS, Wevers RA, Struys EA, et al: Leukoencephalopathy associated with a disturbance in the metabolism of polyols. Ann Neurol 1999; 46:925-928. 316. Huck JH, Verhoeven NM, Struys EA, et al: Ribose-5phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 2004; 74:745751. 317. van der Knaap MS, Naidu S, Pouwels PJ, et al: New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol 2002; 23:1466-1474. 318. van der Knaap MS, van der Voorn P, Barkhof F, et al: A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003; 53:252-258. 319. Henneke M, Preuss N, Engelbrecht V, et al: Cystic leukoencephalopathy without megalencephaly: a distinct disease entity in 15 children. Neurology 2005; 64:1411-1416. 320. Nagae-Poetscher LM, Bibat G, Philippart M, et al: Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology 2004; 62:1206-1209. 321. Chretien F, Servan J, Elghozi D, et al: [Familial orthochromatic leukodystrophy: clinicopathological study of two cases]. Rev Neurol (Paris) 2001; 157:178-186. 322. Shannon P, Wherrett JR, Nag S: A rare form of adult onset leukodystrophy: orthochromatic leukodystrophy with pigmented glia. Can J Neurol Sci 1997; 24:146-150. 323. Axelsson R, Roytta M, Sourander P, et al: Hereditary diffuse leukoencephalopathy with spheroids. Acta Psychiatr Scand 1984; 314:7-65.

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M u lt i p l e S c l e ro s i s a n d D e m y e l i nat i n g D i s o r d e rs

324. van der Knaap MS, Naidu S, Kleinschmidt-Demasters BK, et al: Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids. Neurology 2000; 54:463-468. 325. Harbord MG, Finn JP, Hall-Craggs MA, et al: Early onset leukodystrophy with distinct facial features in 2 siblings. Neuropediatrics 1989; 20:154-157. 326. Leuzzi V, Rinna A, Gallucci M, et al: Ataxia, deafness, leukodystrophy: inherited disorder of the white matter in three related patients. Neurology 2000; 54:2325-2328. 327. Eldridge R, Anayiotos CP, Schlesinger S, et al: Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis. N Engl J Med 1984; 311:948-953. 328. Abe K, Ikeda M, Watase K, et al: A kindred of hereditary adultonset leukodystrophy with sparing of the optic radiations. Neuroradiology 1993; 35:281-283. 329. Hagen K, Boman H, Mellgren SI, et al: Progressive central and peripheral demyelinating disease of adult onset in a Norwegian family. Arch Neurol 1998; 55:1467-1472. 330. Tagawa A, Ono S, Inoue K, et al: A new familial adult-onset leukodystrophy manifesting as cerebellar ataxia and dementia. J Neurol Sci 2001; 183:47-55. 331. Autti T, Muttilainen M, Raininko R, et al: Extensive cerebral white matter abnormality without clinical symptoms: a new hereditary condition? Ann Neurol 1999; 45:801-805. 332. Nomoto N, Iwasaki Y, Arasaki K, et al: Autosomal dominant childhood onset slowly progressive leukodystrophy—a Japanese family with spastic paraparesis, ataxia, mental deterioration, and skeletal abnormality. J Neurol Sci 2004; 221:35-39. 333. Lossos A, Cooperman H, Soffer D, et al: Hereditary leukoencephalopathy and palmoplantar keratoderma: a new disorder with increased skin collagen content. Neurology 1995; 45:331-337. 334. Norton KK, Carey JC, Gutmann DH: Oculodentodigital dysplasia with cerebral white matter abnormalities in a twogeneration family. Am J Med Genet 1995; 57:458-461. 335. Dichgans M, Mayer M, Uttner I, et al: The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998; 44:731-739.

336. Markus HS, Martin RJ, Simpson MA, et al: Diagnostic strategies in CADASIL. Neurology 2002; 59:1134-1138. 337. Pantoni L, Garcia JH: The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke 1995; 26:1293-1301. 338. Kang PB, Hunter JV, Melvin JJ, et al: Infantile leukoencephalopathy owing to mitochondrial enzyme dysfunction. J Child Neurol 2002; 17:421-428. 339. Harpey JP, Heron D, Prudent M, et al: Diffuse leukodystrophy in an infant with cytochrome-c oxidase deficiency. J Inherit Metab Dis 1998; 21:748-752. 340. Rahman S, Brown RM, Chong WK, et al: A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol 2001; 49:797-800. 341. Barone R, Parano E, Trifiletti RR, et al: White matter changes mimicking a leukodystrophy in a patient with mucopolysaccharidosis: characterization by MRI. J Neurol Sci 2002; 195:171-175. 342. Bischof F, Nagele T, Wanders RJ, et al: 3-Hydroxy-3-methylglutaryl–CoA lyase deficiency in an adult with leukoencephalopathy. Ann Neurol 2004; 56:727-730. 343. Surtees R: Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 1998; 157(Suppl 2):S118-S121. 344. Tsao CY, Mendell JR, Rusin J, et al: Congenital muscular dystrophy with complete laminin-α2-deficiency, cortical dysplasia, and cerebral white-matter changes in children. J Child Neurol 1998; 13:253-256. 345. van Engelen BG, Leyten QH, Bernsen PL, et al: Familial adult-onset muscular dystrophy with leukoencephalopathy. Ann Neurol 1992; 32:577-580. 346. Kato T, Funahashi M, Matsui A, et al: MRI of disseminated developmental dysmyelination in Fukuyama type of CMD. Pediatr Neurol 2000; 23:385-388. 347. Eichler FS, Wang P, Wityk RJ, et al: Diffuse metabolic abnormalities in reversible posterior leukoencephalopathy syndrome. AJNR Am J Neuroradiol 2002; 23:833-837.

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ANATOMY AND PHYSIOLOGY MUSCLE AND NERVE ●

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Austin Sumner and Amparo Gutierrez

NERVE The fundamental property of nerve that distinguishes it from other cells in the body is its ability to produce and conduct the regenerative electrical signals known as action potentials. The generation of an action potential takes place at the neuronal surface membrane; once initiated, the signal may be conducted over relatively long distances.1 This extraordinary feat is accomplished because neurons have excitable membranes that are capable of holding a charge. The term motor unit was originally introduced by Sherrington2 as a description to include an individual nerve fiber with the bunch of muscle fibers it activates. A contemporary view would, of course, include the entire motor neuron, dendrites, and cell body, as well as its axon (Fig. 81–1). There are three types of motor neurons and two basic categories of striated muscle fibers. α motor neurons are large cells with fastconducting axons, which innervate the large muscle fibers that make up the bulk of a muscle. These muscle fibers are called extrafusal, to differentiate them from the much smaller specialized intrafusal muscle fibers, which are present only within muscle spindle stretch receptors. Intrafusal muscle fibers are innervated by their own specialized motor neurons and axons, which are referred to as fusimotor or g motor neurons. There is a third group of motor neurons, referred to as skeletofusimotor or b motor neurons, which innervate both extrafusal and intrafusal motor fibers. α motor neurons are among the largest neurons in the mammalian central nervous system and have remarkably extensive dendritic trees. These cells exhibit a twofold range in average soma diameters and up to a fivefold range in cell body volume and total surface area. The size of α motor neurons is correlated with the diameter of their axons and with their physiological properties. The largest of the α motor neurons are classified as type II, which in turn innervate fast-twitch glycolytic muscle fibers. The smaller of the α neurons, type I, innervate slow-twitch oxidative muscle fibers (Table 81–1). The motor neurons that innervate different muscles are grouped into longitudinal columns that lie with the ventrolateral gray matter of the spinal cord. The position of the nuclear column for a particular muscle is predictable, and the number of motor neurons within these columns is approximately the same from one individual to another. α and γ motor neurons innervating a given muscle are mixed more or less randomly within its motor nucleus. On average, between

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25% and 40% of motor neurons in a given motor nucleus are γ. Large muscles generally tend to possess more motor units than do small muscles, but the range of variation is less than might be expected on the basis of relative muscle size. For example, the nerve to the bulky medial gastrocnemius muscle of a human contains about 580 motor axons, whereas the much smaller first dorsal interosseous nerve has 119 axons. The nerve to the tiny lateral rectus muscle contains more than 1700 motor axons. Thus, function as well as muscle volume determine the number of motor neurons present in motor nuclei. In 1874, Ranvier3 recognized a correlation between muscle color and contraction speed. He found that red muscle had slow-twitch properties and pale muscle had fast-twitch properties. These designations derived from the overall characteristics of whole muscles, but within individual muscles, motor unit properties are actually quite heterogeneous. Burke4 characterized three types of motor unit twitch properties: fast-fatiguing (“FF”), fast resistance (“FR”), and slow-twitch fatigue-resistant (“S”) motor units. As noted previously, slow “S”-type muscle units tend to be innervated by relatively slow-conducting motor axons, and motor neurons tend to present greater electrical resistance to currents passed into them through a micropipet electrode. They also have relatively long action potentials after hyperpolarization, which tends to limit their firing rates to slower frequencies. Fast-twitch motor neurons have lower input resistance and shorter-duration hyperpolarization positive action potentials after activation, which are associated with higher firing rates. In both instances, the firing frequencies of the motor unit appear to be physiologically matched to the twitch properties of the innervated muscle fibers. Fast-twitch muscle units have fast-twitch times and high tetanic fusion frequencies and generate high forces, but they fatigue in ways that do not enable these forces to be maintained for long periods. Slow-twitch motor units, in comparison, are activated by motor neurons that fire at relatively lower frequencies to produce the required tetanic fusion.

MUSCLE Skeletal muscle is commonly referred to as striated muscle because of its appearance on both light and electron microscopy. Striated muscle is the major tissue component in

chapter 81 anatomy and physiology of muscle and nerve Spinal ganglion

Epineurium Perineurium Endoneurium Fascicles

Afferent neuron

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Figure 81–1. A diagram of a motor unit and neuromuscular junction.

Peripheral nerve

Sensory ending Anterior horn cell

Efferent neuron Node of Ranvier One nerve fiber

Myelin sheath Axon Neurolemma (sheath of Schwann) Motor ending

T A B L E 81–1. Motor Neurons a Motor Neurons Fast-conducting, largest of the motor neurons Innervate extrafusal muscle fibers Two types: Type I: innervate slow-twitch/oxidative fibers Type II: innervate fast-twitch/glycolytic muscle fiber b Motor Neuron Innervates extrafusal and intrafusal muscle fibers g Motor Neuron Innervates intrafusal muscle fibers-spindles

the body, accounting for 40% to 50% of body weight. Striated muscle is under direct voluntary control and consists of two main categories of fibers: extrafusal and intrafusal.5 Intrafusal muscle fibers are further subdivided into nuclear chain and nuclear bag fibers. These are collectively referred to as the muscle spindle. Spindles are found in all skeletal muscles except facial muscles.6 Spindles are sensory receptors that signal information concerning the degree of stretch applied to a muscle and the velocity of the applied stretch. Extrafusal muscle fibers are the major component of skeletal muscle and are the fibers responsible for the generation of force in movement. The extrafusal fibers are the fibers that are attached to tendons and bone. This section deals primarily with extrafusal muscle fibers.

Histology Individual skeletal muscles consist of a bundle of muscle fibers within a connective tissue framework. These fibers are multinucleated, long cylindrical cells surrounded by the sarcolemma, which includes the plasma membrane and the basal lamina. Of interest is that the muscle membrane is convoluted along its length and that these folds tend to disappear when the muscle stretches.7 The plasma membrane invaginates into

the substance of muscle, forming tunnels, or T (transverse) tubules. The T tubules contain extracellular fluid, forming a channel system throughout the muscle’s interior.8,9 Historically, it was thought that all muscle fibers ran in parallel along the entire length of the muscle. However, it has become increasingly clear that many muscles have a complex array of short fibers or even overlapping fibers.10 Some of these shorter fibers have been noted to be only approximately 2 cm in length.11 Although these morphological arrangements were originally believed to be specific only to long, straplike muscles, there is considerable evidence suggesting that they are common in many muscles with various architectural designs and are seen even across several species.12 On the basis of this information, muscle fibers must be defined as a functional entity rather than an anatomical one. This functional entity can consist of a number of small interdigitating fibers that are then orchestrated into action via intramuscular nerve branches.13 Furthermore, there exists evidence that these in-series short fibers may belong to different motor units.14 Striated muscle is subdivided into three compartments. First, the epimysium provides a tough collagenous elastic envelope, which defines the boundaries of the muscle from adjacent structures and at its ends merges with tendons, aponeurosis, or periosteum. The muscle is then further subdivided into small sections or fascicles by a collagen sheath termed the perimysium. Finally, the individual muscle fibers are separated one from another by the endomysium (Fig. 81–2). Contained within the muscle cell are subcellular components, the myofibrils. The myofibrils are the structures responsible for muscle contraction. Myofibrils are formed by two polymerized protein molecules: myosin and actin. Each myofibril is composed of serially repeating segments, the sarcomeres. An individual sarcomere consists of a dark central band, the A band, with two paler bands on either side. In the center of the A band there is a dark transverse line, the M band. Lying on either side of the M band is a slightly lighter segment. These segments, along with the M band, form the H zone, which lies within the A band. The A band’s major constituent is the protein myosin. The pale I bands are found on either side of the A band and are further subdivided at their

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Perimysium

Bone Epimysium

Blood vessels

Endomysium

Figure 81–2. Striated muscle is subdivided into three compartments: the epimysium, which provides a tough collagenous elastic envelope; the perimysium, which is a collagen sheath; and the endomysium, which separates the individual muscle fibers.

Muscle fiber (cell)

Endomysium

Tendon

midpoint by the Z band or disc. The I bands are composed by the actin filament. The actin filament is formed by three proteins: actin, tropomyosin, and troponin. The Z bands mark the longitudinal boundaries of the individual sarcomeres. Contraction of a myofibril is accomplished by shortening of the sarcomere and apposition of the Z bands to the center A band (Fig. 81–3).15 There are many other known protein structures found in muscle; for an excellent review, refer to an article by Au.16

Physiology Striated muscle can be classified into different fiber types. Muscle fibers can be grouped according to their functional properties, contraction velocity, resistance to fatigue, oxidative and glycolytic capacities, and actin-myosin adenosine triphosphatase (ATPase) activities. Type 1 muscle fibers are also referred to as red fibers,17 because of their greater content of myoglobin. Type 1 muscle fibers are also endowed with more mitochondria, higher capillary density, and greater blood flow. These fibers depend on aerobic respiration and function mainly in postural or sustained activity. Type 2 muscle fibers are white; they are rich in glycogen, have a smaller mitochondrial population and are thus more efficient under anaerobic respiration. Type 2 muscle fibers are more adept at sudden or intermittent activity (Table 81–2).18 ATPase typing is accomplished with the histochemical reaction for myofibrillar ATPase in alkaline or acidic media. It is thus possible to differentiate muscle into type 1 (slow-twitch) and type 2 (fast-twitch), as well as into types 2a, 2b, and 2c fibers.19 At a pH of 9.4, the standard or alkaline ATPase reaction, type 1 fibers stain pale and type 2 fibers stain dark. In an acidic medium, the reverse staining pattern occurs. The oxidative enzyme content of the myofiber reflects its dependence on the tricarboxylic acid cycle, the cytochrome system, and other metabolic pathways for aerobic metabolism. The oxidative enzyme reactions commonly used are the reduced form of nicotinamide adenine dinucleotide– tetrazolium reductase (NADH-TR) and succinic dehydrogenase. Darkly stained fibers are oxidative type 1, and less intensely

■

Figure 81–3. The entire array of thick and thin filaments between the Z lines is called a sarcomere. Shortening of the sarcomeres in a myofibril produces the shortening of the myofibril and, in turn, of the muscle fiber of which it is a part. (From http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/Muscles. html#sarcomere; accessed April 11, 2006.)

T A B L E 81–2. Skeletal Muscle Fiber Types Type 1 Rich in myoglobin, mitochondria, blood vessels Depend on aerobic respiration Function in postural or sustained activity Stain pale with ATPase pH of 9.4 Type 2 Rich in glycogen Depend on anaerobic respiration Function in sudden or intermittent activity Stain dark with ATPase pH of 9.4 ATPase, adenosine triphosphatase.

chapter 81 anatomy and physiology of muscle and nerve stained fibers are type 2. In accordance with this enzymatic reaction, type 2 fibers can be further subdivided into type 2b (virtually unstained) and type 2a, with intermediate staining between type 1 and type 2b. In humans, these muscle fiber types are generally arranged in a checkerboard manner, although the average muscle has about twice the number of type 2 fibers as type 1 fibers. The arrangement of different fiber types in fascicles is determined by the function of the particular muscle. In the vastus lateralis muscle of young healthy men, it was found that the proportion of type 2 fibers was consistently greater at the periphery than internally.20

Common Reaction of Muscle to Injury Histochemical preparations are used to evaluate the health of muscle. Muscle atrophy or hypertrophy can readily be seen with ATPase staining. Type 2 muscle fiber atrophy, the most common type of selective fiber atrophy, occurs with early stages of denervation, with disuse, and as a paraneoplastic complication of systemic malignancy.21 Type 1 fiber atrophy can also occur in some of the congenital myopathies and myotonic dystrophy.22 The most common cause of selective type 2 fiber atrophy is long-term corticosteroid therapy. Selective type 1 fiber hypertrophy is highly suggestive of Werdnig-Hoffman disease.

Effects of Aging on Muscle Aging has been associated with a loss of muscle mass that is referred to as sarcopenia.23 This decrease of muscle mass becomes more pronounced after the sixth decade of life. Several changes take place in muscle during senescence: there is loss of power, strength, and endurance. This decrease in whole muscle size is mirrored by a loss of fiber number.24 The loss of muscle fibers is multifactorial; loss of motor units lead to denervation, a decrease in circulating trophic factors, and an increase in catabolic agents.

K E Y

P O I N T S

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The motor unit includes the motor neuron, dendrites, cell body, axon, and the muscle fibers that they activate.

●

α motor neurons are large, fast-conducting axons that innervate extrafusal muscle fibers.

●

β motor neurous (or skeletofusimotor neurons) innervate both extrafusal and intrafusal muscle fibers.

●

γ motor neurons innervate specialized intrafusal fibers, known as muscle spindles.

●

The sarcomere is the basic repeating unit of muscle; the myofibril is the contractile element of muscle. The myofibril is composed mainly of actin and myosin.

Suggested Reading Au Y: The muscle ultrastructure: a structural perspective of the sarcomere. Cell Mol Life Sci 2004; 61:3016-3033.

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Monti RJ, Roy RR, Edgerton VR: Role of motor unit structure in defining function. Muscle Nerve 2001; 24:848-866. Sumner AJ: The Physiology of Peripheral Nerve Disease. Philadelphia: WB Saunders, 1980.

References 1. Sumner AJ, ed: The Physiology of Peripheral Nerve Disease. Philadelphia: WB Saunders, 1980. 2. Sherrington CS: Ferrier Lecture—some functional problems attaching to convergence. Proc R Soc Lond (Biol) 1929; 105:332-362. 3. Ranvier L: De quelques faits relatifs à l’ histologie et à la physiologie des muscles striés. Arch Physiol Norm Pathol 1874; 1:518. 4. Burke RE: On the central nervous system control of fast and slow twitch motor units. In Desmedt JE, ed: New Developments in Electromyography and Clinical Neurophysiology, vol 1. Basel, Switzerland: Karger, 1973, pp 69-94. 5. Guyton AC: Textbook of Medical Physiology, 8th ed. Philadelphia: WB Saunders, 1991, pp 38-50. 6. Cooper S: Muscle spindles and other muscle receptors. In Bourne GH, ed: The structure and function of muscle. New York: Academic Press, 1960, p 381. 7. Dumitru D, Amato AA, Zwarts MJ: Electrodiagnostic Medicine, 2nd ed. Philadelphia: Hanley & Belfus, 2002, p 12. 8. Fawcett DW: Bloom and Fawcett: A Textbook of Histology. Philadelphia: WB Saunders, 1986. 9. McComas AJ: Neuromuscular Function and Disorders. Boston: Butterworth, 1977. 10. Huber GC: On the form and arrangement of fasciculi of striated voluntary muscle fibers. Anat Rec 1917; 11:149168. 11. Trotter JA, Richmond FJR, Purslow PP: Functional morphology and motor control of series-fibered muscles. Exerc Sport Sci Rev 1995; 23:167-213. 12. Monti RJ, Roy RR, Ederton VE: Role of motor unit structure in defining function. Muscle Nerve 2001; 24:848-866. 13. Loeb GE, Pratt CA, Chanaud CM, et al: Distribution and innervation of short, interdigitated muscle fibers in parallel-fibered muscles of cat hindlimb. J Morphol 1987; 191:1-15. 14. Pratt CA, Loeb GE: Functionally complex muscles of the cat hindlimb. I. Patterns of activation across sartorius. Exp Brain Res 1991; 85:243-256. 15. Mastaglia FL, Walton J: Skeletal Muscle Pathology. Edinburgh: Churchill Livingstone, 1982, pp 12-21. 16. Au Y: The muscle ultrastructure: a structural perspective of the sarcomere. Cell Mol Life Sci 2004; 61:3016-3033. 17. Ashhurst DE: The fine structure of pigeon breast tissue. Tissue Cell, 1969; 1:485. 18. Nelson JS, Parisi JE, Schochet SS: Principles and Practice of Neuropathology. St. Louis: CV Mosby, 1993. 19. Brooke MH, Kaiser KK: Muscle fibre types: how many and what kind? Arch Neurol 1970; 23:369-379. 20. Lexell J, Downham D, Sjostrom M: Distribution of different fibre types in human skeletal muscles. A statistical and computational study of the fibre type arrangement in m. vastus lateralis of young healthy male. J Neurol Sci 1984; 65:353-365. 21. Barron SA, Heffner RR: Weakness in malignancy: evidence for a remote effect on distal axons. Ann Neurol 1978; 4:268-274. 22. Bethlem J: Myopathies, 2nd ed. New York: Elsevier, 1980. 23. Deschenes MR: Effects of aging on muscle fibre type and size. Sports Med 2004; 34:809-824. 24. Lexell J, Henriksson-Larsen K, Winblad B, et al: Distribution of different fibre types in human skeletal muscles: effects of aging studied in whole muscle cross sections. Muscle Nerve 1983; 6:588-595.

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INHERITED NEUROPATHIES ●

●

●

●

Kinga Szigeti and James R. Lupski

During the past decade, molecular genetics research has led to an exponential growth of knowledge of pathogenic genes and has suggested pathways involved in the pathomechanism of disease. In peripheral neuropathies, mutations or altered gene dosages in 25 genes cosegregated with disease, with each disease being due to a single gene in a given family. In vitro functional assays and experiments in animal models of specific genetic alterations elucidated the pathomechanisms by which specific genetic alterations cause disease and identified pathways involved in peripheral nerve biology (Table 82–1). As some of these mutant genes are found in significant numbers of patients with inherited peripheral neuropathy, molecular analysis plays a substantial role in establishing precise and secure etiological diagnoses. If, after excluding common and treatable causes of distal symmetrical peripheral neuropathy, Charcot-Marie-Tooth disease (CMT) is suspected, it is important to (1) establish the clinical diagnosis, (2) confirm and classify the neuropathy by electrophysiology, (3) define the clinical phenotype, (4) determine the inheritance pattern through careful family history, and (5) perform appropriate genetic testing to secure a molecular diagnosis.

CLINICAL DIAGNOSIS The clinical picture combines lower motor neuron–type motor deficits and sensory signs and symptoms. The lower motor deficits manifest as a triad of flaccid paresis, atrophy, and areflexia. The chronic nature of the motor neuropathy results in foot deformity (e.g., pes cavus), hammer toes, and high-arched feet. As is typical in peripheral neuropathies, the longest nerves are affected first and symptoms start distally. Weakness and wasting of distal leg muscles are followed by involvement of the hands in a length-dependent manner. Sensory symptoms are less frequent than in acquired chronic neuropathies but may point to a specific gene defect. Signs of sensory dysfunction are seen in 70% of patients and include loss of vibration and joint position sense and decreased pain and temperature sensation in a stocking-and-glove distribution. Clinical features do not distinguish demyelinating from axonal forms. Ancillary diagnostic tests include electrophysiological studies and sural nerve biopsy. Peripheral nerve MRI and skin biopsy have emerged as diagnostic tools in certain types of

hereditary neuropathies, although further experience is still needed. Electromyography and nerve conduction studies are extremely helpful in the clinical classification of hereditary peripheral neuropathies and in guiding genetic testing. Electrophysiological studies distinguish two major types—the demyelinating form, which is characterized by symmetrically slowed nerve conduction velocity (usually <38 m/sec; normal, >45 m/sec), and the axonal form, which is associated with normal or subnormal nerve conduction velocity and reduced compound muscle action potential. In some cases, an intermediate pattern is recognized with signs of both demyelination and axonal neuropathy (intermediate form). This pattern points toward certain gene defects. Sural nerve biopsies of patients with the demyelinating type show segmental demyelination and onion bulb formation, whereas biopsies from patients with the axonal form show axonal loss, absent or few onion bulbs, and no evidence of demyelination. With the advent of genetic testing, the invasive nerve biopsy is limited to patients in whom a molecular diagnosis is not reached, patients with atypical presentations, or patients in whom inflammatory neuropathy cannot be ruled out by other means. Based on age at onset, severity, and neurophysiological findings, several clinical phenotypes were described. However, with the advent of molecular studies, the genetic and clinical heterogeneity of the hereditary motor-sensory neuropathies has become apparent.

DISEASE PHENOTYPES Charcot-Marie-Tooth Disease (OMIM 118200, 118220) The onset of clinical symptoms is in the first or second decade of life and includes progressive lower motor neuron–type weakness in a length-dependent manner. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Early signs include tripping on uneven surfaces due to diminished dorsiflexion, difficulty walking on the heels, and tight heel cords. To compensate for the diminished ability to dorsiflex the foot, patients flex the hip with each step (steppage or equine-like gait). Neuropathic bony deformities develop,

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T A B L E 82–1. Genotype-Phenotype Correlation Gene

Protein

Protein Domain(s)

Function(s)

Disorder(s)

DNM2 EGR2

Dynamin 2 Early growth response protein 2 Glycyl-tRNA synthetase

GTPase C2H2-type zinc finger

Cellular fusion-fission Transcription factor, cell proliferation Aminoacyl-tRNA synthesis

DI-CMT CMT1, CHN, DSN

Mitochondrial fission

CMT2, CMT4A CMTX CMT2F Distal motor neuropathy

GARS

WHEP-TRS, core catalytic domain, anticodon-binding domain Glutathione S-transferase

GJB1 HSPB1/HSP27

Ganglioside-induced differentiation protein 1 Gap junction protein beta-1 Heat shock protein B1

Connexin Alpha-crystallin

HSPB8/HSP22

Heat shock protein B8

Alpha-crystallin

KIAA1985

SH3TC2

LMNA

150330

Src homology 3 domains, Tetratricopeptide repeat domain Intermediate filament, type-V ATPase

MFN2 MPZ

Mitofusin Myelin protein zero

MTMR2

Myotubularin-related protein 2

NDRG1

NDRG1 protein

Immunoglobin V-type, immunoglobin C-type GRAM, protein tyrosine phosphatase (catalytic), domain in glycosyltransferase, myotubularin and membraneassociated protein Alpha/beta hydrolase fold

NEFL

Neurofilament triplet L protein

Neurofilament, intermediate filament, myosin, hemagglutinin

PMP22

PMP-22/EMP/MP20/Claudin

PRX

Peripheral myelin protein 22 Periaxin

PSD-95, Dlg, ZO-1/2 (PDZ)

RAB7 SBF2/MTMR13 SIMPLE

Ras-related protein Rab-7 SET binding factor 2 SIMPLE

GTPase GRAM, SID, PH RING-finger motif

TDP1

Tyrosyl DNA phosphodiesterase 1

Alpha amylase

GDAP1

including pes cavus (high arched feet) and hammer toes. Early involvement of the peroneus group of muscles gives the legs a stork-like appearance. Patients also complain of leg cramps and lumbar pain after long walks. When the length-dependent progression reaches the length of the arm nerves, weakness and wasting of the intrinsic muscles of the hand appear. The thumb is seen to lie flat in the plane of the hand instead of opposing the other fingers. As a result, patients have difficulty opening jars, holding objects, writing, and buttoning. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature, or vibration in the legs is also noticed in some cases. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome, an irresistible urge to move the legs because of dysesthetic sensations when sitting or lying down, occurs in nearly 40% of patients with the axonal form.1 Neurophysiological studies establish the diagnosis of demyelinating or axonal CMT in most patients, but in a third type of CMT, the intermediate form, features of both demyelination and axonal loss coexist, and this mixed-type neuropathy directs attention to mutations in certain genes.

Gap-junction formation ATP-independent chaperone, prevents aggregation, role in refolding Protein kinase/chaperone

CMT2, dSMA V

Unknown

Distal motor neuropathy, CMT1 CMT4C

Nuclear envelope structure

CMT2

Mitochondrial fusion Myelin structural protein, homophilic adhesion Protein tyrosine phosphatase, dual specificity phosphatase (PI3 phosphatase)

CMT2 CMT1, DSN, CMT2, CHN, RLS CMT4B, CHN

Growth arrest/cell differentiation Neurofilament organization and regulation Myelin structure/growth arrest Cytoskeletal, extracellular signaling Vesicle transport Signaling Transcription factor, ubiquitin ligase DNA replication, hydrolysis of DNA-protein bond

HMSN-L CMT2, CMT1, DSN CMT1, HNPP, DSN, CHN, RLS DSN, CMT4F CMT2 CMT4B2 CMT1, CMT2 CMT2

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP, OMIM 162500) The clinical phenotype is characterized by recurrent and transient nerve dysfunction at sites where the proximity of bony structures or muscle predisposes to nerve compression. Asymmetrical palsies occur after relatively minor compression or trauma of the peripheral nerves. This is a demyelinating neuropathy whose neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula). After repeated attacks, full reversal of neurological signs does not occur and the clinical picture becomes similar to CMT. Electrophysiological findings include mildly slowed nerve conduction velocity and conduction blocks,2 which sometimes lead to confusion with acquired neuropathy.

Dejerine-Sottas Neuropathy (DSN, OMIM 145900) DSN is a clinical entity defined by early onset and developmental delay, followed by signs of lower motor neuron–type involvement, including hypotonia, weakness, and areflexia.

chapter 82 inherited neuropathies Hypertrophic nerves can often be palpated. Neurophysiological studies reveal severe slowing of nerve conduction velocity (<10 m/sec). Neuropathology reveals more pronounced demyelination and greater number of onion bulbs than in CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.

Congenital Hypomyelinating Neuropathy (CHN, OMIM 605253) As the name implies, CHN manifests at birth. However, it is often difficult to distinguish DSN from CHN clinically, as they both may manifest as floppy baby syndrome with absent tendon reflexes. The differential diagnosis between CHN and DSN rests on neuropathology and is based on the presence or absence of onion bulbs associated—in DSN—with absent or thin myelin sheets. CHN may manifest as arthrogryposis multiplex congenita.3

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INHERITANCE PATTERN CMT and related neuropathies exhibit all forms of mendelian inheritance—autosomal dominant, autosomal recessive, and Xlinked. Autosomal dominant demyelinating CMT is the most frequent.4 Thirty-five linked loci (14 autosomal dominant, 12 autosomal recessive, and 3 X-linked; rarely mutations in a gene isolated as a dominant locus behave as recessive alleles in a given family) and 25 CMT-associated genes have been identified. HNPP and RLS show autosomal dominant inheritance, whereas CHN is autosomal recessive or sporadic. DSN shows both autosomal dominant and autosomal recessive inheritance. Genotype-phenotype correlation studies suggest that genetic heterogeneity, age-dependent penetrance, and variable expressivity are key characteristics of the hereditary motor-sensory neuropathies (HMSN). It is estimated that about one third of the mutations occur de novo5-7; thus absence of family history does not preclude genetic testing.

CLASSIFICATION Roussy-Lévy Syndrome (RLS, OMIM 180800) RLS combines sensory ataxia and tremor with the demyelinating CMT phenotype. Molecular data have shown that these patients have the same molecular derangement as those classified clinically as demyelinating CMT.

The classification system for CMT and related peripheral neuropathies is based on clinical phenotype, electrophysiology, and inheritance pattern (Table 82–2). This classification was based on large pedigrees, which were invaluable tools in identifying genes responsible for certain types of CMT. Loci identified from

T A B L E 82–2. Genetic Classification of Charcot-Marie-Tooth Disease and Related Peripheral Neuropathies CMT

Locus

Gene

Product

CMT1A CMT1B CMT1C CMT1D CMT1E CMT1F CMT2A CMT2B CMT2B1 CMT2B2 CMT2C CMT2D CMT2E/F1 CMT2F CMT2G CMT2H CMT2I CMT2J CMT2K CMT2L CMT4A CMT4B1 CMT4B2 CMT4C CMT4D CMT4E CMT4F CMT4G CMT4H DI-CMTA DI-CMTB DI-CMTC DI-CMTD CMTX

17p11.2 1q22 16p13.1-p12.3 10q21.1-q22.1 17p11.2 8p21 1p36 3q21 1q21.2 19q13.3 12q23-q24 7p15 8p21 7q11-q21 12q12-q13 8q21.3 1q22 1q22 8q13-q21.1 12q24 8q13-q21.1 11q22 11p15 5q32 8q24.3 10q21.1-q22.1 19q13.1-q13.2 10q23.3 12p11.21-q13.11 10q24.1-q25.1 19p12-13.2 1p35 1q22 Xq13.1

PMP22 MPZ SIMPLE EGR2 PMP22 NEFL MFN2 RAB7 LMNA Unknown Unknown GARS NEFL HSPB1 Unknown Unknown MPZ MPZ GDAP1 Unknown GDAP1 MTMR2 SBF2/MTMR13 KIAA1985 NDRG1 EGR2 PRX Unknown Unknown Unknown DNM2 Unknown MPZ GJB1

Peripheral myelin protein 22 Myelin protein zero SIMPLE Early growth response protein 2 Peripheral myelin protein 22 Neurofilament triplet L protein Mitofusin 2 Ras-related protein Rab-7 Lamin A/C Unknown Unknown Glycyl-tRNA synthetase Neurofilament triplet L protein Heat shock protein B1 Unknown Unknown Myelin protein zero Myelin protein zero Ganglioside-induced differentiation protein 1 Unknown Ganglioside-induced differentiation protein 1 Myotubularin-related protein 2 SET binding factor 2 SH3TC2 NDRG1 protein Early growth response protein 2 Periaxin Unknown Unknown Unknown Dynamin 2 Unknown Myelin protein zero Gap junction beta-1 protein, connexin 32

OMIM 118220 118200 601098 607678 118220 607684 118210 600882 605588 605589 606071 601472 607684 606595 608591 607731 118200 118200 214400 608673 214400 601382 604563 601596 601455 607678 145900 605285 609311 606483 606482 608323 607791 302800

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N e u ro m u s c u l a r D i s e as e s : N e rv e Proximal CMT1A-REP A

Distal CMT1A-REP

B

C

D

PMP22 A'

A

B

C

B'

JCT ■

C'

B'

D'

C'

D'

A'

D

JCT

Figure 82–1. Reciprocal recombination resulting in duplication causing Charcot-Marie-Tooth disease type 1A (CMT1A) or deletion associated with hereditary neuropathy with liability to pressure palsies (HNPP). Proximal CMT1A-REP is depicted by a red box, distal CMT1AREP is depicted by a blue box, and the PMP22 gene encoding a peripheral myelin proteins depicted by a gray box. A, B, C, D and A′, B′, C′, D′ represent unique sequences flanking the CMT1A-REP low-copy repeats on each of the two chromosome homologues, respectively. Gray lines depict the site of crossover, and the resulting rearrangements are labeled ABCB′C′D′ for the CMT1A duplication and A′D for the reciprocal HNPP deletion. The JCT refers to specific junction fragments detected by probes that are used in diagnostics (PFGE). Homologous meiotic recombination between nonallelic copies of CMT1A-REPs leads to either the CMT1A duplication or HNPP deletion. The CMT1A duplication results in three copies (two on the duplicated chromosome and one on the normal homologue) of the dosage-sensitive PMP22 gene.

these families were named according to this classification as well. However, it became apparent that a substantial number of cases are sporadic and do not fit this classification. Genes associated with specific loci and disease types were found to be responsible for other types of CMT or with different inheritance patterns. Thus, this classification may need revision to make it both simpler and all inclusive. For a genetic overview of CMT, we divide the genes identified into functional groups, describe the clinical phenotypes associated with mutations in those genes, and briefly describe the presumptive pathomechanism deduced from in vitro and in vivo experiments.

GENETICS The more than two dozen genes implicated in hereditary sensorimotor neuropathies belong to various functional classes, all involved in the developmental biology and function of peripheral nerves. They include structural proteins that are important in myelination (e.g., PMP22, MPZ), radial transport proteins (e.g., Cx32), proteins of axonal transport (e.g., NEFL), transcription factors involved in Schwann cell differentiation (EGR2), members of signal transduction pathways (e.g., PRX, MTMR2, SBF2, NDGR1), proteins related to mitochondrial function (e.g., MFN2, GDAP1), proteins related to the endosome (RAB7, SIMPLE), and molecular chaperones (HSP22, HSP27). The products of one gene involved in DNA singlestrand break repair (TDP1) and of other genes (e.g., LMNA, GARS, DNM2) have less clearly defined functions in nerve physiology.

Genes Associated with Peripheral Nerve Structure Peripheral Myelin Protein 22 (PMP22) The first molecular event discovered as responsible for the majority of CMT was the duplication of the chromosomal segment harboring PMP22.8 This discovery introduced a novel molecular mechanism in human mutagenesis, nonallelic homologous recombination (Fig. 82–1), and defined a new group of disorders, the genomic disorders.9,10 The reciprocal molecular event, deletion—instead of duplication—of the same fragment was found in HNPP.11,12 This molecular event and the resulting diseases provided evidence for the presence of dosagesensitive genes in the human genome. Clinical phenotypes: An extra copy of PMP22, due to the CMT1A duplication, is associated with CMT18,13,14 and accounts for 70% of families with dominant CMT15,15 and 76% to 90% of sporadic CMT1.5,7 Reduced compound motor and sensory nerve action potentials correlate with clinical disability, whereas motor nerve conduction velocity does not.16 A prospective study of eight patients with CMT1A17 revealed that motor nerve conduction velocities and clinical motor examinations did not change significantly over a period of 22 years. The CMT1A duplication is also associated with neuropathy in patients with wide variations in clinical phenotypes, including DSN, RLS, calf hypertrophy, and scapuloperoneal atrophy or Davidenkow syndrome.4 Deletion of PMP22 leads to HNPP.11 In one study,18 50% of patients diagnosed with multifocal neuropathy had the 17p11.2 deletion associated with HNPP. Point mutations in PMP22 have been seen in CMT1, HNPP, DSN, and CHN phenotypes.19,20 As anticipated, loss of function mutations21 including frame-shift, nonsense, and splice site mutant alleles result in HNPP; analogous to the HNPP deletion, they effectively result in PMP22 haploinsufficiency.

chapter 82 inherited neuropathies Function: PMP22 is expressed in the peripheral nervous system, but its role is still unclear after 15 years of research. Most of the newly synthesized PMP22 is retained in the endoplasmic reticulum, where it is degraded.22 Only a small percentage of PMP22 is transported from the endoplasmic reticulum to the Golgi apparatus, where it undergoes complex glycosylation and becomes more stable. Axonal contact appears to stimulate the redistribution of PMP22 to the Schwann cell plasma membrane as myelination occurs.23 The ultrastructural pathology of the HNPP phenotype, tomacula, and reduced myelin compaction,24 suggests that PMP22 plays a structural role in myelin formation and/or maintenance. Strategies aimed at normalizing PMP22 expression in transgenic mice have been encouraging25 and clinical trials are under way.

Myelin Protein Zero (MPZ) Clinical phenotypes: About 85 to 90 different myelinopathyassociated MPZ mutations have been described (http://molgenwww.uia.ac.be/CMTMutations/). Most of them are associated with CMT1, but DSN and CMT2 phenotypes are also found, together with a few cases of CHN.26,27 A patient with a severe MPZ mutant allele27 presenting as a floppy baby taught us that innervation may be necessary for proper muscle differentiation and development. The original Roussy-Lévy family reported in 1926 has been shown to harbor a point mutation causing a missense amino acid substitution in the extracellular domain of MPZ.28 Function: MPZ is normally expressed exclusively by myelinating Schwann cells and accounts for 50% of the total PNS myelin protein.29 In vitro functional studies demonstrated that the MPZ truncating mutations associated with a severe form of peripheral neuropathy result in premature stop codons within the terminal or penultimate exons that escape nonsensemediated decay and are stably translated into mutant proteins.30 However, a subset of these mutations, also escaping nonsensemediated decay, resulted in a mild form of peripheral neuropathy. Further in vitro experiments demonstrated that the severity of disease phenotype depends on the amount of residual function of the mutant protein. Mutations altering the cytoplasmic domain and impairing adhesion act as null alleles. If the mutations disrupt the transmembrane domain, the mutant proteins are retained in the endoplasmic reticulum, undergo aggregation, and induce apoptosis.31

Genes Associated With Transport Through Myelin Connexin 32 (Cx32) Clinical phenotypes: Mutations in Cx32 account for nearly 10% of all CMT cases and are the second most frequent cause of CMT after PMP22 duplication. Over 250 different mutations have been described (http://molgen-www.uia.ac.be/CMTMutations/) throughout the entire Cx32 protein, which, unlike the PMP22 and MPZ mutations, are not concentrated in transmembrane or extracellular domains. These mutations behave in a dominant fashion and represent 90% of CMTX. Electrophysiological studies in patients with Cx32 mutations identified three patterns of neuropathy, axonal, demyelinating, and mixed.32,33

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Function: The Cx32 (Gap junction B1; GJB1) gene encodes a gap junction protein containing four transmembrane domains. A connexon (hemichannel) consists of six connexin subunits and two connexons, one from each apposing membrane, which form a functional channel that allows rapid transport of ions and small molecules.34 Cx32 is expressed in myelinating Schwann cells and is localized to noncompact myelin in the paranode and Schmitt-Lanterman incisures, consistent with its role in providing a radial diffusion pathway between the adaxonal and perinuclear cytoplasm of the Schwann cell.35,36 Cx32-deficient mice mimic the human CMT1X phenotype37 with a slowly progressing demyelinating neuropathy. Enlarged periaxonal collars, abnormal noncompacted myelin domains, and axonal sprouts38 suggest that reflexive gap junctions may be required for myelin compaction or that Cx32 may play a structural role in myelin compaction. Mice lacking Cx32 show a distinct pattern of gene dysregulation in Schwann cells,39 indicating that Schwann cell homeostasis is critically dependent on the correct expression of Cx32.

Genes Associated With Axonal Transport Neurofilament-Light (NEFL) Clinical phenotypes: Mutations in NEFL have been identified in two independent families affected with autosomal dominant CMT2.40,41 Studies42,43 have identified additional mutations in NEFL among CMT and DSN cases. These patients had early onset, severe CMT or DSN, and moderate to severely reduced nerve conduction velocities.43 Function: NEFL encodes one of the three neurofilament subunits that are the major types of intermediate filaments found in neurons. In vitro functional studies of mutated neurofilament light chain showed defective assembly of intermediate filament networks, defective targeting of neurofilaments to processes, and altered intracellular distribution of mitochondria, suggesting defective axonal transport as the underlying pathomechanism.44

Transcription Factors Associated With Myelination Early Growth Response 2 (EGR2) Clinical phenotypes: Mutations in human EGR2 are found in patients with CMT1, DSN, and CHN.45,46 Patients with EGR2 mutations frequently have neuropathies affecting cranial nerves III, VII, and XII. Respiratory compromise is a common problem and requires careful monitoring. Function: EGR2, also known as KROX20, encodes a Cys2His2 type zinc finger–containing protein. Most mutations occur in the zinc finger domain. Functional studies have shown that most EGR2 mutations affect the DNA binding and that the amount of residual binding correlates directly with disease severity.47 The same studies have shown that a mutation in the R1 domain of EGR2, which binds to the NAB corepressors and prevents their interaction with NAB proteins, leads to increased transcriptional activity of EGR2. Thus, failure to activate or inactivate downstream genes or deregulation of EGR2 activity could be a pathogenic mechanism.

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Mouse EGR2 is implicated in the establishment of myelination and its subsequent expression is restricted to myelinating Schwann cells.48,49 Homozygous knockout mice for EGR2 show disruption in hindbrain segmentation50,51 and block of Schwann cells at an early stage of differentiation.52

Genes Associated with Signaling

uals affected with hereditary motor and sensory neuropathy, Lom type (HMSNL).68 HMSNL is an autosomal recessive CMT1type disorder with deafness and unusual neuropathological features.69 Function: NDRG1 encodes a phosphatase that is ubiquitously expressed and appears to play a role in cell growth and differentiation.

Periaxin (PRX)

GDAP1

Clinical phenotype: Mutations in PRX are associated with autosomal recessive DSN and CMT4F.53-55 PRX mutations cause early onset but slowly progressive neuropathy with marked sensory component.56 Function: Alternative splicing of human PRX results in two forms: L-periaxin and S-periaxin.57 L-periaxin is first expressed in the nuclei of embryonic Schwann cells and then in the plasma membrane of myelinating Schwann cells.58 Its expression pattern in the rat sciatic nerve parallels the deposition of myelin.59 In mature myelin, periaxin is found in the cytoplasmfilled periaxonal regions of the sheath but is excluded from compact myelin. Mice disrupted for Prx develop PNS compact myelin that degenerates as the animals age,60 consistent with the role of periaxin in myelin stability. These mice are important models to study neuropathic pain in late onset demyelinating disease.

Clinical phenotype: Mutations in GDAP1 are associated with autosomal recessive axonal neuropathies70,71 and autosomal recessive CMT2 with vocal cord paresis and hoarseness.72 In one of these studies,71 the pathological allele (487C>T, Q163X) was observed in three unrelated Hispanic families that had the same haplotype, suggesting a founder mutation that probably arose in Spain and thereby entered the American Hispanic population.73 Function: GDAP1 encodes a ganglioside-induced differentiation protein originally isolated using a tetracycline-regulated expression system from differentiated Neuro2a cells.74 It contains a glutathione-S-transferase domain. It is expressed at high levels in the brain and spinal cord and at lower levels in human sural and mouse sciatic nerves.72 Recent studies suggest that GDAP1 regulates the mitochondrial network. Overexpression of GDAP1 induces fragmentation of mitochondria, while mitochondrial fission proteins (mitofusins 1 and 2 and Drp1) can counterbalance GDAP1-mediated fission. GDAP1-specific knockdown by RNAi results in tubular mitochondrial pathology. However, GDAP1 truncation mutations found in patients with CMT are not targeted to the mitochondria and have lost mitochondrial fragmentation activity in vitro.75

Myotubularin-Related Protein 2 (MTMR2) Clinical phenotype: Mutations in MTMR2 cause a type of autosomal recessive CMT1 (CMT4B1) and CHN.61,62 CMT4B1 is characterized by focally folded myelin. The mutations are distributed throughout the open reading frame. Function: MTMR2 encodes a dual specificity phosphatase. It also contains a GRAM domain, an SET-interacting domain, and a PDZ-binding domain. MTMR2 uses the lipid second messenger, phosphoinositol 3-phosphate, as a physiological substrate. The known63 disease-associated MTMR2 mutations show reduced phosphatase activity,64 indicating that the phosphatase activity of MTMR2 is crucial for its proper function in the peripheral nervous system.

SET Binding Factor 2 (SBF2) or Myotubularin-Related Protein 13 (MTMR13) Clinical phenotype: A homozygous in-frame deletion encompassing exons 11 and 12 was detected in a consangious Turkish family.65 The Japanese family from one of the clinical reports of CMT and glaucoma66 was found to harbor a nonsense mutation in SBF2, which segregated with a phenotype characterized by markedly decreased MCV, myelin folding, and juvenile-onset glaucoma.67 Function: SBF2 encodes an MTMR2-related protein. SBF2 is a member of the pseudo-phosphatase family of myotubularins (also known as MTMR13). It is expressed in various tissues including spinal cord and peripheral nerve. The histopathological hallmarks of the disease are focal outfoldings of myelin in nerve biopsies.

Genes Associated With Endosomes RAB7 Clinical phenotype: Mutations in RAB7 have been associated with CMT2B, an axonopathy.76 Function: RAB7 encodes a GTP-binding protein, a member of the RAB family of small GTPases, which are important regulators of vesicular transport and are located in specific intracellular compartments. RAB7 has been localized to late endosomes and shown to be important in the late endocytic pathway.77

SIMPLE Clinical phenotype: Mutations in SIMPLE may cause both demyelinating and axonal neuropathy.78,79 Function: This gene encodes an unglycosylated small integral membrane protein of the lysosome/late endosome.80 Bioinformatics suggest that SIMPLE may be a member of the RING-finger motif–containing subfamily of E3 ubiquitin ligases.

Mitochondrial Gene

N-myc Downstream Regulated Gene 1 (NDRG1)

Mitofusin 2 (MFN2)

Clinical phenotype: A homozygous C-to-T transition in exon 7 causing a nonsense allele (R148X) was identified in 60 individ-

Clinical phenotype: Mutations in MFN2 were found in seven (19%) CMT2A pedigrees and in several sporadic cases.81 Most

chapter 82 inherited neuropathies patients had moderately severe axonal neuropathy with onset in childhood. In a Japanese study, 8.6% of CMT2 and of unclassified patients had mutations in MFN2, and a recent study found that 23% of CMT2 families had mutations in this gene,82 making MFN2 the gene most commonly involved in CMT2.83 Function: Mitochondria are dynamic and highly motile organelles with frequent fusion and fission events. MFN2 is localized to the outer mitochondrial membrane, and—through fusion—regulates the architecture of the mitochondrial network. Although MFN2 is ubiquitously expressed, in the peripheral nerve the mitochondrial network has to be maintained long distances away from the cell body, which may explain the length-dependent axonal neuropathy developing in patients with MFN2 mutations.83

Chaperones Heat-Shock Protein 27 (HSP27) and Heat-Shock Protein 22 (HSP22) Clinical phenotype: Mutations in the small heat-shock protein 27 were found in patients with distal motor neuropathy and in a family with CMT.84 In this family, distal motor neuropathy and CMT are allelic, suggesting that these two groups of disorders are intimately related. Although HSP22 mutations were originally found only in patients with distal motor neuropathy,84 recently—and not surprisingly—an HSP22 mutation was also identified in a family with CMT.85 Function: The pathomechanism of the neuropathy is less clear. In vitro data show that neuronal cells transfected with mutant HSP27 are less viable than cells transfected with the wild-type protein. When mutant HSP27 is cotransfected with NEFL, neurofilament assembly is altered. In a yeast two-hybrid system, HSP22 and HSP27 were found to interact.86

Genes Associated with DNA Single-Strand Break Repair Tyrosyl DNA Phosphodiesterase 1 (TDP1) Clinical phenotype: A familial homozygous TDP1 mutation has been associated with autosomal recessive spinocerebellar ataxia and axonal neuropathy (SCAN1).87 The phenotype caused by mutations in TDP1 does not quite fit the the CMT definition, as central nervous system involvement is also present. Rather, this clinical presentation belongs to a new group of disorders affecting—in various combinations—oculomotor praxis, the cerebellum, the spinal cord and the peripheral nerves, and all caused by alterations of the DNA repair pathways, with ataxiaoculomotor apraxia (AOA1 and AOA2).88,89 Function: TDP1 encodes a DNA repair enzyme that repairs both abortive single strand breaks created by topoisomerase190 and 3′-phosphoglycolated overhangs of DNA double-strand breaks.91 In the repair of single-strand breaks, TDP1 cleaves the covalent bond formed between the tyrosine moiety of TopoI and the 3′ end of the DNA, thus generating a 3′ end compatible with ligation.92 In the case of double-strand breaks, which leave 3′-phosphoglycolate overhangs, TDP1 removes the glycolate, leaving a 3′ phosphate , which becomes the substrate for ligation. In vitro functional studies revealed that mutations asso-

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ciated with the SCAN1 phenotype alter the sequestration of TDP1 into multiprotein single-strand break repair complexes that are catalitically inactive.93 Another set of in vitro functional studies showed that these mutations abolish the 3′phosphoglycolate processing activity of the enzyme.94

Genes Associated with Other Peripheral Nerve System–Specific Functions Lamin A/C (LMNA) Clinical phenotype: One familial mutation in LMNA is associated with autosomal recessive CMT2 (CMT2B1).95 Other mutations in LMNA are associated with several different disorders, including Emery-Dreifuss muscular dystrophy (EDMD),96 limbgirdle muscular dystrophy,97 dilated cardiomyopathy,98 familial partial lipodystrophy,99 mandibuloacral dysplasia,100 and progeria.101,102 Thus, mutations in a single gene can cause different diseases affecting diverse tissues and organs, including neurons, muscles, cardiovascular and skeletal systems, and fat cells. Function: LMNA encodes a structural protein with similarity to cytoplasmic intermediate filament proteins. Lamins are the major structural proteins of the nuclear lamina underlying the nuclear membrane. They appear to play a role in DNA replication, chromatin organization, spatial arrangements of nuclear pore complexes, nuclear growth, and anchorage of nuclear envelope proteins.103 Mice lacking Lmna develop to term with no overt abnormalities,104 but their postnatal growth is severely retarded and characterized by muscle weakness.

Glycyl tRNA Synthetase (GARS) Clinical phenotype: Mutations in GARS have been found in patients with autosomal dominant CMT axonal neuropathy type 2, designated CMT2D. Distal spinal muscular atrophy type V (DSMAV) is an allelic disorder with a similar phenotype. The clinical picture of patients with GARS mutations differs from that of other axonal CMT2 types in that weakness and atrophy are more severe in the hands than in the feet and that sensory impairment is as frequent as motor involvement.105 Function: The human GARS protein is encoded by a 17-exon gene that spans about 40 kb on chromosome 7p14 and is expressed ubiquitously. The four CMT2D/dSMA-V—associated mutations occured in conserved amino acids. GARS is a member of the family of aminoacyl tRNA synthetases responsible for charging tRNAs with their cognate amino acids. The functional holoenzyme exists as homodimer and contains three major functional domains: the WHEP-TRS domain for conjugation with other aminoacyl tRNA synthetases in enzyme complexes, the core catalytic domain for ligation; and the anticodon-binding domain for recognition of glycine-specific tRNAs.106

Dynamin 2 (DNM2) Clinical phenotype: Mutations in DNM2 were found in three unrelated families with CMT originating from Australia, Belgium, and North America. Two additionally different mutations affecting the same amino acid, Lys558, segregated with CMT and neutropenia, a sign not previously associated with CMT neuropathies.107

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T A B L E 82–3. Mutation Frequencies for CMT and Related Neuropathies in ll Population Studies Population

Cohort (No. of patients) Total/CMT1/HN PP

American15 Spanish113

75/63 52

CMT1A Duplication Total/CMT1

HNPP Deletion Total/HNPP

PMP22 Mutation Total/CMT 1

Cx32 Mutation Total/CMT1

MPZ Mutation Total/CMT1

56/68 Excluded

ND Excluded

7.2 19.2 7.7* 5.4 7.6 ND ND 12 6.8/7.4 6.9 5.3 ND 12%

3.3 9.6 3.8* 0.7 ND ND ND 3.1 3.4 5.6 2.3 5.3 ND 5%

Belgian109 Finnish112 Slovene114 European5 Australian110 Russian115

443 157 71 975/819/156 224 174 /108/3

24.6 40.7 81 59.4/70.7 61 33.9/53.7

10.6 26.1 ND 13.4/84 ND 100

3.9 3.8 0.8* 2.7 ND ND ND 1.3 1.1/1.9

Italian111 Korean108 Brazilian116 Average

172 57/28 53

57.6 26/54 79 34%/66%

ND ND ND 11%/92%

1.2 1.7 ND 2.5%

*Extrapolated total number and mutation frequencies recalculated for the total number. For the estimation of the total number we calculated the average frequencies for CMT1A duplication and HNPP deletion derived from the other studies.

Function: DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus. In vitro experiments showed that mutations of DNM2 substantially diminished binding of DNM2 to membranes by altering the conformation of the beta3/beta4 loop of the plecktrin homology domain.

GENETIC TESTING Parallel to the discovery of more than two dozen genes associated with CMT, the expense of evaluating these many genes for disease-causing mutation has also escalated. When selecting and prioritizing genetic testing one should consider (1) the availability of clinical testing, (2) the yield of a specific molecular test, (3) the aim of establishing a molecular diagnosis, and (4) the frequency of de novo mutations. Evidence-based data from 12 population-based studies from various ethnic backgrounds5,6,15,108-117 reported results on five genes/genomic rearrangements: PMP22 duplication/deletion; and on the following point mutations, MPZ, Cx32, and PMP22. The mutations of individual genes were uniformly distributed in the total population and in phenotypic subgroups. Applying a simple clinical classification (demyelinating versus axonal neuropathy) and considering the inheritance pattern111 improves markedly the diagnostic yield (Table 82–3). We used a cohort of 153 consecutive unrelated CMT cases collected before genetic testing became available in commercial laboratories to estimate the mutation frequencies for the genes that are not reported in the population-based studies. We tested 14 genes/genomic rearrangements (PMP22 dup/del, point mutations in Cx32, MPZ, PMP22, EGR2, PRX, NEFL, SOX10, SIMPLE, GDAP1, LMNA, TDP1, MTMR2) in this cohort. The frequencies of the five mutations screened in the population-based studies were similar to those reported, suggesting that estimates from this cohort are representative. At present, mutations in the genes for which population studies were not available seem to account for only a small minority (<1% to 2%) of patients with the CMT phenotype. Commercial laboratories report similar relative frequencies. Figure 82–2 illus-

Demyelinating

PMP22 mut

EGR2 SIMPLE GDAP1 NDRG1 SBF2 MTMR2 CTDP1 PRX Unknown

MPZ GJB1

PMP22 dup

Axonal MFN2 Unknown

GJB1

RAB7 MPZ GARS HSPB2 HSPB8 NEFL DNM2 TDP1 LMNA ■

Figure 82–2. The approximate expected yield of genetic testing in demyelinating and axonal Charcot-Marie-Tooth disease by using the depicted molecular testing.

chapter 82 inherited neuropathies trates the relative frequencies of genes whose mutations cause CMT1 or CMT2. Duplication of a chromosomal segment harboring PMP22 (i.e., the CMT1A duplication)8 accounts for 43% of all CMT cases but for 70% of CMT1 patients. Thus, PMP22 duplication/deletion testing should be the initial step in demyelinating neuropathies of any severity. Deletion of the same chromosomal segment results in HNPP.11 Although detection of deletion has a low yield in the total CMT population, deletion mutations are found in more than 90% of patients with HNPP. As HNPP occasionally can mimic multifocal neuropathy,18 a correct molecular diagnosis in this group can prevent unnecessary immunosuppressive therapy. Cx32 mutations are the next most common culprits in inherited neuropathy. Dominant inheritance pattern and lack of male-to-male transmission points to this gene on the X chromosome. As the phenotype is intermediate, molecular testing for Cx32 is appropriate in both CMT1 (after duplication testing) and CMT2. Identification of a Cx32 mutation determines an Xlinked dominant inheritance pattern, enabling an accurate estimation of recurrence risk. Population-based studies suggest that in patients with the CMT1 phenotype MPZ and PMP22 mutations are the next most common genetic errors, followed by mutations in rare genes.117

In the CMT2 group, Cx32 mutations are followed by MPZ mutations in frequency, but data, although not population based, suggest that MFN2 mutations may be common causes of CMT2.81,83 Mutations in other genes are responsible for the CMT in only small numbers of patients, and, in the absence of clinical clues, the likelihood of establishing a molecular diagnosis in these patients is low. The high frequency of de novo mutations in duplication/deletion (37% to 90%)7,118 and in point mutations6 explains how genetic disease is commonly sporadic in presentation. The absence of a positive family history does not exclude CMT and related peripheral neuropathies. In fact, if a patient presents with chronic polyneuropathy without other signs or symptoms, and common systemic and treatable causes, such as diabetes, uremia, and nutritional deficiency, have been excluded, a genetic neuropathy is more likely than autoimmune or paraneoplastic neuropathy. A rational diagnostic approach is presented in Figure 82–3. Finally, when performing genetic testing, one must consider the specific question posed and the likelihood that the result would affect medical management. PMP22 duplication and Cx32 mutation analysis establishes the molecular diagnosis in 65% of patients, but if patients with demyelinating neuropathy

Clinical picture Chronic peripheral neuropathies Family history Positive

Negative EMG/NCS Index of suspicion for CMT

Demyelinating

Intermediate

Axonal High

Inheritance

Low Sural nerve biopsy if clinically indicated

AD X

AD AR X

AD AR X

Genetic testing

PMP22 dup 70%

MPZ 5% PMP22 2.5% SIMPLE FGR2

PRX GDAP1 EGR2 MTMR2 MTMR13 NDRG1 KIAA1985

GJB1 8.8% DNM2 MPZ

GJB1

Specific cause not identified MFN2 20% MPZ RAB GARS NEFL HSP27 HSP22

GDAP1 LMNA

Specific cause identified

GJB1

Genetic testing Demyelinating Intermediate PMP22 dup GJB1 PMP22 MPZ

■

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DNM2 GJB1 MPZ PMP22

Axonal MFN2 GJB1 MPZ

Figure 82–3. Suggested testing scheme in hereditary sensory and motor polyneuropathy for patients without a family history of Charcot-Marie-Tooth disease (CMT) based on the genotype-phenotype correlations and frequency data in 12 population-based studies. EMG, electromyography; NCS, nerve conduction studies; AD, autosomal dominant; AR, autosomal recessive; X, X-linked.

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are tested as a group, the diagnostic yield increases to over 80%. A correct diagnosis identifies candidates for the clinical trials, families whose members are at risk for idiosyncratic drug reactions, and determines inheritance pattern, which may suffice to an adult with CMT and no reproductive plans. In the pediatric population, when parents wish to have more children, the aim of testing is to establish prognosis and recurrence risk. As accurate molecular diagnosis is important, after testing for the common causes of peripheral neuropathy, PMP22 duplication and Cx32 mutations, panel testing for all other genes implicated in that phenotype should be considered.

MANAGEMENT Treatment approaches to the hereditary sensorimotor neuropathies can be divided into preventive, symptomatic, and etiological. As CMT is a slowly progressive neurodegenerative disease, patients require periodic assessments. Physical therapy and occupational therapy are helpful in maintaining range of motion and function.119,120 Orthotic devices and assistive equipment can increase safety and function. In some instances, surgical interventions on the hands and feet become necessary.121,122 Symptomatic treatment may have a substantial impact on the quality of life. Maintenance of normal weight prevents strain on weak muscles and joints, prolongs ambulation, and prevents back pain. Nonsteroidal anti-inflammatory drugs may relieve low back or leg pain. Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).123,124 The tremor may respond to β blockers or primidone.125 Caffeine and nicotine can aggravate the fine intentional tremor and should be avoided. Neurotoxic drugs (http://www.charcot-marietooth.org/) and excessive alcohol should also be avoided. Even small doses of vincristine can produce devastating effects in CMT patients, and early detection of HMSN can avoid lifethreatening vincristine neurotoxicity.126 Although etiological treatment is currently unavailable, therapeutic trials with a progesterone antagonist127 and with ascorbic acid127,128 have proved effective in animal models with a CMT-like neuropathy caused by the CMT1A duplication. Clinical trials in patients with the CMT1A duplication are under way.

GENETIC COUNSELING Because CMT is inherited as a mendelian trait, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history of an affected individual is positive. However, the intrafamilial variability in disease expression requires that parental disease status be defined either by finding a mutation previously identified in the propositus or, if no mutation is known, through thorough neurological and electrophysiological examinations. An affected parent with autosomal dominant or X-linked dominant CMT1 or CMT2 has a 50% risk of having a child with the same mutation. Whether this child will be clinically affected sometime during his or her lifetime is not known because penetrance has not been determined in genetically well-defined patient populations. In general, only a few patients with autosomal dominant CMT1 or CMT2 have substantial difficulty

walking before the age of 50 years, but almost all patients express some symptoms by the sixth decade of life.129 For fathers with X-linked dominant CMT, the risk of having an affected son is negligible but the risk of having an affected daughter is 100%. For mothers with X-linked dominant CMT, the risk of having an affected son or daughter is 50%. In the absence of a molecular diagnosis, nerve conduction velocity slowing is detectable by age 2 to 5 years130,131 in patients with autosomal dominant CMT1. Therefore, if a young adult has normal nerve conduction velocities, the risk of developing autosomal dominant CMT1 is negligible, but if nerve conduction velocities are abnormal, the patient has at least a 90% risk of developing symptoms at some point in his or her life. Electrophysiological changes associated with autosomal dominant CMT2 develop with disease progression, such that only about one half of the patients can be identified by age 20 years.132 When unaffected parents have a child with CMT1 or CMT2, four possibilities exist: a de novo dominant mutation, autosomal recessive inheritance, X-linked inheritance, or nonpaternity. Distinction between these possibilities requires either the identification of the causative mutation(s) or identification of affected siblings. The identification of a de novo heterozygous presumed dominant mutation suggests a low recurrence risk for the parents; however, their risk is higher than that for the general population because of germline mosaicism.133 A proband with a heterozygous presumed dominant mutation has a 50% risk of having affected children. For autosomal recessive inheritance, the parental risk of an affected child is 25% because penetrance is nearly complete.

SUMMARY A simple clinical distinction of CMT into demyelinating and axonal improves the yield of genetic testing and determines which genes should be tested for. In the demyelinating form, the combination of CMT1A duplication and Cx32 mutation testing has a yield of approximately 80%. MPZ and PMP22 mutations are the next most common culprits. In cases of axonal CMT, Cx32 mutations are followed by MPZ mutations in population-based studies, and there is a suggestion that MFN2 mutations may be quite common. Discoveries of potential small molecule treatments for a specific subtype of CMT have shifted the emphasis of genetic testing. Instead of seeking a molecular diagnosis in the few patients referred to tertiary care centers, we need to find the most patients with potentially treatable molecular defects. Although genetic testing for all known genes is impractical in clinical practice, it should be used to address specific questions in a logical stepwise fashion based on evidence from population-based studies.

K E Y

P O I N T S

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The clinical picture is a combination of lower motor neuron–type motor deficits and sensory signs and symptoms.

●

Depending on age of onset, neurophysiological findings, and severity, the clinical phenotype can be established.

chapter 82 inherited neuropathies ●

Genetic heterogeneity, age-dependent penetrance, and variable expressivity are key characteristics of the hereditary motor-sensory neuropathies.

●

The most common form of hereditary motor-sensory neuropathy is CMT1A caused by duplication of a chromosomal segment harboring the PMP22 gene. The molecular pathomechanism of the duplication is nonallelic homologous recombination mediated by flanking low-copy repeat sequences as recombination substrates.

●

The plethora of genetic information necessitates a rational approach to genetic testing.

Suggested Reading Chance PF, Alderson MK, Leppig KA et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell. 1993;72:143-151. Emerging pathways for hereditary axonopathies. J Mol Med. 2005 Aug 31. Lupski JR, de Oca-Luna RM, Slaugenhaupt S et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991;66:219-232. Lupski JR, Garcia CA. Charcot-Marie-Tooth Peripheral Neuropathies and Related Disorders. In: The metabolic and molecular bases of inherited disease: McGraw-Hill, 2001. Suter U, Scherer SS. Disease mechanisms in inherited neuropathies. Nat Rev Neurosci. 2003;4(9):714-26.

References 1. Gemignani F, Marbini A, Di Giovanni G, et al: Charcot-MarieTooth disease type 2 with restless legs syndrome. Neurology 1999; 52:1064-1066. 2. Uncini A, Di Guglielmo G, Di Muzio A, et al: Differential electrophysiological features of neuropathies associated with 17p11.2 deletion and duplication. Muscle Nerve 1995; 18:628635. 3. Boylan KB, Ferriero DM, Greco CM, et al: Congenital hypomyelination neuropathy with arthrogryposis multiplex congenita. Ann Neurol 1992; 31:337-340. 4. Lupski JR, Garcia CA: Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Valle D, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001. 5. Nelis E, Van Broeckhoven C, De Jonghe P, et al: Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet 1996; 4:25-33. 6. Boerkoel CF, Takashima H, Garcia CA, et al: Charcot-MarieTooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 2002; 51:190-201. 7. Hoogendijk JE, Hensels GW, Gabreels-Festen AA, et al: Denovo mutation in hereditary motor and sensory neuropathy type I. Lancet 1992; 339:1081-1082. 8. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al: DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991; 66:219-232. 9. Lupski JR: Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 1998; 14:417-422.

1109

10. Stankiewicz P, Lupski JR: Genome architecture, rearrangements and genomic disorders. Trends Genet 2002; 18:74-82. 11. Chance PF, Alderson MK, Leppig KA, et al: DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 1993; 72:143-151. 12. Chance PF, Abbas N, Lensch MW, et al: Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum Mol Genet 1994; 3:223-228. 13. Raeymaekers P, Timmerman V, Nelis E, et al: Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord 1991; 1:93-97. 14. Patel PI, Roa BB, Welcher AA, et al: The gene for the peripheral myelin protein PMP-22 is a candidate for CharcotMarie-Tooth disease type 1A. Nat Genet 1992; 1:159-165. 15. Wise CA, Garcia CA, Davis SN, et al: Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication. Am J Hum Genet 1993; 53:853-863. 16. Krajewski KM, Lewis RA, Fuerst DR, et al: Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 2000; 123( Pt 7):1516-1527. 17. Killian JM, Tiwari PS, Jacobson S, et al: Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy. Muscle Nerve 1996; 19:74-78. 18. Tyson J, Malcolm S, Thomas PK, et al: Deletions of chromosome 17p11.2 in multifocal neuropathies. Ann Neurol 1996; 39:180-186. 19. Valentijn LJ, Bolhuis PA, Zorn I, et al: The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. Nat Genet 1992; 1:166-170. 20. Simonati A, Fabrizi GM, Pasquinelli A, et al: Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22. Neuromuscul Disord 1999; 9:257-261. 21. Nicholson GA, Valentijn LJ, Cherryson AK, et al: A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies. Nat Genet 1994; 6:263266. 22. Sancho S, Magyar JP, Aguzzi A, et al: Distal axonopathy in peripheral nerves of PMP22-mutant mice. Brain 1999; 122 (Pt 8):1563-1577. 23. Pareek S, Suter U, Snipes GJ, et al: Detection and processing of peripheral myelin protein PMP22 in cultured Schwann cells. J Biol Chem 1993; 268:10372-10379. 24. Yoshikawa H, Dyck PJ: Uncompacted inner myelin lamellae in inherited tendency to pressure palsy. J Neuropathol Exp Neurol 1991; 50:649-657. 25. Perea J, Robertson A, Tolmachova T, et al: Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A. Hum Mol Genet 2001; 10:1007-1018. 26. Warner LE, Hilz MJ, Appel SH, et al: Clinical phenotypes of different MPZ (P0) mutations may include Charcot-MarieTooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron 1996; 17:451-460. 27. Szigeti K, Saifi GM, Armstrong D, et al: Disturbance of muscle fiber differentiation in congenital hypomyelinating neuropathy caused by a novel myelin protein zero mutation. Ann Neurol 2003; 54:398-402. 28. Plante-Bordeneuve V, Guiochon-Mantel A, Lacroix C, et al: The Roussy-Lévy family: from the original description to the gene. Ann Neurol 1999; 46:770-773. 29. Lemke G: Unwrapping the genes of myelin. Neuron 1988; 1:535-543. 30. Inoue K, Khajavi M, Ohyama T, et al: Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 2004; 36:361-369.

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Section

XIV

N e u ro m u s c u l a r D i s e as e s : N e rv e

31. Khajavi M, Inoue K, Wiszniewski W, et al: Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants. Am J Hum Genet 2005; 77:841-850. 32. Dubourg O, Tardieu S, Birouk N, et al: Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain 2001; 124:1958-1967. 33. Tabaraud F, Lagrange E, Sindou P, et al: Demyelinating Xlinked Charcot-Marie-Tooth disease: unusual electrophysiological findings. Muscle Nerve 1999; 22:1442-1447. 34. Bruzzone R, Ressot C: Connexins, gap junctions and cell-cell signalling in the nervous system. Eur J Neurosci 1997; 9:16. 35. Neuhaus IM, Bone L, Wang S, et al: The human connexin32 gene is transcribed from two tissue-specific promoters. Biosci Rep 1996; 16:239-248. 36. Bergoffen J, Scherer SS, Wang S, et al: Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 1993; 262:2039-2042. 37. Anzini P, Neuberg DH, Schachner M, et al: Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32. J Neurosci 1997; 17:4545-4551. 38. Kobsar I, Maurer M, Ott T, et al: Macrophage-related demyelination in peripheral nerves of mice deficient in the gap junction protein connexin 32. Neurosci Lett 2002; 320:17-20. 39. Nicholson SM, Gomes D, de Nechaud B, et al: Altered gene expression in Schwann cells of connexin32 knockout animals. J Neurosci Res 2001; 66:23-36. 40. Mersiyanova IV, Perepelov AV, Polyakov AV, et al: A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet 2000; 67:37-46. 41. De Jonghe P, Mersivanova I, Nelis E, et al: Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol 2001; 49:245-249. 42. Yoshihara T, Yamamoto M, Hattori N, et al: Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals. J Peripher Nerv Syst 2002; 7:221-224. 43. Jordanova A, De Jonghe P, Boerkoel CF, et al: Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 2003; 126:590597. 44. Perez-Olle R, Jones ST, Liem RK: Phenotypic analysis of neurofilament light gene mutations linked to Charcot-MarieTooth disease in cell culture models. Hum Mol Genet 2004; 13:2207-2220. 45. Warner LE, Mancias P, Butler IJ, et al: Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 1998; 18:382-384. 46. Timmerman V, De Jonghe P, Ceuterick C, et al: Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype. Neurology 1999; 52:1827-1832. 47. Warner LE, Svaren J, Milbrandt J, et al: Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. Hum Mol Genet 1999; 8:1245-1251. 48. Zorick TS, Syroid DE, Arroyo E, et al: The transcription factors SCIP and Krox-20 mark distinct stages and cell fates in Schwann cell differentiation. Mol Cell Neurosci 1996; 8:129-145.

49. Kioussi C, Gruss P: Making of a Schwann. Trends Genet 1996; 12:84-86. 50. Swiatek PJ, Gridley T: Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev 1993; 7:2071-2084. 51. Schneider-Maunoury S, Topilko P, Seitandou T, et al: Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell 1993; 75:1199-1214. 52. Topilko P, Schneider-Maunoury S, Levi G, et al: Krox-20 controls myelination in the peripheral nervous system. Nature 1994; 371:796-799. 53. Boerkoel CF, Takashima H, Stankiewicz P, et al: Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet 2001; 68:325-333. 54. Guilbot A, Williams A, Ravise N, et al: A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum Mol Genet 2001; 10:415421. 55. Takashima H, Boerkoel CF, De Jonghe P, et al: Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann Neurol 2002; 51:709-715. 56. Kijima K, Numakura C, Shirahata E, et al: Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease. J Hum Genet 2004; 49:376-379. 57. Dytrych L, Sherman DL, Gillespie CS, et al: Two PDZ domain proteins encoded by the murine periaxin gene are the result of alternative intron retention and are differentially targeted in Schwann cells. J Biol Chem 1998; 273:5794-5800. 58. Sherman DL, Brophy PJ: A tripartite nuclear localization signal in the PDZ-domain protein L-periaxin. J Biol Chem 2000; 275:4537-4540. 59. Gillespie CS, Sherman DL, Blair GE, et al: Periaxin, a novel protein of myelinating Schwann cells with a possible role in axonal ensheathment. Neuron 1994; 12:497-508. 60. Gillespie CS, Sherman DL, Fleetwood-Walker SM, et al: Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 2000; 26:523-531. 61. Bolino A, Muglia M, Conforti FL, et al: Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 2000; 25:17-19. 62. Bolino A, Lonie LJ, Zimmer M, et al: Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-MarieTooth disease suggests a low frequency of mutation in inherited neuropathy. Neurogenetics 2001; 3:107-109. 63. Kim SA, Taylor GS, Torgersen KM, et al: Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease. J Biol Chem 2002; 277:4526-4531. 64. Berger P, Bonneick S, Willi S, et al: Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet 2002; 11:1569-1579. 65. Senderek J, Bergmann C, Weber S, et al: Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet 2003; 12:349-356. 66. Kiwaki T, Umehara F, Takashima H, et al: Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma. Neurology 2000; 55:392-397. 67. Hirano R, Takashima H, Umehara F, et al: SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology 2004; 63:577-580. 68. Kalaydjieva L, Gresham D, Gooding R, et al: N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 2000; 67:47-58.

chapter 82 inherited neuropathies 69. Kalaydjieva L, Hallmayer J, Chandler D, et al: Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat Genet 1996; 14:214-217. 70. Baxter RV, Ben Othmane K, Rochelle JM, et al: Gangliosideinduced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002; 30:21-22. 71. Boerkoel CF, Takashima H, Nakagawa M, et al: CMT4A: identification of a Hispanic GDAP1 founder mutation. Ann Neurol 2003; 53:400-405. 72. Cuesta A, Pedrola L, Sevilla T, et al: The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002; 30:22-25. 73. Claramunt R, Pedrola L, Sevilla T, et al: Genetics of CharcotMarie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet 2005; 42:358-365. 74. Liu H, Nakagawa T, Kanematsu T, et al: Isolation of 10 differentially expressed cDNAs in differentiated Neuro2a cells induced through controlled expression of the GD3 synthase gene. J Neurochem 1999; 72:1781-1790. 75. Niemann A, Ruegg M, La Padula V, et al: Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-MarieTooth disease. J Cell Biol 2005; 170:1067-1078. 76. Verhoeven K, De Jonghe P, Coen K, et al: Mutations in the small GTP-ase late endosomal protein RAB7 cause CharcotMarie-Tooth type 2B neuropathy. Am J Hum Genet 2003; 72:722-727. 77. Vitelli R, Chiariello M, Lattero D, et al: Molecular cloning and expression analysis of the human Rab7 GTP-ase complementary deoxyribonucleic acid. Biochem Biophys Res Commun 1996; 229:887-890. 78. Saifi GM, Szigeti K, Wiszniewski W, et al: SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Human Mutations 2005; in press. 79. Street VA, Goldy JD, Golden AS, et al: Mapping of CharcotMarie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am J Hum Genet 2002; 70:244-250. 80. Moriwaki Y, Begum NA, Kobayashi M, et al: Mycobacterium bovis Bacillus Calmette-Guerin and its cell wall complex induce a novel lysosomal membrane protein, SIMPLE, that bridges the missing link between lipopolysaccharide and p53-inducible gene, LITAF(PIG7), and estrogen-inducible gene, EET-1. J Biol Chem 2001; 276:23065-23076. 81. Zuchner S, Mersiyanova IV, Muglia M, et al: Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-MarieTooth neuropathy type 2A. Nat Genet 2004; 36:449-451. 82. Lawson VH, Graham BV, Flanigan KM: Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005:197-204. 83. Kijima K, Numakura C, Izumino H, et al: Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 2004. 84. Evgrafov OV, Mersiyanova I, Irobi J, et al: Mutant small heatshock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004; 36:602-606. 85. Tang BS, Zhao GH, Luo W, et al: Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet 2004. 86. Benndorf R, Sun X, Gilmont RR, et al: HSP22, a new member of the small heat shock protein superfamily, interacts with mimic of phosphorylated HSP27 ((3D)HSP27). J Biol Chem 2001; 276:26753-26761.

1111

87. Takashima H, Boerkoel CF, John J, et al: Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 2002; 32:267-272. 88. Moreira MC, Barbot C, Tachi N, et al: The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. 29(2):189-93. Nat Genet 2001; 29:189-193. 89. Moreira MC, Klur S, Watanabe M, et al: Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 2004; 36:225-227. 90. Pouliot JJ, Yao KC, Robertson CA, et al: Yeast gene for a TyrDNA phosphodiesterase that repairs topoisomerase I complexes. Science 1999; 286:552-555. 91. Inamdar KV, Pouliot JJ, Zhou T, et al: Conversion of phosphoglycolate to phosphate termini on 3’ overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J Biol Chem 2002; 277:27162-27168. 92. Interthal H, Pouliot JJ, Champoux JJ: The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proc Natl Acad Sci U S A 2001; 98:12009-12014. 93. El-Khamisy SF, Saifi GM, Weinfeld M, et al: Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 2005; 434:108-113. 94. Zhou T, J.W. L, Tatavarthi H, et al: Deficiency in 3’phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res 2005; 33:289-297. 95. De Sandre-Giovannoli A, Chaouch M, Kozlov S, et al: Homozygous defects in LMNA, encoding lamin A/C nuclearenvelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 2002; 70:726-736. 96. Bonne G, Di Barletta MR, Varnous S, et al: Mutations in the gene encoding lamin A/C cause autosomal dominant EmeryDreifuss muscular dystrophy. Nat Genet 1999; 21:285-288. 97. Muchir A, Bonne G, van der Kooi AJ, et al: Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000; 9:1453-1459. 98. Fatkin D, MacRae C, Sasaki T, et al: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999; 341:1715-1724. 99. Cao H, Hegele RA: Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2000; 9:109-112. 100. Novelli G, Muchir A, Sangiuolo F, et al: Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002; 71:426-431. 101. Eriksson M, Brown WT, Gordon LB, et al: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003; 423:293-298. 102. Mounkes LC, Kozlov S, Hernandez L, et al: A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 2003; 423:298-301. 103. Stuurman N, Heins S, Aebi U: Nuclear lamins: their structure, assembly, and interactions. J Struct Biol 1998; 122:4266. 104. Sullivan T, Escalante-Alcalde D, Bhatt H, et al: Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol 1999; 147:913-920. 105. Antonellis A, Ellsworth RE, Sambuughin N, et al: Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet 2003; 72:1293-1299. 106. Freist W, Logan DT, Gauss DH: Glycyl-tRNA synthetase. Biol Chem Hoppe Seyler 1996; 377:343-356.

1112

Section

XIV

N e u ro m u s c u l a r D i s e as e s : N e rv e

107. Zuchner S, Noureddine M, Kennerson M, et al: Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet 2005. 108. Choi BO, Lee MS, Shin SH, et al: Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean CharcotMarie-Tooth neuropathy patients. Hum Mutat 2004; 24:185186. 109. Janssen EA, Kemp S, Hensels GW, et al: Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Genet 1997; 99:501-505. 110. Nicholson GA: Mutation testing in Charcot-Marie-Tooth neuropathy. Ann N Y Acad Sci 1999; 883:383-388. 111. Mostacciuolo ML, Righetti E, Zortea M, et al: Charcot-MarieTooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families. Hum Mutat 2001; 18:32-41. 112. Silander K, Meretoja P, Juvonen V, et al: Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies. Hum Mutat 1998; 12:59-68. 113. Bort S, Nelis E, Timmerman V, et al: Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies. Hum Genet 1997; 99:746-754. 114. Leonardis L, Zidar J, Ekici A, et al: Autosomal dominant Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies: detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118Met PMP22 point mutation. Int J Mol Med 1998; 1:495-501. 115. Mersiyanova IV, Ismailov SM, Polyakov AV, et al: Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. Hum Mutat 2000; 15:340-347. 116. Marques WJ, Freitas MR, Nascimento OJM, et al: 17p duplicated Charcot-Marie-Tooth 1A. J. Neurol 2005; 252:972-979. 117. Szigeti K, Garcia C, Lupski J: Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genetics in Medicine 2005; 8:86-92. 118. Warner LE, Roa BB, Lupski JR: Absence of PMP22 coding region mutations in CMT1A duplication patients: further evidence supporting gene dosage as a mechanism for CharcotMarie-Tooth disease type 1A. Hum Mutat 1996; 8:362-365. 119. Lindeman E, Spaans F, Reulen J, et al: Progressive resistance training in neuromuscular patients. Effects on force

120. 121. 122. 123. 124.

125. 126.

127.

128. 129. 130. 131.

132. 133.

and surface EMG. J Electromyogr Kinesiol 1999; 9:379384. Njegovan ME, Leonard EI, Joseph FB: Rehabilitation medicine approach to Charcot-Marie-Tooth disease. Clin Podiatr Med Surg 1997; 14:99-116. Mann DC, Hsu JD: Triple arthrodesis in the treatment of fixed cavovarus deformity in adolescent patients with CharcotMarie-Tooth disease. Foot Ankle 1992; 13:1-6. Guyton GP, Mann RA: The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin 2000; 5:317-326. Backonja MM: Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002; 59:S14-17. Bissar-Tadmouri N, Parman Y, Boutrand L, et al: Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth Type 1 and HNPP patients. Clin Genet 2000; 58:396-402. Koller WC, Hristova A, Brin M: Pharmacologic treatment of essential tremor. Neurology 2000; 54:S30-38. Naumann R, Mohm J, Reuner U, et al: Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity. Br J Haematol 2001; 115:323-325. Sereda MW, Meyer zu Horste G, Suter U, et al: Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 2003; 9:1533-1537. Passage E, Norreel JC, Noack-Fraissignes P, et al: Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 2004; 10:396-401. Harding AE, Thomas PK: The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980; 103:259-280. Kaku DA, Parry GJ, Malamut R, et al: Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy type 1. Neurology 1993; 43:2664-2667. Kaku DA, Parry GJ, Malamut R, et al: Nerve conduction studies in Charcot-Marie-Tooth polyneuropathy associated with a segmental duplication of chromosome 17. Neurology 1993; 43:1806-1808. Harding AE, Thomas PK: Autosomal recessive forms of hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry 1980; 43:669-678. Takashima H, Nakagawa M, Kanzaki A, et al: Germline mosaicism of MPZ gene in Dejerine-Sottas syndrome (HMSN III) associated with hereditary stomatocytosis. Neuromuscul Disord 1999; 9:232-238.

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METABOLIC, IMMUNE-MEDIATED, AND TOXIC NEUROPATHIES ●

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Louis H. Weimer and Yaacov Anziska

Acquired peripheral neuropathy is a highly prevalent and often overlooked condition. Most patients and many physicians are not sufficiently aware of the range of disorders associated with neuropathy outside of the most common cause⎯diabetes mellitus. Although many neuropathies, including the roughly 30% that have no discernible cause, have no effective treatment, symptomatic therapy is available and therapeutic options are continually expanding. In contrast, many disorders discussed in this chapter can be potentially reversed or at least slowed by treating the underlying condition, removing offending toxins or medications, or limiting immune-mediated injury. For this to happen, proper diagnosis is essential. Several immunemediated neuropathies are included here, but other important types of neuropathy are not discussed or are considered in more general sections on specific topics. Noteworthy examples include paraneoplastic neuropathy, hereditary and acquired amyloidosis, axonal paraprotein- and myeloma-associated, and acute immune-mediated neuropathies. Topics discussed in other sections include sarcoidosis, environmental toxins, nerve injury, and collagen vascular diseases.

NEUROPATHIES ASSOCIATED WITH DIABETES MELLITUS Diabetes mellitus is the most common cause of neuropathy in the Western world, as noted since the early 1800s. The most common presentation is distal, predominantly sensory neuropathy; however, diabetes is associated with numerous other forms of neuropathy, ranging from asymptomatic to disabling motor, autonomic, or pain syndromes (Table 83–1). This syndromic list is both clinically and experimentally useful because the differing underlying mechanisms that are likely to occur directly influence treatment choices and efficacy, clinical trial selection, and mechanistic bench research. Most published lists differ slightly in syndrome numbers and entity names, and a separate list could be based on probable pathophysiological mechanisms.1 Important clinical features include nerve modalities, symmetry, speed of onset, distribution, and related diabetic complications, especially renal failure. A consensus statement in 2005 reviewed clinical syndromes, pathogenic mechanisms, and recommended treatment.2 There is growing evidence that symptomatic peripheral neuropathy can occur in the presence of mild diabetes or glucose intolerance even in the

absence of notable damage to other end organs. However, in most large series, neuropathy is associated with both retinopathy and nephropathy.3 Less common forms of diabetic neuropathy are not associated with diabetic complications, suggesting a different pathophysiology, such as inflammatory or immune-mediated injury. Conversely, the coexistence of diabetes and neuropathy in a particular patient is not in itself proof of diabetic neuropathy, as unrelated processes may be present that warrant appropriate diagnostic investigation. In general, any of the entities listed can occur with either type 1 or type 2 diabetes (Table 83–1).

Distal Diabetic Polyneuropathy Foot numbness and paresthesia have gradual onset and ascend slowly. The process can spread to the hands, arms, trunk, and scalp in advanced cases, but more commonly hand and arm involvement is caused by superimposed processes, such as compressive mononeuropathy.3 Loss of light touch, pain, and temperature precede loss of proprioception; distal weakness and atrophy are late findings. Patients generally notice “positive” or unpleasant symptoms, especially burning pain, electrical or stabbing sensations, paresthesia, and deep pain; loss of sensation and anesthesia are less common. Symptoms are frequently worse at night when there are less sensory distractions. Approximately 20% to 50% of diabetic patients have at least one symptom of diabetic neuropathy but even more have asymptomatic disease. Lack of sensation can lead to unperceived injury, ulcers, and Charçot joints⎯a significant form of morbidity. Not surprisingly, objective evidence of functional loss on clinical examination and laboratory testing often exceeds symptoms. Onset may occur after several years of diabetes or with subclinical diabetes, and the neuropathy may lead to the discovery of underlying diabetes. Sensory fibers in the foot and distal leg are predominantly affected, especially small diameter sensory and autonomic fibers. Examination of the lower leg usually reveals loss of vibration, pressure, pain, and temperature perception (both small and large fiber–mediated) and absent ankle deep tendon reflexes. Signs of peripheral autonomic (sympathetic) dysfunction are frequent, including altered skin temperature (cold or warm), dry, often scaly, skin, and calluses in pressure-bearing areas. Loss of sensation for 128-Hz vibration, monofilament touch, and loss of ankle jerks are considered 87%

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T A B L E 83–1. Clinical Neuropathy Patterns Associated With Diabetes Mellitus Distal symmetrical sensory predominant neuropathy Diabetic autonomic neuropathy Ischemic mononeuropathy Cranial neuropathy (pupil-sparing oculomotor) Femoral neuropathy Compression and entrapment syndromes Carpal tunnel syndrome Ulnar neuropathy at the elbow Peroneal neuropathy at the fibular head Lateral femoral cutaneous neuropathy (meralgia paresthetica) Diabetic amyotrophy (diabetic radiculoplexus neuropathy) Lumbosacral form most common, thoracic and cervical forms also occur Painful neuropathy with weight loss and poor glucose control, “diabetic cachexia” Truncal neuropathy Chronic inflammatory demyelinating neuropathy associated with diabetes

sensitive for detecting neuropathy and predicting foot ulcer.2 The diagnosis is ultimately clinical and requires exclusion of other reasonable causes of neuropathy. Even if symptoms remain confined to the legs and feet, objective testing such as nerve or skin biopsy and clinical electrophysiological studies often show evidence of more widespread involvement. Electrodiagnostic studies are an important adjunct to assess severity and to parse out superimposed mononeuropathy, regional syndromes, superimposed radiculopathy, and demyelinating neuropathy. Nerve biopsy is not routinely necessary but in some cases it demonstrates signs of microvascular changes in addition to axonal loss (Fig. 83–1). Skin punch biopsy to assess epidermal nerve fiber density is increasingly available and minimally invasive, as discussed later. Diabetic autonomic neuropathy affects up to one half of diabetics.3 Genitourinary and sexual dysfunction, such as impotence, are most common, but orthostatic intolerance and hypotension, gastrointestinal dysmotility (diarrhea or constipation), gastroparesis, fatigue and exercise intolerance, vasomotor disturbance, and pupil dysfunction are also common. Patients with diabetic autonomic neuropathy have shorter survival than do unaffected diabetic patients, but the relative risk is less than early reports suggested. Patients may become intolerant of autonomically active medications, such as antihypertensive or anticholinergic agents, as the neuropathy slowly worsens, producing symptoms such as orthostatic complaints, syncope, urinary retention, excessively dry eyes, and focusing difficulties. Formal autonomic testing is widely available and is especially helpful when the clinical picture is equivocal or the cause of orthostatic symptoms is unclear. Treatment and assessment are discussed in Chapters 29 through 32. The pathophysiology is presumed to be the same as in distal diabetic polyneuropathy and is discussed later. Ischemic mononeuropathies are presumably due to occlusion of arterioles supplying individual nerves and produce acute ischemia and aching pain, followed by loss of nerve function. The process can affect either cranial or peripheral nerves or nerve roots. Pupil-sparing oculomotor palsy is the most common cranial neuropathy, followed by sixth and seventh neuropathies, but all are relatively uncommon. Diabetics are

■

Figure 83–1. Diabetic neuropathy, sural nerve. The tissue section of the nerve shows a mild loss of myelinated fibers. Endoneurial microvessels show a collar of hyaline pink material, a characteristic feature of diabetic microangiopathy (semithin plastic sections, toluidine blue-basic fuchsin). (Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

more susceptible to compression or entrapment neuropathy, and at least 30% of diabetics have carpal tunnel syndrome, which can range from asymptomatic to very distressing.1 Ulnar neuropathy at the elbow, peroneal neuropathy at the fibular head, and lateral femoral cutaneous neuropathy (meralgia paresthetica) are also common. Diabetic amyotrophy (diabetic radiculoplexus neuropathy) is a monophasic illness seen primarily in type 2 diabetic patients and characterized by subacute proximal leg weakness progressing stepwise over weeks to months, weight loss, atrophy, and aching proximal leg pain. The weakness affects mostly but not exclusively the femoral and obturator nerve distributions, plateaus over weeks, and slowly improves over 12 to 36 months.4 Sensory involvement is less marked and often overshadowed by the underlying distal polyneuropathy. Anatomic boundaries are not respected, and there is often evidence of both nerve root and plexus involvement, hence the descriptive label. Findings may be unilateral or bilateral but asymmetric. If involvement is extensive, a diagnosis of chronic inflammatory demyelinating polyneuropathy, which is more common in diabetic patients, should be considered. Thoracic and cervical forms also occur but are less common and must be distinguished from ischemic injury and unrelated compressive spine disease. Although various neuropathological findings have been reported, an immune-mediated process is suspected and a long-awaited treatment trial is ongoing.

Etiology There are numerous lines of evidence and hypotheses attempting to explain diabetic polyneuropathy but most start with perturbations initiated by excessive glucose levels. Duration of diabetes, hemoglobin A1c levels, and other signs of poor glucose control correlate with neuropathy development and severity. Microvascular injury appears to be a crucial process in

chapter 83 metabolic, immune-mediated, and toxic neuropathies the development of neuropathy as well as in damage of other end organs, and interruption of this process has long been a target of therapeutic intervention. Four major pathways of glucose metabolism are implicated. Excess intracellular glucose is processed, in part, through the polyol pathway in a series of reactions catalyzed by aldose reductase. This pathway leads to sorbitol and fructose accumulation, NAD(P)H-redox imbalances, changes in signal transduction, and excessive production of reactive oxygen radicals.5 Also, nonenzymatic glycation of proteins produces advanced glycation end products in peripheral nerve, and these impair axonal transport, neurotrophic factor production, and gene expression. In addition, protein kinase C activation starts a cascade of stress responses and increases hexosamine pathway flux; both processes lead to oxygen radical generation.5 Specific inhibitors of each pathway, aimed at blocking one or more microvascular complications, have shown considerable promise in rodent models: they include nine different aldose reductase inhibitors, various neurotrophins, blood flow and angiogenesis enhancers, free radical scavengers, and others. Unfortunately, virtually all have failed or have produced equivocal results, but several trials are presently ongoing, including a gene therapy trial of vascular endothelial growth factor. A broader approach targeting several pathways at once may be needed to affect human disease. Other risk factors have gathered recent attention. A large European consortium has found the following independent risks factors for the cumulative incidence of diabetic neuropathy: lowdensity lipoprotein cholesterol and triglycerides, high body mass index, high von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking.6 Several factors are potentially adjustable and some might explain why neuropathy develops in patients with early disease or with simple glucose intolerance, as we discuss later. More acute or subacute entities suggest an immune-mediated mechanism, and some may respond to immunomodulating therapies.

Treatment Tight glycemic control is the most important and only intervention proved to prevent or limit diabetic polyneuropathy and autonomic neuropathy, but it does not reverse existing nerve injury.7,8 Treatment of other modifiable potential risk factors (lipids, blood pressure, weight) is an evolving but likely important approach. The efficacy of preventative medications currently in clinical trials is yet to be determined. Numerous symptomatic treatments are effective in reducing—but usually not eliminating—the discomfort of diabetic and other painful polyneuropathies. Randomized double-blind, controlled trials have demonstrated symptomatic relief, primarily for painful neuropathy, with a number of agents, including several tricyclic antidepressants, gabapentin, pregabalin, tramadol hydrochloride, and the serotonin and norepinephrine reuptake inhibitor duloxetine.1,9-11 The selective serotonin reuptake inhibitor paroxetine was better than placebo but not better than imipramine, and citalopram was similar to paroxetine; fluoxetine showed no significant benefit. However, only pregabalin and duloxetine have received U.S. Food and Drug Administration indications for treatment of painful neuropathy. Numerous other medications and therapies have undergone small randomized or incompletely controlled trials and are empirically used. Proper foot care and prompt attention to injury are essential.

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Glucose Intolerance and Neuropathy There is increasing recognition of impaired glucose tolerance, sometimes designated as prediabetes, in patients with painful sensory neuropathy, as many as 34% in one study.12-14 Fasting plasma glucose of 100 to 125 mg/dL or 2-hour glucose of 140 to 199 mg/dL (impaired glucose tolerance) defines prediabetes. The 2-hour oral glucose tolerance test is the usual detection method and is recommended in patients with otherwise unexplained sensory neuropathy. Autonomic dysfunction appears to be common in these patients.15 The mechanism of nerve damage in hyperglycemia is still unknown, but early indications suggest that aggressive lifestyle modifications affect neuropathy progression and are the target of a multicenter clinical trial. Most patients with neuropathy associated with prediabetes are overweight and show metabolic manifestations of insulin resistance. Treatment of hyperglycemia, insulin resistance, neuropathic pain, and individualized diet and exercise counseling have been more effective than glucose-lowering medications in preventing progression from impaired glucose tolerance to diabetes.14 Diet and exercise also seem to reduce neuropathic pain in these patients.

Other Endocrine Disorders Hypothyroidism is uncommonly associated with peripheral neuropathy and frequently with carpal tunnel syndrome. Acromegaly is associated with entrapment neuropathy.

Small Fiber Neuropathy Small fiber neuropathy is an increasingly diagnosed disorder with pure or predominant involvement of small-diameter myelinated and unmyelinated sensory and autonomic nerve fibers and with minimal or no large fiber sensory or motor impairment. Common manifestations include pain, burning distal paresthesia, impaired temperature perception, trophic signs, distal autonomic dysfunction, especially impaired vasomotor and temperature control, and decreased sweating. Diabetes is the most common cause, and findings are indistinguishable from early distal diabetic polyneuropathy. Other important or common causes include amyloidosis, chronic alcoholism, certain toxins, and rare hereditary entities. However, in a substantial group of patients there is no discernible cause. Because most conventional tests, such as nerve conduction studies, do not assess small-diameter fibers, other objective means to confirm this syndrome are desirable. Quantitative sensory testing assesses small and large sensory fibers by examining temperature and vibratory thresholds; although useful for sequential measures in clinical trials, it is not recommended for routine clinical diagnostic use.16,17 Epidermal nerve fiber density measured from skin punch biopsies is rapidly increasing in popularity and availability as a simple and minimally invasive technique. The small skin sample is stained immunohistochemically with antibodies against nerve-specific protein gene product 9.5 (PGP9.5).18-20 Most frequently, there is a reduction in nerve fiber numbers, worse distally, but axonal swellings also correlate with disease21 (Fig. 83–2). Sensitivity ranges from 74% to 87%. Distal autonomic function measures correlate better with epidermal nerve fiber density than cold perception thresholds and are significantly better than sural sensory nerve amplitude in documenting the selective loss of

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A ■

B Figure 83–2. Epidermal nerve fibers of the calf in a normal individual and a patient with small fiber neuropathy. A, Skin biopsy of a healthy person shows two axons that extend perpendicularly to the skin surface toward the layer of keratin. The epidermal nerve fiber density was 10.5 fibers/mm. B, Skin biopsy from a patient with a small fiber neuropathy demonstrating severe loss of epidermal nerve fibers. Some of the few remaining nerve fibers have focal swelling of the axons as exemplified in this image. The epidermal nerve fiber density was 2.0 fibers/mm. Both skin specimens were fixed by periodic acid-lysine-paraformaldehyde and stained by immunoperoxidase method for the panaxonal marker PGP9.5. (Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

T A B L E 83–2. Clinical and Research Tools for Small Fiber Neuropathy Testing Epidermal nerve fiber density (skin punch biopsy) Quantitative sudomotor axon reflex testing Cardiovascular autonomic reflex testing Quantitative sensory testing Laser Doppler reflex testing (limited availability) Sural nerve biopsy electron microscopy small fiber counts (tedious and rarely performed)

small diameter fiber function.17,19 Quantitative sudomotor axon reflex testing, which evaluates postganglionic sympathetic sudomotor function by measuring evoked sweat after acetylcholine iontophoresis, is the best validated technique in this condition, but other methods are also employed; current clinical and common research methods are listed in Table 83–2. Treatment is similar to that of diabetic and other painful forms of neuropathy covered previously.20,22

Uremic Neuropathy Neuropathy is associated with chronic renal failure; some patients also have coincident diabetes. This is a distal symmetrical sensorimotor polyneuropathy possibly caused by uncharacterized uremic toxins. It is present in as many as 60% to 70% of patients with chronic renal failure, but patients are often asymptomatic and the neuropathy is identified only by nerve conduction studies.23 Symptoms are insidious and include painful dysesthesia, stocking-glove loss of sensation, and mild distal muscle weakness. Autonomic dysfunction is generally not as severe as with diabetes. Neuropathy typically occurs when

the glomerular filtration rate falls below 20 mL/min and undialyzable toxins accumulate.24 Sensory and motor conduction velocities are mildly reduced, and evoked motor and sensory nerve response amplitudes are reduced. Pathologically, there is axonal degeneration of the most distal nerve trunks with secondary segmental demyelination. Without dialysis or renal transplantation, prognosis is poor and the neuropathy progresses. With peritoneal or hemodialysis, the neuropathy stabilizes. Improvement after transplantation, sometimes with complete resolution of symptoms in as few as 1 to 3 months, is reported.25,26

Neuropathy Associated With Hepatic Disease Peripheral neuropathy is rarely associated with primary liver diseases. A painful sensory neuropathy is associated with primary biliary cirrhosis and is probably caused by xanthomas forming in and around nerves. Infectious diseases of the liver and hereditary disorders with liver involvement (porphyria) are also associated with peripheral neuropathy but are discussed elsewhere. Immune-mediated diseases, such as polyarteritis nodosa and sarcoidosis, may cause both liver dysfunction and neuropathy, notably mononeuropathy multiplex.

SELECTED CHRONIC IMMUNE-MEDIATED NEUROPATHIES Acquired Chronic Immune-Mediated Neuropathies There is some disagreement on which entities in this category should be grouped under the unifying term chronic

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inflammatory demyelinating neuropathy and which variants should be separated into discrete entities. The definitive diagnosis of the classic form of chronic inflammatory demyelinating neuropathy is also debated and a number of diagnostic criteria have been proposed.27-32 The cardinal features of classic chronic inflammatory demyelinating neuropathy include progressive symptoms for more than 2 months (to differentiate from Guillain-Barré syndrome), predominant motor findings, symmetrical distal and proximal arm and leg involvement, reduced or absent deep tendon reflexes, increased cerebrospinal fluid protein, primary signs of demyelination on electrodiagnostic studies, and segmental demyelination on nerve biopsy. Not all treatment-responsive patients have all clinical or laboratory characteristics. Elevated cerebrospinal fluid protein and nerve biopsy are not required by all classifications. Magnetic resonance imaging may demonstrate gadolinium enhancement or increased T2-signal abnormalities in proximal nerves or nerve roots. The stringent 1991 American Academy of Neurology subcommittee criteria were intended for uniformity in clinical trial enrollment, not for routine clinical application, but were used for lack of widely accepted scales31; more recent criteria deemphasize some features, sacrificing specificity to improve sensitivity.30,32 The cited prevalence is 0.5 of 100,000 children and 1 to 2 of 100,000 adults.29 The course may be relapsing or progressive but relapsing forms are more common in younger patients.33 Secondary axonal loss occurs, likely as a concomitant injury, but is critical for treatment response, long-term disability, and prognosis. Early effective treatment is the best means to limit this process.

Associated Conditions

Pathogenesis

Although motor findings predominate in chronic inflammatory demyelinating neuropathy, sensory abnormalities are also usually present. However, rare patients have pure motor involvement, which must be distinguished from multifocal motor neuropathy, discussed later.

An autoimmune process with activation of autoreactive T and B cells is presumed but specific targets have not been identified. The migration of activated T cells across the blood-nerve barrier is being actively investigated. Autoantibodies are also presumed to exist, and sera from chronic inflammatory demyelinating neuropathy patients do induce conduction block in animals, but specific antibodies have not been identified other than in some well-defined syndromes.

Treatment Randomized controlled trials have demonstrated the effectiveness of corticosteroids, plasmapheresis, and intravenous immunoglobulin and found no significant difference between these treatments, but intravenous immunoglobulin and steroids are recommended as first line treatment.34 Most studies, however, have been short in duration. Interferon β-1a was effective in open label but not in controlled trials of treatment-resistant patients. Adhering to published criteria does not seem to predict treatment responsiveness.35 Use of other medications is supported by open trials or empiric use: these include azathioprine, cyclophosphamide, mycophenolate mofetil, etanercept, and cyclosporin A. To further complicate matters, a rare treatment-responsive chronic inflammatory demyelinating neuropathy-like illness appears to be triggered by the immunomodulatory agents interferon-α or -β, tumor necrosis factor α antagonists, tacrolimus, and cyclosporin A.

A number of conditions are associated with otherwise typical CIDP, including HIV infection, hepatitis virus B and C infection, collagen vascular disease (especially systemic lupus erythematosus and Sjögren syndrome), lymphoma, melanoma, inflammatory bowel disease, and Charçot-Marie-Tooth disease. Increased incidence of demyelinating neuropathy has been noted in patients with diabetes, who appear to respond well to immunomodulatory treatment.36 The appearance of a subacute predominantly motor, symmetrical proximal and distal subacutely worsening neuropathy should raise this concern.

Chronic Inflammatory Demyelinating Neuropathy Variants Sensory Chronic Inflammatory Demyelinating Neuropathy From 10% to 15% of patients have a predominantly sensory syndrome but also slow motor nerve conduction velocity and other demyelinating signs; treatment response is similar to that for chronic inflammatory demyelinating neuropathy. Cerebrospinal fluid protein is elevated and residual pain is more frequent. A search for a monoclonal paraprotein and differentiation from other large fiber sensory neuropathies are necessary.37

Motor Chronic Inflammatory Demyelinating Neuropathy

Central Involvement Some patients have cortical white matter demyelination demonstrable by magnetic resonance imaging; however, most do not meet clinical criteria for multiple sclerosis.

Paraprotein-Associated Demyelinating Neuropathy Demyelinating polyneuropathy is also associated with paraproteins, most commonly IgM and less clearly IgA or IgG. Overall, polyneuropathy occurs in 5% of patients with paraproteins, but most have only mild distal axonal sensorimotor neuropathy; some have associated amyloidosis. One third of patients with isolated monoclonal gammopathy of uncertain significance eventually develop myeloma or other hematological malignancy. Osteosclerotic myeloma is a rare form of myeloma (3%) in which one half of patients develop neuropathy, usually demyelinating and usually discovered prior to the myeloma. This entity overlaps with POEMS syndrome and associated variants that are characterized—in addition to neuropathy—by organomegaly, endocrinopathy, and skin changes, although only about 15% have the complete syndrome. Sensory

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neuropathy is most commonly associated with antibodies to sulfatide, but 30% of patients with antibody titers have demyelinating neuropathy with or without a paraprotein.38 Some patients have symmetrical but predominantly distal rather than proximal involvement, a condition descriptively labeled distal acquired demyelinating symmetrical neuropathy. Older men are most frequently affected and roughly two thirds of them have IgM paraproteins, some of which are directed against myelin-associated glycoprotein. Anti-myelin–associated glycoprotein antibodies bind to distal nerve segments and produce a distinctive electrophysiological picture with demyelinating signs preferentially affecting the most distal nerve segments and resulting in markedly increased distal motor latencies. These patients generally respond poorly to conventional immunosuppressive therapy. Recent treatment attempts with the anti-B cell monoclonal antibody agent rituximab are promising. ■

Multifocal Motor Neuropathy Multifocal motor neuropathy is an acquired immune-mediated neuropathy characterized by slowly progressive asymmetrical arm and leg weakness sparing cranial nerves, and beginning in a single peripheral nerve distribution. Typically, there is painless weakness, focal wasting, and sporadic fasciculations with preserved or absent tendon reflexes, although minor sensory complaints may also be present.39 These features can be confused with lower motor neuron disease in the early stages. However, unlike motor neuropathy, clinical weakness is generally out of proportion to atrophy, manifestations are characteristically asymmetrical and progression is slow. Men are more frequently affected with an average age of onset around 40 years. Electrophysiological evidence of denervation is accompanied by the defining abnormality⎯multifocal motor conduction block, that is, the failure of a nerve impulse to conduct through an intact axon away from typical sites of nerve compression. However, lesser signs of demyelination, such as temporal dispersion, and minor sensory abnormalities are also described.40 Multifocal conduction block is the diagnostic hallmark but treatment-responsive patients with other electrophysiological abnormalities have prompted a search for additional diagnostic techniques. Ultrasonographic nerve enlargement has been noted.41 More sophisticated nerve stimulation techniques, such as magnetic stimulation and multiple stimuli, have documented proximal conduction block undetectable with conventional techniques.42 The underlying pathology is presumed to be immune mediated but predominantly restricted to motor fibers, making biopsy of a sensory nerve uninformative; a few such biopsy samples have shown little or no pathological changes. Motor nerve biopsies have shown variable features, including demyelination, rare focal inflammatory changes, frequent axonal loss, and signs of axonal regeneration.43 Some of these features are illustrated in Figure 83–3. Increased titers of IgM anti-GM1 gangliosides are found in 30% to 50% or even more patients in different series; anti-GD1a antibodies are found less frequently.39,44 The pathogenicity of these antibodies remains uncertain, especially because most patients have no measurable titers. Other proposed mechanisms include antibody-mediated blockade of Na+ and K+

Figure 83–3. Multifocal motor neuropathy, motor nerve to the gracilis muscle. This transverse section of a motor nerve shows a mild loss of myelinated fibers, prominent regenerative clusters of small myelinated fibers (arrowheads) and small onion bulbs (arrows). A second nerve fascicle (not shown) did not exhibit regenerative clusters or onion bulbs (semithin plastic sections, toluidine blue-basic fuchsin). (Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

channels at the nodes of Ranvier. Sophisticated electrophysiological techniques suggest that focal depolarization or hyperpolarization may explain how conduction may be impaired without easily identifiable conduction block and how some patients may respond promptly to treatment.45 Cerebrospinal fluid protein is generally normal. The prime importance of a correct diagnosis is that the weakness of multifocal motor neuropathy is potentially reversible with intravenous immunoglobulin treatment; there is partial to complete improvement of symptoms and decrease of anti-GM1 antibody titers. Improvement begins within 14 days and lasts an average of 2 months, although intravenous immunoglobulin effectiveness may decrease after years of treatment. Conduction block is not a permanent state and eventual axonal loss may ensue, especially if the condition is not treated. Unlike in chronic inflammatory demyelinating neuropathy, steroids are ineffective. Other immunosuppressive agents have been empirically used on the basis of open label trials, but no controlled trials have been conducted for cyclophosphamide, plasmapheresis, mycophenolate mofetil, azathioprine, rituximab, and some other agents.

Multifocal Sensorimotor Demyelinating Neuropathy Multifocal motor neuropathy is distinctively motor but may include minor sensory symptoms and findings. A separate syndrome, described in 1982 by Lewis and Sumner, is characterized by multifocal motor and sensory involvement, unlike either chronic inflammatory demyelinating neuropathy or multifocal motor neuropathy (Lewis-Sumner syndrome).46 Some prefer the cumbersome descriptive term multifocal

chapter 83 metabolic, immune-mediated, and toxic neuropathies axonal acquired demyelinating sensory and motor neuropathy. Also in contrast to multifocal motor neuropathy, male predominance is not seen, steroid-responsiveness is common, GM1 antibodies are absent, and sensory nerves demonstrate segmental demyelination and inflammatory cells. The clinical picture is closer to vasculitic neuropathy, from which it must be differentiated, but some cases are difficult to distinguish from multifocal motor neuropathy or chronic inflammatory demyelinating neuropathy. Many but not all respond to prednisone or intravenous immunoglobulin, but most respond to some form of immunotherapy.47 Vasculitic neuropathy characteristically manifests as mononeuropathy (mononeuritis) multiplex or distal symmetrical polyneuropathy. The disorder is associated with primary vasculitis, connective tissue disorders, and certain infections and malignancies. The process is most commonly systemic but isolated neuropathy can also occur. Onset is usually acute or subacute with painful severe weakness and sensory loss in the distribution of individual peripheral and cranial nerves. Progress is most commonly stepwise, but 25% to 30% of patients have distal and symmetrical neuropathy with steady progressive worsening.48,49 Rarely, patients have a chronic and indolent course.49 The etiology of vasculitic neuropathies is unknown, but the process is presumed to be immune mediated. One half of the cases occur in the setting of collagen vascular disease, and 10% are associated with malignancy, drug ingestion, or infection. Neuropathology reveals necrotizing arteritis with transmural inflammatory infiltration and fibrinoid vessel wall necrosis, lumen reduction, and signs of focal nerve ischemia, mostly in myelinated fibers. The ischemia leads to focal axonal degeneration of individual nerve fascicles.50 The diagnosis is established by the characteristic findings in biopsy samples of nerve, muscle, or both. The biopsy specimen, however, may show only axonal degeneration if the sample is distal to the infarct or if the specimen includes no affected vessels. Multiple levels may need to be sampled to increase the diagnostic yield. Nerve conduction studies may show electrical inexcitability of nerve segments distal to a site of infarct. If some nerve fascicles are selectively spared, conduction velocity is preserved but the evoked amplitude is diminished. Polyarteritis nodosa affects medium-size vessels and is the most common and most important cause of vasculitic neuropathy. Clinical neuropathy occurs in 50% to 75% of polyarteritis nodosa patients. Skin involvement is frequent and diagnostically useful. The clinically similar Churg-Strauss syndrome, associated with asthma and eosinophilia, is probably a polyarteritis nodosa variant. Vasculitis in association with rheumatoid arthritis is also common and often associated with poor outcome. Other important associations include Sjögren syndrome, systemic lupus erythematosus, systemic sclerosis, and Wegener’s granulomatosis. Important conditions associated with vasculitic neuropathy are cryoglobulinemia, viral infections, and malignancy, especially T cell lymphoma. Sarcoidosis also can produce mononeuropathy multiplex. Immunosuppression is the primary treatment. For systemic vasculitis, prednisone (1 to 1.5 mg/kg) and cyclophosphamide (2 mg/kg) are most commonly used. In nonsystemic vasculitic neuropathy, prednisone is usually given alone. Plasmapheresis is used for cryoglobulinemia; empirical open-label benefit of intravenous immunoglobulin in treatment-resistant patients is reported.51

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Prognosis has been described only in anecdotal studies. Eighty percent of nonsystemic vasculitis patients improve, but the 5-year survival rate is 37% to 48% for treated systemic vasculitis patients and only 15% for untreated patients.48,50

IATROGENIC AND TOXIC NEUROPATHY Iatrogenic and Toxic Neuropathies Although patients frequently suspect medications or toxins to cause otherwise unexplained peripheral neuropathies, drugs and toxins are, in fact, the cause of an estimated 2% to 4% of peripheral neuropathies.52,53 Toxic neuropathies, including medication-induced forms, generally induce axonal degeneration in a “dying back” axonal pattern. Any disturbance of axonoplasmic flow disproportionately affects the distal segments of the most vulnerable nerves, producing a uniform distal stocking-glove pattern of involvement. However, some agents cause segmental demyelination; injure Schwann cells, dorsal root, or autonomic neurons; or damage peripheral myelin. Onset is generally over weeks to months, and causation is best established by a strong dose-response relationship, consistent manifestations, close proximity of symptoms to exposure, stabilization or improvement after drug cessation, reproduction in animal models, and exclusion of other causes.54 However, some agents have idiosyncratic, delayed, or cumulative effects, their mechanisms of clearance are different in animals, and recovery is poor or delayed recovery because of axonal degeneration or neuron loss, making a definitive association problematic. In addition, some patients continue to worsen even after agent cessation, usually for several weeks, a phenomenon termed “coasting,” which clouds definitive diagnosis. A variety of neurotoxic mechanisms are known, including direct toxicity or toxicity mediated by metabolites, secondary vitamin deficiency, interference with DNA or metabolic function, mitochondrial injury, apoptosis, and immune triggers. Other factors, such as preexisting neuropathy, decreased toxin metabolism or clearance, or genetic profile may predispose to neurotoxicity. Despite these limitations, it is critical to look for the associations described above, so that an offending agent can be promptly stopped, which sometimes leads to improvement. Some agents have only a weak temporal association with neuropathy in rare patients, whereas others are clearly linked to neuropathy, which limits their use. Medications continually increase in number, and uncommon side effects may not become apparent until their use is widespread. A number of agents produce tolerable neuropathies given the severity of the underlying disease, notably malignancies and HIV infection. In these cases, evolving research has been directed toward identifying secondary agents or delivery methods that would blunt or prevent toxicity. Identification of a toxic effect is easy when symptoms develop acutely or subacutely soon after initial drug exposure or after a change in medication dosage. Most cases fall into this category. More problematic is diagnosing a slowly progressive neuropathy starting months or years after initiation of therapy. Statins provide a case in point and are discussed below. The blood-nerve barrier is partially protective but is less efficient than its blood-brain barrier counterpart. This and other factors make peripheral nerves more susceptible than central

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T A B L E 83–3. Medications With Probable to WellEstablished Toxic Neuropathy Association Antibiotics and Antivirals Dapsone Ethambutol (optic) Linezolid (Zyvox) Metronidazole (Flagyl) Nitrofurantoin Nucleoside reverse transcriptase inhibitors (some agents) Podophyllin resin Chemotherapeutic Agents Bortezomib (Velcade) Carboplatin Cisplatin Oxaliplatin Suramin Taxoids (Paclitaxel, Docetaxel) Vincristine Thalidomide Cardiovascular Agents Amiodarone Statins Other Agents Colchicine Disulfiram Gold Hydralazine Isoniazide Leflunomide (Arava) Nitrous oxide Phenytoin Penicillamine Proton pump inhibitors (lansoprazole, omeprazole) Pyridoxine Tacrolimus (FK-506, Prograf)

nerves to certain toxins. Decreased drug metabolism or clearance due to impaired hepatic or renal function can lead to the buildup of toxic agent levels, notably in the elderly. The presence of a pre-existing neuropathy, whether hereditary or acquired, can predispose to neurotoxicity. Some common and more clinically relevant associations are briefly discussed; others are listed in Table 83–3.

Antibiotics Nucleoside analogs⎯some, but not all, nucleoside reverse transcriptase inhibitors are associated with a dose-dependent peripheral neuropathy. Examples include zalcitabine (ddC), didanosine (ddI), stavudine (ddT), and lamivudine (3TC). This distal painful sensory axonal neuropathy usually begins 6 to 8 weeks after initiating treatment. Signs and symptoms include burning dysesthesia in the legs, impaired sensation, minimal weakness, and absent ankle jerks. The process may be indistinguishable from AIDS-related neuropathy, including electrophysiological testing. The neuropathy improves after drug discontinuation, often within a month. The mechanism of neuropathy may be related to the inhibition of DNA polymerase gamma and mitochondrial DNA replication. Risk factors for nucleoside reverse transcriptase inhibitor neuropathy include a CD4 count of less than 100 cells/mm3, combination drug therapy, and underlying neuropathy.52

Isoniazid can occasionally cause a dose-related sensory axonal polyneuropathy, typically after 4 to 6 months of use. Toxicity usually occurs at doses over 300 mg/day and can be prevented with pyridoxine supplementation. Isoniazid toxicity is mediated by inhibition of pyridoxine-dependent enzymes and occurs in vulnerable populations, such as alcoholics and malnourished patients. Dapsone can cause a motor-predominant neuropathy, an unusual toxic effect, but one that helps distinguish drug toxicity from lepromatous neuropathy in patients undergoing Dapsone treatment. The distribution is atypical, affecting the arms more than the legs. The neuropathy is dose related and occurs after prolonged exposure. Linezolid, approved in 2000, is an oxazolidinone, the first new class of antibiotics approved in 40 years. It has activity against drug-resistant enterococci, Staphylococcus aureus, and Bacillus tuberculosis, making prolonged use desirable. Optic and sensory neuropathies are both well documented and growing concerns with extended use.55,56 Metronidazole is used to treat both protozoan and anaerobic bacterial infections. A predominantly sensory axonal neuropathy is a potential and underappreciated neurotoxic effect.57 Chronic treatment and high doses are risk factors, although symptomatic polyneuropathy was reported after a total of 1200 mg/day for only 9 days.58 Sural nerve biopsies show degeneration of both myelinated and unmyelinated sensory fibers. The radiosensitizing agent misonidazole is chemically related and also associated with neuropathy. Nitrofurantoin is still used to treat urinary tract infections. Exposure can cause sensorimotor axonal neuropathy. Patients with impaired renal function are at greater risk.

Cardiovascular Agents Statins are notoriously associated with myopathy, but the evidence for toxic polyneuropathy was based on a series of case reports until a well-publicized large case-control series from Denmark suggested a 4- to 14-fold increased risk of developing “idiopathic” neuropathy in patients on statins.59 However, the methodology used in this study has generated some criticism.60 Identifiable causes of neuropathy were carefully excluded but the study was unable to control for undiagnosed or latent diabetes; also, recent evidence suggests that hyperlipidemia may be an independent neuropathy risk factor.6 The ascribed neuropathy is a nonspecific axonal sensorimotor neuropathy. Because these agents are so widely used, concern for causation is frequent in patients with new-onset neuropathy; a period off medication is probably the best current method to test the association in a patient. However, this entity is probably very rare. In amiodarone users, polyneuropathy is the second most common neurological side effect, after tremor, occurring in 6% of those taking it for several months,61,62 usually in dosages greater than 400 mg/day. Sensorimotor neuropathy is most common and can be severe; motor and autonomic involvement is also seen and can also be severe. Nerve conduction studies and neuropathology show evidence of axonal loss, demyelinating features, or a combination of the two. Symptoms usually improve after drug cessation or lowering the dosage. The mechanism of toxicity is unknown but amiodarone enters lysosomes and irreversibly binds polar lipids; characteristic intralysosomal inclusions are seen in many tissues, including Schwann cells and peripheral neurons.63 Drug metabolite levels are 80-fold

chapter 83 metabolic, immune-mediated, and toxic neuropathies higher in nerve than in serum.61 Demyelinating neuropathy and lipid inclusions are also found in patients treated with another lipophilic cardiac drug, perhexiline, which has never been approved in the United States but is still used in Europe.

Chemotherapeutic Agents Some degree of neuropathy is to be expected with certain agents, but the effects of neuropathic symptoms on the quality of life should be considered. Most agents are neurotoxic in a dose-dependent manner, either with a single high dose or with cumulative lower doses64; a lower dose may produce less toxicity but may reduce efficacy. Pretreatment with neuroprotective agents is of prime interest but not adequately investigated. Many agents have shown promise in animal models but few have performed as impressively in clinical trials. To date, amifostine is the only approved medication to blunt chemotherapeutic toxicity, primarily by reducing cisplatin toxicity on the kidney but not on peripheral nerves. Other agents have shown partial benefit in human trials, but the only drugs that appear to markedly blunt or prevent neuropathy in experimental models are neurotrophins; however, none is currently undergoing study. Vincristine, a vinca alkaloid, causes axonal neuropathy in virtually all users, depending on dose, and neuropathy is often a dose-limiting effect. The neuropathy begins with distal pain, paresthesia, and absent ankle jerks, followed by weakness, which can be severe, and generalized areflexia; autonomic and cranial neuropathies are also seen. Electrophysiological studies show reduced sensory and motor responses. Because of the axonal loss, improvement may be delayed or incomplete in severe cases. Vincristine binds to tubulin and disrupts axonal transport. In asymptomatic patients with defects in the peripheral myelin protein-22 gene, vincristine can unmask symptoms of Charçot-Marie-Tooth disease. It can also worsen mild cases of Charçot-Marie-Tooth disease and is contraindicated in these patients and in patients at risk for or showing clinical signs of undiagnosed hereditary neuropathy. Cisplatin dose-limiting neurotoxicity generally occurs at cumulative doses of 250 to 500 mg/m2, based on patient susceptibility. Patients typically have minor tingling in the distal limbs at the start of each cycle, which later resolves. Subacute numbness, paresthesia, and pain spread proximally as the cumulative dose increases; symptoms can become irreversible. Deep tendon reflexes are lost, and proprioception is disproportionately affected. Motor function is generally unaffected. Nerve conduction studies corroborate reduced sensory and normal motor responses. The drug binds to DNA in both prompts DNA repair and cell cycle entry in both dorsal root ganglia neurons and tumor cells. If the repair is unsuccessful, apoptosis may be triggered. The mechanism of toxicity is similar for carboplatin and oxaliplatin, but oxaliplatin can also cause an acute 1- to 2day syndrome of cold-induced paresthesia, jaw and throat tightness, and cramps. Electrophysiological hallmarks of peripheral nerve hyperexcitability are seen and are thought to be caused by sodium channel dysfunction.65 Paclitaxel, docetaxel, and newer emerging toxoids, used in breast, ovarian, and other cancers, cause dose-dependent sensory neuropathy. Toxicity is milder for the more potent docetaxel. In contrast to agents that disassemble microtubules (colchicine, vincristine, podophyllin), taxoids promote the

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assembly of large arrays of disordered microtubules. Interference with axonal transport is postulated. Bortezomib (Velcade) is a member of a new class of anticancer drugs, proteasome inhibitors. This agent is primarily used to treat refractory myeloma. Peripheral neuropathy is a common and often treatment-limiting effect. Monitoring for neuropathy is necessary when using this agent. Thalidomide is currently used in several neoplastic and rheumatological conditions and has antiangiogenic and antiinflammatory properties. It causes a length-dependent sensory neuropathy, affecting both small- and large-diameter fibers. Many cases of sensory neuropathy were produced in the early 1960s but were overshadowed by the more infamous teratogenic effects. Neuropathy incidence ranges from 25% to 70%,66 and recovery is often incomplete. The mechanism is unknown but the drug inhibits the activation of necrosis factor-κB, an important factor in sensory neuron survival. Onset appears to be related to cumulative dose.

Immunosuppressants Tacrolimus (FK-506) is a calcineurin inhibitor and macrolide antibiotic extensively used in transplant medicine. It suppresses both humoral and cellular mediated immune responses. Although central toxicity is more common, numerous cases of peripheral neuropathy are reported: this manifests as a severe multifocal demyelinating neuropathy resembling chronic inflammatory demyelinating neuropathy; patients have been treated successfully with intravenous immunoglobulin or plasmapharesis.67 Interestingly, this agent also has neuroregenerative activity, which differs from the calcineurin effects and is under investigation. Cyclosporin is rarely associated with neuropathy and sirolimus neuropathy has not been described. Leflunomide, a novel disease-modifying rheumatoid arthritis treatment, has been associated with sometimes painful axonal sensorimotor polyneuropathy that had not been predicted in prerelease trials.68 Onset is usually after 3 to 6 months of exposure and recovery is slow but less so if therapy is stopped within 30 days of initiation. The mechanism of neurotoxicity is unknown, although medication-induced vasculitis independent from rheumatoid arthritis vasculitis is suggested in some cases.68,69

Other Agents With chronic high dosages (serum levels greater than 20 μg/mL) of phenytoin, peripheral neuropathy is known to occur, based mostly on case series. Risk factors include prolonged use (longer than 10 years), supratherapeutic levels (greater than 20 μg/mL), and low folate levels.70 Neuropathy is rare at current dosages and usually produces only minimal symptoms. Colchicine can produce a “neuromyopathy” with subacute vacuolar myopathy accompanied by mild distal pansensory axonal neuropathy. Chronic regular use and high serum levels are risk factors, which are presumed to alter axonal transport through microtubule disruption.71 Marked clinical improvement is expected after cessation.

Selected Toxins Toxicity from heavy metals is a common patient concern but a rare cause of neuropathy.

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Arsenic is the most common heavy metal to cause neuropathy: the course is slow in chronic exposure and more acute in cases of intentional poisoning. Arsenic trioxide is used to treat acute promyelocytic leukemia and can cause toxic neuropathy in a minority of treated patients. Sensory symptoms predominate initially, and pain and paresthesia precede leg weakness by days to weeks. Weakness can be severe. Stocking-glove sensory loss, especially of vibration and position sense, and distal loss of deep tendon reflexes are typical. Electrodiagnostic studies and neuropathology demonstrate signs of sensorimotor axonal loss. Chelation therapy is standard treatment. Lead poisoning in adults may cause asymmetrical neuropathy, often more severe in the arms. Toxicity is usually accompanied by other poisoning symptoms, such as abdominal pain, but not by the encephalopathy typically seen in children. Blood levels over 30 μg/dL are considered significant in adults. Motor symptoms predominate and can be multifocal, including the classic presentation of wrist and finger drop or foot drop. Chronic low-level exposure manifests as a distal, symmetrical sensory loss, mainly in the legs. Occupational lead poisoning was common in earlier eras, notably in silver miners, but is still occasionally encountered in battery workers, painters, pottery glazers, and other occupations; other exposure sources are known as well. Lead neuropathy is treated by exposure removal and chelation therapy. Thallium exposure usually occurs through acute intentional poisoning and produces alopecia, gastrointestinal symptoms, and sensory neuropathy. Mercury toxicity depends on the form of mercury⎯ elemental or organic. The organic form (methyl and ethylmercury) is most toxic to the central nervous system, although distal paresthesia and sensory ataxia are prominent (presumably from dorsal root ganglion degeneration). Ventral roots and motor function are spared. Inorganic mercury salts were used in felt hat production, and toxicity produced memory loss and tremor (hence “mad as a hatter”). Inorganic mercury may be absorbed through the gastrointestinal tract, and volatile elemental mercury may be absorbed directly through the skin or lungs. Elemental mercury exposure is a rare cause of weakness and axonal motor and sensory fiber loss. Quicksilver is used in some ethnoreligious practices. Low-level exposure is a popular concern, but no evidence supports significant toxicity from dental amalgams; exposure from dietary fish consumption and thimeresol-containing vaccines is a more controversial issue.72

Drugs of Abuse Alcohol neuropathy is most commonly a slowly progressive predominantly sensory and sometimes painful neuropathy seen in chronic alcoholics. Symptoms and findings vary widely and are often overlooked by both patient and physician. Distal pain and dysesthesia, especially at night, are prominent; distal weakness and autonomic disturbances, although less common, are also seen. Examination reveals distal sensory loss and decreased deep tendon reflexes. Electrodiagnostic studies and nerve and muscle pathology show nonspecific, symmetrical sensory greater than motor axonal loss. Findings are common even in asymptomatic chronic alcoholics.73 Whether the cause is a nutritional deficiency or a direct toxic alcohol effect remains

controversial. Although vitamin levels are often reduced in alcoholics, measures correlate poorly with incidence of neuropathy. One recent study compared alcoholic patients with normal thiamin levels to alcoholic and nonalcoholic patients with thiamin deficiencies. Patients with normal thiamin levels had typical distal sensory neuropathy and nonalcoholic thiamin-deficient patients had subacute motor-predominant neuropathy. Alcoholic thiamin-deficient patients had a mixture of findings.74 This study provided the best evidence to date of a direct toxic effect of ethanol on human peripheral nerve. Improvement after drinking cessation can occur, especially in mildly to moderately severe cases. Alcoholics are also more susceptible to nerve compression and entrapment, not limited to the classic “Saturday night palsy” affecting the radial nerve. The alcohol deterrent Dapsone can itself cause toxic neuropathy, especially at high doses, but this drug affects large-diameter sensory and motor fibers whereas alcohol disproportionately affects small fibers; however, confusion with alcoholic neuropathy sometimes occurs.75 The toxin carbon disulfide (CS2), a Dapsone metabolite, is another cause of toxic neuropathy and one possible mechanism of Dapsone toxicity. Other drugs of abuse may lead to neuropathy, notably nhexane and methyl-N-butyl ketone, found in widely available household solvents, fuels, and cleaning agents. Inhalation through the nose or mouth (huffing) of these materials is not rare in teens and young adults, especially if access to alcohol and hard drugs is limited. Axonal degeneration with sensory and motor impairment is seen, but focal conduction block associated with giant axonal swellings is also characteristic.76,77 Chronic industrial exposures generally lead to symmetrical axonal neuropathy. Selected other toxins are listed in Table 83–4.

T A B L E 83–4. Selected Toxins Associated With Neuropathy Heavy Metals Arsenic Cadmium Gold Lead Mercury Platinum Thallium Miscellaneous Acrylamide Allyl chloride Carbon disulfide Diethylene glycol Diptheria toxin Ethanol Ethylene glycol Hexacarbons (n-hexane) Methyl n-butyl ketone Methyl bromide Organophosphates Vacor Seafood, Insect, and Animal-Borne Neurotoxins Ciguatera Paralytic shellfish poisoning Puffer fish (fugu) Tick paralysis Tropical frog skin toxins

chapter 83 metabolic, immune-mediated, and toxic neuropathies Polyneuropathy Associated With Dietary States Thiamin deficiency may cause two different clinical syndromes: wet beriberi, in which congestive heart failure is the predominant sign, and dry beriberi, in which peripheral neuropathy predominates. Patients with thiamin deficiency have severe burning dysesthesia in the feet more than the hands, weakness and wasting of distal more than proximal muscles, trophic changes (shiny skin, hair loss), and distal sensory loss. Axonal neuropathy is the principal finding on nerve biopsy and electrodiagnostic studies. Treatment of beriberi should initially include parenteral B-complex vitamins followed by oral thiamin. Recovery is slow and may be incomplete. The distinctive features of alcoholic neuropathy were discussed earlier. Niacin (nicotinic acid) deficiency causes pellagra, characterized by hyperkeratotic skin lesions. Peripheral neuropathy is frequent; symptoms usually improve with B-complex vitamins, which is preferable to simple niacin supplements. Vitamin B12 deficiency causes the classic clinical syndrome of subacute combined degeneration. Peripheral neuropathy is a component but the myelopathy is generally predominant. Painful paresthesia is present but sensory ataxia with loss of vibration and joint position sense predominates. Tendon reflexes are often diminished or absent. Malabsorption from a lack of intrinsic factor is the most common cause. Vitamin B12 levels may be normal and the diagnosis can be established by elevated metabolites methylmalonic acid and homocysteine. Nitrous oxide also irreversibly inactivates cobalamin, producing the same syndrome. A single anesthetic dose in a patient with low or borderline vitamin B12 levels or chronic exposure in individuals who abuse nitrous oxide, usually dental supplies or commercial whipped cream propellants, may result in secondary vitamin B12 deficiency. Hematological abnormalities are usually absent in abuse cases. Pyridoxine (B6) deficiency produces a primarily sensory peripheral neuropathy, notably from the antituberculous drug, isoniazid, which increases pyridoxine excretion; hydralazine, phenelzine, and phenytoin also affect pyridoxine function. The neuropathy can be prevented by prophylactic pyridoxine administration. However, pyridoxine excess can itself lead to severe sensory neuropathy. Vitamin E deficiency contributes to neuropathy in fat malabsorption syndromes including abetalipoproteinemia, congenital biliary atresia, pancreatic dysfunction, and surgical removal of large portions of the small intestine. The clinical syndrome resembles spinocerebellar degeneration, ataxia with severe proprioception and vibration loss, and hyporeflexia. Electrodiagnostic studies show sensory but not motor changes. There is limited but preliminary evidence that vitamin E can be neuroprotective in cisplatin ototoxicity and neuropathy.78,79 Strachan syndrome includes visual loss, oral ulcers, skin changes, and painful neuropathy. The syndrome was originally described in Jamaican sugar workers and a similar Cuban epidemic occurred in 1991; a syndrome with additional ataxia is seen in Nigeria. A nutrient-poor diet, especially one deficient in B vitamins, has been implicated.

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neuropathy, develops following surgery in a reported 5% to 16% of patients.80,81 Neuropathy risk factors include rapid and marked weight loss, poor nutritional follow-up, surgical complications, and markers of poor nutrition, such as low serum albumin. Mononeuropathies and radiculoplexus neuropathy are less common. Nerve biopsy has shown axonal degeneration and perivascular inflammation. Malnutrition, especially cobalamin, folate, thiamin, and other vitamin deficiencies, is suspected, and aggressive supplementation and nutritional counseling are recommended. Immune and inflammatory factors are also proposed but not well established.

Celiac Neuropathy Celiac disease is a chronic inflammatory enteropathy and is increasingly recognized, with an estimated prevalence of 0.3% to 1% in Western countries. Patients with HLA-DQ2 and HLADQ8 alleles may show sensitivity to wheat gluten, manifested by the presence of gliadin and transglutaminase autoantibodies. In addition to ataxia, peripheral neuropathy is a common neurological association and is not attributed to nutritional deficiencies.82 Some, however, are skeptical about this association.83 The neuropathy is usually predominantly sensory and may be multifocal. Diagnosis is suspected with elevated antibody titers and confirmed by a duodenal biopsy demonstrating inflammation, crypt hyperplasia, and villous atrophy in small intestinal mucosa. Gastrointestinal—but generally not neurological—symptoms improve with a gluten-free diet. Nerve conduction studies are often normal but skin biopsy studies showed abnormalities in most patients in one small series.84 Some, but not all, recommend testing for celiac disease in idiopathic neuropathy cases, especially if irritable bowel syndrome or other gastrointestinal symptoms are present.

K E Y

P O I N T S

Diabetes Mellitus ●

Distal symmetrical predominantly sensory polyneuropathy is the most common presentation.

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Several other clinical subtypes are recognized.

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Tight glycemic control can slow neuropathy progression.

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Superimposed focal mononeuropathy is common, especially carpal tunnel syndrome.

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Diabetic autonomic neuropathy is common and frequently symptomatic.

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Prediabetes or glucose intolerance is associated with symptomatic polyneuropathy.

Small-Fiber Neuropathy ●

Diabetes and glucose intolerance are the most common identifiable causes.

Postgastrectomy Neuropathy

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A considerable percentage has no identifiable cause.

Bariatric surgery is rapidly increasing in popularity. Complications associated with the procedure are also increasingly noted. Peripheral neuropathy, most commonly sensorimotor axonal

●

Conventional nerve conduction studies are normal or minimally affected.

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Skin biopsy and quantitative sudomotor axon reflex testing are the most sensitive objective tests.

Selected Chronic Immune-Mediated Neuropathies ●

Classic chronic inflammatory demyelinating neuropathy is characterized by symmetrical proximal and distal sensorimotor neuropathy.

●

Several variants are recognized.

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Treatment-responsive patients do not always meet strict diagnostic criteria.

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Corticosteroids and intravenous immunoglobulin are firstline therapies.

Multifocal Motor Neuropathy ●

Painless weakness is slowly progressive but asymmetrical.

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Although multifocal motor conduction block is a hallmark, it is not universally found.

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Many patients have antibodies to GM1 gangliosides.

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Weakness is responsive to intravenous immunoglobulin treatment.

Iatrogenic and Toxic Neuropathies ●

Many agents are suspected buy few are documented to cause toxic neuropathy.

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New medications are found to cause neuropathy only after wide distribution because neuropathy was not suspected in prerelease trials.

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Identification of the offending agent can lead to improvement if exposure is stopped prior to significant axonal injury.

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Coasting (i.e., worsening after drug cessation) is seen with some agents.

Alcohol Neuropathy ●

Ethanol neuropathy can improve with abstinence.

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Symmetrical distal predominantly sensory polyneuropathy is most common.

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Superimposed thiamin deficiency can produce a more acute, motor-predominant syndrome.

●

Disulfiram treatment may produce toxic neuropathy.

ACKNOWLEDGMENTS The authors thank Arthur P. Hays, MD, for kindly supplying the illustrative micrographs for this chapter.

Suggested Reading Lewis RA: Chronic inflammatory demyelinating polyneuropathy and other immune-mediated demyelinating neuropathies. Semin Neurol 2005; 25:217-228.

Pratt RW, Weimer LH: Medication and toxin-induced peripheral neuropathy. Semin Neurol 2005; 25:204-216. Said G, Lacroix C: Primary and secondary vasculitic neuropathy. J Neurol 2005; 252:633-641. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 2005; 11:63-79. Van Asseldonk JT, Franssen H, Van den Berg-Vos RM, et al: Multifocal motor neuropathy. Lancet Neurol 2005; 4:309-319.

References 1. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 2005; 11:63-79. 2. Boulton AJ, Vinik AI, Arezzo JC, et al: Diabetic neuropathy. A statement by the American Diabetic Association. Diabetes Care 2005; 28:956-962. 3. Dyck PJ, Kratz KM, Karnes IL, et al: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort. Neurology 1993; 43:817-824. 4. Dyck PJ, Windebank AJ: Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 2002; 25:477-491. 5. Feldman EL: Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 2003; 111:431433. 6. Tesfaye S, Chaturvedi N, Simon EM, et al: Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:341350. 7. The Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995; 122:561568. 8. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Eng J Med 1993; 329:977986. 9. Mendell JR, Sahenk Z: Painful sensory neuropathy. N Engl J Med 2003; 348:1243-1255. 10. Harati Y, Gooch CL, Swenson M, et al: A double-blind, randomized trial of tramadol for treatment of the pain of diabetic neuropathy. Neurology 1998; 50:1842-1846. 11. Goldstein DJ, Lu Y, Detke MJ, et al: Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005; 116:109118. 12. Singleton JR, Smith AG, Bromberg MB: Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001; 24:1448-1453. 13. Sumner CJ, Sheth S, Griffin JW, et al: The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003; 60:108-111. 14. Singleton JR, Smith AG, Russell J, et al: Polyneuropathy with impaired glucose tolerance: implications for diagnosis and therapy. Curr Treat Options Neurol 2005; 7:33-42. 15. Rezende KF, Melo A, Pousada J, et al: Autonomic neuropathy in patients with impaired glucose intolerance. Arq Neuropsiquiatr 1997:55:703-711. 16. Shy ME, Frohman EM, So YT, et al: Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003; 60:898-904. 17. Tobin K, Giuliani MJ, Lacomis D: Comparison of different modalities for detection of small-fiber neuropathy. Clin Neurophysiol 1999; 110:1909-1912.

chapter 83 metabolic, immune-mediated, and toxic neuropathies 18. Kennedy WR, Wendelschafer-Crabb G, Johnson TL, Tamura E: Use of skin biopsy and skin blister in neurologic practice. J Clin Neuromusc Dis 2000; 1:196-204. 19. Periquet MI, Novak V, Collins MP, et al: Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53:1641-1647. 20. Lacomis D: Small-fiber neuropathy. Muscle Nerve 2002; 26:173-188. 21. Lauria G, Morbin M, Lombardi R, et al: Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology 2003; 61:631-636. 22. Singleton JR: Evaluation and treatment of painful peripheral polyneuropathy. Semin Neurol 2005; 25:185-195. 23. Bolton CF: Peripheral neuropathies associated with chronic renal failure. Can J Neurol Sci 1980:7:89-96. 24. Layzer RB: Neuromuscular Manifestations of Systemic Disease. Philadelphia: FA Davis, 1985, pp 283-296. 25. Bolton CF, McKeown MJ, Chen R, et al: Subacute uremic and diabetic polyneuropathy. Muscle Nerve 1997; 20:59-64. 26. Nielsen VK: The peripheral nerve function in chronic renal failure. Recovery after renal transplantation. Clinical aspects. Acta Med Scand 1974; 195:163-170. 27. Lewis RA: Chronic inflammatory demyelinating polyneuropathy and other immune-mediated demyelinating neuropathies. Semin Neurol 2005; 25:217-228. 28. Berger AR, Bradley WG, Brannagan TH, et al: Guidelines for the diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy. J Periph Nerv Sys 2003; 8:282-284. 29. Köller H, Kieseier BC, Jander S, et al: Chronic inflammatory demyelinating polyneuropathy. N Engl J Med 2005; 352:13431356. 30. Hughes R, Bensa S, Willison H, et al: Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001; 50:195-201. 31. Anonymous: Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology 1991; 41:617-618. 32. Saperstein DS, Katz JS, Amato AA, et al: Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve 2001; 24:311-324. 33. Hattori N, Misu K, Koike H, et al: Age of onset influences clinical features of chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 2001; 184:57-63. 34. Joint Task Force of the EFNS and the PNS: European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2005; 10:220-228. 35. Chan YC, Allen DC, Fialho D, et al: Predicting response to treatment in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg Psychiatry 2006; 77:114116. 36. Haq RU, Pendlebury WW, Fries TJ, et al: Chronic inflammatory demyelinating polyradiculoneuropathy in diabetic patients. Muscle Nerve 2003; 27:465-470. 37. Gorson KC, Allam G, Ropper AH: Chronic inflammatory demyelinating polyneuropathy: clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology 1997; 48:321-328. 38. Dabby R, Weimer LH, Hays AP, et al: Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates. Neurology 2000; 54:1448-1452. 39. Van Asseldonk JT, Franssen H, Van den Berg-Vos RM, et al: Multifocal motor neuropathy. Lancet Neurol 2005; 4:309319.

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40. Chaudhry V, Corse AM, Cornblath DR, et al: Multifocal motor neuropathy: electrodiagnostic features. Muscle Nerve 1994; 17:198-205. 41. Beekman R, van den Berg LH, Franssen H, et al: Ultrasonography shows extensive nerve enlargements in multifocal motor neuropathy. Neurology 2005; 65:305-307. 42. Attarian S, Azulay JP, Verschueren A, et al: Magnetic stimulation using a triple-stimulation technique in patients with multifocal neuropathy without conduction block. Muscle Nerve 2005; 32:710-714. 43. Taylor BV, Dyck PJ, Engelstad J, et al: Multifocal motor neuropathy: pathologic alterations at the site of conduction block. J Neuropathol Exp Neurol 2004; 63:129-137. 44. Kinsella LJ, Lange DJ, Trojaborg W, et al: Clinical and electrophysiologic correlates of elevated anti-GM1 antibody titers. Neurology 1994; 44:1278-1282. 45. Priori A, Bossi B, Ardolino G, et al: Pathophysiological heterogeneity of conduction blocks in multifocal motor neuropathy. Brain 2005; 128:1642-1648. 46. Lewis RA, Sumner AJ, Brown MJ, et al: Multifocal demyelinating neuropathy with persistent conduction block. Neurology 1982; 32:958-962. 47. Viala K, Renié L, Maisonobe T, et al: Follow-up study and response to treatment in 23 patients with Lewis-Sumner syndrome. Brain 2004; 127:2010-2017. 48. Hawke SH, Davies L, Pamphlett R, et al: Vasculitic neuropathy. A clinical and pathological study. Brain 1991; 114:21752190. 49. Kissel JT, Slivka AP, Warmolts JR, et al: The clinical spectrum of necrotizing angiopathy of the peripheral nervous system. Ann Neurol 1985; 18:251-257. 50. Said G, Lacroix C: Primary and secondary vasculitic neuropathy. J Neurol 2005; 252:633-641. 51. Levy Y, Uziel Y, Zandman G, et al: Response of vasculitic peripheral neuropathy to intravenous immunoglobulin. Ann NY Acad Sci 2005; 1051:779-786. 52. Pratt RW, Weimer LH: Medication and toxin-induced peripheral neuropathy. Semin Neurol 2005; 25:204-216. 53. Jain KK: Drug-induced peripheral neuropathies. In: Jain KK, ed. Drug-Induced Neurological Disorders, 2nd ed. Seattle: Hogrefe & Huber, 2001, pp 263-294. 54. Hill AB: The environment and disease: association or causation? Proc R Soc Med 1965; 58:295-300. 55. Zivkovic SA, Lacomis D: Severe sensory neuropathy associated with long-term linezolid use. Neurology 2005; 4:926-927. 56. Frippiat F, Derue G: Causal relationship between neuropathy and prolonged linezolid use. Clin Infect Dis 2004; 39:439. 57. Kapoor K, Chandra M, Nag D, et al: Evaluation of metronidazole toxicity: a prospective study. Int J Clin Pharmacol Res 1999; 19:83-88. 58. Rustscheff S, Hulten S: An unexpected and severe neurological disorder with permanent disability acquired during shortcourse treatment with metronidazole. Scand J Infect Dis 2003; 35:279-280. 59. Gaist D, Jeppesen U, Andersen M, et al: Statins and risk of polyneuropathy: a case control study. Neurology 2002; 58:1333-1337. 60. Leis AA, Stokic D, Olivier J: Statins and polyneuropathy: setting the record straight. Muscle Nerve 2005; 32:428-430. 61. Fraser AG, McQueen IN, Watt AH, et al: Peripheral neuropathy during long-term high-dose amiodarone therapy. J Neurol Neurosurg Psychiatry 1985; 48:576-578. 62. Charness ME, Morady F, Scheinman MM: Frequent neurologic toxicity associated with amiodarone therapy. Neurology 1984; 34:669-671. 63. Santoro L, Barbieri F, Nucciotti R, et al: Amiodarone induced experimental acute neuropathy in rats. Muscle Nerve 1992; 15:788-795.

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64. Quasthoff S, Hartung HP: Chemotherapy-induced peripheral neuropathy. J Neurol 2002; 249:9-17. 65. Lehky TJ, Leonard GD, Wilson RH, et al: Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 2004; 29:387-392. 66. Cavaletti G, Beronio A, Reni L, et al: Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study. Neurology 2004; 62:2291-2293. 67. Wilson JR, Conwit RA, Eidelman BH, et al: Sensorimotor neuropathy resembling CIDP in patients receiving FK-506. Muscle Nerve 1994; 17:528-532. 68. Bonnel RA, Grahm DJ: Peripheral neuropathy in patients treated with leflunomide. Clin Pharm Ther 2004; 75:580-585. 69. Martin K, Bentaberry F, Dumoulin C, et al: Neuropathy associated with leflunomide: a case series. Ann Rheum Dis 2005; 64:649-650. 70. Shovron SD, Reynolds EH: Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. J Neurol Neurosurg Psychiatry 1982; 45:620-626. 71. Kuncl RW, Duncan G, Watson D, et al: Colchicine myopathy and neuropathy. N Eng J Med 1987; 316:1562-1568. 72. Clarkson TW, Magos L, Myers GJ: The toxicology of mercury: current exposures and clinical manifestations. N Engl J Med 2003; 349:1731-1737. 73. Vittadini G, Buonocore M, Colli G, et al: Alcoholic polyneuropathy: a clinical and epidemiological study. Alcohol Alcohol 2001; 36:393-400. 74. Koike H, Iijima M, Sugiura M, et al: Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann Neurol 2003; 54:19-29.

75. Palliyath SK, Schwartz BD, Gant L: Peripheral nerve functions in chronic alcoholic patients on disulfiram: a six month follow up. J Neurol Neurosurg Psychiatry 1990; 53:227230. 76. Chang AP, England JD, Garcia CA, et al: Focal conduction block in n-hexane polyneuropathy. Muscle Nerve 1998; 21:964969. 77. Pastore C, Izura V, Marhuenda D, et al: Partial conduction blocks in n-hexane neuropathy. Muscle Nerve 2002; 26:132135. 78. Argyriou AA, Chroni E, Koutras A, et al: Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 2005; 64:26-31. 79. Leonetti C, Biroccio A, Gabellini C, et al: Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer 2003; 104:243-250. 80. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, et al: A controlled study of peripheral neuropathy after bariatric surgery. Neurology 2004; 63:1462-1470. 81. Koffman BM, Greenfield LJ, Ali II, Pirzada NA: Neurologic complications after surgery for obesity. Muscle Nerve 2006; 33:166-176. 82. Chin RL, Sander HW, Brannagan TH: Celiac neuropathy. Neurology 2003; 60:1581-1585. 83. Rosenberg NR, Vermeulen M: Should coeliac disease be considered in the work up of patients with chronic peripheral neuropathy? J Neurol Neurosurg Psychiatry 2005; 76:14151419. 84. Brannagan TH, Hays AP, Chin SS, et al: Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch Neurol 2005; 62:1574-1578.

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Joshua Kershen and Thomas Sabin

While most peripheral neuropathies encountered by the clinical neurologist will have toxic or metabolic etiologies, it is very important to consider that the syndrome may be caused by an infection. Both bacterial and viral infections are known to cause peripheral neuropathies, as are the autoimmune sequelae of an infectious process. Most infective neuropathies have a distinctive clinical phenotype that will aid in its recognition, especially in the context of a patient’s medical and social histories. The recognition of an infective neuropathy has profound treatment implications, and may offer the rare opportunity to “cure” a peripheral neuropathy.

LEPROUS NEURITIS Leprous neuritis is a true bacterial infection of peripheral nerves, and nerve invasion is a major hallmark of the disease. The disease has been known since biblical times, and archeological studies of human remains have documented that leprosy did exist in that era. Recent studies based on single nucleotide polymorphisms of the bacillus have pinpointed the origins of leprosy to East Africa, with subsequent spread to Europe and Asia before being reimported into West Africa by explorers.1 In earlier times, the disease was very common in Europe, especially in Scandinavia and England. In 1200 AD, there were some 200 “lazar” houses in the British Islands. There had been an endemic focus in the United States within 100 miles of the Gulf Coast of Texas, Louisiana, and Florida, and a smaller focus in the Midwest originating from Scandinavian immigrants. Now, there are only a few thousand cases in the United States, almost all of foreign origin. There has been great recent progress in the control of this disease, which is now most common in underdeveloped countries. Newer methods of treatment, especially the introduction of multiple drug therapy (MDT), have resulted in a dramatic decline in active cases. There are now on the order of 300,000 active cases, whereas there were about 14 million cases 20 years ago.2 Many cases are cleared from the active rolls after therapy is given, without follow-up, but the newer drugs seem to be associated with only a small percentage of resistant or relapse cases. The plan of the World Health Organization (WHO) has been to reduce the caseload to such a low level (1 case per 10,000 population) that further transmission becomes unlikely.3 This idea harkens back to the observation that leprosy

disappeared from most of Europe following the loss of more than a third of the population in the wake of the Black Plague. This was attributed to a critical decline in the number of infective cases in population centers. The history of leprosy is remarkable because of the stigma accompanying the disease in almost all cultures. The dreaded disease was considered to be a punishment of the gods for the sins of venery or egotism. This stigma is due to the chronicity of the disease, combined with the terrible disfigurement of the visible face and hands, which evoke highly negative visceral responses in the beholder. The organism, Mycobacterium leprae, first seen in 1874 by G.H. Armauer Hansen in Norway, is the first bacterium that was associated with a human disease. M. leprae is less acid-fast than M. tuberculosis and requires the Fite modification for acid-fast staining. The ability to invade human nerves is unique, and recent studies of the bacillus have revealed that the actual site of nerve attachment and invasion is the alpha-dystroglycan moiety of Schwann cell myelin.4 The entire genetic sequence of the bacterium has also recently been elucidated, and demonstrates that the organism is highly specialized as an obligate intracellular human pathogen, and has lost many of the enzymatic functions that other acid-fast bacilli have maintained.5 These data may account for the failure to grow M. leprae on artificial media, and the difficulty to infect animals (mouse footpads and genetically susceptible armadillos). M. leprae has a highly thermosensitive growth rate: optimum cell division occurs once per 12.5 days at 27°C to 32°C. There is no growth at core body temperature, and therefore the viscera and central nervous systems are not involved in this disease. This feature limits leprosy to the skin, the anterior third of the eyes, the upper respiratory tract, and the testes. The incubation period varies from several weeks to several years. Children under 16 appear more susceptible to the disease, as are patients with certain types of immunosuppression. Although acquired immunodeficiency syndrome (AIDS) and leprosy are both very common in certain areas such as Africa, AIDS does not seem to increase the vulnerability or severity of coexistent leprosy. The disease is probably spread by infected nasal droplets (where bacteria remain viable for several days) and prolonged skin-to-skin contact. Leprosy may manifest as a neuropathy, and a well-informed neurologist is capable of making a definitive bedside diagnosis, even in cases where the disease has been fully treated and only

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residual neurological deficits remain, or in the more rare patient who is trying to conceal the diagnosis. Early diagnosis is critical because one can expect to halt the progress of the neuropathy, and even obtain some degree of reversal. However, severe deficits may remain in advanced cases even after the patient is successfully treated. Cases may be misdiagnosed at medical centers in developed countries because the possibility of leprosy is not considered. Although there is only one causative organism, the clinical picture of leprosy is wide and related to the host’s innate immune response to M. leprae. In most human populations, 90% to 95% of individuals are genetically equipped to clear the bacilli completely. When resistance is high but insufficient to entirely prevent the disease, “high resistance” tuberculoid or paucibacillary leprosy occurs. Tissue temperature has only a permissive role in shaping this clinical picture. Rather, local invasion by very few bacilli evokes a vigorous epitheloid granulomatous response, which destroys intracutaneous nerves as the lesion forms. The typical patient shows one or a very few asymmetrically dispersed, hypopigmented, anhydrotic skin

lesions (Fig. 84–1). A dry patch with pain and temperature loss coinciding with the skin lesion is the diagnostic picture of paucibacillary leprosy (Fig. 84–2). The skin lesion shows central clearing and a slightly raised edge. The centers of such lesions are often clear of bacilli. For diagnosis, the skin biopsy sample should be taken at the elevated edge. Serial sections may be required to see just one or a few bacilli. When the host has little inborn resistance to the invasion of bacilli, these become widespread and numerous, with hematogenous spread and reproduction in the cooler tissues. Thus, the skin lesions and nerve involvement are roughly symmetric. This form of leprosy is called lepromatous. The palpably enlarged nerves present in this form of leprosy narrow the differential diagnosis. The invasion of intracutaneous nerve networks is manifested by a pattern of temperature-linked sensory loss that starts in the coolest regions of the body, around the breast plate, tip of the nose, lobes and helices of the ears (Fig. 84–3). Once this temperature-linked pattern of sensory loss is discerned, the diagnosis becomes apparent.6 Over the years, the pattern progresses to “less cool” regions and

Pinprick Normal Decreased Lost

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Figure 84–1. Sensory map of tuberculoid leprosy. (From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2088, Figure 91-3.)

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Figure 84–2. Skin lesion of tuberculoid leprosy. (From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2085, Figure 91-2B.)

results in very extensive sensory loss, sparing only areas over the carotid arteries, the anterior neck, armpits, inguinal folds, intergluteal folds, and the precordium (Fig. 84–4). The insulating effect of corium of the hands and feet make the tissue temperatures beneath these surfaces somewhat warmer, so that sensory loss tends to occur over the dorsa of hands and feet rather than over the soles and palms. The distribution of skin lesions is also temperature dependent, and roughly approximates the distribution of sensory loss. There are striking examples of small differences in temperature creating distinctive features on the sensory examination. Facial sensation becomes normal at the hairline because of the insulating effect of hair. For example, the old leprosy atlases depict men who followed the Samurai tradition of shaving their heads and experienced leprosy lesions in the scalp; when they let their hair grow back, there was destruction of the follicles except over the warm areas overlying the temporal arteries. The cooler hemiplegic side of a stroke victim showed more extensive sensory loss. Sensorysparing underbelts, watchbands, and other snug garments have also been documented.

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Figure 84–3. Sensory map of early lepromatous leprosy. (From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2090, Figure 91-5.)

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Figure 84–4. Sensory map of chronic lepromatous leprosy. (From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2091, Figure 91-6.)

The major named nerves, which run closest to the surface of the body, are also affected in a predictable fashion (Fig. 84–5). Thus, the deep peroneal branch to the extensor digitorum brevis of the foot and the ulnar nerve proximal to the olecranon groove are involved early. The median nerve segment from the wrist crease to where it is covered by the forearm flexor muscle group is affected later, with further sensory loss and paralysis of median-innervated intrinsic muscles. Foot drop ensues when the peroneal nerve is affected as it circles around the head of the fibula. Multiple branches of the facial nerve are involved, particularly affecting the medial corrugators of the forehead, the small twigs to the orbicularis oculi and to the muscles composing the nasolabial folds, so as to create a highly diagnostic, patchy paralysis described by Monrad-Krohn.7 If one actually severed the ulnar, median, and peroneal nerves at the sites affected by leprosy, the corresponding deep tendon reflexes would remain intact. The preservation of deep tendon reflexes in the presence of significant peripheral neuropathy is yet another very helpful diagnostic feature.

Although there are many intermediate forms between these polar types of leprosy, complex interplay between the two themes—tissue temperature and natural immunity of the host—can always be discerned. These cases are labeled dimorphous, borderline, or intermediate. Modern leprosy workers tend to divide all cases into paucibacillary and multibacillary for purposes of management. Among the high-resistance dimorphous cases, there is a group called pure neural leprosy. These patients have no skin lesions but extensive nerve damage, and they can be very difficult to diagnosis, even on sophisticated neurological services. A nerve biopsy may be helpful (the sural or cutaneous branches of the radial nerve are good sites), but a fascicular biopsy at a site of clinical involvement will have the best yield. Polymerase chain reaction techniques can also help in this situation.8 Alterations in immune response, known as leprosy reactions, occur in some patients. In high-resistance cases, there may be a sudden increase in cell-mediated immunity causing acute inflammation of existing lesions and rapid onset of

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Ulnar nerve proximal to medial epicondyle Zygomatic branch of facial nerve

Median nerve Ulnar nerve

Great auricular nerve

Radial nerve Tibial nerve Peroneal nerve

Sural nerve Peroneal nerve ■

Figure 84–5. The most commonly affected nerves in leprosy. (From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2089, Figure 91-4.)

deficits in neighboring and subjacent nerves that had already been invaded by bacilli. The nerve damage will be permanent unless this situation is rapidly recognized and treated with steroids. In multibacillary patients, there is an entity called erythema nodosum leprosum. Here, the circulating immune response goes awry and produces what resembles an autoimmune disease. Features of an Arthus reaction, including consumption of complement and arteritis, are present. Although there are systemic symptoms, the brunt of the damage occurs in the area of greatest bacillary density. Except for the distribution, the erythema nodosum looks the same as in other systemic diseases. Rapid, widespread nerve pain and dysfunction results from vasculitis of the vasa nervorum. This is a situation that must also be quickly recognized. The treatment of choice is thalidomide, but steroids can be used if thalidomide is contraindicated or not available. In addition to direct nerve invasion and leprosy reactions, there are additional causes of nerve damage. The enlarged nerves seen in leprosy are much more vulnerable to repeated

trauma and compression, particularly the peroneal nerve at the fibular head, and the ulnar nerve proximal to the olecranon groove. This situation may require nerve repositioning or decompressive surgery. Electrodiagnostic studies are nondiagnostic. In multibacillary forms of the disease, they reveal a mononeuritis multiplex. When early diagnosis is made, most people require only antibacterial treatment. The most effective antibacterial regimen for M. leprae includes the drugs dapsone, clofazimine, rifampin, ofloxacin, and minocycline. The course of antibacterial therapy depends on whether the patient has the paucibacillary or multibacillary forms of leprosy. Paucibacillary patients receive 100 mg of dapsone daily with rifampin 600 mg monthly for 6 months. Multibacillary patients are given the same combination for 1 year, in addition to clofazimine 50 mg daily, with a monthy 300-mg dose of clofazimine. Shorter regimens used by WHO also make the patient noninfectious in a few days and have an extremely low relapse rate for both types of disease.9 The addition of rifampin has made the greatest dif-

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ference in the antibacterial treatment of leprosy since the introduction of dapsone in 1940. Treatment of leprosy reactions is very important because widespread neurological damage can occur in either type. When there is neuritis in paucibacillary reactions, steroids generally control the reactive process. Occasionally, high doses may be needed. With erythema nodosum leprosum reactions seen in multibacillary cases, thalidomide is the treatment of choice in a dose of 300 to 400 mg/day. The reaction generally abates in 24 to 48 hours. If thalidomide is not available, steroids can be used. Obviously, very strict precautions must be used in women of childbearing age who are administered thalidomide. Clofazimine has a role both as an antibacterial and in helping to control erythema nodosum leprosum. Certain surgeries are available for advanced cases, such as nasal reconstruction after bony collapse of the bridge of the nose, and correction of gynecomastia secondary to destructive mycobacterial orchitis. Tendon transfer procedures are used to correct clawing of the hands and foot drop. The management of insensitivity to pain is one of the more challenging aspects of the disease. When there is extensive loss of pain sense in actively used extremities, the patient suffers loss of the digits in a process known as absorption. Without intervention, the patient inevitably accumulates many small wounds and burns. Since these injuries are not painful, they tend to be neglected and this permits infection of deeper tissues. Over a period of years, multiple bouts of mild osteomyelitis result in shrunken, deformed, and eventually useless hands and feet. While these deformities are considered characteristic of leprosy, they also occur in hereditary sensory neuropathy, diabetic neuropathy, and syringomyelia, all situations where there is loss of pain sensation in limbs that can still be actively used. Treatment focuses on educating the patient to the dangers of loss of pain sensation, treating every wound assiduously with splinting, avoidance of infection, prevention of repetitive injury to the same area, and monitoring the hands and feet for signs of tissue stress (heat, redness, callus, and ecchymoses). Special footwear with molded insoles to spread pressure evenly over the sole of the foot is very effective in preventing “trophic” ulcers. Occupational therapists can identify dangerous activities in the home or workplace, where special devices may be used to prevent painless but dangerous injuries. Loss of sweating in the hands and feet results in cracking of the skin, which serves as another portal of entry for infection. This problem can be solved by daily soaking of the hands and feet, followed by application of a cream to seal in the moisture. The patient with early leprosy may be easy to treat by eradication of the bacilli, but an advanced case may require a team approach, including physical therapist, occupational therapist, shoemaker, vocational therapist, reconstructive surgeon, and psychosocial rehabilitation specialist.

HUMAN IMMUNODEFICIENCY VIRUS Human immunodeficiency virus (HIV) is associated with diverse peripheral nervous system complications (Table 84–1). The specific type of peripheral nervous system syndrome is dictated by the severity of the HIV infection, as determined by CD4+ cell counts.10 Prospective studies indicate that the incidence of symptomatic peripheral nervous system complications due to HIV is around 3%, and complications are more common

T A B L E 84–1. Peripheral Nervous System Complications From Human Immunodeficiency Virus Infection Mononeuropathies Guillain-Barré syndrome Chronic inflammatory demyelinating polyneuropathy Mononeuritis multiplex Diffuse infiltrating lymphocytosis syndrome Motor neuron disease syndrome Distal symmetrical polyneuropathy

in more advanced cases.11 If peripheral nervous system complications are assessed by clinical symptoms and electrophysiological tests, the incidence in prospective studies is much higher, at least 30%, and advanced HIV infection again poses a higher risk. Assessing the epidemiology of HIV-related peripheral nervous system complications is confounded by the fact that several common antiretroviral drugs used to treat HIV are themselves toxic to peripheral nerves. HIV seroconversion may be accompanied by an acute peripheral nervous system process, most commonly unilateral but also bilateral facial nerve palsies.12 Guillain-Barré syndrome is known to occur at the time of HIV seroconversion, and Guillain-Barré syndrome may be the presenting feature of HIV infection. The Guillain-Barré syndrome associated with HIV is clinically and electrophysiologically identical to non-HIV Guillain-Barré syndrome,13 and is characterized by acute flaccid paralysis with diminution or loss of reflexes. However, instead of the albuminocytological dissociation of typical GuillainBarré syndrome, the cerebrospinal fluid in HIV-associated Guillain-Barré syndrome often shows a pleocytosis. HIV serology may be initially negative for several weeks following seroconversion. If clinical suspicion for HIV is high, HIV viral load can be used for the diagnosis in the acute setting. The therapeutic approach and therapeutic response is similar in HIV-associated Guillain-Barré syndrome and in idiopathic Guillain-Barré syndrome. The peripheral nervous system complications of early HIV infection, with CD4 cell counts above 500 cells/μL, are similar to the complications of HIV seroconversion, and are dominated by facial nerve palsies and Guillain-Barré syndrome. However, these peripheral nervous system processes are seen in a small minority of HIV patients.10 In moderately advanced HIV infection, with CD4 cell counts between 200 and 500 cells/μL, peripheral nervous system complications are due to immune dysregulation.10 Chronic inflammatory demyelinating polyneuropathy (CIDP) is known to occur in HIV, and, like Guillain-Barré syndrome, CIDP in HIV is clinically and electrophysiologically identical to non-HIV CIDP. Again, a mild mononuclear cerebrospinal fluid pleocytosis is often seen. Pathologically, CIDP in both HIV and non-HIV forms is characterized by macrophage-mediated demyelination. Although there are no therapeutic trials with HIV-infected CIDP patients, it is believed that they respond to treatment like non-HIV CIDP patients.14 Corticosteroids, plasmapheresis, and intravenous immunoglobulin are the usual therapies for CIDP. When immunosuppressant treatment is utilized, prophylaxis against opportunistic infections is warranted.10 Mononeuritis multiplex caused by vasculitis is known to occur with HIV infection of all severities, but especially in moderately advanced cases. The clinical syndrome is characterized

chapter 84 infective neuropathies by a progressive accumulation of individual nerve lesions, leading to multifocal sensory and motor derangement, with electrophysiological evidence of multifocal axonal neuropathies. Axonal degeneration is the most common pathological finding on nerve biopsy, with perivascular or endoneurial inflammatory infiltration. Although the etiology of mononeuritis multiplex in HIV is unknown, it may be due to the deposition of HIV-related antigen and antibody immune complexes in perineural vessels. Treatment with immunotherapy should be reserved for patients with disabling deficits, as all therapies have the potential of worsening the underlying immunodeficiency, and milder cases are known to improve spontaneously. When the degree of immunodeficiency from HIV is profound (CD4+ cell count less than 100) and mononeuritis multiplex is present, the suspicion of cytomegalovirus infection should be high, and these cases should be treated aggressively with ganciclovir, foscarnet, or both.15 Cytomegalovirus infection is discussed in further detail later. Diffuse infiltrative lymphocytosis syndrome is characterized by CD8+ cell infiltration of visceral organs, resulting in enlarged salivary glands and sicca syndrome.16 Peripheral nerves can be infiltrated, resulting in polyneuropathy. This is usually a painful distal symmetric sensory polyneuropathy, which develops subacutely over weeks. Electrophysiological studies reflect an axonal process. Nerve biopsy reveals diffuse CD8+ cell infiltration of the epineurium and endoneurium. Highly active antiretroviral therapy is effective in diffuse infiltrative lymphocytosis syndrome.17 Several recent case reports have described motor neuron disease in the setting of HIV infection, with the potential for clinical improvement after the initiation of highly active retroviral therapy.18,19 These cases are of great interest because they may help us understand the basic mechanisms of motor neuron diseases in general. Approximately one third of patients with AIDS will develop a clinically significant distal symmetric polyneuropathy (DSP).20 DSP is the most common peripheral nervous system complication of HIV infection, and is present on autopsy in nearly all patients who die from AIDS.21 Risk factors for the development of DSP include elevated HIV viral load, low CD4+ cell counts, and exposure to neurotoxic antiretroviral medications. The clinical phenotype of DSP is that of a distal, predominately sensory polyneuropathy. Pain is often present, generally burning in quality, and allodynia may make ambulation difficult. Neurological examination reveals distal loss of pain, temperature, and vibratory senses. Ankle jerks are diminished or abolished in most cases. When ankle jerks are intact, a purely small-fiber neuropathy or a superimposed myelopathy should be considered. Weakness of the distal lower extremities, when present, is mild and is seen only in long-standing cases of DSP. Commonly, DSP is asymptomatic or symptoms are mild enough to be ignored by the patient. Electrophysiological testing in DSP is consistent with a sensory-predominant axonal polyneuropathy. Sural sensory responses are small in amplitude or absent. When DSP is severe, the sensory responses from the hands may be abnormal. Motor nerve abnormalities are generally mild. Notably, when DSP involves purely small-fiber sensory nerves, routine nerve conduction studies and electromyography are normal. Nerve biopsies are not routinely performed in DSP. When obtained, nerve biopsies show distal axonal degeneration,

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affecting both unmyelinated and myelinated axons.21 Perivascular mononuclear infiltrates may be present. The pathogenesis of DSP in HIV infection is not known. As direct neuronal infection is not believed to occur, recent research has focused on indirect mechanisms. Attention has been directed toward the HIV-1 envelope protein gp120. Current hypotheses propose indirect neurotoxicity from gp120 via chemokine receptors on Schwann cells and neurons.14 As with other painful neuropathies, treatment is largely symptomatic. There is some evidence that highly active antiretroviral therapy may mildly improve DSP.22,23 Symptomatic treatments have been based on drugs used in other painful sensory neuropathies (especially diabetic polyneuropathy), including amitriptyline, gabapentin, and lamotrigine. There is no evidence to suggest that any one of these agents is specifically effective in the DSP of HIV. Narcotics may be needed in refractory cases. As with all other aspects of HIV management, careful attention to drug-drug interactions is important when choosing a symptomatic therapy. Several nucleoside analogue reverse transcriptase inhibitors are known to cause a toxic polyneuropathy, and this has been a frequent confounder in the study of DSP. The so-called “d-drugs”—ddC (dideoxycytidine), ddI (didanosine), and d4T (stavudine)—are all known to cause a dose-dependent toxic polyneuropathy.24 The clinical syndrome is identical to DSP, and usually develops after several months of treatment with a d-drug. Distal numbness and painful dysesthesias develop, and exam reveals distal sensory abnormalities with diminished or abolished ankle jerks. Electrophysiological studies demonstrate a distal sensory-predominant axonal polyneuropathy. Serum lactate levels may help in determining if a painful sensory polyneuropathy is drug-related or due to the HIV infection itself.25 Offending drugs should be stopped in all patients with DSP. “Coasting” may occur, whereby the patient’s symptoms continue or worsen for 6 to 8 weeks after removal of the toxic drug.10 Due to similar modes of transmission, co-infections with syphilis, hepatitis C, and human T-lymphotropic virus type 1 (HTLV-1) should be considered in the evaluation of peripheral nervous system syndromes in the HIV-infected patient, as they may act as confounders.10

CYTOMEGALOVIRUS Cytomegalovirus is a common herpesvirus that causes serious peripheral nervous system syndromes in immunosuppressed patients, such as organ transplant recipients or patients with advanced HIV infection. In immunocompetent patients, cytomegalovirus infection can be asymptomatic or result in a mononucleosis-like illness. After infection, cytomegalovirus becomes latent, and may emerge again in the setting of immunosuppression. In the peripheral nervous system, cytomegalovirus is known to cause a polyradiculopathy and mononeuritis multiplex. Cytomegalovirus lumbosacral polyradiculopathy is a severe infectious cauda equina syndrome that affects patients with severe immunosuppression, usually patients with HIV and CD4 counts less than 50 cells/μL. The clinical presentation consists of a rapidly progressive flaccid areflexic paraparesis with urinary retention.26 Weakness of the lower extremities progresses over days and may be asymmetrical. Although there

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may be complaints of numbness, particularly in the perianal region, objective sensory findings are uncommon. Rarely, the syndrome manifests as a polyradiculomyelitis, with a thoracic spinal level and Babinski responses. The prognosis of patients with cytomegalovirus lumbosacral polyradiculopathy is very poor, even with optimal therapy, and the condition is uniformly fatal if left untreated.26 In severely immunosuppressed patients who present with the above syndrome, cerebrospinal fluid examination is of critical importance, typically showing a polymorphonuclear pleocytosis of 50 to 1000 cells/mm3, usually with elevated protein and low glucose.26,27 However, if cerebrospinal fluid does not demonstrate the expected polymorphonuclear pleocytosis, polymerase chain reaction is required for definitive diagnosis.28 While cytomegalovirus can be cultured from cerebrospinal fluid, polymerase chain reaction of cerebrospinal fluid is more sensitive, and will be positive in more than 90% of patients with cytomegalovirus lumbosacral polyradiculopathy. In immunosuppressed patients with the clinical syndrome and cerebrospinal fluid profile of cytomegalovirus lumbosacral polyradiculopathy, empiric treatment should begin before a definitive diagnosis of cytomegalovirus in cerebrospinal fluid is obtained, as test results are often delayed. If needed, evidence of cytomegalovirus infection should be sought in another organ system.29 As with any patient presenting with a cauda equina syndrome, magnetic resonance imaging (MRI) should be obtained. MRI in cytomegalovirus lumbosacral polyradiculopathy may reveal thickened nerve roots and enhancement with gadolinium contrast.30 Electrodiagnostic studies generally reveal a polyradicular pattern, where motor responses are absent or reduced in amplitude, although sensory responses are normal. Motor unit recruitment is reduced on needle electromyography in weak muscles, and there is evidence of denervation (assuming that enough time has elapsed for wallerian degeneration to occur). Reduction or absence of sensory responses may reflect an underlying distal symmetrical polyneuropathy or may reflect direct damage by cytomegalovirus to the dorsal root ganglion. Treatment of cytomegalovirus lumbosacral polyradiculopathy involves intravenous administration of ganciclovir, foscarnet, or both.31 The major dose-related medication side effects are neutropenia with ganciclovir and nephrotoxicity with foscarnet. In HIV patients, antiretroviral therapy should be optimized. In the evaluation of suspected cytomegalovirus lumbosacral polyradiculopathy in a patient with advanced HIV, cerebrospinal fluid should be screened for both cytology and syphilis serology.14 This is because lymphomatous meningitis and syphilis can mimic the presentation and cerebrospinal fluid profile of cytomegalovirus polyradiculopathy.10 Cytomegalovirus can present as a mononeuritis multiplex in HIV patients with CD4+ counts less than 50 cells/μL.15 Symptoms begin as sensory complaints in the distribution of a named nerve, and progress to asymmetrical weakness. Electrophysiological studies demonstrate a multifocal axonal process. Cerebrospinal fluid pleocytosis is present only in a minority of patients, but cytomegalovirus polymerase chain reaction is positive in at least 90% of patients. The prognosis for cytomegalovirus mononeuritis multiplex is better than that of cytomegalovirus polyradiculopathy, as most patients improve after treatment with ganciclovir or foscarnet.

LYME DISEASE Approximately 15% of patients infected with Borrelia burgdorferi, the spirochete that causes Lyme disease, will have neurological manifestations, and these often affect the peripheral nervous system. The broad group of spirochetes that cause Lyme disease is known as Borrelia burgdorferi sensu lato. This group is further subdivided into Borrelia burgdorferi sensu stricto, which is found in the United States, and B. burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, which are found in Europe. These spirochetes are transmitted by the bites of Ixodes ticks. These ticks feed from the spring into the fall, and their feeding pattern mirrors the chronology of new cases of Lyme disease. If an Ixodes tick attaches to a human host and feeds for longer than 24 hours, the host may be injected with B. burgdorferi spirochetes. Lyme borreliosis has a restricted geographic area in the United States. The vast majority of cases are found on the eastern seaboard between Maryland and New Hampshire, and in the Midwest, including Wisconsin and Minnesota. Fewer cases were reported from the American west coast. In Europe, cases occur in central and western Europe, including Denmark, Sweden, Germany, Austria, Switzerland, and France. Lyme disease is a multisystem illness, which initially affects the skin and then causes neurological, cardiac, and rheumatological symptoms. The pathognomonic finding in Lyme borreliosis is erythema migrans, the characteristic rash. Erythema migrans starts as a small erythematous macule or papule at the site of the tick bite, which expands in size over days or weeks. As the rash expands, the border of the lesion remains erythematous while the center clears, leading to a characteristic “bull’s eye” appearance. The rash may be accompanied by fever or malaise. Days to weeks after the primary infection, multifocal erythema migrans may occur in the setting of spirochetal dissemination via the bloodstream (Fig. 84–6). It is at this point that the spirochetes may spread to multiple organ systems, causing a systemic illness with fever, malaise, headache, myalgias and arthralgias. Erythema migrans is neither pruritic nor painful, and thus may be ignored or unnoticed by patients. However, as this skin finding

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Figure 84–6. Disseminated erythema migrans approximately 1 month after tick bite. (From Said G: Lyme disease. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2111, Figure 92-1.)

chapter 84 infective neuropathies is pathognomonic of the disease, a history of prior rashes should be vigorously sought in cases of suspected Lyme disease, as 80% of Lyme patients have this finding in early infection.32 Several weeks or months after the initial exposure to the borrelia spirochete, approximately 15% of untreated patients will develop neurological complications. The classic triad of neurological Lyme disease includes cranial neuropathy, painful radiculopathy, and lymphocytic meningitis. Although these symptoms are generally self-limited, they do improve more rapidly with appropriate antibiotic therapy. The peripheral nervous system complications of Lyme disease are numerous, and a high degree of suspicion should be maintained when evaluating patients who reside in endemic areas and who present with an appropriate syndrome in the warmer months. Cranial neuropathies are very common in neurological Lyme disease, affecting approximately one half of patients. These generally have a cranial neuropathy, typically seen within the first few months of the infection. Lyme infection has been associated with neuropathy of every cranial nerve except the olfactory nerve, although facial nerve palsy is by far the most common. The third, fifth, sixth and eighth cranial nerves are also commonly affected. In one third of patients with facial palsy, the syndrome is bilateral. In patients presenting with bilateral facial palsies, serious consideration should always be given to the diagnosis of Lyme disease, as the differential diagnosis for this presentation is very limited. Painful radiculoneuritis is the other classic peripheral nervous system syndrome of Lyme disease. The syndrome is characterized by the acute presentation of severe radiating dermatomal pain. The affected dermatome may involve limb or trunk. After several weeks from the onset of pain, dermatomal weakness, hyporeflexia, and sensory loss develop. This syndrome can mimic a typical compressive radiculopathy. Thus, when evaluation of radiculopathy does not reveal a compressive etiology, Lyme borreliosis should be considered in patients from endemic areas. The radiculoneuritis of Lyme disease may be electrophysiologically indistinguishable from a compressive radiculopathy as well.33 Patients with chronic Lyme infection may also develop a radiculoneuropathy. This syndrome is typically milder than the acute radiculoneuritis, and is characterized primarily by distal paresthesias or radicular pain. Sensory signs with preserved motor function characterize this syndrome. The diagnosis of neurological Lyme disease is based on the combination of an appropriate neurological syndrome in a patient with exposure to an appropriate endemic area during the spring, summer or early autumn months. Involvement of other organ systems is very supportive of the diagnosis. The presence of erythema migrans or a history consistent with this rash is the most specific clue. The presence of unexplained cardiac conduction abnormality or asymmetrical oligoarticular arthritis is also highly suggestive of Lyme disease. Although lymphocytic meningitis is considered a hallmark syndrome in neurological Lyme disease, it is often asymptomatic or minimally symptomatic. Symptoms and signs of frank meningitis are unusual. In peripheral nervous system syndromes due to Lyme disease, cerebrospinal fluid may or may not be abnormal: therefore, normal cerebrospinal fluid does not exclude the diagnosis. However, the finding of a lymphocytic pleocytosis with elevated protein and normal glucose in a patient with a syndrome consistent with Lyme disease is strongly supportive of the diagnosis.

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Laboratory diagnosis of Lyme disease rests on demonstration of an antibody response to the spirochete. Culture of the organism from blood and cerebrospinal fluid has been disappointing. Multiple laboratory techniques have been devised in an attempt to improve upon the laboratory diagnosis of Lyme disease. The multitude of laboratory approaches (many of which have not undergone rigorous scientific review) has led governmental agencies in the United States, Canada, and Europe to publish guidelines for the use and interpretation of appropriate serological tests.34 However, there are limitations to the diagnostic approach with serological tests. First, it takes several weeks after infection for an individual patient to produce sufficient antibodies to be measured. Thus, patients presenting with an acute neurological syndrome shortly after infection with Borrelia burgdorferi may have negative serological testing. Repeat testing after several weeks should then be abnormal. Second, in endemic areas many patients will have detectable Lyme antibodies, and this laboratory abnormality may or may not have any relevance to the current presenting complaint. Similarly, detectable antibodies may persist after successful treatment. This should not be considered treatment failure and does not warrant exposing patients to unduly long treatment due to persistent serological abnormalities. Third, Lyme serologies may be abnormal in patients with an underlying systemic inflammatory disorder, leading to false positive serological results. To minimize the above problems, and to maximize the diagnostic accuracy of serological testing, current recommendations in the United States are that the initial screening test for Lyme disease be an enzyme-linked immunosorbent assay (ELISA). If the ELISA is borderline-positive or positive, a Western blot should be obtained. Criteria have been published for the laboratory interpretation of Western blot analysis, based on high specificity.35 It is not recommended that Western blots be given diagnostic significance when the ELISA is normal. Polymerase chain reaction testing is not recommended for routine diagnosis. In the cerebrospinal fluid of infected patients it is possible to demonstrate antibodies against the Lyme spirochete. Paired serum and spinal fluids samples are helpful to compare the relative quantity of antibodies that are being produced intrathecally to the small amount of Lyme antibody that diffuses into the cerebrospinal fluid from peripheral blood. The prognosis for appropriately treated Lyme disease is excellent. Early Lyme disease, where the only manifestations are dermatological, is appropriately treated with doxycycline 100 mg by mouth twice a day or amoxicillin 500 mg by mouth three times a day for 14 to 21 days. Some experts advocate also treating the cranial nerve syndromes of Lyme disease with oral antibiotics, unless a lymphocytic meningitis is present, in which case intravenous therapy is recommended. Intravenous therapy is indicated for all Lyme infections with radiculitis or meningitis. Intravenous therapy generally consists of ceftriaxone 2 g daily intravenously for 14 to 28 days.36 The underlying pathology in peripheral nervous system syndromes due to Lyme disease has yet to be defined. There are many reports of lymphocytic inflammatory infiltrates of nerves, without a true vasculitis. Overall, the pathology suggests a multifocal axonal process, consistent with the clinical and electrophysiological observations that Lyme disease causes a mononeuritis multiplex. There is no evidence of direct infection of Borrelia burgdorferi in peripheral nerves.

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HERPES SIMPLEX VIRUS Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) are DNA viruses that remain latent in the ganglion cells of neurons. Both reactivate periodically and cause painful vesicular ulcerations. Both are also associated with syndromes involving the peripheral nervous system. HSV-1 resides in cranial nerve ganglia, generally the trigeminal ganglia, in a latent state and reactivates periodically, causing painful oral and labial ulcerations. The vast majority of adults are infected with HSV-1. There is experimental evidence that HSV-1 may be a cause of Bell’s palsy, based on the detection HSV-1 DNA in endoneurial fluid of patients. This observation has lead to the widespread use of oral antiherpetic agents in idiopathic facial nerve palsy. Although data from controlled trials have not demonstrated a robust effect of oral antiherpetic agents in Bell’s palsy, in general these agents are well tolerated and safe. HSV-2 resides in a latent state in lumbosacral ganglia, and reactivates periodically to cause genital herpes. This syndrome is characterized by painful genital ulcers, which in some cases have been associated with recurrent radiculopathy. HSV-2 can be detected in the cerebrospinal fluid of such patients by polymerase chain reaction.

VARICELLA ZOSTER VIRUS Varicella zoster virus (VZV), the causative agent of chickenpox, is a human herpesvirus that becomes latent in ganglia throughout the nervous system. The majority of adults have latent VZV in cranial nerve, dorsal root, or autonomic nervous system ganglia. The reactivation of VZV produces herpes zoster, also known as shingles. Herpes zoster is characterized by severe burning pain in a dermatomal distribution, followed by a vesicular rash, which ultimately crusts. The development of herpes zoster reflects a deficiency in cell-mediated immunity. Although cases are seen in patients with underlying malignancies, HIV, or immunosuppression due to transplant status, the most common cause is a natural decline in cell-mediated immunity due to age. Zoster becomes fairly common after age 60 and the risk of outbreak is directly proportional to advancing age. Herpes zoster may affect any dermatome or cranial nerve with the exception of the first cranial nerve. Thoracic dermatomal involvement is the most common, followed by involvement of the trigeminal nerve. Involvement of the ophthalmic branch of the trigeminal nerve can result in corneal lesions, and should prompt ophthalmological consultation. The combination of unilateral facial weakness and herpetic vesicles in the ear is known as the Ramsey-Hunt syndrome. When herpes zoster affects either cervical or lumbosacral dermatomes, there is approximately a 5% chance of motor involvement. The weakness that follows the typical herpes zoster rash has a myotomal pattern that reflects the dermatomal pattern of the rash. Sphincteric difficulties can be associated with sacral herpes zoster. Oral antiherpetic agents are efficacious in speeding the recovery from herpes zoster. One week’s treatment with valacyclovir 1000 mg three times a day, famciclovir 500 mg twice a day, or acyclovir 800 mg five times a day all appear equally effective. However, the dosing of valacyclovir and famciclovir is more convenient than the dosing of acyclovir. Narcotic pain control may be required for patients with herpes zoster.

Postherpetic neuralgia is defined as pain in the dermatomal distribution of the prior herpes zoster rash persisting 6 weeks after the appearance of the rash. This syndrome can be a significant source of pain in the elderly population. Commonly used medications for neuropathic pain, including gabapentin, amitriptyline, and carbamazepine, may provide some relief. As these medications are often used in the elderly, they should be started at small doses and titrated up cautiously over time, with close attention to side effects. Topical lidocaine patches may be effective for pain control and are benign from a systemic point of view. Zoster sine herpete is a syndrome identical to postherpetic neuralgia, with burning dermatomal pain. However, there is no antecedent rash. There are cases where VZV DNA has been detected in the cerebrospinal fluid of such patients using polymerase chain reaction.37 Resolution of chronic pain has occurred with high-dose acyclovir at ten to fifteen mg per kilogram intravenously every 8 hours for 2 weeks.

HEPATITIS C VIRUS Infection with the hepatitis C virus, especially in the presence of cryoglobulinemia, is known to cause disease of the peripheral nervous system. Cryoglobulinemia is a condition in which serum contains proteins that reversibly precipitate at low temperatures. Infection with the hepatitis C virus is one of the most common causes of cryoglobulinemia. Although disease of peripheral nerve may be present in hepatitis C–infected patients without cryoglobulinemia, it is much more common for peripheral nervous system disease to be seen in its presence. At least one third of patients with cryoglobulinemia from hepatitis C will have a disorder of peripheral nerve. The most common neuropathy associated with hepatitis C is a distal symmetrical sensory polyneuropathy, which may be associated with purpura of the skin. Electrophysiologically and pathologically, the neuropathy is axonal. The pathological mechanism appears to be ischemia due to vasculitis of vaso nervorum.38 Hepatitis C is also associated with a more severe mononeuritis multiplex. This may be seen either with or without cryoglobulinemia. Large nerve trunks are infarcted, leading to severe sensory and motor deficits. The erythrocyte sedimentation rate is generally elevated. This pattern may be seen in the setting of multisystem involvement, with the patient exhibiting cutaneous purpura, arthralgias, glomulonephritis, and lymphadenopathy. Pathologically, there is a vasculitis of mediumsized vessels. The optimal treatment of peripheral nervous system syndromes in the setting of hepatitis C is not known. Immunosuppression, either with corticosteroids or cytotoxic agents, has been attempted, as has immunomodulation with plasma exchange. Interferon α, in an attempt to treat the underlying viral infection, has also been tried. The efficacy of the above therapies for peripheral nervous system disease is uncertain, and these treatments have been associated with worsening of the overall clinical syndrome.39

HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 HTLV-1 is a common cause of endemic spastic paraparesis in tropical areas. Although generally overshadowed by signs and

chapter 84 infective neuropathies symptoms referable to the central nervous system, a distal symmetric sensory polyneuropathy has been described in isolation.40 The optimal treatment for this infection is not yet defined.

DIPHTHERIA In the past, diphtheria was a common childhood infection. Diphtheric infection occurs in the upper respiratory tract or in skin. In developed countries, vaccination with diphtheria toxoid has made this infection very rare. However, the immunity conferred by immunizations is progressively lost with advancing age. Thus, an outbreak of diphtheria may occur in an area where vaccines are widely available. Infection with Corynebacterium diphtheriae can result in a distinct, delayed polyneuropathy. Days to weeks after the local diphtheria infection, numbness of the pharynx and bulbar weakness develop. Paralysis of the soft palate and inability of the pupils to accommodate are particularly suggestive of diphtheria. Diaphragmatic paralysis may also occur, requiring ventilatory support. Diphtheritic polyneuropathy typically has a biphasic course.41 After bulbar symptoms have been present for several weeks, motor and sensory symptoms appear in limbs, leading to a flaccid paralysis. The limb symptoms of diphtheria may persist for many months, and may recover incompletely. There may also be dysautonomia that is not explained by the myocarditis.42 Electrophysiologically and pathologically, the polyneuropathy of diphtheria infection is demyelinating. Diphtheria secretes a toxin, which is avidly bound by Schwann cells, leading to destruction of myelin. The distinct biphasic course is believed to reflect the local effects of the toxin from pharyngeal infection in the bulbar phase of illness, followed by the disseminated effects of the toxin when the limbs are involved. It is unclear whether administration of diphtheria antitoxin provides any clinical benefit when given after 2 or 3 days of infection. Penicillin can be used to treat the acute infection. Corticosteroids are not effective in preventing diphtheritic polyneuropathy.43

GUILLAIN-BARRÉ SYNDROME Although Guillain-Barré syndrome and its variants are not infective neuropathies per se, they have long been considered postinfectious autoimmune processes. Experimental evidence confirms the long-held view that immune attack on shared epitopes between the infective agent and peripheral nerve results in the acute polyneuropathy. Guillain-Barré syndrome refers to an acute polyneuropathy resulting in flaccid paralysis. Some authors use the terms “Guillain-Barré syndrome” and “acute inflammatory demyelinating polyradiculoneuropathy” (AIDP) equivalently but further subdivide Guillain-Barré syndrome into several variants. Other authors prefer to refer to these groups of disorders as “Guillain-Barré syndromes,” which include AIDP, acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and acute ataxia and ophthalmoparesis (Fisher syndrome). The prototypical presentation of AIDP is acute onset of paresthesias in the distal upper and lower extremities in an otherwise afebrile and systemically well patient. Over hours to days, weakness develops, often in a non–length-dependent

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pattern. The absence of tendon reflexes is so common that the presence of normal reflexes argues against the diagnosis. Facial weakness and dysphagia are also common. About a third of patients will have ventilatory failure requiring intubation. AIDP can progress very rapidly, making admission to the hospital very wise in suspected cases, so that close monitoring of respiratory status can be maintained. The spectrum of motor deficits ranges from trivial to profound. Most patients reach their clinical nadir by the third week of illness. The axonal forms are also characterized by an evolving acute flaccid paralysis. What distinguishes AMAN from AMSAN is the presence or absence of sensory abnormalities on clinical examination and electrodiagnostic testing. Electrodiagnostic testing is usually needed to distinguish the axonal forms of GuillainBarré syndrome from AIDP. The Fisher syndrome is characterized by the acute onset of ataxia, ophthalmoparesis, and areflexia. Some cases progress to involve limb weakness. The critical diagnostic procedures include electrodiagnostic testing and examination of cerebrospinal fluid. In AIDP, electrodiagnostic testing may reveal obvious signs of an acquired demyelinating polyneuropathy. However, in early AIDP electrodiagnostic testing is often nonspecifically and nondiagnostically abnormal, usually suggesting a process involving the more proximal aspects of nerve or nerve root, or simply an acute non-length dependent neurogenic process. Time may be needed to allow a clear differentiation between the demyelinating and axonal forms of Guillain-Barré syndrome. Conversely, in extremely severe cases with electrically inexcitable nerves, it may be impossible to determine whether the neuropathy is demyelinating or axonal. The classic cerebrospinal fluid finding in Guillain-Barré syndrome is albuminocytological dissociation—that is, increased protein concentration without pleocytosis. However, increased protein is not demonstrated in all cases of Guillain-Barré syndrome, especially early in the illness. When pleocytosis is present and the electrophysiology is demyelinating, HIV and Lyme disease should be considered. When pleocytosis is present and the electrophysiology is axonal and purely motor, a poliomyelitis syndrome should be considered. Although in the past the polio virus was the main cause of poliomyelitis, other viruses can also cause this phenotype, including the emerging pathogen West Nile virus.44 Supportive care is the most important aspect in the management of Guillain-Barré syndrome. Respiratory mechanics must be monitored serially, and intubation established if the vital capacity falls below 15 mL/kg, or if vital capacity declines rapidly. Swallowing dysfunction should be expected, and tube feedings started if there is any suspicion of dysphagia. Prophylaxis against deep venous thrombosis is mandatory. Dysautonomia may be present, requiring monitoring of cardiac telemetry and frequent blood pressure measurements. The syndrome of inappropriate secretion of antidiuretic hormone is frequent. Immunomodulation via plasmapheresis and intravenous immunoglobulin have both been shown to hasten recovery in AIDP. Neither modality is clearly superior to the other, and the decision for treatment is often based on availability and the likelihood of adverse events. Both modalities are generally safe, albeit expensive. The primary risks of plasmapheresis are related to the placement and maintenance of the large-bore pheresis catheter, and include pneumothorax, sepsis, and bacterial endocarditis. Risks of intravenous immunoglobulin

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include arterial thrombotic events, renal failure, and aseptic meningitis. The working hypothesis on the pathogenesis of the GuillainBarré syndromes has been the concept of molecular mimicry. Several weeks after a systemic infection, epitopes of peripheral nerve shared with the infective agent are attacked, leading to the clinical syndrome. Most attention has been focused on Campylobacter jejuni, Mycoplasma pneumonia, and the herpesviruses, including cytomegalovirus, as the most common infective triggers. Because the Guillain-Barré syndrome occurs in the postinfective state, there is usually no clinical need to determine the antecedent infective agent or to use antibiotic or antiviral therapies. Evidence suggests that the genetic polymorphism of the infective agent determines the clinical phenotype of the Guillain-Barré syndrome. For example, the genetic polymorphism of Campylobacter jejuni correlates with the clinical variant of Guillain-Barré syndrome.45

K E Y

P O I N T S

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Infection of peripheral nerves by the bacillus (mycobacterium leprae) is a hallmark of leprosy.

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This is a sensorimotor neuropathy, whose severity is modulated by two main factors: temperature and natural host immunity.

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In “paucibacillar” leprosy, skin and intracutaneous nerves are affected (tubercoloid form).

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The characteristic rash, “erythema migrans,” is pathognomonic of Lyme disease.

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The classic triad of neurological Lyme disease includes cranial neuropathy, painful radiculopathy, and lymphocytic meningitis.

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Diagnosis requires ELISA testing followed by Western blot analysis.

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When appropriately treated, Lyme disease has an excellent prognosis.

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HSV-1 is latent in cranial nerve ganglia of most adults.

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When reactivated, HSV-1 can cause Bell’s palsy.

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HSV-2 resides in lumbosacral ganglia: its reactivation causes genital herpes and sometimes recurrent polyneuropathy.

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VZV, the causative agent of chicken pox, is latent in ganglia throughout the central nervous system and, when reactivated, causes herpes zoster (shingles)

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Triggers of VZV reactivation include immunodeficiency, immunosuppression, and aging.

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Herpes zoster may affect any dermatome or cranial nerve except the olfactory nerve.

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Postherpetic neuralgia (pain in the dermatomal distribution of prior herpesvirus infection after disappearance of the rash) is common in the elderly population.

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Hepatitis C infection is a common cause of cryoglobulinemia.

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The association of hepatitis C infection and cryoglobulinemia facilitates the appearance of neuropathy.

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Most commonly, hepatitis C causes a distal symmetrical sensory polyneuropathy.

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Diphtheritic polyneuropathy typically starts with bulbar symptoms followed by motor and sensory limb symptoms leading to flaccid paralysis.

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In “multibacillar” leprosy, major nerves are affected (lepromatous type).

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Early diagnosis is crucial because effective therapy is available.

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The type of the neuropathy is determined by the severity of the HIV infection (CD4+ count).

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Guillain-Barré syndrome and its variants appear to be postinfectious autoimmune processes.

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HIV neuropathy may mimic Guillain-Barré syndrome, CIDP, and mononeuritis multiplex.

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About 30% of patients with AIDS develop distal symmetrical polyneuropathy (DSP).

Subtypes of Guillain-Barré syndrome include acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor-sensory axonal neuropathy, and acute ataxia and ophthalmoparesis (Fisher syndrome).

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Antiretroviral drugs are confounding factors because they can by themselves cause toxic neuropathy.

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The classic cerebrospinal fluid finding in Guillain-Barré syndrome is albuminocytological dissociation (increased protein concentration without pleocytosis).

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Lumbosacral polyradiculopathy due to CMV may be seen in immunosuppressed patients and has a characteristic cerebrospinal fluid pattern (polymorphonuclear pleocytosis, increased protein, low glucose).

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Supportive care is the most important aspect in the management of Guillain-Barré syndrome, followed by immunomodulation.

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Definitive diagnosis of CMV infection requires demonstration of the virus by polymerase chain reaction.

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Electrodiagnostic studies in CMV polyradiculopathy reveal a polyradicular pattern, where motor responses are absent or reduced in amplitude, while sensory responses are normal.

chapter 84 infective neuropathies Suggested Reading Brew BJ: The peripheral nerve complications of human immunodeficiency virus (HIV) Infection. Muscle Nerve 2003; 28:542-552. Halperin JJ: Lyme disease and the peripheral nervous system. Muscle Nerve 2003; 28:133-143. Koga M, Takahashi M, Masuda M, et al: Campylobacter gene polymorphism as a determinant of clinical features of GuillainBarré syndrome. Neurology 2005; 65:1376-1381. Nemni R, Sanvito L, Quattrini A, et al: Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry 2003; 74:1267-1271. Sabin TD, Swift TR, Jacobson RR: Leprosy. In Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders, 2005, pp 2081-2108.

References 1. Monot M, Honore N, Garnier T, et al: On the origin of leprosy. Science 2005; 308:936-937. 2. World Health Organization: Global leprosy situation. 2005. Wkly Epidemiol R 2005; 80:289-295. 3. Lockwood DN, Suneetha S: Leprosy: too complex a disease for a simple elimination paradigm. Bull World Health Organ 2005; 83:230-235. 4. Rambukkana A, Zanazzi G, Tapinos, et al: Contact-dependent demyelination of Mycobacterium leprae in the absence of immune cells. Science 2002; 296:927-931. 5. Vissa VD, Brennan PJ: The genome of Mycobacterium leprae: a minimal mycobacterial gene set. Genome Biol 2001; 2:1023.1-1023.8. 6. Sabin TD: Neurologic features of lepromatous leprosy. Am Fam Phys 1971; 4:84-94. 7. Monrad-Krohn GH. The Neurological Aspect of Leprosy. Cristiana, Norway: Jacob Dybwad. 1923. 8. Jadhav RS, Kamble RR, Shinde VS, et al: Use of reverse transcription polymerase chain reaction for the detection of Mycobacterium leprae in the slit-skin smears of leprosy patients. Indian J Lepr 2005; 77:116-127. 9. World Health Organization: A Guide to Leprosy Control, 2nd ed. Geneva: World Health Organization. 1988. 10. Brew BJ: The peripheral nerve complications of human immunodeficiency virus (HIV) Infection. Muscle Nerve 2003; 28:542-552. 11. Alliegro MB, Petrucci A, Arpino C, et al: Peripheral neuropathies among patients with HIV infection. J Neurol Neurosurg Psychiatry 1998; 64:414-415. 12. Wechsler AF, Ho DD: Bilateral Bell’s palsy at the time of HIV seroconversion. Neurology 1989; 39:747-748. 13. Cornblath DR, McArthur JC, Kennedy PG, et al: Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol 1987; 21:32-40. 14. Höke A, Cornblath DR: Peripheral neuropathies in human immunodeficiency virus infection. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Philadelphia: Elsevier Saunders; 2005, pp 2129-2145. 15. Roullet E, Assueurus V, Gozlan J, et al: Cytomegalovirus multifocal neuropathy in AIDS: analysis of 15 consecutive cases. Neurology 1994; 44:2174-2182. 16. Moulignier A, Autheir FJ, Baudrimont M, et al: Peripheral neuropathy in human immunodeficiency virus–infected patients with the diffuse infiltrative lymphocytosis syndrome. Ann Neurol 1997; 41:438-445. 17. Olney RK: HIV-Associated neuropathies. In: Cros D, ed: Peripheral Neuropathy. Philadelphia: Lippincott Williams & Wilkins, 2001, pp 197-212.

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18. Moulignier A, Maoulonguet A, Pialoux G, et al: Reversible ALSlike disorder in HIV infection. Neurology 2001; 57:995-1001. 19. MacGowen DLJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2001; 57:1094-1097. 20. Tagliati M, Grinnel J, Godbold J, et al: Peripheral nerve function in HIV infection. Arch Neurol 1999; 56:84-89. 21. Griffin JW, Crawford TO, Tyor WR, et al: Predominately sensory neuropathy in AIDS: distal axonal degeneration and unmyelinated fiber loss. Neurology 1991; 41(Suppl 1):374. 22. Markus R, Brew BJ: HIV-1 peripheral neuropathy and combination antiretroviral therapy. Lancet 1998; 352:1906-1907. 23. Martin C, Solders G, Sonnerborg A, et al: Antiretroviral therapy may improve sensory function in HIV-infected patients: a pilot study. Neurology 2000; 54:2120-2127. 24. Simpson DM, Tagliati M: Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 9:153-161. 25. Brew BJ, Tisch S, Law M: Lactate concentrations distinguish between nucleoside neuropathy and HIV neuropathy. AIDS 2003; 17:1094-1096. 26. Anders HJ, Goebel FD: Cytomegalovirus polyradiculopathy in patients with AIDS. Clin Infect Dis 1998; 27:345-352. 27. So YT, Olney RK: Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome: experience in 23 patients. Ann Neurol 1994; 5:53-58. 28. Miller RF, Fox JD, Thomas P, et al: Acute lumbosacral polyradiculopathy due to cytomegalovirus in advanced HIV disease: cerebrospinal fluid findings in 17 patients. J Neurol Neurosurg Psychiatry 1996; 61:456-460. 29. Brew BJ: Infective causes of peripheral neuropathy in advanced HIV disease. In: Brew BJ, ed: HIV Neurology. New York: Oxford University Press, 2001, p 206. 30. Talpos D, Tien RD, Hesselink JR: Magnetic resonance imaging of AIDS-related polyradiculopathy. Neurology 1991; 41:19951997. 31. Anders HJ, Weiss N, Bogner JR, et al: Ganciclovir and foscarnet efficacy in AIDS-related polyradiculopathy. J Infect 1998; 36:29-33. 32. Steere AC: Lyme disease. N Engl J Med 2001; 345:115-125. 33. Krishnamurthy KB, Liu GT, Logigian EL: Acute Lyme neuropathy presenting with polyradicular pain, abdominal protrusion, and cranial neuropathy. Muscle Nerve 1993; 16:1261-1264. 34. CDC: Notice to readers: Caution regarding testing for Lyme disease. MMWR 2005; 54:125. 35. Dressler F, Whalen JA, Reinhardt BN, et al: Western blotting in the serodiagnosis of Lyme disease. J Infect Dis 1993; 167:392-400. 36. Wormser GP, Nadelman RB, Dattwyler RJ, et al: Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 2000; 31(Suppl 1):1-14. 37. Gilden DH, Wright RR, Schneck SA, et al: Zoster sine herpete, a clinical variant. Ann Neurol 1994; 35:530-533. 38. Nemni R, Sanvito L, Quattrini A, et al: Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry 2003; 74:1267-1271. 39. Ammandola A, Sampaolo S, Ambrosone L, et al: Peripheral neuropathy in hepatitis-related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle Nerve 2005; 31:382-385. 40. Leite AC, Silva MT, Alamy AH, et al: Peripheral neuropathy in HTLV-I infected individuals without tropical spastic paraparesis/HTLV-I-associated myelopathy. J Neurol 2004; 251: 877-881. 41. Logina I, Donaghy: Diphtheritic polyneuropathy: a clinical study and comparison with Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 1999; 67:433-438.

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42. Idiaquez J: Autonomic dysfunction in diphtheritic neuropathy. J Neurol Neurosurg Psychiatry 1992; 55:159-161. 43. Thisyakorn U, Wongvanich J, Kumpeg V: Failure of corticosteroid therapy to prevent diphtheritic myocarditis or neuritis. Pediatr Infect Dis 1984; 3:126-128.

44. Jeha LE, Sila CA, Lederman RJ, et al: West Nile virus infection: a new acute paralytic illness. Neurology 2003; 61:55-59. 45. Koga M, Takahashi M, Masuda M, et al: Campylobacter gene polymorphism as a determinant of clinical features of GuillainBarré syndrome. Neurology 2005; 65:1376-1381.

CHAPTER

85

MUSCULAR DYSTROPHIES ●

●

●

●

Maggie C. Walter and Hanns Lochmüller

Muscular dystrophies constitute a clinically and genetically heterogeneous group of skeletal muscle–wasting diseases.1 The molecular causes of the muscular dystrophies remained elusive for many decades, and the muscular dystrophies were classified into relatively few clinical entities. In the late 1980s, major advances in molecular genetics led to the discovery of the dystrophin gene and its protein product, dystrophin.2,3 Mutations in the dystrophin gene result in dystrophin deficiency, which is the pathogenic determinant of the dystrophinopathies.4,5 Several muscular dystrophies are caused by mutations in other genes that cause defects of proteins localized at the sarcolemma, the cytoplasm or the nuclear envelope. Since the mid-1990s, an increasing number of genes have been associated with different forms of muscular dystrophy (Table 85–1, Fig. 85–1). These findings have led to a profound change in the classification of muscular dystrophies, with a new emphasis on molecular genetics rather than on clinical symptoms (which differentiated diseases on the basis of age at onset, severity, mode of inheritance, and muscle groups primarily affected). The most common form is the X-linked recessive Duchenne muscular dystrophy (DMD), named after Guillaume Benjamin Amand Duchenne, who described it in 1861.6,7 Positional cloning of the gene altered in DMD8 led to the discovery of dystrophin2 and to improved molecular diagnosis of DMD and of its milder allelic variant, Becker muscular dystrophy (BMD).9 About 50 years after Duchenne, Batten10 published the first cases of congenital muscular dystrophy (MDC). Unlike patients with the DMD/BMD phenotype, patients with MDC present with weakness and dystrophic changes in the muscle biopsy at birth, but symptoms are less rapidly progressive than in DMD. The term limb girdle muscular dystrophy (LGMD) was introduced in the middle of the 20th century, when it became obvious that there was an additional major group of noncongenital muscular dystrophies that differed from both the X-linked DMD and BMD and from the autosomal-dominant facioscapulohumeral forms.11 Nowadays, the term limb girdle muscular dystrophy has changed from a wastebasket designation to an ever-expanding list of subtypes (18 thus far), for which accurate molecular diagnoses are available. Age at onset usually ranges from early childhood to late adulthood12;

1142

however, the same gene defect can cause allelic forms of MDCs and LGMDs, as shown for the fukutin-related protein deficiencies.13-15 The finding that mutations in nuclear envelope proteins also cause muscular dystrophies—referred to as nuclear envelopathies or Emery-Dreifuss muscular dystrophies—came as a surprise when emerin, the protein shown to be mutated in X-linked Emery Dreifuss muscular dystrophy (EDMD1, XEDMD)16 was also found to be an inner nuclear membrane protein (Fig. 85–2). The importance of the nuclear envelope in neuromuscular disease was bolstered by the discoveries that mutations in the LMNA gene can cause autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2),17 dilated cardiomyopathy with conduction defect (CMD1A),18 limb-girdle muscular dystrophy type 1B (LGMD1B),19 Charcot-Marie-Tooth disorder type 2B1 (CMT2B1),20 and a variety of other, nonneuromuscular diseases, such as Dunnigan’s familial partial lipodystrophy and mandibuloacral dysplasia, or premature aging syndromes, such as Hutchinson-Gilford progeria and atypical Werner’s syndrome.21,22 A new phenotype combining myopathy and progeria has been described.23 Facioscapulohumeral muscular dystrophy (FSHD), first described in 1885,24 is a frequent form of muscular dystrophy that has a distinctive clinical manifestation with autosomal dominant inheritance.11 The gene underlying FSHD was mapped to chromosome 4q35 in 199225 and was shown to be closely linked to locus D4F104S1. Although D4F104S1associated deletions are closely associated with FSHD, the identity and location of the FSHD gene (or genes) still remain elusive, as does the mechanistic basis of the disease. Oculopharyngeal muscular dystrophy (OPMD) is unusual among muscular dystrophies because of its manifestation in late adult life, typically in the sixth decade. Symptoms include progressive ptosis and dysphagia, followed by involvement of other cranial and limb muscles. OPMD is usually inherited as an autosomal dominant trait as a result of an expanded guanine-cytosine-guanine (GCG) repeat detectable in the poly A binding protein 2 gene on chromosome 14.26,27 Distal myopathies are frequent in the Nordic countries and are being increasingly recognized elsewhere. To date, six different distal myopathy phenotypes have been identified, and there has been considerable progress in the understanding

chapter 85 muscular dystrophies

1143

T A B L E 85–1. Different Forms of Muscular Dystrophies Muscular Dystrophies Duchenne (DMD) Becker (BMD) Emery-Dreifuss (EDMD1) Emery-Dreifuss (EDMD2) Emery-Dreifuss (EDMD3) Facioscapulohumeral (FSHD)

OMIM Classification No.

Epidemiology

Mode of Inheritance

Gene Locus

Symbol (Gene Product)

Reference

310200 300376 310300

1/3500 (male) 1/30,000 (male) Not available

XR XR XR

Xp21.2 Xp21.1 Xq28

DMD (dystrophin) DMD (dystrophin) EDM (emerin)

2, 6, 7 9, 102-104 16

181350

Not available

AD

1q21.2

LMNA (lamin A/C)

17

604929

Not available

AR

1q21.2

LMNA (lamin A/C)

54

158900

1/100,000 to 5/100,000

AD

4q35

FSHD

25, 57

1/100,000 Europeans, 1/1000 Oculopharyngeal (OPMD)

164300

Limb girdle (LGMD) LGMD 1A

159000

LGMD 1B

159001

LGMD 1C

607801

LGMD 1D LGMD 1E

603511 602067

LGMD 1F

608423

LGMD 1G LGMD 2A

609115 253600

LGMD 2B

253601

LGMD 2C LGMD 2D

253700 608099

LGMD 2E

604286

LGMD 2F

601287

LGMD 2G

601954

LGMD 2H

254110

LGMD 2I

607155

LGMD 2J

608807

LGMD 2K Epidermolysis bullosa with muscular dystrophy (MDEBS)

French Canadians, 1/600 Jews of Bukhara, Uzbekistan LGMD 1/2: 0.8/100,000 LGMD 2: 0.57/100,000 LGMD 1: 10%-25% of all LGMD LGMD 2: 75%-90% 1 American, 1 Argentinean pedigree Not available Some families, single patients 2 families 1 large French-Canadian family 1 large Spanish family

26, 27, 66, 67, 69, 70 AD

14q11.2-q13

PABP2 (polyA binding protein 2) 46, 47, 105, 106

AD

5q31

TTID (myotilin)

107-109

AD

1q21.2

LMNA (lamin A/C)

AD

3p25

CAV3 (caveolin-3)

19, 110, 111 112-114

AD AD

7q 6q23

Unknown Unknown

115 116

AD

117, 118

AD AR AR

2p13.3-p13.1

DYSF (dysferlin)

29, 124-129

AR AR

13q12 17q12-q21.33

SGCG (γ-sarcoglycan) SGCA (α-sarcoglycan)

130 131

AR

4q12

SGCB (β-sarcoglycan)

132

AR

5q33

SGCD (δ-sarcoglycan)

133

AR

17q12

TCAP (telethonin)

134, 135

AR

9q31-q34.1

136, 137

AR

19q13.3

TRIM32 (E3-ubiquitin ligase) FKRP1 (fukutin-related protein 1)

AR

2q24.3

TTN (titin)

609308

1 Brazilian family 10%-30% in unrelated patients, 6.9/100,000 in the Basque population 10% in unrelated patients, 22% in Brazilian, 35%-45% in Cajun/ Arcadian 0.56/100,000, 10% of LGMD in unrelated patients 2D most frequent, followed by 2E and 2C; 2F is rare worldwide 2C most frequent in Tunisia, North Africa and in Gypsies; 2D in Europe, United States, and Brazil; 2E in Brazil Only in the Brazilian population Only in the Manitoba Hutterite population In 10% of LGMD2 patients, caused by 826C>A point mutation Mainly in the Finnish population Turkish families

7q31.33Unknown 7q32.3 4p21 Unknown 15q15.1-q21.1 CAPN (calpain 3)

AR

9q34.1, 9q31

226670

Not available

AR

8q24

POMT1 (O-mannosyltransferase-1) MD-EBS (plectin)

30, 31, 148, 149 50, 150

119 120-123

13-15, 138-147

151, 152

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Section

XV

Neuromuscular Diseases: Muscle

T A B L E 85–1. Different Forms of Muscular Dystrophies—cont’d Muscular Dystrophies

OMIM Classification No.

Congenital (MDC) Fukuyama MDC (FCMD) Muscle-eye-brain disease (MEB) Walker-Warburg syndrome (WWS) MDC 1A

Epidemiology

Mode of Inheritance

Gene Locus

253280

Worldwide incidence not known; in Italy, 4.7/100,000 Common in Japan, 40% of DMD, rare elsewhere Worldwide

236670

Worldwide

AR

9q34.1, 9q31

607855

AR

6q22-q23

AR AR

1q42 19q13.3

253800

Symbol (Gene Product)

Reference 4, 51-53, 153

AR

9q31

FCMD (fukutin)

154, 155

AR

1p34-p33

POMGnT (O-mannose β1,2-Nacetylglucosaminyltransferase) POMT1 (Omannosyltransferase-1) LAMA2 (laminin α2 chain)

156, 157

162, 163 13, 14, 164

166-168

158, 159

MDC 1B MDC 1C

604801 606612

Largest group within MDC, 50% of European patients Arab and German families Worldwide

MDC 1D

608840

1 patient

AR

22q12.3-13.1

602771

Moroccan, Turkish, Iranian, Scandinavian families 3 unrelated Japanese patients Not available

AR

1p35-p36

Unknown FKRP1 (fukutin-related protein 1) LARGE (glycosyltransferaselike protein) SEPN1 (selenoprotein N)

AR

12q13

ITGA7 (integrin α7)

169

AR

21q22.3, 21q22.3, 2q37

UCMD (α1, α2, α3 chains of collagen 6)

170-179

MDC with rigid spine (RSMD1) MDC with integrin deficiency Ullrich’s scleroatonic (UCMD)/ Bethlem’s myopathy Distal myopathies (MPD) MPD1 (GowersLaing) MPD2 (VCPDM) MPD3 (single Finnish family) Tibial (TMD) (Udd/ MarkesberyGriggs) Welander (WDM) Distal dystrophy with rimmed vacuoles (MDRV) MM (Miyoshi)/ distal anterior compartment myopathy (DMAT) NM (Nonaka)

Hereditary inclusion body myopathies (HIBM) HIBM1

600536 254090/ 158810

160, 161

165

28 160500

Australian, German, Italian, Austrian families 1 large American family 1 Finnish family

AD

14q12

MYH7 (myosin heavy chain 7)

180-182

AD AD

5q Unknown

Unknown Unknown

183, 184 185

Finnish population (5/100,000), some English and French families Swedish and Finnish families 2 Italian families

AD

2q24.3

TTN (titin)

149, 186, 187

AD

2p13

Unknown

188-190

AD

19p-13.3

Unknown

191-193

254130

33% of DMT, common in Japanese and in Libyan Jews

AR

2p13.3p13.1

DYSF (dysferlin)

126, 194

605820

Common in Japanese population, Jews of Persian ancestry (1 : 500), other families worldwide

AR

9p12-p11

GNE (UDP-Nacetylglucosamine 2epimerase/Nacetylmannosamine kinase)

38, 195

606070 Missing 600334

604454 601846

196 147420

HIBM2

600737

HIBM3 HIBMERF (with early respiratory failure) IBMPFD (with Paget’s disease and dementia)

605637 607569

1 Japanese family, 4 caucasian families Jews of Persian ancestry (1 : 500), Japanese, other families worldwide 1 Swedish family 1 caucasian family

605382

>10 U.S. families

AD

Unknown

Unknown

34

AR

9p12-p11

197-201

AD AD

17p-13.1 6q27

GNE (UDP-Nacetylglucosamine 2epimerase/Nacetylmannosamine kinase) MYH2 (myosin heavy chain IIa) Unknown

36, 37 202

AD

9p13-p12, 9p13.3-p12

VCP (valosin-containing protein)

203

AD, autosomal dominant; AR, autosomal recessive; UDP, uridine diphosphate; XR, X-linked recessive.

chapter 85 muscular dystrophies

1145

Ullrich syndrome Bethlem myopathy Laminin-2

MDC1A

Biglycan

Dystroglycan complex

LGMD1C

␣

Caveolin-3

␤ CR

LGMD2C-F

␣

␤1 ␣ 7

COOH

␣ -DTN Calpain-3

LGMD2B Miyoshi myopathy

␥

UR

Syn

Dysferlin

Syn

Intracellular

␦

Integrin complex

Sarcoglycan complex

␤

Extracellular

NH2

ITGA7

Collagen VI

COOH

Filamin C

LGMD2A

COOH

NH2 POMGnT1

Dystrophin

NH

Actin

TRIM32

ex

DMD SEPN1

MEB

pl

LGMD2H

POMT1

gi

BMD

ol

om

c

G

Fukutin Fukuyama CMD

FKRP MDC1C Rigid spine syndrome Walker-Warburg syndrome ■

Figure 85–1. Muscular dystrophies and the membrane and enzymatic proteins they are associated with. This schematic shows the locations of various membrane and enzymatic proteins associated with muscular dystrophies. The diseases these molecules cause when mutated are shown in boxes. Dystrophin, through its interaction with the dystroglycan complex, connects the actin cytoskeleton to the extracellular matrix. Intracellularly, it interacts with dystrobrevin (α-DTN) and syntrophins (Syn) (shown in blue). Extracellularly, the sarcoglycan complex (orange) interacts with biglycan, which connects this complex to the dystroglycan complex and the extracellular matrix collagen. Intracellularly, δ- and γ-sarcoglycans interact with filamin C. The majority of filamin C is at the Z-disc of the sarcolemma shown in Figure 85–2. The four proteins shown in the Golgi complex have been demonstrated to affect the glycosylation state of the αdystroglycan and mediate its binding to the extracellular matrix. Fukutin and fukutin-related protein have been shown to localize to the medial Golgi complex. The localization of POMT1 and POMGnT1 is unknown so far, but the authors hypothesize that they are in the Golgi complex, because they are involved in the glycosylation process. BMD, Becker muscular dystrophy; CMD and MDC, congenital muscular dystrophy; DMD, Duchenne muscular dystrophy; LGMD, limb girdle muscular dystrophy; MEB, muscle-eye-brain disease. (Reprinted from Dalkilic I, Kunkel LM: Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev 2003; 13:231-238.)

of the molecular pathophysiology underlying the distal myopathies.28 Mutations in membrane-associated dysferlin cause two different distal phenotypes, allelic to LGMD2B,29 whereas mutations in titin can cause either a distal myopathy (type Udd/Markesbery-Griggs) or LGMD2J,30,31 another example of the diversity between clinical and genetic disease definitions. Hereditary inclusion body myopathies (HIBM) belong to the heterogeneous group of myopathies with rimmed vacuoles. So far, autosomal recessive (HIBM2)32 and autosomal dominant forms33-37 have been linked to different gene loci. Interestingly, distal myopathy with rimmed vacuoles (Nonaka myopathy) has been attributed to mutations in the GNE gene and is therefore allelic to HIBM2.38

DYSTROPHINOPATHIES Definition DMD and BMD are caused by mutations in the dystrophin gene, which is located on the short arm of the X chromosome. The disease is inherited as an X-linked recessive trait and predominantly affects boys.

Clinical Features In DMD, children usually come to medical attention between ages 3 and 5 years because of frequent falls, awkward running,

1146

Section

XV

Neuromuscular Diseases: Muscle Laminin-2

Dystroglycan complex Extracellular

Collagen VI

Integrin complex

Sarcoglycan complex

Caveolin-3

Intracellular Dysferlin

Calpain-3

LGMD1B

Filamin C

EDMD EDMD

Dystrophin

Emerin LGMD1A

Lamin-A/C

LGMD2G Nucleus

Telethonin UR

Sarcomere Titin

Calpain-3

Calpain-3 Myosin

NH2

Filamin C

Actin

LGMD2A ■

COOH

Myotilin

Tibial MD

Z-disc

Figure 85–2. Sarcomeric and nuclear proteins involved in the muscular dystrophies. The schematic for the sarcomere and the nucleus shows the localization of the proteins involved in muscular dystrophies. The diseases they give rise to are shown in boxes. EDMD, EmeryDreifuss muscular dystrophy; LGMD, limb girdle muscular dystrophy; MD, muscular dystrophy. (Reprinted from Dalkilic I, Kunkel LM: Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev 2003; 13:231-238.)

and waddling gait. At this stage, weakness is most pronounced in the hips and proximal leg muscles but over time will affect neck flexors, proximal arm muscles (especially biceps), ankle dorsiflexors, and respiratory muscles, necessitating ventilation at some point during the course of the disease. Calf hypertrophy is a distinctive feature, whereas facial and bulbar muscles are largely spared. Creatine kinase levels are massively elevated, 50 to 100 times normal. The disease progresses relentlessly, and ambulation is lost between 7 and 12 years of age. Prednisone, the primary pharmacological therapy for DMD, may modestly prolong ambulation. BMD is an allelic variant of DMD and has a more benign and variable manifestation with later onset and slower progression. Onset of symptoms after age 6 or walking after age 13 are typical features. In rare cases, BMD is not diagnosed until adulthood and the patients never lose ambulation (Fig. 85–3). Female carriers of DMD or BMD are usually asymptomatic but may also have limb weakness, elevated creatine kinase levels, and nonmuscular symptoms such as cardiac involvement. The extent of clinical severity depends in part on the degree of skewed X chromosome inactivation in somatic cells.39 Skeletal muscle weakness in DMD and BMD is frequently accompanied by cardiac muscle dysfunction. Approximately 95% of patients have cardiac involvement by the time of death. This includes electrocardiographic abnormalities, arrhythmias,

and myocardial dilatation and thickening. Patients with DMD and BMD may have normal intelligence, but the mean Wechsler full IQ is below average: 25% of BMD and 31% of DMD patients have an IQ of less than 75. Scoliosis is frequently severe. Contractures develop in hips, ankles, and elbows. On occasion, involvement of smooth muscle leads to gastrointestinal complications, including pseudo-obstruction.40

Etiology and Pathophysiology Dystrophin is the largest human gene, covering 2.5 megabases and including 79 exons. The enormity of the gene, along with the spontaneous mutation rate of each base pair allows a high frequency of novel mutations, which explains how 30% of all DMD and BMD cases result from spontaneous mutations. The gene encodes a 427-kD subsarcolemmal protein. Dystrophin has several well-characterized domains, including an aminoterminal domain with homology to α-actinin, a large “rod” domain with spectrin-like repeats, a cysteine-rich domain, and a carboxy-terminal domain with homology to other dystrophinrelated proteins. Dystrophin interacts with and stabilizes a large membrane-associated protein complex, the dystroglycan complex, whose components are involved in other muscular dystrophies (see Fig. 85–1). It links the actin cytoskeleton

chapter 85 muscular dystrophies

A

B ■

Figure 85–3. Patient with Becker muscular dystrophy caused by an in-frame deletion of exons 45 to 47 in the dystrophin gene. Clinically, the patient shows mild proximal weakness and atrophy (A) and typical calf hypertrophy (B).

through its amino-terminal binding domain to the sarcolemma and extracellular matrix through interactions with its carboxyterminal binding domains. In addition to physically connecting and stabilizing this large protein network, dystrophin may play a role in signal transduction because of its association with nitric oxide synthase and highly phosphorylated postsynaptic proteins.

1147

Approximately two thirds of disease-causing mutations in dystrophin are large deletions; an additional 5% are duplications within hot spots of the dystrophin gene. These common mutations can be detected by commercially available multiplex polymerase chain reaction, which amplifies 18 to 25 of the gene’s 79 exons from genomic DNA obtained from blood samples. Additional deletions and duplications may be detected by amplifying and quantifying all exons. There is no simple relation between size of the deletion and resultant clinical phenotype. For example, deletion of small exons, such as exon 44, often results in classic DMD, whereas large deletions that may involve nearly 50% of the gene have been described in patients with BMD. The central and distal rod domains seem to be functionally almost dispensable, inasmuch as some deletions in this region are associated only with myalgia or muscle cramps, not with weakness. Some patients may even present solely with an isolated increase in creatine kinase level. This has been shown in patients with in-frame deletions in exons 32 to 44, 48 to 51, or 48 to 53, all of whom had normal or near-normal dystrophin levels at the sarcolemma. The effects on the phenotype depend, therefore, not so much on the size of a deletion (or duplication) but on whether it disrupts the reading frame. A further observation is that deletions very different in size and position may produce very similar severe phenotypes. The reason for this effect might be the occurrence of nonsense-mediated RNA decay. This phenomenon may account for the lack of rescue of dystrophin function, as well as for the phenotypic variability related to variations in the efficiency of RNA decay control. Mutations that maintain the reading frame (in-frame mutation) generally result in abnormal but partially functional dystrophin and are associated with BMD. In patients with DMD, deletions and duplications disrupt the reading frame (frame-shift mutations), resulting in unstable RNA and nearly undetectable truncated proteins. The reading frame hypothesis holds true for over 90% of cases and is commonly used both as a diagnostic confirmation of dystrophinopathies and for the differential diagnosis of DMD and BMD.41 If knowledge of a specific small mutation is desired, complementary DNA may be generated from muscle messenger RNA and sequenced. Single-strand conformation polymorphism analysis42 and single-condition amplification/internal primer sequencing43 of genomic DNA have also been proposed for identification of small mutations. Furthermore, Buzin and associates reported mutation rates in the dystrophin gene with a mutational hot spot at a cytosine-guanine island (CpG) dinucleotide.44 Approximately 30% are point mutations and 10% to 15% are nonsense mutations that produce premature stop codons. If genomic DNA testing does not reveal a deletion or duplication, a muscle biopsy is frequently performed to confirm the diagnosis. Histological features include marked variability of fiber size with aberrant large fibers and hypercontracted muscle fibers along with groups of atrophic, degenerating, and regenerating fibers. Endomysial fibrosis and fatty infiltration are invariably present along with some mononuclear inflammatory cell infiltration. Dystrophin immunostaining shows absence of the protein in DMD and patchy staining in BMD and may reveal a mosaic pattern of expression in female carriers. Dystrophin immunoblotting shows absence of the dystrophin band in DMD, shows weak expression and/or abnormal molecular weight in BMD, and usually yields normal results in female carriers (Fig. 85–4).

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Dys–1

Neuromuscular Diseases: Muscle ■

Spectrin

Figure 85–4. A, Immunhistochemistry panel of patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and dystrophinopathy carrier and of a healthy control. Immunostaining with dystrophin (Dys-1) shows negative staining with some revertant fibers in the patient with DMD, only weak staining in the patient with BMD, and selectively reduced staining in single fibers in a female dystrophinopathy carrier. B, Immunoblotting of patients with DMD and BMD and healthy controls (N). The patient with DMD has no typical band for dystrophin at 427 kD, whereas the patient with BMD has only a weak band along with a reduced molecular weight in comparison with normal controls.

DMD

BMD

Carrier

Control

A

B

N

N

DMD

N

N

LIMB GIRDLE MUSCULAR DYSTROPHIES Definition Because of molecular discoveries since the mid-1990s, LGMD has emerged as an entire field within the inherited myopathies; at least six autosomal dominant and ten autosomal recessive gene defects have been identified. Redefined in 1995, the LGMD are face-sparing, predominantly proximal, progressive muscular dystrophies with elevated creatine kinase levels, and dystrophic features are demonstrated on muscle biopsy (Fig. 85–5).12,45-47 In the current classification system, LGMDs are divided into autosomal dominant (LGMD1) and autosomal recessive (LGMD2) disorders with an additional lettering system that denotes the chronological order of chromosomal linkage (thus far, A through G for autosomal dominant LGMD and A through K for autosomal recessive LGMD). Accurate diagnosis is now possible for most LGMDs and is important for genetic counseling. Certain LGMDs are characterized by treatable cardiac and respiratory complications.45,48 The causes of the LGMD include mutations in a wide range of proteins and protein systems. Calpain, mutated in LGMD2A,

BMD

N

is a calcium-activated neutral protease, and this is the first known genetic defect in muscular dystrophy stemming from an enzyme defect. Other mutations impair membrane signaling and repair (caveolin, dysferlin), sarcolemmal integrity (sarcoglycans), and contractile dysfunction (myotilin, telethonin, titin). The subcellular localization of these proteins also varies from the nuclear membrane (lamin A/C) to the sarcomere (myotilin, calpain, telethonin, titin), the sarcoplasm (TRIM32, a putative E3-ubiquitin-ligase), the sarcolemma (caveolin, sarcoglycans, dysferlin), and even the extracellular space (fukutin-related protein). Of note, involvement of one nuclear membrane protein, emerin, causes X-linked Emery Dreifuss syndrome (X-EDMD, EDMD1), whereas mutations in the related protein, lamin A/C, cause EDMD2. It remains unclear how mutations in apparently unrelated proteins can cause similar phenotypes, and it is difficult at present to see a common final pathway of action. Likewise, identical genotypes often yield substantially different phenotypes even within the same family. Dysferlinopathies can cause LGMD2B or distal myopathies, and caveolinopathies have been associated with LGMD1C, rippling muscle disease, persistent elevated creatine kinase levels (hyperCKemia), or distal myopathy. Fukutinrelated protein gene (FKRP) mutations manifest high clinical

chapter 85 muscular dystrophies

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Figure 85–5. Different patients with limb girdle muscular dystrophy (LGMD) with similar phenotypes but different genotypes. A, A patient with calpainopathy (LGMD2A). B, A patient with dysferlinopathy (LGDM2B). C, A patient with α-sarcoglycanopathy (LGMD2D). D, A patient with laminopathy (LGMD1B). E, A patient with fukutin-related proteinopathy (LGMD2I).

variability, with onset at birth or later in adulthood (LGMD2I) (Fig. 85–6). Titinopathies exhibit phenotypic variability depending on the amount of genes involved: A single mutated allele causes a late adult-onset distal myopathy (Finnish tibial muscular dystrophy), whereas two abnormal alleles cause LGMD2J. This remarkable phenotypic variability remains enigmatic, but explanations may be forthcoming through investigations of modifier genes, DNA microarrays, and proteomic studies.49 LGMD2K has been described as an allelic form of WalkerWarburg syndrome in Turkish patients.50 Further phenotypic differentiation of the LGMDs is provided in Table 85–2 and Figure 85–7.

Autosomal Dominant Limb Girdle Muscular Dystrophy Autosomal dominant LGMDs tend to have an altogether slower course and later onset with less elevation of serum creatine kinase level in comparison with autosomal recessive LGMDs. They are also clinically much more heterogeneous (see Table 85–2 and Fig. 85–7). Except for LGMD1C (caveolinopathy), immunohistochemistry and immunoblotting are of little help in differentiating dominant LGMD subtypes.

Autosomal Recessive Limb Girdle Muscular Dystrophy The autosomal recessive forms of LGMD for which the genetic bases are known can be further subdivided on the basis of the genes and proteins involved (see Table 85–1). The first autosomal recessive form, LGMD2A, was mapped to chromosome 15q

in 1991 in patients from the Reunion Island. Ten additional forms have been mapped since the mid-1990s, most recently LGMD2K. The protein products of these 11 genes have been identified (see Fig. 85–1): calpain-3 for LGMD2A, dysferlin for LGMD2B, γ-sarcoglycan for LGMD2C, α-sarcoglycan for LGMD2D, β-sarcoglycan for LGMD2E, δ-sarcoglycan for LGMD2F, the sarcomeric protein telethonin for LGMD2G, TRIM32 for LGMD2H, fukutin-related protein for LGMD2I, titin for LGMD2J, and POMT1 for LGMD2K. Genotype-phenotype correlation studies have been reported for the different forms of LGMD in an attempt to enhance comprehension of the underlying pathological mechanisms, to better characterize each of the subgroups and, of more importance, to identify modifier genes or epigenetic factors that might modulate the clinical course in patients who carry the same pathological mutation. Immunohistochemistry and immunoblotting are pivotal for LGMD2 subtype differentiation and for directing the molecular genetic analysis (see Table 85–2 and Fig. 85–7).

CONGENITAL MUSCULAR DYSTROPHIES Definition The MDCs are a group of genetic disorders in which weakness and abnormal muscle histological features are present at birth. Muscle weakness tends to be more stable, but complications can become more prominent over time. A firm diagnosis of MDC requires a muscle biopsy. Pathological findings include variation in fiber size, internal nuclei, and increased endomysial and fatty tissue. Signs of ongoing degeneration and Text continued on p. 1155.

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Tyr307Asn Tyr307Asn ■

Leu276lle Tyr307Asn

Leu276lle Lue276lle

Figure 85–6. Different patients with fukutin-related proteinopathy, ranging phenotypically— according to the type of disease-causing mutation—between severe childhood forms (fukutin-related protein Tyr307Asn homozygous) (left), Duchenne-like manifestations (fukutin-related protein Tyr307Asn/Leu276Ile compound heterozygous) (middle) and mild adult forms (fukutin-related protein Leu276Ile homozygous) (right).

LGMD

Thigh weakness?

Quadriceps

Hamstrings

Scapular winging?

yes

Sarcoglycanopathy

no

Dystrophinopathy (Becker, female carrier)

Calf hypertrophy

Calf atrophy

Muscular hyperirritability? (PIRCs, ripping, mounding)

Scapular winging?

yes

Caveolinopathy ■

no

yes

FKRP

Calpainopathy

no

Dysferlinopathy

Figure 85–7. Flowchart for the diagnosis of the major forms of limb girdle muscular dystrophy (LGMD). FKRP, fukutin-related protein; PIRC, percussion-induced rapid muscle contractions.

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T A B L E 85–2. Phenotypic Differentiation of the Muscular Dystrophies Creatine Kinase Level

Muscular Dystrophies

Age at Onset

Duchenne (DMD)

3-5 years

50- to 100-fold elevated

Becker (BMD)

>6 years

50- to 100-fold elevated

Emery-Dreifuss (EDMD1)

Neonatal hypotonia to third decade; mean onset in the teens

Mildly elevated to 10-fold elevated

Emery-Dreifuss (EDMD2)

First or second decade

Normal to mildly elevated

Emery-Dreifuss (EDMD3)

First or second decade

Normal to mildly elevated

Facioscapulohumeral (FSHD)

First to fifth decades

Normal to fivefold elevated

Oculopharyngeal (OPMD)

Heterozygotes: fourth to sixth decades Homozygotes: second to fourth decades

Normal to mildly elevated

Mean, 27 years; sporadic cases, 50-77 years

Twofold elevated

Mild LGMD phenotype with proximal onset, slow progression with late loss of ambulation

50% of patients have dysarthria, nasal speech and cardiomyopathy

<20 years

Mild

Weakness mild and slowly progressive

Possible cardiac involvement with conduction block

Limb girdle (LGMD) LGMD 1A

LGMD 1B

LGMD 1C

Variable

Fourfold to 15-fold elevated

LGMD 1D

Mean 38 years

Normal to threefold elevated

Distinctive Clinical Features

Organ Involvement

Calf hypertrophy, waddling gait, loss of ambulation at 7-12 years More benign, variable manifestation with later onset and slower progression Early onset of contractures of the elbows, Achilles tendons, and neck extensor muscles Slowly progressive muscle wasting and weakness in humeroperoneal distribution

Severe cardiac and respiratory involvement Severe cardiac and respiratory involvement

Early contractures of ankles, elbows, and spine Progressive wasting and weakness in the humeroperoneal muscles Early contractures of ankles, elbows and spine Progressive wasting and weakness in the humeroperoneal muscles Prominent facial weakness; extraocular, eyelid, and bulbar muscles spared Typical contour with straight clavicles, forward sloping, rounding of the shoulders, involvement of foot lifters, often asymmetrical Slowly progressive ptosis of the eyelid and dysphagia All extraocular and other voluntary muscles may become affected

Moderate proximal weakness, calf hypertrophy, cramps after exercise Phenotypes: asymptomatic hyperCKemia, myalgia, rippling muscle disease, distal myopathy Weakness prominent in proximal leg muscles; arm muscles and distal muscles may also become affected

Specific Findings in Muscle Biopsy, Immunohistochemistry, and Immunoblot Dystrophin staining and blot absent Dystrophin staining and blot reduced

Heart block Myopathic changes; in necessitating pacing, immunohistochemistry or severe profiles, emerin is dysrhythmias, absent in myonuclei in sometimes >95% of patients necessitating an implantable defibrillator Left ventricular dilation and cardiac failure can occur Cardiac disease by Myopathic changes adulthood, high risk for sudden death

Unknown

Myopathic changes

Hearing loss, retinal telangiectasias, atrial arrhythmias

Myopathic changes; inflammation in 75% of cases with perivascular CD4+ and endomysial CD8+ cells Myopathic changes, small angulated fibers and rimmed vacuoles

Nasal voice as result of palatal weakness

Not described

20% of patients suffer from dysphagia but not from other systemic features

Numerous rimmed vacuoles and hyaline inclusions, possibly increased myotilin staining Mildly myopathic

Myopathic changes; caveolin staining and immunoblot reduced; dysferlin staining may be co-reduced Myopathic changes

Continued

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T A B L E 85–2. Phenotypic Differentiation of the Muscular Dystrophies—cont’d

Muscular Dystrophies

Age at Onset

Creatine Kinase Level

Distinctive Clinical Features

Organ Involvement Cardiac involvement is leading symptom; sudden death occurs without prior cardiac symptoms Respiratory involvement

LGMD 1E

Second decade or later

Twofold to fourfold elevated

Adult-onset limb girdle weakness

LGMD 1F

Mean, 16 years; range, 1-58 years

Normal in 40%

Early proximal weakness, ankle contractures, scapular winging

LGMD 1G

30-47 years

Normal to ninefold elevated

LGMD 2A

14-20 years

Sevenfold to 80-fold elevated

LGMD 2B

Mean, 19 years; range, 12-39 years

Very high: 10- to 72fold elevated

Mild adult-onset form of LGMD; most patients show finger and toe flexion contractures Scapular-humeral-pelvic distribution of muscle weakness and atrophy, early development of contractures, scapular winging Proximal weakness at onset, early involvement of the gastrocnemius, difficulties in walking on tiptoes

LGMD 2C LGMD 2D

5-6 years 2-15 years, rare adult onset

LGMD 2E

3 years to teens

LGMD 2F

2-10 years

LGMD 2G

9-15 years

Threefold to 30-fold elevated

LGMD 2H

Second or third decade

Fourfold elevated

LGMD 2I

Highly variable, 0.5-27 years

Fivefold to 40fold elevated

LGMD 2J

Childhood, ranges <10 years to third decade

High

Clinical picture, although more variable, resembles in many aspects DMD 10- to 50-fold elevated Loss of ambulation in second decade; in cases with later onset, ambulation may be preserved until adult life Proximal involvement and marked weakness; some patients have atrophy in the distal muscles of the legs, whereas others have calf hypertrophy Loss of ambulation in third to fourth decades Mild with proximal weakness; patients stay ambulatory to sixth decade Muscle pain and myoglobinuria are often first symptoms; possible calf and tongue hypertrophy; malignant hyperthermia-like reactions to general anesthesia described Proximal weakness, anterior tibial wasting, loss of ambulation at <30 years, some patients still ambulatory at 60 years

Not described

Respiratory involvement with reduced vital capacity

Specific Findings in Muscle Biopsy, Immunohistochemistry, and Immunoblot Mild myopathic changes

Myopathic changes, sometimes with rimmed vacuoles; desmin staining may be mildly increased in some fibers Myopathic pattern with rimmed vacuoles Total, partial, or, more rarely, no apparent deficiency of CALP-3 in immunoblot

Not described

Total or partial deficiency of dysferlin in immunohistochemistry study and immunoblot; caveolin staining may be co-reduced Cardiac and respiratory Primary loss or deficiency involvement of any one of the four sarcoglycans leads to a secondary deficiency of the whole subcomplex in immunohistochemistry and immunoblot

Heart involvement in 55% of patients

Muscle biopsy reveals myopathic changes with rimmed vacuoles; immunohistochemistry profile reveals lack of telethonin

Not described

Myopathic changes

Dilative cardiomyopathy and respiratory failure in one third of patients

Reduced staining for αdystroglycan, especially in severe forms

Not described

Myopathic changes, loss of calpain-3 as a downstream effect of the deficient TMD gene product in immunoblot

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T A B L E 85–2. Phenotypic Differentiation of the Muscular Dystrophies—cont’d

Muscular Dystrophies

Age at Onset

Creatine Kinase Level

Distinctive Clinical Features

Organ Involvement

LGMD 2K

First decade

Ninefold to 40-fold elevated

Early milestones normal; proximal weakness, joint contractures

Mental retardation, IQ 50-76

Epidermolysis bullosa with muscular dystrophy (MDEBS) Congenital (MDC) Fukuyama MDC (FCMD)

Congenital

>1000 U/L (normal <190 U/L)

Proximal, distal, facial, and ocular weakness; many patients in wheelchair by 10 years

Infantile respiratory complications, brain atrophy

Months to 1 year

Moderately elevated

Muscle-eyebrain disease (MEB)

Congenital

Mildly elevated

Severe hypotonia, weakness and wasting; only patients with mildest forms are ambulatory Severe hypotonia, slow development, death at 6-42 years

WalkerWarburg syndrome (WWS)

Congenital

Variable, up to 1500 U/L (normal <190 U/L)

Most severe MDC; severe hypotonia, death in utero or infancy at <1 year

MDC type 1A

Up to 12 years

Moderately elevated

Hypotonia, contractures, respiratory and feeding problems, facial weakness, delayed motor development

MDC type 1B

Congenital

1700-7600 U/L (normal <190 U/L)

MDC type 1C

First weeks after birth

MDC type 1D

First months after birth

3000-8000 U/L (normal <190 U/L) 400-4500 U/L (normal <190 U/L)

Proximal weakness, generalized muscle hypertrophy, spine rigidity, contractures Diffuse weakness, hypotonia, calf hypertrophy

Seizures (50%), severe mental retardation, hydrocephalus Brain malformation (lissencephaly II/pachygyria), cerebellopontine hypoplasia, severe ocular abnormalities Congenital cataracts, microphthalmia, hydrocephalus, occipital encephalocele, fusion of the hemispheres, absence of corpus callosum Respiratory insufficiency; cognitive function usually normal, sometimes structural brain changes, epilepsy, and neuropathy Early respiratory failure

MDC with rigid spine (RSMD1)

Birth to 1 year

Normal

Congenital

Mildly elevated

Congenital

Normal to mildly elevated

1.5-25 years

Up to threefold elevated

MDC with integrin deficiency Ullrich’s scleroatonic (UCMD)/ Bethlem’s myopathy Distal myopathies (MPD) MPD1 (GowersLaing)

Specific Findings in Muscle Biopsy, Immunohistochemistry, and Immunoblot α-Dystroglycan level reduced in immunohistochemistry profile Myopathic changes

α-Dystroglycan and merosin levels reduced α-Dystroglycan absent or at reduced level, merosin level mildly reduced

α-Dystroglycan absent or at reduced level, merosin level normal or mildly reduced

Myopathy with neurogenic features; merosin staining reduced or absent

Merosin staining reduced

Left ventricular dilative α-Dystroglycan and cardiomyopathy merosin levels reduced

Hypotonia, muscle hypertrophy, contractures

Profound mental retardation

Hypotonia, poor head control, improvement with development, nonprogressive Hypotonia, delayed milestones, proximal weakness Hypotonia, congenital contractures, hyperlaxity of distal joints

Respiratory involvement

α-Dystroglycan immunolabeling reduced, merosin level normal Myopathic changes, minicores

Mental retardation possible

Reduced staining of integrin α7

Respiratory involvement

Reduced staining of Col-6

Not described

Mildly myopathic, some vacuoles

Onset in anterior compartment of legs

Continued

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T A B L E 85–2. Phenotypic Differentiation of the Muscular Dystrophies—cont’d

Muscular Dystrophies MPD2 (VCPDM) MPD3

Age at Onset 35-57 years; mean, 46 years 32-45 years

Creatine Kinase Level

Specific Findings in Muscle Biopsy, Immunohistochemistry, and Immunoblot

Distinctive Clinical Features

Organ Involvement

Normal to eightfold elevated Normal to mildly elevated Normal to mildly elevated

Onset in anterior distal legs, hands, or voice; peroneal distribution in legs Onset in anterior compartments of legs and hands Onset in anterior legs

Voice hoarse and hypernasal; dysphagia Not described

Mildly myopathic with vacuoles

Not described

Myopathic with vacuoles

Respiratory failure, dysphonia, dysphagia, and tremor in some patients Not described

Myopathic, some vacuoles

Mildly myopathic with vacuoles

Tibial (TMD) (Udd/ MarkesberyGriggs) Welander (WDM)

40-50 years

>40 years

Normal to mildly elevated

Onset in hand extensor

Distal dystrophy with rimmed vacuoles (MDRV) MM (Miyoshi)/ distal anterior compartment myopathy (DMAT)

10-50 years

Normal to mildly elevated

Legs: distal

20-50 years

10- to 15fold elevated

Onset in posterior compartment of legs

Not described

NM (Nonaka)

20-40 years

Twofold to fivefold elevated

Onset in anterior compartment of legs

Not described

Myopathic without vacuoles; total or partial deficiency of dysferlin in immunohistochemistry profile and immunoblot; caveolin staining may be co-reduced Myopathic with vacuoles

Hereditary inclusion body myopathies (HIBM) HIBM1

25-40 years

LGMD phenotype, early quadriceps involvement

Not described

Myopathic with vacuoles

HIBM2

20-40 years

Quadriceps-sparing muscle involvement, distal onset

Not described

Myopathic with vacuoles

HIBM3

Congenital

Normal to mildly elevated Twofold to fivefold elevated Normal to 10-fold elevated

Not described

Myopathic with rimmed vacuoles and minicores

HIBMERF (with early respiratory failure) IBMPFD (with Paget’s disease and dementia)

35-75 years

Normal to mildly elevated

Joint contractures at birth, slowly progressive myopathy, ophthalmoplegia Weakness in anterior distal legs, later proximal legs

Respiratory involvement

Myopathic, eosinophilic inclusions, vacuoles

20-40 years

Normal to mildly elevated

Not described

Myopathic with vacuoles

HyperCKemia, persistent elevated creatine kinase levels.

LGMD phenotype, Paget’s disease, dementia

Myopathic with vacuoles

chapter 85 muscular dystrophies regeneration may be less prominent than in muscular dystrophies of later onset (e.g., DMD, BMD, or sarcoglycanopathies). Creatine kinase concentrations are variable and can be normal. The mode of inheritance for most MDCs is autosomal recessive with significant genetic heterogeneity.51-53 For clinical differentiation, see Table 85–2 and Figs. 85–8 and 85–9.

Clinical Features, Etiology, and Pathophysiology A useful clinical approach segregates the MDCs into two subgroups, one with normal mental development and the other with mental retardation. Magnetic resonance imaging of the brain is indispensable in the clinical approach to MDC because it may show alterations of brain formation and neuronal migration or white matter abnormalities, or it may be completely normal. Although this clinical approach does not coincide fully with the protein-based classification, most MDC forms with abnormalities of brain formation demonstrate alterations of α-dystroglycan O-linked glycosylation, whereas mutations of laminin-2 and other proteins of the extracellular matrix generally allow normal mental development, even though abnormalities of the white matter are seen in laminin-2 mutations. The main phenotypes in the group of MDCs with abnormal brain development and mental retardation have been delineated

■

on clinical grounds and include Fukuyama’s MDC, muscle-eyebrain disease, and Walker-Warburg syndrome, but variants and overlap phenotypes are not uncommon. All three syndromes are caused by mutations in genes that encode glycosyltransferases and related proteins involved in the post-translational modification of α-dystroglycan. Common characteristics include severe muscular dystrophy, neuronal migration defects such as lissencephaly type II (cobblestone complex), pachygyria, cerebellar and brainstem abnormalities, and variable ocular anomalies. Immunohistochemistry and immunoblotting help to distinguish between merosin-positive and merosin-negative forms of MDC. Reduction or absence of α-dystroglycan immunostaining indicates a defect of one of the glycosylation genes (see Tables 85–1 and 85–2 and Fig. 85–6).

NUCLEAR ENVELOPATHIES Definition Emery Dreifuss muscular dystrophies are characterized by early contractures of the elbows, Achilles tendons, and spine; slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution; and cardiomyopathy, usually

Figure 85–8. Typical phenotype of Ullrich’s congenital muscular dystrophy with contractures, spine rigidity, kyphoscoliosis, and hyperlaxity of distal joints.

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Neuromuscular Diseases: Muscle hypothesis could partly explain the muscle-specific phenotypes of some of these diseases. Nuclei with mutant structural proteins may be more fragile. During muscle contraction, nuclei in muscle cells may be under more stress than are nuclei of other cells and therefore may be sensitive to defects in the nucleoskeleton.56 Direct genetic testing in patients with clinical Emery Dreifuss muscular dystrophy phenotypes detects mutations in the emerin or lamin A/C gene in about 30% of the patients.

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Definition

■

Figure 85–9. Typical rigid spine and severe scoliosis in a patient with congenital muscular dystrophy caused by a homozygous missense mutation G315S in SEPN1.

manifesting as heart block. There are two main modes of inheritance: X-linked (X-EDMD, EDMD1) and autosomal dominant (ADEDMD, EDMD2/LGMD1B). However, a rare autosomal recessive mode of inheritance (EDMD3) has also been reported.54 In 1999, the nuclear lamin A/C gene, LMNA, at locus 1q11-q23 was found to be responsible for EDMD2 and EDMD3.17 Whereas mutations in the emerin gene, STA, at locus Xq28, give rise to one phenotype, the X-linked form of Emery Dreifuss muscular dystrophies, mutations in LMNA cause at least nine (and probably more) different neuromuscular and non-neuromuscular phenotypes.55 For clinical differentiation, see Table 85–2.

Etiology and Pathophysiology One of the most intriguing questions regarding the role of emerin and lamins A and C in disease is how mutations in nearly ubiquitously expressed proteins can cause different tissue-specific illnesses. Several hypothetical pathophysiological mechanisms have been proposed. Protein complexes of the nuclear envelope, which include lamins and emerin, may function in the regulation of gene expression, inasmuch as there are several examples of nuclear envelope proteins that interact with chromatin proteins. The functional effects of these interactions are not yet understood, but they suggest a potential role for the nuclear envelope in chromatin organization. Therefore, alterations in the nuclear envelope that result from mutations in emerin and lamins A and C may change the expression of genes involved in striated muscle function. Another hypothesis is that mutations in nuclear envelope proteins cause neuromuscular disease by altering the structural integrity of the nucleus. This so-called “mechanical stress”

FSHD is a highly variable disorder in which weakness appears from infancy to late life but typically in the second decade. Usually, the disease initially involves the face and scapulae, followed by foot dorsiflexors and hip girdles. Typical features include the often striking asymmetry of muscle involvement and the sparing of bulbar extraocular and respiratory muscles.57

Clinical Features Clinical diagnosis rests on the distinctive pattern of muscle involvement (Fig. 85–10). Although several inherited myopathies can include facial and shoulder girdle weakness, the following features are specific to FSHD: (1) Facial weakness is prominent and typically more severe in the lower facial musculature. (2) Extraocular, eyelid, and bulbar muscles are spared. (3) The shoulders anteriorly have a typical contour with straight clavicles, forward sloping, and rounding. (4) Pectoral, biceps, and triceps muscles are typically involved, whereas deltoid and forearm muscles are spared. (5) Lower abdominal muscles are selectively involved, resulting in lumbar lordosis. (6) Leg involvement frequently starts with foot dorsiflexor weakness, but quadriceps weakness can also be manifest early in the disease.57 (7) Contractures are rarely present, but during the course of the disease, patients may develop additional weakness of wrist extensors. (8) Muscle weakness is often asymmetrical. Extramuscular manifestations of FSHD include highfrequency hearing loss, retinal telangiectasias, and a tendency to develop atrial arrhythmias.58 These manifestations, if present, are mostly mild. Symptomatic cardiac involvement, present in approximately 5% of patients with molecularly confirmed FSHD, consists of conduction abnormalities with frequent supraventricular tachyarrhythmias. Inheritance is autosomal dominant with a high degree of penetrance, but sporadic cases caused by de novo mutations account for up to 30% of cases.59 Creatine kinase concentration is normal (25%) or mildly (less than fivefold) elevated, and the electromyogram shows myopathic changes. Muscle biopsy reveals variable fiber size, small rounded and angular fibers, and hypertrophic fibers, often with few internal nuclei. Inflammation is seen in 75% of cases, with perivascular CD4+ and endomysial CD8+ cells. However, muscle biopsy is rarely necessary to establish the diagnosis of FSHD.

chapter 85 muscular dystrophies

A ■

1157

B Figure 85–10. Typical phenotype of facioscapulohumeral muscular dystrophy with facial and scapular weakness, atrophy of scapulohumeral muscles with deltoid muscles spared (A) and scapular winging (B). Genetically, a shortened 4q35-specific p13E1/EcoRI-DNA fragment (25 kb in each of six copies) was detected.

Etiology and Pathophysiology Understanding the pathophysiology of FSHD is hampered by the unique molecular genetic lesion. Despite the identification of a causal deletion on chromosome 4q35 in 1990, the molecular pathophysiology of FSHD remains unclear. When FSHD was linked to chromosome 4q35, subtelomeric rearrangements consisting of deletions of an integral number of copies of a 3.3 kb DNA repeat named D4Z4 were identified.25 Whereas normal individuals have 15 or more repeats on each copy of 4q35, individuals with FSHD have 12 or fewer repeats on each copy. The deletions do not appear do disrupt an expressed gene. Rare FSHD kindreds fail to show linkage to 4q35, but alternative genetic loci have not been identified thus far. Whereas it is clear that a critical deletion within the 4q35 D4Z4 repeats results in FSHD, no expressed sequences are present within the deleted segments. Investigators have found 4q35 genes located upstream of D4Z4 to be inappropriately overexpressed in FSHD muscle. An element within D4Z4 has been shown to behave as a silencer that provides a binding site for a transcriptional repressing complex. These results are suggestive of a model in which deletion of D4Z4 leads to inappropriate transcriptional repression of 4q35 genes, resulting in disease.60 FRG2, an FSHD candidate gene, has been found to be transcriptionally upregulated in differentiating primary myoblast cultures from patients with FSHD and is an attractive candidate culprit.61 In most cases, diagnosis can be achieved by blood genetic testing without a prior muscle biopsy.

OCULOPHARYNGEAL MUSCULAR DYSTROPHY Definition OPMD was first clearly described by Taylor in 1915 in four members of a French Canadian family.62 They had late-onset ptosis in association with progressive swallowing difficulties (dysphagia), which led to starvation and death. This paper and a few other case reports63-65 were largely overlooked until the classic publication by Victor and associates in 1962.66 They were

the first to refer to this myopathy as oculopharyngeal muscular dystrophy.

Clinical Features OPMD usually manifests in the fifth or sixth decade with two cardinal symptoms: ptosis of the eyelid and dysphagia, both of which have a slowly progressive course (Fig. 85–11). Later, all extraocular and other voluntary muscles may become affected. In most cases, ptosis is the first symptom. As the disease evolves, there may be impairment of eye movements and, occasionally, diplopia; nevertheless, complete external ophthalmoplegia is infrequent.26,67,68 With time, the dysphagia results in undernutrition and may result in death from aspiration pneumonia. Other symptoms and signs are caused by involvement of other muscles. In most patients, the voice becomes nasal as a result of palatal weakness. Weakness and atrophy of the tongue are common.69 Mild facial, temporal, and masseter muscle involvement may become apparent after the ptosis has become obvious. Weakness often affects pelvic girdle muscles and, to a lesser extent, the shoulder girdle. The disease has a slowly progressive course. Life expectancy is not diminished by the condition.70 Until recently, death usually occurred at an advanced age as a result of starvation or aspiration pneumonia. With progress in the treatment of pharyngeal dysfunction and better nutrition, the life spans of patients have become longer, and the prognosis and quality of life have improved. Creatine kinase levels are normal or mildly elevated, and the electromyogram often exhibits myopathic changes and, in some patients, denervation. The pathological changes of extraocular and other voluntary muscles vary according to the stage of the disease and the muscle examined. Probably all skeletal muscles are affected, but extraocular, lingual, pharyngeal, and diaphragmatic muscles are found to be more severely involved in autopsy studies.67 Muscles studied by classic histological methods show changes that are common to many muscular dystrophies. Histochemical studies reveal two particular changes: (1) small angulated fibers that often react strongly for oxidative enzymes and are

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DISTAL MYOPATHIES Definition

■

Figure 85–11. Characteristic facies of oculopharyngeal muscular dystrophy: bilateral ptosis and raised eyebrows. Genetically, a guanine-cytosine-guanine repeat expansion (10 repeats) in the PABP2 gene was detected.

Distal myopathies are a heterogeneous group of genetic disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands or in the feet and pathologically by myopathic changes in skeletal muscles. Eight distinct distal myopathies have been identified, and four have been defined at the molecular level. They are classified according to age at onset, mode of inheritance, and muscle groups initially involved. Since 2000, much has been learned about the molecular etiologies of these myopathies. All have been linked to specific chromosome regions. One of the most interesting conclusions of the molecular studies is that the same gene can be responsible for diverse clinical phenotypes.71 The diagnostic process for the common forms of distal myopathy is simplified in Figure 85–12. Except for Miyoshi myopathy, in which the serum creatine kinase level is markedly elevated and the pathological findings are typical of muscular dystrophy, most distal myopathies are characterized by normal or mildly elevated creatine kinase levels and share in common the pathological feature of rimmed vacuoles.

Etiology and Pathophysiology more frequently type 1 than type 2 and (2) rimmed vacuoles within the muscle fibers. Rimmed vacuoles have been observed in several other disorders, particularly inclusion body myositis. However, their presence supports the clinical diagnosis of OPMD. The most significant ultrastructural change is the presence of intranuclear tubular filaments with an 8.5-nm outer diameter and a 3-nm inner diameter.

The concept of distal myopathies may soon become obsolete. Instead, these conditions may become known by their genetic mutations or abnormal gene products, much like DMD and BMD. The mechanisms by which a mutation in the same gene can produce strikingly different phenotypes remains to be elucidated. Whether a mutation in a particular gene produces distal or proximal weakness may depend on the action of one or more additional genes. Further progress in the field of molecular genetics will probably lead to more appropriate classification systems for the inherited distal myopathies.

Etiology and Pathophysiology Autosomal dominant and recessive forms of OPMD have been described. The OPMD locus was first mapped to chromosome 14q11.1 by linkage analysis in large French Canadian families.27 A positional cloning strategy led to the identification of short (GCG)8 to (GCG)13 expansions in the PABPN1 gene in all autosomal dominant OPMD cases.26 They consist of mitotically and meiotically stable expansions of a (GCG)n repeat in the first exon of the gene. Dominant mutations consist of the addition of two to seven (GCG) repeats to the usual (GCG)6 stretch. In populations with founder effects, such as French Canadians or Jews from Bukhara, Uzbekistan, most families share the same historical mutation, which only rarely change in size.26 OPMD is one of the few triplet repeat diseases in which it is not known whether there is an inverse correlation between the severity of the phenotype and the size of the mutation. It is clear, however, that the severity of the phenotype varies even among carriers of the same size (GCG)n PABPN1 mutation.26,69 Only carriers of the smallest (GCG)8 PABPN1 mutation appear to have a milder phenotype, with an age at onset in the seventh decade and only mild dysphagia. Persons who are compound heterozygotes for dominant and recessive mutations have more severe phenotypes.26 Diagnosis is usually achieved by direct blood genetic testing.

HEREDITARY INCLUSION BODY MYOPATHIES Definition The morphological hallmarks of inclusion body myopathies are the rimmed vacuoles and characteristic inclusion bodies. Inclusion bodies contain a variety of proteins, such as amyloid and the prion protein. Ultrastructurally, there are typical 15- to 18-nm filaments. Clinically, most cases of inclusion body myopathies are sporadic, manifest at an older age than HIBM, and demonstrate inflammatory muscle infiltrations similar to those of polymyositis. Although the degree of inflammation is variable, sporadic inclusion body myopathy is considered an autoimmune disorder. In contrast to the sporadic cases, muscle biopsy specimens of patients with HIBM usually (but not always) lack inflammatory infiltrates, and HIBM belongs to the heterogeneous group of myopathies with rimmed vacuoles, characterized clinically by progressive muscular weakness and atrophy beginning in the hands or feet. However, there is considerable phenotypic and genotypic overlap with distal myopathies and muscular dystrophies (see Tables 85–1 and 85–2).

chapter 85 muscular dystrophies

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Distal myopathy

Autosomal dominant

Age onset <20 y

Age onset >35 y

Onset hands

MPD1 (MYH7) ■

Autosomal recessive

Onset distal leg (anterior compartment)

Onset distal leg

WDM (2p13)

TMD (TTN)

Onset distal leg (posterior compartment)

CK >10-fold

NM (GNE)

MM (DYSF)

Figure 85–12. Flowchart for the diagnosis of the major forms of distal myopathies. CK, creatine kinase; DYSF, dysferlin; GNE, uridine diphosphate–N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase; MM, Miyoshi myopathy; MPD1, Gowers-Laing distal myopathy; MYH7, myosin heavy chain 7; NM, Nonaka myopathy; TMD, tibial muscular dystrophy; TTN, titin; WDM, Welander distal myopathy.

Etiology and Pathophysiology The unusual constellation of proteins present in the inclusions of this condition is characteristic and does not occur in vacuolated or nonvacuolated fibers of other muscle diseases. In the various inclusion body myopathies, different etiologies may lead to a common pathogenic cascade, which is ultimately responsible for the characteristic muscle fiber degeneration.72

TREATMENT OF MUSCULAR DYSTROPHIES In general, putative therapeutic strategies for muscular dystrophies may be classified into three groups on the basis of their approach: (1) gene therapy, including viral, plasmid, and oligonucleotide-based approaches; (2) cell therapy (myoblast and stem cell); and (3) pharmacological therapy. The advantage of the first two approaches is that they would correct both primary and secondary problems associated with the disease, especially if initiated early. However, except for small clinical trials, these treatments have not yet reached patients. Most pharmacological approaches target specific downstream events of the pathophysiological cascade, not the primary genetic defect. They can at best slow down disease progression. In contrast to most compounds that were tested in clinical trials for muscular dystrophies, corticosteroids, such as prednisone and deflazacort, proved to be of some real benefit in terms of muscle strength.73-77 However, side effects (weight gain, fluid retention, growth retardation, cataract) are prominent and often prohibitive of long-term treatment. There is still no general consensus among specialists on corticosteroid treatment, which varies among and within different countries. In general, European clinicians prescribe corticosteroids more restrictively but pay more attention to supportive treatment. Even in the United States, where most of the positive trials were

performed, the use of corticosteroids is not uniform. Some patients respond dramatically well to corticosteroids with minimal side effects. Low-dosage and alternate-day regimens may help reduce side effects.78,79 Many uncertainties remain about the best regimen and the type of corticosteroid to obtain maximal efficacy with minimal side effects. Corticosteroid treatment with deflazacort appears to cause fewer side effects, particularly less weight gain, in comparison with prednisone.80,81 The efficacy of corticosteroids in other muscular dystrophies has not yet been tested systematically, but steroids are also used in patients with BMD82 and sarcoglycanopathies.83,84 An international European Neuromuscular Centre workshop has combined efforts to define the “gold standards” in the use of steroids for DMD.85 Aminoglycosides, including gentamicin, have been known to promote “read-through” of premature stop codons and thus suppression of nonsense mutations. Therefore, considerable interest followed a report showing gentamicin-induced readthrough in mdx mice that generated full-length dystrophin and raised hopes that DMD may be treatable by a conventional drug.86 Unfortunately, several human and animals trials were unable to replicate the beneficial results of gentamicin treatment.87,88 Creatine supplementation results in increased highintensity strength in patients with different types of neuromuscular diseases. A controlled study showed significant improvement of strength and daily life activities in patients with different types of muscular dystrophies (DMD, BMD, LGMD, FSHD) during short-term creatine supplementation.89 Short-term administration of creatine produces few side effects. Minor adverse effects result from increase of muscle mass, muscular cramps, and entrapment syndromes that were seen in athletes but not in patients with muscle diseases so far. In a Cochrane Review on drug treatment for FSHD,90 researchers did not find evidence from two randomized

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controlled trials to support any drug treatment for FSHD, but only two high-quality trials that fulfilled the selection criteria have been published. In one, creatine supplementation was compared with placebo, and in the other, high- and low-dose albuterol was compared with placebo. (Another randomized controlled trial of albuterol in FSHD has not been published.) The creatine trial demonstrated a nonsignificant difference in favor of creatine. The albuterol trial demonstrated no significant difference in muscle strength at 1 year, but some secondary measures such as lean body mass and hand grip strength did improve.89,91 Potentially causative treatment strategies are conducted mainly for dystrophinopathy and include cellular approaches, such as myoblast transplantation and stem cell transplantation; gene therapy, such as direct delivery of dystrophin or other therapeutic genes; and new techniques, such as exon skipping by antisense oligonucleotides. Introduction of normal muscle precursor cells (myoblasts) into dystrophic muscle results in their incorporation into myofibers, so that a proportion of the nuclei in each newly formed myofiber carry a functional copy of the dystrophin gene. This approach was successful in demonstrating relocalization of dystrophin to the sarcolemma in mdx muscle and expression of dystrophin transcripts in DMD patients by reverse-transcriptase polymerase chain reaction. However, clinical trials have not shown any objective benefit in patients injected with donor myoblasts. The ability of cell populations such as transplanted stem cells to adapt to a tissue phenotype is of potential therapeutic use, inasmuch as previous studies have shown that such cells can contribute to muscle repair in mice that have undergone bone marrow transplantation. Stem cells derived from a dystrophinpositive donor have also been shown to contribute to dystrophin-positive muscle and cardiac tissue in mdx mice in vivo. In addition, bone marrow transplantation from a dystrophin-positive donor to a patient with DMD has been shown to be a viable means by which to deliver these cells to muscle. However, the poor efficiency of the procedure currently precludes clinical use.92 Gene therapy approaches aim to deliver DNA encoding dystrophin or other therapeutic genes (e.g., utrophin) to muscle. Results of studies with mdx mice indicate that this approach is effective in principle and that the level of dystrophin expression required is not critical as long as threshold levels of therapeutic genes are achieved. To date, most dystrophin-delivery approaches are hampered by the large size of the gene (which is larger than the cargo capacity of most current viral vectors), by the immune responses to protein and viral antigens, and by vector delivery to skeletal and heart muscle. “Mini-dystrophin” genes (in which a large proportion of the rod domain is deleted) retain some function and have the advantage of being within viral cloning capacities, similar to “mini-utrophin” to provoke a less vigorous immune reaction, but systemic delivery remains a formidable difficulty. Use of naked plasmid DNA and plasmid DNA-liposome complexes has been described for the delivery of genes to skeletal muscle. The advantage of this technique is that plasmid DNA appears to be nonantigenic. Postmitotic myofibers can sustain episomal expression of plasmids for long periods of time, but this approach is hampered by transfection inefficiency, with the exception of neonatal muscle, and the difficulty of introducing plasmid DNA into a sufficiently high proportion of myofibers to effect phenotypic recovery in vivo. Nevertheless, there is remarkable progress in this direction. It

is encouraging to note that in the relatively short time since the DMD gene was identified, this approach was used for the first gene therapy trial in patients with DMD, demonstrating that exogenous dystrophin expression can be obtained in patients with DMD or BMD after intramuscular transfer of plasmid, without adverse effects, and hence paving the way for future developments in gene therapy.93 One technique appears to reestablish an open reading frame mutant dystrophin messenger RNA through modification of endogenous dystrophin. In this approach, antisense oligonucleotides complementary to intron/exon boundaries or exonic sequences are used to induce exon skipping of mutant regions of the dystrophin protein (point mutations), which leads to inframe translation. In cultured muscle cells of six patients with DMD who carried different deletions and a nonsense mutation, this approach removed the targeted exon, restoring the reading frame and thereby dystrophin synthesis in 75% of the cells.94 In 2005, Lu and colleagues showed that systemic delivery of antisense oligoribonucleotide restores dystrophin expression in bodywide skeletal muscles of mdx mice.95 Similarly, persistent exon skipping was achieved in mdx mice with a single administration of an adenovirus-associated virus expressing antisense sequences linked to a modified U7 small nuclear RNA.96 The importance of rehabilitation in the management of muscular dystrophies is frequently underestimated. The ongoing muscle damage in muscular dystrophies, regardless of their etiology, affects mobility, activities of daily living, communication, and cardiorespiratory fitness. The overall goal of rehabilitation is to enhance function and quality of life. Surgical treatment along with physiotherapy and bracing may control contractures and prolong walking ability in DMD patients. Along with physiotherapy, supportive measures such as ortheses, wheelchair, communication technology, invasive and non-invasive ventilation, palliative care, and terminal care should be offered to patients with muscular dystrophy some time before these measures become urgent. Patients and their families should also consult social advice centers for possible financial support from the authorities of their community or state. Surgery is an important treatment modality in patients with DMD, but patients with other types of muscular dystrophy may also profit from similar techniques. In specific types of muscular dystrophy, surgical fixation of joints or limbs with instability and secondary muscle weakness can greatly improve the patient’s quality of life. In FSHD, scapulothoracic arthrodesis and scapulopexy may improve upper limb function and performance of activities of daily living, and they may also fulfill esthetic purposes. According to a Cochrane Database review, surgical interventions appear to produce significant benefits, although these have to be balanced against postoperative immobilization, need for physiotherapy, and potential complications.97 Patients with OPMD may profit from ptosis correction. Within a symptom-oriented therapeutical concept for DMD, early lower limb surgery, possibly combined with symptomatic pharmacological treatment, is the first step, followed by stabilization of the spine at an early wheelchair stage. Cardiorespiratory involvement is frequent in most muscular dystrophies and a dominant symptom in some of them. Therefore, close monitoring of pulmonary function, electrocardiography, 24-hour electrocardiography, and echocardiography are necessary. If pulmonary function deteriorates,

chapter 85 muscular dystrophies noninvasive methods of ventilation should be offered to the patient, thereby improving quality of life and survival.98 Early recognition of cardiac involvement is warranted as adequate, and timely cardiac therapy may be pivotal in the survival and disease course of patients with muscular dystrophy.99 Therapeutic options in impulse generation and conduction abnormalities range from drugs (digitalis, amiodarone, β blockers, Ca2+ antagonists, anticoagulants) to cardioversion or insertion of a pacemaker or implanted defibrillator. In heart failure caused by diastolic or systolic dysfunction, angiotensinconverting enzyme inhibitors play an important role. Successful cardiac transplantation has been described in patients with DMD, BMD, Emery Dreifuss muscular dystrophies, LGMD, and myotonic dystrophy.

CONCLUSIONS AND RECOMMENDATIONS Numerous genes coding for sarcolemmal, extracellular, sarcomeric, and nuclear proteins have been found to cause different forms of muscular dystrophies, whereas post-translational processing, which plays a major role in the correct assembly and function of muscle proteins, is only becoming a focus of pathogenetic research. Glycosylation is the most frequent posttranslational modification of proteins. It is of great interest that primary glycosylation defects have now been discovered in, so far, five severe MDCs, in association with prominent developmental abnormalities in the central nervous system (Fukuyama MDC, muscle-eye-brain disease, Walker-Warburg syndrome, MDC type 1C, MDC type 1D) and in a milder allelic variant of fukutin-related protein deficiency, LGMD2I. The altered processing of α-dystroglycan as a result of its abnormal glycosylation represents a novel pathogenic mechanism in muscular dystrophy. In these diseases, the pathogenic protein abnormality is caused by mutation not of the gene that encodes that protein but rather of the gene that encodes an enzyme responsible for the protein’s post-translational modification. In view of the widespread occurrence of post-translational modification of proteins (including both glycosylation and phosphorylation), additional, currently mysterious muscle diseases may have a similar pathogenesis. As the gene mutations responsible for many types of muscular dystrophy and myopathy have been discovered, protein and gene testing has been integrated into the standard patient diagnostic workup. However, diagnosis of most muscular dystrophies remains a challenge. Few laboratories are proficient in the many complex methods needed (immunostaining, Western blot, mutation analysis). The large size and numerous exons of some muscular dystrophy genes preclude gene sequencing with today’s technology. However, specific genetic diagnosis remains important. Future developments will include simpler and less expensive molecular diagnostics, advances in the understanding of downstream consequences of these defects, and the genetic predispositions underlying acquired muscle disease. A promising technique for improving efficacy of future molecular diagnostics is the development of microarrays. Progress within this field not only improves the diagnostic workup and accuracy but also optimizes genetic counseling, assessment of individual prognosis, and future therapies of affected patients. Curative therapy is not currently available, although the development of promising new treatment modalities is

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under way.92,100 In the future, molecular therapy may be the best way to reverse the molecular defects that cause muscular dystrophies, but practical and effective treatment in humans may still be years away. For evaluating different treatment modalities, symptomatic strategies, such as pharmacological therapies and supportive treatment, are differentiated from causative treatment schedules, such as gene or cell therapy. Although no major therapeutic breakthrough has been achieved and curative treatment modalities are not yet applicable, life expectancy and quality of life in patients with muscular dystrophy have steadily improved since the 1960s. This achievement has been reached by improved symptomatic treatment and care, such as assisted ventilation, drug therapy for heart failure, and surgical therapy to prevent complications. However, there are still few pharmacological options to specifically prevent or delay the dystrophic process in muscle fibers.101 Currently, corticosteroids are the most effective drugs in DMD, but therapy is limited by the high frequency and severity of side effects. Therefore, new treatment modalities, such as alternate-day administration aiming at a reduction of side effects, should be evaluated. The exact mechanism of how steroids work in muscular dystrophies remains unknown. Future studies should attempt to unravel this mechanism; it is hoped that this will lead to an equally potent but less toxic drug. Creatine seems to be of limited efficacy without remarkable side effects; therefore, short-term administration may be helpful in individual cases. Long-term studies are required for evaluation of long-term safety and efficacy. New molecular therapeutic approaches have been invented and are currently investigated in cell and animal models of muscular dystrophies. The first phase I clinical trials for plasmid-based gene therapy of dystrophinopathies have yielded promising results.93 Although molecular therapies promise causal intervention and curative treatment, a large number of technical and methodological problems need to be solved. Furthermore, molecular therapies should be applied to patients with muscular dystrophy only if they are considered reasonably safe. Therefore, the majority of patients with muscular dystrophy today must rely on standard symptomatic therapy, while molecular approaches continue to hold promise for the future.

K E Y

P O I N T S

●

Muscular dystrophies are clinically and genetically heterogeneous inherited muscle-wasting disorders; more than 30 genetic disease entities are known.

●

Mutated molecules in muscular dystrophies are located at the sarcolemma, the cytoplasm, or the nucleus of myofibers and are involved in various cellular pathways.

●

Precise molecular diagnosis can be achieved by combining clinical, histological, and genetic investigations.

●

Symptomatic and palliative therapy has dramatically increased the quality of life and life expectancy in patients.

●

Curative therapy requires further progress in the field of molecular genetics.

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Suggested Reading Bushby K, Muntoni F, Urtizberea A, et al: Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2-4 April 2004, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:526-534. Kirschner J, Bonnemann CGL: The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries. Arch Neurol 2004; 61:189-199. Lu QL, Rabinowitz A, Chen YC, et al: Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in bodywide skeletal muscles. Proc Natl Acad Sci U S A 2005; 102:198203. Muntoni F, Valero de Bernabe B, Bittner R, et al: 114th ENMC International Workshop on Congenital Muscular Dystrophy (CMD) 17-19 January 2003, Naarden, The Netherlands: (8th Workshop of the International Consortium on CMD; 3rd Workshop of the MYO-CLUSTER project GENRE). Neuromuscul Disord 2003; 13:579-588.

References 1. Kissel JT, Mendell JR: Muscular dystrophy: historical overview and classification in the genetic era. Semin Neurol 1999; 19:5-7. 2. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51:919-928. 3. Koenig M, Hoffman EP, Bertelson CJ, et al: Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987; 50:509-517. 4. Mendell JR, Sahenk Z, Prior TW: The childhood muscular dystrophies: diseases sharing a common pathogenesis of membrane instability. J Child Neurol 1995; 10:150-159. 5. van den Bergh PY, Tome FM, Fardeau M: Etiology and pathogenesis of the muscular dystrophies. Acta Neurol Belg 1995; 95:123-141. 6. Duchenne G: De l’Electrisation Localisée et de Son Application à la Pathologie et à la Therapeutique. Paris: Bailliere et Fils, 1861. 7. Duchenne G: Recherches surla paralysis musculaire pseudohypertrophique on paralysis myosclerosique. Ach Gen Med 1868; (11):5-25. 8. Monaco AP, Neve RL, Colletti-Feener C, et al: Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 1986; 323:646-650. 9. Monaco AP, Bertelson CJ, Liechti-Gallati S, et al: An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 1988; 2:90-95. 10. Batten F: Three cases of myopathy, infantile type. Brain 1903; 26:147-148. 11. Bell J: On pseudohypertrophic and allied types of progressive muscular dystrophy. In Fischer RA, ed: The Treasury of Human Inheritance. London: Cambridge University Press, 1943, pp 283-342. 12. Bushby KM: Diagnostic criteria for the limb-girdle muscular dystrophies: report of the ENMC Consortium on Limb-Girdle Dystrophies. Neuromuscul Disord 1995; 5:71-74. 13. Brockington M, Blake DJ, Brown SC, et al: The gene for a novel glycosyltransferase is mutated in congenital muscular dystrophy MDC1C and limb girdle muscular dystrophy 2I. Neuromuscul Disord 2002; 12:233-234. 14. Brockington M, Blake DJ, Prandini P, et al: Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 defi-

15.

16. 17.

18.

19.

20.

21. 22.

23. 24. 25. 26. 27.

28. 29. 30. 31.

32. 33.

ciency and abnormal glycosylation of α-dystroglycan. Am J Hum Genet 2001; 69:1198-1209. Brockington M, Yuva Y, Prandini P, et al: Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 2001; 10:2851-2859. Bione S, Maestrini E, Rivella S, et al: Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 1994; 8:323-327. Bonne G, Di Barletta MR, Varnous S, et al: Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999; 21:285288. Fatkin D, MacRae C, Sasaki T, et al: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999; 341:1715-1724. Muchir A, Bonne G, van der Kooi AJ, et al: Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000; 9:1453-1459. de Sandre-Giovannoli A, Chaouch M, Kozlov S, et al: Homozygous defects in LMNA, encoding lamin A/C nuclearenvelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 2002; 70:726-736. Bonne G, Levy N: LMNA mutations in atypical Werner’s syndrome. Lancet 2003; 362:1585-1586; author reply, Lancet 2003; 362:1586. Bonne G, Yaou RB, Beroud C, et al: 108th ENMC International Workshop, 3rd Workshop of the MYO-CLUSTER project: EUROMEN, 7th International Emery-Dreifuss Muscular Dystrophy (EDMD) Workshop, 13-15 September 2002, Naarden, The Netherlands. Neuromuscul Disord 2003; 13:508-515. Kirschner J, Brune T, Wehnert M, et al: p.S143F mutation in lamin A/C: a new phenotype combining myopathy and progeria. Ann Neurol 2005; 57:148-151. Landouzy L, Dejerine J: De la myopathie atrophique progressive. Rev Med 1885; 81-117, 253-366. Wijmenga C, Hewitt JE, Sandkuijl LA, et al: Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 1992; 2:26-30. Brais B, Bouchard JP, Xie YG, et al: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 1998; 18:164-167. Brais B, Xie YG, Sanson M, et al: The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13. Hum Mol Genet 1995; 4:429-434. Penisson-Besnier I: Distal myopathies. Rev Neurol (Paris) 2004; 160:211-216. Ueyama H, Kumamoto T, Horinouchi H, et al: Clinical heterogeneity in dysferlinopathy. Intern Med 2002; 41:532536. Hackman JP, Vihola AK, Udd AB: The role of titin in muscular disorders. Ann Med 2003; 35:434-441. Hackman P, Vihola A, Haravuori H, et al: Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 2002; 71:492-500. Argov Z, Tiram E, Eisenberg I, et al: Various types of hereditary inclusion body myopathies map to chromosome 9p1-q1. Ann Neurol 1997; 41:548-551. Clark JR, D’Agostino AN, Wilson J, et al: Autosomal dominant myofibrillar inclusion body myopathy: clinical, histologic,

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34. 35.

36.

37.

38. 39. 40. 41. 42. 43. 44. 45.

46. 47.

48.

49. 50.

51. 52.

histochemical, and ultrastructural characteristics. Neurology 1978; 28:399. Abe K, Kobayashi K, Chida K, et al: Dominantly inherited cytoplasmic body myopathy in a Japanese kindred. Tohoku J Exp Med 1993; 170:261-272. Kovach MJ, Waggoner B, Leal SM, et al: Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol Genet Metab 2001; 74:458-475. Martinsson T, Darin N, Kyllerman M, et al: Dominant hereditary inclusion-body myopathy gene (IBM3) maps to chromosome region 17p13.1. Am J Hum Genet 1999; 64: 1420-1426. Martinsson T, Oldfors A, Darin N, et al: Autosomal dominant myopathy: missense mutation (Glu-706→Lys) in the myosin heavy chain IIa gene. Proc Natl Acad Sci U S A 2000; 97:14614-14619. Nishino I, Noguchi S, Murayama K, et al: Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 2002; 59:1689-1693. Hoffman EP, Arahata K, Minetti C, et al: Dystrophinopathy in isolated cases of myopathy in females. Neurology 1992; 42:967-975. Wagner KR: Genetic diseases of muscle. Neurol Clin 2002; 20:645-678. Muntoni F, Torelli S, Ferlini A: Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2003; 2:731-740. Mendell JR, Buzin CH, Feng J, et al: Diagnosis of Duchenne dystrophy by enhanced detection of small mutations. Neurology 2001; 57:645-650. Flanigan KM, von Niederhausern A, Dunn DM, et al: Rapid direct sequence analysis of the dystrophin gene. Am J Hum Genet 2003; 72:931-939. Buzin CH, Feng J, Yan J, et al: Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide. Hum Mutat 2005; 25:177-188. Bushby KM, Beckmann JS: The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies, Naarden, April 12-14, 2002. Neuromuscul Disord 2003; 13:80-90. Zatz M, de Paula F, Starling A, et al: The 10 autosomal recessive limb-girdle muscular dystrophies. Neuromuscul Disord 2003; 13:532-544. Zatz M, Vainzof M, Passos-Bueno MR: Limb-girdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes. Curr Opin Neurol 2000; 13:511517. Beckmann JS, Brown RH, Muntoni F, et al: 66th/67th ENMC sponsored international workshop: the limb-girdle muscular dystrophies, 26-28 March 1999, Naarden, The Netherlands. Neuromuscul Disord 1999; 9:436-445. Wicklund MP, Hilton-Jones D: The limb-girdle muscular dystrophies: genetic and phenotypic definition of a disputed entity. Neurology 2003; 60:1230-1231. Balci B, Uyanik G, Dincer P, et al: An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord 2005; 15:271-275. Kirschner J, Bonnemann CG: The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries. Arch Neurol 2004; 61:189-199. Muntoni F, Valero de Bernabe B, Bittner R, et al: 114th ENMC International Workshop on Congenital Muscular Dystrophy (CMD) 17-19 January 2003, Naarden, The Netherlands: (8th Workshop of the International Consortium on CMD; 3rd

53. 54.

55.

56. 57. 58.

59. 60. 61.

62. 63. 64. 65. 66.

67. 68. 69. 70. 71.

72. 73.

1163

Workshop of the MYO-CLUSTER project GENRE). Neuromuscul Disord 2003; 13:579-588. Muntoni F, Voit T: The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord 2004; 14:635-649. Di Barletta MR, Ricci E, Galluzzi G, et al: Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2000; 66:1407-1412. Walter MC, Witt TN, Weigel BS, et al: Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery-Dreifuss muscular dystrophy. Neuromuscul Disord 2005; 15:40-44. Ostlund C, Worman HJ: Nuclear envelope proteins and neuromuscular diseases. Muscle Nerve 2003; 27:393406. Tawil R: Facioscapulohumeral muscular dystrophy. Curr Neurol Neurosci Rep 2004; 4:51-54. Padberg GW, Brouwer OF, de Keizer RJ, et al: On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve 1995; 2:S73-S80. Padberg GW, Frants RR, Brouwer OF, et al: Facioscapulohumeral muscular dystrophy in the Dutch population. Muscle Nerve 1995; 2:S81-S84. Tupler R, Gabellini D: Molecular basis of facioscapulohumeral muscular dystrophy. Cell Mol Life Sci 2004; 61:557566. Rijkers T, Deidda G, van Koningsbruggen S, et al: FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients. J Med Genet 2004; 41:826-836. Taylor EW: Progressive vagus-glossopharyngeal paralysis with ptosis: a contribution to the group of family diseases. J Nerv Ment Dis 1915; 42:129-139. Amyot R: Hereditary, familial and acquired ptosis of late onset. CMAJ 1948; 59:434-438. Amyot R: Ptosis héréditaire familiale et tardif des paupières supérieures, in Pharyngoplégie également héréditaire et familiales concomittante. Union Med Can 1948; 77:1287. Saucier J: The clinical significance of ptosis with special reference to ptosis of late onset. J Nerv Ment Dis 1954; 119:148158. Victor M, Hayes R, Adams RD: Oculopharyngeal muscular dystrophy. A familial disease of late life characterized by dysphagia and progressive ptosis of the evelids. N Engl J Med 1962; 267:1267-1272. Brais B: Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res 2003; 100:252260. Brais B, Rouleau GA, Bouchard JP, et al: Oculopharyngeal muscular dystrophy. Semin Neurol 1999; 19:59-66. Bouchard JP, Brais B, Brunet D, et al: Recent studies on oculopharyngeal muscular dystrophy in Quebec. Neuromuscul Disord 1997; 7(Suppl 1):S22-S29. Becher MW, Morrison L, Davis LE, et al: Oculopharyngeal muscular dystrophy in Hispanic New Mexicans. JAMA 2001; 286:2437-2440. Udd B, Bushby K, Nonaka I, et al: 104th European Neuromuscular Centre (ENMC) International Workshop: distal myopathies, 8-10th March 2002 in Naarden, The Netherlands. Neuromuscul Disord 2002; 12:897-904. Askanas V, Engel WK: Unfolding story of inclusion-body myositis and myopathies: role of misfolded proteins, amyloidbeta, cholesterol, and aging. J Child Neurol 2003; 18:185-190. Brooke MH, Fenichel GM, Griggs RC, et al: Clinical investigation of Duchenne muscular dystrophy. Interesting results in a trial of prednisone. Arch Neurol 1987; 44:812-817.

1164

Section

XV

Neuromuscular Diseases: Muscle

74. DeSilva S, Drachman DB, Mellits D, et al: Prednisone treatment in Duchenne muscular dystrophy. Long-term benefit. Arch Neurol 1987; 44:818-822. 75. Griggs RC, Moxley RT 3rd, Mendell JR, et al: Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol 1991; 48:383388. 76. Mendell JR, Moxley RT, Griggs RC, et al: Randomized, doubleblind six-month trial of prednisone in Duchenne’s muscular dystrophy. N Engl J Med 1989; 320:1592-1597. 77. Fenichel GM, Florence JM, Pestronk A, et al: Long-term benefit from prednisone therapy in Duchenne muscular dystrophy. Neurology 1991; 41:1874-1877. 78. Fenichel GM, Mendell JR, Moxley RT 3rd, et al: A comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular dystrophy. Arch Neurol 1991; 48:575-579. 79. Sansome A, Royston P, Dubowitz V: Steroids in Duchenne muscular dystrophy; pilot study of a new low-dosage schedule. Neuromuscul Disord 1993; 3:567-569. 80. Bonifati MD, Ruzza G, Bonometto P, et al: A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve 2000; 23:1344-1347. 81. Campbell C, Jacob P: Deflazacort for the treatment of Duchenne dystrophy: a systematic review. BMC Neurol 2003; 3:7. 82. Johnsen SD: Prednisone therapy in Becker’s muscular dystrophy. J Child Neurol 2001; 16:870-871. 83. Angelini C, Fanin M, Menegazzo E, et al: Homozygous αsarcoglycan mutation in two siblings: one asymptomatic and one steroid-responsive mild limb-girdle muscular dystrophy patient. Muscle Nerve 1998; 21:769-775. 84. Connolly AM, Pestronk A, Mehta S, et al: Primary αsarcoglycan deficiency responsive to immunosuppression over three years. Muscle Nerve 1998; 21:1549-1553. 85. Bushby K, Muntoni F, Urtizberea A, et al: Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2-4 April 2004, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:526-534. 86. Barton-Davis ER, Cordier L, Shoturma DI, et al: Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest 1999; 104:375-381. 87. Dunant P, Walter MC, Karpati G, et al: Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscle. Muscle Nerve 2003; 27:624-627. 88. Wagner KR, Hamed S, Hadley DW, et al: Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann Neurol 2001; 49:706-711. 89. Walter MC, Lochmüller H, Reilich P, et al: Creatine monohydrate in muscular dystrophies: A double-blind, placebocontrolled clinical study. Neurology 2000; 54:1848-1850. 90. Rose MR, Tawil R: Drug treatment for facioscapulohumeral muscular dystrophy. Cochrane Database Syst Rev 2004; (2):CD002276. 91. Kissel JT, McDermott MP, Mendell JR, et al: Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology 2001; 57:1434-1440. 92. Bogdanovich S, Perkins KJ, Krag TO, et al: Therapeutics for Duchenne muscular dystrophy: current approaches and future directions. J Mol Med 2004; 82:102-115. 93. Romero NB, Braun S, Benveniste O, et al: Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum Gene Ther 2004; 15:1065-1076. 94. Aartsma-Rus A, Janson AA, Kaman WE, et al: Therapeutic antisense-induced exon skipping in cultured muscle cells

95.

96. 97. 98.

99.

100.

101. 102. 103. 104.

105. 106. 107. 108. 109.

110. 111.

112. 113. 114.

from six different DMD patients. Hum Mol Genet 2003; 12:907-914. Lu QL, Rabinowitz A, Chen YC, et al: Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc Natl Acad Sci U S A 2005; 102:198-203. Goyenvalle A, Vulin A, Fougerousse F, et al: Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science 2004; 306:1796-1799. Mummery CJ, Copeland SA, Rose MR: Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev 2003; (3):CD003278. Wallgren-Pettersson C, Bushby K, Mellies U, et al: 117th ENMC workshop: ventilatory support in congenital neuromuscular disorders—congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA (II) 4-6 April 2003, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:56-69. Bushby K, Muntoni F, Bourke JP: 107th ENMC International Workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th-9th June 2002, Naarden, The Netherlands. Neuromuscul Disord 2003; 13:166-172. van Deutekom JC, Bremmer-Bout M, Janson AA, et al: Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum Mol Genet 2001; 10:1547-1554. Walter MC, Lochmüller H: Novel approaches to treat muscular dystrophies. Expert Opin Investig Drugs 2001; 10:695-707. Becker PE: Two new families of benign sex-linked recessive muscular dystrophy. Rev Can Biol 1962; 21:551-566. Becker PE: Eine neue X-chromosomale Muskeldystrophie. Acta Psychiat Neurol Scand 1955; 193:427. Fadda S, Mochi M, Roncuzzi L, et al: Definitive localization of Becker muscular dystrophy in Xp by linkage to a cluster of DNA polymorphisms (DXS43 and DXS9). Hum Genet 1985; 71:33-36. Mathews KD, Moore SA: Limb-girdle muscular dystrophy. Curr Neurol Neurosci Rep 2003; 3:78-85. Urtasun M, Saenz A, Roudaut C, et al: Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain). Brain 1998; 121(Pt 9):1735-1747. Hauser MA, Conde CB, Kowaljow V, et al: myotilin Mutation found in second pedigree with LGMD1A. Am J Hum Genet 2002; 71:1428-1432. Selcen D, Engel AG: Mutations in myotilin cause myofibrillar myopathy. Neurology 2004; 62:1363-1371. Speer MC, Yamaoka LH, Gilchrist JH, et al: Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: linkage of an autosomal dominant form to chromosome 5q. Am J Hum Genet 1992; 50:1211-1217. van der Kooi AJ, Ledderhof TM, de Voogt WG, et al: A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement. Ann Neurol 1996; 39:636-642. van der Kooi AJ, van Meegen M, Ledderhof TM, et al: Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac involvement (LGMD1B) to chromosome 1q11-21. Am J Hum Genet 1997; 60:891-895. Betz RC, Schoser BG, Kasper D, et al: Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nat Genet 2001; 28:218-219. de Paula F, Vainzof M, Bernardino AL, et al: Mutations in the caveolin-3 gene: when are they pathogenic? Am J Med Genet 2001; 99:303-307. Minetti C, Sotgia F, Bruno C, et al: Mutations in the caveolin3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet 1998; 18:365-368.

chapter 85 muscular dystrophies 115. Speer MC, Vance JM, Grubber JM, et al: Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7. Am J Hum Genet 1999; 64:556-562. 116. Messina DN, Speer MC, Pericak-Vance MA, et al: Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet 1997; 61:909-917. 117. Gamez J, Navarro C, Andreu AL, et al: Autosomal dominant limb-girdle muscular dystrophy: a large kindred with evidence for anticipation. Neurology 2001; 56:450-454. 118. Palenzuela L, Andreu AL, Gamez J, et al: A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2. Neurology 2003; 61:404-406. 119. Starling A, Kok F, Passos-Bueno MR, et al: A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Eur J Hum Genet 2004; 12:1033-1040. 120. Fardeau M, Hillaire D, Mignard C, et al: Juvenile limb-girdle muscular dystrophy. Clinical, histopathological and genetic data from a small community living in the Reunion Island. Brain 1996; 119(Pt 1):295-308. 121. Richard I, Broux O, Allamand V, et al: Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 1995; 81:27-40. 122. Richard I, Roudaut C, Saenz A, et al: Calpainopathy—a survey of mutations and polymorphisms. Am J Hum Genet 1999; 64:1524-1540. 123. Saenz A, Leturcq F, Cobo AM, et al: LGMD2A: genotypephenotype correlations based on a large mutational survey on the calpain 3 gene. Brain 2005; 128(Pt 4):732-742. 124. Bansal D, Miyake K, Vogel SS, et al: Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 2003; 423:168-172. 125. Bashir R, Britton S, Strachan T, et al: A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 1998; 20:37-42. 126. Illa I, Serrano-Munuera C, Gallardo E, et al: Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol 2001; 49:130134. 127. Miyoshi K, Saijo K, Kuryu T, et al: Four cases of distal myopathy in two families. Jpn J Hum Genet 1967; 12:113. 128. Walter MC, Braun C, Vorgerd M, et al: Variable reduction of caveolin-3 in patients with LGMD2B/MM. J Neurol 2003; 250:1431-1438. 129. Weiler T, Bashir R, Anderson LV, et al: Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s). Hum Mol Genet 1999; 8:871-877. 130. Noguchi S, McNally EM, Ben Othmane K, et al: Mutations in the dystrophin-associated protein γ-sarcoglycan in chromosome 13 muscular dystrophy. Science 1995; 270:819-822. 131. Roberds SL, Leturcq F, Allamand V, et al: Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell 1994; 78:625-633. 132. Bonnemann CG, Modi R, Noguchi S, et al: β-Sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nat Genet 1995; 11:266-273. 133. Nigro V, de Sa Moreira E, Piluso G, et al: Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the δ-sarcoglycan gene. Nat Genet 1996; 14:195198. 134. Moreira ES, Vainzof M, Marie SK, et al: The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12. Am J Hum Genet 1997; 61:151-159.

1165

135. Moreira ES, Wiltshire TJ, Faulkner G, et al: Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 2000; 24:163-166. 136. Frosk P, Weiler T, Nylen E, et al: Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet 2002; 70:663-672. 137. Weiler T, Greenberg CR, Zelinski T, et al: A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus. Am J Hum Genet 1998; 63:140-147. 138. de Paula F, Vieira N, Starling A, et al: Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet 2003; 11:923-930. 139. Driss A, Amouri R, Ben Hamida C, et al: A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3. Neuromuscul Disord 2000; 10:240-246. 140. Driss A, Noguchi S, Amouri R, et al: Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I. Neurology 2003; 60:1341-1344. 141. Esapa CT, McIlhinney RA, Blake DJ: Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. Hum Mol Genet 2005; 14:295-305. 142. Frosk P, Greenberg CR, Tennese AA, et al: The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. Hum Mutat 2005; 25:3844. 143. Karpati G, Holland P: Sweetening the pot in muscle: genetic defects of protein glycosylation causing muscle disease. Neurology 2002; 59:1674-1676. 144. Mercuri E, Brockington M, Straub V, et al: Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol 2003; 53:537-542. 145. Poppe M, Bourke J, Eagle M, et al: Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann Neurol 2004; 56:738-741. 146. Poppe M, Cree L, Bourke J, et al: The phenotype of limb-girdle muscular dystrophy type 2I. Neurology 2003; 60:1246-1251. 147. Walter MC, Petersen JA, Stucka R, et al: FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. J Med Genet 2004; 41:e50. 148. Udd B: Limb-girdle type muscular dystrophy in a large family with distal myopathy: homozygous manifestation of a dominant gene? J Med Genet 1992; 29:383-389. 149. Udd B, Vihola A, Sarparanta J, et al: Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 2005; 64:636-642. 150. Dincer P, Balci B, Yuva Y, et al: A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of α-dystroglycan. Neuromuscul Disord 2003; 13:771-778. 151. Koss-Harnes D, Hoyheim B, Jonkman MF, et al: Life-long course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation. Acta Derm Venereol 2004; 84:124-131. 152. Shimizu H, Takizawa Y, Pulkkinen L, et al: Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature. J Am Acad Dermatol 1999; 41:950-956. 153. Mostacciuolo ML, Miorin M, Martinello F, et al: Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy. Hum Genet 1996; 97:277-279.

1166

Section

XV

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154. Fukuyama Y, Osawa M, Suzuki H: Congenital progressive muscular dystrophy of the Fukuyama type—clinical, genetic and pathological considerations. Brain Dev 1981; 3:129. 155. Silan F, Yoshioka M, Kobayashi K, et al: A new mutation of the fukutin gene in a non-Japanese patient. Ann Neurol 2003; 53:392-396. 156. Santavuori P, Somer H, Sainio K, et al: Muscle-eye-brain disease (MEB). Brain Dev 1989; 11:147-153. 157. Yoshida A, Kobayashi K, Manya H, et al: Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 2001; 1:717724. 158. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al: Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002; 71:10331043. 159. Dobyns WB, Pagon RA, Armstrong D, et al: Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 1989; 32:195-210. 160. Helbling-Leclerc A, Zhang X, Topaloglu H, et al: Mutations in the laminin α2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 1995; 11:216218. 161. Jones KJ, Morgan G, Johnston H, et al: The expanding phenotype of laminin α2 chain (merosin) abnormalities: case series and review. J Med Genet 2001; 38:649-657. 162. Brockington M, Sewry CA, Herrmann R, et al: Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Am J Hum Genet 2000; 66:428-435. 163. Muntoni F, Taylor J, Sewry CA, et al: An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary α2 laminin deficiency unlinked to the LAMA2 locus on 6q22. Eur J Paediatr Neurol 1998; 2:1926. 164. Topaloglu H, Brockington M, Yuva Y, et al: FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 2003; 60:988-992. 165. Longman C, Brockington M, Torelli S, et al: Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of α-dystroglycan. Hum Mol Genet 2003; 12:2853-2861. 166. Ferreiro A, Ceuterick-de Groote C, Marks JJ, et al: Desminrelated myopathy with Mallory body–like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 2004; 55:676-686. 167. Ferreiro A, Quijano-Roy S, Pichereau C, et al: Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002; 71:739-749. 168. Moghadaszadeh B, Desguerre I, Topaloglu H, et al: Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36. Am J Hum Genet 1998; 62:1439-1445. 169. Hayashi YK, Chou FL, Engvall E, et al: Mutations in the integrin α7 gene cause congenital myopathy. Nat Genet 1998; 19:94-97. 170. Baker NL, Morgelin M, Peat R, et al: Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 2005; 14:279-293. 171. Camacho Vanegas O, Bertini E, et al: Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci U S A 2001; 98:75167521.

172. Demir E, Ferreiro A, Sabatelli P, et al: Collagen VI status and clinical severity in Ullrich congenital muscular dystrophy: phenotype analysis of 11 families linked to the COL6 loci. Neuropediatrics 2004; 35:103-112. 173. Demir E, Sabatelli P, Allamand V, et al: Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet 2002; 70:14461458. 174. Higuchi I, Shiraishi T, Hashiguchi T, et al: Frameshift mutation in the collagen VI gene causes Ullrich’s disease. Ann Neurol 2001; 50:261-265. 175. Mercuri E, Yuva Y, Brown SC, et al: Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study. Neurology 2002; 58:1354-1359. 176. Pan TC, Zhang RZ, Sudano DG, et al: New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet 2003; 73:355-369. 177. Pepe G, Bertini E, Bonaldo P, et al: Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC International Workshop, 23-24 November 2001, Naarden, The Netherlands. Neuromuscul Disord 2002; 12:984-993. 178. Pepe G, de Visser M, Bertini E, et al: Bethlem myopathy (BETHLEM) 86th ENMC International Workshop, 10-11 November 2000, Naarden, The Netherlands. Neuromuscul Disord 2002; 12:296-305. 179. Ullrich O: Kongenitale atonisch-sklerotische Muskeldystrophie, ein weiterer Typus der heredodegenerativen Erkrankungen des neuromuskulären Systems. Z Ges Neurol Psychiatr 1930; 126:171-201. 180. Bohlega S, Abu-Amero SN, Wakil SM, et al: Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 2004; 62:1518-1521. 181. Meredith C, Herrmann R, Parry C, et al: Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). Am J Hum Genet 2004; 75:703-708. 182. Tajsharghi H, Thornell LE, Lindberg C, et al: Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003; 54:494-500. 183. Feit H, Silbergleit A, Schneider LB, et al: Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am J Hum Genet 1998; 63:1732-1742. 184. Young ID, Harper PS: Hereditary distal spinal muscular atrophy with vocal cord paralysis. J Neurol Neurosurg Psychiatry 1980; 43:413-418. 185. Mahjneh I, Haravuori H, Paetau A, et al: A distinct phenotype of distal myopathy in a large Finnish family. Neurology 2003; 61:87-92. 186. Markesbery WR, Griggs RC, Leach RP, et al: Late onset hereditary distal myopathy. Neurology 1974; 24:127-134. 187. Udd B, Partanen J, Halonen P, et al: Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol 1993; 50:604-608. 188. Ahlberg G, von Tell D, Borg K, et al: Genetic linkage of Welander distal myopathy to chromosome 2p13. Ann Neurol 1999; 46:399-404. 189. Welander L: Homozygous appearance of distal myopathy. Acta Genet Stat Med 1957; 7:321-325. 190. Welander L: Myopathia distalis tarda hereditaria. Acta Med Scand 1951; 141(Suppl 265):1-124. 191. Di Blasi C, Moghadaszadeh B, Ciano C, et al: Abnormal lysosomal and ubiquitin-proteasome pathways in 19p13.3 distal myopathy. Ann Neurol 2004; 56:133-138. 192. Sangiuolo F, Bruscia E, Capon F, et al: Fine mapping of a distinctive autosomal dominant vacuolar neuromyopathy using

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193. 194. 195. 196. 197.

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11 novel microsatellite markers from chromosome band 19p13.3. Eur J Hum Genet 2000; 8:809-812. Servidei S, Capon F, Spinazzola A, et al: A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13. Neurology 1999; 53:830-837. Liu J, Aoki M, Illa I, et al: Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998; 20:31-36. Nonaka I, Sunohara N, Ishiura S, et al: Familial distal myopathy with rimmed vacuoles and lamellar (myeloid) body formation. J Neurol Sci 1981; 51:141-155. Argov Z, Eisenberg I, Grabov-Nardini G, et al: Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 2003; 60:1519-1523. Eisenberg I, Avidan N, Potikha T, et al: The UDP-Nacetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 2001; 29:83-87. Eisenberg I, Grabov-Nardini G, Hochner H, et al: Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat 2003; 21:99.

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199. Eisenberg I, Hochner H, Shemesh M, et al: Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13. Eur J Hum Genet 2001; 9:501-509. 200. Eisenberg I, Thiel C, Levi T, et al: Fine-structure mapping of the hereditary inclusion body myopathy locus. Genomics 1999; 55:43-48. 201. Krause S, Hinderlich S, Amsili S, et al: Localization of UDPGlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells. Exp Cell Res 2005; 304:365-379. 202. Chinnery PF, Johnson MA, Walls TJ, et al: A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci. Ann Neurol 2001; 49:443-452. 203. Watts GD, Wymer J, Kovach MJ, et al: Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004; 36:377-381.

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86

THE CONGENITAL MYOPATHIES ●

●

●

●

Heinz Jungbluth, Caroline A. Sewry, and Francesco Muntoni

The congenital myopathies are a clinically and genetically heterogeneous group of congenital muscle disorders with characteristic structural abnormalities evident on muscle biopsy, visible after preparation with specific histochemical stains and/or on electron microscopy. Central core disease (CCD),1,2 nemaline myopathy,3 myotubular (centronuclear) myopathy,4 and minicore myopathy (or multi-minicore disease [MmD])5 are the major disease entities. Other conditions with more unusual structural abnormalities are very rare, and it is not clear whether all are genetic entities.6 In the congenital myopathies, structural abnormalities of the central nervous system or the peripheral nerves are not evident, and intelligence is usually normal. Although generally nonprogressive, respiratory involvement may be disproportionate to overall muscle weakness and is the main prognostic factor. The term congenital myopathy applies only to conditions with defined structural abnormalities, not to other neuromuscular disorders with congenital onset such as congenital muscular dystrophies and mitochondrial and other metabolic myopathies. Whereas most of these conditions manifest at birth or in early childhood, milder variants manifesting in adulthood have been reported. It is currently unclear whether those are part of a clinical and genetic spectrum or are separate entities with similar histopathological features. Autosomal dominant, autosomal recessive, and X-linked inheritance are all recognized in this group of disorders, and some conditions such as nemaline myopathy, CCD, and myotubular myopathy may have more than one mode of inheritance. Genetic advances have implicated several genes encoding sarcomeric and sarcotubular proteins (Table 86–1). The boundaries between these conditions, originally defined according to histopathological and clinical criteria, are often indistinct and do not necessarily reflect underlying molecular mechanisms: Mutations in the same gene can indeed give rise to diverse clinical and histopathological phenotypes, and, conversely, a similar histopathological and clinical phenotype may arise from mutations in a variety of genes. Although clinical management is currently the main form of treatment of the congenital myopathies, further advances in the understanding of the precise molecular mechanisms underlying each disorder may result in more rational therapeutic options in the future. This chapter summarizes the epidemiology, clinical features, investigations, and management of the congenital

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myopathies as a group and outlines specific features, genetics, and pathogenesis of the major disease entities in more detail. The authors have intentionally adhered to a clinical and pathological categorization rather than a molecular one, because the assessment of clinical and histopathological features directs the molecular analysis, but the molecular assessment is not the starting point. The histopathological features used to classify each disorder are not specific. Molecular analyses have highlighted the overlap of histopathological features within genetically defined disorders and are helping clarify the spectrum of features associated with each defective gene. Several cases in the literature classified according to histopathological criteria were reported before molecular analysis became available, and it is not clear whether these historical cases are part of a spectrum relating to a single disorder or whether they are, in fact, heterogeneous.

EPIDEMIOLOGY Epidemiological data on the congenital myopathies are few, and larger geographical surveys are limited. The overall incidence of the congenital myopathies is estimated at 6 per 100,000 live births, representing approximately 10% of all neuromuscular disorders.7 Studies in northern Ireland8 and western Sweden9 suggest that the prevalence of the congenital myopathies in a pediatric population is between 3.5 and 5.0 per 100,000. The relative frequency of individual conditions is unknown, but CCD and conditions associated with mutations in the skeletal muscle ryanodine receptor gene (RYR1) appear to be more common in the patient population (see later discussion) than are nemaline myopathy and the much rarer centronuclear myopathies. Also, the prevalence of specific congenital myopathies may have been previously underestimated, inasmuch as not all muscle biopsy specimens from individuals carrying disease-causing mutations exhibit the characteristic structural abnormalities.10

CLINICAL FEATURES Most of the clinical features are nonspecific, despite some variations in overall severity, distribution of weakness, and associated features. The diagnosis of a specific congenital myopathy can therefore be made only tentatively on clinical grounds

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T A B L E 86–1. Major Gene Defects in the Congenital Myopathies Disorder

Gene Location

Gene Symbol

Gene Product

Mode of Inheritance

Key References

Central core disease With additional rods With additional minicores Multi-minicore disease Nemaline myopathy

19q13.1 19q13.1 19q13.1 1p36 2q21.2-q22 1q42.1 1q21-q23 9p13.2-p13.1 Xq28 1q42.1

RYR1 RYR1 RYR1 SEPN1 NEM2 ACTA1 TPM3 TPM2 MTM1 ACTA1

Ryanodine receptor Ryanodine receptor Ryanodine receptor Selenoprotein N Nebulin α-Actin, skeletal α-Tropomyosin β-Tropomyosin Myotubularin α-Actin, skeletal

AD, AR AD AD, AR AR AR AD, AR AD, AR AD XL AD

66, 67 49, 50 37, 87 108 147, 149 34 144, 146 151 215, 232 162

Myotubular myopathy Congenital fiber type disproportion

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked.

alone, and muscle biopsy is required for a precise diagnosis in individual cases. Presentation of the patient is either as a “floppy infant” with generalized hypotonia at birth followed by developmental delay or with weakness of variable severity and distribution later in childhood. Presentation in adulthood has also been described, but other disease processes mimicking the appearance of a congenital myopathy should be considered.11 Presentation at birth is often associated with “myopathic” facial features, feeding difficulties, and respiratory difficulties; thinning of the ribs and chest deformities may indicate antenatal onset. Arthrogryposis may be present in the most severe cases of nemaline myopathy12 and CCD13 but is not a common feature. Most cases manifest later in infancy or childhood with motor developmental delay or predominantly proximal weakness that mimics a limb girdle muscular dystrophy or a mild form of spinal muscular atrophy. In other patients, there is marked weakness of the axial muscles and/or the face; a minority have prominent distal involvement. Extraocular involvement is common in centronuclear myopathy and specific subgroups of minicore myopathy, but not in CCD and nemaline myopathy. Spinal deformities include exaggerated lordosis, scoliosis, and spinal rigidity.14 Scoliosis may be present at birth but typically manifests in a progressive manner around the time of the pubertal growth spurt. Ligamentous laxity is common. Joint contractures, mainly of the Achilles tendon, tend to progress over time. Tendon reflexes are weak or absent. Congenital dislocation of the hips is a common feature in CCD15 but can occur in several other neuromuscular disorders. Respiratory involvement secondary to diaphragmatic and/ or intercostal muscle weakness is the main prognostic factor.16,17 Respiratory impairment is common in centronuclear myopathy, nemaline myopathy, and subgroups of minicore myopathy; it may occur only rarely in CCD,18 with the exception of the severe congenital variant, in which it is common.13 Susceptibility to respiratory infections is frequent, particularly early in life, but may improve with time.13,19 Cardiac involvement other than cor pulmonale secondary to respiratory impairment is not usually a feature, although structural abnormalities such as mitral valve prolapse have been occasionally documented. However, a few patients have had congenital myopathy with rods and/or cores and cardiac involvement in association with mutations in the skeletal muscle α-actin gene (ACTA1).20

There are no associated structural central nervous system or peripheral nerve abnormalities, and intelligence is usually normal. In the few cases in which an autopsy was performed, no central or peripheral nerve abnormalities could be identified.21-23 Progression of muscle weakness in the absence of substantial respiratory impairment does not usually occur, but deterioration is occasionally associated with growth spurts or marked weight gain. The most severely affected neonates may die from respiratory failure, but long-term survival has been reported even in infants with severe hypotonia and marked respiratory impairment.13,19,24,25

INVESTIGATIONS Histochemical studies of muscle biopsy specimens, supplemented selectively by immunocytochemistry and electron microscopic findings, remain the principal tests for confirming the diagnosis of a clinically suspected congenital myopathy and for directing molecular analysis. Muscle biopsy is also important for ruling out other neuromuscular conditions with congenital onset and similar clinical features, such as mitochondrial myopathies, glycogenoses, and lipid storage myopathies. Other investigations may support the suspicion of an underlying myopathic process, but, with the possible exception of muscle imaging, they rarely aid in the diagnosis. Diseased muscle exhibits characteristic changes in echogenicity and signal intensity on ultrasonography, computed tomography, and magnetic resonance imaging (MRI), which reflect an increase in adipose and connective tissue.7,25-27 Muscle MRI in particular may reveal a characteristic pattern of selective involvement in conditions such as CCD and nemaline myopathy, thereby guiding the molecular diagnosis in clinically and histopathologically equivocal cases.28,29 The serum creatine kinase level is usually normal or only mildly elevated. The electromyogram may appear normal in the young patients or in mild cases but usually reveals nonspecific myopathic features, comprising small-amplitude polyphasic potentials.30,31 Additional “neurogenic” changes may be present in distal muscles, particularly of patients with nemaline myopathy.31-33 Spontaneous activity resembling findings in spinal muscular atrophy have been reported in the most severely affected neonates.34

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MANAGEMENT No cure is currently available for any of the congenital myopathies, and treatment is therefore largely supportive. Respiratory impairment is the most important complication and should be anticipated by regular monitoring of respiratory function: regular measurement of forced vital capacity, in sitting and lying positions in order to evaluate diaphragmatic function, and annual overnight oxygen saturation monitoring if the forced vital capacity falls under 60% or, if clinically indicated by symptoms of nocturnal hypoventilation such as early morning headaches, loss of appetite, and daytime tiredness.35 Respiratory impairment may be disproportionately severe, and respiratory failure may occur even in ambulant patients.16,17,19,35-37 Nighttime noninvasive ventilation offers an effective means of improving quality of life and overall prognosis in otherwise only moderately disabled patients. Respiratory infections should be treated aggressively. A cardiac ultrasound study should be performed to document baseline cardiac function and occasionally associated structural cardiac abnormalities. Regular cardiac ultrasonography should be performed in patients with respiratory impairment, although appropriate respiratory management should prevent cor pulmonale.16 Primary cardiomyopathies are rare in the congenital myopathies but have been reported in individual cases with mutations in the ACTA1 gene20 and in a few patients with minicores evident in muscle biopsy specimens (see later discussion). Dysarthria and feeding difficulties are common and ought to be monitored by a speech language therapist. Gastrostomy might be indicated in selected cases to prevent failure to thrive and the risk of aspiration. Spinal posture should be monitored closely and surgical procedures for scoliosis planned carefully to ensure that respiratory function is still sufficient at the time of operative intervention.38 Regular physiotherapy is aimed at preservation of muscle power and prevention of contractures. When orthopedic intervention is planned, the potential benefit has to be weighed against adverse effects of prolonged immobilization. Patients with CCD and other congenital myopathies associated with mutations in the RYR1 gene are at increased risk of malignant hyperthermia susceptibility,39 and potentially triggering anesthetic agents should be rigorously avoided in these cases. Although a higher anesthetic risk is not clearly documented in other congenital myopathies, similar precautions should be taken in the anesthetic preparation of other patients,35 particularly in those in whom the genetic background is unclear. Pharmacological interventions have not been widely used in the treatment of the congenital myopathies. A small pilot study has demonstrated some beneficial effect of salbutamol in the treatment of patients with CCD and minicore myopathy,40 but this has yet to be confirmed in a larger controlled trial.

CENTRAL CORE DISEASE Histopathology The term central core disease (Mendelian Inheritance in Man [MIM] number 117000)41 was introduced in 195842 after the original description of a family with five affected individuals in three generations who showed amorphous central areas in muscle fibers with the modified Gomori trichrome stain1;

absence of oxidative enzyme activity within the core area was subsequently identified as the characteristic histopathological feature (Fig. 86–1A).27 The cores have a predilection for type 1 fibers and extend along a significant length of the longitudinal muscle fiber axis43; localization is characteristically single and central, but multiple, peripheral, and eccentric cores may occur within the same sample.10 In some cases, large typical cores may not be apparent, but only unevenness of oxidative enzyme stain or small core areas are visible, producing a confusing pathological overlap with minicore disease. Pronounced type 1 predominance or uniformity is common and may be the only feature at presentation, particular in very young patients.10,43 The degree of associated increases in fat and connective tissue depends both on the age of the patient and on the sampling site, because the degree of selective muscle involvement may be considerable29; centrally placed nuclei may also be present but are not a consistent feature. Necrosis and regeneration are not usually seen in CCD. Ultrastructurally, typical cores show a reduction or absence of mitochondria, reflected in the absence of oxidative enzyme staining, accompanied by varying degrees of sarcomeric disruption and accumulation of Z line material.43 In most cases, cores are “structured” with hypercontracted myofibrils that retain adenosine triphosphatase activity but are depleted in mitochondria and sarcoplasmic reticulum; “unstructured” cores, on the contrary, show an absence of adenosine triphosphatase activity, marked disruption of myofibrils, and accumulation of Z line material. Immunohistochemical studies have demonstrated accumulation of the intermediate filament protein desmin within cores and at their perimeter.10,44,45 Accumulation of other proteins also occurs, including the actin cross-linking protein γ-filamin, αβ-crystallin, small heat shock protein 27, and myotilin46; however, these are nonspecific findings and may be observed in core formation of different etiology. Core formation is a nonspecific secondary phenomenon and is not correlated with the degree of the muscle weakness. Core formation can be observed after tenotomy,47 in the muscle of patients with long-standing neurogenic atrophy (“target fibers”), and in association with several other gene defects. Central corelike structures may be found in association with dilated cardiomyopathy in patients with mutations in ACTA120 or in the β-myosin heavy-chain gene (MYH7)48; however, in the latter group, there is usually no or little associated weakness. Central core and nemaline rods are occasionally observed in the same biopsy specimen in patients with mutations in the RYR1 gene.49,50

Clinical Features “Classical” CCD is usually inherited as a dominant trait with a fairly consistent clinical phenotype; sporadic cases with similar clinical features are increasingly recognized. Presentation is in infancy with hypotonia or in early childhood with motor developmental delay or proximal weakness17; however, more severe presentations with features of the fetal akinesia sequence have been reported.13,51 Most of these infants required ventilation from birth, and their course was severe and eventually fatal; however, one infant was eventually weaned off the ventilator and became independently mobile.13 Weakness in most familial cases is pronounced in the hip girdle and in the axial muscle groups17; in rare cases, there is associated muscle wasting.52 Facial involvement is usually mild,

chapter 86 the congenital myopathies

A

C ■

100 ␮m

50 ␮m

B

D

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200 ␮m

20 ␮m

Figure 86–1. Characteristic histopathological changes in the congenital myopathies. A, Central core disease: Biopsy specimen from the quadriceps of a 3-year-old boy, stained for cytochrome oxidase. Large cores devoid of activity (arrows) are central or peripheral. Note also the lack of fiber type differentiation. B, Mini-multicore disease: multiple minicores and unevenness of the reduced form of nicotinic adenine dinucleotide–tetrazolium reductase (NADH-TR) stain (arrow) in a case with a selenoprotein N 1 (SEPN1) mutation. Note the two fiber pattern and unevenness of stain of both fiber types. C, Nemaline myopathy: specimen from a patient with nemaline myopathy with a skeletal muscle α-actin gene (ACTA1) mutation, stained with Gomori trichrome. Note the dark rodlike structures in most fibers (arrows). D, Centronuclear (myotubular) myopathy: specimen from a patient with X-linked myotubular myopathy, stained with hematoxylin and eosin. Large central nuclei (arrows) are apparent in several large fibers.

and lack of complete eye closure may be the only finding. Bulbar and extraocular involvement is usually absent. Some patients may have prominent exercise-induced myalgia.53 Orthopedic complications are common and comprise congenital dislocation of the hips, foot deformities, and scoliosis.15,18,54 Contractures other than Achilles tendon tightness are rare, and many affected individuals have marked ligamentous laxity, occasionally in association with patellar instability.54 Cardiac abnormalities other than occasional mitral valve prolapse have rarely been reported.55 Respiratory involvement is typically milder than in other congenital myopathies but may be severe in some sporadic and recessive cases.51 Malignant hyperthermia susceptibility (MHS) is a frequent complication39,55,56 and should be anticipated in the anesthetic preparation of patients with CCD. Some patients with MHS may show consistent dysmorphic features (King-Denborough syndrome), including ptosis, down-slanting palpebral fissures, neck webbing, scoliosis, pectus deformity, short stature, and cryptorchism57,58; additional findings in other families may include vertebral fusion, eventration of the diaphragm, and spinal cord tethering.58,59

Except for patients with the most severe neonatal cases and some patients with congenital dislocation of the hips,37,60 most patients achieve the ability to walk independently. The course of CCD is static or only slowly progressive, even over prolonged periods of follow-up.61 The serum creatine kinase level is usually normal or only mildly elevated.62,63 Muscle ultrasonography often shows a striking increase in echogenicity and differential muscle involvement, even in paucisymptomatic individuals.64 Muscle MRI reveals a characteristic pattern of selective muscle involvement in patients with typical CCD29 (Fig. 86–2A and D) and may complement clinical assessment.

Genetics of Central Core Disease and Malignant Hyperthermia Susceptibility MHS was recognized in 1960 as a familial, autosomal dominant trait by M. A. Denborough and R. R. H. Lovell in Australia and has been linked to several loci. Both CCD and MHS show considerable clinical overlap and have been associated with

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RF

RF

RF S VL

S

VL

S

VL AL

AL G

AM

G

AM

G

ST ST

A

B

C

TA TA

TA

PG PG SO

SO GL

■

SO

GL

GM

D

PG GM

E

F

Figure 86–2. Muscle magnetic resonance imaging in the congenital myopathies: T1-weighted transverse images from the proximal thigh (A to C) and the lower leg (D to F). A and D, Central core disease associated with dominant mutations in the skeletal muscle ryanodine receptor gene (RYR1). There is a marked signal increase in the thigh (A) within the vastus lateralis (VL), sartorius (S), and adductor magnus (AM) muscles, with relative sparing of rectus femoris (RF), adductor longus (AL), gracilis (G), and semitendinosus (ST). In the lower leg (D), abnormal signal is increased in the soleus muscle (SO), the peroneal group (PG), and the gastrocnemius medialis muscle (GM), with relative sparing of tibialis anterior (TA) and gastrocnemius lateralis (GL) muscles. B and E, Nemaline myopathy associated with recessive mutations in the nebulin gene (NEB). The thigh (B) is largely normal. In the lower leg (E), there is an increase in abnormal signal in soleus (SO) and tibialis anterior (TA) muscles, with relative sparing of the peroneal group (PG) and both heads of the gastrocnemius. C and F, Nemaline myopathy associated with a dominant mutation in the skeletal muscle α-actin gene (ACTA1). In the thigh (C), there is diffuse involvement of all muscle groups with marked atrophy and fatty replacement. In the lower leg (F), there is a marked and diffuse increase in abnormal signal within the anterior and posterior compartments and relatively milder involvement of the soleus (SO). AL, adductor longus; AM, adductor magnus.

mutations in the RYR1 gene at chromosome 19q13.1.65-67 CCD is usually inherited as a dominant trait; however, sporadic cases either caused by de novo dominant mutations or associated with recessive inheritance are increasingly recognized. Although it is now apparent that mutations in the RYR1 gene (MHS1) account for the majority of familial MHS cases,68 locus heterogeneity has been suggested by variable degrees of linkage evidence for several loci (MHS2 to MHS6) and cosegregation of MHS susceptibility with mutations in candidate genes.69-74 There is also the possibility that the MHS phenotype may reflect the compound influence of several genes rather than a major gene defect.75 Genetic homogeneity in CCD has been suggested by RYR1 linkage in most families without con-

firmed mutation. Although dominant mutations in the ACTA1 gene20 and the MYH7 genes48 may mimic the histopathological appearance, clinical features such as an associated cardiomyopathy are divergent from those in classic CCD. More than 50 RYR1 mutations have been reported to date in association with CCD, MmD (described later), and MHS with or without cores evident on muscle biopsy specimens.76-80 Most RYR1 mutations are missense mutations; a few small deletions78,79,81 and a cryptic splicing site mutation51 have also been documented. The first reported RYR1 mutations gave rise predominantly to the MHS phenotype and affected mainly two regions of the protein: the cytoplasmic N-terminal domain (MHS/CCD region 1, amino acids 35 to 614) and the cytoplas-

chapter 86 the congenital myopathies mic central domain (MHS/CCD region 2, amino acids 2163 to 2458). Although mutations associated with a congenital myopathy phenotype have been identified in these regions,66,67,82,83 there has been increasing evidence that mutations affecting the C-terminal portion of the receptor molecule (MHS/CCD region 3, amino acids 4550 to 4940) are common in patients with CCD.49,78-80,84 Although the mutations are occasionally reported in the C-terminal portion of the protein,85 a series of 124 unrelated North American patients with MHS confirmed the Nterminal and central portion of the protein as the predominant sites of MHS-related RYR1 mutations.86 Although the majority of RYR1 mutations associated with MHS or CCD described to date are dominant missense mutations, recessive inheritance of RYR1 mutations has been reported in mild cases with histopathological features of MmD and CCD37,87 and in a severe form of CCD manifesting with a fetal akinesia syndrome.13 These findings suggest that clinically silent MHS mutations may give rise to a severe phenotype in the compound heterozygous or homozygous state, caused by a combined deleterious effect on the tetrameric RyR1 protein. The effects of specific RYR1 mutations on excitability and calcium homeostasis have been studied in various homologous and heterologous expression systems. Two models for mutation-induced receptor malfunction have been proposed: depletion of sarcoplasmic reticulum calcium stores with resulting increases in cytosolic calcium levels (the “leaky channel” hypothesis)88 and a specific disturbance of excitation-contraction coupling (the “E-C uncoupling” hypothesis).89 The “ectopic” RYR1 expression in B lymphocytes has been recognized; this offers an easily accessible model for studying the effects of RYR1 mutations in vitro. B lymphocytes harboring CCD-related RYR1 mutations exhibit unprompted calcium release with resulting depletion of sarcoplasmic reticulum stores78,90; increased release of inflammatory cytokines in the same study91 may also indicate a role of RYR1 in immunomodulation.

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entire fiber diameter may be involved (focal loss of crossstriations).93,94 Pathological distinction between CCD and MmD is occasionally difficult, because in some biopsy specimens from patients with RYR1 mutations, only unevenness of oxidative enzyme stain or minicores are seen, and minicores may evolve into central cores with time.10,87 Commonly associated features are predominance or uniformity of type 1 fibers, often hypotrophic, with or without type 2 hypertrophy.95 This is particularly true for cases secondary to RYR1 but not selenoprotein N, 1 (SEPN1) mutations (see later discussion). Although central nuclei may be a feature in cases caused by RYR1 mutations, they are not usually associated with SEPN1 mutations. The presence of whorled fibers and increases in fat and connective tissue in some affected families43 are suggestive of a potential overlap with the milder congenital muscular dystrophies. On electron microscopy, minicores are characterized by focal areas of myofibrillar disruption with paucity of mitochondria.43 The sizes of minicores and the degree of myofibrillar disruption are variable, ranging from mild Z line streaming to areas with complete loss of sarcomeric organization. These may be observed in the same biopsy speciment.5 In some areas, ultrastructural abnormalities may consist only of subtle misalignment of myofibrils accompanied by an absence of mitochondria. In immunohistochemical studies, authors have reported abnormalities on staining with desmin45 and γ-filamin antibodies,46 similar to those observed in CCD. Minicores are nonspecific; they may be found in various disorders such as muscular dystrophies; denervation; and inflammatory, endocrine, and metabolic myopathies. Also, minicore-like structures may coexist with central cores, central nuclei, and nemaline rods in the same biopsy specimen10,20,96-102 and in association with various gene defects.

Clinical Features MULTI-MINICORE DISEASE 41

Multicore disease (MIM numbers 255320 and 157550) was originally described in two unrelated children with hypotonia and muscle weakness dating from infancy and a characteristic histopathological appearance of multiple, small, well-circumscribed foci of myofibrillar degeneration with reduction of oxidative enzyme staining.5 Since the original description, at least 100 other cases with similar histopathological features and a wide range of clinical phenotypes have been reported, under different names such as minicore myopathy, myopathy with multiple minicore, pleocore disease, or myopathy with focal loss of cross-striations. The designation multi-minicore disease92 used in this chapter reflects the larger number and smaller size of characteristic lesions compared with classic CCD.

Histopathology Minicores are areas of focal myofibrillar disruption with a variable degree of Z line disorganization and may occur in both type 1 and type 2 fibers (see Fig. 86–1B). They extend only a short distance along the longitudinal axis of the muscle fiber, affecting a variable number of sarcomeres.5,43 In rare cases, the

MmD usually manifests in infancy or childhood with hypotonia or proximal weakness95,103; cases with antenatal onset or presentation in adulthood104-107 have been reported, but the molecular defect in these is not known. Clinical features associated with the histopathological appearance of MmD are markedly heterogeneous, and at least four different subgroups have been recognized and are gradually being resolved molecularly (see later discussion). The most instantly recognizable classic phenotype of MmD95,103,108 usually manifests in infancy with hypotonia and is characterized by spinal rigidity, scoliosis, and early respiratory impairment. There is predominant truncal and proximal weakness, often in association with wasting pronounced in the shoulder girdle and the hip adductors (“bracket-like thighs”). There may be mild facial weakness and a high-pitched nasal voice. Severe scoliosis and respiratory failure have usually evolved by the early teens.95,103,109 Respiratory impairment is often disproportionate to the overall degree of muscle weakness and has to be anticipated even in ambulant patients. Most of these cases are secondary to mutations in the SEPN1 gene (discussed later). In a subset of patients with a similar phenotype, extraocular muscle involvement pronounced on abduction and upward gaze may evolve over time.94,95,110 With the exception of the most

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severely affected neonatal cases,51 respiratory impairment is usually milder than in the classic form and may improve with time. Mutations in the RYR1 gene have been identified in these patients (discussed later). Another group has a milder phenotype similar to CCD and characterized by predominant hip girdle weakness with relative sparing of respiratory and bulbar muscles.37 A common complaint is exercise-induced myalgia. In male patients, cryptorchism may be an additional feature (personal observation). Patients in this group may also demonstrate muscle imaging findings similar to those observed in classic CCD caused by mutations in the RYR1 C-terminal portion.37,87,110 In some patients, there is additional marked distal weakness and wasting, predominantly affecting the hands.37,87 The observation of extraocular muscle involvement evolving over time in this group is suggestive of a clinical continuum between the latter groups rather than distinct clinical entities.110 Mutations in the RYR1 gene also account for this group of disorders. A severe form with antenatal onset, generalized arthrogryposis, dysmorphic features, and moderate respiratory impairment has been described in only a few patients.103 Congenital cardiac defects—namely, mitral valve prolapse— have been occasionally reported.5,37 Secondary right ventricular impairment is common in the classic phenotype with untreated respiratory impairment but not in other clinical subgroups.37 A primary cardiomyopathy has been reported in some cases with minicores on muscle biopsy specimens,55,106,111,112 but these were genetically unresolved, and additional desmin accumulation in muscle and dominant inheritance were suggestive of a pathogenic mechanism distinct from that in other families (see later discussion). Malignant hyperthermia has been reported occasionally113,114 and has to be anticipated in the anesthetic management of these patients. Minicores have been noted in muscle biopsy specimens from a few families with mutations in the RYR1 gene and MHS but no other clinical features of a congenital myopathy.115,116 Minicores have been reported in the multiple pterygium syndrome117 and in two siblings with mental retardation and dysmorphic features similar to the King-Denborough syndrome118; the molecular basis of these associations is currently unclear. The clinical course is usually static or only slowly progressive37,119 but depends largely on the degree of cardiorespiratory impairment.

Genetics MmD is usually inherited as an autosomal recessive trait, and only a few families with manifestations compatible with dominant inheritance have been reported; however, the molecular defects in these families have not been characterized. The marked phenotypic variability associated with the presence of minicores is reflected in genetic heterogeneity, as demonstrated by recessive mutations in both the SEPN1 and RYR1 genes identified in clinically distinct groups. Investigation of SEPN1 on chromosome 1p36 as a candidate for causing MmD was prompted by the considerable clinical and histopathological overlap between the classic phenotype of MmD and congenital muscular dystrophy with rigidity of the spine, previously attributed to SEPN1 muta-

tions.120 SEPN1 involvement in the classic phenotype of MmD was suggested both by linkage data and by direct mutational analysis in approximately 50% of patients with these clinical features.108 More than 30, mainly truncating SEPN1 mutations associated with a congenital myopathy phenotype have been identified to date. Mutations in the SEPN1 gene were also identified in cases with unusual pathological structures resembling Mallory bodies (Mallory body myopathy), further expanding the pathological spectrum of the condition.121 Homozygous mutations are unexpectedly common even in nonconsanguineous families, which reflects the presence of a few founder mutations in different European populations. The precise function of selenoprotein N, a glycoprotein localized in the endoplasmic reticulum, is unclear, but a structural motif similar to those observed in calcium-binding proteins120 is suggestive of possible involvement in calcium homeostasis in muscle. Although selenoprotein N is expressed in all adult tissues, prominent expression in fetal muscle precursor cells is suggestive of a potential role in myogenesis. Involvement of the RYR1 gene as a cause of multi-minicores was to some extent unexpected, in view of differences in core structure and mode of inheritance between recessively inherited MmD and CCD caused by dominant mutations in the same gene. Attempting to classify individual cases as MmD or CCD may be difficult because there is a histopathological and clinical continuum between the two conditions. Although the histopathologic appearance of MmD appears to be more closely associated with recessively inherited RYR1 mutations, dominant RYR1 mutations occasionally give rise to minicores on muscle biopsy specimens10 and may have accounted for a proportion of MmD pedigrees with autosomal dominant inheritance reported before the molecular area. Also, the histopathological appearance of MmD caused by recessive RYR1 mutations may evolve into the classic picture of CCD over long periods of follow-up.87 A particular feature of RYR1-related recessive cases with minicores is extraocular involvement, not present in dominant CCD. MmD with external ophthalmoplegia in an isolated case from a consanguineous Tunisian family was attributed to a homozygous RYR1 mutation, introducing a cryptic splice site in intron 101,51 carried by asymptomatic parents. RYR1 involvement was also suggested by linkage evidence in four additional families with a similar phenotype,110 including the original family reported by Swash and Schwartz.94 RYR1 involvement in the moderate form of MmD with hand involvement was suggested by considerable clinical overlap with CCD and an identical pattern of selective involvement on muscle imaging.37,87 In a consanguineous Algerian family and a consanguineous British family, homozygous RYR1 mutations were subsequently identified, and RYR1 involvement has been suggested by linkage evidence in other families. The RYR1 gene is also a likely candidate for causing the severe form of MmD with neonatal onset and arthrogryposis, in view of phenotypic overlap with the form of CCD with fetal akinesia sequence.13 There is evidence for further genetic heterogeneity in MmD, because only one half of all cases with the classic phenotype have linkage or mutational evidence of SEPN1 involvement.108 Also, although a proportion of MmD in pedigrees with autosomal dominant inheritance are likely to be caused by dominant RYR1 mutations, unusual clinical features such as a primary cardiomyopathy55,111 are suggestive of a different genetic background in other families with this unusual mode of transmission. Specimens from patients with dominantly inherited

chapter 86 the congenital myopathies desmin myopathy may demonstrate minicores in addition to inclusions on muscle biopsy. This observation and the desmin accumulation reported in some patients with MmD and cardiomyopathy111 suggest that the desmin gene is a possible candidate for causing this subgroup disorder. Also, a cardiomyopathy associated with cores on muscle biopsy has been described as part of the expanding clinical spectrum associated with dominant mutations in the ACTA1 gene.20

NEMALINE MYOPATHY Nemaline myopathy was first described in 1963.3 The name nemaline myopathy is derived from the abundance of threadlike or rodlike structures (Greek nema means “thread”) in muscle that turn red with the modified Gomori trichrome technique (see Fig. 86–1C).

Histopathology Nemaline rods are often in subsarcolemmal clusters (see Fig. 86–1C) but may also be observed within the fiber and/or intranuclearly, particularly in severe cases122 caused by mutations in the ACTA1 gene; these may also feature additional accumulation of actin filaments.34,123 The number of rods varies between fibers and between muscles and is not correlated with clinical severity of the disease. Associated features include type 1 predominance or uniformity with or without type 1 hypotrophy43 and deficiency of type 2B muscle fibers in patients and heterozygous persons in the recessive form.124 Necrosis, regeneration, fibrosis, and internal nuclei are not usually seen in nemaline myopathy. Because the presence of nemaline rods is highly nonspecific and has been described in a number of different clinical contexts43 and in association with histopathological features of other congenital myopathies,96 a diagnosis of nemaline myopathy can be made only in the context of specific clinical features. On electron microscopy, nemaline rods are often observed in continuity with the Z lines and have a similar lattice structure.43 They are often, but not consistently, orientated parallel to the long axis of the fiber. The close structural relationship between nemaline rods and the Z line has been further supported by immunohistochemical studies demonstrating the Z line component α-actinin as the main component of nemaline bodies.125 Nemaline bodies are associated with actin and tropomyosin and are also labeled with antibodies against myotilin and telethonin.126,127 In immunohistochemical studies, researchers have also investigated the effect of specific genetic defects on the expression of affected proteins,128,129 and these investigations may in a few selected cases be helpful in directing molecular genetic studies.23,130 Research studies with noncommercial antibodies to nebulin suggested that absence of antibody binding to the C-terminal SH3 domain occurs in some cases with mutations in the nebulin gene (NEB)129; however, secondary alterations in nebulin may also occur in cases with an ACTA1 mutation and in Duchenne muscular dystrophy.

Clinical Features The clinical spectrum of nemaline myopathy is wide. A classification suggested by the European Neuromuscular Consortium on nemaline myopathy131 distinguishes six different

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clinical phenotypes; the “typical” form is a reference point and other forms are defined on the basis of differences in onset or severity and the presence of unusual features: The “typical” congenital form of nemaline myopathy is characterized by onset in infancy or early childhood with pronounced facial and bulbar involvement.131 Achievement of motor milestones is usually delayed, and in the absence of substantial respiratory problems, the course is slowly progressive or static. Feeding difficulties may be disproportionately severe. The severe congenital form is characterized by absence of both spontaneous movements and respiration at birth, occasionally preceded by signs of antenatal onset within the spectrum of the fetal akinesia sequence.12,132 Other forms of nemaline myopathy include the intermediate congenital form, in which patients move and breathe at birth but are later unable to achieve ambulation or respiratory independence; mild nemaline myopathy, with childhood onset; adult-onset nemaline myopathy, which may or may not be genetic in origin; and other manifestations with unusual associated features such as cardiomyopathy, ophthalmoplegia, or an uncommon distribution of weakness.19,23,130,133 Patients with the typical congenital form commonly have marked axial weakness and facial and bulbar involvement.134,135 Distal involvement may evolve later and mimic the appearance of a peripheral neuropathy or a distal myopathy. Skeletal involvement consisting of facial dysmorphism, scoliosis, spinal rigidity,136 and foot deformities is frequent both in the typical and intermediate forms. Although there is considerable phenotypic overlap between genetically distinct forms of nemaline myopathy, one study of 60 patients with mutations in the nebulin or actin genes revealed clinically distinct selective involvement of specific muscles, depending on the underlying gene defect.130 These observations have been corroborated by comparisons of muscle MRI results in molecularly characterized patients with nemaline myopathy (see Fig. 86–2).28 Respiratory involvement is frequent in all forms of nemaline myopathy, and respiratory failure may occur at any age. Nocturnal hypoventilation may be the presenting symptom in adulthood101 and may be frequently underestimated in otherwise paucisymptomatic patients. Patients with nemaline myopathy must be closely monitored for signs and symptoms of nocturnal hypoventilation, and noninvasive nighttime ventilation ought to be commenced early when indicated.35,137 Respiratory infections are frequent and must be treated vigorously. Cardiac evaluation of a large series of patients with the typical congenital form of nemaline myopathy revealed normal cardiac function.138 Although cardiac involvement has been suggested in some genetically unresolved cases with nemaline rods in skeletal or cardiac muscles, those were only rarely associated with a congenital myopathy phenotype.139,140 Furthermore, nemaline bodies may develop in evolving cardiac hypertrophy in the absence of a clinically overt cardiomyopathy or muscle weakness.141 Although to the authors’ knowledge there have been no reports of clear malignant hyperthermia reactions in nemaline myopathy, a respiratory decompensation with anesthesia needs to be anticipated.142 Also, RYR1 mutations may give rise to both cores and rods on muscle biopsy,49,79 and MHS thus must be considered in genetically unresolved cases with unusual histopathological features. The course of the “typical” form of congenital nemaline myopathy is slowly progressive or nonprogressive, but the severe neonatal form is often fatal. Neonatal respiratory failure

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and arthrogryposis are indicators of a poor outcome, whereas achievement of motor milestones within the first year of life is correlated with a good prognosis.142 The degree of cardiorespiratory involvement is the main prognostic factor in all age groups. There is a potential for deterioration in affected women during pregnancy.143

Genetics Nemaline myopathy is inherited in both an autosomal recessive and, less frequently, an autosomal dominant manner. To date, five genes have been implicated in nemaline rod formation: the gene for slow α-tropomyosin (TPM3)144-146 (WallgrenPettersson, 2003), NEB,135,147-149 ACTA13234 (Sparrow et al, 2003), the muscle troponin T gene (TNNT1),150 and the β-tropomyosin gene (TPM2).151 Recessive mutations in NEB and dominant mutations in ACTA1 are the most common genetic causes. The typical form of nemaline myopathy131,134 is usually caused by mutations in the NEB147,149,152,153 (Wallgren-Pettersson et al, 2003) but sometimes by de novo dominant mutations in the actin gene.130,154,155 In sporadic cases, mutations in the relatively small ACTA1 ought to be ruled out first before screening of the giant NEB is considered.156 Further genetic heterogeneity in nemaline myopathy is expected, because some families show no linkage to any of the known loci.135,142,151 NEB on chromosome 2q22 is large, with 249 kilobases of genomic sequence and 183 exons.156,157 NEB encodes nebulin, a giant protein that both stabilizes the length of actin filaments and forms a composite Ca2+-linked regulatory complex on the thin filament.157,158 NEB mutations reported to date have been exclusively recessive and are most commonly involved in the typical congenital form of nemaline myopathy149,152,153; a more severe phenotype with neonatal presentation159 and milder cases occasionally occur. A particular NEB deletion has been described in the Ashkenazi Jewish population with a carrier frequency of approximately 1:100.153 ACTA1 on chromosome 1q42 contains only six exons.34 A study of Australian patients with nemaline myopathy revealed a heterozygosity frequency of 15% for ACTA1 missense mutations,154 which suggests that changes in this gene are the second most common cause of nemaline myopathy. ACTA1 mutations are predominantly autosomal dominant and only rarely autosomal recessive missense mutations.19,34,130,133,154,155 There is a high rate of de novo mutations, accounting for many sporadic cases, often with a severe congenital phenotype34,123,133,154,155,160,161; muscle biopsy specimens from those patients may feature intranuclear rods with or without cytoplasmic rods. Parental somatic mosaicism has been reported in two families.155 Less frequently, dominant ACTA1 mutations give rise to much milder cases with significant clinical overlap with the form caused by mutations in NEB.34,101,154 Mutations in the actin gene can also cause accumulation of thin filaments with or without nemaline bodies,34 congenital fiber type disproportion,162 or cores.20 There is an overall correlation between genotype and phenotype; the most severely affected patients carry nonsense mutations. Interestingly, cardiac actin can functionally compensate for the defective skeletal actin, and in a few patients, this has led to improved muscle function (F. Muntoni, N. G. Laing, and C. A. Sewry, personal observation, July 2005). A mouse model is currently being generated to investigate whether the upregulation of cardiac actin may alleviate the myopathy caused by ACTA1 mutations.163

The tropomyosin genes are rarely involved in nemaline myopathy. A dominant mutation in the first exon of TPM3 at chromosome 1q22-q23 has been identified in a large Australian pedigree with a mild form of the condition and predominant lower limb weakness144,145; in addition, another dominant de novo164 and a few recessive mutations146,165 have also been reported. Dominant mutations in TPM2 have so far been identified in only two families with a mild form of nemaline myopathy.151 TPM2 mutations may also give rise to autosomal dominant distal arthrogryposis without features of nemaline myopathy.166 Nemaline myopathy caused by mutations in TNNT1 appears to be limited to the Old Order Amish community,150 and symptoms may include tremor and progressive contractures. The concurrence of rods and cores has been associated with ACTA1 mutations,101 mutations in RYR1,49,50 and mutations in an as yet unidentified gene on chromosome 15.167 Muscle MRI may help in the selection of genetic tests in cases with equivocal histopathological features (see Fig. 86–2B, C, E, and F).28,110 Nemaline myopathy exemplifies how individual structural congenital myopathies may represent syndromes with different genetic etiologies but similar histopathological appearances, caused by the involvement of defective gene products in a common pathway. All genes identified in nemaline myopathy to date code for thin filament associated proteins, several of which are also associated with Z line proteins, which suggests that disturbed assembly or interplay of myofibrillar structure is a pivotal mechanism in the evolution of rod pathology. Other genes encoding proteins involved in thin filament assembly or function are likely candidates for as yet genetically unresolved forms of nemaline myopathy.162 The pathogenetic effects of specific mutations associated with nemaline myopathy have been studied in transgenic mice,168-170 in cultured cardiomyocytes,171-173 in cultured myocytes transfected with mutant proteins,174 and through functional studies of RNA and proteins.175 Transgenic mice harboring mutations in TPM3 and ACTA1 show nemaline bodies163,168-170 whose number appears to be correlated with the degree of muscle weakness. In the mouse with TPM3 mutation, muscle weakness is correlated with the degree of type 1 hypotrophy and appears to be delayed by compensatory type 2 hypertrophy,168 and muscle regeneration may be abnormal.169 When expressed in rat adult cardiomyocytes, TPM3 mutations associated with skeletal muscle phenotypes produce hyposensitivity of Ca2+-activated force production that may underlie the muscle weakness observed in nemaline myopathy.171-173

CENTRONUCLEAR (MYOTUBULAR) MYOPATHY Myotubular myopathy was initially described by Spiro and associates4 and is characterized by centrally located nuclei, often large, surrounded by a zone devoid of myofibrils and containing mitochondrial aggregates. The term myotubular myopathy was derived from the resemblance to fetal myotubes with central nuclei, and the presence in these fibers of high levels of desmin and vimentin was considered an indicator of maturational arrest; the descriptive term centronuclear myopathy avoids the ongoing controversy over the occurrence of maturational arrest.45,176-180 The term myotubular myopathy, however, continues to be widely used for the X-linked form,

chapter 86 the congenital myopathies whereas the designation centronuclear myopathy is usually applied to autosomal forms.

Histopathology In the X-linked form of centronuclear myopathy (myotubular myopathy), type 1 predominance and hypotrophy are common; these changes may progress over time with marked increases in fat and connective tissue (see Fig. 86–1D).102,181 Despite a superficial resemblance to fetal myotubes, lack of fetal myosin in fibers with central nuclei is suggestive of normal maturation in terms of myosin transition. Histopathological findings in carriers of the X-linked form range from absent to the fullfledged centronuclear myopathy pathology seen in affected male patients.102,182 In presumably autosomal forms, oxidative stains may reveal radial distribution of sarcoplasmic strands in fibers with central nuclei183; similar radial strands may be seen on periodic acid–Schiff stains. It is not clear whether this is simply an agerelated effect, inasmuch as biopsy specimens from patients with autosomal cases are often taken at later ages than those from patients with the X-linked form. Corelike structures are occasionally present.99,184 On electron microscopy studies, immaturity of neuromuscular junctions has been suggested because of simplification of the postsynaptic membrane with paucity of secondary synaptic clefts. Central internal nuclei are not specific, and other neuromuscular disorders with an associated increase in internal nuclei must be ruled out in the differential diagnosis of myotubular myopathy. In particular, patients with congenital myotonic dystrophy may exhibit histopathological findings identical to those in X-linked myotubular myopathy.185

Clinical Features The clinical phenotype of centronuclear myopathy is highly variable, depending on the mode of inheritance. All forms of centronuclear myopathy are frequently associated with ophthalmoplegia. The X-linked form of centronuclear myopathy (myotubular myopathy) usually causes a severe phenotype in male patients, who present at birth with marked hypotonia, external ophthalmoplegia, and respiratory failure.143,180,186,187 The family history often includes miscarriages and male neonatal deaths in the mother’s family. Signs of antenatal onset include reduced fetal movements, polyhydramnios, and thinning of the ribs evident on chest radiographs,188 features rarely seen in other congenital myopathies. Birth asphyxia may be the presenting feature.182,189 Affected infants are often long and have increased head circumference, which may serve as a diagnostic clue.190 Many affected infants lack spontaneous antigravity movements, and some fail to establish spontaneous respiration at birth.187 Contractures of the hips and knees are commonly present. The course is usually fatal over days or weeks, but a proportion of affected boys may survive into their teens or beyond, sometimes with little residual disability and usually with normal intellect.191 Other patients may be mildly affected from the neonatal period onward.24,143,187,192-194 A range of medical complications in long-term survivors includes pyloric stenosis and cavernous liver hemangiomas191 and indicates widespread expression of

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the defective protein. Genital abnormalities have been described in affected boys with a contiguous gene syndrome.195 Most carriers of the X-linked form are either normal or show mild weakness196,197; the manifestation may be more severe if there are additional genetic abnormalities such as skewed X-inactivation102,196,198-201 or X chromosome abnormalities.202 Urinary incontinence may indicate smooth muscle involvement.102,197 Carrier status is best determined by molecular genetic methods. Manifesting heterozygosity should therefore always be considered in a female patient with histopathological features of myotubular myopathy. Autosomal recessive and autosomal dominant forms differ from the X-linked form in age at onset, severity, clinical characteristics, and prognosis and are likely to be genetically heterogeneous.203,204 The autosomal recessive form of centronuclear myopathy is characterized by facial weakness, including extraocular muscle involvement182,203,205; Jeannet and coworkers reported two families with manifestations compatible with recessive inheritance and seven sporadic cases, and they distinguished between an early-onset form with or without ophthalmoplegia and a lateonset form without ophthalmoplegia.183 Weakness and wasting may be pronounced distally in the lower limbs. Skeletal deformities, including high arched palate, foot deformities, and scoliosis, are common.206 Respiratory involvement may be severe and cardiomyopathy has been associated in few probably recessive cases207-209 and in two sporadic cases.210,211 In the absence of severe cardiorespiratory involvement, the prognosis is favorable. Jeannet and coworkers183 suggested autosomal dominant inheritance in two forms of centronuclear myopathy, both with onset occurring from infancy to adulthood and with only a slowly progressive course, one of which included diffuse muscle hypertrophy. Autosomal dominant centronuclear myopathy has to be differentiated from myotonic dystrophy and other autosomal dominant disorders with increased central nuclei evident on muscle biopsy specimens. Clinical findings such as cataracts or electrical myotonia98,212 strongly suggest that some of the families reported before the molecular era had, in fact, myotonic dystrophy rather than autosomal dominant centronuclear myopathy. Facioscapulohumeral distribution of weakness was reported in other families,213 which indicates that facioscapulohumeral muscular dystrophy should be considered in the differential diagnosis. Clinical findings in families without features suggestive of other neuromuscular disorders are usually milder than those of the recessive form. The creatine kinase level is normal or only slightly elevated in all forms of centronuclear myopathy. Malignant hyperthermia has been reported in a patient with adult-onset centronuclear myopathy.214

Genetics Initial linkage studies assigned a locus on chromosome Xq28 to the severe X-linked form of myotubular myopathy and recessive mutations in the myotubularin gene (MTM1) at this locus have subsequently been identified.215-219 In addition, a contiguous gene syndrome characterized by clinical and histopathological features of myotubular myopathy and additional abnormal genital development resulting in intersexual genitalia or severe hypospadias has been described in male patients

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harboring large deletions on Xq28.195,216,219 The initial suggestion of genetic heterogeneity of X-linked myotubular myopathy220 was later refuted.221 MTM1, a small gene with 15 exons,222 encodes myotubularin, a lipid phosphatase acting on phosphatidylinositol-3monophosphate (PI3P). Myotubularin is involved in regulating intracellular and endosomal trafficking and vesicular transport processes thought to be required for myogenesis.223-230 There are homologues of myotubularin in many species, including mice and yeast, as well as many human homologues.215,231-234 Myotubularin shows structural homology to the hMTMR5/ SBF1 protein, involved in the differentiation of myoblasts231; to the hMTMR2 protein, mutated in autosomal recessive CharcotMarie-Tooth disease type 4B1234; and to the SBF2 protein, mutated in autosomal recessive Charcot-Marie-Tooth disease type 4B2.235,236 Mutations in MTM1 that are associated with the human disease affect residues preserved in drosophila homologues231 and markedly compromise the ability of the phosphatase to regulate PI3P levels; this illustrates the importance of this function for normal muscle metabolism. Observations in myotubularin knockout mice supports the previous suggestion of a structural maintenance defect in myotubularindeficient muscle rather than a degenerative process. To date, more than 200 mutations affecting all four active sites of the MTM1 gene have been identified in families with X-linked myotubular myopathy.215,218,232,237,238 Exons 12, 8, and 14 are more commonly affected, harboring about 50% of mutations, and seven mutations account for about 25% of cases.184,217-219,232,238-241 Most point mutations are truncating, but almost one third are missense mutations affecting conserved residues.184,232 Disease-causing mutations in the MTM1 gene have not been identified in all patients with typical features of X-linked myotubular myopathy, which suggests that the remainder may harbor mutations in a functionally related gene or in noncoding regions of the MTM1 gene. The latter hypothesis is supported by the finding of abnormal myotubularin expression in a number of patients without confirmed mutation in MTM1 coding regions.228 Intronic variants causing partial exon skipping238 and splice site mutations242 have been reported. De novo mutations are rare,232 and most mothers of affected patients are carriers184; somatic mosaicism has been occasionally documented.232,243,244 Genotype-phenotype correlation studies are complicated by the fact that many of the mutations identified to date are unique.238 Moreover, marked intrafamilial phenotypical variability24 indicates that mutations in MTM1 may not be the only determinants of phenotype. A recent genotype-phenotype correlation study187 suggested that some nontruncating mutations are associated with a milder clinical course,24,193,194 whereas other nontruncating and all known truncating mutations are associated with the common very severe neonatal form. The genetic defects underlying the autosomal recessive and the autosomal dominant forms of centronuclear myopathy have not yet been identified. On Western blot, specimens from presumed autosomal recessive cases exhibit normal myotubularin expression.228 Several human myotubularin-related genes have been mapped to autosomal chromosomes233 and are candidates for causing autosomal dominant and autosomal recessive forms of myotubular myopathy. An autosomal recessive canine disorder resembling myotubular myopathy has been identified,245 but no obvious candidate gene in the orthologous human genomic region has yet been identified.

OTHER CONGENITAL MYOPATHIES WITH STRUCTURAL DEFECTS In addition to the more common congenital myopathies previously described, a number of unusual structural defects have characterized rarer myopathies. Some are familial and may have a genetic basis; others are sporadic and may not be distinct genetic entities. Some are early-onset disorders with hypotonia and can be considered congenital myopathies; others have later onset and are better considered myopathies with structural defects. These unusual disorders include cap disease, reducing body myopathy, fingerprint body myopathy, tubular aggregate myopathy, sarcotubular myopathy, zebra body myopathy, broad A band disease, and cylindrical spiral myopathy, lamellar body myopathy.6,246 The molecular basis of some cases of hyaline body myopathy has been attributed to a mutation in the gene encoding slow/MYH7247 and can therefore be considered a myofibrillar/myosin storage myopathy.

K E Y

P O I N T S

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The congenital myopathies are a clinically and genetically heterogeneous group of inborn muscle disorders with characteristic structural abnormalities on muscle biopsy.

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CCD, MmD, nemaline myopathy, and centronuclear myopathy are the major disease entities.

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The molecular diagnosis of a congenital myopathy is directed by muscle biopsy; muscle MRI may complement a comprehensive clinical assessment.

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The most common conditions are the core myopathies, associated with recessive and dominant mutations in RYR1, encoding the principal sarcoplasmic reticulum calcium release channel. Mutations in this gene confer a high risk of malignant hyperthermia susceptibility.

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Treatment is largely supportive. Respiratory impairment is the most important complication; monitoring and management of respiratory function are crucial.

Suggested Reading Bertini E, Biancalana V, Bolino A, et al: 11th ENMC International Workshop on Advances in Myotbular Myopathy. 26-28 September 2003, Naarden, The Netherlands (5th Workshop of the International Consortium on Myotubular Myopathy). Neuromuscul Disord 2004; 14:387-396. Jungbluth H, Beggs A, Bonnemann C, et al: 111th ENMC International Workshop on Multi-minicore Disease. 2nd International MmD Workshop, 9-11 November 2002, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:754-766. Sparrow JC, Nowak KJ, Durling HJ, et al: Muscle disease caused by mutation in the skeletal muscle α-actin gene (ACTAQ1). Neuromuscul Disord 2003; 13:519-531. Treves S, Anderson AA, Ducreux S, et al: Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. Neuromuscul Disord 2005; 15:577-587.

chapter 86 the congenital myopathies Wallgren-Pettersson C, Laing NG: 109th ENMC International Workship: 5th workshop on nemaline myopathy, 11th-13th October 2002, Naarden, The Netherlands. Neuromuscul Disord 2003; 13:501-507.

References 1. Shy GM, Magee KR: A new congenital nonprogressive myopathy. Brain 1956; 79:610-621. 2. Treves S, Anderson AA, Ducreux S, et al: Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. Neuromuscul Disord 15:577-587. 3. Shy GM, Engel WK, Somers JE, et al: Nemaline myopathy. A new congenital myopathy. Brain 1963; 86:793-810. 4. Spiro AJ, Shy GM, Gonatas NK: Myotubular myopathy. Persistence of fetal muscle in an adolescent boy. Arch Neurol 1966; 14:1-14. 5. Engel AG, Gomez MR, Groover RV: Multicore disease. Mayo Clin Proc 1971; 10:666-681. 6. Goebel HH, Anderson JR: Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies): 56th European Neuromuscular Centre (ENMC) sponsored International Workshop. December 1214, 1997, Naarden, The Netherlands. Neuromuscul Disord 1999; 9:50-57. 7. Wallgren-Pettersson C, Kivisaari L, Jääskeläinen J, et al: Ultrasonography, CT and MRI of muscles in congenital nemaline myopathy. Pediatr Neurol 1990; 6:20-28. 8. Hughes MI, Hicks EM, Nevin NC, et al: The prevalence of inherited neuromuscular disease in Northern Ireland. Neuromuscul Disord 1996; 6:69-73. 9. Darin N, Tulinius M: Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden. Neuromuscular Disorders 2000; 10:1-9. 10. Sewry CA, Muller C, Davis M, et al: The spectrum of pathology in central core disease. Neuromuscul Disord 2002; 12:930-938. 11. Naumann M, Reiners K, Gold R, et al: Mitochondrial dysfunction in adult-onset myopathies with structural abnormalities. Acta Neuropathol 1995; 89:152-157. 12. Lammens M, Moerman P, Fryns JP, et al: Fetal akinesia sequence caused by nemaline myopathy. Neuropediatrics 1997; 28:116-119. 13. Romero NB, Monnier N, Viollet L, et al: Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain 2003; 126:2341-2349. 14. Merlini L, Granata C, Ballestrazi P, et al: Rigid spine in myopathies. J Neurol Sci 1990; 98:435. 15. Ramsey PL, Hensinger RN: Congenital dislocation of the hip associated with central core disease. J Bone Joint Surg Am 1975; 57:648-651. 16. Howard RS, Wiles CM, Hirsch NP, et al: Respiratory involvement in primary muscle disorders: assessment and management. Q J Med 1993; 86:175-189. 17. Dubowitz V: Muscle Disorders in Childhood, 2nd ed. London: WB Saunders, 1995. 18. Quinlivan RM, Muller CR, Davis M, et al: Central core disease: clinical, pathological, and genetic features. Arch Dis Child 2003; 88:1051-1055. 19. Ryan MM, Schnell C, Strickland CD, et al: Nemaline myopathy: a clinical study of 143 cases. Ann Neurol 2001; 50:312-320. 20. Kaindl AM, Ruschendorf F, Krause S, et al: Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet 2004; 41:842-848. 21. McComb RD, Markesbery WR, O’Connor WN: Fatal neonatal nemaline myopathy with multiple congenital anomalies. J Pediatr 1979; 94:47-51.

1179

22. McMenamin JB, Curry B, Taylor GP, et al: Fatal nemaline myopathy in infancy. Can J Neurol Sci 1984; 11:305-309. 23. North KN, Laing NG, Wallgren-Pettersson C, et al: Nemaline myopathy: current concepts. J Med Genet 1997; 34:705-713. 24. Barth PG, Dubowitz V: X-linked myotubular myopathy—a long-term follow up study. Eur J Pediatr Neurol 1998; 1:4956. 25. Tsuji M, Higuchi Y, Shiraishi K, et al: Congenital fiber type disproportion: severe form with marked improvement. Pediatr Neurol 1999; 21:658-660. 26. Heckmatt JZ, Leeman S, Dubowitz V: Ultrasound imaging in the diagnosis of muscle disease. J Pediatr 1982; 5:656-660. 27. Dubowitz V, Pearse AGE: Oxidative enzymes and phosphorylase in central core disease of muscle. Lancet 1960; 2:23-24. 28. Jungbluth H, Sewry CA, Councell S, et al: Magnetic resonance imaging of muscle in nemaline myopathy. Neuromuscul Disord 2004; 14:779-784. 29. Jungbluth H, Davis MR, Muller C, et al: Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Neuromuscul Disord 2004; 14:785-790. 30. Dietzen CJ, D’Auria R, Fesenmeier J, et al: Electromyography in benign congenital myopathies. Muscle Nerve 1993; 16:328. 31. Bertorini TE, Staålberg E, Yuson CP, et al: Single fiber electromyography in neuromuscular disorders: correlation of muscle histochemistry, single fiber electromyography, and clinical findings. Muscle Nerve 1994; 17:345-353. 32. Coers C, Telerman Toppet N, Gerard JM, et al: Changes in motor innervation and histochemical pattern of muscle fibers in some congenital myopathies. Neurology 1976; 26:10461053. 33. Cruz Martinez A, Ferrer MT, Lopez Terradas JM, et al: Single fiber electromyography in central core disease. J Neurol Neurosurg Psychiatry 1979; 42:662-667. 34. Nowak KJ, Wattanasirichaigoon D, Goebel HH et al: Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet 1999; 23:208-212. 35. Wallgren-Pettersson C, Bushby K, Mellies U, et al: 117th ENMC workshop: Ventilatory Support in Congenital Neuromuscular Disorders: Congenital Myopathies, Congenital Muscular Dystrophies, Congenital Myotonic Dystrophy and SMA (II). April 4-6th 2003, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:56-69. 36. Heckmatt JZ, Loh L, Dubowitz V: Night time nasal ventilation in neuromuscular disease. Lancet 1990; 335:579582. 37. Jungbluth H, Müller CR, Halliger-Keller B, et al: Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology 2002; 59:284-287. 38. Drennan JC: Surgical management of neuromuscular scoliosis. In Serratrice G, Cros D, Desnuelle C, et al, eds: Neuromuscular Diseases. New York: Raven Press, 1984, p 551. 39. Denborough MA, Dennett X, Anderson R: Central core disease and malignant hyperpyrexia. BMJ 1973; 1:272-273. 40. Messina S, Hartley L, Main M, et al: Pilot trial of salbutamol in central core and multi-minicore diseases. Neuropediatrics 2004; 35:262-266. 41. McKusick VA: Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders, 12th ed. Baltimore: Johns Hopkins University Press, 1998. 42. Greenfield JG, Cornman T, Shy GM: The prognostic value of the muscle biopsy in the “floppy infant.” Brain 1958; 81:461484. 43. Dubowitz V: Muscle Biopsy: A Practical Approach, 2nd ed. London: Baillière Tindall, 1985. 44. Vita C, Migliorato A, Baradello A, et al: Expression of cytoskeleton proteins in central core disease. J Neurol Sci 1994; 124:71-76.

1180

Section

XV

Neuromuscular Diseases: Muscle

45. Sewry CA: The role of immunocytochemistry in congenital myopathies. Neuromuscul Disord 1998; 8:394-400. 46. Bonnemann CG, Thompson TG, van der Ven PF, et al: Filamin C accumulation is a strong but nonspecific immunohistochemical marker of core formation in muscle. J Neurol Sci 2003; 206:71-78. 47. Shafig SA, Gorycki MA, Asiedu SA, et al: Tenotomy. Effects on the fine structure of the soleus of the rat. Arch Neurol 1969; 20:625-633. 48. Fananapazir L, Dalakas MC, Cyran F, et al: Missense mutations in the β myosin heavy chain gene cause central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 1993; 90:3993-3997. 49. Scacheri PC, Hoffman EP, Fratkin JD, et al: A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology 2000; 55:1689-1696. 50. Monnier N, Romero NB, Lerale J, et al: An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet 2000; 9:25992608. 51. Monnier N, Ferreiro A, Marty I, et al: A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 2003; 12:1171-1178. 52. Dubowitz V, Platts M: Central core disease of muscle with focal wasting. J Neurol Neurosurg Psychiatry 1965; 28:432437. 53. Bethlem J, van Gool J, Haålsmann WC, et al: Familial non progressive myopathy with muscle cramps after exercise. A new disease associated with cores in the muscle fibers. Brain 1966; 89:569-588. 54. Gamble JG, Rinsky LA, Lee JH: Orthopaedic aspects of central core disease. J Bone Joint Surg Am 1988; 70:1061-1066. 55. Shuaib A, Paasuke RT, Brownell AKW: Central core disease. Clinical features in 13 patients. Medicine (Baltimore) 1987; 66:389-396. 56. Robinson RL, Brooks C, Brown SL, et al: RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mutat 2002; 20:88-97. 57. King JO, Denborough MA: Anaesthetic-induced malignant hyperpyrexia in children. J Pediatr 1973; 83:37-40. 58. Graham GE, Silver K, Arlet V, et al: King syndrome: further clinical variability and review of the literature. Am J Med Genet 1998; 78:254-259. 59. Rueffert H, Olthoff D, Deutrich C, et al: A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation. Am J Med Genet 2004; 124:248-254. 60. Manzur AY, Sewry CA, Ziprin J, et al: A severe clinical and pathological variant of central core disease with possible autosomal recessive inheritance. Neuromuscul Disord 1998; 8:467-473. 61. Lamont PJ, Dubowitz V, Landon DN, et al: Fifty year followup of a patient with central core disease shows slow but definite progression. Neuromuscul Disord 1998; 8:385-391. 62. Isaacs H, Barlow MB: Central core disease associated with elevated creatine phosphokinase levels. Two members of a family known to be susceptible to malignant hyperpyrexia. S Afr Med J 1974; 48:640-642. 63. Patterson VH, Hill TR, Fletcher PJH, et al: Central core disease. Clinical and pathological evidence of progression within a family. Brain 1979; 102:581-594. 64. Heckmatt JZ, Dubowitz V: Ultrasound imaging and directed needle biopsy in the diagnosis of selective involvement in muscle disease. J Child Neurol 1987; 2:205-213.

65. Gillard EF, Otsu K, Fujii J, et al: A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 1991; 11:751-755. 66. Zhang Y, Chen HS, Khanna VK, et al: A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet 1993; 5:46-49. 67. Quane KA, Healy JMS, Keating KE, et al: Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 1993; 5:51-55. 68. Robinson RL, Anetseder MJ, Brancadoro V, et al: Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing? Eur J Hum Genet 2003; 11:342-348. 69. Levitt RC, Olckers A, Meyers S, et al: Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q. Genomics 1992; 14:562566. 70. Moslehi R, Langlois S, Yam I, et al: Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree. Am J Med Genet 1998; 76:21-27. 71. Sudbrak R, Procaccio V, Klausnitzer M, et al: Mapping of a further malignant hyperthermia susceptibility locus to chromosome 3q13.1 Am J Hum Genet 1995; 56:684-691. 72. Monnier N, Procaccio V, Stieglitz P, et al: Malignant-hyperthermia susceptibility is associated with a mutation of the α1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 1997; 60:1316-1325. 73. Robinson RL, Monnier N, Wolz W, et al: A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. Hum Mol Genet 1997; 6:953-961. 74. Stewart SL, Hogan K, Rosenberg H, et al: Identification of the Arg1086His mutation in the α subunit of the voltagedependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet 2001; 59:178-184. 75. Robinson RL, Curran JL, Ellis FR, et al: Multiple interacting gene products may influence susceptibility to malignant hyperthermia. Ann Hum Genet 2000; 64:307-320. 76. McCarthy TV, Quane KA, Lynch PJ: Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat 2000; 15:410-417. 77. Jurkat-Rott K, McCarthy T, Lehmann-Horn F: Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4-17. 78. Tilgen N, Zorzato F, Halliger-Keller B, et al: Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. Hum Mol Genet 2001; 10:2879-2887. 79. Monnier N, Romero NB, Lerale J, et al: Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum Mol Genet 2001; 10:2581-2592. 80. Davis MR, Haan E, Jungbluth H, et al: Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. Neuromuscul Disord 2003; 13:151-157. 81. Sambuughin N, McWilliams S, de Bantel A, et al: Single–amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype. Am J Hum Genet 2001; 69:204-208. 82. Quane KA, Keating KE, Manning BM, et al: Detection of a novel common mutation in the ryanodine receptor gene in malignant hyperthermia: implications for diagnosis and heterogeneity studies. Hum Mol Genet 1994; 3:471-476.

chapter 86 the congenital myopathies 83. Shepherd S, Ellis F, Halsall J, et al: RYR1 mutations in UK central core disease patients: more than just the C-terminal transmembrane region of the RYR1 gene. J Med Genet 2004; 41(3):e33. 84. Lynch PJ, Tong J, Lehane M, et al: A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease. Proc Natl Acad Sci U S A 1999; 96:4164-4169. 85. Galli L, Orrico A, Cozzolino S, et al: Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region. Cell Calcium 2002; 32:143-151. 86. Sei Y, Sambuughin NN, Davis EJ, et al: Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824-830. 87. Ferreiro A, Monnier N, Romero NB, et al: A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol 2002; 51:750759. 88. Tong J, McCarthy TV, MacLennan DH: Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels. J Biol Chem 1999; 274:693-702. 89. Dirksen RT, Avila G: Altered ryanodine receptor function in central core disease: leaky or uncoupled Ca(2+) release channels? Trends Cardiovasc Med 2002; 12:189-197. 90. Zorzato F, Yamaguchi N, Xu L, et al: Clinical and functional effects of a deletion in a COOH-terminal luminal loop of the skeletal muscle ryanodine receptor. Hum Mol Genet 2003; 12:379-388. 91. Ducreux S, Zorzato F, Muller C, et al: Effect of ryanodine receptor mutations on interleukin-6 release and intracellular calcium homeostasis in human myotubes from malignant hyperthermia-susceptible individuals and patients affected by central core disease. J Biol Chem 2004; 279:43838-43846. 92. Ferreiro A, Fardeau M: 80th ENMC International Workshop on Multi-Minicore Disease: 1st International MmD Workshop. 12-13th May, 2000, Soestduinen, The Netherlands. Neuromuscul Disord 2002; 12:60-68. 93. van Wijngaarden GK, Bethlem J, Dingemans KP, et al: Familial focal loss of cross striations. J Neurol 1977; 216:163172. 94. Swash M, Schwartz MS: Familial multicore disease with focal loss of cross-striations and ophthalmoplegia. J Neurol Sci 1981; 52:1-10. 95. Jungbluth H, Sewry C, Brown SC, et al: Minicore myopathy in children—a clinical and histopathological study of 19 cases. Neuromuscul Disord 2000; 10:264-273. 96. Bethlem J, Arts WF, Dingemans KP: Common origin of rods, cores, miniature cores, and focal loss of cross striations. Arch Neurol 1978; 35:555-566. 97. Lee YS, Yip WCL: A fatal congenital myopathy with severe type I fiber atrophy, central nuclei and multicores. J Neurol Sci 1981; 50:277-290. 98. Hulsmann N, Gullotta F, Okur H: Cytopathology of an unusual case of centronuclear myopathy. J Neurol Sci 1981; 50:311-333. 99. Fitzsimons RB, McLeod JG: Myopathy with pathological features of both centronuclear myopathy and multicore disease. J Neurol Sci 1982; 57:395-405. 100. Vallat JM, de Lumley L, Loubet A, et al: Coexistence of minicores, cores, and rods in the same muscle biopsy. A new example of mixed congenital myopathy. Acta Neuropathol 1982; 58:229-232.

1181

101. Jungbluth H, Sewry CA, Brown SC, et al: Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle α-actin (ACTA1) gene. Neuromuscul Disord 2001; 11:35-40. 102. Jungbluth H, Sewry CA, Buj-Bello A, et al: Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation. Neuromuscul Disord 2003; 13:55-59. 103. Ferreiro A, Estournet B, Chateau D, et al: Multi-minicore disease—searching for boundaries: phenotype analysis of 38 cases. Ann Neurol 2000; 48:745-757. 104. Bonnette H, Roelofs R, Olson WH: Multicore disease: report of a case with onset in middle age. Neurology 1974; 24:10391044. 105. Shuaib A, Martin JME, Mitchell LB, et al: Multicore myopathy: not always a benign entity. Can J Neurol Sci 1988; 15:1014. 106. Magliocco AM, Mitchell LB, Brownell AK, et al: Dilated cardiomyopathy in multicore myopathy. Am J Cardiol 1989; 63:150-151. 107. Zeman AZJ, Dick DJ, Anderson JR, et al: Multicore myopathy presenting in adulthood with respiratory failure. Muscle Nerve 1997; 20:367-369. 108. Ferreiro A, Quijano-Roy S, Pichereau C, et al: Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002; 71:739-749. 109. Rowe PW, Eagle M, Pollitt C, et al: Multicore myopathy: respiratory failure and paraspinal muscle contractures are important complications. Dev Med Child Neurol 2000; 42:340-343. 110. Jungbluth H, Beggs A, Bonnemann C, et al: 111th ENMC International Workshop on Multi-minicore Disease. 2nd International MmD Workshop, 9-11 November 2002, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:754-766. 111. Bertini E, Bosman C, Bevilacqua M, et al: Cardiomyopathy and multicore myopathy with accumulation of intermediate filaments. Eur J Pediatr 1990; 149:856-858. 112. Willemsen MAAP, Oort AM van, ter Laak HJ, et al: Multicore myopathy with restrictive cardiomyopathy. Acta Paediatr 1997; 86:1271-1274. 113. Koch BM, Bertorini TE, Eng GD, et al: Severe multicore disease associated with reaction to anesthesia. Arch Neurol 1985; 42:1204-1206. 114. Osada H, Masuda K, Seki K, et al: Multi-minicore disease with susceptibility to malignant hyperthermia in pregnancy. Gynecol Obstet Invest 2004; 58:32-35. 115. Barone V, Massa O, Intravaia E, et al: Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families. J Med Genet 1999; 36:115-118. 116. Guis S, Figarella-Branger D, Monnier N, et al: Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol 2004; 61:106-113. 117. Ohkubo M, Ino T, Shimazaki S, et al: Multicore myopathy associated with multiple pterygium syndrome and hypertrophic cardiomyopathy. Pediatr Cardiol 1996; 17:53-56. 118. Chudley AE, Rozdilsky B, Houston CS, et al: Multicore disease in sibs with severe mental retardation, short stature, facial anomalies, hypoplasia of the pituitary fossa, and hypogonadotrophic hypogonadism. Am J Med Genet 1985; 20:145158. 119. Penegyres PK, Kakulas BA: The natural history of minicoremulticore myopathy. Muscle Nerve 1991; 14:411-415. 120. Moghadaszadeh B, Petit N, Jaillard C, et al: Mutations in SEPN1 cause congenital muscular dystrophy with spinal

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121.

122. 123.

124. 125.

126. 127. 128. 129. 130.

131. 132.

133. 134. 135. 136. 137. 138. 139. 140.

Section

XV

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rigidity and restrictive respiratory syndrome. Nat Genet 2001; 29:17-18. Ferreiro A, Ceuterick-de Groote C, Marks JJ, et al: Desminrelated myopathy with Mallory body–like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 2004; 55:676-686. Barohn RJ, Jackson CE, Kagan Hallet KS: Neonatal nemaline myopathy with abundant intranuclear rods. Neuromuscul Disord 1994; 4:513-520. Schröder JM, Durling H, Laing N: Actin myopathy with nemaline bodies, intranuclear rods, and a heterozygous mutation in ACTA1 (Asp154Asn). Acta Neuropathol 2004; 108:250-256. Wallgren-Pettersson C, Kääriäinen H, Rapola J, et al: Genetics of congenital nemaline myopathy: a study of ten families. J Med Genet 1990; 27:480-487. Jockusch BM, Veldman H, Griffiths G, et al: Immunofluorescence microscopy of a myopathy. α Actinin is a major constituent of nemaline rods. Exp Cell Res 1980; 127:409420. Vainzof M, Moreira ES, Suzuki OT, et al: Telethonin protein expression in neuromuscular disorders. Biochim Biophys Acta 2002; 1588:33-40. Schröder R, Reimann J, Salmikangas P, et al: Beyond LGMD1A: myotilin is a component of central core lesions and nemaline rods. Neuromuscul Disord 2003; 13:451-455. Gurgel-Giannetti J, Reed U, Bang ML, et al: Nebulin expression in patients with nemaline myopathy. Neuromuscul Disord 2001; 11:154-162. Sewry CA, Brown SC, Pelin K, et al: Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy. Neuromuscul Disord 2001; 11:146-153. Wallgren-Pettersson C, Pelin K, Nowak KJ, et al: Genotypephenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle αactin. Neuromuscul Disord 2004; 14:461-470. Wallgren-Pettersson C, Laing NG: Report of the 70th ENMC International Workshop: nemaline myopathy. Neuromuscul Disord 2000; 10:299-306. Lacson AG, Donaldson G, Barness EG, et al: Infant with higharched palate, bell-shaped chest, joint contractures and intrauterine fractures. Pediatr Pathol Mol Med 2002; 21:569584. Agrawal PB, Strickland CD, Midgett C, et al: Heterogeneity of nemaline myopathy cases with skeletal muscle α-actin gene mutations. Ann Neurol 2004; 56:86-96. Wallgren-Pettersson C: Congenital nemaline myopathy: a clinical follow up study of twelve patients. J Neurol Sci 1989; 89:1-14. Wallgren-Pettersson, C, Pelin, K, Hilpela, P, et al: Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord 1999; 9:564-572. Topaloglu H, Gögüs S, Yalaz K, et al: Two siblings with nemaline myopathy presenting with rigid spine syndrome. Neuromuscul Disord 1994; 4:263-267. Iannaccone S, Guilfoile T: Long term mechanical ventilation in infants with neuromuscular disease. J Child Neurol 1988; 3:30-32. Airenne AL, Wallgren-Pettersson C: Normal cardiac contractility in patients with congenital nemaline myopathy. Neuropediatrics 1988; 19:115-117. Ishibashi Ueda H, Imakita M, Yutani C, et al: Congenital nemaline myopathy with dilated cardiomyopathy: an autopsy study. Hum Pathol 1990; 21:77-82. Müller-Höcker J, Schafer S, Mendel B, et al: Nemaline cardiomyopathy in a young adult: an ultraimmunohistochemical study and review of the literature. Ultrastruct Pathol 2000; 24:407-416.

141. Davies MJ, Ballantine S, Darracott S, et al: Nemaline bodies in the heart: anomalous Z bands with a periodic structure suggesting tropomyosin in human cardiac muscle biopsies. Cardiovasc Res 1973; 7:408-411. 142. Wallgren-Pettersson C, Laing NG: 83rd ENMC International Workshop: 4th Workshop on nemaline myopathy. 22-24 September, 2000, Naarden, The Netherlands. Neuromuscul Disord 2001; 11:589-595. 143. Wallgren-Pettersson C, Hiilesmaa VK, Paatero H: Pregnancy and delivery in congenital nemaline myopathy. Acta Obstet Gynecol Scand 1995; 74:659-661. 144. Laing NG, Majda BT, Akkari PA, et al: Assignment of a gene (NEM1) for autosomal dominant nemaline myopathy to chromosome 1. Am J Hum Genet 1992; 50:576-583. 145. Laing NG, Wilton SD, Akkari PA, et al: A mutation in the α tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy NEM1. Nat Genet 1995; 9:75-79. 146. Tan P, Briner J, Boltshauser E, et al: Homozygosity for a nonsense mutation in the α-tropomyosin gene TPM3 in a patient with severe congenital nemaline myopathy. Neuromuscul Disord 1999; 9:573-579. 147. Wallgren-Pettersson C, Avela K, Marchand S, et al: A gene for autosomal recessive nemaline myopathy assigned to chromosome 2q by linkage analysis. Neuromuscul Disord 1995; 5:441-443. 148. Pelin K, Ridanpaa M, Donner K, et al: Refined localisation of the genes for nebulin and titin on chromosome 2q allows the assignment of nebulin as a candidate gene for autosomalrecessive nemaline myopathy. Eur J Hum Genet 1997; 5:229234. 149. Pelin K, Hilpela P, Donner K, et al: Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A 1999; 96:2305-2310. 150. Johnston JJ, Kelley RI, Crawford TO, et al: A novel nemaline myopathy in the Amish caused by mutation in troponin T1. Am J Hum Genet 2000; 67:814-821. 151. Donner K, Ollikainen M, Ridanpaa M et al: Mutations in the β-tropomyosin (TPM2) gene—a rare cause of nemaline myopathy. Neuromuscul Disord 2002; 12:151-158. 152. Pelin K, Donner K, Holmberg M, et al: Nebulin mutations in autosomal recessive nemaline myopathy: an update. Neuromuscul Disord 2002; 12:680-686. 153. Anderson SL, Ekstein J, Donnelly MC, et al: Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 2004; 115:185-190. 154. Ilkovski B, Cooper ST, Nowak K, et al: Nemaline myopathy caused by mutations in the muscle α-skeletal-actin gene. Am J Hum Genet 2001; 68:1333-1343. 155. Sparrow JC, Nowak KJ, Durling HJ, et al: Muscle disease caused by mutations in the skeletal muscle α-actin gene (ACTA1). Neuromuscul Disord 2003; 13:519-531. 156. Donner K, Sandbacka M, Lehtokari VL, et al: Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts. Eur J Hum Genet 2004; 12:744-751. 157. Labeit S, Kolmerer B: The complete primary structure of human nebulin and its correlation to muscle structure. J Mol Biol 1995; 248:308-315. 158. Wang K, Knipfer M, Huang QQ, et al: Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture. Sequence motifs and affinity profiles of tandem repeats and terminal SH3. J Biol Chem 1996; 271:43044314. 159. Wallgren-Pettersson C, Donner K, Sewry C, et al: Mutations in the nebulin gene can cause severe congenital nemaline myopathy. Neuromuscul Disord 2002; 12:674-679. 160. Buxmann H, Schlösser R, Schlote W, et al: Congenital nemaline myopathy due to ACTA1-gene mutation and carnitine

chapter 86 the congenital myopathies

161.

162. 163.

164.

165. 166.

167. 168.

169.

170. 171.

172. 173.

174.

175.

176.

177. 178.

insufficiency: a case report. Neuropediatrics 2001; 32:267270. Ohlsson M, Tajsharghi H, Darin N, et al: Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle α-actin gene (ACTA1). Neuromuscul Disord 2004; 14:471-475. Laing NG, Clarke NF, Dye DE, et al: Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol 2004; 56:689-694. Wallgren-Pettersson C, Laing NG: 109th ENMC International Workshop: 5th workshop on nemaline myopathy, 11th-13th October 2002, Naarden, The Netherlands. Neuromuscul Disord 2003; 13:501-507. Durling HJ, Reilich P, Müller-Höcker J, et al: De novo missense mutation in a constitutively expressed exon of the slow α-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy. Neuromuscul Disord 2002; 12:947-951. Wattanasirichaigoon D, Swoboda KJ, Takada F, et al: Mutations of the slow muscle α-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. Neurology 2002; 59:613-617. Sung SS, Brassington A-M, Grannatt K, et al: Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet 2003; 72:681690. Gommans IM, Davis M, Saar K, et al: A locus on chromosome 15q for a dominantly inherited nemaline myopathy with corelike lesions. Brain 2003; 126:1545-1551. Corbett MA, Robinson CS, Dunglison GF, et al: A mutation in α-tropomyosin(slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Hum Mol Genet 2001; 10:317-328. Joya JE, Kee AJ, Nair-Shalliker V, et al: Muscle weakness in a mouse model of nemaline myopathy can be reversed with exercise and reveals a novel myofiber repair mechanism. Hum Mol Genet 2004; 13:2633-2645. Nair-Shalliker V, Kee AJ, Joya JE, et al: Myofiber adaptational response to exercise in a mouse model of nemaline myopathy. Muscle Nerve 2004; 30:470-480. Michele DE, Albayya FP, Metzger JM: A nemaline myopathy mutation in α-tropomyosin causes defective regulation of striated muscle force production. J Clin Invest 1999; 104:1575-1581. Michele DE, Metzger JM: Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies. J Mol Med 2000; 78:543-553. Michele DE, Coutu P, Metzger JM: Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins. Physiol Genomics 2002; 9:103-111. Ilkovski B, Nowak KJ, Domazetovska A, et al: Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Hum Mol Genet 2004; 13:1727-1743. Marston S, Mirza M, Abdulrazzak H, et al: Functional characterisation of a mutant actin (Met132Val) from a patient with nemaline myopathy. Neuromuscul Disord 2004; 14:167174. Sarnat HB: Myotubular myopathy: arrest of morphogenesis of myofibers associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle. Can J Neurol Sci 1990; 17:109-123. Sarnat HB: Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 1992; 42:16161624. Mora M, Morandi L, Merlini L, et al: Fetus-like dystrophin expression and other cytoskeletal protein abnormalities in

179. 180. 181. 182. 183. 184.

185. 186. 187. 188. 189. 190. 191. 192. 193.

194. 195.

196.

197.

198.

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centronuclear myopathies. Muscle Nerve 1994; 17:11761184. Helliwell TR, Ellis IH, Appleton RE: Myotubular myopathy: morphological, immunohistochemical and clinical variation. Neuromuscul Disord 1998; 8:152-161. Wallgren-Pettersson C: 58th ENMC workshop: myotubular myopathy 20-22 March, 1998, Naarden, The Netherlands. Neuromuscul Disord 1998; 8:521-525. van der Ven PFM, Jap PHK, Wetzels RHW, et al: Postnatal centralization of muscle fiber nuclei in centronuclear myopathy. Neuromuscul Disord 1991; 1:211-220. Heckmatt JZ, Sewry CA, Hodes D, et al: Congenital centronuclear (myotubular) myopathy: a clinical, pathological and genetic study in eight children. Brain 1985; 108:941-964. Jeannet PY, Bassez G, Eymard B, et al: Clinical and histologic findings in autosomal centronuclear myopathy. Neurology 2004; 62:1484-1490. Bertini E, Biancalana V, Bolino A, et al: 118th ENMC International Workshop on Advances in Myotubular Myopathy. 26-28 September 2003, Naarden, The Netherlands. (5th Workshop of the International Consortium on Myotubular Myopathy). Neuromuscul Disord 2004; 14:387-396. Dubowitz V: Lesson for the month: genetic counselling. Neuromuscul Disord 1992; 2:85-86. Wallgren-Pettersson C, Thomas N: Report on the 20th ENMC sponsored international workshop: myotubular/centronuclear myopathy. Neuromuscul Disord 1994; 4:71-74. McEntagart M, Parsons G, Buj-Bello A, et al: Genotypephenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord 2002; 12:939-946. Osborne JP, Murphy EG, Hill A: Thin ribs on chest X-ray: a useful sign in the differential diagnosis of the floppy newborn. Dev Med Child Neurol 1983; 25:343-345. Barth PG, van Wijngaarden GK, Bethlem J: X linked myotubular myopathy with fatal neonatal asphyxia. Neurology 1975; 25:531-536. LeGuennec JC, Bernier JP, Lamarche J: High stature in neonatal myotubular myopathy. Acta Paediatr Scand 1988; 77:610-611. Herman GE, Finegold M, Zhao W, et al: Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr 1999; 134:206-214. Chanzy S, Routon MC, Moretti S, et al: Unusual good prognosis for X-linked myotubular myopathy. Arch Pediatr 2003; 10:707-709. Biancalana V, Caron O, Gallati S, et al: Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet 2003; 112:135-142. Yu S, Manson J, White S, et al: X-linked myotubular myopathy in a family with three adult survivors. Clin Genet 2003; 64:148-152. Hu LJ, Laporte J, Kress W, et al: Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430 kb region. Hum Mol Genet 1996; 5:139-143. Wallgren-Pettersson C: Report of the 72nd ENMC International Workshop on Myotubular Myopathy, Hilversum, The Netherlands, 1-3 October 1999. Neuromuscul Disord 2000; 10:521-525. Hammans SR, Robinson DO, Moutou C, et al: A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy. Neuromuscul Disord 2000; 10:133137. Tanner SM, Orstavik KH, Kristiansen M, et al: Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother. Hum Genet 1999; 104:249-253.

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199. Sutton IJ, Winer JB, Norman AN, et al: Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations. Neurology 2001; 57:900-902. 200. Schara U, Kress W, Tucke J, et al: X-linked myotubular myopathy in a female infant caused by a new MTM1 gene mutation. Neurology 2003; 60:1363-1365. 201. Kristiansen M, Knudsen GP, Tanner SM, et al: X-inactivation patterns in carriers of X-linked myotubular myopathy. Neuromuscul Disord 2003; 13:468-471. 202. Dahl N, Hu LJ, Chery M, et al: Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600 kb region. Am J Hum Genet 1995; 56:1108-1115. 203. De Angelis MS, Palmucci L, Leone M, et al: Centronuclear myopathy: clinical, morphological and genetic characters. A review of 288 cases. J Neurol Sci 1991; 103:2-9. 204. Wallgren-Pettersson C, Clarke A, Samson F, et al: The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant and autosomal recessive forms and present state of DNA studies. J Med Genet 1995; 32:673-679. 205. Zanoteli E, Oliveira AS, Kiyomoto BH, et al: Centronuclear myopathy. Histopathological aspects in ten patients with childhood onset. Arq Neuropsiquiatr 1998; 56:1-8. 206. Pages M, Cesari JB, Pages AM: Centronuclear myopathy. Complete review of the literature apropos of a case. Ann Pathol 1982; 2:301-310. 207. Verhiest W, Brucher JM, Goddeeris P, et al: Familial centronuclear myopathy associated with “cardiomyopathy.” Br Heart J 1976; 38:504-509. 208. Gospe SM Jr, Armstrong DL, Gresik MV, et al: Life-threatening congestive heart failure as the presentation of centronuclear myopathy. Pediatr Neurol 1987; 3:117-120. 209. Bataille J, Guillon F, Urtizberea A, et al: [Pathological anatomy of the heart in myopathies and infantile muscular atrophies]. Ann Med Interne (Paris) 1991; 142:5-8. 210. Bethlem J, van Wijngaarden GK, Meijer AEFH, et al: Neuromuscular disease with type 1 fiber atrophy, central nuclei, and myotube like structures. Neurology 1969; 19:705-710. 211. Al-Ruwaishid A, Vajsar J, Tein I, et al: Centronuclear myopathy and cardiomyopathy requiring heart transplant. Brain Dev 2003; 25:62-66. 212. Hawkes CH, Absolon MJ: Myotubular myopathy associated with cataract and electrical myotonia. J Neurol Neurosurg Psychiatry 1975; 38:761-764. 213. Felice KJ, Grunnet ML: Autosomal dominant centronuclear myopathy: report of a new family with clinical features simulating facioscapulohumeral syndrome. Muscle Nerve 1997; 20:1194-1196. 214. Quinn RD, Pae WE, McGary SA, et al: Development of malignant hyperthermia during mitral valve replacement. Ann Thorac Surg 1992; 53:1114-1116. 215. Laporte J, Hu LJ, Kretz C, et al: A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 1996; 13:175182. 216. Laporte J, Kioschis P, Hu LJ, et al: Cloning and characterization of an alternatively spliced gene in proximal Xq28 deleted in two patients with intersexual genitalia and myotubular myopathy. Genomics 1997; 41:458-462. 217. de Gouyon BM, Zhao W, Laporte J, et al: Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy. Hum Mol Genet 1997; 6:1499-1504. 218. Buj-Bello A, Biancalana V, Moutou C, et al: Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy. Hum Mutat 1999; 14:320-325.

219. Herman GE, Kopacz K, Zhao W, et al: Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum Mutat 2002; 19:114-121. 220. Samson F, Mesnard L, Heimburger M, et al: Genetic linkage heterogeneity in myotubular myopathies. Am J Hum Genet 1995; 57:120-126. 221. Guiraud-Chaumeil C, Vincent MC, Laporte J, et al: A mutation in the MTM1 gene invalidates a previous suggestion of nonallelic heterogeneity in X-linked myotubular myopathy. Am J Hum Genet 1997; 60:1542-1544. 222. Laporte J, Guiraud-Chaumeil C, Tanner SM et al: Genomic organization of the MTM1 gene implicated in X-linked myotubular myopathy. Eur J Hum Genet 1998; 6:325-330. 223. Cui X, De V, I, Slany R, et al: Association of SET domain and myotubularin-related proteins modulates growth control. Nat Genet 1998; 18:331-337. 224. Laporte J, Blondeau F, Buj-Bello A, et al: Characterization of the myotubularin dual specificity phosphatase gene family from yeast to human. Hum Mol Genet 1998; 7:17031712. 225. Blondeau F, Laporte J, Bodin S, et al: Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3phosphate pathway. Hum Mol Genet 2000; 15:2223-2229. 226. Taylor GS, Maehama T, Dixon JE: Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci U S A 2000; 97:89108915. 227. Laporte J, Blondeau F, Buj-Bello A, et al: The myotubularin family: from genetic disease to phosphoinositide metabolism. Trends Genet 2001; 17:221-228. 228. Laporte J, Kress W, Mandel JL: Diagnosis of X-linked myotubular myopathy by detection of myotubularin. Ann Neurol 2001; 50:42-46. 229. Chaussade C, Pirola L, Bonnafous S, et al: Expression of myotubularin by an adenoviral vector demonstrates its function as a phosphatidylinositol 3-phosphate [PtdIns(3)P] phosphatase in muscle cell lines: involvement of PtdIns(3)P in insulin-stimulated glucose transport. Mol Endocrinol 2003; 17:2448-2460. 230. Tsujita K, Itoh T, Ijuin T, et al: Myotubularin regulates the function of the late endosome through the gram domainphosphatidylinositol 3,5-bisphosphate interaction. J Biol Chem 2004; 279:13817-13824. 231. Kioschis P, Wiemann S, Heiss NS, et al: Genomic organization of a 225-kb region in Xq28 containing the gene for Xlinked myotubular myopathy (MTM1) and a related gene (MTMR1). Genomics 1998; 54:256-266. 232. Laporte J, Biancalana V, Tanner SM, et al: MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 2000; 15:393409. 233. Appel S, Reichwald K, Zimmermann W, et al: Identification and localization of a new myotubularin-related protein gene, MTMR8, on 8p22-p23. Genomics 2001; 75:6-8. 234. Bolino A, Muglia M, Conforti FL, et al: Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein–2. Nat Genet 2000; 25:1719. 235. Azzedine H, Bolino A, Taieb T, et al: Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet 2003; 72:1141-1153. 236. Senderek J, Bergmann C, Weber S, et al: Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet 2003; 12:349-356.

chapter 86 the congenital myopathies 237. Laporte J, Guiraud-Chaumeil C, Vincent MC, et al: Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center. Hum Mol Genet 1997; 6:1505-1511. 238. Tanner SM, Schneider V, Thomas NS, et al: Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients. Neuromuscul Disord 1999; 9:41-49. 239. Nishino I, Minami N, Kobayashi O, et al: MTM1 gene mutations in Japanese patients with the severe infantile form of myotubular myopathy. Neuromuscul Disord 1998; 8:453-458. 240. Donnelly A, Haan E, Manson J, et al: A novel mutation in exon b (R259C) of the MTM1 gene is associated with a mild myotubular myopathy. Mutations in brief no. 125. Online. Hum Mutat 1998; 11:334. 241. De Luca A, Torrente I, Mangino M, et al: A novel mutation (R271X) in the myotubularin gene causes a severe miotubular myopathy. Hum Hered 1999; 49:59-60.

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242. Watanabe T, Watanabe M, Saito T, et al: X-linked recessive myotubular myopathy with a splice-site mutation in the myotubularin gene. No To Hattatsu 1998; 30:523-527. 243. Vincent MC, Guiraud-Chaumeil C, Laporte J, et al: Extensive germinal mosaicism in a family with X linked myotubular myopathy simulates genetic heterogeneity. J Med Genet 1998; 35:241-243. 244. Hane BG, Rogers RC, Schwartz CE: Germline mosaicism in X-linked myotubular myopathy. Clin Genet 1999; 56:77-81. 245. Tiret L, Blot S, Kessler JL, et al: The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome 2. Hum Genet 2003; 113:297-306. 246. North K: Congenital myopathies. In Engel AG, Franzini-Armstrong C, eds: Myology, 3rd ed. New York: McGraw-Hill, 2004, pp 1473-1533. 247. Tajsharghi H, Thornell LE, Lindberg C, et al: Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003; 54:494-500.

CHAPTER

87

CHANNELOPATHIES OF MUSCLE (INCLUDING THE MYOTONIC DYSTROPHIES) ●

●

●

●

Fiona Norwood and Michael Rose

Channelopathies are disorders resulting from alterations in function of the ion channels found in cell membranes throughout the body. Disorders such as episodic ataxia types 1 and 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and benign familial neonatal convulsions are examples of channelopathies affecting the central nervous system. These disorders are outside the scope of this chapter. In muscle cells, several types of voltage-gated ion channels are critical in regulating membrane excitability. Dysfunction of these ion channels causes a variety of muscle symptoms. Ion channels consist of multiple transmembrane glycoprotein subunits that form pores in the membrane. Charged ions may pass selectively through these pores, subject to regulation by voltage gating, thus altering the charged ion distribution across the membrane and hence its excitability. The muscle cell membrane has a negative resting potential of approximately −60 mV that becomes a positive action potential of approximately +40 mV once the membrane is stimulated. In normal muscle cells, this transient depolarization swiftly returns to the resting state and the muscle relaxes; however, in ion channel disorders depolarization may be prolonged and lead to a longer phase of muscle contraction (myotonia) or to inexcitability (periodic paralysis). Each ion channel type has a different role in sarcolemmal function (Fig. 87–1). Chloride channels are important in stabilizing the membrane potential at the resting level; inward flow of ions through sodium channels induces membrane depolarization and hence action potential; outflow through a voltage-gated subset of potassium channels is involved in the depolarization of the action potential. Calcium channels may be involved in action potential generation or in the regulation of other channel types. Action potential generation in the membrane is coupled to activation of the contractile machinery in the skeletal muscle and to muscle contraction. Myotonia may be detectable clinically by employing certain simple maneuvers, especially after a period of rest. Grip myotonia may be elicited by asking the patient to hold his/her fist tightly closed for 10 seconds and then to release it and extend the fingers; the patient may be unable to do this for 10 to 20 seconds. If asked to repeat the maneuver, the time taken to release the grip may decrease; this is known as the warm-up phenomenon. Paramyotonia is the opposite; that is, grip release becomes progressively more difficult with successive contrac-

tions. Percussion myotonia may be evident on tapping the thenar or larger limb muscles with a tendon hammer—these muscles may indent due to sustained contraction. Sometimes tapping the thenar with an abducted thumb may cause it to adduct across the palm. Eyelid myotonia may be seen when the patient is asked to close his or her eyes tightly for about 10 seconds and then to open them wide—some patients cannot open their eyes at all initially. During episodes of periodic paralysis, weakness may range from focal to generalized paralysis. Respiratory muscle involvement is usually less severe than might be expected and patients rarely need respiratory support. Precipitants are discussed under individual disorders. Recovery time varies from less than an hour for a mild attack to several hours or days in a severe episode. Electromyography in patients with myotonia congenita or myotonic dystrophy should demonstrate repetitive generation of muscle cell membrane action potentials (Fig. 87–2) in resting muscle, although the test may be unnecessary in clinically evident cases, particularly of myotonic dystrophy. The myotonic discharges are described as high-frequency repetitive biphasic spikes or positive waves with varying frequency or amplitude. Electromyography in periodic paralysis will be normal between attacks in patients without a myopathy. During an attack, features such as reduced compound muscle action potential amplitude are seen.

NONDYSTROPHIC MYOTONIAS AND PERIODIC PARALYSES Chloride Channel Disorders (CLCN1) Epidemiology Thomsen’s and Becker’s myotonia congenita are allelic disorders due to mutations in the CLCN1 gene, which encodes the voltage-gated chloride channel. Myotonia congenita, Thomsen type, first described in 1876, is an autosomal dominant condition with a prevalence of about 1 : 400,000. Becker’s myotonia congenita, described in 1957, is an autosomal recessive condition, more common than Thomsen’s myotonia, with a prevalence of between 1 : 23,000 and 1 : 50,000.1

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Neuromuscular Diseases: Muscle Sodium channels open More sodium channels open Sodium channels close Potassium channels open Potassium channels close

+30 mV 0 mV

–70 mV

LONG EXERCISE TEST 120

Amp or Area (% initial)

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100 Amp 80

60

40

20 Exercise

1 ms ■

0

Figure 87–1. Ion flux at the sarcolemma. In the resting state, the negative potential across the muscle cell membrane is maintained through relatively higher extracellular sodium and calcium ion concentrations and relatively higher intracellular potassium and chloride ion concentrations. When the membrane is depolarized, an action potential is generated through sodium ion flow into the cell through voltage-gated sodium channels followed by outflow of potassium ions through potassium channels and inflow of chloride ions through chloride channels, thus repolarizing the membrane.

Clinical Features Thomsen’s myotonia congenita is the less severe of the two disorders, but onset of generalized myotonia is in childhood. Both upper and lower limbs are involved, and the myotonia may be evident on attempting to make rapid movements such as rising from a chair after sitting for 30 minutes. The prolonged sarcolemmal excitation leads to muscle hypertrophy, giving the impression of an athletic physique, even in women. Some of these patients are good at certain sports in their youth, although later the worsening myotonia may limit their ability. Becker’s myotonia congenita has more severe myotonia than the Thomsen type, with onset in childhood or adolescence. Severe myotonia in the legs may make walking difficult and painful and can lead to falls as rapid movements are impaired. Muscles are hypertrophied as in the Thomsen variant, although shoulder muscles may be relatively less enlarged than those in the lower limbs. These patients may be quite disabled in later life due to a combination of severe myotonia and limb contractures.

Investigation Creatine kinase levels may be normal or only mildly raised to twice the upper limit of the normal range in Becker’s patients. Electromyographic studies will show repetitive firing in all muscles of both subsets of patients. Muscle biopsy is not indicated as it shows normal appearances or hypertrophied muscle fibers with alterations of fiber type proportions resulting from muscle overactivity. Molecular genetic analysis of the CLCN1 gene on chromosome 7q should provide a specific diagnosis, although it is not a trivial undertaking. Depending on the degree of clinical confidence that the patient has myotonia congenita, it may be wise

Amp decrease: 82% (NR<40%)

0

5

10

15

20

25

30

Time (min) ■

Figure 87–2. Change in amplitude of muscle fiber compound action potentials in patient with hypokalemic periodic paralysis following long exercise test. Intermittent strong exercise over 5 minutes of the abductor digiti minimi muscle was performed in control subjects and patients. Compound muscle action potentials (CMAPs) in patients showed a greater than normal increase in CMAP amplitude immediately after exercise followed by a decline in CMAP amplitude thereafter. This was seen particularly in those with hypokalemic periodic paralysis but was also seen in the other channelopathy patients, making it a useful test. (From Kuntzer et al: Muscle Nerve 2000;23:10891094.)

to exclude myotonic dystrophies 1 and 2 first, particularly as these genetic tests are well established and relatively straightforward.

Molecular Pathophysiology CLCN1 mutations are spread throughout the sequence of the gene (Pusch) and are predicted to produce functional changes in the chloride channel protein (CIC-1) with faulty assembly of subunits, impaired ion channel formation, and channel dysfunction (Fig. 87–3). The resulting reduction in chloride ion conductance lowers the threshold for depolarization through sodium channel activation and hence leads to sustained excitability, that is, myotonia. Studies in the two animal models with chloride channel mutations, the myotonic goat and the myotonic mouse, and studies of in vitro ion channel expression have suggested that mutations have a dominant negative effect; this implies that loss-of-function mutations may result in a greater than 50% reduction in channel function, explaining how mutations in the same gene may cause dominant or recessive disease.

Treatment To alleviate the myotonia, mexiletine is currently the first-line agent; it acts as a “membrane-stabilizing” agent, reducing sodium channel activation, but it has no direct effect on chloride channels. Mexilitene should be used with care as toxicity may develop at higher doses. If mexilitene is not effective, it

chapter 87 channelopathies of muscle (including the myotonic distrophies) ■

Central pore DI S1–6

DII S1–6

DIV S1–6

DIII S1–6

DI S1–6 DIV S1–6

Intramembranous loop between segments 5 and 6 forms lining of channel pore

DII S1–6 DIII S1–6

Fast inactivation — gate or hinge between domains III and IV

A Voltage sensor

Transmembrane (hydrophobic) helices

S1

Voltagedependent inactivation (gate)

S2

S3

++ ++ S4 ++ ++ + ++

Ion-selective pore Extracellular S5

NH2

B

may be worth switching to carbamazepine or phenytoin. Acetazolamide is not beneficial (although it may be in sodium channel myotonias, see later) and—along with other diuretics—may worsen symptoms of myotonia. Many patients believe that treatment for their myotonia is not necessary as they have adapted to their condition and manage their activities without undue disruption. However, even mild untreated myotonia may lead to subsequent muscle weakness. Care should be taken that depolarizing agents and anticholinesterases are avoided during anesthesia.

Sodium Channel Disorders (SCN4A) Epidemiology Hyperkalemic periodic paralysis (prevalence, approximately 1 : 200,000) and paramyotonia congenita are autosomal dominant conditions. Cases of myotonia permanens are sporadic, probably partly due to the severity of the condition.

Clinical Features Hyperkalemic periodic paralysis is characterized by intermittent episodes of weakness following a potassium load, hence the name of the condition. Also, potassium concentration in the serum may rise during a spontaneous attack. Other precipitants include resting after exercise, stress, and pregnancy. Cold exposure may also precipitate an attack of weakness, indicating an overlap between hyperkalemic periodic paralysis and paramyotonia congenita (see later).

S6

Membrane Intracellular

COOH

1189

Figure 87–3. Schematic drawing of voltage-gated cation channel α subunit structure. (A) Four domains assemble into α subunit with central pore. (B) Representation of secondary structure of each domain of α subunit. The sodium channel consists of the main (α) subunit and an accessory (β) subunit. The α subunit consists of four homologous domains which assemble to form a central pore (A). Each domain comprises six transmembrane helices (S1-6) connected by interlinkers (B). The interlinker between S5 and S6 lines the ion pore. The S4 helix is positively charged and acts as a voltage sensor, moving extracellularly and resulting in channel opening through conformational change. The “gate” for fast inactivation is within the interlinker between domains III and IV; three amino acids move on a “hinge,” the so-called hinged-lid model. The voltage-gated L-type calcium channel complex comprises the α subunit, which is of similar structure to that of the sodium channel as well as accessory subunits.

Attacks usually start in childhood and tend to worsen during subsequent years. Patients often describe spontaneous attacks of weakness first thing in the morning, which may then either resolve or continue to progress. In later years, some patients develop fixed weakness, usually of the lower limbs, independent of episodes of paralysis. Paramyotonia congenita refers to a condition in which myotonia increases with repeated muscle contractions instead of diminishing as in the other myotonias; this is termed paradoxical myotonia or paramyotonia. In addition, muscle stiffness in paramyotonia congenita is increased by cold temperatures, a feature sometimes reported in other myotonias but only truly seen in paramyotonia congenita. Some patients may experience weakness of their muscles after the stiffness has resolved, indicating an overlap with hyperkalemic periodic paralysis. Symptoms are present from early childhood and tend not to worsen. In fact, many patients dismiss their symptoms as innocent family traits so as to reduce the interference of these symptoms with their lifestyles and occupations. Those patients who do seek medical advice may demonstrate eyelid closure or handgrip paramyotonia even at room temperature, but exposure to a cold environment may accentuate these, particularly in the facial muscles and fingers. The potassium-aggravated myotonias comprise a group of conditions characterized by myotonia of varying degrees that develops after vigorous exercise or administration of a potassium load. Typically, there is a short delay before the onset of the myotonia, which, in the most severe cases, may then take several hours to resolve.

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Myotonia fluctuans is a mild version of potassiumaggravated myotonia in which the muscle stiffness is variable but not generally severe and there is no weakness. The myotonia may show a warm-up phenomenon. Myotonia permanens is at the severe end of the spectrum for potassium-aggravated myotonia and produces a condition of continuous depolarization at the cellular level with consequent sustained muscle contraction, myotonia, and hypertrophy. In severe cases, respiratory muscle compromise and hypoventilation may ensue. The situation may be worsened by exercise or potassium loads. There is an intermediate-severity potassium-aggravated myotonia called potassium- and cold-aggravated myotonia congenita, which clinically resembles Thomsen’s myotonia congenita and probably explains earlier overestimates of its frequency. The two may be distinguishable only on molecular testing.

Investigation In contrast to the myotonia congenita conditions, creatine kinase levels may be raised up to 5 to 10 times the upper limit of normal. Serum potassium concentration may rise by 1.5 to 3 mM during spontaneous attacks in hyperkalemic periodic paralysis. Interictal sodium and potassium levels are normal. Muscle biopsy is only occasionally helpful. Older hyperkalemic periodic paralysis patients with fixed weakness may have a vacuolar myopathy, but this may also be seen in those with hypokalemia periodic paralysis. In paramyotonia congenita, muscle biopsy may be normal or show nonspecific changes. In potassium-aggravated myotonia, electron microscopy of biopsies from patients with myotonia fluctuans or permanens may show subsarcolemmal disruption or vacuole formation. Provocation tests have traditionally been used to assist in making a diagnosis but have been largely superseded by genetic investigations. In suspected hyperkalemic periodic paralysis, the provocation test enhances the likelihood of inducing an attack by having the fasting patient exercise and then rest. If this does not result in an attack, an oral potassium load is given. In suspected paramyotonia congenita, cold immersion of the long finger flexor muscles results in slower relaxation times and reduced compound muscle action potential or contractile force. Oral potassium loading may also be helpful in making the diagnosis of potassium-aggravated myotonia; a strong voluntary contraction followed by short contractions produces a delayed relaxation time. However, provocation tests can be difficult to perform, need careful monitoring, and are contraindicated in myotonia permanens, where there is significant risk of causing life-threatening respiratory muscle stiffness, or in periodic paralyses with preexisting cardiac conduction abnormalities.

Molecular Pathophysiology The gene encoding the α subunit of the skeletal muscle sodium channel is located on chromosome 17q23-25. The α subunit is responsible for most of the channel’s functionality and comprises four domains, each of which is composed of six transmembrane stretches of α helix. Voltage gating is mediated from within the α subunit and regulates the opening or closing of the channel. Pathogenic mutations in the SCN4A gene result in impaired inactivation of the sodium channel following generation of the

action potential, which results in delayed depolarization of the sarcolemma. This leads to continued muscle cell activation at the cellular level, which is evident clinically as slowed muscle relaxation (myotonia). If the sarcolemma becomes completely depolarized, it is inexcitable and this manifests clinically as (periodic) paralysis. Hyperkalemic periodic paralysis mutations probably affect binding to and inactivation of the channel, an adverse situation amplified by potassium efflux from the cell. Potassium loading may make depolarization more difficult and precipitate paralysis. The myopathy seen in association with hyperkalemic periodic paralysis seems to occur in patients with the T704M mutation. In paramyotonia congenita, mutations are also believed to impair sodium channel inactivation, an effect enhanced by cold temperatures. Mutations found in potassiumaggravated myotonia patients again affect inactivation of the channel through disrupting binding. This is a graded effect: in functional studies, mutations seen in myotonia fluctuans patients cause less marked changes than the G1306E missense mutation seen in myotonia permanens.

Treatment Modification of environmental and lifestyle may help to reduce the need for medication. In hyperkalemic periodic paralysis, patients learn to eat regular carbohydrate-rich meals, particularly at breakfast. They should not stop exercising abruptly but rather should “cool down” gradually to prevent the onset of paralysis that occurs with rest after exercise. Patients with potassium-aggravated myotonia should also be advised to avoid sudden bursts of vigorous exercise. In paramyotonia congenita, avoidance of cold temperatures is clearly helpful. Patients with hyperkalemic periodic paralysis or potassiumaggravated myotonia should be given dietary advice to help them avoid potassium-rich foods. Awareness of concomitant conditions such as hypothyroidism is important as this worsens paramyotonia. Symptoms of paramyotonia congenita should improve with mexilitene, which acts partly as a sodium channel stabilizer. All patients with myotonia permanens should be treated with either mexilitene or agents such as carbamazepine. Some cases of paramyotonia respond to acetazolamide. Acetazolamide or thiazide diuretics may also be helpful in hyperkalemic periodic paralysis patients, probably due to their tendency to lower serum potassium via a specific channel effect. Precautions for general anesthetics are advised, and agents such as suxamethonium and anticholinesterases should not be given. Even so, anesthetic recovery may be prolonged, especially in hyperkalemic periodic paralysis patients. Optimization of perioperative serum potassium concentration is important in improving outcome.

Calcium Channel Disorders (CACNL1A3) Epidemiology Hypokalemic periodic paralysis is an autosomal dominant condition with a prevalence of approximately 1 : 100,000, which makes it twice as common as hyperkalemic periodic paralysis.

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Clinical Features

Treatment

Hypokalemic periodic paralysis is a periodic paralysis without myotonia that varies in severity from mild, infrequent episodes beginning in adult life to prolonged, frequent attacks starting in childhood. Intrafamilial variability may be marked. Patients at the more severe end of the spectrum may have weakness that is present constantly but varies in degree. In all patients, many factors may affect strength, including serum potassium levels (influenced by diet and drugs and preceding vigorous exercise), glucose levels (dependent on carbohydrate intake and concomitant illnesses), and emotional stress and lifestyle (affecting the degree of activity). Episodes of paralysis in hypokalemic periodic paralysis may be heralded by vague nonspecific symptoms followed by attacks of localized or generalized weakness that tend to be more prolonged than in hyperkalemic periodic paralysis. As in hyperkalemic periodic paralysis, older patients may develop fixed weakness due to vacuolar myopathy.

Awareness and modification of environmental and lifestyle are again important. High-carbohydrate and high-salt meals are potential precipitants of episodic paralysis. Extremes of exercise or inactivity should be avoided. Both patients and clinicians should be alert to the possibility that unavoidable factors, such as viral illnesses, can precipitate an episode. Potassium supplements may be helpful on a daily basis and higher doses should be given if an episode of paralysis occurs. Intravenous potassium is rarely indicated and should be administered only with cardiac monitoring. Low-dose acetazolamide may help prevent attacks in patients with CACN1AS mutations. General anesthetics may precipitate a severe paralytic episode, so awareness of the patient’s condition is important.

Investigation Creatine kinase levels are normal or slightly raised, in contrast to sodium channel disorders. Serum potassium concentration is usually normal between attacks, and it can be either lower than normal or within the low-normal range during attacks. After an episode of paralysis, serum potassium concentration may be misleadingly high. The electromyography in hypokalemic periodic paralysis does not show myotonic discharges, in contrast to hyperkalemic periodic paralysis, where myotonia is part of the condition. Interictal electromyography in mildly affected patients is usually normal. Ictal recordings show small or absent compound muscle action potentials. In patients who develop fixed weakness, there are electromyographic changes consistent with myopathy and muscle biopsy shows a vacuolar myopathy similar to that in hyperkalemic periodic paralysis. Provocative tests are used occasionally but great care should be exercised. The principle is to induce hypokalemia by administering glucose with or without insulin, thus provoking an episode of paralysis.

Molecular Pathophysiology The voltage-gated skeletal muscle L-type calcium channel α1S subunit (dihydropyridine receptor) is encoded by the CACN1AS gene located on chromosome 1q31-32; three missense mutations in CACN1AS account for about 60% of hypokalemic periodic paralysis cases. Mutations in this gene are also responsible for some cases of malignant hyperthermia. The calcium channel α1S subunit and its associated subunits form a transmembrane pore through which calcium ions pass. In hypokalemic periodic paralysis patients, calcium flux through the channel is reduced, which may reduce muscle membrane excitability. The channel may also be involved in the initial phase of excitation-contraction coupling, although its exact role in this process is unclear. Surprisingly, four missense mutations in the sodium channel gene SCN4A have been associated with 20% of hypokalemic periodic paralysis cases. Inactivation of sodium channels is increased, thus making the muscle cell membrane less excitable.

Andersen’s Syndrome Andersen’s syndrome is an autosomal dominant condition associated with mutations in the Kir2.1 potassium channel α subunit gene KCNJ2. Features comprise episodes of periodic paralysis associated with high- or low-serum potassium levels, potentially life-threatening cardiac dysrhythmias, and a mildly dysmorphic appearance. The Kir2.1 channels are expressed in both skeletal and cardiac muscles and are required to maintain the high negative resting membrane potential in resting skeletal muscle and in the depolarization phase of the action potential in cardiac muscle; dominant negative mutations in patients with Andersen’s syndrome reduce potassium ion flow. Treating the cardiac dysrhythmias and periodic paralysis is difficult.

Thyrotoxic Periodic Paralysis Thyrotoxic periodic paralysis is a late-onset disorder, usually occurring in patients of east Asian descent, in whom thyrotoxicosis is associated with episodes of paralysis precipitated by hypokalemia. Acute treatment is based on administration of potassium and/or propranolol. Once the thyroid dysfunction is corrected, the attacks of periodic paralysis disappear.

Secondary Hypokalemic Periodic Paralysis Paralytic episodes may occur in conditions where hypokalemia is due to a variety of chronic disorders such as renal tubular acidosis, gastrointestinal potassium loss, or Cushing’s syndrome. Investigation should reveal the underlying metabolic disturbance, and treatment directed at the cause often abolishes paralytic attacks.

MYOTONIC DYSTROPHIES Myotonic dystrophy as a clinical syndrome has been recognized for many years, and its features typically comprise myotonia, distal muscle wasting, and early appearance of cataracts. Detailed inspection and investigation of these patients have revealed the presence of many additional characteristics; myotonic dystrophy is a multisystem disease and its myriad manifestations are discussed here. Recognition of myotonic dystrophy as an autosomal dominantly inherited condition was straightforward. However, it was

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not so easy to understand why successive generations seemed to become progressively more severely affected. Current genetic concepts and theories of pathogenesis are outlined in the following sections. These are suggested strategies for targeted therapies, which may lead to a cure. Patients with myotonic dystrophy develop a fairly predictable set of complications, and clinical care aims to anticipate and prevent these as far as possible. Currently, this provides the most practical avenue for a satisfying management of this condition.

Epidemiology Myotonic dystrophy type 1 (DM1) is a relatively common muscle disorder, with estimated prevalence figures ranging from 5 to 8.4 per 100,000, which reflects either true differences in prevalence rates or differences in case acquisition methods. Type 2 (DM2) appears to be much less common and with marked geographical variation.

T A B L E 87–1. Comparison of Features of DM1 and DM2

Prevalence Congenital cases Onset Inheritance Genetic mutation Affected gene Chromosomal locus Limb myotonia Myotonia on electromyography Distribution of weakness Presence of myalgia Facial weakness Bulbar weakness Cardiac involvement Respiratory involvement Anesthetic risks Cognitive abilities Somnolence

DM1

DM2

Yes Earlier Autosomal dominant CTG triplet repeat exp DMPK (3′ UTR) 19q13 Frequent Yes

No Later Autosomal dominant CCTG quad repeat exp ZNF9 (intron 1) 3q21 Less frequent Yes

Distal

Proximal

Common Yes Yes Yes Yes

Common No No Less common No

Yes Affected Frequent

No Normal Infrequent

Clinical Features Myotonic Dystrophy Type 1 It is often possible to recognize a patient with DM1 through careful observation; there is often a characteristic facial appearance due to weakness of the facial muscles, with ptosis and a myopathic face, wasting of the temporalis muscles, and early frontal balding. Bulbar muscle weakness may produce dysarthric speech. Hand muscles are commonly weak and give the fingers an elongated appearance; myotonia of handgrip may confirm the clinical diagnosis. Targeted clinical examination seeks to elicit percussion myotonia of thenar muscles (and sometimes larger muscle groups) and grip and eyelid closure myotonia. Neurophysiological demonstration of myotonic discharges is often used but is rarely of additional benefit in the presence of other suggestive features. The presence of cataracts in a “young” person should be sought. The remainder of the neurological examination is usually normal. The phenotype of congenital DM1 is seen infrequently by adult neurologists due to the poor outlook for these patients. In the neonatal unit, however, infants with congenital DM1 are considered in the differential diagnoses of the “floppy baby syndrome”; these babies may need respiratory support after birth, sometimes for weeks, and usually feed poorly. It requires an astute clinician to think of this diagnosis, a process that may be aided by recognition of the myopathic facial appearance of one of the parents, usually the mother.

Myotonic Dystrophy Type 2 A minority of patients with clinical myotonic dystrophy not explained by the genetic errors identified in DM1 have revealed mutations in another gene, and this condition is termed DM2 (previously known as proximal myotonic myopathy). However, DM1 and DM2 do not account for all cases, and further genetic loci are under investigation. Patients with DM2 have in common with DM1 patients the presence of myotonia, early cataracts, and autosomal dominant family history but tend to have proximal more than distal

weakness. Table 87–1 compares the salient features of the two conditions.

Investigations In general, serum creatine kinase is only slightly raised in patients with DM1 and DM2. Electromyography shows myotonic discharges in both conditions. Muscle biopsy is not usually indicated but may show the presence of fiber size variation and central nuclei.2 When the diagnosis is suspected, genetic testing should provide confirmation of this fairly rapidly. In DM1, estimation of CTG repeat number on chromosome 19q13.3 is achieved through Southern blotting for repeat sizes over 100 and by polymerase chain reaction for smaller expansions. Normal individuals have 5 to 35 repeats; 35 to 50 repeats are considered premutation and have the potential to expand in successive generations; over 50 repeats are likely to be seen in clinically affected patients. In DM2, detection of CCTG expansions in chromosome 3q21 confirms the diagnosis. Genetic counseling and testing should be offered to members of the family who may be at risk of having the condition. Ancillary investigations may reveal the existence of occult changes such as atrial flutter or fibrillation on a 12-lead electrocardiogram or reduced respiratory capacity on spirometry. These aspects are discussed later.

Theories of Molecular Pathogenesis In DM1, the expanded CTG repeat within the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene is unstable through successive generations and thus explains the anticipation phenomenon whereby offspring have increased repeat numbers (and earlier onset) than their parents. Extreme

chapter 87 channelopathies of muscle (including the myotonic distrophies) numbers of repeats (in excess of 1000) may occur in infants with congenital DM1. It seems that the phenotype is maintained in populations by the “premutation” repeat size, which is prone to expansion and maintains the population prevalence. Establishing the precise pathogenesis has been a challenge and there are three main theories. The first postulates that haploinsufficiency of DMPK adversely affects cell function; the second posits that the expanded CTG repeats alter the chromatin structure and affect the expression of neighboring genes, including the upstream DMWD or the downstream SIX5 genes; the third theory postulates that the CUG repeat expansion in DMPK RNA produces abnormal nuclear foci and a dominant gain of function. In DM2, the detection of large (over 5000) CCTG repeat expansions in intron 1 of the ZNF9 gene did not immediately explain the pathogenetic mechanism. Deleterious effects of mutant RNA are postulated to be important in the etiology as in DM1.

Principles of Care Care of the patient with myotonic dystrophy begins when the diagnosis is made. Patients should be made aware of important precautions, such as informing anesthetists about their condition. A patient-held record or alert card may be helpful. Annual assessments are advisable, as this allows both an ordered review of symptoms and a reminder of interval checks of electrocardiograms and respiratory function. Electrocardiographic evidence of arrhythmias may already be present in patients at their first assessment, even if they are asymptomatic, or may be heralded on subsequent visits by prolongation of the PR interval or by widening of the QRS complex. These features should be sought specifically and may require referral to a cardiologist for subsequent management, including placement of a permanent pacemaker, if necessary. Sudden cardiac death is described in both DM1 and DM2. Assessment of respiratory muscle strength through spirometry can be performed easily in the outpatient clinic and provides a serial record. The suspicion of nocturnal hypoventilation is raised by the patient’s description of symptoms such as lassitude and morning headache and can be assessed by overnight oximetry performed at home. Nocturnal noninvasive respiratory support may be helpful for relief of symptoms in the motivated patient. Excessive daytime sleepiness as quantified by the Epworth Sleepiness Score may be troublesome and has been attributed to a central mechanism in DM1. Modafanil may be helpful but is not successful in all patients. Sleep-disordered breathing due to obstructive sleep apnea may also be present and may be treated by nocturnal noninvasive respiratory support as described. Personality changes are well recognized in patients with DM1 and may be best described as a lack of motivation,3 although it is not clear how these cognitive changes relate to changes seen on brain imaging. Dysphagia is frequent and may improve with speech therapy. Constipation or diarrhea may be a prominent symptom and requires active management. Other problems, such as myalgia,

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may be more difficult to treat. Overall, the patient with DM1 requires systematic evaluation to ascertain areas of difficulty and a sympathetic approach to resolving chronic problems.

K E Y

P O I N T S

●

The channelopathies are a group of disorders in which the underlying molecular mechanisms of altered muscle membrane excitability have become clearer in recent years.

●

Precise diagnosis may be achieved through a combination of clinical assessment, targeted neurophysiological testing, and genetic investigation.

●

Establishing the nature of the primary ion channel defect may be important in choosing the best treatment.

●

Some of the channelopathies may be encountered only rarely, even in specialist clinics, whereas myotonic dystrophy type 1 is commonly seen in clinical neurological practice.

●

Myotonic dystrophy affects many organ systems, and some of these aspects are potentially more detrimental to life expectancy than is the skeletal muscle involvement.

●

Although there are currently no cures, it is important that patients are actively managed with treatment of the symptoms and possible complications.

●

Understanding of the cellular pathophysiology in the myotonic dystrophies is advancing and may lead to the development of treatments based on specific defects.

Suggested Reading Harper P, et al, eds: Myotonic Dystrophy. Present Management, Future Therapy. 2004. Lehmann-Horn F, Rudel R, Jurkat-Rott K: Nondystrophic myotonias and periodic paralyses. In Engel A, Franzini-Armstrong C, eds: Myology, 3rd ed. 2004. Ranum L, Day J: Pathogenic RNA repeats: an expanding role in genetic disease. Trends Genet 2004; 20:506-512. Surtees R: Inherited ion channel disorders. Eur J Pediatr 2000; 159(Suppl 3):S199-S203. van Engelen B, Eymard B, Wilcox D: 123rd ENMC International Workshop: Management and Therapy in Myotonic Dystrophy. Neuromuscular Disord 2005; 15:389-394.

References 1. Lehmann-Horn F, Rudel R, Jurkat-Rott K: Nondystrophic myotonias and periodic paralyses. In Engel A, FranziniArmstrong C, eds: Myology, 3rd ed. 2004. 2. Schoser BG, Schneider-Gold C, Kress W, et al: Muscle pathology in 57 patients with myotinic dystrophy type 2. Muscle Nerve 2004; 29:275-281. 3. Winblad, S, Lindberg C, Hansen S: Temperament and character in patients with classical myotonic dystrophy type 1 (DM-1). Neuromuscul Disord 2005; 15:287-292.

CHAPTER

88

METABOLIC MYOPATHIES (INCLUDING MITOCHONDRIAL DISEASES) ●

●

●

●

Patrick F. Chinnery and Douglass M. Turnbull

Muscle contraction is dependent on the high-energy molecule adenosine triphosphate (ATP), and deficiency of ATP synthesis leads to premature muscle fatigue and weakness. Carbohydrate metabolism, fatty acid oxidation, and the oxidative phosphorylation are all important in the generation of ATP from metabolic fuels, and defects in all three pathways result in metabolic myopathies. Although this chapter is primarily concerned with the muscle symptoms of these metabolic disorders, it is important to remember that many of them also affect other tissues and organs, particularly when the final common pathway of energy metabolism is involved—mitochondrial oxidative phosphorylation.

the liberation of glucose from muscle glycogen stores. Phosphofructokinase catalyzes the rate-limiting step in glycolysis. Under anaerobic conditions, glycolysis ultimately results in the conversion of pyruvate to lactate. This generates only a fraction of the ATP that would be produced if the glucose were fully oxidized to carbon dioxide and water by aerobic metabolism. The accumulation of lactate and of the major components of ATP hydrolysis (inorganic phosphate, adenosine diphosphate, and adenosine monophosphate) play an important role in causing muscle fatigue. For a full description of the metabolic pathways, see Matthews and van Holder.1

GLYCOGEN STORAGE DISORDERS

Clinical Features, Diagnosis, and Management

Glycogen storage disorders (the glycogenoses) are a group of rare inherited metabolic diseases caused by abnormal synthesis or breakdown of glycogen. Most involve cytoplasmic enzymes, except α-glucosidase (acid maltase) deficiency, which involves the lysosomal glycogen degradation pathway. Most glycogen storage disorders are autosomal recessive; phosphorylase b kinase may be either autosomal or X-linked recessive, and phosphoglycerate kinase deficiency is X-linked recessive. The glycogen storage disorders generally manifest clinically in one of two ways: either with exercise intolerance, muscle cramps, and intermittent rhabdomyolysis or with slowly progressive proximal weakness (Table 88–1). Unusual manifestations include insidious neuromuscular ventilatory failure observed in some adults with α-glucosidase deficiency. Although the biochemical and genetic bases are well established for most of these disorders, the reasons for the phenotypical variability are unknown, and both environmental and epistatic genetic factors play roles (such as the interaction between phosphofructokinase deficiency and adenosine monophosphate deaminase/myoadenylate kinase).

a-Glucosidase Deficiency (Acid Maltase Deficiency, Pompe’s Disease, Type II Glycogenosis)

The Glycolytic Pathway Glycolysis provides energy for high-intensity muscle activity when oxygen availability limits aerobic respiration (Fig. 88–1). Muscle phosphorylase (also called myophosphorylase) initiates

α-Glucosidase deficiency can manifest in three ways. In the neonatal period, it typically causes hypotonia, cardiomyopathy and, less frequently, hepatomegaly, and enlargement of the tongue. Cardiac and respiratory difficulties usually lead to death by 2 years of age.2 The childhood manifestations are less dramatic, with progressive proximal weakness and no cardiac involvement. Adult patients usually present with a slowly progressive proximal myopathy, but up to one third of them may have respiratory failure.3 The serum creatine kinase level is typically raised, and electromyography reveals myopathic features, often in association with myotonic discharges. Muscle biopsy reveals a vacuolar myopathy: Vacuoles contain glycogen and show increased acid phosphatase activity. These features are nonspecific, and the diagnosis must be confirmed by enzyme assay either in muscle, fibroblasts, or lymphocytes. Genetic analysis of the αglucosidase (GAA) gene often reveals the underlying mutation, and there is often a good relationship among type of mutation, biochemical defect, and clinical phenotype.4 Treatment is largely supportive, often involving nocturnal respiratory support after presentation in childhood or adulthood. Clinical trials of enzyme replacement therapy show promise, providing some hope for the future.5,6

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II Lysosome glycogen

Figure 88–1. Glycogen and glucose metabolism. the principal enzyme defects causing glycogen storage disorders are shown (see Table 88–1). CoA, coenzyme A; UDP, uridine diphosphate.

Glucose ␣-Glucosidase Phosphorylase b kinase

Glycogen Branching enzyme (GBE)

V IV

VIII

Phosphorylase a

Phosphorylase b

VI

UDP-glucose

Limit dextrin IIIa

Debranching enzyme

Glucose 1-phosphate Glucose 6-phosphatase Glucose

Glucose 6-phosphate I Fructose 6-phosphate VII

Phosphofructokinase (PFK)

Fructose 1,6-bisphosphate XII

Aldolase

Glyceraldehyde 3-phosphate

1,3-Bisphosphoglycerate IX

Phosphoglycerate kinase (PGK)

3-Phosphoglycerate X

Phosphoglycerate mutase

2-Phosphoglycerate

Pyruvate XI

Acetyl-CoA

Lactate dehydrogenase (LDH)

Lactate

Debranching Enzyme Deficiency (Type III Glycogenosis)

Branching Enzyme Deficiency (Type IV Glycogenosis)

Debranching enzyme deficiency can manifest in childhood or adulthood. Symptoms are more prominent in childhood and can include episodes of hypoglycemia. Manifestation in adulthood is usually with a slowly progressive distal myopathy without hepatosplenomegaly. The serum creatine kinase level is usually elevated, and electromyography demonstrates myopathy with occasional myotonic discharges.l Muscle biopsy reveals a vacuolar myopathy, and the diagnosis is confirmed by biochemical assay in red or white blood cells or in muscle. Different clinical subtypes of debranching enzyme deficiency appear to be associated with different mutations in the AGL gene.7

Branching enzyme deficiency can manifest in infants with muscle hypotonia and hepatosplenomegaly, leading to fatal liver cirrhosis. An infantile neuromuscular manifestation, often with cardiac or central nervous system involvement and sometimes simulating spinal muscular atrophy, is probably more common than previously suspected and should be considered in the differential diagnosis of the floppy infant syndrome.8,9 The muscle biopsy reveals periodic acid–Schiff stain–positive, diastase-fast deposits. The diagnosis is confirmed by enzyme assay, and mutations may be found in the GBE gene.9 Treatment is supportive, including liver transplantation in early childhood.

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T A B L E 88–1. Glycogen Storage Diseases Manifesting with Neurological Features Type

Enzyme Deficiency

Alternative Names

Inheritance Pattern

Clinical Manifestation

II

Lysosomal α-glucosidase

Acid maltase deficiency Pompe’s disease

AR

III

Debranching enzyme Cori-Forbes disease Branching enzyme

AR

IV

Amylo-1,6-glucosidase, 4α-glucantransferase enzyme Amylo-(1,4→1,6)-transglycosylase

V

Myophosphorylase

McArdle’s disease

AR

VI

Phosphorylase b kinase

VII IX X XI XII XIII

Phosphofructokinase Phosphoglycerate kinase Phosphoglycerate mutase Lactate dehydrogenase Aldolase β-Enolase

Infant: hypotonia, cardiomyopathy Child: Progressive proximal weakness Adult: Proximal myopathy, ventilatory failure Infant: hepatosplenomegaly, weakness Adult: distal weakness Child: hepatosplenomegaly, cirrhosis, weakness, congenital myopathy, cardiomyopathy Myoglobinuria, exercise intolerance, muscle cramps, reversible contracture Child: hepatosplenomegaly, hypotonia Adult: exercise intolerance, weakness Adult: muscle cramps, myoglobinuria, weakness Child: hemolytic anemia, seizures, myopathy Adult: cramps, myoglobinuria, weakness Adult: myoglobinuria Child: myopathy, rhabdomyolysis Adult: exercise intolerance, increased creatine kinase level

AR

XR, AR Tarui’s disease

AR XR AR AR AR AR

AR, autosomal recessive; XR, X-linked recessive.

Myophosphorylase Deficiency (McArdle’s Disease, Type V Glycogenosis) Myophosphorylase deficiency typically manifests in late childhood or the early teenage years with muscle pain and weakness in the early stages of moderate exertion. Mild symptoms are rapidly relieved by rest, but after prolonged exercise, the symptoms may persist for days, accompanied by reversible painful contractures. Some patients are able to work through the initial symptoms and find that prolonged exercise becomes possible (the so-called “second wind” phenomenon), because of the mobilization of fatty acids as a fuel. By gradually “warming up” with light exercise, some patients reduce the intensity of their symptoms and increase exercise tolerance, presumably through the same mechanism. Myoglobinuria is common (often microscopic), and rhabdomyolysis may occur, even as a presenting feature. The serum creatine kinase level is usually elevated between acute attacks but rises dramatically immediately after an episode of muscle pain. Electromyography may reveal nonspecific myopathic features, but the appearance is often normal. Forearm exercise testing characteristically reveals a high or even supranormal ammonia response, with a minimal or no increase in venous blood lactate levels during or immediately after exercise. This test is not without risk, inasmuch as it may provoke rhabdomyolysis or a forearm compartment syndrome. Skeletal muscle histochemistry study demonstrates glycogen storage and the absence of phosphorylase activity. Muscle phosphorylase deficiency can be confirmed biochemically (levels usually <5% of normal), but this is rarely necessary. In the majority of patients of European descent, molecular genetic analysis reveals the R49X mutation (>70%) in the PYGM gene,10 which is either homozygous or compound heterozygous, with another mutation in the coding region of the gene. Different common mutations are found in other populations.11 Most patients adapt their lifestyles to avoid precipitating factors. There is evidence that an oral sucrose load before activity can increase exercise tolerance, but this may not be practi-

cal in every circumstance.12 Myoglobinuria and rhabdomyolysis should be treated aggressively by increasing the fluid intake. Careful monitoring of the serum creatine kinase and phosphate levels is essential. Intravenous fluids, furosemide, and hemodialysis are sometimes required.

Phosphorylase b Kinase (Type VIII Glycogenosis) Phosphorylase kinase is multimeric, with four subunits: α, β, γ, and δ. The enzyme is regulated by the α and β subunits, γ is the catalytic subunit, and δ regulates calcium sensitivity. The α subunit gene is on the X chromosome, and the other genes are on autosomes, which explains why phosphorylase b kinase deficiency can be either X-linked recessive or autosomal recessive. In infancy, the disorder typically manifests with hepatosplenomegaly, hypotonia, and hypoglycemia or with cardiomyopathy. In later life, myopathic features are more prominent, including exercise intolerance, muscle stiffness, and weakness. Respiratory failure and cardiomyopathy can occur. The serum creatine kinase level is often elevated. Glycogen is deposited within muscle fibers (typically type II), but with normal muscle phosphorylase activity. The diagnosis is confirmed by enzyme assay. Genetic analysis is complex because of the many subunits, and even with exhaustive sequencing of known genes, the results are often negative.13 Management is essentially supportive.

Phosphofructokinase Deficiency (Tarui’s Disease, Type VII Glycogenosis) Approximately 90 cases of phosphofructokinase deficiency have been described in the literature.13a The disorder has a clinical manifestation similar to that of myophosphorylase deficiency (McArdle’s disease, type V glycogenosis). In both disorders, the forearm ischemic exercise test produces a flat lactate response and a marked rise in ammonia levels. In myophosphorylase

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deficiency, the rise in venous ammonia can be abolished by infusing 5% dextrose, but in phosphofructokinase deficiency, this causes an even more dramatic rise in the ammonia level. Both disorders show a similar pattern of subsarcolemmal glycogen storage, but pockets of polyglucosan deposits are present in phosphofructokinase deficiency. The diagnosis is confirmed by biochemical assay of the muscle specific isoform of phosphofructokinase, followed by PFK-M gene analysis.14 Management is largely supportive. A high-protein diet may help, and rhabdomyolysis must be treated vigorously.

Disorders of the Distal Glycolytic Pathway These disorders share similar clinical features, related to residual enzyme activity in skeletal muscle. Attacks of muscle pain and weakness are provoked by severe exercise, histochemical accumulation of glycogen may be scant or absent, and forearm exercise testing often yields a mildly positive result.

Phosphoglycerate Kinase Deficiency (Type IX Glycogenosis) Phosphoglycerate kinase deficiency is an X-linked disorder that can manifest with either prominent myopathic or hemolytic features. A mixed phenotype has been observed, and central nervous system features may include mental retardation and epilepsy. A range of different mutations have been found in the PGK gene.15

Phosphoglycerate Mutase Deficiency (Type X Glycogenosis) Phosphoglycerate mutase deficiency typically causes prominent exercise intolerance and is associated with a moderate rise in lactate level with a massive increase in ammonia on forearm exercise testing. This disorder has been associated with mutations in the PGAMM gene, which encodes the muscle-specific subunit of this dimeric enzyme.

Lactate Dehydrogenase Deficiency (Type XI Glycogenosis) Lactate dehydrogenase deficiency typically manifests with exercise intolerance, myalgia, and, sometimes, a nonitchy erythematous rash on the extensor surfaces of the ankles and feet. The disorder is diagnosed by a biochemical assay of muscle lactate dehydrogenase activity and by mutation analysis of the LDH gene.16

Aldolase Deficiency (Type XII Glycogenosis) Aldolase deficiency 2004 was described for the first time in one child. It is characterized by rhabdomyolysis, often linked to fever and associated with viral infection, leading to fixed weakness. The diagnosis is confirmed by measuring aldolase activity in skeletal muscle and by mutation analysis of the ALDOA gene.17

b-Enolase Deficiency (Type XIII Glycogenosis) This enzyme defect has also been described in a single patient, a man with adult-onset exercise intolerance and chronically

increased serum creatine kinase.17a The patient was a compound heterozygote for mutations in the ENO3 gene, which encodes β-enolase, the isoform expressed predominantly in skeletal muscle.

FATTY ACID OXIDATION DISORDERS Since the first description of carnitine palmitoyltransferase (CPT) deficiency in 1973,18 there has been a steady increase in both the number of different fatty acid oxidation disorders recognized and the number of affected patients identified. Defects involving many of the different enzymes and transport proteins involved in fatty acid oxidation have been described.19 The clinical features in these patients are diverse and depend on the nature and severity of the biochemical defect. However, the most prevalent symptoms are related to neuromuscular, cardiac, and hepatic involvement.

Fatty Acid Oxidation Mitochondrial fatty acid β-oxidation is especially important in conditions of fasting and exercise.20 The switch from predominantly carbohydrate metabolism in early exercise to fatty acid oxidation depends on several factors, including the intensity of exercise and the relative fitness of the individual. When glycogen reserves are depleted, triglycerides are mobilized from lipid stores, and free fatty acids are released at the endothelial walls of the capillaries by the action of lipoprotein lipase. The free fatty acids are then transported across the muscle plasma membrane by tissue-specific fatty acid transporters. Also transported across the plasma membrane is carnitine, which is crucial for the transport of long-chain fatty acid into mitochondria. The muscle carnitine transporter “pumps” carnitine from blood up a tissue gradient, so that the level of muscle carnitine is approximately 50 times greater than that in blood. At the outer mitochondrial membrane, fatty acids are converted into their acyl-coenzyme A (CoA) esters by the ATPdependent acyl-CoA synthetases (Fig. 88–2). These acyl-CoA esters are then converted into acylcarnitine and free CoA by CPT-I at the outer mitochondrial membrane. The resulting acylcarnitine is then transported across the inner mitochondrial membrane by the carnitine:acylcarnitine translocase in exchange for free carnitine. Once inside the mitochondrial matrix, the acyl-CoA ester is reformed by CPT-II, and carnitine is released for further exchange by the carnitine:acylcarnitine translocase. The β-oxidation of fatty acids involves the concerted action of a series of four chain length–specific reactions, which remove a molecule of acetyl-CoA (C2) per cycle from the original fatty acid molecule. The fatty acid therefore is eventually completely broken down to acetyl-CoA, which is the main substrate of the citric acid cycle. The first reaction is catalyzed by the acyl-CoA dehydrogenases, a family of flavin adenine dinucleotide–requiring oxidoreductases. The electrons generated by this process are transferred via electron-transfer flavoprotein (ETF) and ETF ubiquinone oxidoreductase to the respiratory chain. Very-long-chain acyl-CoA dehydrogenase (VLCAD) is responsible for reducing acyl-CoA esters of chain length C12 to C18. Medium-chain acyl-CoA dehydrogenase (MCAD) is responsible for the acyl-CoA esters of chain length C6 to C10, and short-chain acyl-CoA dehydrogenase for C4 to C6 substrates.

chapter 88 metabolic myopathies (including mitochondrial diseases) C14-C18 fatty acids

Carnitine

C4-C12 fatty acids

Carnitine transporter

Long-chain fatty acid transporter

1199

Plasma membrane

CPT I Carnitine

OMM Acylcarnitine CoASH

Carnitine

ADP⫹Pi

Enoyl-CoA H2O

3-OH acyl-CoA 3

H⫹

12

Acyl-CoA

NAD⫹ NADH⫹H⫹

TFP 3-ketoacyl-CoA

4

1

-CH⫽CH-

-CH2-CH2-

OH

III

3

FADH2

-C-CH2Acetyl-CoA

O NAD⫹

NADH⫹H⫹

H⫹

Ketogenesis

4

Acetyl-CoA ■

H⫹

CoQ

TCA cycle

2

-CH-CH2-

Cyt c

FAD⫹

FADH2

H2O

H⫹

IV

H2O

Steroidogenesis FADH2

2

1/2 O2 CoASH

Carnitine

FAD⫹

1

V

ATP

Acylcarnitine

Acyl-CoA

VLCAD

H⫹

Carnitine

CPT II

18 16 14

IMM

CACT

Acyl-CoA

II

FAD⫹ NADH⫹H⫹ I

H⫹

NAD⫹

Figure 88–2. Mitochondrial fatty acid oxidation. Long-chain fatty acids are transported into mitochondria by a specific transport system involving the carnitine palmitoyltransferases (CPT-I and CPT-II) and the carnitine:acylcarnitine translocase (CACT). Medium- and short-chain fatty acids enter the mitochondria directly as their acyl-coenzyme A (CoA) esters. Fatty acyl-CoA esters are then converted to acetyl-CoA by β-oxidation. This involves the action of four chain length–specific reactions, which remove a molecule of acetyl CoA (C2) per cycle from the fatty acyl-CoA. The four reactions involve three acyl-CoA dehydrogenases, two enoyl-CoA hydratases, two 3hydroxyacyl-CoA dehydrogenases, and three thiolases. The acetyl-CoA generated by β-oxidation is a substrate for the tricarboxylic acid (TCA) cycle and is linked to the respiratory chain by electron-transferring flavoprotein (ETF) and ETF ubiquinone oxidoreductase. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoASH, uncombined coenzyme A; CoQ, coenzyme Q; Cyt c, cytochrome c; FAD+, flavin adenine dinucleotide; FADH2, reduced form of flavin adenine dinucleotide; IMM, inner mitochondrial membrane; NAD+, nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; OMM, outer mitochondrial membrane; Pi, inorganic phosphate; TFP, trifunctional protein; VLCAD, very-long-chain acyl-CoA dehydrogenase.

Long-chain acyl-CoA dehydrogenase has substrate specificity intermediate between VLCAD and MCAD; this is the least characterized of the enzymes, and its deficiencies have not yet been described. The second reaction of β-oxidation involves the hydration of the double bond in the 2,3 position to produce the L-hydroxyacyl-CoA ester. Two enzymes catalyze this reaction. The longchain enoyl-CoA hydratase is responsible for hydrating the long-chain esters and is part of a membrane-bound trifunctional protein (TFP), which includes the subsequent enzyme in the sequence: long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and then the final stage, long-chain 3-ketothiolase activity. The second hydratase, short-chain enoyl-CoA hydratase, is responsible for the hydration of short- and medium-chain enoyl-CoA esters.

The third reaction of β-oxidation involves the reduction of the l-3-hydroxyacyl-CoA to a 3-ketoacyl-CoA ester. In this reaction, nicotinamide adenine dinucleotide is converted to its reduced form, which is subsequently oxidized at complex I of the respiratory chain. LCHAD is part of the TFP and is responsible for the oxidation of long-chain substrates, whereas a shortchain 3-hydroxyacyl-CoA dehydrogenase has broad specificity and is responsible for the medium- and short-chain substrates. The final step of β-oxidation involves the thiolytic cleavage of the 3-ketoacyl-CoA ester into acetyl-CoA and an acyl-CoA that is two carbon units shorter. The enzyme responsible for the thiolysis of long chain species is the long-chain 3ketothiolase activity, which is part of the TFP. There are also a medium-chain thiolase and a short-chain thiolase, which are active for the medium- and short-chain 3-ketoacyl-CoA esters.

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Clinical Features of Mitochondrial Fatty Acid Oxidation Disorders Many of the different enzyme deficiencies have similar clinical features. Muscle involvement is frequent, which reflects the importance of fatty acid oxidation for normal muscle function. In some patients, this is reflected by exercise-induced muscle pain and rhabdomyolysis. The pain is characteristically caused by prolonged exercise and may occur after the exercise has been completed. In some patients, physiological fasting or fasting secondary to infection or illness can induce an episode. The rhabdomyolysis can be severe and lead to renal failure. In some patients, there is no pain but marked proximal weakness, severe enough to lead to respiratory compromise. In other patients, there is cardiac involvement and, sometimes, liver involvement. In severe cases, the manifestation is in early childhood and associated with metabolic changes such as hypoglycemia and even sudden death.

Carnitine Uptake Defect A genetic defect of the carnitine transporter typically manifests early in life with hypoglycemia and sudden death. In older patients, progressive myopathy and cardiomyopathy are present. The cardiomyopathy can be fatal; timely diagnosis is crucial because carnitine supplementation is curative.

described. LCHAD deficiency tends to manifest with profound liver disease and death in infancy. Clinical features may also include cardiomyopathy, myopathy, pigmentary retinopathy, peripheral neuropathy, and sudden death.25 TFP deficiency manifests in a similar manner26 but seems to be less common than isolated LCHAD deficiency, because of a common point mutation in the α subunit (1528G>C) of LCHAD.27

Medium-Chain Acyl-CoA Dehydrogenase Deficiency MCAD deficiency is the most frequent inborn error of fatty acid oxidation, and the overall frequency of the disease is estimated between 1 per 6500 and 1 per 17,000. Most affected patients present with acute metabolic crises in childhood,28 and muscle symptoms are rarely encountered.

Short-Chain 3-Hydroxyacyl–Coenzyme A Dehydrogenase Deficiency Few patients affected with this condition have been described, but muscle involvement with rhabdomyolysis and cardiomyopathy is one phenotype.29

Medium-Chain Thiolase Deficiency This is another rare condition, often associated with death in infancy from rhabdomyolysis.

Carnitine Palmitoyltransferase I Defect There are three tissue-specific isoforms of CPT-I: the so-called liver (CPT-IA), muscle (CPT-IB), and brain (CPT-IC) isoforms. At present, only patients with deficiency of the liver enzyme have been well documented; they have severe hepatic encephalopathy.21

Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency This is a rather poorly defined condition whose natural history remains uncertain. However, hypotonia and developmental delay have been prominent among the symptoms reported.

Carnitine:Acylcarnitine Translocase Defect

Glutaric Aciduria Type 2

These patients usually have severe liver and cardiac problems early in life, but a milder form in which muscle weakness is common has been described.22

This condition is caused by deficiency of either ETF or ETF ubiquinone oxidoreductase. There are different phenotypes:30 one with severe congenital abnormalities, one manifesting in the neonatal period with severe metabolic abnormalities and cardiomyopathy, and one manifesting with muscle weakness later in life. It is particularly important to recognize the third phenotype: Affected patients may have relapsing-remitting weakness, often involving the neck muscles, and many of them respond to treatment with riboflavin at high doses.31

Carnitine Palmitoyltransferase II Defect The myopathic form of this deficiency usually manifests with exercise-induced muscle pain and no involvement of other tissues. A neonatal form is severe and often associated with neonatal death. The difference between the two forms of the disease is related to the degree of residual enzyme activity.21

Investigation of Fatty Acid Oxidation Disorders Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Defect Severe VLCAD manifests in newborns, but milder defects of this enzyme mimic CPT-II deficiency, with exercise-induced muscle pain.23,24

Trifunctional Protein Deficiency and Isolated Long-Chain L-3-Hydroxyacyl–Coenzyme A Dehydrogenase Deficiency Although LCHAD is part of the TFP complex, isolated deficiencies of LCHAD and deficiencies of the whole TFP have been

The investigation of fatty acid oxidation disorders requires biochemical and genetic studies. There are few indications for muscle biopsy in these patients. Although fat accumulation may be present and dramatic in primary carnitine deficiency, the authors have observed normal biopsy findings in many adult patients with proved fatty acid oxidation defects. Moderate fat accumulation can also occur in normal subjects, contingent on diet and activity levels.

Biochemical Evaluation The introduction of sophisticated biochemical screening methods, particularly tandem mass spectrometry of free carni-

chapter 88 metabolic myopathies (including mitochondrial diseases) tine and acylcarnitines, has revolutionized the investigation of fatty acid oxidation disorders.32-36 In the authors’ view, the ease of these investigations mandates that clinicians always explore the possibility of fatty acid oxidation disorders in patients with unexplained weakness or muscle pain. Quantitative profiles of carnitine, acylcarnitines, and fatty acids in plasma and of organic acids and acylglycines in urine are major diagnostic tools. In children, the diagnostic possibilities are more varied and the manifestations often more acute, necessitating consultation with metabolic pediatricians. In adults, the authors measure fasting acylcarnitine levels in blood first thing in the morning. If the diagnosis is in doubt or if a fatty acid oxidation defect is still highly suspected despite normal acylcarnitine levels, then in vitro measures of fatty acid oxidation or quantitative metabolic profiles in cultured skin fibroblasts may be appropriate.

Genetic Studies Defects of mitochondrial fatty acid oxidation are autosomal recessive, and genetic defects have now been defined in several disorders. For some defects, there are common mutations that make genetic screening possible, although the advantage of genetic studies over biochemical assays is questionable. Patients with CPT-II deficiency often have a common point mutation (439C>T, S113L),37 which has been reported in several different series and is present in about 50% of mutant alleles. The common point mutation for LCHAD deficiency is 1538G>C,27 and the common mutation for MCAD (985A>G, K304E) is present in homozygous form in 80% of all affected patients. These point mutations have proved useful in assessing the frequency of fatty acid oxidation defects within populations; for example, the carrier frequency of the K304E mutation is approximately 1:40 in people of Northern European descent.

Treatment The primary treatment for patients with fatty acid oxidation defects is avoidance of catabolism resulting from excessive fasting or other exacerbating factors such as infection or prolonged exercise. In adult patients, it is often the combination of fasting and infection that precipitates an episode of rhabdomyolysis. Other treatments for long-chain fatty acid oxidation disorders include dietary modifications to maintain a low intake of natural long-chain fats and supplementation with medium-chain triglycerides, high intake of complex carbohydrate, and adequate intake of essential fatty acids. Prompt intervention during intercurrent illness is important; patients should be admitted under the care of physicians who are aware of the diagnosis and of appropriate management, or patients should carry alert tags stressing the need to avoid fasting and to provide calories in the form of carbohydrate during the crises. For certain defects, treatment with specific therapy is important. For patients with primary carnitine deficiency caused by defects of the carnitine transporter, carnitine administration is crucial. However, carnitine supplementation in other defects of fatty acid oxidation, especially of long-chain fatty acids, is controversial. Long-chain acylcarnitines have detergent properties and have been reported to cause arrhythmias. In adult clinical neurology, few treatments are more rewarding than riboflavin

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and a low-fat diet in patients with adult-onset glutaric aciduria type 2. Most of these patients respond to riboflavin, and their weakness resolves.

DEFECTS OF MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION Defects of mitochondrial oxidative phosphorylation are now recognized as common causes of neurological disease. The biochemistry and genetics of these disorders are much more complex than those of either glycogen storage diseases or fatty acid oxidation disorders, because oxidative phosphorylation is controlled by two genomes, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). In addition, mitochondrial oxidative phosphorylation disorders may manifest with a vast array of clinical features, which makes their clinical diagnosis difficult.

Mitochondrial Oxidative Phosphorylation and Mitochondrial Genetics The major function of the respiratory chain is the coupling of reducing equivalents generated by the oxidation of fatty acids and carbohydrates to generate readily usable energy in the form of ATP (Fig. 88–3). This process involves the transfer of electrons along the respiratory chain to molecular oxygen. The respiratory chain involves four multi-subunit complexes (I, II, III, and IV) and two mobile electron carriers, ubiquinone and cytochrome c, which transfer the electrons between the complexes. The electrons are transferred to molecular oxygen at complex IV (also called cytochrome c oxidase), and at complexes I, III, and IV, an electrochemical gradient is developed. ATP is generated at complex V (also called ATP synthetase) by the discharge of this gradient and the conversion of adenosine diphosphate to ATP. The overall process is called oxidative phosphorylation. Mitochondria are under the dual genetic control of both nuclear DNA and the mitochondrial genome. The mitochondrial genome consists of a circular double-stranded DNA molecule (16.6 kilobases in humans) that encodes 13 essential polypeptides of the oxidative phosphorylation system and the necessary RNA machinery (2 ribosomal RNAs and 22 transfer RNAs) for their translation within the organelle (Fig. 88–4). The remaining protein subunits that make up the respiratory chain complexes, together with those required for mtDNA maintenance, are nuclear DNA–encoded; they are synthesized on cytoplasmic ribosomes and specifically targeted and sorted to their correct location within the organelle. As a result, mitochondrial disorders can result from mutations in mtDNA or nuclear DNA. This has important implications for the recurrence risks within families. Mitochondrial disorders can be sporadic, maternally inherited, X-linked, or transmitted as autosomal dominant and recessive traits. The genetics of mtDNA is very different from mendelian genetics. From a clinical perspective, two features stand out. The polyploid nature of the mitochondrial genome, consisting of up to several thousand copies per cell, gives rise to two important features of mitochondrial genetics: homoplasmy (when all copies of the mitochondrial genome are identical) and heteroplasmy (the mixture of two or more mitochondrial

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Neuromuscular Diseases: Muscle WORK Cytosol ATP Outer membrane

ADP⫹Pi

c Hⴙ

Hⴙ

Hⴙ

e-

Hⴙ

c

e-

ATP

e-

ADP⫹Pi

Q Q

FADH2

ANT

FAD 1/2 O2

Inner membrane Matrix

H2O

NAD e-

NADH

ADP⫹Pi

ATP Hⴙ

COMPLEX

I

II

III

IV

NADH ubiquinone oxidoreductase

Succinate: ubiquinone oxidoreductase

Ubiquinolcytochrome c reductase

Cytochrome c oxicase

V

■

ATP synthase

Figure 88–3. The mitochondrial respiratory chain. Reduced cofactors (reduced nicotinamide adenine dinucleotide [NADH] and reduced flavin adenine dinucleotide [FADH2]) are produced from the intermediary metabolism of carbohydrates, proteins, and fats. These cofactors donate electrons (e−) to complex I (NADH ubiquinone oxidoreductase) and complex II (succinate ubiquinone oxidoreductase). These electrons flow between the complexes down an electrochemical gradient (black arrow), shuttled by ubiquinone (Q) and cytochrome c (C), involving complex III (ubiquinol-cytochrome c oxidase reductase) and complex IV (cytochrome c oxidase). Complex IV donates an electron to oxygen which results in the formation of water. Protons (H+) are pumped from the mitochondrial matrix into the intermembrane space (orange arrows). This proton gradient generates the mitochondrial membrane potential, which is harnessed by complex V to synthesize adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate (Pi). The adenine nucleotide translocator (ANT) exchanges ADP for ATP across the mitochondrial membrane. FAD, flavin adenine dinucleotide; NAD, nicotinamide adenine dinucleotide. (Courtesy of Dr. Z. Chrzanowska-Lightowlers.)

genotypes). The relevance of these terms is apparent in consideration of mtDNA mutations that lead to disease. Some mutations appear to affect all copies of the mitochondrial genome (homoplasmic mutations), whereas others are present only in some copies of the mitochondrial genome (heteroplasmic mutations). In the presence of heteroplasmy, a threshold level of mutation is needed both for clinical expression of the disease and for the development of biochemical defects.38 The standard paradigm of mtDNA inheritance is that it is strictly maternal.39 This model has been challenged by several findings: (1) Low levels of paternal transmission of mtDNA have been seen in interspecies crosses; (2) recombination may have affected the distribution of mtDNA polymorphisms within the human population; and (3) paternal mtDNA was documented in muscle of a patient with a single deletion of the mitochondrial genome.40-42 At present, however, such observations are

rare, and the maternal pattern of inheritance is the model for genetic counseling.43

Clinical Features of Mitochondrial Disease Mitochondria are vital components of all nucleated cells. It is therefore not surprising that mitochondrial diseases affect many different tissues and that the clinical features are so variable (Table 88–2).

Classic Mitochondrial Syndromes Genetic defects of the human mitochondrial genome were first described in 198844,45 and arose from investigation of two syndromes: Kearns-Sayre syndrome and Leber’s hereditary optic

chapter 88 metabolic myopathies (including mitochondrial diseases)

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D-loop 12S RNA

F

T CYT b

V

16S RNA P OH

L(UUR)

E ND6

ND1

ND5

I Q

mtDNA 16,569 b.p.

M

L(CUN) S(AGY) H

ND2 A W

N ND4

C Y R

S(UCN)

OL

ND4L G ND3

CO I

D

K CO II

■

CO III ATP 6 ATP 8

Figure 88–4. The human mitochondrial genome (mitochondrial DNA [mtDNA]) is a small 16,569-base pairs molecule of double-stranded DNA. mtDNA encodes for 13 essential components of the respiratory chain. ND1 to ND6 and ND4L encode seven subunits of complex I (reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase). Cytochrome b (CYT b) is the only mtDNA-encoded complex III subunit (ubiquinol-cytochrome c oxidase reductase). Cytochrome c oxidases I to III (CO I to CO III) encode for three of the complex IV (cytochrome c oxidase) subunits, and the adenosine triphosphate (ATP) 6 and ATP 8 genes encode for two subunits of complex V (ATP synthase). Two ribosomal RNA genes (12S and 16S ribosomal RNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intramitochondrial protein synthesis. The D-loop is the 1.1-kilobase noncoding region that is involved in the regulation of transcription and replication of the molecule and is the only region not directly involved in the synthesis of respiratory chain polypeptides. OH and OL are the origins of heavyand light-strand mtDNA replication.

neuropathy. In Kearns-Sayre syndrome, single, large-scale mtDNA deletions (usually sporadic) were detected in muscle biopsy specimens, and mitochondrial ultrastructural and cytochemical abnormalities in muscle were apparent. In Leber’s hereditary optic neuropathy, strict maternal pattern of inheritance was evident, and point mutations involving the MTND genes encoding subunits of complex I were identified. Since 1988, a large number of mutations46 of the mitochondrial genome have been identified and associated with disease (Table 88–3).

Clinical Syndromes with High Risk of Mitochondrial DNA Involvement Since the mid-1990s, clinicians have become aware of several clinical syndromes in which an mtDNA mutation is either likely or possible. The increasing recognition of mtDNA involvement

in disease is partially a result of the relative ease of sequencing the mitochondrial genome, although defining pathogenicity of specific base substitutions can be difficult.47 Examples of mtDNA-related disorders include progressive external ophthalmoplegia,48 Pearson’s syndrome,49 Leigh’s syndrome,47,50 exercise-induced muscle pain, premature fatigue and rhabdomyolysis,51 and aminoglycoside-induced hearing loss.52 For some of these conditions, such as progressive external ophthalmoplegia, mtDNA mutations are the predominant causes, whereas for others, such as Leigh’s syndrome there is a long list of potential genetic causes, only some of which involve mtDNA.

Mitochondrial DNA Involvement in Common Disease Phenotypes The principal difficulties for clinical neurologists are that patients with mtDNA-related disease rarely present with classic

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T A B L E 88–2. Common Features Observed in Patients with Defects of Oxidative Phosphorylation Neurological Adult: migraine, strokes, epilepsy, dementia, myopathy, peripheral neuropathy, ophthalmoplegia, ataxia, dysarthria, sensorineural deafness Pediatric: epilepsy, myopathy, psychomotor retardation, ataxia, spasticity, dystonia, sensorineural deafness Gastrointestinal Adult: constipation, irritable bowel, dysphagia, pseudo-obstruction Pediatric: vomiting, failure to thrive, dysphagia Ophthalmology Adult: optic atrophy, cataract, ophthalmoplegia, ptosis Pediatric: optic atrophy, ophthalmoplegia, nystagmus Cardiac Adult: heart failure, heart block, cardiomyopathy Pediatric: biventricular hypertrophic cardiomyopathy, rhythm abnormalities Respiratory Adult: respiratory failure, nocturnal hypoventilation, recurrent aspiration, pneumonia Pediatric: central hypoventilation/apnea Endocrine Adult: diabetes, thyroid disease, parathyroid disease, ovarian failure Pediatric: diabetes, adrenal failure Mainly Pediatric Hematological: anemia, pancytopenia Renal: renal tubular defects Hepatic: hepatic failure

phenotypes and that mtDNA enters into the differential diagnosis of many common neurological syndromes. The list of common clinical features seen in patients with mtDNA disease shows how difficult it is to decide which patients, children or adults, should undergo investigation for possible mtDNA disease. Important clinical clues in favor of mtDNA-related disease include the presence of a maternal family history, the coexistence of symptoms (such as myopathy and diabetes), or the presence of abnormal laboratory test results (see later discussion).

Nuclear Genetic Mitochondrial Disorders Recessive mutations in the nuclear genes coding for respiratory chain subunits or for assembly factors usually manifest in childhood with myopathy or encephalopathy, which can be associated with other systemic features (cardiomyopathy and hepatic and renal involvement). Recessive mutations in genes important for the maintenance of mtDNA can also manifest in childhood, with mtDNA depletion causing myopathy or liver disease, which may be associated with cardiac and central neurological features (thymidine kinase deficiency and deoxyguanosine kinase deficiency). Recessive mutations in the thymidine phosphorylase gene (TP) cause mitochondrial neurogastrointestinal encephalomyopathy. Recessive mutations in POLG1, which codes for the mtDNA polymerase γ, can cause Alpers’ disease or late-onset ataxia, whereas dominant mutations in the same gene cause autosomal chronic progressive external ophthalmoplegia (PEO), which may be associated with

sensory ataxia, parkinsonism, ovarian failure, and depression. Mutations in two other genes, ANT1 and C10Orf2 (which codes for the protein Twinkle), also cause dominant PEO.

Diagnosis of Mitochondrial Respiratory Chain Disease Histopathological and Histochemical Assessments of Mitochondrial Function The histological and histochemical assessments of the muscle biopsy remain diagnostic tests crucial for documenting mitochondrial dysfunction. Classic changes include “ragged red” fibers visible with Gomori trichrome stain and abnormal mitochondria visible on electron microscopy study. However, these methods have been superseded by direct histochemical measurements of enzyme activity: succinate dehydrogenase and cytochrome c oxidase. The succinate dehydrogenase reaction shows subsarcolemmal accumulation of mitochondria, which is characteristic of the “ragged red fiber” (Fig. 88–5C and D). The cytochrome c oxidase reaction is particularly useful in the evaluation of mitochondrial myopathies because cytochrome c oxidase contains subunits that are encoded by both the mitochondrial and the nuclear genomes. A mosaic pattern of cytochrome c oxidase activity is highly suggestive of a heteroplasmic mtDNA disorder, and most ragged red fibers are deficient in cytochrome c oxidase (see Fig. 88–5B). In cases in which only a low percentage of cytochrome c oxidase–deficient fibers are present, the sequential cytochrome c oxidase– succinate dehydrogenase histochemistry study is especially valuable for identifying abnormal fibers, which might otherwise go undetected against a background of normal cytochrome c oxidase activity. A global decrease in the activity of cytochrome c oxidase is usually suggestive of a nuclear mutation in one of the ancillary proteins required for cytochrome c oxidase assembly and function, such as SURF1,52,53 although a similar pattern is observed in some patients with pathogenic, homoplasmic mitochondrial transfer RNA gene mutations.54

Biochemical Assessment of Mitochondrial Function The biochemical assessment of respiratory chain activity is performed in specialized laboratories and is particularly important in pediatric cases. The choice of different techniques depends on the laboratory and the sample. In frozen tissue, individual complex activities can be measured, whereas in fresh tissues, flux through the whole respiratory chain can be measured.

Molecular Genetic Analyses The molecular genetic investigation of suspected mitochondrial disease can be complex. Pediatric cases are less likely to represent one of the classic mtDNA-related clinical syndromes and are more likely than adults to manifest nuclear DNA defects. A clear autosomal inheritance pattern (usually recessive) provides evidence of a nuclear DNA defect, but is not usually apparent. Patients with isolated complex IV deficiency may harbor mutations in one of five genes identified thus far that encode accessory proteins necessary for assembly of the cytochrome c oxidase holoenzyme complex: SURF1,52,53 SCO1,55

chapter 88 metabolic myopathies (including mitochondrial diseases)

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T A B L E 88–3. Clinical Disorders Caused by Mutations in Mitochondrial DNA Mitochondrial DNA Disorder Pearson’s syndrome Kearns-Sayre syndrome Chronic progressive external ophthalmoplegia MELAS

MERRF NARP Maternally inherited Leigh’s syndrome Maternally inherited diabetes and deafness Leber’s hereditary optic neuropathy

Clinical Phenotype

Gene*

Heteroplasmic or Homoplasmic

Inheritance

Several deleted

Heteroplasmic

Usually sporadic

Several deleted

Heteroplasmic

Usually sporadic

Pancytopenia, lactic acidosis Progressive myopathy, ophthalmoplegia, cardiomyopathy Ophthalmoplegia

Single, large-scale deletion Single, large-scale deletion Single or multiple deletions

Several deleted

Heteroplasmic

Usually sporadic

Myopathy, encephalopathy, lactic acidosis, strokelike episodes Myoclonic epilepsy, myopathy Neuropathy, ataxia, retinitis pigmentosa Progressive brainstem disorder Diabetes, deafness

3243A→G, 3271T→C

MTTL1

Heteroplasmic

Maternal

Individual mutations

Heteroplasmic

Maternal

8344A→G, 8356T→C

MTND1 and MTND5 MTTK

Heteroplasmic

Maternal

8993T→G

MTATP6

Heteroplasmic

Maternal

8993T→C

MTATP6

Heteroplasmic

Maternal

3243A→G

MTTL1

Heteroplasmic

Maternal

Optic neuropathy

3460G→A

MTND1

Heteroplasmic/homoplasmic

Maternal

11778G→A 14484T→C 14709T→C

MTND4 MTND6 MTTE

Heteroplasmic/homoplasmic Heteroplasmic/homoplasmic Heteroplasmic/homoplasmic

Maternal Maternal Maternal

1555A→G

MTRNR1

Homoplasmic

Maternal

Individual mutations Individual mutations

MTTS1 MTCYB

Heteroplasmic/homoplasmic Heteroplasmic

Maternal Sporadic

10158T→C, 10191T→C

MTND3

Heteroplasmic

Sporadic

Myopathy and diabetes Sensorineural hearing loss

Myopathy, weakness, diabetes Deafness

Exercise intolerance

Fatigue, muscle weakness Encephalopathy, lactic acidosis

Fatal, infantile encephalopathy (Leigh/Leigh-like)

Mitochondrial DNA Genotype

*Gene symbols: MTCYB, cytochrome b; MTND, reduced form of nicotinic adenine dinucleotide (NADH) dehydrogenase (complex I); MTTE, transfer RNA glutamate; MTTK, transfer RNA lysine; MTATP6, adenosine triphosphatase 6; MTTL1, leucine (UUR) transfer RNA; MTRNR1, 12S ribosomal RNA; MTTS1, serine (UCN). MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy and ragged-red fibers; NARP, neurogenic weakness, ataxia, and retinitis pigmentosa.

SCO2,56 COX10,57 and COX1558 or LRPPRC, the protein product of which is required for the translation of mtDNA subunits.59 Children with isolated complex I deficiency, in whom myopathy may be a feature, are more likely to harbor mutations in one of the many nuclear DNA–encoded structural subunits of this enzyme (reviewed by Triepels and coworkers60). Data from a 2004 publication indicate that pathogenic mtDNA mutations are also important in this pediatric population.61 Finally, mtDNA depletion syndrome commonly manifests in infancy. This clinically heterogeneous group of disorders is characterized by a significant reduction in mtDNA copy number. Some affected patients present with severe myopathy caused by mutations in the mitochondrial thymidine kinase (TK2) gene62 or in the SUCLA2 gene63; others present with hepatic or hepatocerebral syndromes caused by mutations in DGUOK64 or POLG1.65 Clues useful in directing the investigation in adults may also come from understanding genotype-phenotype relationships for specific mitochondrial mutations and from information concerning inheritance pattern. Patients with histochemical evidence of a mosaic distribution of cytochrome c oxidase deficiency and autosomal dominant inheritance should be screened for multiple mtDNA deletions, a disorder of intergenomic

communication that results from mutations in one of several nuclear genes.66 Multiple mtDNA deletions may also be inherited in an autosomal recessive manner or may manifest with no family history at all.67 Patients with this abnormal genotype typically present with chronic PEO and proximal myopathy, but this may be complicated by cerebellar ataxia or sensory ataxia caused by peripheral neuropathy. A clear pattern of maternal transmission indicates a pathogenic mtDNA point mutation, although mtDNA heteroplasmy and the late onset of syndromes related to such mutations means that relatives may report few symptoms suggestive of mitochondrial disease and that a family history is not always clear. In addition, many point mutations, particularly those in the cyt b gene, which cause exercise intolerance, are sporadic in nature.68 This is also true of patients with chronic PEO or Kearns-Sayre syndrome resulting from single, large-scale mtDNA deletions,69 although rare cases of maternal transmission have been reported in this latter group.70,71 In chronic PEO, mtDNA deletions are reliably detected only in skeletal muscle, and investigation of this tissue is essential for confirming the diagnosis. Some mtDNA-related disorders may be reliably diagnosed in blood, but in others the mtDNA mutations are expressed at high

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A

B

C

D

■

Figure 88–5 Skeletal muscle pathology in mitochondrial respiratory chain disease. Serial sections with hematoxylin and eosin stain (A), cytochrome c oxidase histochemistry (B), succinate dehydrogenase histochemistry (C), and sequential cytochrome c oxidase–succinate dehydrogenase histochemistry (D), showing a mosaic cytochrome c oxidase defect as seen in patients with mtDNA disorders.

levels only in muscle. Patients suspected of having the T14709C (myopathy, ataxia and diabetes) or the A8344G (MERRF) mutations affecting transfer RNA(Glu) and transfer RNA(Lys), respectively, commonly exhibit high levels of heteroplasmy in blood cells. In contrast, other point mutations may be present at only very low levels or may even be undetectable in circulating lymphocytes.72 In addition, all patients in whom mitochondrial disorder is strongly suspected clinically but with unremarkable histochemical and biochemical test results should, in the authors’ opinion, undergo investigation at the molecular level. More than 70% families with dominant PEO (associated with multiple secondary mtDNA deletions in skeletal muscle) have mutations in one of three nuclear genes: POLG1, ANT1, and C10Orf2. Mutations in POLG1 have also been identified in sporadic cases of PEO with multiple deletions.

Treatment Although much progress has been made in defining the clinical features and in establishing the molecular diagnosis of mitochondrial respiratory chain disease, treatment is still very limited. Apart from the very rare occurrence of primary ubiquinone deficiency, there is no curative therapy. There is evidence that supportive therapy—such as correction of ptosis, provision of pacemakers for cardiac conduction defects, and provision of digital hearing aids for deafness—can all significantly improve the quality of life for patients. A Cochrane review of all published clinical trials in this area showed very few properly controlled clinical studies,72a and these did not show a definite effect for any specific treatment. One approach that may be helpful is exercise. In control subjects, lack of exercise leads to an overall reduction in mito-

chapter 88 metabolic myopathies (including mitochondrial diseases) chondrial enzyme activity. This can be reversed by endurance training. Endurance training may therefore improve function in patients with mtDNA disease by increasing wild-type mtDNA levels. There do exist concerns, however, that mutated mtDNA might be preferentially amplified and that this increase might become clinically relevant after deconditioning.73,74 Studies are currently under way to address both the improvements and the concerns arising from these earlier reports. Resistance training or muscle necrosis stimulates the incorporation of satellite cells into existing muscle fibers.73,75 It is postulated that in patients with sporadic mutations, resistance training might lead to an overall reduction in the proportion of mutated mtDNA versus wild-type mtDNA, inasmuch as satellite cells contain low or negligible levels of mutated mtDNA.75,76

K E Y

P O I N T S

●

Glycogen storage disorders are a group of rare, genetically determined metabolic diseases that often manifest with proximal myopathy and rhabdomyolysis. Muscle biopsy is usually necessary to make the diagnosis, although molecular genetic tests are increasingly becoming the first line investigation. Management involves dietary manipulation and genetic counseling. Enzyme replacement therapy is under development for some disorders.

●

Fatty acid oxidation disorders also cause myopathy and rhabdomyolysis, often with a cardiomyopathy. Fasting acylcarnitine analysis usually confirms the diagnosis, followed by molecular genetic tests. Management involves dietary manipulation and genetic counseling.

●

Mitochondrial respiratory chain disorders are the most common inherited metabolic disorders. They often manifest with neurological features, and multisystem involvement is common, particularly of the eye, the heart, and the endocrine organs. Mitochondrial disorders can be sporadic, maternally inherited, autosomal dominant, autosomal recessive, or X-linked. Diagnosis usually involves muscle biopsy, although some disorders can be diagnosed with a molecular genetic test. Treatment is largely supportive, with genetic counseling and disability management, although new approaches are under development.

Suggested Reading DiMauro S, Schon EA: Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348:2656-2668. McFarland R, Taylor RW, Turnbull DM: The neurology of mitochondrial DNA disease. Lancet Neurol 2002; 1:343-351. Moxley RT, Chinnery P, Turnbull DM: The metabolic myopathies. In Karpati G, Hilton-Jones D, Griggs RC, eds: Disorders of Voluntary Muscle, 7th ed. Cambridge, UK: Cambridge University Press, 2001, pp 560-579.

References 1. Matthews CK, van Holder KE: Biochemistry, 2nd ed. San Francisco: Benjamin Cummings, 1995, pp 445-516.

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2. van den Hout HM, Hop W, van Diggelen OP, et al: The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics 2003; 112:332340. 3. Hagemans ML, Janssens AC, Winkel LP, et al: Late-onset Pompe disease primarily affects quality of life in physical health domains. Neurology 2004; 63:1688-1692. 4. Hermans MM, van Leenen D, Kroos MA, et al: Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat 2004; 23:4756. 5. Brady RO, Schiffmann R: Enzyme-replacement therapy for metabolic storage disorders. Lancet Neurol 2004; 3:752-756. 6. Winkel LP, Van den Hout JM, Kamphoven JH, et al: Enzyme replacement therapy in late-onset Pompe’s disease: a threeyear follow-up. Ann Neurol 2004; 55:495-502. 7. Lucchiari S, Donati MA, Parini R, et al: Molecular characterisation of GSD III subjects and identification of six novel mutations in AGL. Hum Mutat 2002; 20:480. 8. Bruno C, Servidei S, Shanske S, et al: Glycogen branching enzyme deficiency in adult polyglucosan body disease. Ann Neurol 1993; 33:88-93. 9. Bruno C, van Diggelen OP, Cassandrini D, et al: Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 2004; 63:1053-1058. 10. Martin MA, Rubio JC, Buchbinder J, et al: Molecular heterogeneity of myophosphorylase deficiency (McArdle’s disease): a genotype-phenotype correlation study. Ann Neurol 2001; 50:574-581. 11. Tsujino S, Shanske S, Nonaka I, et al: The molecular genetic basis of myophosphorylase deficiency (McArdle’s disease). Muscle Nerve 1995; 3:S23-S27. 12. Vissing J, Haller RG: The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 2003; 349:2503-2509. 13. Burwinkel B, Hu B, Schroers A, et al: Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. Eur J Hum Genet 2003; 11:516-526. 13a. Nakajima H, Raben N, Hamaguchi T, Yamasaki T: Phosphofructokinase deficiency: past, present and future. Curr Mol Med 2002; 2:197-212. 14. Raben N, Sherman JB: Mutations in muscle phosphofructokinase gene. Hum Mutat 1995; 6:1-6. 15. Tsujino S, Shanske S, DiMauro S: Molecular genetic heterogeneity of phosphoglycerate kinase (PGK) deficiency. Muscle Nerve 1995; 3:S45-S49. 16. Tsujino S, Shanske S, Brownell AK, et al: Molecular genetic studies of muscle lactate dehydrogenase deficiency in white patients. Ann Neurol 1994; 36:661-665. 17. Yao DC, Tolan DR, Murray MF, et al: Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr). Blood 2004; 103:24012403. 17a. Comi GP, Fortunato F, Lucchiari S, et al: Beta-enolase deficiency, a new metabolic myopathy of distal glycolysis. Ann Neurol 2001; 50:202-207. 18. DiMauro S, DiMauro PM: Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science 1973; 182:929-931. 19. Rinaldo P, Matern D, Bennett MJ: Fatty acid oxidation disorders. Annu Rev Physiol 2002; 64:477-502. 20. Eaton S, Bartlett K, Pourfarzam M: Mammalian mitochondrial beta-oxidation. Biochem J 1996; 320(Pt 2):345-357. 21. Bonnefont JP, Djouadi F, Prip-Buus C, et al: Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 2004; 25:495-520.

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22. Stanley CA, Hale DE, Berry GT, et al: Brief report: a deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane. N Engl J Med 1992; 327:19-23. 23. Yamaguchi S, Indo Y, Coates PM, et al: Identification of verylong-chain acyl-CoA dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 1993; 34:111-113. 24. Andresen BS, Olpin S, Poorthuis BJ, et al: Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet 1999; 64:479494. 25. Wanders RJ, IJlst L, van Gennip AH, et al: Long-chain 3hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 1990; 13:311-314. 26. Jackson S, Kler RS, Bartlett K, et al: Combined enzyme defect of mitochondrial fatty acid oxidation. J Clin Invest 1992; 90:1219-1225. 27. IJlst L, Ruiter JP, Vreijling J, et al: Long-chain 3-hydroxyacylCoA dehydrogenase deficiency: a new method to identify the G1528C mutation in genomic DNA showing its high frequency (approximately 90%) and identification of a new mutation (T2198C). J Inherit Metab Dis 1996; 19:165-168. 28. Stanley CA, Hale DE, Coates PM, et al: Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. Pediatr Res 1983; 17:877884. 29. Tein I, De Vivo DC, Hale DE, et al: Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause for recurrent myoglobinuria and encephalopathy. Ann Neurol 1991; 30:415-419. 30. Loehr JP, Goodman SI, Frerman FE: Glutaric acidemia type II: heterogeneity of clinical and biochemical phenotypes. Pediatr Res 1990; 27:311-315. 31. Gregersen N, Rhead W, Christensen E: Riboflavin responsive glutaric aciduria type II. Prog Clin Biol Res 1990; 321:477-494. 32. Millington DS, Norwood DL, Kodo N, et al: Application of fast atom bombardment with tandem mass spectrometry and liquid chromatography/mass spectrometry to the analysis of acylcarnitines in human urine, blood, and tissue. Anal Biochem 1989; 180:331-339. 33. Rashed MS, Ozand PT, Bucknall MP, et al: Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res 1995; 38:324-331. 34. Chace DH, Hillman SL, Van Hove JL, et al: Rapid diagnosis of MCAD deficiency: quantitatively analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry. Clin Chem 1997; 43:2106-2113. 35. Vreken P, van Lint AE, Bootsma AH, et al: Quantitative plasma acylcarnitine analysis using electrospray tandem mass spectrometry for the diagnosis of organic acidaemias and fatty acid oxidation defects. J Inherit Metab Dis 1999; 22:302-306. 36. Costa CG, Struys EA, Bootsma A, et al: Quantitative analysis of plasma acylcarnitines using gas chromatography chemical ionization mass fragmentography. J Lipid Res 1997; 38:173182. 37. Taroni F, Verderio E, Dworzak F, et al: Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 1993; 4:314-320. 38. Sciacco M, Bonilla E, Schon EA, et al: Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum Mol Genet 1994; 3:13-19. 39. Giles RE, Blanc H, Cann HM, et al: Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A 1980; 77:6715-6719.

40. Gyllensten U, Wharton D, Josefsson A, et al: Paternal inheritance of mitochondrial DNA in mice. Nature 1991; 352:255257. 41. Awadalla P, Eyre-Walker A, Smith JM: Linkage disequilibrium and recombination in hominid mitochondrial DNA. Science 1999; 286:2524-2525. 42. Schwartz M, Vissing J: Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347:576-580. 43. Filosto M, Mancuso M, Vives-Bauza C, et al: Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann Neurol 2003; 54:524-526. 44. Holt IJ, Harding AE, Morgan-Hughes JA: Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331:717-719. 45. Wallace DC, Singh G, Lott MT, et al: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242:1427-1430. 46. Brandon MC, Lott MT, Nguyen KC, et al: MITOMAP: a human mitochondrial genome database—2004 update. Nucl Acid Res 2005; 33(Database Issue):D611-D613. 47. McFarland R, Kirby DM, Fowler KJ, et al: De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol 2004; 55:58-64. 48. Moraes CT, DiMauro S, Zeviani M, et al: Mitochondrial DNA deletions in progressive external ophthalmoplegia and KearnsSayre syndrome. N Engl J Med 1989; 320:1293-1299. 49. Rotig A, Cormier V, Blanche S, et al: Pearson’s marrow pancreas syndrome. A multisystem mitochondrial disorder of infancy. J Clin Invest 1990; 86:1601-1608. 50. de Vries DD, van Engelen BG, Gabreels FJ, et al: A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome. Ann Neurol 1993; 34:410-412. 51. Andreu AL, Hanna MG, Reichmann H, et al: Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999; 341:1037-1044. 52. Tiranti V, Hoertnagel K, Carrozzo R, et al: Mutations of SURF1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998; 63:1609-1621. 53. Zhu Z, Yao J, Johns T, et al: SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998; 20:337-343. 54. McFarland R, Clark KM, Morris AA, et al: Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet 2002; 30:145-146. 55. Valnot I, Osmond S, Gigarel N, et al: Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 2000; 67:1104-1109. 56. Jaksch M, Ogilvie I, Yao J, et al: Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum Mol Genet 2000; 9:795-801. 57. Valnot I, von Kleist-Retzow JC, Barrientos A, et al: A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet 2000; 9:1245-1249. 58. Agostino A, Valletta L, Chinnery PF, et al: Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 2003; 60:1354-1356. 59. Mootha VK, Lepage P, Miller K, et al: Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A 2003; 100:605-610. 60. Triepels RH, van den Heuvel L, Trijbels F, et al: Respiratory chain complex I deficiency. Am J Med Genet 2001; 106:37-45. 61. Kirby DM, McFarland R, Ohtake A, et al: Mutations of the mitochondrial ND1 gene as a cause of MELAS. J Med Genet 2004; 41:784-789.

chapter 88 metabolic myopathies (including mitochondrial diseases) 62. Saada A, Shaag A, Mandel H, et al: Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 2001; 29:342. 63. Elpeleg O, Miller C, Hershkovitz E, et al: Deficiency of the ADPforming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 2005; 76:1081-1086. 64. Mandel H, Szargel R, Labay V, et al: The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 2001; 29:337. 65. Davidzon G, Mancuso M, Ferraris S, et al: POLG mutations and Alpers syndrome. Ann Neurol 2005; 57:921-923. 66. Suomalainen A, Kaukonen J: Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet 2001; 106:53-61. 67. Antonicka H, Mattman A, Carlson CG, et al: Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet 2003; 72:101-114. 68. Andreu AL, Hanna MG, Reichmann H, et al: Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999; 341:1037-1044. 69. Holt IJ, Cooper JM, Morgan-Hughes JA, et al: Deletions of muscle mitochondrial DNA. Lancet 1988; 1:1462. 70. Bernes SM, Bacino C, Prezant TR, et al: Identical mitochondrial DNA deletion in mother with progressive external

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ophthalmoplegia and son with Pearson marrow-pancreas syndrome. J Pediatr 1993; 123:598-602. 71. Shanske S, Tang Y, Hirano M, et al: Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with Pearson syndrome. Am J Hum Genet 2002; 71:679-683. 72. Chinnery P, Howell N, Lightowlers R, et al: Molecular pathology of MELAS and MERRF: the relationship between mutation load and clinical phenotype. Brain 1997; 120:1713-1721. 72a. Chinnery P, Majamaa K, Turnbull D, Thorbura D: Treatment for mitochondrial disorders. Cochrane Database Syst Rev 2006; CD004426. 73. Taivassalo T, Fu K, Johns T, et al: Gene shifting: a novel therapy for mitochondrial myopathy. Hum Mol Genet 1999; 8:10471052. 74. Taivassalo T, Shoubridge EA, Chen J, et al: Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol 2001; 50:133-141 75. Clark KM, Bindoff LA, Lightowlers RN, et al: Reversal of a mitochondrial DNA defect in human skeletal muscle. Nat Genet 1997; 16:222-224. 76. Fu K, Hartlen R, Johns T, et al: A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Hum Mol Genet 1996; 5:1835-1840.

CHAPTER

89

INFLAMMATORY MYOPATHIES ●

●

●

●

Mohammad Salajegheh and Marinos C. Dalakas

The inflammatory myopathies are a heterogeneous group of acquired diseases of skeletal muscle. They have in common the presence of varying degrees of muscle weakness and inflammation. Based on clinical, histological, and immunopathological criteria, they form three major groups: polymyositis, dermatomyositis, and sporadic inclusion-body myositis.1,2 Dermatomyositis is easily recognized by specific skin changes that occur early in the course of the disease. Sporadic inclusionbody myositis is easily suspected based on its slow progression, unique distribution of weakness and atrophy, characteristic muscle biopsy findings, and resistance to conventional immunotherapies.2,3 Polymyositis, however, remains a diagnostic challenge and is often misdiagnosed as inclusion-body myositis, dystrophy, or toxic or metabolic myopathy.4 The old assumption that dermatomyositis is like polymyositis without a rash, and inclusion-body myositis is like polymyositis without vacuoles, is overly simplistic and incorrect.5,6

CLINICAL PRESENTATION Dermatomyositis Dermatomyositis is seen in both children and adults, and more often in women than in men1 (Table 89–1). Juvenile dermatomyositis is the most common form of inflammatory myopathy in children.7,8 Although the most obvious manifestations are due to involvement of skeletal muscle and skin, rarely other organ systems are affected, including the gastrointestinal tract, heart, and lungs. The muscle weakness in dermatomyositis is classically proximal, symmetrical, and frequently progressive. It can vary from mild to severe, occasionally resulting in quadriparesis. The weakness usually develops slowly, over weeks to months, but in rare cases there is an acute onset. Patients usually have problems with physical tasks such as rising up from a chair or climbing steps, stepping onto a curb, lifting objects, or combing their hair. Fine motor movements that depend on the strength of distal muscles, such as manipulating small objects, are spared until late in the course of the disease. Involvement of the neck extensor muscles may lead to head drop. In advanced stages of the disease or during an acute course, patients might have respiratory muscle weakness or dysphagia, causing choking episodes. Facial muscles are spared

and extraocular muscles are never affected.1 Sensation remains normal, and tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles. Myalgia is not a common feature and occurs in less than 30% of the patients.1 The cutaneous manifestations of dermatomyositis usually precede or accompany the weakness and include the following: erythematous (and later dry and scaly) lesions over the metacarpophalangeal, proximal interphalangeal, or distal interphalangeal joints (Gottron papules); a violaceous hue over the eyelids (heliotrope rash) and periorbital edema; periungual telangiectasia characterized by dilated capillary loops at the base of the fingernails, with irregular, thickened, and distorted cuticle; malar erythema; and erythematous scaly rash over the neck and upper back (shawl sign), anterior chest (V sign), and extensor surfaces of the extremities (Fig. 89–1). The rash can be exacerbated after exposure to the sun and is pruritic in some cases.1 At times, muscle strength appears normal—hence the term dermatomyositis sine myositis, or amyopathic dermatomyositis. When a muscle biopsy is performed in such cases, however, perivascular and perimysial inflammation can be seen. Juvenile dermatomyositis resembles dermatomyositis in adults, except for the presence of more frequent extramuscular manifestations. A child with evolving dermatomyositis is irritable, does not socialize, is uncomfortable, complains of fatigue, and has a red flush on the face with varying degrees of muscle weakness.9 A tiptoe gait due to flexion contracture of the ankles is also common in juvenile dermatomyositis.1 In 3% to 5% of children with juvenile dermatomyositis, the cutaneous manifestations of the disease are present in the absence of clinically evident muscle weakness: these patients are classified as amyopathic.10 Subcutaneous calcinosis is not an uncommon finding in juvenile dermatomyositis, especially when initiation of therapy is delayed, or when applied therapies have not been fully effective, resulting in chronicity of the disease, muscular atrophy, and joint contractures8,11,12 (Fig. 89–1).

Polymyositis Polymyositis is usually seen after the second decade of life, rarely in children.2,1 It is manifested by muscle weakness of subacute onset, similar to what is seen in dermatomyositis but without any of the cutaneous manifestations. Polymyositis can mimic many other myopathies and remains a diagnosis of

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T A B L E 89–1. Presentation of Inflammatory Myopathies Characteristics

Dermatomyositis

Polymyositis

Inclusion Body Myositis

Age at onset Familial association Muscular manifestations Skin changes Associated conditions Connective tissue disease

Adulthood and childhood None Symmetrical proximal muscle weakness Characteristic Scleroderma and mixed connective tissue disease (overlap syndrome)

Systemic diseases† Malignancy Viruses‡ Drugs§ Parasites and bacteria¶ Muscle biopsy Inflammation Class I MHC Other

Infrequent Yes (up to 15% of cases) Unproven Yes, rarely No

>18 years None Symmetrical proximal muscle weakness None Yesa Frequent None Yes Yes Yes

>50 years Yes in some Asymmetrical weakness, preferential in finger flexors and quadriceps None Yes* (up to 20% of cases) Infrequent None Yes No No

Endomysial CD8+ T cells and macrophages All muscle fibers None Myopathic Elevated

Endomysial CD8+ T cells and macrophages All muscle fibers Vacuoles (red-rimmed) and amyloid deposits Myopathic with mixed potentials Elevated or normal

Electromyography Muscle enzymes¶¶

Perivascular/interfascicular CD4+ and B cells Perifascicular fibers Perifascicular atrophy Myopathic Elevated or normal

MHC, major histocompatibility. *Systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease. †Crohn’s disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behçet’s syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto’s disease, granulomatous diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, IgA deficiency. ‡HIV (human immunodeficiency virus) and HTLV-I (human T cell lymphotrophic virus type I). §Drugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), and contaminated tryptophan (dermatomyositis-like illness). Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details). ¶ Parasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis). ¶¶ Most sensitive muscle enzyme is creatine kinase (CK), but liver transaminases (ALT and AST), lactic dehydrogenase (LDH), and aldolase may also be elevated.

exclusion. The most common myopathy misdiagnosed as polymyositis is inclusion-body myositis. This disease is often suspected in retrospect, when a patient with presumed polymyositis has not responded to therapy.2 Other myopathies erroneously diagnosed and treated as polymyositis include acute necrotizing myopathies, toxic and endocrine myopathies, dermatomyositis sine dermatitis, certain dystrophies, and some slowly progressive myopathies starting in late childhood.1 One of the main reasons for misdiagnosing these disorders as polymyositis is that several myopathies, especially certain dystrophies such as Duchenne’s, Becker’s, fascioscapulohumeral, or dysferlinopathies, may also show prominent inflammation in their muscle biopsies.4 Thus, we have to apply new diagnostic criteria that more specifically characterize the type of inflammation seen in polymyositis, as discussed later.

Inclusion Body Myositis Inclusion-body myositis is the most common form of inflammatory myopathy, especially in patients above the age of 50.2 The weakness and atrophy are usually observed first in the quadriceps femoris muscles of the legs, leading to instability of the knees and increased falls, and in the flexor digitorum profundus muscles in the forearm, resulting in difficulties with fine motor movements such as holding golf clubs, turning keys, or tying knots.13 The weakness and atrophy frequently affect the iliopsoas, triceps, biceps, and foot extensor muscles9 and it may be asymmetrical, resembling lower motor neuron disease or motor neuropathies. The facial muscles are very often affected

even early in the disease. Dysphagia is common, occurring in up to 60% of inclusion-body myositis patients, and may lead to episodes of choking. Sensory examination is generally normal, although some patients have mildly diminished vibratory sensation at the ankles that is presumably age related.9 Disease progression is slow but steady, and most patients require assistive devices such as a cane, walker, or a wheelchair after several years.

Associated Clinical Manifestations Inflammatory myopathies, in particular dermatomyositis and polymyositis, can have non–skeletal muscle manifestations. Constitutional symptoms such as fever, malaise, weight loss, arthralgia, or Raynaud’s phenomenon can occur in the subacute stages of dermatomyositis and polymyositis, especially when the disease is associated with another connective-tissue disorder.14 Cardiovascular abnormalities, including conduction defects, tachyarrhythmias, or myocarditis, are rarely seen during the active phase of the disease. Hypertension and heart failure are more frequently seen late in the course of the disease, probably as a result of long-term steroid therapy or lung disease.1 Pulmonary involvement may occur, either due to thoracic muscle weakness or interstitial lung disease. The latter is most commonly seen in patients with autoantibodies against t-RNA synthetases (Jo-1), signal recognition particle (SRP),15 or a mucin-like glycoprotein (KL-6).16,17 Antisynthetase syndrome refers to the presence of inflammatory myopathy, anti-Jo-1 antibodies, and interstitial lung disease, often in association

chapter 89 inflammatory myopathies

■

A

1213

Figure 89–2. Perifascicular atrophy in a cross section of a muscle biopsy in a patient with dermatomyositis.

with low-grade fever, subluxation of the phalangeal joints, Raynaud’s phenomenon, and thick cracked skin on the fingers (mechanic’s hands).18

Malignancy Among the inflammatory myopathies, dermatomyositis is associated with increased incidence of malignant diseases, in up to 15% of the adult cases.19 The most common cancers are those of the ovaries, gastrointestinal tract, lung, breast, and nonHodgkin lymphomas20 or nasopharyngeal cancer in Asian populations. Increased vigilance, with careful periodic clinical examination and the prudent use of appropriate laboratory studies, are required for early detection of cancer, especially in older patients, and during the first 3 years after disease onset.2,21

B

DIAGNOSIS

C ■

Figure 89–1. Gottron’s rash (A) and telangiectasias with microinfarcts at the base of the fingernails (B) are characteristic features of dermatomyositis. C, Typical calcifications at the elbow extruding on to the skin.

The criteria of Bohan and Peter22 used for several years, have now become obsolete because they do not distinguish polymyositis from inclusion-body myositis or certain muscular dystrophies (Table 89–2). The need for new criteria was recognized in 1991.2 The inclusion of simple immunopathology in processing the muscle biopsy specimens was recently emphasized as the best means of differentiating inflammatory from noninflammatory myopathies.1 The diagnosis is based on the characteristic clinical features of polymyositis, dermatomyositis, or inclusion-body myositis outlined earlier, combined with the triad of serum muscle enzyme levels, electromyography, and muscle biopsy. Imaging studies have a limited role in the diagnosis of inflammatory myopathies. Subcutaneous calcinosis, an uncommon finding in adult but more common in juvenile dermatomyositis, can be detected on plain radiographs.11 Magnetic resonance imaging (MRI) may reveal the involved muscles in inclusion-body myositis23,24 but is not needed for diagnostic purposes. The only usefulness of MRI is to help us select the appropriate site for biopsy, when the clinical pattern of weakness is not uniform or typical. We do not recommend routine MRI for our patients; we select the biopsy site on the basis of clinical assessment. In the chronic stages of these diseases, when muscle atrophy and fatty infiltration dominate the picture, MRI is of no diagnostic value.

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Neuromuscular Diseases: Muscle

T A B L E 89–2. Criteria for the Diagnosis of Inflammatory Myopathies Criterion

Definite Polymyositis

Probable Polymyositis

Dermatomyositis

Inclusion-Body Myositis

Myopathic muscle weakness*

Yes

Yes

Yes†

Electromyographic findings Muscle enzymes

Myopathic Elevated (up to 50-fold)

Myopathic Elevated (up to 50-fold)

Muscle biopsy findings‡

“Primary” inflammation with the CD8/MHC-I complex and no vacuoles

Ubiquitous MCH-I expression but minimal inflammation and no vacuoles§

Rash or calcinosis

Absent

Absent

Myopathic Elevated (up to 50-fold) or normal Perifascicular, perimysial, or perivascular infiltrates, perifascicular atrophy Present¶¶

Yes; slow onset, early involvement of distal muscles, frequent falls Myopathic with mixed potentials Elevated (up to 10-fold) or normal Primary inflammation with CD8/MHC-I complex; vacuolated fibers with β-amyloid deposits; cytochrome oxygenase–negative fibers; signs of chronic myopathy¶ Absent

*Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a subacute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy findings). †In some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness. ‡See text for details. §An adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion-body myositis. ¶ If the muscle biopsy does not contain vacuolated fibers but shows chronic myopathy with hypertrophic fibers, primary inflammation with the CD8/MHC-I complex and cytochrome c oxygenase–negative fibers, the diagnosis is probable inclusion-body myositis. ¶¶ If rash is absent but muscle biopsy findings are characteristic of dermatomyositis, the diagnosis is probable dermatomyositis.

Muscle Enzymes Creatine kinase, aspartate and alanine aminotransferases, lactate dehydrogenase, and aldolase levels are usually increased in inflammatory myopathies, particularly in the active phases of the disease, and parallel the disease activity.1 Elevation of serum creatine kinase, although not specific to inflammatory myopathies, is a useful laboratory marker.9 Creatine kinase, however, may remain within the normal range in some patients, especially with dermatomyositis or inclusion-body myositis, and should not be used as the sole marker for determining disease activity.

Electrodiagnostic Studies Needle electromyography shows myopathic potentials, characterized by increased spontaneous activity, fibrillations, complex repetitive discharges, and positive sharp waves. The voluntary motor units have low amplitude and short duration and are polyphasic. Mixed potentials (polyphasic units of short and long duration) indicating a chronic process or muscle fiber regeneration are often present in inclusion-body myositis.9 These findings, however, are not disease specific, as they can occur in any other active myopathy.9 At times, the presence of active myopathic potentials can distinguish exacerbation of the primary disease from steroid-induced myopathy.1

Muscle Biopsy Muscle biopsy is the most important test for establishing the diagnosis, but it can also lead to misdiagnosis due to erroneous interpretation.1 Occasionally, due to the spotty nature of the inflammation, a repeat muscle biopsy may become necessary. This needs to be

especially considered in the patients who meet the clinical criteria described earlier but whose initial muscle biopsies are nondiagnostic.1 We also recommend a repeat muscle biopsy when a patient carries the diagnosis of polymyositis but remains unresponsive to therapies. The histopathology of dermatomyositis is characterized by inflammation, which is predominantly perivascular and in the interfascicular septa rather than in the fascicles.3,9,25 Necrosis and phagocytosis of muscle fibers commonly occur in groups (microinfarcts) and involves the peripheral portion of the muscle fascicle. The resultant perifascicular atrophy (Fig. 89–2) is characterized by 2 to 10 layers of atrophic fibers and is diagnostic of dermatomyositis irrespective of the presence of inflammation. In the absence of typical features of inflammatory infiltrates or perifascicular atrophy, increased perifascicular class I major histocompatibility (MHC) expression, may be of diagnostic value.26 Biopsy of skin lesions in dermatomyositis shows perivascular inflammation in the dermis with CD4+ cells and dilatation of superficial capillaries in more chronic stages.1 Muscle biopsies of patients with polymyositis show varying degrees of endomysial inflammation (Fig. 89–3). In polymyositis and inclusion-body myositis, the inflammation is characterized as primary to denote the partial invasion of still intact and nonnecrotic muscle fibers by activated CD8+ T lymphocytes. B lymphocytes form a minor fraction of perivascular infiltrates, but they are mostly absent from the endomysium.27,28 In chronic stages of the disease, there is an increase in connective tissue, which may react with alkaline phosphatase. Both invaded and noninvaded muscle fibers express class I MHC antigen on their surface29 (Fig. 89–4). The ubiquitous sarcolemmal expression of class I MHC antigen has now become essential in diagnosing polymyositis, not only because it is part of the specific lesion but also because it is not present in other non-immune myopathies and it is not affected by the use of immunosuppressive agents. The “CD8+/MHC-I complex”

chapter 89 inflammatory myopathies (MHC-I along with CD8+ cells) is specific for the inflammation in polymyositis and inclusion-body myositis and needs to be incorporated into the histological evaluation of polymyositis patients, in an effort to rule out the secondary inflammation seen in various dystrophies or toxic myopathies.1 Muscle biopsies from patients with inclusion-body myositis show the same pattern of CD8/MHC-I expression as in polymyositis, even in the late stages of the disease. In inclusion-body myositis, however, in addition to inflammation,

1215

a number of muscle fibers not invaded by T cells contain single or multiple vacuoles, which seem to increase as the disease progresses4 (see Fig. 89–3). The vacuoles contain small, basophilic granules in their centers or against their walls and appear as “red-rimmed vacuoles” on the trichrome stain. Frozen sections and enzyme histochemistry are required for optimal visualization of vacuoles, because the granules dissolve on paraffin sections and might be easily overlooked if the biopsy is processed only with paraffin.4 Deposits of amyloid can be seen in vacuolated fibers as green birefringence on Congo red staining30 or as red dichroism when visualized with Texas red filters.31 Characteristically, the vacuolated fibers in inclusion-body myositis are not invaded by T cells, and those fibers that are partially invaded by inflammatory cells are never vacuolated.4 Vacuolated fibers, even the ones containing amyloid deposits, are not specific for inclusion-body myositis but can be seen in other chronic distal myopathies (e.g., myofibrillar, facioscapulohumeral, and dysferlin myopathies), and even in chronic neurogenic disorders such as old paralytic poliomyelitis.32 Other findings in inclusionbody myositis include ragged red fibers or cytochrome c oxidase–negative fibers, which contain abnormal mitochondria harboring multiple mitochondrial DNA deletions.33 These fibers are common in inclusion-body myositis and more frequent than expected for the patient’s age. On electron microscopy, the basophilic granules seen in cryostat sections represent membranous whorls of various sizes. In their vicinity, abnormal filaments 12 to 18 nm in diameter can be found. They have a tubular structure with a central lumen approximately 3.5 nm in diameter. On longitudinal view, these filaments often have a periodic cross-hatched appearance, which seems to be outside the axial core of the filament. The nature of the inclusion-body myositis filaments remains obscure. They immunoreact with various amyloid-related proteins, identical to those seen in Alzheimer’s disease, such as ubiquitin, phosphorylated tau, presenilin-1, apolipoprotein E (apoE), and others.34

Immunopathogenesis ■

Figure 89–3. Cross-section of muscle from patients with polymyositis (top) and inclusion-body myositis (bottom). Top, Note the scattered endomysial inflammation in polymyositis, with lymphocytes invading non-necrotic muscle fibers. Bottom, Note two red-rimmed vacuolated fibers (left and right upper corners) not invaded by inflammatory cells in inclusion-body myositis. If the same vacuolated fibers are followed at considerable length in longitudinal sections, they remain devoid of autoinvasive inflammatory T cells. In contrast, the fibers surrounded by T cells are not vacuolated, degenerating, or necrotic but rather appear to be healthy.

Polymyositis, dermatomyositis, and inclusion body myositis, although immunopathologically distinct, share common histopathological features of inflammation, fibrosis, and loss of muscle fibers.9 In all three, the transmigration of activated T cells, and their adhesion to the muscle fibers, are facilitated by cytokines, chemokines, and adhesion molecules.5 Rare familial occurrences and association with certain HLA genes, such as DRB1*0301 alleles for polymyositis and inclusion-body myositis and HLA DQA1*0501 for juvenile dermatomyositis,35 suggest that genetic factors may also play a role in their pathogenesis. ■

Figure 89–4. In both polymyositis and inclusion-body myositis, cytotoxic CD8-positive T cells invade a muscle fiber (left). Ubiquitous expression of MHC class 1 is also noted (right). The CD8/MHC lesion (right) is a characteristic finding in the immunopathogenesis of polymyositis and inclusion-body myositis.

C1

?

D

Endothelial cell wall

C3

C4 C2

B

?

B

? Molecular mimicry (tumors, viruses?)

B

C3

C3a

C3b

C3bNEO MAC

MAC

Cytokines

T

LFA-1

ICAM-1

Cytokines T

T

VLA-4

STAT-1, Chemokines, Cathepsin, TGF-␤

VCAM-1 M␾

M␾

Mac-1

ICAM-1 NO TNF-␣

Chemokines ■

Figure 89–5. Proposed sequence of immunopathologic changes in dermatomyositis. The disease probably begins with activation of complement and formation of C3 through the classic or alternative pathway by putative antibodies (Y) against endothelial cells. Activated C3 leads to formation of C3b, C3bNEO, and membranolytic attack complex (MAC), which is deposited in and around the endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction and reduced number of capillaries, with ischemia or microinfarcts most prominent in the periphery of the fascicle. Finally, a smaller than normal number of capillaries with a dilated diameter remain, and perifascicular atrophy ensues. Not only the complement-fixing antibodies (Y) but also B cells, CD4+ T cells, and macrophages (MO) traffic to the muscle. The migration of cells from the circulation is facilitated by the vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) whose expression on the endothelial cells is upregulated by the released cytokines. T cells and macrophages through their integrins very late activation antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1, bind to the VCAM and ICAM and transgress to the muscle through the endothelial cell wall.

Dermatomyositis

Polymyositis and Inclusion-Body Myositis

Dermatomyositis is a microangiopathy, involving arterioles and endomysial capillaries. The primary antigenic target in dermatomyositis is unknown but is believed to be the endothelium of the endomysial capillaries.1 The disease begins when putative antibodies directed against endothelial cells activate complement, leading to the formation and deposition of the membrane attack complex (MAC) on the endomysial microvasculature.1,36,37 This leads to lysis of endothelial cells, capillary necrosis, ischemia and microinfarcts, inflammation, endofascicular hypoperfusion, and eventual perifascicular atrophy1,4 (Fig. 89–5). The predominant cells infiltrating the muscle are B lymphocytes and CD4+ T cells, consistent with a humorally mediated process.1,28 Recently, a large number of plasmacytoid dendritic cells have been observed.38 Cytokines, including signal transducer and activator of transcription (STAT) and chemokines, are activated and overexpressed in the muscle of patients with dermatomyositis, facilitating the transmigration of T cells and further enhancing the inflammatory cascade and eventual tissue necrosis. Fibrogenic cytokines, such as transforming growth factor-β, and chemokines are also overexpressed in the perimysium and may have a role in facilitating the formation of fibrosis, as seen in later stages of the disease.39,40 Genes induced by interferon-α/β are also overexpressed in the patient’s muscle; one of them, the interferon-α/β inducible myxovirus resistanceA protein, is upregulated in the perifascicular region and in the capillaries and to a lesser degree in the myofibers.38

The immunopathogenesis in polymyositis is the same as in inclusion-body myositis. In these disorders, there is evidence for a MHC class I antigen-restricted process mediated by cytotoxic CD8+ T cells directed against muscle fibers.5 This concept is supported by several observations. First, endomysial T cells are cytotoxic to autologous myotubes in vitro and perforin granules are expressed in vivo and are released toward the muscle fibers they invade, leading to muscle fiber necrosis.41-43 Second, there is clonal expansion of the autoinvasive T cells, with restricted use of T cell receptor gene families.44-47 Third, costimulatory molecules are upregulated.43,48,49 The increased expression of co-stimulatory molecules on T cells, such as inducible co-stimulatory molecule and CD28, along with upregulation of their respective counterreceptors (inducible co-stimulatory ligand and BB1) on muscle fibers, suggests that muscle fibers in polymyositis and inclusion-body myositis can behave as antigen-presenting cells5,46 (Fig. 89–6). Although in both polymyositis and inclusion-body myositis the exact antigens that trigger the inflammatory process remain unknown, the presence of similar T cell clones in different muscles and their persistence over time in each patient suggest that the same antigenic stimuli may continue to drive the inflammatory response.5,44,45,47 In inclusion-body myositis, in addition to the inflammatory process, a degenerative mechanism is taking place. This conclusion is based on the presence of vacuolated muscle fibers away from the inflammation and on the intracellular accumu-

Immunopathogenesis of Inclusion-Body Myositis

Systemic immune compartment

Viruses (i.e., retrovirus) M␾ Antigen

CD8 MHC

Co-stimulation

TCR CD8

CD8

CD8

LFA-1

CD8

CD8

CD8 VLA-4 CCR

CXCR

VCAM-1 ICAM

Chemokines (MCP-1, IP-10)

CD8

MMPs CD8

CD8 CD8 TCR ␣ ␤

CD28 CTLA-4

ICOS

Cytokines (IFN-␥, IL-1, 2, TNF-␣)

CD40L

MMP-9

1 LFA-

MHC-I

BB1

ICOS-L

CD40

M-1

MMP-9 MMP-2

ICA

Perfo

rin

Necrosis ■

Figure 89–6. Molecules, receptors and their ligands involved in the transgression of T cells through the endothelial cell wall and recognition of antigens on muscle fibers. LFA-1/ICAM-1 binding and TCR scanning for antigen initiate the formation of an immunologic synapse. Stimulation is supported and enhanced by the engagement of BB1, CD40, and perhaps additional co-stimulatory molecules with their ligands CD28, CTLA, and CD40L. Metalloproteinases facilitate the migration of T cells and their attachment to the muscle surface. Muscle fiber necrosis occurs via the perforin granules released by the autoaggressive T cells. A direct myocytotoxic effect exerted by the released IFN-γ, IL-1, or TNF-α may also play a role. Death of the muscle fiber is mediated by a form of necrosis rather than apoptosis.

lation of various degeneration-associated molecules, such as amyloid, β-amyloid precursor protein, phosphorylated tau, ubiquitin, α1-antichymotrypsin, presenelin-1, prion proteins, and others.50 Although these features are characteristics of inclusion-body myositis, they are not specific to this disease. Similar vacuoles are observed in several other myopathies, such as hereditary inclusion-body myopathy, Emery-Dreifuss muscular dystrophy, rigid spine syndrome, and distal myopathies and even in chronic neurogenic conditions such as postpolio syndrome.9,32,51,52 In sporadic inclusion-body myositis, there may be a relationship between cytokines, amyloid, and chronic inflammation. The increase in cytokines such as interleukin 1β, their co-localization with β-amyloid precursor protein β-APP, and the ability of interleukin 1β and amyloid to upregulate the production of one another suggests an interaction between amyloid and inflammatory mediators.53 Preliminary observations at the mRNA level have shown a linear relationship between cytokines and amyloid-related molecules, such as tau and βAPP.54 In Alzheimer’s disease, the presence of strong βamyloid–reactive and HLA-restricted T cell responses against βamyloid 1–4255 suggest an immunogenic role for amyloid and its presentation to T cells by antigen-presenting cells.56 Whether in inclusion-body myositis the antigen-presenting cell– functioning muscle fibers are able to present amyloid and lead to an antigen-specific T cell response remains unclear.5 Recent findings suggest that thrombospondin-1 and its binding

partners, CD36 and CD47, may also play a role in the inflammatory process of inclusion-body myositis and might provide a link between inflammation and degeneration.57 CD36 has been shown to be important in the uptake of antigen by immature dendritic cells,58 and it is a key player in the inflammatory response to β-amyloid in Alzheimer’s disease.59

Autoantibodies Antibodies to nuclear or cytoplasmic constituents can be seen in patients with polymyositis, dermatomyositis, and inclusionbody myositis. Although some are classified as myositis specific, their specificity for these disorders has not been proved. Some of the myositis-associated autoantibodies seen in polymyositis, dermatomyositis, and, rarely, inclusion-body myositis include antisynthetase antibodies, such as anti–Jo-1, directed against various aminoacyl tRNA synthetases. With the possible exception of anti–Jo-1, which has a high specificity for the antisynthetase syndrome, none of the other antibodies are of sufficient specificity or sensitivity to be of diagnostic or prognostic value.60

TREATMENT The goal of therapy in inflammatory myopathies is to improve the patient’s ability to carry out activities of daily living by

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Neuromuscular Diseases: Muscle

increasing muscle strength and ameliorating the extramuscular manifestations of rash, dysphagia, dyspnea, arthralgia, and fever. Overall, dermatomyositis shows the best response to treatment, whereas inclusion-body myositis is the most resistant.1 Although immunosuppressive therapy may decrease the level of serum creatine kinase and increase strength, the reverse is not always true. Treatment decisions, therefore, should be based on clinical response and not on chasing the creatine kinase levels. It is also prudent to discontinue a particular drug if an adequate trial fails to cause an objective improvement in strength, regardless of the change in creatine kinase levels.9

Dermatomyositis and Polymyositis Oral prednisone is the initial treatment of choice, at dosages of at least 1 mg/kg per day. Steroid treatment, as most other therapies, remains empirical because their efficacy has not been tested in a controlled study. After 3 to 4 weeks, prednisone is tapered slowly over a period of 10 weeks to 1 mg/kg every other day. It is further decreased, by 5 or 10 mg every 3 to 4 weeks, until the lowest possible dose sufficient to control the disease is attained.9 Most patients with dermatomyositis and polymyositis show a positive response to prednisone, as evidenced by an objective increase in muscle strength and in the activities of daily living.9 The failure of prednisone to provide such a benefit after 3 months of high-dose therapy should be taken as a sign of unresponsiveness to the drug. In these circumstances, tapering should be accelerated and consideration should be given to initiating therapy with another immunosuppressive agent or with intravenous immunoglobulin (IVIg).9 In acute cases, intravenous steroid, at a dose of 1 g/day, has been used for a faster response. In most patients, immunosuppressive agents other than prednisone may also be required. The decision to initiate such therapy is based on the need for a steroid-sparing effect when, despite steroid responsiveness, the patients develop complications or show any of the following: resistance to steroid therapy, relapse of the disease with attempts at lowering the prednisone dose, or a rapidly progressive disease course with severe weakness and respiratory failure.1,9 The drugs most commonly used, but never tested in randomized trials, include the following:1,9 ■ Azathioprine, which is well tolerated and has few side effects.

■

■ ■

■

The maximum dose is 3 mg/kg daily, but requires 4-6 months to have an effect. Methotrexate has a faster onset of action than azathioprine and can be given orally. The starting dose is 7.5 mg weekly, for the first 3 weeks (2.5 mg every 12 hours for three doses), with gradual dose escalations of 2.5 mg/wk to a maximum total of 25 mg weekly. Mycophenolate mofetil is used at a dosage of 2 g/day and is emerging as a promising and well-tolerated drug.61 Cyclophosphamide has significant toxicity and limited success. It can be used at a dosage of 0.5 to 1 g intravenous monthly for 6 months. Cyclosporine may be of benefit in some cases of juvenile dermatomyositis. Cyclosporine can be used at a dosage of 100 to 150 mg twice daily. The overall results with cyclosporine, however, are disappointing.

In our experience, the benefit of these drugs is mostly to maintain, rather than induce, a response. For this reason, if pred-

T A B L E 89–3. Treatment Sequence in Inflammatory Myopathies STEP 1: High-dose prednisone STEP 2: Azathioprine, methotrexate, or mycophenolate mofetil for steroid-sparing effect STEP 3: Intravenous immunoglobulin STEP 4: Trial of one of the following agents: cyclophosphamide, tacrolimus, sirolimus, or rituximab

nisone is not sufficient to control the disease, we recommend high-dose IVIg, which has been shown to improve strength and diminish the rash in controlled trials of patients with refractory dermatomyositis. Repeated infusions, every 6 to 8 weeks, are often needed to maintain improvement. A dose of 2 g/kg, divided over 2 to 5 days, is recommended per course. Uncontrolled observations suggest that IVIg is also beneficial for the management of patients with polymyositis.9 Plasmapheresis is not effective in polymyositis and dermatomyositis.62 Accordingly, we apply a following step-by-step approach to the treatment of polymyositis and dermatomyositis (Table 89–3). For difficult cases, newer agents such as tacrolimus or sirolimus may be used; for monoclonal antibody against CD20, rituximab may be considered.

Inclusion-Body Myositis Inclusion-body myositis is generally resistant to immunosuppressive therapies. Prednisone, azathioprine, and methotrexate have been often tried for a few months in newly diagnosed patients, but the results have been generally disappointing. Occasionally, patients feel subjectively weaker after discontinuing these drugs, thus forcing the clinicians to maintain lowdose every-other-day prednisone or weekly methotrexate regimens even in the absence of objective evidence supporting this practice.9 Controlled trials have shown that IVIg does not offer a statistically significant improvement in inclusion-body myositis,63,64 although one third of the patients experience transient benefit.14 However, in our controlled study as well as in other uncontrolled observations, IVIg has shown to be effective in transiently improving swallowing function.9,65 Therefore, IVIg can be tried for 2 or 3 months in selected patients who exhibit significant dysphagia.

Associated Clinical Manifestations Various immunosuppressive medications have been suggested for the treatment of interstitial lung disease, although a standard regimen has not been established. Oral prednisone can result in improved pulmonary function, particularly when used at an early inflammatory stage. High-dose intravenous pulse methylprednisolone, given as 1 g of methylprednisolone daily for 3 consecutive days, has been used in patients who do not respond to oral prednisone or during acute relapses. In corticosteroid-resistant patients with interstitial lung disease, other immunosuppressive agents have been used, including cyclophosphamide, azathioprine, cyclosporine, and tacrolimus.17

chapter 89 inflammatory myopathies DIFFERENTIAL DIAGNOSIS The typical skin rash of dermatomyositis, along with the presence of subacute onset of proximal muscle weakness, very rarely raises confusion about the correct diagnosis. The skin rash of lupus is different from that of dermatomyositis, and if a myopathy occurs in patients with lupus, it is usually multifactorial and occurs in patients with a known disease. The skin changes of scleroderma may overlap with those of dermatomyositis, and scleroderma is the main disease from which dermatomyositis needs to be distinguished.9 Polymyositis is a diagnosis of exclusion, and any myopathy of subacute onset needs to be considered and excluded. The following myopathies should be considered in the differential diagnosis of polymyositis: 1. Drug-induced myopathies should be excluded by a careful drug history. The most common myotoxic drugs are D-penicillamine or procainamide; AZT, which causes a mitochondrial myopathy; the cholesterol-lowering agents, such as clofibrate, lovastatin, simvastatin, or pravastatin, especially when combined with cyclosporine or gemfibrozil; amphotericin B, that may cause rhabdomyolysis and myoglobinuria; aminocaproic acid, fenfluramine, heroin, and phencyclidine; chloroquine and colchicines that cause vacuolar myopathy; carbimazole, emetine, etretinate, ipecac syrup, chronic laxatives, or licorice resulting in hypokalemia; glucocorticoids or growth hormone; and neuromuscular blocking agents such as pancuronium, in combination with glucocorticoids, especially in patients with underlying neurogenic diseases. 2. Chronic myopathies with inflammatory cell infiltration early in the disease process, especially facioscapulohumeral muscular dystrophy, dysferlin myopathy, dystrophinopathies, and necrotizing myopathy. Immunohistochemistry should be used to look for CD8/MHC-I complexes, as discussed earlier, and for the presence of specific mutant structural proteins. Doubtful cases require screening for the respective genetic defects. 3. Metabolic and mitochondrial myopathies are often associated with characteristic clinical signs, abnormalities on forearm exercise test, and histochemical and biochemical changes in the muscle biopsy.9 4. Endocrine myopathies, such as those due to hypercorticosteroidism, hyperthyroidism and hypothyroidism, and hyperparathyroidism and hypoparathyroidism, require appropriate laboratory investigations.9 5. Muscle wasting can be seen in patients with underlying neoplasm and might be due to disuse atrophy, cachexia, rarely to paraneoplastic effects.9 6. Myasthenia gravis and other disorders of the neuromuscular junction cause fatigue and facial and extraocular muscle involvement, which is not seen in inflammatory myopathies. Repetitive nerve stimulation, single-fiber electromyography, and acetylcholine receptor antibodies can help in their diagnosis.9

PROGNOSIS Although the outcome of polymyositis and dermatomyositis has improved, at least one third of patients are left with mild to severe disability. Dermatomyositis responds more favorably to

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therapy than does polymyositis and has a better prognosis. Most patients improve with therapy, and many make a full functional recovery, which is often sustained with maintenance therapy, although relapses may occur at any time.9 A small cohort study showed a 5-year survival of 95% and a 10-year survival of 84%.66,67 Death is usually due to pulmonary, cardiac, or other systemic complications.9 Older patients, those with associated cancer, severely affected patients, or those not treated early and effectively carry a poorer prognosis.1,9 Pulmonary fibrosis, frequent aspiration pneumonias due to esophageal dysfunction, and extensive calcinosis in dermatomyositis are associated with increased morbidity.66,67 Of children with juvenile dermatomyositis, 34% to 40% have a monocyclic disease, and after an acute course that resolves within a 2-year period, they enter into indefinite remission.68 The remaining patients have a chronic disease that can be progressive or characterized by remissions and exacerbations (polycyclic course), and may require chronic immunosuppressive therapy.69 Inclusion-body myositis has the least favorable prognosis, and most patients will require assistive devices such as canes, walkers, or wheelchairs within 5 to 10 years of onset. In general, the older the age of onset in inclusion-body myositis, the more rapidly progressive the course of the disease.9

K E Y

P O I N T S

●

Based on unique clinical, histological, and immunopathological criteria, the most common inflammatory myopathies are dermatomyositis (dermatomyositis), polymyositis (polymyositis), and inclusion-body myositis.

●

Dermatomyositis and inclusion-body myositis have characteristic clinical findings and should not pose a diagnostic challenge; in contrast, polymyositis lacks characteristic clinical features and needs to be differentiated from other forms of myopathies or dystrophies.

●

Dermatomyositis is a complement-mediated microangiopathy. Polymyositis and inclusion-body myositis have identical immunopathology, characterized by CD8+ cytotoxic T cells invading MHC-I–expressing muscle fibers; inclusion-body myositis, in addition to the primary T cell–mediated process, has degenerative features as evidenced by the presence of vacuolated fibers, not invaded by T cells, with deposits of various neurodegenerative molecules.

●

The MHC-I/CD8+ lesion, which defines the T cell–mediated cytotoxicity of polymyositis and inclusion-body myositis, is a unique feature of these disorders and should be included in the diagnostic criteria that characterize the inflammation of polymyositis and inclusion-body myositis.

●

Dermatomyositis and polymyositis are generally responsive to immunosuppressive agents, whereas inclusion-body myositis is mostly resistant to these therapies.

●

Therapeutic decisions should be based on changes in the patient’s strength and not on the level of serum muscle enzymes or other biomarkers.

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Suggested Reading Amato AA, Griggs RC. Treatment of idiopathic inflammatory myopathies. Curr Opin Neurol 2003;16:569-575. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362:971-982. Dalakas MC. Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 2004;17:561-567. Kissel JT. Misunderstandings, misperceptions, and mistakes in the management of the inflammatory myopathies. Semin Neurol 2002;22:41-51. Mastaglia FL, Garlepp MJ, Phillips BA, Zilko PJ. Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve 2003;27:407-425.

References 1. Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis. Lancet 2003; 362:971-982. 2. Dalakas MC: Polymyositis, dermatomyositis and inclusionbody myositis. N Engl J Med 1991; 325:1487-1498. 3. Mastaglia FL, Phillips BA: Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria. Rheum Dis Clin North Am 2002; 28:723-741. 4. Dalakas MC: Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am 2002; 28:779-798, vi. 5. Dalakas MC: Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 2004; 17:561-567. 6. Amato AA, Griggs RC: Unicorns, dragons, polymyositis, and other mythological beasts. Neurology 2003; 61:288-289. 7. Ramanan AV, Feldman BM: Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin North Am 2002; 28:833-857. 8. Pachman LM: Juvenile dermatomyositis: immunogenetics, pathophysiology, and disease expression. Rheum Dis Clin North Am 2002; 28:579-602, vii. 9. Dalakas MC: Polymyositis, dermatomyositis and inclusion body myositis. In: Braunwald E, Fauci AS, Kasper DL, eds. Harrison’s Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2004. 10. Sontheimer RD: Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin 2002; 20:387-408. 11. Dalakas MC: Images in clinical medicine. Calcifications in dermatomyositis. N Engl J Med 1995; 333:978. 12. Fisler RE, Liang MG, Fuhlbrigge RC, et al: Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol 2002; 47:505-511. 13. Sekul EA, Dalakas MC: Inclusion body myositis: new concepts. Semin Neurol 1993; 13:256-263. 14. Dalakas MC: Progress in inflammatory myopathies: good but not good enough. J Neurol Neurosurg Psychiatry 2001; 70:569573. 15. Kao AH, Lacomis D, Lucas M, et al: Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004; 50:209-215. 16. Douglas WW, Tazelaar HD, Hartman TE, et al: Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 2001; 164:1182-1185. 17. Hirakata M, Nagai S: Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 2000; 12:501-508. 18. Imbert-Masseau A, Hamidou M, Agard C, et al: Antisynthetase syndrome. Joint Bone Spine 2003; 70:161-168.

19. Sigurgeirsson B, Lindelof B, Edhag O, et al: Risk of cancer in patients with dermatomyositis or polymyositis. A populationbased study. N Engl J Med 1992; 326:363-367. 20. Hill CL, Zhang Y, Sigurgeirsson B, et al: Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357:96-100. 21. Callen JP: When and how should the patient with dermatomyositis or amyopathic dermatomyositis be assessed for possible cancer? Arch Dermatol 2002; 138:969-971. 22. Bohan A, Peter JB: Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975; 292:344-347. 23. Sekul EA, Chow C, Dalakas MC: Magnetic resonance imaging of the forearm as a diagnostic aid in patients with sporadic inclusion body myositis. Neurology 1997; 48:863-866. 24. Kane D, Grassi W, Sturrock R, et al: Musculoskeletal ultrasound—a state of the art review in rheumatology. Part 2: clinical indications for musculoskeletal ultrasound in rheumatology. Rheumatology (Oxford) 2004; 43:829-838. 25. Hilton-Jones D: Inflammatory muscle diseases. Curr Opin Neurol 2001; 14:591-596. 26. Civatte M, Schleinitz N, Krammer P, et al: Class I MHC detection as a diagnostic tool in noninformative muscle biopsies of patients suffering from dermatomyositis (dermatomyositis). Neuropathol Appl Neurobiol 2003; 29:546-552. 27. Arahata K, Engel AG: Monoclonal antibody analysis of mononuclear cells in myopathies. I: quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984; 16:193-208. 28. Engel AG, Arahata K: Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigenspecific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies. Hum Pathol 1986; 17:704-721. 29. Karpati G, Pouliot Y, Carpenter S: Expression of immunoreactive major histocompatibility complex products in human skeletal muscles. Ann Neurol 1988; 23:64-72. 30. Mendell JR, Sahenk Z, Gales T, et al: Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments. Arch Neurol 1991; 48:1229-1234. 31. Askanas V, Engel WK, Alvarez RB: Enhanced detection of Congo-red-positive amyloid deposits in muscle fibers of inclusion body myositis and brain of Alzheimer’s disease using fluorescence technique. Neurology 1993; 43:12651267. 32. Semino-Mora C, Dalakas MC: Rimmed vacuoles with betaamyloid and ubiquitinated filamentous deposits in the muscles of patients with long-standing denervation (postpoliomyelitis muscular atrophy): similarities with inclusion body myositis. Hum Pathol 1998; 29:1128-1133. 33. Santorelli FM, Sciacco M, Tanji K, et al: Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients. Ann Neurol 1996; 39:789-795. 34. Askanas V, Engel WK: Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 2001; 60:1-14. 35. Shamim EA, Rider LG, Miller FW: Update on the genetics of the idiopathic inflammatory myopathies. Curr Opin Rheumatol 2000; 12:482-491. 36. Kissel JT, Mendell JR, Rammohan KW: Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986; 314:329-334. 37. Kissel JT: Misunderstandings, misperceptions, and mistakes in the management of the inflammatory myopathies. Semin Neurol 2002; 22:41-51. 38. Greenberg SA, Pinkus JL, Pinkus GS, et al: Interferonalpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 2005; 57:664-678.

chapter 89 inflammatory myopathies 39. Amemiya K, Semino-Mora C, Granger RP, et al: Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol 2000; 94:99-104. 40. Figarella-Branger D, Civatte M, et al: Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve 2003; 28:659-682. 41. Hohlfeld R, Engel AG: The immunobiology of muscle. Immunol Today 1994; 15:269-274. 42. Goebels N, Michaelis D, Engelhardt M, et al: Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Invest 1996; 97:2905-2910. 43. Schmidt J, Rakocevic G, Raju R, et al: Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity. Brain 2004; 127:1182-1190. 44. Hofbauer M, Wiesener S, Babbe H, et al: Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR, and CDR3-spectratype analysis. Proc Natl Acad Sci U S A 2003; 100:4090-4095. 45. Amemiya K, Granger RP, Dalakas MC: Clonal restriction of Tcell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain 2000; 123(Pt 10):2030-2039. 46. Benveniste O, Cherin P, Maisonobe T, et al: Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomyositis patients. J Immunol 2001; 167:3521-3529. 47. Benveniste O, Herson S, Salomon B, et al: Long-term persistence of clonally expanded T cells in patients with polymyositis. Ann Neurol 2004; 56:867-872. 48. Murata K, Dalakas MC: Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28, and their mRNA in inflammatory myopathies. Am J Pathol 1999; 155:453-460. 49. Wiendl H, Mitsdoerffer M, Schneider D, et al: Muscle fibres and cultured muscle cells express the B7.1/2-related inducible costimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies. Brain 2003; 126:1026-1035. 50. Askanas V, Engel WK: Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta, misfolded proteins, predisposing genes, and aging. Curr Opin Rheumatol 2003; 15:737-744. 51. Fidzianska A, Kaminska A: Congenital myopathy with abundant ring fibres, rimmed vacuoles and inclusion body myositis-type inclusions. Neuropediatrics 2003; 34:40-44. 52. Fidzianska A, Rowinska-Marcinska K, HausmanowaPetrusewicz I: Coexistence of X-linked recessive EmeryDreifuss muscular dystrophy with inclusion body myositis-like morphology. Acta Neuropathol (Berl) 2004; 107:197-203. 53. Dalakas MC: Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol 1998; 55:1509-1512.

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54. Schmidt J, Raju R, Salajegheh M, Rakocevic G, et al: Distinct interplay between inflammatory and degeneration-associated molecules in sporadic inclusion body myositis (sIBM). Neurology (suppl 1) 2005; 64:A337-338. 55. Monsonego A, Zota V, Karni A, et al: Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 2003; 112:415-422. 56. Monsonego A, Weiner HL: Immunotherapeutic approaches to Alzheimer’s disease. Science 2003; 302:834-838. 57. Salajegheh M, Raju R, Schmidt J, et al: Thrombospondin-1 (TSP1) and its binding partners CD36 and CD47, as mediators of inflammation in sporadic inclusion body myositis (sIBM). Neurology 2005; (Suppl 1)64:A158. 58. Albert ML, Pearce SF, Francisco LM, et al: Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 1998; 188:1359-1368. 59. El Khoury JB, Moore KJ, Means TK, et al: CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003; 197:1657-1666. 60. Mastaglia FL, Garlepp MJ, Phillips BA, et al: Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve 2003; 27:407-425. 61. Chaudhry V, Cornblath DR, Griffin JW, et al: Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology 2001; 56:94-96. 62. Miller FW, Leitman SF, Cronin ME, et al: Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med 1992; 326:1380-1384. 63. Dalakas MC: The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidencebased indications and safety profile. Pharmacol Ther 2004; 102:177-193. 64. Walter MC, Lochmuller H, Toepfer M, et al: High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 2000; 247:22-28. 65. Cherin P, Pelletier S, Teixeira A, et al: Intravenous immunoglobulin for dysphagia of inclusion body myositis. Neurology 2002; 58:326. 66. Marie I, Hachulla E, Hatron PY, et al: Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol 2001; 28:2230-2237. 67. Sultan SM, Ioannou Y, Moss K, et al: Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology (Oxf) 2002; 41:22-26. 68. Rennebohm R: Juvenile dermatomyositis. Pediatr Ann 2002; 31:426-433. 69. Wargula JC: Update on juvenile dermatomyositis: new advances in understanding its etiopathogenesis. Curr Opin Rheumatol 2003; 15:595-601.

CHAPTER

90

NEUROMUSCULAR JUNCTION DISORDERS ●

●

●

●

Angela Vincent, Camilla Buckley, and Georgina Burke

The neuromuscular junction is a prototype synapse but one that is accessible to circulating factors, which makes it a target for neurotoxins and autoantibodies, as well as for genetic disorders. The defects in neuromuscular transmission are associated with well-recognized “myasthenic” symptoms of fatigable weakness, but muscle hyperexcitability syndromes are also recognized. Before the different disorders are discussed, it is important to appreciate the anatomy and function of the neuromuscular junction. The terminal boutons of the motor nerve axon contain mitochondria and small spherical synaptic vesicles that store the neurotransmitter acetylcholine (ACh). Between the presynaptic and postsynaptic membranes is the synaptic cleft, which contains an amorphous-looking basal lamina that, among many functions, anchors the enzyme acetylcholinesterase (AChE) via its collagen tail, ColQ. The peaks of the postsynaptic folds are particularly electron dense because of their high concentration of acetylcholine receptors (AChRs) (Fig. 90–1). When the action potential reaches the motor nerve terminal, the depolarization opens voltage-gated calcium channels (VGCCs), resulting in the Ca2+-dependent release of ACh into the synaptic space. ACh diffuses rapidly to the postsynaptic membrane and binds to the AChRs, leading to opening of the ACh-gated ion channel and a local depolarization called the end plate potential (EPP). If the EPP exceeds a certain threshold, voltage-gated sodium channels that lie at the bottom of the postsynaptic folds are opened, which results in generation of the muscle action potential that propagates along the muscle fiber and activates muscle contraction. The action of ACh is terminated by its dissociation from the AChR, which closes spontaneously after 1 to 4 milliseconds; by hydrolysis by AChE; and by diffusion from the synaptic cleft. Meanwhile, in the motor nerve terminal, the resting membrane potential is restored through the opening of voltage-gated potassium channels (VGKCs). Autoantibodies and neurotoxins can access the neuromuscular junction from the peripheral circulation, as illustrated by the rapid onset of muscle paralysis and potentially fatal respiratory failure produced by some forms of envenomation, such as that occurring with bites of certain species of snakes, scorpions, and spiders. Their toxins bind with high affinity and specificity to different ion channels and receptors at the neuromuscular junction, providing a library of tools for investigation of disorders of the neuromuscular junction.

MYASTHENIA GRAVIS The evidence for autoimmunity at the neuromuscular junction is overwhelming. The observations first made in myasthenia gravis have been extended to other conditions, as summarized in Table 90–1. After observing the thymic pathology in young women with myasthenia gravis, the association with other autoimmune diseases, and the maternal-to-neonatal transfer, John A. Simpson was the first to propose formally that myasthenia gravis was an autoimmune disease. He hypothesized that myasthenia gravis was caused by antibodies directed against an end plate protein. Support for this hypothesis came from two seminal papers published in 1973: (1) a report of reduced AChRs at the neuromuscular junctions of patients with myasthenia gravis1 and (2) the observation that immunization against affinity-purified AChRs could induce AChE inhibitor–sensitive weakness and paralysis in rabbits.2 It remained only to demonstrate antibodies to AChRs in patients,3 as was done by a number of groups over the following years.

Clinical Features and Diagnosis The weakness often starts in the extraocular muscles, resulting in double vision and ptosis (drooping eyelids), and in 85% of patients, these muscles become involved at some stage. Some patients never develop weakness of other muscles (ocular myasthenia gravis, discussed later), whereas others also develop weakness of bulbar, respiratory, neck, and limb muscles (generalized myasthenia gravis). They complain of difficulty chewing and swallowing, which may result in choking episodes or nasal regurgitation, and their speech becomes slurred, particularly after long conversations. They may develop shortness of breath, especially on exertion and when lying flat (as a result of diaphragmatic weakness). Proximal limb muscles are preferentially affected; hence, the patients have difficulty walking, especially uphill or upstairs, and difficulty holding their arms above their head (e.g., when washing their hair). The characteristic feature of myasthenia gravis that helps to differentiate it from myopathies is the fatigable nature of the weakness. Thus, the weakness varies in distribution and severity from day to day, is often worse at the end of the day, increases with stress, and tends to improve with rest and with use of AChE inhibitors. Table 90–2 lists features that help to differentiate myasthenia

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Figure 90–1. The neuromuscular junction. The membrane proteins targeted by autoantibodies are listed on the left, and the most commonly reported membrane proteins, enzymes, and structural proteins involved in genetic disorders on the right.

Targets for Autoantibodies

Targets for Genetic Defects

Voltage-gated calcium channel (VGCC)

Choline acetyltransferase (CHAT)

Voltage-gated potassium channel (VGKC)

Acetylcholinesterase (AChE)

Acetylcholine receptor (AChR)

Acetylcholine receptor (AChR)

Muscle specific kinase (MuSK)

Receptor aggregating protein at the synapse (RAPsyn)

T A B L E 90–1. Autoimmune Diseases of the Neuromuscular Junction Disease Myasthenia gravis AChR antibodynegative myasthenia Lambert-Eaton myasthenic syndrome Neuromyotonia

Other Autoimmune Disorders

Antibody to Suitable Target Protein

Response to Plasma Exchange

Neonatal Transfer

Passive Transfer to Mice

Tumor Association

Yes Not frequent

AChR MuSK and other(s) unknown

Yes Yes

Yes Yes

Yes Yes

Thymoma None

Yes

VGCC

Yes, but slower than in MG

Not reported

Yes

SCLC

Yes

VGKC, but detected in only 40%

Yes

Yes (authors’ unpublished observations)

Yes, but modest effects

Thymoma, SCLC

AChR, acetylcholine receptor; MuSK, muscle-specific receptor tyrosine kinase; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channels; VGKC, voltage-gated potassium channels.

gravis from other causes of muscle weakness. Myasthenia gravis was reviewed by Pascuzzi (2004).4 Neurological examination reveals normal tone, reflexes, coordination, and sensation, with weakness particularly in the distribution discussed previously, often accompanied by overactivity of frontalis muscles in an attempt to counteract ptosis. Fatigability can be demonstrated either by repetitive testing of a limb muscle, followed by comparison with the contralateral rested muscle, or by asking the patient to sustain an upward gaze for 60 seconds and observing the worsening ptosis. Vital capacity measured with a spirometer is the most sensitive indicator of respiratory compromise. The diagnosis is usually suspected from the characteristic clinical features, especially the fatigability. Confirmatory investigations include detection of AChR or muscle-specific

receptor tyrosine kinase (MuSK) antibodies in the serum, electrophysiological testing that reveals a decrement in the compound muscle action potential on 3-Hz stimulation or increased jitter on single-fiber electromyography, and/or a clinical response to short-acting AChE inhibitors (Table 90–3). Rapid improvement after administration of intravenous edrophonium (Tensilon test) is confirmatory in some centers, but objectivity is a problem, and there is a small chance of precipitating cardiorespiratory arrest even if the patient is pretreated with atropine. All patients should undergo thyroid function tests (because thyroid dysfunction is the most common autoimmune disease associated with myasthenia gravis), and imaging of the thorax for detection of an associated thymoma should be performed in patients with AChR antibodies.

chapter 90 neuromuscular junction disorders

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T A B L E 90–2. Differential Diagnosis of Myasthenia Gravis Symptom

Differential Diagnosis

Distinguishing Feature of Alternative Diagnosis*

Ptosis and diplopia

Congenital ptosis

Usually obvious from history; if in doubt, ask patient for photos from childhood No associated diplopia Check family history, especially on mother’s side Diplopia less marked despite extensive limitation of eye movements Less fluctuation in symptoms There may be other organ involvement Family history; genetic diagnosis available Onset in sixth decade Diplopia is rare; ptosis is prominent early, then dysphagia Look for associated ocular signs, such as proptosis, eyelid lag Systemic signs and goiter Muscles often painful There may be associated features (e.g., rash in dermatomyositis) Serum creatine kinase level usually elevated History of high-dose daily steroid use Hip flexors commonly affected Muscle wasting Family history Raised serum creatine kinase level Tongue wasting and fasciculation Look for upper motor neuron signs Increased jitter may also be present on single-fiber EMG Onset is usually more sudden Patients with less fluctuation usually show steady improvement

Mitochondrial cytopathy

Oculopharyngeal muscular dystrophy Thyroid ophthalmopathy Limb muscle weakness

Inflammatory myopathies Steroid myopathy Muscular dystrophy

Bulbar weakness (especially in elderly patients)

Motor neuron disease Posterior circulation stroke

*The feature that differentiates myasthenia gravis from other diseases is the fatigable muscle weakness. EMG, electromyography.

T A B L E 90–3. Electrophysiological and Diagnostic Features of Neuromuscular Junction Disorders

3-Hz Stimulation

50-Hz Stimulation or After Voluntary Contraction

Disease

Reflexes

Compound Muscle Action Potential

Myasthenia gravis Lambert-Eaton myasthenic syndrome Neuromyotonia

Normal or reduced Absent

Normal Reduced

Decrement Decrement

Decrement Increment

Absent Dry mouth, constipation, male impotence

Hyperactive or normal

Normal amplitude Repetitive response to single stimulus Multiple spontaneous motor unit discharges Normal in AChR deficiency Repetitive response to single stimulus in AChE deficiency and slow channel syndrome

Normal or decrement

Not performed

Increased sweating, constipation

Normal or decrement

Not performed

Absent

Congenital myasthenic syndromes

Usually normal

Autonomic Symptoms

Note: Jitter on single-fiber electromyography is a more sensitive test than repetitive stimulation but does not distinguish between different neuromuscular junction disorders. AChE, acetylcholinesterase; AChR, acetylcholine receptor.

Etiology and Pathophysiology In myasthenia gravis, the numbers of AChRs at the neuromuscular junction are reduced to approximately 20% of normal levels.1 As a result, the EPP is reduced in amplitude and fails to reach threshold in a proportion of muscle fibers, which results in muscle weakness. During repeated effort, the EPP becomes smaller still, and fatigue thus increases. Electron microscopy reveals a normal nerve terminal, loss of the secondary postsynaptic folds, and debris within the synaptic cleft (see Engel5).

About 80% of patients with generalized myasthenia gravis have antibodies to the muscle AChR, which are detected by immunoprecipitation of iodine 125 (125I)–α-Bungarotoxin (αBuTx)–AChR complexes (α-BuTx is a toxin from Bungarus multicinctus that binds with high affinity and specificity to the AChR). The AChR is a pentameric membrane protein that exists in adult and fetal forms (Fig. 90–2), and α-BuTx binds to each of the two α subunits. The AChR has not been crystallized, but Unwin demonstrated many of the features of the molecule.6 AChR antibodies are high affinity (around 1010 mol), polyclonal, and mainly in the immunoglobulins G1 and G3

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Epidemiology

Individual subunits

M1 M2 M3 M4

Fetal

Adult ε

γ α

α δ

β

ACh/α-BuTx binding site Developing muscle ■

α

α δ

β

Main immunogenic region NMJ

Figure 90–2. Diagrammatic scheme of the acetylcholine (ACh) receptor and the topology of each of its five subunits. The adult and fetal isoforms are shown as viewed from the nerve terminal. ACh and the snake toxin α-Bungarotoxin (α-BuTx) bind to sites between each of the two α subunits and the adjacent subunits. The main immunogenic region, where the largest proportion of patients’ antibodies bind, is on the α subunits. ACh receptor antibodies are measured by immunoprecipitation of iodine 125–α-BuTx–labeled ACh receptors. NMJ, neuromuscular junction.

subclasses (which are complement-activating). In a proportion of patients, many of the antibodies are directed toward the main immunogenic region on the α subunits7,8 (see Fig. 90–2). Titers of AChR antibody are very variable between patients (ranging from 0 to >1000 nmol) and are not correlated strongly with clinical severity of the disorder. However, the level of antibody within an individual generally changes in parallel with clinical scores after plasma exchange,9 thymectomy,10,11 or immunosuppressive treatments. Moreover, myasthenia gravis can be passively transferred from patients to mice12; the mice may become weak and have reduced numbers of AChRs at the neuromuscular junction. There are three ways in which the antibodies cause AChR loss in myasthenia gravis. First, the immunoglobulin G (IgG) antibodies can activate complement, causing morphological damage.5 Second, the antibodies, particularly those against the AChR α subunits, can, by binding divalently, crosslink the AchRs, which results in increased internalization and degradation.13 Third, some antibodies can directly inhibit ACh binding to the AChR, which results in direct loss of function.14 Loss of voltage-gated sodium channels, which are located in the secondary folds,15 may increase the threshold for generation of the action potential, thus enhancing the neuromuscular junction defect. However, there is also evidence of a compensatory increase in ACh release16 and of increased AChR synthesis.17 The final distribution and severity of muscle weakness must reflect not only the antibody-induced AChR and secondary sodium channel loss but also these compensatory changes.

Myasthenia gravis is reported to occur in between 7 and 15 per 100,000 people. These prevalences may be underestimates, inasmuch as current experience suggests that the incidence of new cases may be as high as 1.5 per 100,000 per year,18 and myasthenia gravis remits spontaneously only at the rate of about 1% per year. Patients with myasthenia gravis can be divided into subgroups (Table 90–4), on the basis of age at onset, human leukocyte antigen (HLA) association, thymic involvement, and AChR antibody status.19 However, there may be significant geographical variation; there are few comparative international studies, but in Asian countries more children are affected, and most have ocular myasthenia gravis.

Clinical Heterogeneity Ocular Myasthenia Gravis Ocular myasthenia gravis, defined by symptoms that remain restricted to extraocular muscles for at least 2 years, has often been considered a distinct condition (although there may be electrophysiological defects in other muscle groups). AChR antibody levels are generally low or undetectable in about 50% of affected patients. The thymus gland was normal in the few patients examined, and most studies show no apparent HLA association (reviewed by Sommer et al20). There are differences between ocular muscles and other striated muscles that may determine their selective susceptibility to myasthenic weakness.21 However, ocular weakness is often the presenting symptom in neurotoxin poisoning (e.g., botulism and Bungarus krait envenoming), and it may be that physiological factors or accessibility of the ocular muscle neuromuscular junctions to circulating factors are a major reason for their susceptibility to clinical involvement.

Generalized Myasthenia Gravis with Acetylcholine Receptor Antibodies Early Onset There is a 3 : 1 female : male ratio among patients who develop myasthenia gravis in early adulthood, usually defined as younger than 40 years at onset. In Northern Europeans, there is a very strong association with the HLA A1 B8 DRB1*0301 DRB*0101 DQB1*0201 DQA1*0501 ancestral haplotype.22,23 In patients with young-onset myasthenia gravis, the thymus gland is often reported to be “hyperplastic” with many T cell areas in the medulla, some containing lymphoid follicles (for reviews, see Hohlfeld and Wekerle24). Lymphocytes cultured from the thymus gland synthesize AChR antibody,25 and serum AChR antibody levels frequently decline, albeit slowly, after thymectomy.10,11 AChR in its native conformation has been demonstrated in “myoid” cells found in situ between the epithelial cells in thymic medullae both from normal individuals and from patients with myasthenia gravis,26 and these myoid cells may be targets for autoantibody attack, provoking the germinal center formation.27 Affected patients tend to do well with thymectomy and conventional immunosuppressive agents.

chapter 90 neuromuscular junction disorders

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T A B L E 90–4. Different Forms of Myasthenia Gravis Subgroup

Age at Onset

Thymic Pathology

HLA Association

Antibody

Comments

Ocular myasthenia gravis

Wide variation

Insignificant

None known

AChR antibody in only 50% is positive; more sensitive test perhaps required

Early onset

<50 years

B8 DR3

AChR antibody positive by definition

Late onset

>49 years

Thymitis with lymphocytic infiltrates and germinal centers No clear thymic pathology

Only cases that do not progress to generalized myasthenia gravis within 2 years should be included Patients often respond well to thymectomy

B7 DR2 but no large studies

AChR antibody positive by definition

Thymoma

Mainly 30-60 years

Thymoma, usually WHO classification B1 or B2

No clear association

AChR antibody positive by definition

MuSK antibody positive

Wide but peak incidence in young women

Insignificant

DR5 in one study

MuSK antibody

AChR/MuSK antibody negative

Wide

Thymitis in about 50%, similar to early-onset form

None known

No defined antibody

Thymectomy not usually performed; good response to immunosuppression Thymectomy must be performed but further treatments are usually required Thymectomy not indicated; condition may be difficult to treat; severe bulbar symptoms and muscle atrophy may develop Thymectomy may be indicated, but data as yet are insufficient

AChR, acetylcholine receptor; HLA, human leukocyte antigen; MuSK, muscle-specific receptor tyrosine kinase; WHO, World Health Organization.

Late Onset

Thymoma-Associated Myasthenia Gravis Patients with myasthenia gravis and thymoma can present at any age, but presentation usually occurs between the ages of 30 and 60 years. Thymomas associated with myasthenia gravis are epithelial in origin and correspond mainly to the World Health Organization types B1 and B2 (see Muller-Hermelink and Marx30). More than 90% of patients with thymoma have antibodies to antigens of striated and cardiac muscle,31 including

300 Number of individuals positive for AChR antibody

Surveys of AChR antibodies have shown a striking increase in incidence after the age of about 60 years, peaking in the late 70s (Fig. 90–3), and even when the declining numbers of the population are taken into account, there is a decrease in frequency of diagnosis of myasthenia gravis after the age of 75 years.18 This suggests that the diagnosis of myasthenia gravis may be missed in elderly persons, partially because of diagnostic confusion with disorders such as motor neuron disease and stroke and partially because of underreporting of symptoms among more elderly patients. In these patients with late-onset disease, the thymus is mainly atrophic or involuted, and there are weak HLA associations. These patients do not have thymomas but nevertheless produce positive results for “thymomaassociated antibodies” to titin, ryanodine receptor, and cytokines.28,29 Thymectomy is seldom performed in patients older than 60 years, and its role in the management of lateonset disease remains unclear. Most patients respond well to low doses of corticosteroids, but often the patients with lateonset disease are slower to respond. They also appear to have a higher incidence of steroid-related complications, such as intestinal perforation.

Years 2001–2004

350 M F

250 200 150 100 50 0 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 Age at referral of serum for testing

■

Figure 90–3. Age at referral of 2400 patients with positive acetylcholine receptor (AChR) antibodies as determined by routine diagnostic testing during the period of 2001 to 2004. The samples represent about 50% of the total number of positive AChR results in the United Kingdom. Numbers of male (M) and female (F) patients are approximately equal overall, but women predominate (3 : 1) among patients younger than 40 years, and men predominate at older ages. It is striking that approximately 75% of the patients present after the age of 40 years; the peak is at approximately 75 years. Statistical analysis suggests that there is a substantial decline in diagnosis of myasthenia gravis after the age of 75 years.18

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myosin, actin, α-actinin, ryanodine receptor, and titin.32-34 Moreover, antibodies to the cytokines interferon α and interleukin-12, which are found in patients with late-onset disease, are also present in patients with thymoma-related myasthenia gravis and may be predictive of thymoma recurrence.29 Because the thymoma can invade adjacent structures such as the pleura, pericardium, and great vessels and can occasionally metastasize, it should be removed. After removal of the thymoma, however, the myasthenia rarely improves,35,36 AChR antibody levels seldom fall,11 and additional immunosuppressive therapy is usually required. Why the presence of a thymoma leads to myasthenia gravis is not clear, but the gland appears to export large numbers of mature T cells.37

Neonatal Myasthenia Gravis and Arthrogryposis Multiplex Congenita A proportion of babies born to mothers with myasthenia gravis have transient respiratory and feeding difficulties, as a result of transplacental transfer of maternal anti-AChR antibodies.38 On occasion, neonatal myasthenia gravis occurs without maternal disease or when the mother has myasthenia gravis but does not have AChR antibodies. A few cases of severe arthrogryposis multiplex congenita (fixed joint contractures associated with inadequate development of jaws and lungs), have been found in consecutive pregnancies in a few mothers with myasthenia gravis and in a very small number of women with AChR antibodies but no clinical evidence of myasthenia gravis. These antibodies specifically block the function of the fetal isoform of the AChR and lead to fetal paralysis, resulting in the developmental deformities.39 However, arthrogryposis is a fairly common developmental disorder, and maternal AChR antibodies are identified in only a small proportion of cases. Plasma exchange and intravenous immunoglobulins have been administered during pregnancy in two unreported cases; the babies were born normal and have thrived.

Generalized Myasthenia Gravis without Acetylcholine Receptor Antibodies About 10% to 15% of all patients with myasthenia gravis and generalized symptoms do not have anti-AChR antibodies detectable by current laboratory methods. In these patients, clinical manifestations and response to plasma exchange are similar to those of patients with AChR antibody–positive generalized myasthenia gravis, and passive transfer to mice has been demonstrated in a few studies (e.g., Mossman et al40). There are at least two forms of what was previously called “seronegative” myasthenia gravis.

Muscle-Specific Receptor Tyrosine Kinase Antibody–Associated Myasthenia Gravis Antibodies to MuSK are present in a proportion of AChR antibody–negative patients,41 varying from 0% to 50%, depending on geographical origin. They are mainly immunoglobulin G4 and are found in fewer than 1% of patients with AChR antibody–positive myasthenia gravis, with persistent ocular myasthenia gravis, or with thymoma.42 To date, these antibodies are

predominantly detected in younger women, with marked ocular, bulbar, neck, or respiratory symptoms.43,44 The thymus does not show marked changes,45,46 and there is doubtful benefit from thymectomy. Immunosuppression with prednisolone and azathioprine may be sufficient, but some patients require alternative immunosuppressive treatments such as mycophenolate or cyclosporine. It is not yet clear how the antibodies cause the neuromuscular junction defect, and single-fiber electromyographic studies in limb muscles may yield normal results, although there is almost always increased jitter in the orbicularis oculi (Farrugia et al, in preparation).

Acetylcholine Receptor/Muscle-Specific Receptor Tyrosine Kinase Antibody–Negative Myasthenia Gravis Despite these advances, there remain approximately 10% of patients with typical generalized myasthenia gravis in whom no serum antibody is defined by a diagnostic test. There is experimental evidence for an IgM antibody that interferes with AChR function, but it is not clear whether it interacts via a signaling pathway47 or directly on the AChR. Other IgG antibodies may exist with similar specificity. These patients tend to have less severe symptoms and are more responsive to standard treatments than are the MuSK antibody–positive patients. Interestingly, the defects evident in single-fiber electromyography in limb muscles, their thymic pathology, and their response to thymectomy are more similar to those in patients with early-onset myasthenia gravis with AChR antibodies than to those seen in patients with myasthenia gravis and MuSK antibodies (M. I. Leite, N. Willcox, and A. Vincent, unpublished observations).

Treatment The basic principles for treatment of all the autoimmune disorders of the neuromuscular junction are outlined in Table 90–5. AChE inhibitors are the first-line treatment for a patient with myasthenia gravis. The most commonly used is pyridostigmine, which takes effect within 30 to 60 minutes but wears off within 3 to 4 hours and thus must be taken five times a day. The main side effects result from stimulation of the gastrointestinal tract, which can be minimized by starting with a small dose of propantheline and increasing it gradually if necessary. There is a theoretical risk of desensitization of the neuromuscular junction, with precipitation of a cholinergic crisis, if too much pyridostigmine is used. Treatments were reviewed by Pascuzzi (2004).4 The role of thymectomy has never been subjected to a randomized controlled trial, but analysis of previous studies suggests some benefit,48 and most clinicians recommend thymectomy for patients younger than 40 years who have AChR antibodies and some for patients up to 60 years of age. In the patients in whom thymectomy does not control symptoms or in whom it is not appropriate, the immunomodulatory drugs listed in Table 90–6 can be used. Steroids must be introduced slowly, because they may precipitate a myasthenic crisis if introduced at high dosages. Once symptoms are controlled, the corticosteroids are tapered to the lowest dosage that maintains pharmacological remission. Steroid-sparing agents are usually

chapter 90 neuromuscular junction disorders T A B L E 90–5. Agents Used in the Treatment of Different Neuromuscular Junction Disorders Pharmacological AChE inhibitors; avoid side effects with propantheline 3,4-Diaminopyridine to increase ACh release; can be helpful alone or in combination with AChE inhibitors Anticonvulsants (carbamazepine and phenytoin) for muscle hyperactivity in neuromyotonia Open-channel blockers (e.g., quinidine sulfate, fluoxetine) for slow channel syndrome Immunological Remove or treat tumor if present Plasma exchange, by removing circulating antibodies; provides shortterm improvement Thymectomy in patients younger than 60 if AChR antibody positive (not recommended in MuSK antibody–positive patients but may be helpful in AChR/MuSK antibody–negative patients) Intravenous immunoglobulin or immunoadsorption on a protein A column; are effective short-term treatments and may be the treatments of choice for some patients Immunosuppression with corticosteroids; start low, increase slowly until symptoms stabilize, taper slowly Azathioprine (takes >6 months to be effective) or mycophenolate mofetil (≈3 months) as steroid-sparing agents If poor response or intolerance, consider additional immunosuppression with cyclosporine, tacrolimus, cyclophosphamide ACh, acetylcholine; AChE, acetylcholinesterase; AChR, acetylcholine receptors; MuSK, muscle-specific receptor tyrosine kinase.

introduced to reduce the cumulative corticosteroid dose and associated complications.

THE LAMBERT-EATON MYASTHENIC SYNDROME Clinical Features and Diagnosis In 1957, Eaton and Lambert49 described a myasthenic syndrome with greatly reduced compound muscle action potential amplitudes after supramaximal nerve stimulation, which became even smaller at low rates of repetitive nerve stimulation (<10/second) but increased during stimulation at higher rates or after a few seconds of voluntary contraction. These findings were in contrast to those in myasthenia gravis, in which the compound muscle action potential is not usually reduced initially and fails to show an increment after high-frequency stimulation. The Lambert-Eaton myasthenic syndrome (LEMS) is associated with small cell lung cancer in about 50% of cases. Thus, LEMS is a member of the expanding family of paraneoplastic autoimmune conditions (see Chapter 101). LEMS is more common in men than in women. In contrast to myasthenia gravis, the weakness predominantly involves proximal limb muscles and nearly always initially affects the lower limbs, causing the characteristic “waddling gait.”50 Ocular symptoms can occur but are much less common than in myasthenia gravis. Reflexes are absent or depressed but may increase after voluntary contraction of the relevant muscle. Autonomic symptoms (dry mouth, constipation, impotence), if sought, are found to be present in most patients.51 LEMS is diagnosed from the clinical features, especially the improve-

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ment in strength after voluntary contraction, and confirmed by electromyographic findings and detection of antibodies to VGCCs in the serum. The neurological symptoms can precede the clinical appearance of the associated tumor by several years, and in patients at risk (e.g., smokers) it is mandatory to perform high-resolution imaging of the thorax regularly, especially in the first few years after diagnosis.

Etiology and Pathophysiology In vitro recordings from intercostal muscle biopsies of patients with LEMS revealed very small EPPs and shows that the number of packets of ACh released per nerve impulse was reduced.52 The EPPs increased during repetitive stimulation, probably because during high-frequency stimulation, Ca2+ accumulates in the nerve terminal, overcoming the reduced Ca2+ entry. Freeze-fracture electron microscope studies of motor nerve terminals in LEMS showed that the “active zone” particles, which are believed to represent VGCCs, are reduced in number and disorganized.53 Evidence of an autoimmune pathogenesis comes from clinical and experimental observations similar to those for myasthenia gravis: Lennon and associates54 found one or more organ-specific autoantibodies in almost one half of their series of 64 LEMS patients, particularly in patients without a tumor. There is an HLA B8 association in patients with LEMS without small cell lung cancer.55,56 Plasma exchange or intravenous immunoglobulin therapy leads to clinical and electrophysiological improvement, and most patients also respond to immunosuppressive drugs. Moreover, passive transfer of the patient’s plasma or immunoglobulins into experimental animals leads to changes in electrophysiology and structure of the neuromuscular junction that are very similar to those demonstrated in the patients with LEMS,57,58 and IgG can be detected on the presynaptic nerve terminal.59 The results of passive transfer were not dependent on complement activity but did require divalent antibodies, which suggests that the antibodies act by crosslinking and internalizing the antigen.59,60 VGCCs are transmembrane proteins comprising α1, β, and α2/δ subunits. The α1 subunit is believed to contain the central Ca2+-conducting channel. Several VGCC subtypes are known and may be present within a single neuron,61 but the use of neurotoxins derived from snail and spider venoms has made it possible to define the subtype of VGCC present at the neuromuscular junction. These VGCCs are blocked by ω-Conotoxin (ω-CmTx) MVIIC.62 Antibodies in LEMS patients are, therefore, detected by radioimmunoprecipitation of VGCCs extracted from rabbit or human cerebellum, prelabeled with 125I–ω-CmTx MVIIC.63 The binding sites of the anti-VGCC antibodies have not been mapped but probably include sites on the α1 subunit, because this appears to determine the channel subtype. LEMS IgG substantially reduced calcium currents through VGCCs expressing the α1 subtype but not through those expressing the other subtypes.64 Autonomic dysfunction is common in LEMS, which suggests that LEMS IgG may interfere with neurotransmission at autonomic synapses. Multiple subtypes of VGCC, including P, Q, N, and R types, are involved in the release of neurotransmitter in mouse bladder muscle and the vas deferens.65 Mice injected with LEMS IgG show reduced muscle tension as a result of reduced activity of the P-type VGCCs, with relatively little change in N-type VGCCs.66

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T A B L E 90–6. Immunomodulatory Drugs Used in the Treatment of Acquired Disorders of Neuromuscular Junction* Drug

Principal Action

Common Side Effects

Serious Side Effects

Monitoring

Prednisolone

Decreased production of cytotoxic T cells + many other poorly understood functions

Numerous, including poor sleep, excess sweating, acne, weight gain, indigestion, premature cataracts, tremor

Numerous, including osteoporosis, diabetes, fluid retention, hypertension, and mood change (can be severe depression or mania)

Azathioprine

Prodrug of 6mercaptopurine, which interrupts DNA + RNA production in lymphocytes, thus killing the cells

Nausea, vomiting, anorexia

Hypersensitivity reaction, abnormal liver function measurements, skin lesions, dose-related bone marrow suppression, increased risk of lymphoma

Cyclosporine

Calcineurin inhibitor that blocks T cell activation and growth by inhibiting cytokine release

Gum hyperplasia, increased body hair, tremor, nausea, vomiting

Hypertension, impaired renal function, hypercholesterolemia, increased risk of lymphoma

Methotrexate

Inhibits dihydrofolate reductase; thus affects all dividing cells

Nausea, vomiting, mouth ulcers

Bone marrow suppression, pulmonary fibrosis, hepatic fibrosis, infertility

Mycophenolate mofetil

Inhibits inosine monophosphate dehydrogenase; thus inhibits guanosine nucleotide synthesis

Nausea and diarrhea, mouth ulcers, tremor, dizziness

Bone marrow suppression, gastrointestinal hemorrhage, hypercholesterolemia, infertility, increased risks of lymphoma and skin cancer

Question patient about mood change Measure urine or serum glucose Measure weight Bone density scan Appropriate investigations if patient (especially if elderly) complains of gastrointestinal symptoms Consider checking thiopurine methyltransferase genotype status Weekly FBC and LFT for first 8 weeks, then every 3 months for duration of treatment Measure blood pressure and weight Assess renal function, FBC, and LFT every 2 weeks for first 3 months, then every 2 months for duration of treatment Pretreatment FBC, renal function measurement, LFT, and chest radiograph Folic acid to reduce toxicity Monthly FBC and LFT for duration of treatment Blood pressure Weekly FBC, glucose measurement, renal function tests, LFT for first 3 months and then monthly thereafter

Note: All drugs increase the risk of infections; patients should carry steroid cards if on prednisolone; patients should be warned about drug interactions, especially with methotrexate. FBC, full blood count; LFT, liver function tests.

Treatment Appropriate treatment of the associated tumor, if present, is essential and often improves the LEMS symptoms.67 3,4Diaminopyridine increases ACh release and produces symptomatic relief. In a double-blind crossover trial of eight patients with LEMS, intravenous immunoglobulin therapy resulted in the improvement of strength and in an associated decline in specific antibody.68 To attain pharmacological remission in the long term, many patients require regular immunomodulatory therapy (see Table 90–6).

ACQUIRED NEUROMYOTONIA Neuromyotonia, sometimes called Isaacs’ syndrome, is characterized by spontaneous and continuous muscle fiber contraction resulting from hyperexcitability of motor nerves. It may be part of a spectrum of diseases that includes cramp fasciculation

syndrome.69 Although rare, it is of particular interest because it may be associated with central nervous system symptoms.

Clinical Features and Diagnosis Patients most commonly present between the ages of 25 and 60 years with a variety of symptoms, including muscle stiffness, cramps, myokymia (visible undulation of muscle), pseudomyotonia, and weakness. Increased sweating is common. Myokymia characteristically continues during sleep and general anesthesia. A minority of patients have sensory symptoms, including transient or continuous paresthesia, dysesthesia, and numbness. The clinical presentation is heterogeneous both in terms of the predominant symptoms and their severity and in terms of the disease associations; about 20% of patients have a thymoma, occasional patients have a small cell lung cancer, and some patients have other autoimmune diseases.70 The diagnosis is confirmed by electromyography, which shows the characteristic spontaneous motor unit discharges

chapter 90 neuromuscular junction disorders that occur in distinctive doublets, triplets, or longer runs, with high intraburst frequency (40 to 300 per second). The abnormal muscle activity may be generated at different sites throughout the length of the nerve. In most cases, these sites are distal, but in others they may be proximal, perhaps even including the anterior horn cell (see Vincent71). On occasion, there is an associated sensory neuropathy. Antibodies to VGKCs are present in approximately 40% of patients and are more commonly present in patients with an associated thymoma.

Etiology and Pathophysiology Neuromyotonia may be associated with other autoimmune diseases or other autoantibodies, and cerebrospinal fluid analysis may reveal oligoclonal bands.70 Thymoma was found in 10 of 52 patients with neuromyotonia or cramp fasciculation syndrome.69 Seven of the patients with thymoma had myasthenia gravis and two others had raised anti-AChR antibody titers, as previously described by other authors.72 In addition, a few patients with bronchial carcinoma have developed neuromyotonia, and at least one of these had a small cell lung cancer. Evidence for an antibody-mediated pathology includes the beneficial results of plasma exchange,73 passive transfer of disease to mice,73,74 and effects of purified IgG on dorsal root ganglia cultures. The effects of IgG were, in each case, very similar to those obtained with low concentrations of the VGKC blockers, 4-amino-pyridine or 3,4-diaminopyridine,74 which suggests that the potassium channel was a likely target for the autoantibodies. A functional VGKC consists of four transmembrane α subunits that combine as homomultimeric and heteromultimeric tetramers.75 At least eight VGKC α subunits have been identified, and each is encoded by a different gene. VGKCs of the subtypes Kv1.1 and Kv1.2 are highly expressed in the peripheral nervous system (and also in the central nervous system). Antibodies to VGKCs can be detected in about 40% of patients with neuromyotonia by radioimmunoprecipitation of 125I–αdendrotoxin–labeled VGKCs extracted from human frontal cortex.69,73 The 60% of sera negative for these antibodies may contain antibodies to some other (as yet unidentified) peripheral nerve or motor nerve terminal protein. Central nervous system symptoms such as insomnia, hallucinations, delusions, and personality changes may also be present in patients with neuromyotonia. In some particularly rare cases, there are additional autonomic features, such as constipation, cardiac irregularities, and increased sweating. When peripheral, autonomic, and central nervous system symptoms are present, neuromyotonia is sometimes called Morvan’s syndrome.76 Increasingly common, in contrast, are patients presenting without obvious peripheral involvement but with a nonparaneoplastic form of limbic encephalitis associated with high levels of VGKC antibodies77 (C. Buckley, L. Clover, and A. Vincent, unpublished observations). In contrast to the other two main autoimmune disorders of the neuromuscular junction, there are anecdotal reports of neuromyotonia, Morvan’s syndrome, or limbic encephalitis occurring in association with infections, and some patients seem to have a monophasic illness that recovers spontaneously within 1 to 2 years.78 These observations suggest that there may be infections, as well as thymomas and small cell lung cancers, that can predispose to development of the antibodies and a range of peripheral, autonomic, and central nervous system dysfunction.

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Treatment Symptomatic relief can be obtained with the anticonvulsant drugs carbamazepine and phenytoin, which are believed to act by reducing nerve hyperexcitability. Some patients remain disabled by their symptoms despite these measures, in which case immunomodulatory therapies (see Table 90–6) can be used, although with more caution than in the other neuromuscular junction disorders, because neuromyotonia is not life-threatening. Plasma exchange can be effective,73 and intravenous immunoglobulins have also been useful in some patients.

CONGENITAL MYASTHENIC SYNDROMES Congenital myasthenic syndromes (CMSs) constitute a heterogeneous group of rare inherited disorders that result from mutations in different key proteins at the neuromuscular junction (reviewed by Engel et al, 200379). These disorders account for probably around 2% of all myasthenias; AChR deficiency is most common, with a prevalence of approximately 3 per one million. The main disorders identified so far are summarized in Table 90–7, in order of their frequency in the United Kingdom population. Other, even rarer types of CMS exist, and in some of these (e.g., limb girdle CMS), the genetic defect remains elusive. Apart from slow channel syndrome, all the CMSs demonstrate recessive inheritance. Most patients present at birth or in early childhood with ptosis, poor suck and feeding problems, and delayed motor milestones. However, some patients with CMS do not present until adolescence or young adulthood, and their condition may thus be mistaken for autoimmune seronegative myasthenia gravis. Several of the CMSs have characteristic features such as arthrogryposis multiplex congenita (rapsyn mutations), marked ophthalmoplegia (AChR ε-subunit mutations) or apnea attacks (choline acetyltransferase or rapsyn mutations). However, remarkable differences in severity or age of onset can be seen, even in patients with the same genetic mutation. AChR deficiency syndromes are treated with AChE inhibitors, often with the addition of 3,4-diaminopyridine (see Table 90–5). Regimens are tailored to the individual, because response to treatment can be unpredictable. In autosomal dominant slow channel syndrome, the AChR openings are prolonged, resulting in excess entry of ions and progressive excitotoxic damage to the neuromuscular junction. Openchannel blockers such as quinidine sulfate and fluoxetine may be appropriate for long-term treatment.80 There are no specific treatments for CMS involving mutations in ColQ (AChE deficiency), but supportive care is essential because many patients develop restrictive ventilatory defects.

CONCLUSIONS AND RECOMMENDATIONS The autoimmune disorders are not very common, but their incidence appears to be increasing with the increasing age of the population and improved diagnosis, and they are treatable diseases that can be misdiagnosed as stroke or motor neuron disease, particularly among older patients. The diagnosis rests on the clinical manifestations and examination but is increasingly confirmed by highly specific autoantibody tests. Nevertheless, in each autoimmune system–mediated neuromuscular junction disease, there are patients with classic symptoms who are “seronegative” for the appropriate autoantibodies. Thymec-

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T A B L E 90–7. Congenital Myasthenic Syndromes Target

Presentation

Prognosis

Treatment

AChR deficiency

AChR, mainly ε subunit

Good; may improve with age

AChE inhibitors and 3,4diaminopyridine

AChR deficiency

AChR-clustering protein, rapsyn

Good; early-onset patients improve with age

AChE inhibitors and 3,4diaminopyridine

Slow channel syndrome AChE deficiency

AChR subunits

Within first 2 years of life, marked ptosis and ophthalmoplegia At birth with arthrogryposis and episodic exacerbations with infections, or in adulthood Any time from early childhood to adulthood Usually early childhood

Progressive weakness and wasting common Variable phenotypical expressivity; may progress

Choline acetyltransferase deficiency

Enzyme that synthesizes acetylcholine

Quinidine sulfate and fluoxetine can be helpful Supportive management only Treatment with AChE inhibitors may be deleterious AChE inhibitors can be lifesaving

ColQ, which anchors AChE at the NMJ

Usually early childhood with episodic apnea

Good as long as treated during apneic attacks

AChE, acetylcholinesterase; AChR, acetylcholine receptors; ColQ, collagen tail of AChE; NMJ, neuromuscular junction.

tomy is widely used only in the patients with early-onset disease, and immunosuppression with steroids and steroidsparing agents are required by most patients with generalized weakness. Similar treatment strategies can be used for LEMS and neuromyotonia, although the latter often respond adequately to antiepileptic drugs. Although the CMSs are rare, awareness of them will prevent inappropriate immunological therapy and, in some infants, allow rapid introduction of treatment that can be lifesaving.

K E Y

P O I N T S

●

The neuromuscular junction is a prototype synapse that is accessible to circulating factors.

●

There are neurotoxic, autoimmune, and genetic disorders of the neuromuscular junction.

●

The main targets are presynaptic or postsynaptic ion channels, proteins involved in maintaining their localization, or specific enzymes.

●

These diseases manifest most often with weakness, usually without obvious wasting, but muscle hyperactivity and pseudomyotonia can be present.

●

Weakness and fatigue result from a failure of the EPP to reach the threshold for firing an action potential.

●

Drugs that modify the EPP amplitude are used to alleviate the symptoms of both autoimmune and genetic neuromuscular junction disorders.

●

The autoimmune disorders can often be diagnosed by detection of an autoantibody in the serum and can be treated with nonspecific immunotherapies.

●

The congenital disorders can be diagnosed by DNA analysis, but specific genetic therapies are not yet available.

Suggested Reading Engel AG, Ohno K, Sine SM: Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci 2003; 4:339-352. Mareska M, Gutmann L: Lambert-Eaton myasthenic syndrome. Semin Neurol 2004; 24:149-153. Newsom-Davis J: Neuromyotonia. Rev Neurol (Paris) 2004; 160(5, Pt 2):S85-S89. Pascuzzi RM: Myasthenia gravis. Semin Neurol 2004; 24:1-133. Vincent A: Unravelling the pathogenesis of myasthenia gravis. Natl Rev Immunol 2002; 2:797-804.

References 1. Fambrough DM, Drachman DB, Satyamurti S: Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science 1973; 182:293-295. 2. Patrick J, Lindstrom J: Autoimmune response to acetylcholine receptor. Science 1973; 180:871-872. 3. Lindstrom JM, Seybold ME, Lennon VA, et al: Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976; 26:10541059. 4. Pascuzzi RM: Myasthenia gravis. Semin Neurol 2004; 24:1-133. 5. Engel AG: Myasthenia gravis and myasthenic syndromes. Ann Neurol 1984; 16:519-534. 6. Unwin N: The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission. Philos Trans R Soc Lond B Biol Sci 2000; 355:1813-1829. 7. Tzartos SJ, Barkas T, Cung MT, et al: Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol Rev 1998; 163:89120. 8. Tzartos SJ, Seybold ME, Lindstrom JM: Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies. Proc Natl Acad Sci U S A 1982; 79:188-192. 9. Newsom-Davis J, Pinching AJ, Vincent A, et al: Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange. Neurology 1978; 28:266-272.

chapter 90 neuromuscular junction disorders 10. Vincent A, Newsom-Davis J, Newton P, et al: Acetylcholine receptor antibody and clinical response to thymectomy in myasthenia gravis. Neurology 1983; 33:1276-1282. 11. Kuks JB, Oosterhuis HJ, Limburg PC, et al: Anti-acetylcholine receptor antibodies decrease after thymectomy in patients with myasthenia gravis. Clinical correlations. J Autoimmun 1991; 4:197-211. 12. Toyka KV, Brachman DB, Pestronk A, et al: Myasthenia gravis: passive transfer from man to mouse. Science 1975; 190:397399. 13. Stanley EF, Drachman DB: Effect of myasthenic immunoglobulin on acetylcholine receptors of intact mammalian neuromuscular junctions. Science 1978; 200:1285-1287. 14. Burges J, Wray DW, Pizzighella S, et al: A myasthenia gravis plasma immunoglobulin reduces miniature endplate potentials at human endplates in vitro. Muscle Nerve 1990; 13:407413. 15. Ruff RL, Lennon VA: End-plate voltage-gated sodium channels are lost in clinical and experimental myasthenia gravis. Ann Neurol 1998; 43:370-379. 16. Plomp JJ, Van Kempen GT, De Baets MB, et al: Acetylcholine release in myasthenia gravis: regulation at single end-plate level. Ann Neurol 1995; 37:627-636. 17. Guyon T, Levasseur P, Truffault F, et al: Regulation of acetylcholine receptor alpha subunit variants in human myasthenia gravis. Quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction. J Clin Invest 1994; 94:16-24. 18. Vincent A, Clover L, Buckley C, et al: Evidence of underdiagnosis of myasthenia gravis in older people. J Neurol Neurosurg Psychiatry 2003; 74:1105-1108. 19. Compston DA, Vincent A, Newsom-Davis J, et al: Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 1980; 103:579-601. 20. Sommer N, Melms A, Weller M, et al:, Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects. Doc Ophthalmol 1993; 84:309-333. 21. Kaminski HJ, Richmonds CR, Kusner LL, et al: Differential susceptibility of the ocular motor system to disease. Ann N Y Acad Sci 2002; 956:42-54. 22. Vieira ML, Caillat-Zucman S, Gajdos P, et al: Identification by genomic typing of non-DR3 HLA class II genes associated with myasthenia gravis. J Neuroimmunol 1993; 47:115-122. 23. Carlsson B, Wallin J, Pirskanen R, et al: Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis. Immunogenetics 1990; 31:285-290. 24. Hohlfeld R, Wekerle H: The role of the thymus in myasthenia gravis. Adv Neuroimmunol 1994; 4:373-386. 25. Scadding GK, Vincent A, Newsom-Davis J, et al: Acetylcholine receptor antibody synthesis by thymic lymphocytes: correlation with thymic histology. Neurology 1981; 31:935-943. 26. Schluep M, Willcox N, Vincent A, et al: Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol 1987; 22:212-222. 27. Roxanis I, Micklem K, McConville J, et al: Thymic myoid cells and germinal center formation in myasthenia gravis; possible roles in pathogenesis. J Neuroimmunol 2002; 125:185-197. 28. Meager A, Vincent A, Newsom-Davis J, et al: Spontaneous neutralising antibodies to interferon-alpha and interleukin-12 in thymoma-associated autoimmune disease. Lancet 1997; 350:1596-1597. 29. Buckley C, Newsom-Davis J, Willcox N, et al: Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology 2001; 57:1579-1582. 30. Muller-Hermelink HK, Marx A: Towards a histogenetic classification of thymic epithelial tumours? Histopathology 2000; 36:466-469.

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31. Aarli JA: Titin, thymoma, and myasthenia gravis. Arch Neurol 2001; 58:869-870. 32. Ohta M, Ohta K, Itoh N, et al: Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a Western blotting analysis. Clin Chim Acta 1990; 187:255-264. 33. Aarli JA, Stefansson K, Marton LS, et al: Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin. Clin Exp Immunol 1990; 82:284-288. 34. Gautel M, Lakey A, Barlow DP, et al: Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin. Neurology 1993; 43:1581-1585. 35. Palmisani MT, Evoli A, Batocchi AP, et al: Myasthenia gravis associated with thymoma: clinical characteristics and longterm outcome. Eur Neurol 1994; 34:78-82. 36. Somnier FE: Exacerbation of myasthenia gravis after removal of thymomas. Acta Neurol Scand 1994; 90:56-66. 37. Buckley C, Douek D, Newsom-Davis J, et al: Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol 2001; 50:64-72. 38. Morel E, Eymard B, Vernet-der Garabedian B, et al: Neonatal myasthenia gravis: a new clinical and immunologic appraisal on 30 cases. Neurology 1988; 38:138-142. 39. Riemersma S, Vincent A, Beeson D, et al: Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function. J Clin Invest 1996; 98:2358-2363. 40. Mossman S, Vincent A, Newsom-Davis J: Myasthenia gravis without acetylcholine-receptor antibody: a distinct disease entity. Lancet 1986; 1:116-119. 41. Hoch W, McConville J, Helms S, et al: Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 7:365-368. 42. McConville J, Farrugia ME, Beeson D, et al: Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55:580-584. 43. Evoli A, Tonali PA, Padua L, et al: Clinical correlates with antiMuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003; 126(Pt 10):2304-2311. 44. Sanders DB, El-Salem K, Massey JM, et al: Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003; 60:1978-1980. 45. Lauriola L, Ranelletti F, Maggiano N, et al: Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 2005; 64:536-538. 46. Leite MI, Strobel P, Jones M, et al: Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol 2005; 57:444-448. 47. Plested CP, Tang T, Spreadbury I, et al: AChR phosphorylation and indirect inhibition of AChR function in seronegative MG. Neurology 2002; 59:1682-1688. 48. Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55:7-15. 49. Eaton LM, Lambert EH: Electromyography and electric stimulation of nerves in diseases of motor unit; observations on myasthenic syndrome associated with malignant tumors. J Am Med Assoc 1957; 163:1117-1124. 50. Wirtz PW, Sotodeh M, Nijnuis M, et al: Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2002; 73:766-768. 51. Oh SJ: The Eaton-Lambert syndrome. Report of a case. Arch Neurol 1972; 27:91-94.

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52. Lambert EH, Elmqvist D: Quantal components of end-plate potentials in the myasthenic syndrome. Ann N Y Acad Sci 1971; 183:183-199. 53. Engel AG: Review of evidence for loss of motor nerve terminal calcium channels in Lambert-Eaton myasthenic syndrome. Ann N Y Acad Sci 1991; 635:246-258. 54. Lennon VA, Lambert EH, Whittingham S, et al: Autoimmunity in the Lambert-Eaton myasthenic syndrome. Muscle Nerve 1982; 5:S21-S25. 55. Demaine A, Willcox N, Welsh K, et al: Associations of the autoimmune myasthenias with genetic markers in the immunoglobulin heavy chain region. Ann N Y Acad Sci 1988; 540:266-268. 56. Wirtz PW, Willcox N, van der Slik AR, et al: HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome. J Neuroimmunol 2005; 159:230-237. 57. Lang B, Newsom-Davis J, Prior C, et al: Antibodies to motor nerve terminals: an electrophysiological study of a human myasthenic syndrome transferred to mouse. J Physiol 1983; 344:335-345. 58. Engel AG, Nagel A, Fukuoka T, et al: Motor nerve terminal calcium channels in Lambert-Eaton myasthenic syndrome. Morphologic evidence for depletion and that the depletion is mediated by autoantibodies. Ann N Y Acad Sci 1989; 560:278290. 59. Fukuoka T, Engel AG, Lang B, et al: Lambert-Eaton myasthenic syndrome: I. Early morphological effects of IgG on the presynaptic membrane active zones. Ann Neurol 1987; 22:193199. 60. Fukuoka T, Engel AG, Lang B, et al: Lambert-Eaton myasthenic syndrome: II. Immunoelectron microscopy localization of IgG at the mouse motor end-plate. Ann Neurol 1987; 22:200211. 61. Tsien RW, Fox AP, Hess P, et al: Multiple types of calcium channel in excitable cells. Soc Gen Physiol Ser 1987; 41:167187. 62. Protti DA, Reisin R, Mackinley TA, et al: Calcium channel blockers and transmitter release at the normal human neuromuscular junction. Neurology 1996; 46:1391-1396. 63. Motomura M, Johnston I, Lang B, et al: An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995; 58:85-87. 64. Pinto A, Gillard S, Moss F, et al: Human autoantibodies specific for the α1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons. Proc Natl Acad Sci U S A 1998; 95:8328-8333. 65. Waterman SA: Multiple subtypes of voltage-gated calcium channel mediate transmitter release from parasympathetic neurons in the mouse bladder. J Neurosci 1996; 16:4155-4161.

66. Waterman SA, Lang B, Newsom-Davis J: Effect of LambertEaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 1997; 42:147-156. 67. Chalk CH, Murray NM, Newsom-Davis J, et al: Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology 1990; 40:15521556. 68. Bain PG, Motomura M, Newsom-Davis J, et al: Effects of intravenous immunoglobulin on muscle weakness and calciumchannel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996; 47:678-683. 69. Hart IK, Maddison P, Newsom-Davis J, et al: Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 2002; 125:1887-1895. 70. Newsom-Davis J, Mills KR: Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Report of five cases and literature review. Brain 1993; 116(Pt 2):453469. 71. Vincent A: Understanding neuromyotonia. Muscle Nerve 2000; 23:655-657. 72. Halbach M, Homberg V, Freund HJ: Neuromuscular, autonomic and central cholinergic hyperactivity associated with thymoma and acetylcholine receptor–binding antibody. J Neurol 1987; 234:433-436. 73. Sinha S, Newsom-Davis J, Mills K, et al: Autoimmune aetiology for acquired neuromyotonia (Isaacs’ syndrome). Lancet 1991; 338:75-77. 74. Shillito P, Molenaar PC, Vincent A, et al: Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Ann Neurol 1995; 38:714-722. 75. Wang H, Kunkel DD, Martin TM, et al: Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature 1993; 365:75-79. 76. Liguori R, Vincent A, Clover L, et al: Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001; 124:2417-2426. 77. Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127(Pt 3):701-712. 78. Buckley C, Oger J, Clover L, et al: Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 2001; 50:73-78. 79. Engel AG, Ohno K, Sine SM: Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Natl Rev Neurosci 2003; 4:339-352. 80. Harper CM, Fukodome T, Engel AG: Treatment of slow-channel congenital myasthenic syndrome with fluoxetine. Neurology 2003; 60:1710-1713.

CHAPTER

91

BACTERIAL MENINGITIS ●

●

●

●

John E. Greenlee

Meningitis has long been known as a clinical disorder. Unequivocal descriptions of meningitis date to the seventeenth century,1 and tuberculous meningitis and syphilitic meningitis have been known as discreet entities for nearly as long.2 In contrast, Lyme disease is a much more recently recognized entity. Prior to the advent of antibiotics, bacterial and tuberculous meningitis were, with very rare exceptions, fatal disorders, and even today, despite antibiotic therapy, both entities carry significant mortality and appreciable morbidity. The spirochetal meningitides, in contrast, usually pursue a more protracted course, and although both syphilitic or Lyme meningitis may result in significant neurological impairment, death from either condition is unusual. At present, meningitis is an area of both exciting progress and significant challenges: exciting, because the introduction of conjugate vaccines for Haemophilus influenzae has led to the almost complete disappearance of that agent as a cause of meningitis in small children, because similar hope of effective vaccines exists for other agents, and because we are beginning to understand early events in meningitis which lead to death or severe neurological injury. Challenges exist, however, because bacterial and tuberculous meningitis remain conditions with significant morbidity and mortality, and because changes in antibiotic susceptibility may considerably complicate early therapy. This chapter is divided into two sections. The first of these will deal with acute bacterial meningitis as it exists as a diagnostic and therapeutic problem for clinicians. The second part will deal with the less common meningitides associated with tuberculosis, syphilis, and Lyme disease.

BACTERIAL MENINGITIS Epidemiology Approximately 15,000 cases of acute bacterial meningitis occur in the United States each year.3 The overall incidence of acute bacterial meningitis has fallen over time, however, largely due to the sharp decline in early childhood cases of H. influenzae meningitis. Schlech,4 in a review of cases of meningitis in 27 states from 1978 through 1981, noted an incidence of three cases per 100,000 of population. In contrast, Shuchat and colleagues,1 in a study encompassing acute care hospitals in 22 counties of four states, found a decline in cases of meningitis

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from 2.9 cases per 100,000 population in 1986 to 0.2 case in 1995. In earlier studies, the most common organisms, in descending order, were H. influenzae, Neisseria meningitidis, and Streptococcus pneumoniae. By the time of Shuchat’s report, H. influenzae accounted for only 0.2% of cases. Prior to the advent of conjugated vaccines for H. influenzae type B (Hib), the median age of meningitis cases was 15 months, whereas by 1995 the median age had risen to 25 years.1 Meningitis in developed countries has thus changed from being a disease of infants to a disease of older adults. This is in sharp contrast to developing countries in which immunization against Hib has not been used: there, as in Western countries before the advent of Hib vaccination, meningitis remains a disease of early childhood, with the greatest number of cases occurring in children from 6 months to 2 years of age.5-7 A trend worldwide over this same period of time has been the emergence of clusters of meningococcal meningitis and meningococcemia, in particular within sub-Saharan Africa, with over 300,000 cases and 30,000 deaths.8 A key event in these outbreaks has been the introduction of virulent strains of meningococci into populations without strain-specific antibody.

Causative Agents The agents causing bacterial meningitis vary with both the age of the patient (Table 91–1) and with the route by which infection is acquired (Table 91–2).

Causative Agents of Meningitis by Patient Age The most common cause of bacterial meningitis in neonates and infants is Streptococcus agalactiae (group B streptococci), followed in order of frequency by E. coli, other gram-negatives, and L. monocytogenes1,9 (see Table 91–1). Meningitis due to S. agalactiae occurs at two points in time: within the first 48 hours of the postnatal period or between 7 days and 6 weeks of age.10 Cases occurring in the immediate postnatal period represent acquisition of the agent from the mother at the time of birth, and meningitis often occurs as part of a systemic infection; cases in older infants more frequently occur as an isolated meningitis. Less common agents include Listeria monocytogenes, Staphylococcus epidermidis, Staphylococcus aureus, and S. pneumoniae. Listeria and S. aureus are discussed later. Prior to the development of an effective vaccine, H. influenzae

chapter 91 bacterial meningitis T A B L E 91–1. Agents of Acute Bacterial Meningitis According to Patient Age Age

Agent

Neonates

Streptococcus agalactiae: in particular type III E. coli and other gram-negative organisms (Proteus mirabilis, Klebsiella, Enterobacter sp., Pseudomonas aeruginosa, Citrobacter diversus, Salmonella sp.) Listeria monocytogenes Staphylococcus epidermidis Staphylococcus aureus S. pneumoniae N. meningitidis S. pneumoniae S. aureus S. pneumoniae S. aureus S. pneumoniae S. aureus L. monocytogenes Gram-negatives

Childhood-early adulthood Mid-adulthood Old age

T A B L E 91–2. Agents of Acute Bacterial Meningitis According to Route of Acquisition Condition

Probable Organism(s)

Sinusitis or otitis

S. pneumoniae, H. influenzae, microaerophilic and anaerobic streptococci, Bacteroides, S. aureus S. aureus

Penetrating head trauma Shunt infections Complications of neurosurgery

S. epidermidis Gram-negative bacteria (Klebsiella pneumonia, Acinetobacter calcoaceticus-baumannii complex, E. coli)

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and gram-negatives may cause meningitis in the setting of neurosurgical procedures.

Causative Agents in Immunocompromised Patients The organisms associated with bacterial meningitis in immunocompromised patients vary with the type of immune deficiency. Individuals with defects of cell-mediated immunity, as in AIDS or Hodgkin disease, have an increased prevalence of meningitis due to L. monocytogenes.13-15 Patients with defects of humoral immune response⎯and patients who have undergone splenectomy⎯are prey to fulminant meningitis with S. pneumoniae, H. influenzae type B, and, less frequently N. meningitidis. Patients with neutropenia are susceptible to meningitis caused by Pseudomonas aeruginosa and by gramnegative enteric bacteria.16

Meningitis Due to L. monocytogenes and S. aureus These agents deserve specific comment. L. monocytogenes differs from the other organisms previously listed in that it is an obligate intracellular parasite whose control depends on T cell–mediated immunity as well as opsonization. For this reason, L. monocytogenes appears as a cause of meningitis in three groups of patients: very young infants, especially in the setting of prematurity; patients who are immunocompromised; and the very elderly.17 S. aureus is the major agent associated with meningitis in patients with penetrating head trauma.16 In addition, however, S. aureus is a cause of meningitis in a minority of patients of all ages. Conditions in which S. aureus meningitis is particularly likely include known meningitis in the setting of endocarditis, intravenous drug abuse, burns, or superficial or deep abscesses or decubiti.

Pathogenesis and Pathology type B was the most common cause of meningitis below the age of 6 and the most common organism overall in total number of cases. Today, H. influenzae is rarely associated with meningitis in the United States or western Europe.1,9 In areas where vaccination is not yet widely used, however, H. influenzae remains a major cause of disease. Meningitis in older children and young adults is usually caused by N. meningitidis or, less frequently, S. pneumoniae. In older adults, S. pneumoniae causes over 50% of cases, with the incidence of meningitis due to gram-negatives, Listeria, and S. aureus rising in later life.

Causative Agents According to Route of Infection Here, meningitis is the result of extension or introduction of organisms into the subarachnoid space, by spread through emissary veins from infected sinuses or other cranial structures, penetrating trauma, or neurosurgical procedures (see Table 91–2). The most common agent associated with cases of sinusitis or otitis is S. pneumoniae. In this setting, H. influenzae may cause meningitis in adults as well as children, and infection may also be caused by anaerobic or microaerophilic organisms or by S. aureus.11 S. aureus is particularly associated with penetrating trauma. S. epidermidis tends to be associated with infection of ventricular shunts.12 S. aureus, S. epidermidis,

The pathogenesis of bacterial meningitis involves three separate steps: colonization of the host, entry of bacteria across the blood-brain barrier, and development of infection within the subarachnoid space and ventricular system. Once established, bacteria may invade the central nervous system to cause meningitis via one of three routes. In the majority of cases of meningitis, colonization of the nasopharynx is a key initial event.18 Studies by Kim and coworkers19 indicate that entry of E. coli across the blood-brain barrier requires a high level of bacteremia, followed by entry of the organism into brain microvascular endothelial cells and movement across these cells into the subarachnoid space. Less frequently, meningitis may be caused by direct spread of agents from infected pericranial structures such as sinuses, middle ear, or mastoid via emissary veins. Bacteria may also enter the subarachnoid space directly, either through introduction of bacteria during penetrating trauma or, occasionally, via entry of organisms through congenital or acquired defects in the skull or spinal column.20-22 The ability of blood-borne bacteria to invade the meninges is determined to a considerable degree by properties of the bacterium itself, and many of the organisms associated with meningitis have a particular ability to adhere to mucous membranes, promoting their entry into the host’s bloodstream.20,23 Thus, most cases of S. agalactiae meningitis are associated with type III organisms; the majority of cases of E. coli meningitis

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Section

XVI

Infections and Granulomatous Diseases

are caused by those bearing the K1 capsular antigen24; virtually all cases of H. influenzae meningitis are caused by type b strains; and many cases of meningococcal meningitis are associated with those bearing groups B and C antigens. The reasons for the association of these serotypes with meningitis are not completely understood, but in each of these cases, the bacterial capsule contains sialic acid, making the organisms more closely resemble host cell surfaces; furthermore, there is antigenic cross-reactivity between the K100 antigen of E. coli, the capsular antigens of H. influenzae b, and those of group B N. meningitidis.20,23,25 Although more than 90 strains of S. pneumoniae are known to exist, only 18 of these are commonly associated with meningitis. Despite pathogenesis studies extending back over 50 years, the actual routes by which bacteria penetrate the blood-brain barrier are still not fully defined. S. pneumoniae has been shown in vitro to bind to isolated human endothelial cells and to be detected in vacuoles within cells, suggesting that the organism may cross the blood-brain barrier via transcellular spread. Work in experimental animals with both E. coli and N. meningitidis suggests that binding of bacterial fimbriae is important in adherence of organisms to the luminal surfaces of brain microvascular endothelial cells. Transformation of organisms to nonfimbriated forms may then enhance transmural spread into the subarachnoid space.19,20,23 In vitro data suggest that neuroinvasion by E. coli involves interaction of bacterial proteins with cellular proteins present in brain but not systemic endothelia.19,26,27 In addition, certain brain regions, such as the choroid plexus, lack tight junctions, and meningitis of hematogenous origin might also begin with the entry of bacteria into brain ventricles across these structures. This hypothesis is supported both by morphological studies and by the frequent occurrence of ventriculitis as a concomitant of meningitis.28 Once within the subarachnoid space, bacteria multiply in an environment that is devoid of complement or leukocytes, and the initial stage of meningitis is essentially noninflammatory.28 Endotoxin, teichoic acid, and other products released from bacteria, however, elicit a brisk inflammatory response. This response includes not only leukocytes but also tumor necrosis factor and other chemical mediators of inflammation that alter blood-brain barrier permeability. Cerebrospinal fluid (CSF) protein concentrations rise and glucose characteristically falls, due not only to consumption of glucose by bacteria but also to altered transport of glucose across brain capillaries. Inflammation within the subarachnoid space is often accompanied by cortical encephalitis and ventriculitis, at times with hydrocephalus. Spread of inflammation into superficial areas of the brain may result in thrombosis of superficial cerebral vessels.29,30 This combination of factors results in vasogenic as well as cytotoxic cerebral edema, often complicated by arterial, venous, and capillary thrombosis, resulting in focal infarction, hemorrhage, or both. Death during the acute stages of bacterial meningitis is almost always due to brain herniation, resulting from cerebral edema and, in some cases, accompanying hydrocephalus. Delayed death or neurological disability in meningitis results from the combined effects of direct brain involvement, vascular compromise, and elevated intracranial pressure. In the process, any of several cranial nerves may be affected, in particular cranial nerve VIII. A major challenge in bacterial meningitis is that antibiotic therapy has no immediate effect on this cascade of events.

Meningitis is often viewed as a disease involving solely the meninges and, in some cases, the ventricular ependyma. The disease, however, is considerably more complex and destructive and may include communicating or obstructive hydrocephalus, cerebritis, vasculitis with axonal injury and/or arterial or venous infarcts, and actual myelitis.30-32 Actual cortical abscesses have been described in gram-negative meningitis and also may occur in cases of meningitis due to other disorders. Suppurative labyrinthitis has been described in experimental S. pneumoniae meningitis and may account for the hearing loss seen in meningitis. S. pneumoniae meningitis may also be accompanied by myelitis.30

Clinical Features Bacterial meningitis typically presents in one of three ways.33,34 Most commonly, meningitis is preceded by 3 to 5 days of insidiously progressive symptoms of fever, malaise, irritability, or vomiting. In a smaller number of cases, meningitis develops over 1 to 2 days. In a minority of cases, bacterial meningitis begins fulminantly and may be so rapid that it remains one of the few neurological conditions capable of causing death within hours in an otherwise healthy young person. Typical symptoms are fever, headache, photophobia, and changes in mental status. Patients may or may not complain of neck stiffness, and some patients, in particular those with meningitis due to S. aureus, may complain of back pain. Seizures may occur early in meningitis in up to 40% of affected children and may also occur in adults. Presentation with focal seizures or focal neurological symptoms, however, should raise concern of brain abscess or other localized process. Physical examination typically reveals fever, tachycardia, and nuchal rigidity.16,33 Many patients will also have altered mental status. Presentation in coma, seen in up to 12% of patients, is an ominous prognostic sign. Papilledema may be present in severe cases. Papilledema develops over time (often over 24 hours), however, and the rapid progression of meningeal infection may result in severely increased intracranial pressure before papilledema has had a chance to appear. In many patients, evidence of systemic infection is also present. Particular attention should be paid to identifying cutaneous rashes, petechiae, or purpura suggestive of meningococcemia, pulmonary consolidation, which may be present in S. pneumoniae meningitis, or cardiac murmurs suggesting endocarditis.

Tests of Meningeal Irritation The classic tests for bacterial meningitis are resistance to passive flexion of the neck (nuchal rigidity), Kernig’s sign, and Brudzinski’s sign. Kernig’s sign represents resistance to passive extension of the leg at the knee. Brudzinski developed several tests of meningeal irritation, but the maneuver most commonly referred to as Brudzinski’s sign involves spontaneous flexion of the hips and knees when the neck is passively flexed. Both signs are strongly suggestive of meningeal irritation. Brudzinski’s sign is the more sensitive of the two, in particular where the observer takes pain to note even a slight degree of spontaneous flexion. Both signs, however, were developed long prior to the advent of antibiotic therapy, when meningitis was frequently advanced at the time of presentation, and both may be absent early in the course of illness. In awake patients, a

chapter 91 bacterial meningitis more sensitive test is to ask the patient to put the chin on the chest with the mouth closed, because patients experiencing pain on flexion may hold the neck still but touch the chin to the chest by opening the jaw widely. Perhaps the most sensitive test of nuchal rigidity is a test developed during days of epidemic polio and involves asking the patient either to kiss the knee or to touch his or her forehead to the knee: this test will often detect meningeal irritation at a time when the other tests are negative. One should keep in mind that very elderly patients with extensive cervical spine disease may have neck stiffness, and occasional patients with influenza and severe myalgias may also complain of neck pain. In both cases, pain and resistance to movement occur not only on flexion but also on turning the head, whereas in meningitis, one can usually turn the head even if neck stiffness to flexion is present.

detectable signs. Meningitis may also be deceptively asymptomatic in the elderly, and the only sign of meningitis may be confusion in a previously alert older patient or altered responsiveness in a patient who is already demented.35,36 In these patients, threshold for lumbar puncture should also be low. However, alcoholics and elderly patients are also at risk for falls and subdural hematomas; and immunosuppressed patients may also have brain abscesses or other space-occupying lesions. In such patients, it may thus be prudent to begin appropriate antibiotics presumptively and obtain appropriate head imaging (magnetic resonance imaging [MRI] or head computed tomography [CT] scanning) before performing the lumbar puncture. The onset of bacterial meningitis following neurosurgical procedures may also be insidious, developing over hours or days. Patients in this setting are at increased risk, because alteration of consciousness or neck stiffness may be attributed to the preceding surgical intervention, and CSF cell count and chemistries are often altered by the preceding surgery.

Atypical Presentations of Meningitis Signs of meningeal irritation are often absent in four groups of patients: neonates, immunocompromised patients, the elderly, and patients with meningitis related to neurosurgical procedures.16 Neonates often do not exhibit nuchal rigidity, and the presence of meningitis may be signaled only by tachypnea, apneic spells, changes in heart rate, atypical seizures, or simply vague decline.10 The typical high-pitched “meningeal cry” may or may not be present. Similarly, the presence of a bulging fontanel is a late sign, indicating significantly increased intracranial pressure. Because the presentation of meningitis in neonates and infants may be so atypical, the threshold for lumbar puncture must be very low. Immunocompromised individuals, like neonates, may not develop fever or nuchal rigidity. Alcoholics, in particular those presenting in the setting of severe inebriation, may also have meningitis without clearly

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Diagnosis Bacterial meningitis is suspected on the basis of clinical presentation and physical findings. MRI may show cortical meningeal or meningovascular enhancement (Fig. 91–1). Definitive diagnosis, however, is almost always made on the basis of lumbar puncture. Bacterial meningitis usually produces diffuse meningeal involvement, so that relatively little brain shift may occur, even when intracranial pressure is significantly increased. Brain herniation may occur, however, if intracranial pressure is greatly increased, and the likelihood of fatal herniation cannot be predicted from CT.37,38 In severely ill patients, in whom very high intracranial pressure is suspected,

B Figure 91–1. MRI changes in acute bacterial meningitis. There are increased perivascular signal (A) and enhancement (B) overlying the right cerebral hemisphere. (Courtesy of Dr. Ann Osborn; reproduced with permission of the Department of Radiology, University of Utah School of Medicine.)

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T A B L E 91–3. Typical Cerebrospinal Fluid Findings in Bacterial Meningitis Opening pressure Fluid Cells Cell type Protein Glucose Gram’s stain

Usually elevated Turbid >100/mm3; often >1000 cells/mm2 Polymorphonuclear leukocytes Elevated: usually >100 Depressed: usually <50% of blood glucose Positive in 60-80% of cases

the most prudent course may be to begin empirical treatment and wait until CSF pressure has been controlled before performing lumbar puncture. Typical CSF findings are shown in Table 91-3. These include elevated pressure, fluid which is often turbid, elevated protein, depressed glucose, and elevated white blood cell count, consisting predominantly of polymorphonuclear leukocytes.39 The degree to which glucose is depressed in bacterial meningitis has been a matter of debate. Silver and Todd, in a study of 181 pediatric patients with CSF glucose levels under 50 mg/dL identified 35 patients with bacterial meningitis.40 Of these, 22 (77%) had glucose levels of 20 or below, and of 37 patients with glucose levels under 20 mg/dL, 22 (73%) had bacterial meningitis. A CSF : blood glucose ratio of less than 0.3 was highly correlated with bacterial meningitis. Bacterial meningitis was less likely if the CSF glucose levels of 20 to 50 or if the CSF/blood glucose ratio was greater than 0.30. Spanos and colleagues41 found that a CSF glucose of 18 mg/dL or less or a CSF/blood glucose ratio of less than 0.23 was associated with bacterial rather than viral meningitis in 99% of patients studied. It should be remembered, in evaluating blood glucose, that CSF glucose values will be higher in severely hyperglycemic patients and that changes in CSF glucose levels may lag 30 to 120 minutes behind those in blood. Protein levels in meningitis are a reflection of blood-brain barrier injury and usually range between 100 and 500 mg/dL.39 Not all patients with bacterial meningitis exhibit the characteristic findings listed earlier.39 CSF, especially early in the course of meningitis, may have normal cell count and chemistries yet contain bacteria. Severely immunosuppressed patients may also fail to develop CSF leukocytosis. Approximately 14% of patients with bacterial meningitis will have a CSF cellular response that is predominantly lymphocytic; CSF lymphocytosis is particularly likely in neonatal meningitis and in infections caused by L. monocytogenes.39 Although a high CSF cell count, in particular, with a large percentage of polymorphonuclear leukocytes, suggests a bacterial infection, similar CSF leukocytosis with polymorphonuclear predominance may be seen in tuberculous or fungal meningitis, spirochetal meningitis, or viral meningitis. Approximately 9% of patients with bacterial meningitis have normal CSF glucose. Prior antibiotic treatment of bacterial meningitis may have little effect on CSF cell count, glucose, and protein within the first 2 to 3 days but will reduce the yield on Gram’s stain and culture.39 In some instances, prior antibiotic treatment will cause a shift from a polymorphonuclear to a lymphocytic CSF pleocytosis. Specific identification of the infecting organism has traditionally involved Gram’s stain and bacterial culture.39 Gram’s

stain provides the most rapid initial identification of the organism. Gram’s stain will be positive in approximately 25% of cases in which the CSF contains 103 colony-forming units (CFU)/mL and 97% of cases with greater than 105CFU. Errors in Gram’s stain may result from inadequate efforts to resuspend bacteria if CSF has been allowed to settle and errors in decolorization or reading of the slide. Bacterial culture and determination of antibiotic sensitivity are routine in virtually all hospital laboratories. It may be useful, however, to review culture requirements with the laboratory in advance if anaerobic infection or other unusual organisms or culture requirements are anticipated. Yield on culture can be reduced by prior antibiotic therapy. Several adjunctive tests exist for the diagnosis of bacterial meningitis.39 Determination of lactic acid levels, in particular, D-lactate, and C-reactive protein may help differentiate bacterial from viral meningitis. Tests for bacterial antigens have proved disappointing as diagnostic tools and have been abandoned by many laboratories. Polymerase chain reaction is a promising tool in the diagnosis of meningitis.39,42 This test, which involves amplification of bacterial DNA sequences from CSF, has far greater sensitivity than do conventional culture methods and is also much less readily affected by prior antibiotic treatment. To date, the major use of polymerase chain reaction has been in the diagnosis of viral meningoencephalitides (e.g., herpes simplex encephalitis, enterovirus meningitis, or polymorphonuclear leukocytes) or of tuberculous meningitis. Several promising reports, however, have demonstrated rapid and successful use of polymerase chain reaction in meningitis due to N. meningitis, S. pneumoniae, β-hemolytic streptococci, and E. coli, including detection of penicillin-resistant strains of S. pneumoniae.42

Treatment of Acute Bacterial Meningitis Antibiotic Therapy Antimicrobial agents used for the treatment of bacterial meningitis must meet two requirements.16,43,44 First, they must be bactericidal for the causative agent. Second, they must be able to penetrate the blood-brain barrier to reach the infected meninges. Penetration across the blood-brain barrier is a function of three factors: the degree to which the antibiotic is protein bound, the degree to which it is lipid soluble, and the degree to which the blood-brain barrier has been disrupted by the meningitis. The first two of these factors, protein binding and lipid solubility of the antimicrobial agent, are constants for the given drug. Blood-brain permeability, however, is a function of inflammation and decreases as inflammation resolves, so that CSF antibiotic levels will often fall to some degree during treatment; as discussed later, this becomes a theoretical concern in the use of corticosteroids, because these agents may diminish antibiotic penetration into CSF at a time when high levels of antibiotics are particularly important. Bloodbrain barrier integrity is also different in the neonatal period than it is in later infancy or thereafter, so that systemically administered aminoglycosides such as gentamicin will reach therapeutically effective levels in neonatal meningitis, whereas the drug will not reach bactericidal CSF levels in older infants, children, or adults. For many years, five major groups of antibiotics have been used to treat bacterial meningitis: penicillins for infections due

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T A B L E 91–4. Provisional Antibiotic Therapy of Bacterial Meningitis According to Gram’s Stain Gram’s Stain

Probable Organism

Gram-positive diplococci

S. pneumoniae

Gram-positive cocci

S. aureus S. epidermidis Streptococci N. meningitidis

Gram-negative intracellular diplococci Gram-negative bacilli

Enterobacteraciae (P. aeruginosa)

to S. pneumoniae and N. meningitidis; ampicillin or trimethoprim-sulfamethoxazole for L. monocytogenes; nafcillin, oxacillin, and vancomycin for infections due to S. aureus; thirdgeneration cephalosporins such as cefotaxime and ceftazidime for gram-negative meningitis; and metronidazole for anaerobic organisms such as Bacteroides fragilis. Currently, however, the increasing prevalence of S. pneumoniae resistant to both penicillin and cephalosporins dictates that selection of antibiotics for the treatment of meningitis take into account local prevalence of resistant organisms.45 Thus, where the incidence of penicillinresistant S. pneumoniae is known to be low, one might safely use ceftriaxone or cefotaxime. In general, however, and in particular if there is any suspicion that one may be dealing with penicillinor cephalosporin-resistant organisms, vancomycin should be added to the regimen as a first-line agent.46 Similarly, vancomycin, rather than nafcillin or oxacillin, should be used if methicillin-resistant S. aureus is at all a consideration. Recommendations for provisional antibiotic treatment of bacterial meningitis are shown in Tables 91–4 and 91–5.

Corticosteroid Therapy in Bacterial Meningitis The realization that neurological injury in bacterial meningitis was due in part to tumor necrosis factor and other mediators of host inflammation led to attempts to control this aspect of meningitis with intravenous corticosteroids. Work by Lebel and coworkers in 198847 and Odio and colleagues in 199148 demonstrated more rapid control of CSF inflammatory response and decreased incidence of deafness in children with H. influenzae meningitis who were treated with cefotaxime plus dexamethasone compared with cefotaxime alone. In contrast, several studies failed to detect a beneficial effect of dexamethasone in infants with S. agalactiae meningitis.49,50 However, a European cooperative trial has demonstrated the effectiveness of dexamethasone in reducing both mortality and overall unfavorable outcome in adults with acute bacterial meningitis.51 The regimen used in this study was dexamethasone, 10 mg, administered intravenously 15 to 20 minutes before or with the first dose of antibiotic and every 6 hours for 4 days. Outside of the neonatal period at least, early treatment with dexamethasone should be strongly considered in the initial treatment of acute bacterial meningitis. Although dexamethasone treatment, with its resultant influence on meningeal inflammation and blood-brain barrier permeability, may theoretically reduce antibiotic penetration into CSF, this does not seem to have been of actual clinical importance.

Provisional Antibiotic Therapy Vancomycin Plus Cefotaxime or ceftriaxone Vancomycin Penicillin G, or ampicillin Cefotaxime or ceftriaxone is also effective Cefotaxime or ceftriaxone (ceftazidime if clinical setting suggests P. aeruginosa)

Other Measures to Treat Cerebral Edema Patients presenting with papilledema or signs of impending brain herniation warrant emergent treatment for increased intracranial pressure. Elevation of the head of the bed to 30° helps reduce intracranial pressure. Hyperventilation to a PCO2 of 27 to 30 mm Hg will cause intracranial vasoconstriction with resultant reduction in intracranial pressure. This usually requires intubation and paralysis. Hyperventilation may occasionally be lifesaving acutely, but its effect wanes over hours. In some cases as well, the patient will already be hyperventilating, and further forced hyperventilation may be of little value. Mannitol is given intravenously in children as 0.5 to 2.0 g/kg over 30 minutes and repeated as needed. The adult dosage is a 1.0-g/kg bolus repeated as needed every 3 to 4 hours or as 0.25 g/kg every 2 to 3 hours. Pentobarbital coma has been used in extreme cases of bacterial meningitis, but there are no controlled data for its use in this setting. Similarly, data do not exist concerning the role of decompressive craniotomy in meningitis. Surgery may be required, however, to drain an accompanying brain abscess or parameningeal focus of infection.

Other Complications of Bacterial Meningitis Requiring Treatment Bacterial meningitis may be accompanied by a variety of neurological and systemic complications. Meningitis accompanying sinusitis or otitis may be accompanied by epidural abscess, subdural empyema, brain abscess, or venous sinus thrombosis, any of which may require emergent surgery. Hydrocephalus is common in bacterial meningitis. It is often transient but may require shunting in some cases. Seizures may require emergent treatment with lorazepam, phenytoin (fosphenytoin) or more aggressive therapy such as midazolam, propofol, phenobarbital or pentobarbital coma in patients who fail to respond. Hypothalamic involvement may lead to either diabetes insipidus or, more commonly, the syndrome of inappropriate antidiuretic hormone.52 Subdural effusions are common in children with meningitis; these do not usually require drainage and may be followed by CT or MRI. Bacterial sepsis and shock may be present, as may disseminated intravascular coagulation and, in the case of N. meningitidis, Waterhouse-Friederichsen syndrome with widespread hemorrhage and adrenal failure. Cases of meningitis associated with S. aureus and, less often,

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T A B L E 91–5. Provisional Antibiotic Therapy of Bacterial Meningitis When Organisms Are Not Seen on Gram’s Stain Setting

Probable Organism

Provisional Antibiotic Therapy

Preterm infants

S. aureus (nosocomial) Gram-negatives Group B streptococci E. coli Other gram-negatives L. monocytogenes (S. aureus)* N. meningitidis S. pneumoniae (H. influenzae) (S. aureus) S. pneumoniae N. meningtidis (S. aureus) S. pneumoniae L. monocytogenes§ Gram-negatives (S. aureus) S. pneumoniae H. influenzae Gram-negatives, including P. aeruginosa Anaerobic or microaerophilic streptococci B. fragilis (S. aureus*) S. aureus S. epidermidis Gram-negatives, including P. aeruginosa S. pneumoniae L. monocytogene§ Gram-negatives, including P. aeruginosa S. pneumoniae S. aureus

Vancomycin plus ceftazidime

Infants <3 mo

Age 3 mo-18 yr

Age 18-50 yr Adults >50 yr Meningitis in the setting of sinusitis, otitis, or known CSF leak† Head trauma, neurosurgical procedures, shunt infections AIDS or other states of impaired cellular immunity

Ampicillin plus Cefotaxime or ceftriaxone: Cefotaxime or ceftriaxone (vancomycin‡) Cefotaxime or ceftriaxone (vancomycin‡) Ampicillin plus cefotaxime or ceftriaxone (vancomycin‡) Vancomycin plus ceftazidime plus metronidazole

Vancomycin plus ceftazidime

Ampicillin plus ceftazidime

*S. aureus is an uncommon cause of meningitis in every group of patients except those with penetrating head trauma or neurosurgical procedures. Nonetheless, the organism causes meningitis in all patient groups, and anti-staphylococcal coverage should be added if any possibility of the organism is suspected. † S. pneumoniae is the most common causative agent in patients with CSF leaks and with acute otitis, and in these cases one might treat simply with vancomycin and ceftriaxone or cefotaxime. In more chronic infections, however, or in cholesteatoma, there is increased likelihood of other organisms, including P. aeruginosa; here, initial treatment should include vancomycin plus ceftazidime plus metronidazole. ‡ Vancomycin should be added to the regimen of empirical therapy in regions where there is significant occurrence of S. pneumoniae resistant to third-generation cephalosporins. Rifampin should be considered if corticosteroids are used. § Trimethoprim-sulfamethoxazole should be used where Listeria is suspected and the patient is allergic to penicillin.

S. pneumoniae may be accompanied by bacterial endocarditis. Meningitis in the presence of S. pneumoniae endocarditis may be accompanied by pneumonia and by rapid destruction of the aortic valve (Austrian syndrome).

Prophylaxis for Bacterial Meningitis The occurrence of meningitis in a given patient always raises concern about the risk of meningitis in family members or other close contacts, and although outbreaks of meningitis within families are uncommon, temporary nasal carriage occurs frequently with S. pneumoniae, N. meningitidis, and H. influenza. Prophylaxis is not usually an issue with close contacts of patients with S. pneumoniae meningitis. In cases of meningitis due to N. meningitidis or H. influenzae, however, consideration should be given to antimicrobial chemoprophylaxis, aimed at eliminating nasal carriage.53 As a rule, chemoprophylaxis should be administered only to individuals who frequently eat and sleep in the same dwelling as the index case, that is, family members, close associates, girlfriends, or boyfriends. The most frequently used regimen for prophylaxis

involves rifampin or ceftriaxone (Table 91–6). Ciprofloxacin, ofloxacin, and azithromycin have also been used in adults but are not used in children. Although not used for immediate prophylaxis, the role of vaccination in the prevention of H. influenzae meningitis is well established. Initial work suggests that immunization against S. pneumoniae or N. meningitidis are as effective in reducing the incidence of meningitis.50

Prognosis Bacterial meningitis remains a disease with significant mortality and morbidity.21,30,54 Mortality in several studies has been in the range of 17% for individuals under 60 years of age but up to 37% in individuals above 60. In the study by Kastenbauer and Pfister,30 21 of 87 adult patients with pneumococcal meningitis died (24.1% mortality), 9 of these because of brain herniation and 12 because of cardiocirculatory or multiorgan failure, often in the setting of neuroradiological evidence of severe, irreversible cerebral injury. Fewer than one half of the patients studied (48.3%) made a good recovery. Level of con-

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T A B L E 91–6. Regimens of Antimicrobial Prophylaxis for Contacts of Meningitis Cases Caused by N. meningitidis or Haemophilus influenzae Antimicrobial

Adults

Children

Rifampin

600 mg twice daily × 2 days

Ceftriaxone (intramuscular) Ciprofloxacin Azithromycin

250 mg intramuscular; one dose

N. meningitidis: 10 mg/kg twice daily for 2 days H. influenzae: 20 mg/kg once daily for 4 days 125 mg intramuscular; one dose

500-750 mg by mouth; one dose 500 mg by mouth; one dose

Not recommended for children Not recommended for children

Adapted from Peltola et al.: Infect Dis Clin N Am 1999; 13:684-710.

sciousness is a major prognostic factor.30 Prognosis is worse in the elderly.30,54 In many studies, seizures have been associated with increased mortality. Elevated CSF pressure or, more accurately, brain perfusion pressure (brain perfusion pressure = systemic blood pressure—intracranial pressure) is an adverse prognostic sign.55,56 Other factors associated with adverse outcome have included immunosuppression, the presence of a high CSF protein level or cell count, severely depressed glucose, and, in some series, failure to generate a CSF leukocyte response.54 Asplenic patients have a worse prognosis in pneumococcal meningitis, as they do in invasive pneumococcal disease overall.30 Although meningococcal meningitis may pursue a fulminantly lethal course, mortality in most series is worse for pneumococcal meningitis than for meningococcal meningitis.

MENINGITIS ASSOCIATED WITH TUBERCULOSIS, SYPHILIS, AND LYME DISEASE Tuberculous Meningitis Although meningitis due to Mycobacterium tuberculosis is usually grouped with the chronic meningitides, the infection more often manifests subacutely or, at times, as rapidly as acute bacterial meningitis. Cases of much more indolent infection exist, but they are the minority.

Pathogenesis M. tuberculosis is an obligate intracellular pathogen. Thus, like Listeria, its control depends more heavily on cell-mediated immunity than on antibody. Tuberculosis is acquired by inhalation. Organisms initially replicate in pulmonary macrophages, then in pulmonary and hilar lymphatics. Prior to development of specific lymphocyte-mediated immune response (usually after an interval of 2 to 4 weeks), there may be seeding of multiple other organs, including the central nervous system. Development of effective cell-mediated immunity is followed by granuloma formation and destruction of organisms. In many patients, however, organisms are not destroyed but, rather merely contained, remaining viable and capable of reactivating to cause reactivated infection months or years later. Approxi-

mately 5% to 15% of patients exposed to M. tuberculosis will develop clinical disease. Of these, 5% to 10% will develop neurological involvement. The pathogenesis of tuberculous meningitis was elucidated in 1933 by Rich and McCordock,57 who found that the initial event in tuberculous meningitis was rupture of a subpial or subependymal granuloma into the subarachnoid space or ventricles. Classically, tuberculosis meningitis was a disease of children and occurred as a complication of miliary tuberculosis, having its onset during the initial weeks or months after primary infection, before effective containment of organisms.58-61 At present, tuberculosis is more frequently a complication of reactivated infection. Reactivated infection most often begins in the lungs or systemic organs; in such cases, the diagnosis of tuberculosis may be made by chest radiography, detection of M. tuberculosis in urine, or (as was done historically) detection of the agent in gastric washings. In a minority of cases, however, reactivation may occur within the central nervous system itself; in this setting, tuberculous meningitis may occur with no systemic evidence of infection.62

Clinical Features As mentioned, the onset of tuberculous meningitis is usually subacute and may also be as fulminant as that of acute bacterial meningitis. Most patients present within 2 to 3 weeks of onset. In children, the condition typically manifests with nausea, vomiting, headache, and change in mental status. Initial misdiagnoses include acute otitis media and a variety of abdominal complaints. Seizures, although occurring in up to 50% of children during their clinical course, are a presenting feature in only 10% to 20% of cases. Adults more frequently present with headaches, malaise, and, at times, behavioral changes. A system of staging introduced by the British Medical Research Council in 1947 has been widely used. In stage I, individuals exhibit nonspecific symptoms, without clouding of consciousness or neurological deficits. Patients in stage II exhibit clouding of consciousness, signs of meningeal irritation, and minor neurological deficits, including cranial nerve palsies. Stage III is characterized by coma, seizures, abnormal movements, and/or severe neurological deficits.63 Many patients present with stage II disease, however, and in some patients, the course of illness is so rapid that presentation is at stage III.

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Patients presenting with tuberculous meningitis may or may not exhibit signs of meningeal irritation. In most cases, a prior history of tuberculosis is not obtained, nor may patients always give a history of prior exposure. Characteristically, M. tuberculosis produces a basilar meningitis. This has three consequences over time: hydrocephalus, due to obstruction of the foramina of Luschka and Magendie or the aqueduct of Sylvius; vasculitis with arterial or venous occlusion, due to involvement of vessels within inflamed meninges; and cranial nerve palsies, due to involvement of exiting cranial nerves in inflamed basilar meninges are present. Cranial nerve VI is most frequently involved, followed by cranial nerves III, IV, VII, and VIII. Occasionally, presentation of tuberculous meningitis may be as an acute ischemic event rather than as meningitis, and focal signs, including hemiparesis, chorea, hemiballismus, and cerebellar ataxia, have all been described. A minority of patients, usually those presenting with miliary disease, may exhibit choroidal tubercles on funduscopic examination. The wide variability in the presentation of tuberculous meningitis, however, makes specific diagnosis difficult on clinical grounds alone.

Diagnosis Diagnosis of tuberculous meningitis may be difficult.39,64 Evidence of systemic tuberculosis may or may not be present. MRI in some but not all cases may show a characteristic basilar meningitis (Fig. 91–2). The tuberculin skin test, where both first- and second-strength reagents are used, may be positive in up to 85% to 90% of children but is positive in only 35% to 65% of adults. CSF findings vary greatly but characteristically show a mixed pleocytosis with lymphocytic predominance, low glucose (which may develop before cells are present), and elevated protein. Mean glucose values in most studies have ranged between 18 and 40 mg/dL; protein levels have usually been in the range of 150 to 250 mg/dL.39 Detection of organisms may also prove difficult. Although some laboratories have reported success rates as high as 58%, most experienced laboratories have found acid fast stains to be positive in only about 30% of cases.39,65 In most community hospitals, the yield is well below 10% and may be totally unsuccessful.39 Mycobacterial cultures are positive in only about 70% cases and may require up to 6 weeks. Determination of adenosine deaminase levels in CSF has been highly diagnostic in a few series, but other studies have found the test lacking in both sensitivity and specificity.39,66 Polymerase chain reaction is emerging as a valuable tool in rapid diagnosis. At present, however, the yield of polymerase chain reaction is 50% to 70%.39,67,68

Treatment Because of its rapid and destructive course and because diagnostic tests are limited, tuberculous meningitis should be treated on suspicion. Current World Health Organization recommendations are that cases be treated with INH, rifampin, pyrazinamide, and ethambutol for 2 months followed by 6 to 7 months of INH and rifampin. Others, however, use considerably longer periods of treatment (12 to 24 months) depending on the severity of infection at the time of presentation (Table 91–7). When multidrug resistance is suspected, a four- to seven-drug regimen is used, and streptomycin may be added.

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Figure 91–2. Gadolinium-enhanced T1-weighted MRI in tuberculous meningitis, showing enhancement of the basilar meninges. (Courtesy of Dr. Ann Osborn; reproduced with permission of the Department of Radiology, University of Utah School of Medicine.).

T A B L E 91–7. Agents for the Treatment of Tuberculous Meningitis Drug* Isoniazid† Rifampin† Pyrazinamide† (Ethambutol or) (Streptomycin)

Usual Daily Dose (mg/kg)

Maximum Dose (mg)

Duration (mo)

5 to 10 10 to 20 15 to 30 15 to 25 15

300 600 2500 ⎯ 1000

6 to 9 6 2 2 2

*When there is low probability of drug resistance. Multiple drug regimens (four or more) should be used when there is a high probability of drug resistance, † First-line drugs.

Corticosteroids (prednisone or dexamethasone) may be added in cases manifesting with stupor, coma, or neurological deficits. Their use may be lifesaving; paradoxically, however, steroid-treated survivors may have a higher incidence of neurological deficits.69 Surgery, including ventricular shunting, may be required to treat obstructive hydrocephalus or to manage intraparenchymal tuberculomas. Earlier work by Schoeman and colleagues70 suggests that nonobstructive hydrocephalus may be managed by the addition of furosemide and acetazolamide to the antituberculous regimen.

Prognosis Mortality in tuberculous meningitis is influenced heavily by clinical status at presentation. Both are low in patients presenting with stage I disease; in patients presenting with stage

chapter 91 bacterial meningitis III disease, however, mortality is 30%.71 Mortality is higher in the very young, the very old, and patients with miliary disease. Individual studies have also associated higher mortality with pregnancy, positive CSF cultures, markedly elevated protein concentrations, and very low CSF glucose levels. Long-term cognitive changes have been observed in children with tuberculous meningitis, correlating with the clinical stage at presentation.72 The course of disease in patients with HIV infection is similar to that in non–HIV-infected individuals; in this setting, however, duration of illness for more than 14 days is a poor prognostic sign, as is a CD4+ cell count of less than 200/mm3.73

Syphilitic Meningitis The neurological complications of syphilis acquired after birth have traditionally been divided into three major categories: syphilitic meningitis (meningovascular syphilis), parenchymal neurosyphilis (general paresis), and tabes dorsalis.74,75 The clinical presentation of the disease has been highly variable, however, and in days prior to penicillin therapy, neurosyphilis was considered to account for roughly 10% of neurological consultations and 25% of psychiatric hospitalizations. The observed clinical features of patients presenting with syphilis changed greatly following the introduction of penicillin therapy76 and with the advent of AIDS.77,78 Central nervous system invasion is common in systemic syphilis and, in the preantibiotic era, occurred in 60% to 70% of patients with secondary syphilis. In contrast, true, symptomatic syphilitic meningitis⎯as opposed to meningovascular or parenchymatous neurosyphilis⎯is an uncommon disorder, ranging from 0.2% to 1.6% of cases of primary or secondary syphilis.79 Syphilitic meningitis most commonly occurs within 1 year of initial infection, often during secondary syphilis, but has also been observed to develop many years after primary infection.79 Symptoms and signs have usually resembled those seen in viral meningitis, with the exception that patients may also develop optic neuritis or perineuritis, chorioretinitis, or retinal vasculitis.78 CSF may at times be normal. More usually, however, CSF contains a predominantly lymphocytic pleocytosis that is usually less than 300 cells/mm3 but may be as high as 1500 cells/mm3. Protein may be elevated to as high as 250 to 300 mg/dL. Glucose is usually normal but may be depressed.75,79 These values may be significantly blunted in patients with AIDS. On occasion, in non-AIDS patients, syphilitic meningitis may manifest acutely, with symptoms and signs resembling acute bacterial meningitis, with neutrophilic predominance, and with depressed glucose.80 There is no universally successful test for the diagnosis of syphilitic meningitis. Diagnosis is suggested by positive serum rapid plasma reagin (RPR) and fluorescent treponemal antibody-absorption (FTA-ABS) determinations and by the presence of a positive Venereal Disease Research Laboratory (VDRL) test on CSF. VDRL is positive in approximately 70% of patients.81 In patients with negative CSF VDRL, diagnosis may be made by the presence of CSF-FTA-ABS or serum FTA-ABS in the setting of a CSF pleocytosis.81,82 Treatment is usually with aqueous crystalline penicillin G; 18 to 24 million units intravenously per day for 10 to 14 days is most commonly used. Intramuscular procaine penicillin plus probenecid has also been used in adults but is contraindicated in individuals severely allergic to sulfa. Limited

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experience exists with ceftriaxone, 2 g intravenously per day. Patients with HIV are at greater risk of relapse and may warrant more careful follow-up.

Lyme Meningitis The agent of Lyme disease, Borrelia bergdorferi, is endemic in North America, Europe, and Asia, its distribution corresponding with that of ticks of the Idoxes genus. The organism produces a highly variable systemic illness83,84 as well as protean reported neurological manifestations, which include encephalitis, encephalopathy, myelopathy, cranial neuritis, radiculitis, plexopathies, and Guillain-Barré syndrome.83,85 Neurological involvement has been reported in 5% to 20% of North American patients and a higher percentage of patients in Europe. The frequency of meningeal symptoms has been reported to range from 30% to 90% of patients and is more common in children; the meningitis may occur alone or in combination with the other complications of neuroborreliosis listed earlier. Symptoms include headache, myalgias, athralgias, and weight loss. Lyme meningitis may spontaneously remit but may also recur. Gadolinium-enhanced MRI may show enhancement of meninges or of cranial or spinal nerve roots (Fig. 91–3). CSF findings in Lyme meningitis are similar to those in viral meningitis, with lymphocytic pleocytosis, mild to moderate elevation of protein, and normal glucose. Presentation as an acute purulent meningitis has also been reported but is rare.86 Diagnosis is made by positive serum serology (enzyme-linked immunosorbent assay, confirmed by Western blot analysis). Detection of CSF antibody and of intrathecal antibody production is occasionally helpful, but the yield of CSF antibodies in individuals who have negative serum studies is less than 1%.87

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Figure 91–3. Gadolinium-enhanced MRI in Lyme disease. There is enhancement of left cranial nerve V (arrows), as well as one small focus of enhancement within the brainstem (single arrow). (Courtesy of Dr. Ann Osborn; reproduced with permission of the Department of Radiology, University of Utah School of Medicine.).

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Direct tests for Borrelia DNA or proteins have not proved reliable. Treatment of choice for Lyme meningitis is ceftriaxone, 2 g intravenously daily for 2 to 4 weeks. Cefotaxime, 2 g intravenously every 8 hours for 2 to 4 weeks has also been used.

K E Y

P O I N T S

●

Both bacterial and tuberculous meningitis represent medical emergencies. Mortality remains high, especially in older patients. Prognosis depends heavily on clinical status at presentation and may be worsened by delay in therapy. Usual symptoms of meningitis may be absent in infants, the elderly, the immunocompromised, and the severely inebriated.

●

Tuberculous meningitis usually manifests subacutely. CSF shows a mixed pleocytosis with lymphocytic predominance, elevated protein, and depressed glucose. Rapid diagnosis of tuberculous meningitis may be made using polymerase chain reaction methods or acid-fast stain of centrifuged CSF. Both of these methods have limitations, however, and culture of Mycobacterium tuberculosis may take up to 8 weeks. For this reason, tuberculous meningitis should be treated on suspicion. Diagnostic yield of culture can be increased by culture of centrifuged CSF from a large (20 to 30 mL) volume of fluid.

●

Cerebral edema is an important component of both bacterial and tuberculous meningitis. Prompt treatment with dexamethasone has been shown to reduce mortality in meningitis due to S. pneumoniae and H. influenzae meningitis and should be considered in acute bacterial meningitis due to other agents, as well as in tuberculous meningitis.

●

Meningitis in syphilis and Lyme disease most usually resembles viral (“aseptic”) meningitis, with lymphocytic pleocytosis, moderate elevation of protein, and normal glucose. Both conditions, however, may rarely mimic purulent meningitis. Diagnosis of both conditions depends heavily on serology.

Suggested Reading Cadavid D: Lyme disease and relapsing fever. In: Scheld WM, Whitley RJ, Marra CM, editors. Infections of the Central Nervous System. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 659-690. de Gans J, van de BD: Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:1549-1556. Kastenbauer S, Pfister HW: Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain 2003; 126:1015-1025. Marra CM: Neurosyphilis. Curr Neurol Neurosci Rep 2004; 4:435440. Thwaites GE, Nguyen DB, Nguyen HD, et al: Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351:1741-1751. van de Beek D, de Gans J, Spanjaard L, et al: Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351:1849-1859.

References 1. Schuchat A, Robinson K, Wenger JD, et al: Bacterial meningitis in the United States in 1995. N Engl J Med 1997; 337:970976. 2. Whytt R: Observations on the nature, causes, and cure of those disorders which are commonly called nervous, hypoochondriac, or hysteric. In: Robinson DN, editor. Significant Contributions to the History of Psychiatry. Washington, DC: University Publications of America, 1978, p 551. 3. Roos KL, Tunkel AR, Scheld WM: Acute bacterial meningitis. In: Scheld WM, Whitney CG, Marra CM, editors. Infections of the Central Nervous System. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 347-422. 4. Schlech WF III: The epidemiology of bacterial meningitis. Antibiot Chemother 1992; 45:5-17. 5. Asturias EJ, Soto M, Menendez R, et al: Meningitis and pneumonia in Guatemalan children: the importance of Haemophilus influenzae type b and Streptococcus pneumoniae. Rev Panam Salud Publica 2003; 14:377-384. 6. Kojouharova M, Gatcheva N, Setchanova L, et al: Epidemiology of meningitis due to Haemophilus influenzae type b in children in Bulgaria: a prospective, population-based surveillance study. Bull World Health Organ 2002; 80:690-695. 7. Mwangi I, Berkley J, Lowe B, et al: Acute bacterial meningitis in children admitted to a rural Kenyan hospital: increasing antibiotic resistance and outcome. Pediatr Infect Dis J 2002; 21:1042-1048. 8. Koedel U, Scheld WM, Pfister HW: Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect Dis 2002; 2:721-736. 9. Gold R: Epidemiology of bacterial meningitis. Infect Dis Clin North Am 1999; 13:515-525. 10. Pong A, BradLey JS: Bacterial meningitis and the newborn infant. Infect Dis Clin North Am 1999; 13:711-1734. 11. Giannoni C, Sulek M, Friedman EM: Intracranial complications of sinusitis: a pediatric series. Am J Rhinol 1998; 12:173178. 12. Bayston R: Hydrocephalus shunt infections. J Antimicrob Chemother 1994; 34(Suppl A):75-84. 13. Levidiotou S, Charalabopoulos K, Vrioni G, et al: Fatal meningitis due to Listeria monocytogenes in elderly patients with underlying malignancy. Int J Clin Pract 2004; 58:292296. 14. Rivero GA, Torres HA, Rolston KV, et al: Listeria monocytogenes infection in patients with cancer. Diagn Microbiol Infect Dis 2003; 47:393-398. 15. Singh N, Husain S: Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000; 2:101111. 16. Roos KL, Tunkel AR, Scheld WM: Acute bacterial meningitis in children and adults. In: Scheld WM, Durack DT, Whitley RJ, editors. Infections of the Central Nervous System. Philadelphia: Lippincott-Raven, 1997, pp 335-401. 17. Pollock SS, Pollock TM, Harrison MJG: Infection of the central nervous system by Listeria moncytogenes: a review of 54 adult and juvenile cases. Q J Med 1984; 211:331-340. 18. Scheld WM, Koedel U, Nathan B, Pfister HW: Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis 2002; 186(Suppl 2):S225-S233. 19. Kim KS: E. coli invasion of brain microvascular endothelial cells as a pathogenetic basis of meningitis. Subcell Biochem 2000; 33:47-59. 20. Leib SL, Tauber MC: Pathogenesis of bacterial meningitis. Infect Dis Clin North Am 1999; 13:527-547. 21. Hosoglu S, Ayaz C, Geyik MF, et al: Acute bacterial meningitis in adults: analysis of 218 episodes. Ir J Med Sci 1997; 166:231234.

chapter 91 bacterial meningitis 22. Osma U, Cureoglu S, Hosoglu S: The complications of chronic otitis media: report of 93 cases. J Laryngol Otol 2000; 114:97100. 23. Kim KS: Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nat Rev Neurosci 2003; 4:376385. 24. Schiffer MS, Oliveira E, Glode MP, et al: A review: relation between invasiveness and the K1 capsular polysaccharide of Escherichia coli. Pediatr Res 1976; 10:82-87. 25. Alkmin MG, Shimizu SH, Landgraf IM, et al: Production and immunochemical characterization of Neisseria meningitidis group B antiserum for the diagnosis of purulent meningitis. Braz J Med Biol Res 1994; 27:1627-1634. 26. Ring A, Weiser JN, Tuomanen EI: Pneumococcal trafficking across the blood-brain barrier. Molecular analysis of a novel bidirectional pathway. J Clin Invest 1998; 102:347-360. 27. Cundell DR, Gerard C, Idanpaan-Heikkila I, et al: PAf receptor anchors Streptococcus pneumoniae to activated human endothelial cells. Adv Exp Med Biol 1996; 416:89-94. 28. Koedel U, Pfister H-W: Models of experimental bacterial meningitis: role and limitations. Infect Dis Clin North Am 1999; 13:549-577. 29. Pfister HW, Feiden W, Einhaupl KM: Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study. Arch Neurol 1993; 50:575-581. 30. Kastenbauer S, Pfister HW: Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain 2003; 126:1015-1025. 31. Kaiser AB, McGee ZA: Aminoglycoside therapy of gramnegative bacillary meningitis. N Engl J Med 1975; 293:12151220. 32. Nau R, Gerber J, Bunkowski S, et al: Axonal injury: a neglected cause of CNS damage in bacterial meningitis. Neurology 2004; 62:509-511. 33. Kaplan SL: Clinical presentation, diagnosis, and prognostic factors of bacterial meningitis. Infect Dis Clin North Am 1999; 13:570-594. 34. Radetsky M: Duration of symptoms and outcome in bacterial meningitis: an analysis of causation and the implications of a delay in diagnosis. Pediatr Infect Dis J 1992; 11:694. 35. Proulx N, Frechette D, Toye B, et al: Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 2005; 98:291-298. 36. Choi C: Bacterial meningitis in aging adults. Clin Infect Dis 2001; 33:1380-1385. 37. Rennick G, Shann F, de Campo J: Cerebral herniation during bacterial meningitis in children. Brit Med J 1993; 306:953955. 38. Winkler F, Kastenbauer S, Yousry TA, et al: Discrepancies between brain CT imaging and severely raised intracranial pressure proven by ventriculostomy in adults with pneumococcal meningitis. J Neurol 2002; 249:1292-1297. 39. Greenlee JE, Carroll KC: Cerebrospinal fluid in central nervous system infections. In: Scheld WM, Whitley RJ, Marra CM, editors. Infections of the Central Nervous System. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 6-30. 40. Silver TS, Todd JK: Hypoglychorrhachia in pediatric patients. Pediatrics 1976; 58:67-71. 41. Spanos A, Harrell FE, Durack DT: Differential diagnosis of acute meningitis, an analysis of the predictive value of initial observations. JAMA 1989; 262:2700-2707. 42. du Plessis M, Smith AM, Klugman KP: Rapid detection of penicillin-resistant Streptococcus pneumoniae in CSF by a seminested-PCR strategy. J Clin Microbiol 1998; 36:453-457. 43. Quagliarello VJ, Scheld WM: Treatment of bacterial meningitis. N Engl J Med 1997; 336:708-716. 44. Tunkel AR, Scheld WM: Treatment of Bacterial Meningitis. Curr Infect Dis Rep 2002; 4:7-16.

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45. Spach DH: New issues in bacterial meningitis in adults. Antibiotic resistance has complicated treatment. Postgrad Med 2003; 114:43-50. 46. Chang WN, Lu CH, Wu JJ, et al: Staphylococcus aureus meningitis in adults: a clinical comparison of infections caused by methicillin-resistant and methicillin-sensitive strains. Infection 2001; 29:245-250. 47. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al: Dexamethasone therapy for bacterial meningitis. Results of two doubleblind, placebo-controlled trials. N Engl J Med 1988; 319: 964-971. 48. Odio CM, Faingezicht I, Paris M, et al: The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med 1991; 324:15251531. 49. Daoud AS, Batieha A, Al Sheyyab M, et al: Lack of effectiveness of dexamethasone in neonatal bacterial meningitis. Eur J Pediatr 1999; 158:230-233. 50. Williams AJ, Nadel S: Bacterial meningitis: current controversies in approaches to treatment. CNS Drugs 2001; 15:909-919. 51. de Gans J, van de Beek D: Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:1549-1556. 52. Kaplan SL, Fishman MA: Supportive therapy for bacterial meningitis. Pediatr Infect Dis J 1987; 6:670-677. 53. Peltola H: Prophylaxis of bacterial meningitis. Infect Dis Clin North Am 1999; 13:685-710. 54. van de Beek D, de Gans J, Spanjaard L, et al: Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351:1849-1859. 55. Goh D, Minns RA: Cerebral blood flow velocity monitoring in pyogenic meningitis. Arch Dis Child 1993; 68:111-119. 56. Lindvall P, Ahlm C, Ericsson M, et al: Reducing intracranial pressure may increase survival among patients with bacterial meningitis. Clin Infect Dis 2004; 38:384-390. 57. Rich AR, McCordock HA: The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933; 52:5-37. 58. Dube MP, Holtom PD, Larsen RA: Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992; 93:520-524. 59. Kennedy DH, Fallon RJ: Tuberculous meningitis. JAMA 1979; 241:264-268. 60. Lincoln EM, Sordillo SVR, Davies PA: Tuberculous meningitis in children: a review of 167 untreated and 74 treated patients with special reference ot early diagnosis. J Pediatr 1960; 57: 807-823. 61. Sutlas PN, Unal A, Forta H, et al: Tuberculous meningitis in adults: review of 61 cases. Infection 2003; 31:387-391. 62. Slavin RE, Walsh TJ, Pollack AD: Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine (Baltimore) 1980; 59:352-366. 63. British Medical Research Council: Streptomycin treatment of tuberculous meningitis. Lancet 1947; 1:582-596. 64. Davis LE, Rastogi KR, Lambert LC, et al: Tuberculous meningitis in the southwest United States: a community-based study. Neurology 1993; 43:1775-1178. 65. Thwaites GE, Chau TT, Farrar JJ: Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol 2004; 42:378-379. 66. Corral I, Quereda C, Navas E, et al: Adenosine deaminase activity in CSF of HIV-infected patients: limited value for diagnosis of tuberculous meningitis. Eur J Clin Microbiol Infect Dis 2004; 23:471-476. 67. Narayanan S, Parandaman V, Narayanan PR, et al: Evaluation of PCR using TRC and IS6110 primers in detection of tuberculous meningitis. J Clin Microbiol 2001; 39:2006-2008. 68. Caws M, Wilson SM, Clough C, et al: Role of IS6110-targeted PCR, culture, biochemical, clinical, and immunological crite-

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ria for diagnosis of tuberculous meningitis. J Clin Microbiol 2000; 38:3150-3155. Thwaites GE, Nguyen DB, Nguyen HD, et al: Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351:1741-1751. Schoeman J, Donald P, van ZL, Keet M, et al: Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Dev Med Child Neurol 1991; 33:396-405. Kent SJ, Crowe SM, Yung A, et al: Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993; 17:987-994. Schoeman CJ, Herbst I, Nienkemper DC: The effect of tuberculous meningitis on the cognitive and motor development of children. S Afr Med J 1997; 87:70-72. Berenguer J, Moreno S, Laguna F, et al: Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 1992; 326:668-672. Merritt HH, Adams RD, Solomon HC: Neurosyphilis. New York: Oxford University Press, 1946. Marra CM: Neurosyphilis. In: Scheld WM, Whitley RJ, Marra CM, editors. Infections of the Central Nervous System. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 649-657. Hooshmand H, Escobar RM, Kopf SW: Neurosyphilis. A study of 241 patients. JAMA 1972; 219:726-729. Johns DR, Tierney M, Felsenstein D: Alteration in the natural history of neurosyphilis by concurrent infection with the

78. 79. 80. 81. 82. 83. 84. 85. 86. 87.

human immunodeficiency virus. N Engl J Med 1987; 316:15691572. Marra CM: Neurosyphilis. Curr Neurol Neurosci Rep 2004; 4:435-440. Merritt HH, Moore M: Acute syphilitic menngitis. Medicine 1935; 14:119-183. Fishman RA: Cerebrospinal Fluid in Diseases of the Nervous System, 2nd ed. Philadelphia: WB Saunders, 1992. Timmermans M, Carr J: Neurosyphilis in the modern era. J Neurol Neurosurg Psychiatry 2004; 75:1727-1730. Marra CM, Tantalo LC, Maxwell CL, et al: Alternative CSF tests to diagnose neurosyphilis in HIV-infected individuals. Neurology 2004; 63:85-88. Coyle PK, Schutzer SE: Neurologic aspects of Lyme disease. Med Clin North Am 2002; 86:261-284. Steere A: Lyme disease. N Engl J Med 1989; 321:586-595. Halperin JJ: Nervous system Lyme disease. J Neurol Sci 1998; 153:182-191. Bourke SJ, Baird A, Bone FJ, et al: Lyme disease with acute purulent meningitis. Brit Med J 1988; 297:460-461. Cadavid D: Lyme disease and relapsing fever. In: Scheld WM, Whitley RJ, Marra CM, editors. Infections of the Central Nervous System. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 659-690.

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VIRAL MENINGITIS ENCEPHALITIS ●

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Alan C. Jackson

Acute viral infections of the central nervous system (CNS) are normally classified into two clinical syndromes, meningitis and encephalitis, which reflects the anatomical localization of the infection. They are inflammatory conditions of the leptomeninges and brain, respectively. In general, both are caused by the same viral agents, although there is often a propensity for an agent to be more associated with one condition than with the other. Many of these infections are related to neuroinvasion during the course a systemic infection (e.g., arbovirus and enterovirus infections), and only a small subset of patients with the infection actually develops either meningitis or encephalitis. In contrast, rabies virus produces encephalomyelitis and does not cause systemic infection.

EPIDEMIOLOGY Viral Meningitis The incidence of aseptic meningitis has been estimated at 10.9 per 100,000 people per year.1 Viral meningitis is more common in men and boys, with a male-to-female ratio of at least 1.5. For reasons that are unclear, the disease is relatively uncommon among people older than 40. There is a striking seasonal incidence, with peak incidence during the months of July, August, and September, which reflects the dissemination of both enteroviruses and arboviruses (see the following sections).

Specific Viral Etiologies Enteroviruses are ubiquitous, infect individuals of all ages, and cause a wide spectrum of clinical illnesses. Humans are infected by multiple enteroviruses during their lifetime. There is a predominance of enterovirus infections during the summer and fall, although sporadic cases occur all year. Enteroviruses belong to the family Picornaviridae and include the polioviruses, coxsackieviruses, echoviruses, and the numbered human enteroviruses 68 to 71. The enteroviruses are the most common cause of viral meningitis and are responsible for more than 80% of cases in which a specific etiology can be identified.2 Less commonly, enteroviruses cause encephalitis. The enteroviruses replicate in the gastrointestinal tract and are transmitted via the fecal-oral route. Most enteroviral infections are asymptomatic, and gastrointestinal symptoms are usually

absent. Recognized cases of viral meningitis represent only a small fraction of enteroviral infections.3 Patients with agammaglobulinemia may develop chronic enterovirus meningitis, and therapy with intravenous immunoglobulin has proved useful in these patients.4,5 Mumps virus was at one time responsible for more cases of viral meningitis than any other single virus. Mumps virus is transmitted via the respiratory route. Outbreaks of mumps peak in the late winter and early spring in northern temperate climates, and major outbreaks traditionally occur at intervals of 2 to 7 years. Mumps virus infection confers lifelong immunity. Mumps virus infection may be associated with parotiditis, orchitis, and deafness. In mumps meningitis, mumps virus may frequently be isolated from the cerebrospinal fluid (CSF). Mumps meningitis has become much less common in the United States since the introduction of live attenuated mumps vaccine in the late 1960s. The Jeryl-Lynn strain of mumps vaccine, which is in trivalent vaccines currently used in the United States, has not been associated with neurological complications. However, the Urabe strain of mumps vaccine, which has been used in other countries, is associated with occasional cases of meningitis.6 Lymphocytic choriomeningitis virus is an arenavirus that causes inapparent infection in rodents and is present in their excreta, and direct contact may result in human infection. In humans, a biphasic illness is common: a mild systemic illness with fever, malaise, and myalgias that improves before the onset of meningitis. Lymphocytic choriomeningitis infection may be associated with severe respiratory symptoms, with pulmonary infiltrates, parotitis, orchitis, or rash.7 Although most cases of lymphocytic choriomeningitis virus infection manifest with meningitis, encephalitis may also occur. Herpes simplex virus (HSV) type 2 is associated with viral meningitis, particularly at the time of an initial episode of genital herpes infection and especially in girls and women. Meningitis may be preceded by genital or pelvic pain. A minority of these patients go on to have recurrent episodes of meningitis, which may meet the criteria for Mollaret’s meningitis, in which the virus usually cannot be cultured from CSF, but HSV type 2 (occasionally type 1) DNA can often be detected in CSF with polymerase chain reaction (PCR) amplification.8,9 With regard to other viruses, viral meningitis is associated with primary infection with human immunodeficiency virus (HIV) in 5% to 10% of patients, which usually occurs just before the time of seroconversion. Cranial nerve palsies, particularly

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involving cranial nerves V, VII, and VIII, are more common in HIV meningitis than in viral meningitis with other causes.10 Varicella-zoster virus (VZV) may produce meningitis associated with chickenpox or shingles and rash may not be associated.11,12 PCR amplification is useful in the diagnosis of varicella-zoster virus CNS infections.

Viral Encephalitis Although many of the same viruses cause viral meningitis and encephalitis, the relative frequencies of the two conditions are different. The incidence of encephalitis has been estimated at 7.4 per 100,000 people per year.1 More than 100 viruses are known to cause acute viral encephalitis, and specific etiological viral agents vary in frequency from year to year13 (Table 92–1). After thorough investigation, one study demonstrated a confirmed or probable viral agent in only 9% of cases of encephalitis, which included those with nonviral causes.14

Specific Viral Etiologies HSV type 1 is the most common cause of sporadic encephalitis and herpes simplex encephalitis has been identified in about 5% to 10% of cases of acute viral encephalitis in the United States15 with an estimated incidence of about 1 per 250,000 to 500,000 people per year.16 There is no seasonal preponderance or gender predilection. There is a bimodal age distribution in which about one third of cases occur in patients younger than 20 and one half in patients older than 50; this may reflect the occurrence of primary infections in younger individuals and reactivation of latent infections in older patients.17,18 About 90% of cases of herpes simplex encephalitis are caused by HSV type 1, and 10% T A B L E 92–1. Significant Causes of Viral Encephalitis in the United States Herpesviridae Herpes simplex virus Varicella-zoster virus Cytomegalovirus Epstein-Barr virus Human herpesvirus 6 B virus Bunyaviridae California encephalitis serogroup La Crosse virus Jamestown Canyon virus Snowshoe hare virus Togaviridae Eastern equine encephalitis virus Western equine encephalitis virus Venezuelan equine encephalitis virus Flaviviridae St. Louis encephalitis virus West Nile virus Dengue virus Powassan virus Reoviridae Colorado tick fever virus

Picornaviridae Echovirus Coxsackievirus Poliovirus Enterovirus Retroviridae Human immunodeficiency virus type 1 Papovaviridae JC virus Orthomyxoviridae Influenza virus Paramyxoviridae Measles virus Mumps virus Nipah virus Miscellaneous Viruses Adenovirus Rubella virus Lymphocytic choriomeningitis virus Rabies virus

Adapted from Griffin DE, Inouye RT: Acute viral encephalitis. In Schlossberg D, ed: Current Therapy of Infectious Disease, 2nd ed. St. Louis: Mosby, 2001, pp 270-276.

are caused by HSV type 2.19 Familial herpes simplex encephalitis has been reported infrequently.20 Arboviral infections have a seasonal (usually in the summer and early fall) and geographical distribution that depends on complex ecological cycles between arthropod vectors (mosquitoes and ticks) and their natural hosts. The arboviruses are a biological classification of viruses based on transmission by hematophagous arthropod vectors, and they include viruses in different families, including togaviruses, flaviviruses, bunyaviruses, and reoviruses. Most arboviral infections produce a subclinical or mild clinical illness and go undiagnosed. A minority of patients develop a febrile illness, and a much smaller minority develop encephalitis or, less commonly, meningitis. Epidemics of eastern equine encephalitis are relatively small, with fewer than 35 human cases, and they usually occur in the coastal regions of the eastern United States. Western equine encephalitis occurs in the western United States and in Canada. Venezuelan equine encephalitis has occurred in large outbreaks in Central and South America, and in 1971, a large epidemic in Mexico crossed the Texas border.21 In Venezuelan equine encephalitis, horses are important amplifying hosts, whereas in eastern and western equine encephalitis, horses, like humans, are dead-end hosts. St. Louis encephalitis occurs in both urban and rural outbreaks, and it is an important cause of epidemic encephalitis in North America. In 1975, an epidemic of St. Louis encephalitis included cases in 30 states and in Canada.22 About 25 sporadic cases of Powassan encephalitis have occurred in the northern United States and Canada (Ontario and Quebec).23,24 Powassan virus is transmitted by Ixodes ticks. Most cases of California serogroup encephalitis are caused by La Crosse virus and occur in the central United States. Japanese encephalitis is the most common cause of epidemic encephalitis in the world. Large summer epidemics and endemic disease in Asia are responsible for an estimated 50,000 cases and 15,000 deaths annually.25 Japanese encephalitis virus is transmitted by the mosquito Culex tritaeniorhychnus that breeds in rice fields. Water birds are natural hosts, and pigs may be important amplifying hosts in many countries. In 1999, West Nile virus was responsible for an outbreak of encephalitis in New York City and neighboring counties. The mechanism of introduction of the virus into North America is unknown. The virus has quickly moved across the North American continent. In the United States during 2003, there were 2866 cases of West Nile virus infection causing meningitis or encephalitis and 264 deaths26 (Fig. 92–1). Elderly and immunosuppressed patients are particularly at risk for disease and a fatal outcome. Transmission of West Nile virus may also occur by organ transplantation, infected blood products, and breast milk. Nipah virus was associated with an epidemic of encephalitis in pig farmers and abattoir workers in Malaysia in 1998 and 1999, which affected 265 people and killed 105.27 Two species of large fruit bats (flying foxes) are the natural hosts of the virus.28 Infected pigs developed respiratory disease and transmitted the virus to humans via the respiratory route, but subsequent outbreaks of Nipah virus encephalitis in Bangladesh and India have not been traced to pig infections.

CLINICAL FEATURES AND INVESTIGATIONS The diagnosis of viral meningitis or encephalitis can often be made on the basis of the clinical evaluation without specific

chapter 92 viral meningitis and encephalitis 2003

Indicates human disease case(s) Avian, animal, or mosquito infections

WA OR

MT (222) ID (1)

WY (375)

NV (2)

CA (3)

UT (1) AZ (13)

3 VT

ND (617)

MN (148)

SD (1039) NE (1942)

CO (2947)

KS (91) OK (79)

NM (209) TX (720)

AK

IA (147)

WI (17)

MI (19)

ME

NY (71) PA (237)

IL IN OH (54) (47) (108) VA MO KY WV (26) (64) (14) NC (24) TN (26) AR SC (25) AL GA (6) MS (37) (50) LA (87) (124) FL (94)

NH 3 MA 17 RI 7 CT 17 NJ 34 DE 17 MD 73 DC 3 WV 2

HI

■

Figure 92–1. Distribution of human cases of West Nile virus infection by state in the United States during 2003 and 2004. (From the Centers for Disease Control and Prevention, http://www.cdc.gov/ncidod/dvbid/westnilel)

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laboratory or imaging investigations. Patients with viral meningitis have fever, headache, and neck stiffness and rigidity. There is an inflammatory response involving proinflammatory cytokines that play a role in producing fever. The leptomeninges are pain-sensitive structures that account for headache and neck pain and stiffness. Patients may have mild drowsiness, but the level of consciousness is not severely altered, and there are no seizures, focal neurological signs, or other clinical evidence of involvement of the brain parenchyma. In contrast, patients with viral encephalitis have one or more of these features. Some patients with encephalitis have prominent focal features, including hemiparesis or aphasia, whereas others have diffuse brain involvement with depression in the level of consciousness without lateralizing signs. Specific arboviruses are associated with regional involvement of the CNS, including the basal ganglia with Japanese encephalitis virus, the rhombencephalon with West Nile virus, and the spinal cord with tickborne encephalitis virus and West Nile virus. Examination of the CSF is the mainstay of diagnosis in viral meningitis and encephalitis. In viral meningitis, there is typically mild mononuclear pleocytosis, a normal or mildly elevated protein concentration, and a normal or mildly decreased glucose concentration. In meningitis arising from mumps and lymphocytic choriomeningitis virus infections, the CSF cell counts may be in the thousands. Polymorphonuclear leukocytes may predominate in the CSF, particularly early in the illness. In this case, a repeat examination several hours later usually shows a shift to mononuclear cells.29 Viruses may be cultured from the CSF, or nucleic acids may be detected with PCR amplification techniques. Serological testing may also be helpful for making a specific etiological diagnosis in viral meningitis. Patients with encephalitis should also undergo brain imaging, preferably magnetic resonance imaging (MRI), and CSF examination if there is no concern about brain herniation or other contraindications to lumbar puncture.

Specific Clinical Syndromes Enteroviral meningitis manifests with fever, headache, and nuchal rigidity, and nausea, vomiting, and photophobia are common. Young children or neonates may exhibit irritability and nonspecific findings. Exanthemata, hand-foot-and-mouth disease, herpangina, pleurodynia, myocarditis, pericarditis, and hemorrhagic conjunctivitis are associated with enterovirus infections. The duration of illness is usually about 1 week, but some symptoms may persist for several weeks, particularly in adults. Serological testing is of only very limited value in enteroviral meningitis because of the large number of enteroviral serotypes. Enteroviruses may be cultured from the oropharynx and stool and also in blood, CSF, urine, and tissues. However, viral growth in culture may take 4 to 8 days, and some enterovirus serotypes grow poorly.30 PCR amplification on CSF for enteroviruses has proved diagnostically superior to viral cultures and has an important effect in reducing the use of antibiotics and in shortening hospitalizations.31 Enteroviruses can also cause encephalitis. In 1998 there was an enterovirus 71 epidemic in Taiwan with many cases of rhombencephalitis.32 Epstein-Barr virus meningitis may occur with or without an infectious mononucleosis syndrome, and meningitis is the

most common neurological manifestation of Epstein-Barr virus infection. Encephalitis is less common, and its prognosis is fairly good. Atypical lymphocytes may be present in peripheral blood specimens or in CSF. Epstein-Barr virus is rarely cultured from CSF. PCR amplification may reveal Epstein-Barr virus DNA in the CSF, but the sensitivity and specificity of the test have not yet been determined.33 Serological tests may show evidence of acute Epstein-Barr virus infection with immunoglobulin M (IgM) antibody to viral capsid antigen or with antibody to the diffuse component of the early antigen in association with the absence of antibody to nuclear antigen.34 Herpes simplex encephalitis is characterized by headache, fever, and alteration of consciousness, which may develop over a period of hours or more slowly, over days. Headache is usually a prominent early symptom, and fever is almost always present. Focal neurological features are frequently present, including aphasia, hemiparesis, and visual field defects (superior quadrant). Focal or generalized seizures and olfactory or gustatory hallucinations may occur as well. Behavioral disturbances (sometimes bizarre), personality changes, or psychotic features may occur and be prominent, and psychiatric disease is sometimes suspected. Signs of autonomic dysfunction are also often present. Papilledema is present in a minority of patients. Mild or atypical forms of herpes simplex encephalitis have been recognized without focal features, and they have been associated with both HSV types 1 and 2 infections, immunosuppression with corticosteroids or coexisting HIV infection, or disease predominantly involving the nondominant temporal lobe.35,36 Herpes simplex encephalitis may occur with unusual clinical features, including the anterior opercular syndrome.37 Focal electroencephalographic abnormalities are present in about 80% of cases of herpes simplex encephalitis.38 Sharp- and slow-wave activity is usually localized to the temporal region, and periodic complexes may be present.39 Brain imaging studies, particularly MRI, usually reveal abnormalities in involved areas, including the frontal and temporal lobes, although rare patients with normal MRI studies have been reported.40 Computed tomography reveals hypodense lesions in the temporal lobe and orbitofrontal region, which may demonstrate mass effect, regions of hemorrhage, and irregular contrast enhancement. On MRI, hyperintense signal intensities are typically seen on T2-weighted images in typical sites (Fig. 92–2A), including one or both inferomedial temporal lobes, insular cortex, inferior frontal lobes, cingulate gyrus, and thalamus, with foci of hemorrhage caused by the presence of degradation products of hemoglobin, whereas T1-weighted images show hypointense signal in the same areas, and meningeal enhancement may be demonstrated after administration of gadolinium.41 Fluid-attenuated inversion recovery imaging sequences demonstrate superior definition of temporal lobe abnormalities in comparison with standard T1- and T2weighted images36 (see Fig. 92–2B). Diffusion MRI studies may also be useful for early detection of lesions.42,43 A lumbar puncture may reveal an elevated opening pressure. CSF examination usually demonstrates a mononuclear cell pleocytosis with mildly elevated protein and normal glucose levels. Pleocytosis is present is about 97% of cases,38 but it may be absent in either immunocompetent44 or immunosuppressed45,46 patients. Leukocyte counts exceeding 500 cells/μL are found in fewer than 10% of patients. Erythrocytes in the CSF in a nontraumatic lumbar puncture are present with similar frequency in patients with encephalitis of other

chapter 92 viral meningitis and encephalitis

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Figure 92–2. Magnetic resonance images of a 20-year-old woman with herpes simplex encephalitis. T2-weighted image (A) shows signal in the right temporal lobe. On fluid-attenuated inversion recovery imaging sequences (B) there is signal in the left temporal lobe and insular cortex.

causes.38 HSV can be cultured from CSF in only about 4% of cases.47 A number of reports have demonstrated high sensitivity and specificity of PCR amplification assays for the detection of HSV DNA in the CSF of patients with suspected herpes simplex encephalitis. Primers from a HSV sequence that is common to both HSV types 1 and 2 (either the glycoprotein or HSV DNA polymerase) identify HSV DNA in the CSF.48 CSF specimens from patients with brain biopsy–proved herpes simplex encephalitis and from those with other proved diseases have a diagnostic sensitivity of 98% at the time of clinical presentation, as well as a specificity that approaches 100%.49 Falsenegative results may occur when there is contamination of CSF by medical or laboratory staff or by the presence of inhibitors. Inhibitory activity for the Taq polymerase used in PCR amplification can be assessed by assays after “spiking” CSF specimens with multiple copies of HSV DNA.49 Inhibitory activity may result from porphyrin compounds from degradation of hemoglobin, or it may be present without any evidence of hemolysis of erythrocytes in the CSF.50,51 The specificity of positive PCR assays can be confirmed with restriction enzyme analysis, hybridization, and sequencing; false-positive results may be a problem in some laboratories.52 If a PCR assay for HSV DNA yields negative results on the first or second day of illness, it should, if clinical suspicion is high, be repeated because results that are initially negative may be followed by positive results on testing of a subsequent CSF specimen.53 The CSF remains positive for HSV DNA by PCR in more than 80% of patients at the

end of one week of antiviral therapy.49 Before the development of PCR technology and widespread use of MRI, brain biopsy was an important diagnostic test for herpes simplex encephalitis. The utility of diagnostic brain biopsy for the management of encephalitis is currently controversial, especially in view of empirical antiviral drugs and rivaling sensitivity and specificity of PCR-based assays. At present, diagnostic brain biopsy is normally reserved for only a minority of cases of undiagnosed encephalitis that fail to respond to initial therapy. Arboviral encephalitis occurs in a minority of patients with arboviral infections, and the majority of patients have inapparent infections or mild nonspecific illnesses. Meningitis is less common than encephalitis. Focal signs are occasionally prominent in arboviral encephalitis. Patients may also have evidence of spinal cord involvement.54,55 Muscle weakness has been noted in patients with West Nile encephalitis, and ventilatory support may be required.56,57 Many cases with muscle weakness have ventral horn cell involvement as a result of the viral infection,55 and rare patients have features of an atypical Guillain-Barré syndrome.58 Movement disorders may occur in Japanese encephalitis59 and West Nile encephalitis.60 Seizures and raised intracranial pressure may be common causes of death.61 Clinical illness usually develops with arboviral infections a few days after transmission of the arbovirus from a mosquito or tick vector. There is a wide range in the severity of encephalitides caused by arboviruses, from mild to severe and fatal. The frequency and severity of neurological sequelae are also variable.

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Certain arboviruses typically cause more severe disease and higher fatality rates than do others. For example, eastern equine encephalitis virus causes a severe encephalitis with a mortality rate of about 70%. In contrast, La Crosse virus causes a relatively mild encephalitis (California serogroup encephalitis) with a low fatality rate. Arboviruses may cause disease in certain age groups. Encephalitis caused by La Crosse virus usually occurs in children, although infection can occur at any age. Adults in epidemic areas seldom develop Japanese encephalitis because they have developed immunity from childhood infection. Infants often have severe sequelae from western equine encephalitis,62 and elderly patients are more likely to have more severe disease in St. Louis encephalitis63 and West Nile encephalitis. In West Nile encephalitis, there is an associated broad spectrum of neurological involvement, including meningitis, cerebellar disorder, myelitis, and parkinsonism and other movement disorders.60 Computed tomography or MRI scans have demonstrated lesions in the basal ganglia, thalamus, and brainstem in eastern equine encephalitis.64 MRI scans in Japanese encephalitis show lesions in the thalami in most patients and also lesions in the basal ganglia, midbrain and pons, cerebral cortex, and cerebellum.65,66 MRI lesions may be present in the thalamus, basal ganglia, and brainstem in tickborne encephalitis.67 A minority of patients with West Nile encephalitis have MRI abnormalities, and these often involve the basal ganglia, thalamus, and brainstem.60 There is usually pleocytosis with a modest number of leukocytes that are predominantly mononuclear cells. CSF protein levels are often elevated, but the CSF glucose level is usually normal. Viral cultures on CSF for arboviruses usually yield negative results, although Japanese encephalitis virus may be isolated from CSF in up to one third of patients.68 Venezuelan equine encephalitis virus, tickborne encephalitis viruses, and Colorado tick fever virus may be isolated from blood.69,70 Arboviruses may be cultured from the brain and spinal cord in fatal cases. In rare cases, a diagnosis may be made by using brain biopsy.71 Most arboviral infections are diagnosed serologically. A serological diagnosis is commonly made on the basis of a fourfold or greater rise (or fall) in the titer of viral antibodies (immunofluorescent, hemagglutination inhibition, complement fixation, or neutralizing) during the infection. Both acute and convalescent sera should be obtained, the latter 2 to 6 weeks after the first. Serological cross-reactions can occur in areas where closely related viruses (e.g., flaviviruses) circulate or when patients have been vaccinated against a closely related virus.28 This problem can be resolved by parallel serological testing against the closely related viruses or by further assessment at a specialized laboratory with plaque reduction neutralization assays. The presence of viral specific serum IgM indicates primary infection, although IgM may remain present for many weeks. A diagnosis may be made at the time of admission to the hospital or soon afterward by demonstration of virus-specific IgM in the CSF by capture enzyme immunoassay.72,73 About one half of patients with West Nile encephalitis have IgM in CSF on admission to the hospital, and the majority develop IgM by the seventh day of admission; patients who do not develop IgM are more likely to have West Nile virus isolated and are more likely to die of the illness.74 Assays with PCR amplification may be useful in detecting viral RNA from arboviruses in CSF or brain tissues.75-77 In West Nile encephalitis, real-time PCR, the most sensitive of PCR techniques, is positive in only about one half of cases.74

Nipah virus encephalitis in Malaysia was characterized by fever, altered mental status, segmental myoclonus, seizures, cerebellar ataxia, and brainstem and cervical spinal cord signs, and there was a high mortality rate.78 T2-weighted MRI revealed multiple small, hyperintense lesions in brain white matter.79 CSF demonstrated pleocytosis and elevated protein levels.78 Pathological studies revealed infection of endothelial cell and neurons and microinfarctions caused by small vessel vasculitis in both the gray and white matter.80,81 Rabies usually develops 1 to 3 months (or, rarely, a few days or more than a year) after exposure, which is most often from an animal bite. However, there may be no history of an animal bite, particularly in association with transmission from bats. Patients with rabies often have distinctive clinical features,82 but physicians must have a high index of suspicion. Prodromal symptoms, including fever, chills, malaise, fatigue, insomnia, anorexia, headache, anxiety, and irritability, may last for a few days. About one half of patients develop pain, paresthesias, or pruritus at or close to the bite site, which may reflect infection in dorsal root ganglia. About 80% of patients develop an encephalitic (also called furious) form of rabies, and 20% develop a paralytic form. In the encephalitic form, patients have episodes of generalized arousal or hyperexcitability, which are separated by lucid periods.83 They may have aggressive behavior, confusion, and hallucinations. Fever is common, and signs of autonomic dysfunction, including hypersalivation, sweating, and piloerection, may be present. Nuchal rigidity and seizures may occur. About one half of patients develop hydrophobia, a characteristic manifestation of rabies (Fig. 92–3). Patients may initially experience pain in the throat or have difficulty swallowing. On attempts to swallow, they experience contractions of the diaphragm and other inspiratory muscles, which last for about 5 to 15 seconds. Subsequently, the sight, sound, or even mention of water (or of any liquids) may trigger the spasms. A draft of air on the skin may have the same effect (aerophobia). The disease may progress through paralysis, coma, and multiple organ failure, and eventually it causes death. In paralytic rabies, flaccid muscle weakness develops early in the course of the disease, and patients may survive longer.

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Figure 92–3. Hydrophobic spasm of inspiratory muscles associated with terror in a patient with rabies encephalitis attempting to swallow water. (Copyright D. A. Warrell, Oxford, United Kingdom.)

chapter 92 viral meningitis and encephalitis Computed tomographic scans of the head are usually normal in rabies. There has been limited experience with MRI, although both normal features84 and increased signals on T2weighted images in the medulla and pons85 have been observed. CSF analysis often yields abnormal findings. Anderson and colleagues found pleocytosis in 59% of cases during the first week of illness and in 87% after the first week.86 Mononuclear cells predominate in the CSF, the protein level may be mildly elevated, and the glucose level is usually normal. Serum neutralizing antibodies against rabies virus are not usually present in unimmunized patients until after the 10th day of illness,87 and death may occur without their development. Early in the illness, rabies virus is occasionally isolated from the saliva or CSF.86 A skin biopsy may confirm a diagnosis of rabies while the patient is alive.88 Rabies virus antigen may be detected in skin biopsies with the fluorescent antibody technique. Antigen may be demonstrated in small nerves of skin taken from the nape of the neck, which is rich in hair follicles. Detection of antigen in corneal impression smears is less sensitive than in skin biopsies.88 Diagnosis of rabies with brain biopsies has not been adequately evaluated. Postmortem CNS tissues can be assessed for rabies virus antigen and viral isolation. Rabies virus RNA has been demonstrated from brain tissues, saliva, and CSF with PCR amplification.89,90 Postinfectious encephalitis frequently affects children and young adults. The encephalitis usually follows a viral infection, including exanthematous agents (measles, rubella, vaccinia, varicella-zoster), nonspecific upper respiratory tract infections, and other nonviral infections.91 The illness is similar to that seen in neuroparalytic complications after a variety of immunizations, including rabies (e.g., Semple vaccine) and smallpox. Postinfectious encephalitis normally has a monophasic clinical course. The clinical features develop over a period of a few days and include mental status changes, seizures, and corticospinal tract, cerebellar, and brainstem signs, and fever may be present. MRI of the brain typically reveals multiple large, asymmetrical, T2-hyperintense lesions in the white matter, which may exhibit mass effect and contrast enhancement. CSF analysis often reveals mild mononuclear pleocytosis with elevated protein levels, but CSF may be normal; oligoclonal bands are usually absent.

ETIOLOGY AND PATHOGENESIS Viruses produce inflammation in the leptomeninges and in the brain parenchyma in viral meningitis and encephalitis, respectively. Viruses usually gain access to the CNS by either a hematogenous or neuronal route of spread. Hematogenous spread is more common. With replication in systemic tissues— for example, in lymphatic tissues or in muscle—a transient viremia develops, and virus spreads to the brain. Viruses may replicate in brain capillary endothelial cells, or there may be passive transfer of virus across the endothelium or via pinocytotic vesicles in epithelial cells of the choroid plexus with seeding of virus into CSF.13 HSV and rabies virus spread within axons of peripheral nerves and gain access to the CNS.92,93 The frontotemporal localization of herpes simplex encephalitis in adults is believed to relate to the route of viral entry of HSV into the brain94 (Fig. 92–4). Davis and Johnson hypothesized that reactivated HSV, which is often latent in trigeminal ganglia, may spread along

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Figure 92–4. Possible anatomical explanations for the orbitalfrontal and temporal localization of herpes simplex encephalitis. Direct invasion of the olfactory bulb (arrow, right) could produce orbital-frontal infection with spread to the temporal lobes. Small sensory fibers from the trigeminal ganglia (arrows, left) send fibers to the basilar meninges of the anterior and middle fossae. (From Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1998.)

the trigeminal nerve fibers in tentorial nerves that innervate the basal meninges of the anterior and middle fossae.95 It has also been postulated that HSV may enter the brain along an olfactory pathway and spread along the base of the brain,94 particularly during primary HSV infection. Rabies virus also spreads to the CNS along peripheral nerves after inoculation of virus in a bite exposure, and the virus may also take an olfactory pathway in laboratory accidents with inhalation of aerosolized rabies virus96,97 or in caves containing millions of bats.98 Once rabies virus invades the CNS, the virus rapidly disseminates within axons along neuroanatomical connections by fast axonal transport. Postinfectious encephalomyelitis, or acute disseminated encephalomyelitis, is discussed in Chapter 79. It frequently affects children and young adults. This form of encephalitis usually follows a viral infection, including exanthematous agents and nonspecific respiratory tract infections.

TREATMENT By definition, viral meningitis is a benign, self-limited condition, and there is only very limited experience with antiviral therapy. Pleconaril is an antiviral drug that interferes with enterovirus attachment and coating by binding to the viral capsid.30 In a multicenter trial, efficacy was not demonstrated in infants with enteroviral meningitis,99 although a preliminary study showed that therapy resulted in shortening of the period of symptoms in meningitis in older individuals.100 Because it is a self-limited condition, specific antiviral therapy is not required for HSV type 2 meningitis. However, oral acyclovir, valacyclovir, and famciclovir have been used, although there have not yet been clinical trials.

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Therapy with intravenous acyclovir is of proven efficacy in herpes simplex encephalitis. The mortality rate in untreated herpes simplex encephalitis was 70% in the placebo group of an early clinical trial.101 A multicenter clinical trial showed a mortality rate of 28% (at 18 months) after a 10-day course of intravenous acyclovir.102 Age and level of consciousness at the time of initiation of therapy were found to be important determinants of neurological outcome; patients older than 30 years of age or either semicomatose or comatose at the time therapy was begun had much less favorable outcomes. Therapy with intravenous acyclovir should be initiated in most patients with suspected viral encephalitis and continued until the diagnosis is excluded or believed highly unlikely. Acyclovir, 10 mg/kg every 8 hours (30 mg/kg/day), is given and usually continued for 14 to 21 days; higher dosages in the range of 30 to 60 mg/kg/day have also been used. There is anecdotal evidence that shorter courses of therapy (e.g., 10 days) have been associated with a higher incidence of recurrent disease or relapse. The viral enzyme thymidine kinase activates the drug to produce acyclovir-5′-monophosphate, and host cell enzymes further phosphorylate this compound to form a triphosphate derivative, which inhibits viral DNA polymerase and acts as a viral chain terminator. Adjustments in the acyclovir dosage are necessary in patients with renal insufficiency. Oral therapy has not yet been evaluated in herpes simplex encephalitis. A multicenter clinical trail is currently in progress by the Collaborative Antiviral Study Group (Principal Investigator, Dr. Richard J. Whitley, University of Alabama at Birmingham) to assess the efficacy and safety of additional therapy with oral valacyclovir at a dose of 2 g three times a day for 90 days versus placebo after conventional therapy with 14 to 21 days of intravenous acyclovir. Cytomegalovirus encephalitis is normally a disease of immunocompromised individuals, especially patients with the acquired immunodeficiency syndrome (AIDS). Highly active antiretroviral therapy is effective in patients with HIV/AIDS to control cytomegalovirus infection and reduce the mortality rate associated with cytomegalovirus disease.103 Intravenous ganciclovir, intravenous foscarnet, or a combination of the two drugs is recommended for treatment of cytomegalovirus ventriculoencephalitis.104 Although this therapy may stabilize the neurological condition of the patient, it probably does not improve survival rates.103 Cytomegalovirus encephalitis is rare in immunocompetent patients, and treatment protocols have not been established. There is no therapy of proven benefit for arboviral encephalitis, including West Nile encephalitis.105 A multicenter clinical trial by the Collaborative Antiviral Study Group evaluating an intravenous immunoglobulin preparation from Israel containing high-titer antibody against West Nile virus is now in progress, and there is also a randomized, unblinded clinical study in progress using interferon α-2b.106 With regard to therapy for Japanese encephalitis, a double-blind, placebocontrolled clinical trial in Vietnam failed to demonstrate a difference in mortality rates or functional outcome with intramuscular administration of interferon α-2a (10 million units/m2 body surface area daily for 7 days).106 For postinfectious encephalitis, there have been no clinical trials documenting benefit from any treatment, and spontaneous improvement occurs. Most studies have showed a temporal benefit of corticosteroids, although others have shown no difference in the clinical course or have revealed higher

morbidity and mortality rates.107 Plasma exchange108 and intravenous immunoglobulin109 have also been reported to be associated with improvement in postinfectious encephalitis.

CONCLUSIONS AND RECOMMENDATIONS A large number of viruses may cause viral meningitis and encephalitis, and specific viruses are usually more associated with one disorder than with the other. Viral entry into meninges or brain parenchyma, an uncommon event in the course of a systemic infection, may lead to the development of meningitis or encephalitis, respectively. A knowledge of the epidemiology and clinical features associated with viral infections affecting the nervous system allows the clinician to make a presumptive diagnosis or differential diagnosis, which can be subsequently confirmed with specific laboratory or imaging investigations. Previously unknown viruses (e.g., Nipah virus) causing encephalitis are emerging, and other viruses (e.g., West Nile virus) have dramatically extended their geographical range into and across new continents. Detection of viral nucleic acids in CSF, secretions, or tissues with PCR amplification has enhanced clinicians’ ability to make a specific laboratory diagnosis of many viral infections of the nervous system. Antiviral therapy with intravenous acyclovir is particularly important in the case of herpes simplex encephalitis, in which the mortality rate among untreated patients is 70%; with therapy, this rate is reduced to less than 30%. Antiviral therapy is also useful in other specific clinical syndromes. With the development of improved diagnostic investigations and early interventions with new antiviral therapies and also with neuroprotective therapies, the outcome of patients with viral encephalitis may be improved in the future.

K E Y

P O I N T S

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A diagnosis of viral meningitis or encephalitis can often be strongly suspected on the basis of the clinical evaluation, and confirmation of the diagnosis requires laboratory and/or imaging investigations.

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Viral meningitis and encephalitis are usually caused by the same viral agents, but specific viruses often have a greater propensity for causing one clinical syndrome more than the other.

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Specific therapy is not available for many viral CNS infections, but therapy with intravenous acyclovir is essential for herpes simplex encephalitis, and a high index of suspicion is needed in order to make an early diagnosis of this disorder.

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New antiviral and neuroprotective therapies are needed for viral encephalitis, including herpes simplex encephalitis.

Suggested Reading Booss J, Esiri MM: Viral Encephalitis in Humans. Washington, DC: ASM Press, 2003. Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1998.

chapter 92 viral meningitis and encephalitis Nathanson N, Ahmed R, Gonzalez-Scarano F, et al: Viral Pathogenesis. Philadelphia: Lippincott-Raven, 1997. Roos KL: Principles of Neurologic Infectious Diseases. New York: McGraw-Hill, 2005. Scheld WM, Whitley RJ, Marra CM: Infections of the Central Nervous System, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004.

20. 21. 22. 23.

References 1. Beghi E, Nicolosi A, Kurland LT, et al: Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981: I. Epidemiology. Ann Neurol 1984; 16:283-294. 2. Rotbart HA: Enteroviral infections of the central nervous system. Clin Infect Dis 1995; 20:971-981. 3. Torphy DE, Ray CG, Thompson RS, et al: An epidemic of aseptic meningitis due to echovirus type 30: epidemiologic features and clinical and laboratory findings. Am J Public Health 1970; 60:1447-1455. 4. McKinney RE, Katz SL, Wilfert CM: Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987; 9:334-356. 5. Misbah SA, Spickett GP, Ryba PC, et al: Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol 1992; 12:266-270. 6. Miller E, Goldacre M, Pugh S, et al: Risk of aseptic meningitis after measles, mumps, and rubella vaccine in UK children. Lancet 1993; 341:979-982. 7. Lewis JM, Utz JP: Orchitis, parotitis and meningoencephalitis due to lymphocytic-choriomeningitis virus. N Engl J Med 1961; 265:776-780. 8. Tedder DG, Ashley R, Tyler KL, et al: Herpes simplex virus infection as a cause of benign recurrent lymphocytic meningitis. Ann Intern Med 1994; 121:334-338. 9. Kupila L, Vainionpaa R, Vuorinen T, et al: Recurrent lymphocytic meningitis: the role of herpesviruses. Arch Neurol 2004; 61:1553-1557. 10. Levy RM, Bredesen DE: Central nervous system dysfunction in acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr 1988; 1:41-64. 11. Johnson R, Milbourn PE: Central nervous system manifestations of chickenpox. CMAJ 1970; 102:831-834. 12. Jhaveri R, Sankar R, Yazdani S, et al: Varicella-zoster virus: an overlooked cause of aseptic meningitis. Pediatr Infect Dis J 2003; 22:96-97. 13. Johnson RT: Viral Infections of the Nervous System. Philadelphia: Lippincott-Raven, 1998. 14. Glaser CA, Gilliam S, Schnurr D, et al: In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000. Clin Infect Dis 2003; 36:731742. 15. Centers for Disease Control: Encephalitis Surveillance Annual Summary 1978, Issued May 1981. Washington, DC: U.S. Department of Health and Human Services, 1981. 16. Whitley RJ, Lakeman F: Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis 1995; 20:414-420. 17. Koskiniemi M, Piiparinen H, Mannonen L, et al: Herpes encephalitis is a disease of middle aged and elderly people: polymerase chain reaction for detection of herpes simplex virus in the CSF of 516 patients with encephalitis. J Neurol Neurosurg Psychiatry 1996; 60:174-178. 18. Tyler KL: Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s. Herpes 2004; 11(Suppl 2):57A-64A. 19. Aurelius E, Johansson B, Skoldenberg B, et al: Encephalitis in immunocompetent patients due to herpes simplex virus

24. 25. 26. 27.

28. 29. 30. 31. 32. 33. 34. 35.

36. 37. 38. 39. 40.

41. 42.

1257

type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid. J Med Virol 1993; 3:179-186. Jackson AC, Melanson M, Rossiter JP: Familial herpes simplex encephalitis [Letter]. Ann Neurol 2002; 51:406-407. Ehrenkranz NJ, Ventura AK: Venezuelan equine encephalitis virus infection in man. Annu Rev Med 1974; 25:9-14. Luby JP: St. Louis encephalitis. Epidemiol Rev 1979; 1:55-73. Artsob H: Powassan encephalitis. In Monath TP, ed: The Arboviruses: Epidemiology and Ecology, vol 4. Boca Raton, FL: CRC Press, 1989, pp 29-49. Gholam BIA, Puksa S, Provias JP: Powassan encephalitis: a case report with neuropathology and literature review. CMAJ 1999; 161:1419-1422. Solomon T: Recent advances in Japanese encephalitis. J Neurovirol 2003; 9:274-283. Solomon T: Flavivirus encephalitis. N Engl J Med 2004; 351:370-378. Parashar UD, Sunn LM, Ong F, et al: Case-control study of risk factors for human infection with a new zoonotic paramyxovirus, Nipah virus, during a 1998-1999 outbreak of severe encephalitis in Malaysia. J Infect Dis 2000; 181:17551759. Chua KB, Koh CL, Hooi PS, et al: Isolation of Nipah virus from Malaysian Island flying-foxes. Microbes Infect 2002; 4:145-151. Feigin RD, Shackelford PG: Value of repeat lumbar puncture in the differential diagnosis of meningitis. N Engl J Med 1973; 289:571-574. Sawyer MH: Enterovirus infections: diagnosis and treatment. Curr Opin Pediatr 2001; 13:65-69. Ramers C, Billman G, Hartin M, et al: Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 2000; 283:2680-2685. Huang CC, Liu CC, Chang YC, et al: Neurologic complications in children with enterovirus 71 infection. N Engl J Med 1999; 341:936-942. Portegies P, Corssmit N: Epstein-Barr virus and the nervous system. Curr Opin Neurol 2000; 13:301-304. Gotlieb-Stematsky T, Arlazoroff A: Epstein-Barr virus. In Vinken PJ, Bruyn GW, Klawans HL, et al, eds: Viral Disease. Amsterdam: Elsevier, 1989, pp. 249-261. Domingues RB, Tsanaclis AM, Pannuti CS, et al: Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis 1997; 25:8691. Fodor PA, Levin MJ, Weinberg A, et al: Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology 1998; 51:554-559. McGrath NM, Anderson NE, Hope JK, et al: Anterior opercular syndrome, caused by herpes simplex encephalitis. Neurology 1997; 49:494-497. Whitley RJ, Soong SJ, Linneman C, et al: Herpes simplex encephalitis: clinical assessment. JAMA 1982; 247:317320. Ch’ien LT, Boehm RM, Robinson H, et al: Characteristic early electroencephalographic changes in herpes simplex encephalitis. Arch Neurol 1977; 34:361-364. Domingues RB, Fink MC, Tsanaclis AM, et al: Diagnosis of herpes simplex encephalitis by magnetic resonance imaging and polymerase chain reaction assay of cerebrospinal fluid. J Neurol Sci 1998; 157:148-153. Demaerel P, Wilms G, Robberecht W, et al: MRI of herpes simplex encephalitis. Neuroradiology 1992; 34:490-493. McCabe K, Tyler K, Tanabe J: Diffusion-weighted MRI abnormalities as a clue to the diagnosis of herpes simplex encephalitis. Neurology 2003; 61:1015-1016.

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43. Kuker W, Nagele T, Schmidt F, et al: Diffusion-weighted MRI in herpes simplex encephalitis: a report of three cases. Neuroradiology 2004; 46:122-125. 44. Schlageter N, Jubelt B, Vick NA: Herpes simplex encephalitis without CSF leukocytosis. Arch Neurol 1984; 41:1007-1008. 45. Price R, Chernik NL, Horta-Barbosa L, et al: Herpes simplex encephalitis in an anergic patient. Am J Med 1973; 54:222228. 46. Tan SV, Guiloff RJ, Scaravilli F, et al: Herpes simplex type 1 encephalitis in acquired immunodeficiency syndrome. Ann Neurol 1993; 34:619-622. 47. Nahmias AJ, Whitley RJ, Visintine AN, et al: Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. J Infect Dis 1982; 145:829-836. 48. Whitley RJ, Kimberlin DW, Roizman B: Herpes simplex viruses. Clin Infect Dis 1998; 26:541-553. 49. Lakeman FD, Whitley RJ, National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brainbiopsied patients and correlation with disease. J Infect Dis 1995; 171:857-863. 50. Aurelius E, Johansson B, Skoldenberg B, et al: Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991; 337:189192. 51. Dennett C, Klapper PE, Cleator GM, et al: CSF pretreatment and the diagnosis of herpes encephalitis using the polymerase chain reaction. J Virol Meth 1991; 34:101-104. 52. Tyler KL: Positive CSF HSV PCR in patients with GBM: a note of caution [Letter]. Neurology 2000; 55:604. 53. Weil AA, Glaser CA, Amad Z, et al: Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis 2002; 34:1154-1157. 54. Misra UK, Kalita J: Anterior horn cells are also involved in Japanese encephalitis. Acta Neurol Scand 1997; 96:114-117. 55. Li J, Loeb JA, Shy ME, et al: Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection. Ann Neurol 2003; 53:703-710. 56. Asnis DS, Conetta R, Teixeira AA, et al: The West Nile virus outbreak of 1999 in New York: the Flushing Hospital experience. Clin Infect Dis 2000; 30:413-418. 57. Nash D, Mostashari F, Fine A, et al: The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 2001; 344:1807-1814. 58. Ahmed S, Libman R, Wesson K, et al: Guillain-Barré syndrome: an unusual presentation of West Nile virus infection. Neurology 2000; 55:144-146. 59. Murgod UA, Muthane UB, Ravi V, et al: Persistent movement disorders following Japanese encephalitis. Neurology 2001; 57:2313-2315. 60. Sejvar JJ, Haddad MB, Tierney BC, et al: Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003; 290:511-515. 61. Solomon T, Dung NM, Kneen R, et al: Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis. Brain 2002; 125:1084-1093. 62. Earnest MP, Goolishian HA, Calverley JR, et al: Neurologic, intellectual, and psychologic sequelae following western encephalitis: a follow-up study of 35 cases. Neurology 1971; 21:969-974. 63. Finley KH, Riggs N: Convalescence and sequelae. In Monath TP, ed: St. Louis Encephalitis. Washington, DC: American Public Health Association, 1980, pp 535-550. 64. Deresiewicz RL, Thaler SJ, Hsu L, et al: Clinical and neuroradiographic manifestations of eastern equine encephalitis. N Engl J Med 1997; 336:1867-1874.

65. Kumar S, Misra UK, Kalita J, et al: MRI in Japanese encephalitis. Neuroradiology 1997; 39:180-184. 66. Kalita J, Misra UK: Comparison of CT scan and MRI findings in the diagnosis of Japanese encephalitis. J Neurol Sci 2000; 174:3-8. 67. Marjelund S, Tikkakoski T, Tuisku S, et al: Magnetic resonance imaging findings and outcome in severe tick-borne encephalitis. Report of four cases and review of the literature. Acta Radiol 2004; 45:88-94. 68. Lowry PW: Arbovirus encephalitis in the United States and Asia. J Lab Clin Med 1997; 129:405-411. 69. Goodpasture HC, Poland JD, Francy DB, et al: Colorado tick fever: clinical, epidemiologic, and laboratory aspects of 228 cases in Colorado in 1973-1974. Ann Intern Med 1978; 88:303-310. 70. Ho M: Acute viral encephalitis. In Vinken PJ, Bruyn GW, eds: Handbook of Clinical Neurology, vol 34. New York: NorthHolland, 1978, pp 63-81. 71. McJunkin JE, Khan R, de los Reyes EC, et al: Treatment of severe La Crosse encephalitis with intravenous ribavirin following diagnosis by brain biopsy. Pediatrics 1997; 99:261-267. 72. Burke DS, Nisalak A, Ussery MA, et al: Kinetics of IgM and IgG responses to Japanese encephalitis virus in human serum and cerebrospinal fluid. J Infect Dis 1985; 151:1093-1099. 73. Petersen LR, Roehrig JT, Hughes JM: West Nile virus encephalitis. N Engl J Med 2002; 347:1225-1226. 74. Solomon T, Whitley RJ: Arthropod-borne viral encephalitides. In Scheld WM, Whitley RJ, Marra CM, eds: Infections of the Central Nervous System. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 205-230. 75. Tomazic J, Poljak M, Popovic P, et al: Tick-borne encephalitis: possibly a fatal disease in its acute stage. PCR amplification of TBE RNA from postmortem brain tissue. Infection 1997; 25:41-43. 76. Chandler LJ, Borucki MK, Dobie DK, et al: Characterization of La Crosse virus RNA in autopsied central nervous system tissues. J Clin Microbiol 1998; 36:3332-3336. 77. Lanciotti RS, Kerst AJ, Nasci RS, et al: Rapid detection of West Nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a TaqMan reverse transcriptase–PCR assay. J Clin Microbiol 2000; 38:40664071. 78. Goh KJ, Tan CT, Chew NK, et al: Clinical features of Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med 2000; 342:1229-1235. 79. Lim CC, Lee KE, Lee WL, et al: Nipah virus encephalitis: serial MR study of an emerging disease. Radiology 2002; 222:219226. 80. Chua KB, Goh KJ, Wong KT, et al: Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet 1999; 354:1257-1259. 81. Wong KT, Shieh WJ, Kumar S, et al: Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 2002; 161:2153-2167. 82. Jackson AC: Human disease. In Jackson AC, Wunner WH, eds: Rabies. San Diego: Academic Press, 2002, pp 219-244. 83. Warrell DA: The clinical picture of rabies in man. Trans R Soc Trop Med Hyg 1976; 70:188-195. 84. Sing TM, Soo MY: Imaging findings in rabies. Australas Radiol 1996; 40:338-341. 85. Pleasure SJ, Fischbein NJ: Correlation of clinical and neuroimaging findings in a case of rabies encephalitis. Arch Neurol 2000; 57:1765-1769. 86. Anderson LJ, Nicholson KG, Tauxe RV, et al: Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis, and prevention. Ann Intern Med 1984; 100:728-735. 87. Hattwick MAW: Human rabies. Public Health Rev 1974; 3:229-274.

chapter 92 viral meningitis and encephalitis 88. Warrell MJ, Looareesuwan S, Manatsathit S, et al: Rapid diagnosis of rabies and post-vaccinal encephalitides. Clin Exp Immunol 1988; 71:229-234. 89. Noah DL, Drenzek CL, Smith JS, et al: Epidemiology of human rabies in the United States, 1980 to 1996. Ann Intern Med 1998; 128:922-930. 90. Trimarchi CV, Smith JS: Diagnostic evaluation. In Jackson AC, Wunner WH, eds: Rabies. San Diego: Academic Press, 2002, pp 307-349. 91. Johnson RT, Griffin DE, Gendelman HE: Postinfectious encephalomyelitis. Semin Neurol 1985; 5:180-190. 92. Ploubidou A, Way M: Viral transport and the cytoskeleton. Curr Opin Cell Biol 2001; 13:97-105. 93. Von Bartheld CS: Axonal transport and neuronal transcytosis of trophic factors, tracers, and pathogens. J Neurobiol 2004; 58:295-314. 94. Johnson RT, Mims CA: Pathogenesis of viral infections of the nervous system. N Engl J Med 1968; 278:23-30. 95. Davis LE, Johnson RT: An explanation for the localization of herpes simplex encephalitis. Ann Neurol 1979; 5:2-5. 96. Winkler WG, Fashinell TR, Leffingwell L, et al: Airborne rabies transmission in a laboratory worker. JAMA 1973; 226:1219-1221. 97. Tillotson JR, Axelrod D, Lyman DO: Rabies in a laboratory worker—New York. MMWR Morbid Mortal Wkly Rep 1977; 26:183-184. 98. Constantine DG: Rabies transmission by nonbite route. Public Health Rep 1962; 77:287-289. 99. Abzug MJ, Cloud G, Bradley J, et al: Double blind placebocontrolled trial of pleconaril in infants with enterovirus meningitis. Pediatr Infect Dis J 2003; 22:335-341. 100. Shafran SD, Halota W, Gilbert D, et al: Pleconaril is effective for enteroviral meningitis in adolescents and adults: a

101.

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105. 106. 107. 108. 109.

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randomized placebo-controlled multicenter trial [Abstract]. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, September 28, 1999. Whitley RJ, Soong SJ, Dolin R, et al: Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis: National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study. N Engl J Med 1977; 297:289294. Whitley RJ, Alford CA, Hirsch MS, et al: Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314:144-149. Griffiths P: Cytomegalovirus infection of the central nervous system. Herpes 2004; 11(Suppl 2):95A-104A. Whitley RJ, Jacobson MA, Friedberg DN, et al: Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society–USA. Arch Intern Med 1998; 158:957-969. Jackson AC: Therapy of West Nile virus infection [Editorial]. Can J Neurol Sci 2004; 31:131-134. Solomon T, Dung NM, Wills B, et al: Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebocontrolled trial. Lancet 2003; 361:821-826. Boe J, Solberg CO, Saeter T: Corticosteroid treatment for acute meningoencephalitis: a retrospective study of 346 cases. BMJ 1965; 1:1094-1095. Keegan M, Pineda AA, McClelland RL, et al: Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 2002; 58:143-146. Kanter DS, Horensky D, Sperling RA, et al: Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 1995; 45:824-827.

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NEUROLOGICAL DISORDERS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION ●

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Lysa Boissé, M. John Gill, and Christopher Power

Neurological disorders caused by the retrolentivirus human immunodeficiency virus (HIV), occur at all levels of the neural axis, including the central (CNS) and peripheral (PNS) nervous systems throughout the entire course of HIV infection.1 Indeed, the prevalence of neurological syndromes during HIV infection is high, affecting up to 90% of untreated patients with the acquired immunodeficiency syndrome (AIDS).2-4 Approximately 55 million people worldwide have been infected with HIV since it was first identified in the early 1980s. With the advent of highly active antiretroviral therapy (HAART) in the mid 1990s, many individuals infected with HIV are living more than 20 years after their initial infection in industrialized countries.5 Nonetheless, despite the availability of HAART, HIV-related neurological disease continues to represent substantial personal, economic, and societal burdens. In developed countries, conversion to AIDS usually occurs approximately 10 years after initial infection (Fig. 93–1). It is defined by the Centers for Disease Control and Prevention as either a decline in CD4+ T lymphocyte levels below 200 cells/μL or an AIDS-defining illness, such as Pneumocystis carinii pneumonia, cryptococcal meningitis, or toxoplasmosis encephalitis. There are also infection-driven malignancies, such as Kaposi’s sarcoma and primary CNS lymphoma, that are commonly associated with progression to AIDS. There are two major strains of HIV: type 1 (HIV-1), which predominates globally, and type 2 (HIV-2), which is limited largely to West Africa and is less virulent. Because of HIV’s remarkable capacity for replication and subsequent mutation, significant viral molecular and antigenic diversity has occurred, which has precluded the development of an effective vaccine to date. In the industrialized world, HIV-1 B subtype (also termed B clade) predominates and is the source of most of the current understanding of HIV-related neurological disease.

NEUROLOGICAL DISORDERS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION Early in the HIV epidemic, two groups of neurological disorders arising as consequences of HIV infection were recognized. The first group of neurological syndromes includes the primary HIV-induced disorders, which reflect HIV’s immediate deleterious effects on neural cells and result in damage to the brain,

spinal cord, and peripheral nerves. These primary HIVassociated illnesses include HIV-associated dementia (HAD) (also termed AIDS dementia complex and HIV encephalopathy) and its antecedent syndrome, minor cognitive and motor deficit (MCMD); vacuolar myelopathy; and several types of peripheral neuropathy6 (Fig. 93–2). Indeed, other neurological disorders, including entrapment neuropathies, headache, seizures, and myopathy, appear to be more frequently encountered among patients with HIV or AIDS than noninfected persons, although these conditions are not necessarily linked to the direct effects of virus (HIV) infection. The second group is composed of the opportunistic infections of the CNS and PNS, which arise as direct consequences of HIV-induced immunosuppression. These include toxoplasmosis encephalitis, cryptococcal meningitis, cytomegalovirus encephalitis and radiculitis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, and neurotuberculosis (meningitis and tuberculoma) and are dealt with in detail in other publications.7,8 In the current era of HAART availability, the primary HIVinduced conditions constitute the major burden of neurological disease and are the focus of this chapter. An essential consideration in the evaluation of HIV-infected patients with neurological signs or symptoms is the level of immunosuppression, best defined by the CD4+ lymphocyte count in blood. Most opportunistic infections of the nervous system emerge during stages of marked immunosuppression, after the development of AIDS. Similarly, HAD, vacuolar myelopathy, and distal sensory neuropathy are usually features of AIDS. Other neurological complications, including antiretroviral toxic neuropathy, may manifest with higher CD4+ T cell counts. Nonetheless, CD4+ T cell levels may have been below 200 cells/μL before HAART initiation, and thus the lowest recorded CD4+ level (nadir) can be a helpful predictor of the type of neurological complication.

HUMAN IMMUNODEFICIENCY VIRUS NEUROPATHOGENESIS AND NEUROPATHOLOGY Under healthy conditions, the CNS and PNS are well protected by the blood-brain barrier or blood-nerve barrier from toxins

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Figure 93–1. Systemic course of human immunodeficiency virus

Chronic meningitis

(HIV) infection. In the first 4 to 8 weeks after infection, there is a dramatic increase in viral load, which drops precipitously after seroconversion. During the asymptomatic period of infection, viral load remains relatively low. An increase in viral load after approximately 10 years of infection is associated with progression to acquired immunodeficiency syndrome (AIDS). CD4+ lymphocyte numbers drop after initial infection, rise again, and then decline slowly over the course of infection.

MCMD HAD Myelopathy

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and infectious pathogens circulating in the blood (Fig. 93–3). However, HIV is able to traverse the blood-brain barrier, and probably the blood-nerve barrier, soon after primary infection via circulating HIV-infected (and activated) leukocytes, including macrophages and lymphocytes, which adhere to endothelia within the neural compartment and subsequently enter the parenchyma. On entry, HIV establishes infection of perivascular macrophages, resident microglia, and to a lesser extent, astrocytes or Schwann cells. In contrast HIV infection of neurons is minimal or nonexistent. This process by which HIV enters the CNS or PNS is termed the “Trojan Horse” hypothesis. HIV infects macrophages and microglia through binding to the CD4+ molecule, which acts as the primary receptor in association with the chemokine receptors (CCR5 and CXCR4) as co-receptors for infection. HIV-1 exerts its neuropathogenic effects through two principal mechanisms; one is stimulation of neuroimmune cells within the CNS or PNS to produce host proinflammatory molecules, such as cytokines, chemokines, prostaglandins, redox reactants, excitotoxic amino acids or derivatives thereof, and enzymes, which damage neurons and the proximate astrocytes that support them. The alternative mechanism by which neural cells are injured is through direct (neurotoxic) interactions between HIV-encoded proteins (including glycoprotein 120, glycoprotein 41, Tat, and Vpr) and the target cell (including neurons or astrocytes). In fact, these mechanisms overlap in a complementary manner, inasmuch as perivascular macrophages and microglia are the chief sources of both the host neuropathogenic molecules and the secreted neurotoxic viral proteins; whereas some of the host molecules activate viral replication, most of the viral proteins can also activate neuropathogenic host gene responses. The CNS pathological hallmarks of HIV infection include multinucleated giant cells, diffuse white matter pallor, perivas-

Figure 93–2. Primary human immunodeficiency virus (HIV)–induced neurological syndromes occurring during the course of infection. Individual syndromes arise in accordance with the degree of immune suppression; for example, acute meningitis and Guillain-Barré syndrome (GBS) tend to arise earlier in the disease course, whereas HIV-associated dementia (HAD) and distal sensory polyneuropathy (DSP) tend to arise much later. All levels of the nervous system can be affected by HIV. AIDS, acquired immunodeficiency syndrome; ATN, antiretroviral toxic neuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; MCMD, minor cognitive and motor deficit.

cular cuffs composed of monocytes and lymphocytes, microglial nodules, and the presence of HIV-1 antigens9-11 (Fig. 93–4). The diffuse white matter pallor exhibits preserved myelin protein expression but concurrent deposition of serum proteins in white matter, which implies that altered permeability of the blood-brain barrier rather than frank demyelination underlies diffuse myelin pallor.12,13 Neuronal and astrocyte injury and death are defined by dendritic “pruning,” together with cell death involving both necrotic and apoptotic mechanisms, depending on the effector molecule and the selective vulnerability of the target cell (Fig. 93–5). For example, neurons in the basal ganglia represent a highly susceptible population, in part because of the high density of microglia in this region of the CNS but also because of the intrinsic properties of this group of neurons. In the PNS, infiltrating macrophages and lymphocytes are present during HIV infection and often exhibit HIV antigens and genome. Damage to dorsal root ganglia neurons and a dying-back (wallerian) pattern of axonal injury, chiefly affecting small-diameter axons, is apparent.14,15 A limited correlation exists between the clinical entity HAD and the pathological entity HIV encephalitis, defined by the

chapter 93 neurological disorders associated with hiv

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Cytokines, chemokines, ROS

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Cytokines, ROS, gp120, and Tat

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Figure 93–3. Neuropathogenesis of human immunodeficiency virus (HIV) infection. HIV infects macrophages and lymphocytes in the periphery. The virus binds to and enters immune cells by engaging the CD4+ receptor coupled with CCR5 (white receptor) or CXCR4 (red receptor), respectively. The infected immune cells then travel across the blood-brain barrier (BBB), or the blood-nerve barrier, and the accompanying virus is free to infect microglia and astrocytes in the nervous system. Subsequently, infected cells release a spectrum of inflammatory and neurotoxic molecules, including cytokines, chemokines, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs). Coupled with HIV’s intrinsic neurotoxic proteins Tat and glycoprotein 120 (gp120), the released mediators result in neuronal apoptosis and death.

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Figure 93–4. Pathological features of human immunodeficiency virus (HIV) encephalitis. These include (A) perivascular cuffing and (B) multinucleated giant cells (arrow).

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Figure 93–5. Immunohistochemical staining of brains from patients with acquired immunodeficiency syndrome (AIDS) (A and C) and from patients with human immunodeficiency virus (HIV)–associated dementia (HAD) (B and D). The neurons of HAD patients are fewer and significantly smaller and have fewer dendritic and axonal processes. MAP-2, microtubule-associated protein 2.

presence of multinucleated giant cells or the presence of viral antigens.9,16,17 There may also be a correlation between HIV antigen load and HAD,18 although other studies have suggested that macrophage and microglia presence and activation in the basal ganglia are better predictive markers for HAD.19 Although neuronal injury and death in the frontal cortex and deep gray matter occur in the brains of patients with AIDS,20-22 the degree of neuronal loss is correlated with the severity of HAD. Results of a 2001 study also imply that the astrocyte death is associated with rapidly progressive HAD.23

NEUROCOGNITIVE SYNDROMES IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION Unlike acute viral infections of the CNS, the pathogenic effects of HIV usually manifest long after initial infection, with ensuing cognitive, motor, and behavioral dysfunction among affected patients. Nevertheless, rare cases of acute encephalopathy have been reported during HIV seroconversion. HAD represents a constellation of progressive symptoms and signs associated that usually begin once an individual’s CD4+ T cell counts dips below

T A B L E 93–1. Clinical Features of HIV-Associated Dementia (Typical of a Subcortical Dementia) Neurocognitive decline: forgetfulness, poor concentration, psychomotor slowing Emotional disturbance: apathy, mania, irritability Motor dysfunction: tremor, hyperreflexia, spasticity, ataxia Often preceded by minor cognitive and motor deficits HIV, human immunodeficiency virus.

200 cells/μL of blood; not surprisingly, HAD is an AIDS-defining illness (Table 93–1). With the availability of HAART, HAD is now manifesting with CD4+ cell levels exceeding 200 cells/μL. Of most importance, the diagnosis of HAD heralds a worsened survival prognosis with or without HAART.24 Before the era of HAART, the annual incidence of HAD was 53%, although the overall prevalence was only 6%,24 probably a consequence of the high mortality rate after HAD onset, as survival time after diagnosis was only 5.1 months.25,26 With the advent of HAART, the incidence of HAD has fallen to less than 10%, survival time after

chapter 93 neurological disorders associated with hiv T A B L E 93–2. Risk Factors for HIV-Associated Dementia Low CD4+ count and high plasma viral load at diagnosis Anemia Extremes of age: elderly people and children Intravenous drug abuse (rapid progression) High viral RNA load in cerebrospinal fluid HIV, human immunodeficiency virus.

T A B L E 93–3. Radiological, CSF, and Neuropathological Features of HIV-Associated Dementia Central (caudate, putamen) and cortical atrophy Reduced N-acetyl aspartate levels on MRS Patchy hyperintensity of periventricular white matter in T2-weighted MRI Increased protein and IgG levels together with pleocytosis in 66% of patients with HIV-associated dementia Increased HIV RNA in CSF as measured by PCR is correlated with severity of dementia Neuropathology includes multinucleated giant cells, diffuse myelin pallor, microglia nodules, neuronal death, and dendritic pruning CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IgG, immunoglobulin G; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; PCR, polymerase chain reaction.

diagnosis has leapt to 38.5 months, and longer survival times have resulted in overall higher prevalence rates. Risk factors for HAD include low CD4+ levels, high viral loads in cerebrospinal fluid or plasma, anemia, extremes of age, and intravenous drug use (Table 93–2). Also, patients with marked immunosuppression who have no experience with antiretroviral therapy may experience an exaggerated immune response, the immune reconstitution inflammatory syndrome (IRIS), after HAART introduction.27 Indeed, IRIS occasionally manifests as transient cognitive dysfunction together with signs and symptoms of acute meningoencephalitis, although preexisting neurological complications of AIDS may also be exacerbated with IRIS.28,29 It has also been postulated that MCMD is a risk factor for progression to HAD.30 MCMD is a syndrome exhibiting many clinical aspects of HAD, although the signs and symptoms are less severe. Because MCMD has been identified in patients with higher CD4+ counts, there is some suggestion that it may be the precursor to HAD.31 MCMD may affect as many as 30% of patients with HIV or AIDS in North American clinics.32 Nonetheless, comorbid conditions, including chronic drug abuse, head injury, and other risk factors for neurocognitive impairments, may contribute to the diagnosis of MCMD. Because HIV preferentially affects the basal ganglia and deep white matter, HAD predictably manifests with many of the features of a subcortical dementia (Table 93–3). Affected patients typically display neurocognitive impairment, emotional disturbances, and progressive motor decline,33 although HAD has remarkably diverse clinical phenotypes that may include movement disorders.34-36 1. Neurocognitive impairments: Patients frequently complain of an advancing process of mental slowing and find they are no longer as “quick” as they once were. They initially complain of minor forgetfulness, especially the inability to remember simple items such as phone numbers and names, although memory function declines steadily. Concentration

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is also impaired, and this is one of the most disturbing features of HAD for affected patients. They often lose the ability to read books or focus on television. These symptoms are usually confirmed by family members’ and caregivers’ reports, although employment history can be a useful indicator of neurocognitive difficulty. 2. Behavioral disturbances: Patients with HAD frequently display marked apathy and social withdrawal, despite not feeling depressed. These symptoms prevent patients from being part of the workforce and are a significant cause for concern in family members and care providers. Other behavioral manifestations can include marked irritability and mental inflexibility, together with decreased sex drive. HAD can result in psychosis or mania, although these manifestations are not common.37,38 3. Motor dysfunctions: As HAD progresses, patients begin to experience generalized weakness, imbalance, and clumsy gait. They can also display slowing of motor function. Physical examination often reveals a diffuse increase in tone, tremor, and hyperreflexia, together with saccadic smoothpursuit eye movements. Parkinsonian signs, including a masklike facies and slowed stooped gait, are also frequently present. Frontal release signs and myoclonus are occasionally present, particularly in advanced stages of the disease.39 Of importance is that HAD is difficult to detect with the Mini-Mental Status Examination unless the patient is severely demented, most likely because HAD is a subcortical dementia. If there is a suspicion that an HIV-seropositive patient is suffering from HAD, more useful screening tools are applicable, including the HIV Dementia Scale,40 the Mental Alteration Test,41 the Executive Interview,42 and the HIV Dementia Assessment.43 A widely accepted tool for clinical staging of HAD is the Memorial Sloan-Kettering Scale, which provides a qualitative measure of dementia severity, allowing the physician to track progression of the dementia over time.44 Radiological features accompanying HAD (Fig. 93–6) include cerebral and basal ganglia atrophy and diffuse periventricular white matter hyperintensities on T2-weighted MRI (Fig. 93–7).45,46 Unfortunately, it is difficult to correlate the presence of these radiological changes with the presence of HAD, as nondemented patients with HIV infection or AIDS also display these changes on neuroimaging.47 Magnetic resonance spectroscopy studies show diminished N-acetyl aspartate levels in the brain, which imply neuronal injury or loss.48 Other critical investigations include cerebrospinal fluid analyses, chiefly to exclude opportunistic processes and also to assess the levels of viral replication in the neural compartment. The course of the dementia is variable; some individuals experience an abrupt decline in function over weeks, whereas others display a protracted course over several years that culminates in death.49 The most effective management of HAD is treatment of the underlying cause. HAART routinely consists of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and either a potent protease inhibitor (PI) or a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI). Clinical trials have shown that neuropsychological testing scores improve in patients with HIV or AIDS who are treated with two NRTIs and the NNRTI nevirapine,50 as well as with two NRTIs and a protease inhibitor.51,52 Specific antiretroviral drugs, including zidovudine (AZT) (an NRTI), stavudine (an NRTI), abacavir (an NRTI), nevirapine (an NNRTI), and indinavir (a

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Figure 93–6. T2-weighted magnetic resonance image (MRI) of the brain of a 38-year-old human immunodeficiency virus (HIV)–seropositive man with HIV-associated dementia (HAD). The CD4+ count was 100 cells/μL, and the viral load was 106. This MR image demonstrates atrophy of the caudate and cortex, as well as patchy hyperintensity of periventricular white matter. The patient presented with a 3- to 6-month history of increasing forgetfulness, poor concentration, irritability, apathy, slowed cognition, and slowed motor activity with gait ataxia, tremor, hyperreflexia, and parkinsonian symptoms. He responded to highly active antiretroviral therapy (HAART) and returned to work 1 year after initiation of treatment.

protease inhibitor), can permeate the blood-brain barrier better than others.39 The resulting high cerebrospinal fluid drug levels may act to decrease viral load in the CNS. Neuropsychological assessment is an invaluable tool in confirming the diagnosis of HAD and also in facilitating evaluation of the response to therapy among patients with HAD or MCMD. If a particular patient is having symptoms of mania or psychosis, it is best to avoid use of efavirenz (an NNRTI), because this particular drug may cause hallucinations, vivid dreams, and behavioral changes, all of which may exacerbate an individual’s existing symptoms. The addition of methylphenidate and amantidine as adjunct therapies may alleviate some symptoms of psychomotor retardation, thus increasing quality of life.53 Unfortunately, HAART has limited efficacy in reversing HAD, and thus clinicians must consider other treatments that have potential neuroprotective properties. Several agents have been investigated in the past, although few have had significant beneficial effects. Selegiline may have an antiapoptotic effect and slow the progression of HAD.31,54 Memantine has been shown to block neurotoxicity induced by the HIV viral proteins Tat and glycoprotein 120.55 A phase II multicenter trial to test the efficacy of memantine in alleviating symptoms of HAD and HIV-associated peripheral neuropathy is ongoing. Prinomastat

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Figure 93–7. HIV patients with neurological disease exhibit significantly lower Health Related Quality of Life (HRQoL) scores compared with matched controls. This is the most evident among HIV/AIDS patients with cognitive impairment and sensory neuropathy. HAART, appropriate pain management, and counseling lead to progressive and sustained improvement in HRQoL scores.

is a matrix metalloproteinase inhibitor that has been shown to inhibit HIV Tat-associated neurotoxicity and may be a potential neuroprotective agent in HAD.56 Human growth hormone has been shown to be neuroprotective and may also be a component of HAD treatment in the future.57 CPI-1189 blocks the effect of tumor necrosis factor α but was not beneficial in clinical trials.58 Antioxidants such as OPC-14117, which is structurally similar to vitamin E, also had no effect in clinical trials.59 The L-type Ca2+ blocker nimodipine also had no effect on HAD, although it shows some promise for HIV-associated peripheral neuropathies.60

MYELOPATHY HIV-associated vacuolar myelopathy affects 10% to 15% of untreated patients with AIDS (Table 93–4), usually manifesting as gait ataxia, leg weakness, spasticity, and incontinence.61,62 Impaired proprioception with sensory ataxia may also be present. It can occur independently or in conjunction with HAD or with opportunistic infections and malignancies. Progression is insidious over months without back pain. Physical examination reveals symmetrical spastic paraparesis, with lower extremity hyperreflexia and extensor plantar responses. Upper limb signs are less common, although hyperreflexia of

chapter 93 neurological disorders associated with hiv T A B L E 93–4. Clinical Features of Vacuolar Myelopathy Gait ataxia Leg weakness Spasticity Incontinence Hyperreflexia, extensor plantar response Impaired proprioception with sensory ataxia may be present

the arms is occasionally present. There is no defined sensory level. Subclinical vacuolar myelopathy, indicated by hyperreflexia, spasticity, and extensor plantar reflexes, may be evident on examination in an otherwise asymptomatic patient, but other causes of myelopathy should be ruled out. The incidence of vacuolar myelopathy has dropped with HAART to a point that it is infrequently seen in HIV clinics except in severely immunosuppressed patients.62 Although HAART appears to reduce the incidence of vacuolar myelopathy, limited reversal of the signs or symptoms is observed after therapy is implemented. The diagnosis is one of exclusion of other conditions causing chronic myelopathy, such as human T cell lymphotropic virus type I or II infection, vitamin B12 deficiency, or varicella-zoster virus–related myelopathy, all of which must be ruled out by a complete blood cell count, vitamin B12 measurement, cerebrospinal fluid analysis, and neuroimaging studies. The neuropathological correlates of vacuolar myelopathy are axonal injury and intense macrophage infiltration. The vacuolar appearance localized primarily in the lateral and dorsal columns of thoracic spinal cord may reflect intramyelinic edema and inflammation. Approximately 25% of patients with symptoms or signs suggestive of a myelopathy subsequently have pathologically confirmed vacuolar myelopathy. Symptomatic treatment for painful spasticity, clonus, and tremor, including baclofen and gabapentin, is frequently beneficial to patients with vacuolar myelopathy.

PERIPHERAL NEUROPATHIES Peripheral neuropathy has become the major complication of HIV infection in the developed world; substantial numbers of patients with HIV or AIDS seek assistance for control of their symptoms.63 There are two major groups of neuropathy associated with HIV infection64 (Table 93–5). The first group is the HIV-associated neuropathies, which include distal sensory polyneuropathy, autonomic neuropathy, acute and chronic demyelinating neuropathies, and mononeuritides multiplex.65 The second group of neuropathies encountered among treated patients with HIV or AIDS includes the antiretroviral toxic neuropathies. These arise as a result of the use of antiretroviral agents, including didanosine, zalcitabine, and stavudine.66 Both groups of these neuropathies warrant investigation and treatment because of their remarkably disabling features and outcomes. It is also imperative to rule out other causes of painful neuropathy, including diabetes, amyloidosis, nutritional deficiency or ethanol abuse, and concomitant drugs (chemotherapeutics, metronidazole), when possible. As life expectancies among patients with HIV or AIDS increase, clinicians must be suspicious about the onset of diabetic peripheral neuropathy, especially when considering the metabolic side effects of different HAART regimens.

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T A B L E 93–5. Clinical Features of HIV Sensory Neuropathies, Including Distal Sensory Polyneuropathy and Antiretroviral Toxic Neuropathy Paresthesias, dysesthesias, allodynia, burning sensation, diminished pinprick and temperature sensation Symptoms more apparent in feet than in hands, with diminished or absent ankle deep tendon reflexes Associated autonomic symptoms and signs (postural hypotension, impotence) For antiretroviral toxic neuropathy, neurotoxic antiretroviral therapy (d4T, ddI, ddC) preceding onset of symptoms and signs by 3-6 months Loss of small-diameter axons with accompanying inflammation of nerve; normal electrophysiological studies (EMG and NCS) Responsive to anticonvulsants and opiates d4T, stavudine; ddC, zalcitabine; ddI, didanosine; EMG, electromyography; HIV, human immunodeficiency virus; NCS, nerve conduction study.

Sensory Neuropathies Distal sensory polyneuropathy is the most common neuropathy, affecting 30% of patients with AIDS. It is associated with advanced HIV infection and usually manifests as neuropathic pain indicated by a subacute burning sensation, paresthesia, or dysesthesia that worsens as the day progresses, especially on the soles and dorsa of the feet. Patients often report nighttime awakening caused by foot discomfort, but symptoms in the hands can also be present, albeit less frequently. Physical examination usually reveals a stocking distribution loss of pain and temperature sensation with diminished or absent distal deep tendon reflexes, accompanied by atrophic skin changes in the feet and venous pooling.67 If proprioception is also abnormal, there is likely to be a concomitant vacuolar myelopathy. Patients often exhibit an antalgic gait and may require a cane or wheelchair in severe cases, although foot weakness is a very late component of the neuropathy. The symptoms and signs of antiretroviral toxic neuropathies are identical to those of distal sensory polyneuropathy, and the two entities are frequently indistinguishable except by a history of recent-onset neuropathy with initiation of a neurotoxic drug within several months. Nerve conduction studies with electromyography are useful for ruling out other conditions but frequently yield normal results in both distal sensory polyneuropathy and antiretroviral toxic neuropathy because both syndromes usually involve smalldiameter fibers and are principally sensory neuropathies.68 Nerve biopsies are also helpful in ruling out other diagnoses; several groups have developed a quantitative evaluation of skin biopsy samples from the leg to aid in the diagnosis of sensory neuropathies. The treatment modalities for these two latter types of neuropathy clearly require different strategies; distal sensory polyneuropathy necessitates initiation of HAART, preferably without the potentially neurotoxic antiretroviral drugs (PIs, especially indinavir),68a whereas antiretroviral toxic neuropathy entails replacing the neurotoxic antiretroviral drugs with nonneurotoxic agents. Indeed, introduction of HAART frequently improves symptoms, if not signs, of distal sensory polyneuropathy over months, and cessation of the incriminated neurotoxic antiretroviral agent also improves symptoms. Symptomatic treatment options include antiepileptic agents

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such as gabapentin, lamotrigine, or topiramate, although definitive studies support the use of only gabapentin.69 Despite clinical trials indicating that amitriptyline is not beneficial in the control of pain associated with distal sensory polyneuropathy, experienced clinicians continue to use it in selected patients.70 Opioids are highly effective in the control of neuropathic pain but elicit the potential for establishing or reestablishing drug dependence and may interfere with neurocognitive function in patients who are already at risk for HAD. Similarly, lidocaine gel is used by many clinicians, but it has no proven efficacy.71 A previous trial suggested that human nerve growth factor may have potential uses in the future.72

Mononeuritis Multiplex A history of asymmetrical sensory and motor dysfunction affecting distal nerves and occurring over weeks is suggestive of mononeuritis multiplex. This condition is hypothesized to result from immune complex deposition in the vasculature surrounding the affected nerve, which leads to vasculitis.73,74 Evidence of vasculitis is occasionally found in the skin and joints. It is important to rule out hepatitis B or C infection, because cryoglobulinemia can manifest with mononeuritis multiplex in a manner similar to that of HIV during infection.75,76 A sural nerve biopsy specimen can reveal epineural and endoneural perivascular inflammatory infiltrates.77 In patients with spontaneous remission, treatment may not be necessary. Short-term prednisone has been used with some success in small groups of patients, although no large-scale clinical trials have been conducted.78 Only 1% of patients with clinically defined AIDS are affected by mononeuritis multiplex, and thus it is relatively rare among the neuropathies.

Inflammatory and Demyelinating Polyneuropathies Patients can present with ascending neuropathy indistinguishable from Guillain-Barré syndrome at any stage of HIV infection. Analysis of the cerebrospinal fluid in HIV-associated Guillain-Barré syndrome reveals pleocytosis and raised protein levels.79,80 Treatment of HIV-associated Guillain-Barré syndrome is no different than that of sporadic Guillain-Barré syndrome, and plasmapheresis or intravenous immunoglobulin can thus be tried. The overall outcome is also no different, especially if the CD4+ count is above 200 cells/μL.81 HIVseropositive patients can recover completely from GuillainBarré syndrome, although some residual weakness may linger. After an episode of Guillain-Barré syndrome, patients may be at increased susceptibility to other forms of peripheral neuropathy, such as distal sensory polyneuropathy or antiretroviral toxic neuropathy. Chronic inflammatory demyelinating polyneuropathy tends to manifest in patients with CD4+ T cell counts in the range of 200 to 500 cells/μL with features typical of sporadic inflammatory demyelinating polyneuropathy, although pleocytosis and an elevated protein level are frequent findings in HIV-associated chronic disease. Electrophysiology is helpful for confirming the diagnosis, showing conduction block with slowed velocities, distal slowing, and reduced compound motor action potentials. Conventional treatments with gluco-

corticoids, intravenous immunoglobulin, or plasmapheresis are effective; at least 20% of patients achieve complete remission, and 80% experience at least some improvement.

Entrapment Neuropathy HIV-seropositive patients are at increased risk for entrapment neuropathy, most commonly carpal tunnel syndrome. In addition to repetitive wrist motions, risk factors for developing carpal tunnel syndrome in the general population include metabolic syndromes such as diabetes, weight gain, and hypothyroidism. Another common entrapment neuropathy in HIV infection is meralgia paresthetica. Because treatment with protease inhibitors causes metabolic abnormalities, treatment with protease inhibitors may predispose patients to entrapment neuropathy by enhancing deposition of myxedematous material or fat in the carpal tunnel.82 Results of one case series have suggested that carpal tunnel syndrome in HIV-seropositive patients is simply related to repeated stress injury.32 A third possibility is that subclinical inflammation of the median nerve caused by HIV infection is exacerbated by friction within the carpal tunnel, causing symptoms that might not occur in a HIV-seronegative individual. Regardless of the cause, carpal tunnel syndrome can be treated with the use of splints or by surgical intervention.83

Miscellaneous Neuropathies Two other distinct neuromuscular syndromes occur in HIV infection. Among patients with CD4+ levels in the range of 200 to 500 cells/μL, a sensorimotor neuropathy associated with diffuse infiltrative lymphocytosis syndrome (DILS) may be present. The neuropathy accompanying DILS has a subacute and frequently asymmetrical onset, together with the occurrence of parotidomegaly and sicca syndrome. The neuropathy often progresses to a symmetrical pattern with neuropathic pain. Electrophysiological study findings are usually abnormal, and nerve biopsy specimens showing CD8 lymphocyte infiltrates provide confirmation of the diagnosis. DILS responds to HAART; more than 60% of patients make an excellent recovery. Glucocorticoids may also be helpful in the treatment of DILS among patients who do not respond to HAART. A motor neuron–like condition has also been recognized among patients with HIV or AIDS.84 Affected patients are usually immunosuppressed and present with unexplained distal weakness that may progress rapidly. Electromyography discloses features indicative of symmetrical denervation and motor neuron dysfunction. This syndrome is ameliorated by HAART, with complete resolution of neurological signs in some cases. Autonomic neuropathy is present in 12% of HIVseropositive patients and is frequently found in conjunction with distal sensory polyneuropathy.85,86 The most common manifestations are postural hypotension, followed closely by gastroparesis and impotence. Postural hypotension can be treated with fludrocortisone, and cisapride and sildenafil can be effective in combating gastroparesis and impotence, respectively. Isolated mononeuropathies are more common in early HIV infection. Interestingly, these neuropathies tend to manifest themselves in the cranial nerves. A cranial nerve VII palsy that is indistinguishable from Bell’s palsy has been reported fre-

chapter 93 neurological disorders associated with hiv quently in patients with HIV or AIDS87 and may be recurrent. Likewise, cranial nerve V palsies can also occur during HIV infection. As with patients who do not have HIV infection, these palsies resolve over the course of several weeks, rarely leaving residual neurological deficit. A retrobulbar optic neuritis should be given special consideration in a patient with advanced HIV infection, because it may be secondary to herpes zoster infection and thus necessitate aggressive treatment.88 In addition, the possibility of underlying multiple sclerosis must be considered, because multiple sclerosis and HIV or AIDS can coexist despite the depletion of lymphocytes in HIV infection.89,90

MYOPATHIES In patients with HIV or AIDS presenting with proximal muscle weakness and myalgias, a wide range of diagnostic possibilities need to be considered. However, specific entities to be aware of include polymyositis, zidovudine-induced myopathy, and statin-associated rhabdomyolysis. Polymyositis occurs in HIV or AIDS, in part because of the marked immune dysregulation that coexists in HIV infection and the increasingly frequent co-infection with hepatitis B and C viruses, depending on the population. Although not different with regard to clinical findings, polymyositis in HIV infection exhibits distinct pathological features, including CD8 T cell and macrophage infiltrates, together with the presence of HIV genome or antigens. Zidovudine-induced myopathy is another common cause of weakness and myalgias in patients with HIV or AIDS. This myopathy usually manifests with insidious onset of signs and symptoms and elevated serum creatine kinase levels, and the diagnosis is confirmed by muscle biopsy, which reveals ragged red fibers and other features indicative of mitochondrial dysfunction. Statin-induced rhabdomyolysis has become an increasing problem among patients with HIV or AIDS as this population ages and with the increased use of statins to combat hyperlipidemia associated with different HAART regimens. Electromyography, creatine kinase and thyroid-stimulating hormone measurements, and muscle biopsy are often helpful in facilitating the diagnosis in each of these disorders. Intravenous immunoglobulin and glucocorticoids may hasten recovery of polymyositis, although it is usually self-limited, whereas cessation of zidovudine or the implicated statin leads to improvement in these latter conditions.

HEADACHE There are three general categories of headache among individuals with HIV. The first category of headache includes aseptic meningitis, which frequently manifests as part of the constellation of symptoms associated with HIV seroconversion.91 The second (and most important to rule out) is headache as a result of opportunistic infections such as cryptococcal meningitis, toxoplasmosis encephalitis, or tuberculous meningitis. The third category of HIV-associated headache is primary headache of no other known etiology, which is present in 25% of patients with HIV infection.92 There is an association between HAD and headache with an unclear mechanism,93 and primary HIVassociated headache may be merely a chronic form of aseptic meningitis that occurs long after seroconversion has taken place. Most HIV-associated primary headaches progress slowly

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over the course of several weeks. They are nonthrobbing and have a component of photophobia. Unfortunately, these headaches tend not to respond well to conventional pain control medications, although treatment with low-dose tricyclic medication (amitriptyline, 10 to 25 mg every hour before sleep) can be effective in some patients.94 Because the headaches frequently occur in conjunction with depression and polypharmacy, psychiatric consultation may be warranted.

SEIZURE DISORDERS Among patients with HIV infection, new-onset seizures occur in 8% of adults and up to 20% of children. The majority of seizures are generalized tonic-clonic seizures that progress to status epilepticus in 8% to 18% of affected patients. There are many potential causes of seizures in HIV-seropositive patients, including opportunistic infections, medications, substance use or withdrawal, metabolic disturbance, and HIV infection itself. Seizures are most commonly associated with toxoplasmosis encephalitis, followed by cryptococcal meningitis and primary CNS lymphoma.95 The seizure may be the only sign that the patient is suffering from an infectious or malignant process, especially in the case of CNS lymphoma. Certain medications are associated with a decrease in seizure threshold, including selective serotonin reuptake inhibitors, tricyclic antidepressants, ganciclovir, and foscarnet. Cocaine and heroine use are also associated with an increased risk of seizures, as is alcohol withdrawal. Disturbances of electrolyte balance can also cause seizures, as in patients without HIV infection. In up to 50% of HIV-seropositive individuals, no underlying cause of the seizure is found except HIV itself.96,97 Interestingly, 25% of patients with seizures of unknown etiology have features of HAD39 and have an increased likelihood of developing HAD within 6 months of the seizure.96 Without treatment, seizures are highly likely to recur. Because HIV-seropositive patients inherently have a higher rate of adverse drug reactions, as many as 25% of patients develop a rash with phenytoin. Because many anticonvulsants are metabolized by the cytochrome P-450 system, there is a high likelihood of drug interactions with HAART. In addition, protease inhibitors can bind to albumin and compete with the anticonvulsants, thus altering drug levels. Despite these concerns, carbamazepine is well tolerated when coupled with close monitoring of anticonvulsant levels and viral load. Valproate has been shown to induce viral replication in vitro, although this has not been demonstrated in vivo.98 The next generation of anticonvulsants, such as gabapentin, topiramate, and tiagabine, are safer choices.99 Topiramate, however, may hasten weight loss and thus should perhaps be avoided in individuals with low body mass indices.

FUTURE PERSPECTIVES Because of the rising prevalence of HIV infection and AIDS in the developed world and the increasing incidence of HIV infection in the developing world, it is likely that new HIVassociated neurological syndromes will emerge with time. Immediate concerns include identification and characterization of the neurological illnesses associated with HIV-1 non–B subtype infections, which remain poorly defined at present. In

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addition, the appearance and transmission of drug-resistant HIV-1 strains is a growing problem for which there exist few data describing the accompanying neurological disorders.29 The extent to which the nervous system serves as a covert reservoir for HIV, from which it can then spread to the rest of the body, remains uncertain but is a topic of keen interest and investigation.100 As the population with HIV infection and AIDS grows and ages, neurological diseases associated with aging, including stroke and primary dementias, are becoming more prevalent. In addition, the long-term neurological effects of antiretroviral therapy remain incompletely understood. Indeed, the risk of stroke is increasing in patients with HIV or AIDS, in part because of the marked metabolic abnormalities (hyperglycemia and hyperlipidemia) associated with different antiretroviral regimens, together with advancing age and improved overall survival. Finally, the growing importance of HIV infection and co-infection with hepatitis C virus or human T cell lymphotropic virus types I and II may also have substantial effects on neurological disease manifestations and outcomes.

K E Y

P O I N T S

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The neurological sequelae of HIV infection are common and are as a result of (1) the immediate neurotoxic and neuroinflammatory effects of HIV on the CNS and PNS and (2) opportunistic infections.

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HAART has improved overall survival and diminished the severity and frequency of HIV-associated neurological disorders.

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HAD and vacuolar myelopathy occur as a result of HIV’s direct effects on the CNS.

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Peripheral sensory neuropathies arise directly from HIV infection or from peripheral nerve toxicity induced by specific antiretroviral drugs (didanosine, zalcitabine, stavudine).

●

Current treatment options for AIDS-related neurological disease include HAART and symptomatic treatments.

Suggested Reading Estanislao L, Carter K, McArthur J, et al: A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr 2004; 37:15841586. Hahn K, Arendt G, Braun JS, et al: A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol 2004; 251:1260-1266. Miller RF, Isaacson PG, Hall-Craggs M, et al: Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol (Berl) 2004; 108:17-23. Vendrely A, Bienvenu B, Gasnault J, et al: Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 2005; 109:449-455. World Health Organization “3 by 5” Progress Report, December 2004. Geneva: World Health Organization and Joint United Nations Programme on HIV/AIDS, 2004. Available at: http://

www.who.int/3by5/progressreportfinal.pdf (accessed April 20, 2006).

References 1. Janssen RS, Cornblath DR, Epstein LG, et al: Human immunodeficiency virus (HIV) infection and the nervous system: report from the American Academy of Neurology AIDS Task Force. Neurology 1989; 39:119-122. 2. Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1998. 3. Rausch DM, Davis MR: HIV in the CNS: pathogenic relationships to systemic HIV disease and other CNS diseases. J Neurovirol 2001; 7:85-96. 4. Sacktor N: 2002; The epidemiology of human immunodeficiency virus–associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol 8(Suppl 2):115-121. 5. World Health Organization “3 by 5” Progress Report, December 2004. Geneva: World Health Organization and Joint United Nations Programme on HIV/AIDS, 2004. Available at: http://www.who.int/3by5/progressreportfinal.pdf (accessed April 20, 2006). 6. McArthur JC: Neurologic manifestations of AIDS. Medicine (Baltimore) 1987; 66:407-437. 7. Mamidi A, DeSimone JA, Pomerantz RJ: Central nervous system infections in individuals with HIV-1 infection. J Neurovirol 2002; 8:158-167. 8. Roullet E: Opportunistic infections of the central nervous system during HIV-1 infection (emphasis on cytomegalovirus disease). J Neurol 1999; 246:237-243. 9. Navia BA, Cho ES, Petito CK, et al: The AIDS dementia complex: II. Neuropathology. Ann Neurol 1986; 19:525535. 10. Sharer LR: Pathology of HIV-1 infection of the central nervous system. A review. J Neuropathol Exp Neurol 1992; 51:3-11. 11. Vinters HV, Anders KH: Neuropathology of AIDS. Boca Raton, FL: CRC Press, 1990. 12. Petito CK, Cash KS: Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol 1992; 32:658-666. 13. Power C, Kong PA, Crawford TO, et al: Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier. Ann Neurol 1993; 34:339-350. 14. Herrmann DN, Griffin JW, Hauer P, et al: Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999; 53:1634-1640. 15. McCarthy BG, Hsieh ST, Stocks A, et al: Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 1995; 45:1848-1855. 16. Glass M, Faull RL, Bullock JY, et al: Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res 1996; 710:56-68. 17. Sharer LR, Epstein LG, Cho ES, et al: Pathologic features of AIDS encephalopathy in children: evidence for LAV/HTLV-III infection of brain. Hum Pathol 1986; 17:271-284. 18. Achim CL, Heyes MP, Wiley CA: Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J Clin Invest 1993; 91:27692775. 19. Glass JD, Fedor H, Wesselingh SL, et al: Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 1995; 38:755762.

chapter 93 neurological disorders associated with hiv 20. Everall IP, Luthert PJ, Lantos PL: Neuronal loss in the frontal cortex in HIV infection. Lancet 1991; 337:1119-1121. 21. Masliah E, Ge N, Achim CL, et al: Selective neuronal vulnerability in HIV encephalitis. J Neuropathol Exp Neurol 1992; 51:585-593. 22. Masliah E, Ge N, Morey M, et al: Cortical dendritic pathology in human immunodeficiency virus encephalitis. Lab Invest 1992; 66:285-291. 23. Thompson KA, McArthur JC, Wesselingh SL: Correlation between neurological progression and astrocyte apoptosis in HIV-associated. Ann Neurol 2001; 49:745-752. 24. McArthur JC, Hoover DR, Bacellar H, et al: Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 1993; 43:2245-2252. 25. Dore GJ, McDonald A, Li Y, et al: Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. Aids 2003; 17:1539-1545. 26. Portegies P, de Gans J, Lange JM, et al: Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. BMJ 1989; 299:819-821. 27. Shelburne SA 3rd, Hamill RJ: The immune reconstitution inflammatory syndrome. AIDS Rev 2003; 5:67-79. 28. Miller RF, Isaacson PG, Hall-Craggs M, et al: Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol (Berl) 2004; 108:17-23. 29. Vendrely A, Bienvenu B, Gasnault J, et al: Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 2005; 109:449455. 30. Ellis RJ, Deutsch R, Heaton RK, et al: Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group. Arch Neurol 1997; 54:416-424. 31. A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus–associated cognitive impairment. Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Neurology 1998; 50:645-651. 32. Asensio O, Caso JA, Rojas R: Carpal tunnel syndrome in HIV patients? AIDS 2002; 16:948-950. 33. Power C, Johnson RT: HIV-1 associated dementia: clinical features and pathogenesis. Can J Neurol Sci 1995; 22:92-100. 34. Maher J, Choudhri S, Halliday W, et al: AIDS dementia complex with generalized myoclonus. Mov Disord 1997; 12:593-597. 35. Mirsattari SM, Power C, Nath A: Parkinsonism with HIV infection. Mov Disord 1998; 13:684-689. 36. Navia BA, Jordan BD, Price RW: The AIDS dementia complex: I. Clinical features. Ann Neurol 1986; 19:517-524. 37. Alciati A, Fusi A, D’Arminio Monforte A, et al: New-onset delusions and hallucinations in patients infected with HIV. J Psychiatry Neurosci 2001; 26:229-234. 38. Koutsilieri E, Scheller C, Sopper S, et al: Psychiatric complications in human immunodeficiency virus infection. J Neurovirol 8 Suppl 2002; 2:129-33. 39. Nath A, Berger J: HIV dementia. Curr Treat Options Neurol 2004; 6:139-151. 40. Power C, Selnes OA, Grim JA, et al: HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8:273-278. 41. Jones BN, Teng EL, Folstein MF, et al: A new bedside test of cognition for patients with HIV infection. Ann Intern Med 1993; 119:1001-1004. 42. Berghuis JP, Uldall KK, Lalonde B: Validity of two scales in identifying HIV-associated dementia. J Acquir Immune Defic Syndr 1999; 21:134-140.

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43. Grassi MP, Perin C, Borella M, et al: Assessment of cognitive function in asymptomatic HIV-positive subjects. Eur Neurol 1999; 42:225-229. 44. Price RW, Brew BJ: The AIDS dementia complex. J Infect Dis 1988; 158:1079-1083. 45. Dal Pan GJ, McArthur JH, Aylward E, et al: Patterns of cerebral atrophy in HIV-1–infected individuals: results of a quantitative MRI analysis. Neurology 1992; 42:2125-2130. 46. Simpson DM, Tagliati M: Neurologic manifestations of HIV infection Ann Intern Med 1994; 121:769-785 [Erratum in Ann Intern Med 1995; 122:317]. 47. McArthur JC, Cohen BA, Farzedegan H, et al: Cerebrospinal fluid abnormalities in homosexual men with and without neuropsychiatric findings. Ann Neurol 1988; 23:S34-S37. 48. Chang L, Ernst T, Leonido-Yee M, et al: Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology 1999; 52:100-108. 49. Power C, McArthur JC, Johnson RT, et al: Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J Virol 1994; 68:4643-4649. 50. Price RW, Yiannoutos T, Clifford DB, et al: Neurological outcomes in late HIV infection: adverse impact of neurological survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS 1999; 13:1677-1685. 51. Sacktor NC, Lyles RH, Skolasky RL, et al: Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS). Neurology 1999; 52:1640-1647. 52. von Giesen HJ, Koller H, Theisen A, et al: Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HIV-1–infected patients. J Acquir Immune Defic Syndr 2002; 29:363-367. 53. Brown GR: The use of methylphenidate for cognitive decline associated with HIV disease. Int J Psychiatry Med 1995; 25:2137. 54. Sacktor NC, Skolasky RL, Lyles RH, et al: Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors. J Neurovirol 2000; 6:8488. 55. Nath A, Haughey NJ, Jones M, et al: Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine. Ann Neurol 2000; 47:186194. 56. Zhang K, McQuibban GA, Silva C, et al: HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci 2003; 6:1064-1071. 57. Silva C, Zhang K, Tsutsui S, et al: Growth hormone prevents human immunodeficiency virus–induced neuronal p53 expression. Ann Neurol 2003; 54:605-614. 58. Clifford DB: Human immunodeficiency virus–associated dementia. Arch Neurol 2000; 57:321-324. 59. Safety and tolerability of the antioxidant OPC-14117 in HIVassociated cognitive impairment. The Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Neurology 1997; 49:142-146. 60. Navia BA, Dafni U, Simpson D, et al: A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 1998; 51:221-228. 61. Dal Pan GJ, Berger JR: Spinal cord disease in human immunodeficiency virus infection. In Berger JR, Levy RM, eds: AIDS and the Nervous System, 2nd ed. Philadelphia: LippincottRaven, 1997, pp 173-187. 62. DiRocco L, Dalton T, Liang D, et al: Nonallelism for the audiogenic seizure prone (Asp1) and the aryl hydrocarbon receptor (Ahr) loci in mice. J Neurogenet 1998; 12:191-203.

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63. Brinley FJ Jr, Pardo CA, Verma A: Human immunodeficiency virus and the peripheral nervous system workshop. Arch Neurol 2001; 58:1561-1566. 64. Fuller GN, Jacobs JM, Guiloff RJ: Nature and incidence of peripheral nerve syndromes in HIV infection. J Neurol Neurosurg Psychiatry 1993; 56:372-381. 65. Brannagan TH, McAlarney T, Latov N: Peripheral neuropathy in HIV-1 infection. In Latov N, Wokke JH, Kelly JJ, eds: Immunological and Infectious Diseases of the Peripheral Nerves. Cambridge, UK: Cambridge University Press, 1998, pp 285-307. 66. Dalakas MC, Cupler EJ: Neuropathies in HIV infection. Baillieres Clin Neurol 1996; 5:199-218. 67. Price RW: Neurological complications of HIV infection. Lancet 1996; 348:445-452. 68. Pardo CA, McArthur JC, Griffin JW: HIV neuropathy: insights in the pathology of HIV peripheral nerve disease. J Peripher Nerv Syst 2001; 6:21-27. 68a. Pettersen JA, Jones G, et al: Sensory neuropathy in human immunodeficiency virus. Ann Neurol 2006; 59:816824. 69. Hahn K, Arendt G, Braun JS, et al: A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol 2004; 251:1260-1266. 70. Kieburtz K, Simpson D, Yiannoutsos C, et al: A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998; 51:1682-1688. 71. Estanislao L, Carter K, McArthur J, et al: A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr 2004; 37:1584-1586. 72. Schifitto G, Yiannoutsos C, Simpson DM, et al: Long-term treatment with recombinant nerve growth factor for HIVassociated sensory neuropathy. Neurology 2001; 57:13131316. 73. Mahadevan A, Gayathri N, Taly AB, et al: Vasculitic neuropathy in HIV infection: a clinicopathological study. Neurol India 2001; 49:277-283. 74. Verma A: Epidemiology and clinical features of HIV-1 associated neuropathies. J Peripher Nerv Syst 2001; 6:8-13. 75. Cacoub P, Maisonobe T, Thibault V, et al: Systemic vasculitis in patients with hepatitis C. J Rheumatol 2001;28:109-118. 76. Stricker RB, Sanders KA, Owen WF, et al: Mononeuritis multiplex associated with cryoglobulinemia in HIV infection. Neurology 1992; 42:2103-2105. 77. Lipkin WI, Parry G, Kiprov D, et al: Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology 1985; 35:1479-1483. 78. Bradley WG, Verma A: Painful vasculitic neuropathy in HIV1 infection: relief of pain with prednisone therapy. Neurology 1996; 47:1446-1451. 79. Bani-Sadr F, Neuville S, Crassard I, et al: Acute Guillain-Barré syndrome during the chronic phase of HIV infection and dramatic improvement under highly active antiretroviral therapy. AIDS 2002; 16:1562. 80. Cornblath DR, McArthur JC, Kennedy PG, et al: Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol 1987; 21:32-40.

81. Schleicher GK, Black A, Mochan A, et al: Effect of human immunodeficiency virus on intensive care unit outcome of patients with Guillain-Barré syndrome. Crit Care Med 2003; 31:1848-1850. 82. Sclar G: Carpal tunnel syndrome in HIV-1 patients: a metabolic consequence of protease inhibitor use? AIDS 2000; 14:336-338. 83. Verdugo RJ, Salinas RS, Castillo J, et al: Surgical versus nonsurgical treatment for carpal tunnel syndrome. Cochrane Database Syst Rev 2003; (3):CD001552. 84. Moulignier A, Moulonguet A, Pialoux G, et al: Reversible ALSlike disorder in HIV infection. Neurology 2001; 57:995-1001. 85. Evenhouse M, Haas E, Snell E, et al: Hypotension in infection with the human immunodeficiency virus. Ann Intern Med 1987; 107:598-599. 86. Gluck T, Degenhardt E, Scholmerich J, et al: Autonomic neuropathy in patients with HIV: course, impact of disease stage, and medication. Clin Auton Res 2000; 10:17-22. 87. Schielke E, Pfister HW, Einhaupl KM: Peripheral facial nerve palsy associated with HIV infection. 1989; Lancet 1:553-554. 88. Meenken C, van den Horn GJ, de Smet MD, et al: Optic neuritis heralding varicella zoster virus retinitis in a patient with acquired immunodeficiency syndrome. Ann Neurol 1998; 43:534-536. 89. Berger JR, Sheremata WA, Resnick L, et al: Multiple sclerosis–like illness occurring with human immunodeficiency virus infection. Neurology 1989; 39:324-329. 90. Berger JR, Tornatore C, Major EO, et al: Relapsing and remitting human immunodeficiency virus-associated leukoencephalomyelopathy. Ann Neurol 1992; 31:34-38. 91. Cooper DA, Gold J, Maclean P, et al: Acute AIDS retrovirus infection. Definition of a clinical illness associated with seroconversion. Lancet 1985; 1:537-540. 92. Mirsattari SM, Power C, Nath A: Primary headaches in HIVinfected patients. Headache 1999; 39:3-10. 93. Singer EJ, Kim J, Fahy-Chandon B, et al: Headache in ambulatory HIV-1–infected men enrolled in a longitudinal study. Neurology 1996; 47:487-494. 94. Brew BJ, Miller J: Human immunodeficiency virus-related headache. Neurology 1993; 43:1098-1100. 95. Garg RK: HIV infection and seizures. Postgrad Med J 1999; 75:387-390. 96. Dore GJ, Law MG, Brew BJ: Prospective analysis of seizures occurring in human immunodeficiency virus type-1 infection. J Neuro-AIDS 1996; 1:59-69. 97. Holtzman DM, Kaku DA, So YT: New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med 1989; 87:173-177. 98. Romanelli F, Jennings HR, Nath A, et al: Therapeutic dilemma: the use of anticonvulsants in HIV-positive individuals. Neurology 2000; 54:1404-1407. 99. Romanelli F, Ryan M: Seizures in HIV-seropositive individuals: epidemiology and treatment. CNS Drugs 2002; 16:9198. 100. Smit TK, Brew BJ, Tourtellotte W, et al: Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment. J Virol 2004; 78:10133-10148.

CHAPTER

PARASITIC

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94

FUNGAL INFECTIONS ●

●

●

Francois Lette and Zelalem Temesgen

PARASITIC INFECTIONS OF THE CENTRAL NERVOUS SYSTEM In 1909 John D. Rockefeller declared, “Deprivation in the agriculturally rich Southern States is not due to stupidity or laziness, but to parasite infestation.”1 The human immunodeficiency virus pandemic and global warming have resurrected the study of parasitology. In general, parasitic diseases are treatable and should be considered when geography, patient susceptibility, and exposure make infection possible. More than 2 million people die each year of falciparum malaria; 200 million are infected with schistosomiasis. Toxoplasma species flourish in patients with acquired immunodeficiency syndrome (AIDS). Epilepsy from neurocysticercosis affects more than 1% of the population in some regions. Most cases of neurocysticercosis in Mexico remain undiagnosed despite the people having cognitive and psychiatric problems throughout life. Sleeping sickness affects 300,000 Africans and threatens many more. Intestinal helminths dull children’s minds.2 This chapter addresses the major neuroparasites, as is customary in the neurosciences, by location and clinical presentation. The aim is to present the clinician with a catalog of possibilities so that a treatable disease is not overlooked (Table 94–1). The pathophysiology of parasites illustrates how they have adapted to evade the host’s immune system through pleomorphism and antigenic variation (malaria and sleeping sickness) or how they avoid killing their host to ensure their survival (hookworms). Parasites stimulate the secretion of prostaglandins, nitric oxide, and interleukin-10, which down-regulate the immune response (Plasmodium, Trypanosoma, and Toxoplasma), ensuring their quiet multiplication and perhaps teaching us how to find and eliminate them when they cause disease.

Entamoeba histolytica Epidemiology Brain abscess from Entamoeba histolytica occurs in immunocompetent young men with amebic lung or liver abscess. Nevertheless, patients treated with corticosteroids are particularly at risk for extracolonic disease.

Pathophysiology Hematogenous spread to the brain has been described.33

Clinical Presentation Single or multiple brain abscesses are seen with variable presentation.

Diagnosis Diagnosis is by use of microscopy after staining tissue with Gomori trichrome or the iron hematoxylin method. The sensitivity of microscopy is low. The organism may not be found in stool. Enzyme-linked immunosorbent assay (sensitivity, 87%) and polymerase chain reaction (sensitivity, 85%) are used on stool or serum.34-36

Treatment Treatment consists of using metronidazole followed by a luminal agent.

African Trypanosomiasis Epidemiology

Amebic Encephalitis Various features of primary amebic meningoencephalitis (a fulminant encephalitis) and granulomatous amebic encephalitis (a subacute granulomatous disease) are summarized in Table 94–2.

David Livingstone first attributed nagana to the tsetse fly (Glossina) in 1857. The disease is transmitted by male and female tsetse flies through a bite that is painful and does not go unnoticed. Trypanosoma brucei gambiense is found in West Africa; the infection takes months or years to affect the central nervous system (CNS). Trypanosoma brucei rhodesiense causes an acute

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T A B L E 94–1. Clinical Findings Associated with Neuroparasites Coma Falciparum malaria: delirium and symmetrical motor signs Hepatic encephalopathy from late-stage hepatosplenic schistosomiasis See “Meningoencephalitis” Headache Malaria See “Meningoencephalitis” See “Neuroimaging Findings” Hydrocephalus Ascaris: ventriculoperitoneal shunt obstruction Coenurus of Taenia multiceps: arachnoiditis, hydrocephalus (rare)3 Cysticercus of Taenia solium: arachnoiditis and ventricular cysts are associated with hydrocephalus See “Meningoencephalitis” Meningoencephalitis African trypanosomiasis (African sleeping sickness): chronic meningoencephalitis, tremor, ataxia, sleepiness, lymphadenopathy, fluctuating fevers, painful chancre in 50% of Trypanosoma brucei rhodesiense infections, cognitive decline American trypanosomiasis (Chagas disease): immunosuppressed patients or congenital infection4-8 Angiostrongylus cantonensis: eosinophilic meningitis Babesia microti: encephalopathy after splenectomy (temperate climates) Gnathostoma spinigerum: eosinophilic meningitis, transverse myelitis Naegleria fowleri, acanthamebiasis: fulminant meningoencephalitis Paragonimus: insidious mild eosinophilic meningitis Schistosoma japonicum: Katayama fever Strongyloides stercoralis: in immunosuppressed patients, brain abscess and pyogenic meningitis from concurrent gram-negative bacteria carried in gut of parasite Toxocara canis: eosinophilic meningoencephalitis with granulomas, hemorrhagic tracts9,10 Toxoplasma gondii: subacute meningoencephalitis Trichinella spiralis: acute meningoencephalitis11,12 Metabolic/Multiple Levels Diphyllobothrium latum causing vitamin B12 deficiency Hepatic encephalopathy from late-stage hepatosplenic schistosomiasis Muscle Pain or Weakness Cysticercus of Taenia solium: muscular pseudohypertrophy from massive infestation; cysts are palpable and may cause aching Trichinella spiralis Trypanosoma cruzi (Chagas disease): myositis and neuritis Visceral leishmaniasis (uncommon): neuropathy, Guillain-Barré syndrome13 Neuroimaging Findings All these infections, except nonfetal toxoplasmosis, may occur in immunocompetent hosts: Angiostrongylus cantonensis: sharply enhancing brain abscesses; multiple enhancing nodules in the brain and linear enhancement in the leptomeninges; tendency for meningeal, subarachnoid, and brain surface localization14 Coenurus of Taenia multiceps: budding daughter cysts (rare) Cysticercus of Taenia solium: the most common worldwide chronic central nervous system parasite and a common cause of epilepsy There are four stages: Vesicular—small multifocal cysts; mural nodules may be seen (the scolex is alive in this stage); cystic fluid is the same density as CSF; the cysts do not enhance. Colloidal vesicular—the larva is dead or dying and the cyst contracts with a thicker wall; cystic fluid is denser than CSF; inflammation and ring enhancement are likely. Granular nodular—punctate to large calcified nodules with striking edema, usually ring enhancing; a calcified scolex may be seen within the cyst, which is isodense to brain on T1-weighted images and isodense or hypodense on T2-weighted images. Nodular calcified—the lesion is completely calcified, does not enhance, and is without mass effect. CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.

Cysticercosis is characterized further by the following: Cysts may be intraventricular and difficult to see in 20% to 50% of neurocysticercoses and may cause mass effect or ball-valve intermittent hydrocephalus. Subarachnoid basilar arachnoiditis may also cause hydrocephalus. A solitary cysticercus granuloma is the most common presentation in India. Negative imaging does not eliminate a diagnosis of cysticercosis. MRI helps differentiate neurocysticercosis from tuberculosis. Echinococcus (not common) Echinococcus granulosus: large, nonenhancing, often parietal, cyst may be multilobular15,16 Echinococcus multilocularis: multiple, small, enhancing alveoli, which may be metastatic; in a child, single large parenchymal cyst without enhancement or edema and little or no mass effect17 Entamoeba histolytica: single or multiple brain abscesses Gnathostoma spinigerum: MRI shows cervical cord enlargement, hemorrhagic brain tracts, and scattered deep intracerebral hemorrhages18 Onchocercus medinensis: optic nerve atrophy Paragonimus westermani (not common): ring-enhancing, abscess-like cysts with much edema, hemorrhages, and calcifications; typically occipital and temporal lobes; may be space occupying19,20 Schistosoma mansoni and Schistosoma haematobium: myelitis and enlargement of lower spinal cord Schistosoma japonicum: multiple brain granulomas, lucencies, and severe edema21,22 Spirometra mansoni Strongyloides stercoralis: ring-enhancing lesions and lacunae Toxocara canis: small granulomas; multiple subcortical, cortical, or white matter lesions, hypoattenuating on computed tomography scans; hyperintense on T2-weighted MRI and enhancing after administration of contrast medium Toxoplasma gondii: multifocal abscesses and granulomas; nodular or ring lesions with edema; poor prognosis if lack of enhancement Trichinella spiralis: numerous small hypodense lesions on computed tomography; small lacunae in white matter and pons23 Seizure Angiostrongylus cantonensis Cysticercus of Taenia solium (common) Echinococcus granulosus or Echinococcus multilocularis Entamoeba histolytica: abscesses, focal seizures Falciparum malaria with or without hypoglycemia (common) Paragonimus Schistosoma japonicum Spirometra mansoni Toxoplasma canis (common) See “Stroke” Consider tuberculosis or human immunodeficiency virus encephalitis Chloroquine toxicity may cause seizures Mefloquine shortens valproate half-life24 Spinal cord Cysticercus of Taenia solium (not common) Dracunculus medinensis: paraspinal abscess (rare) Echinococcus Gnathostoma spinigerum: very painful radiculitis Paragonimus: radicular pain, spastic paraplegia Schistosoma haematobium: myelitis Schistosoma mansoni: myelitis Toxocara canis: myelitis (rare) See “Metabolic/Multiple Levels” Stroke Trypanosoma cruzi (Chagas disease): cerebrovascular emboli Coenurus of Taenia multiceps (rare) Cysticercus of Taenia solium: lacunar infarcts from arachnoiditis at the base of the brain, which may result in meningitis or vasculitis with stroke Gnathostoma spinigerum: hemorrhages, infarcts Paragonimus (rare) Strongyloides stercoralis hyperinfection Toxocara canis: stroke, mostly in young children Trichinella spiralis25,26

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T A B L E 94–2. Central Nervous System Amebiasis Feature

PAM

GAE

Risk factors

Swimming

Organism

Naegleria

Route to CNS

Olfactory epithelium/nerves

CNS disease

Culture-negative, fulminant, purulent meningitis; mostly PMN, unlike TB or viral Yes30

Diabetes, pregnancy, alcohol/cirrhosis, corticosteroids, AIDS, chemotherapy/radiotherapy Acanthamoeba27,28 Balamuthia Intranasal/intracranial vasculitis leading to thrombosis and infarction Focal or diffuse encephalitis with meningism, giant cell reaction29 Yes

Organism can harbor Legionella, Vibrio cholerae CSF laboratory findings CSF microscopic findings

Glucose variable; protein >1 g/L Motile Naegleria move 1-3 body lengths/min11

Glucose variable Lymphocytic pleocytosis; trophozoite seldom found in CSF31,32

AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; GAE, granulomatous amebic encephalitis; PAM, primary amebic meningoencephalitis; PMN, polymorphonuclear neutrophils; TB, tuberculosis.

illness in East Africa, affecting the brain within a few months of the original bite. Transplacental transmission also occurs. Trypanosomiasis affects several hundred thousand people in Africa because of widespread civil disturbance and war, declining economies, reduced health financing, and the dismantling of disease control programs.

Clinical Presentation A painful chancre is seen in approximately 50% of patients infected with T. b. rhodesiense but is seldom seen in patients infected with T. b. gambiense. The chancre is more common in non-Africans. It develops 5 to 15 days after the bite and heals in 3 to 4 weeks. It occasionally ulcerates and may be associated with regional lymphadenopathy. The first stage of illness is associated with intermittent fever, headache, intense pruritus, facial edema, ocular symptoms, and arthralgia. Posterior cervical lymphadenopathy (Winterbottom’s sign) is prominent in T. b. gambiense infections. This is followed by an asymptomatic phase for several months or years. The second stage, the meningoencephalitic stage, occurs after months to years (earlier with T. b. rhodesiense infections) and is associated with various neurological abnormalities. The parasite is found in the basal ganglia of laboratory animals, which is confirmed with magnetic resonance imaging in case reports. Fasciculations, tremor, rigidity, chorea, and ataxia are observed. Typically, the patient complains of severe frontal head pain, tremors, delayed hyperesthesia (Kerandel sign, which is pain elicited by a tap on a tendon and is common in Caucasians), pronounced lethargy, and day-night inversion (sleeping sickness). Cognitive decline is common, with memory loss, dementia, depression, agitation, and hallucinations. In addition, T. b. rhodesiense can cause myocarditis, pericardial effusion, and heart failure.

Diagnosis The card agglutination trypanosomiasis test for T. b. gambiense infection is simple and rapid in the field. The infection can be diagnosed from a lymph node aspirate, from chancre fluid, or from bone marrow. It is seldom found in blood.

T. b. rhodesiense, however, can be found in blood. Concentration techniques are used for blood and cerebrospinal fluid (CSF) samples. Inoculation of rodents, which are killed after 21 days, is useful for identification of T. b. rhodesiense, but serological results are positive only after the onset of clinical symptoms, limiting its use in the asymptomatic traveler who is bitten in an endemic area where cattle are dying.37 Staging requires a lumbar puncture, which shows lymphocytosis. Parasites may be seen in CSF. World Health Organization criteria require 5 white blood cells/μL; other criteria require 20 white blood cells/μL in a patient with a positive card agglutination trypanosomiasis test for T. b. gambiense in order to diagnose the cerebral stage, which requires a specific drug regimen. Positive card agglutination trypanosomiasis test results alone do not justify treatment because therapy is potentially toxic. Concentrations of CSF IgM are very high in CNS involvement and may be useful for diagnosis and for monitoring relapses. Polymerase chain reaction on CSF is promising, with a sensitivity of 96%.

Treatment If CSF is positive for leukocytes and IgM concentrations are high, melarsoprol (a trivalent arsenic compound) is the drug of choice (Table 94–3). Relapse rates are high, and up to 20% of patients infected with T. b. gambiense do not respond to melarsoprol. Eflornithine is an alternative therapy for infections from T. b. gambiense but not from T. b. rhodesiense. Melarsoprol may cause post-treatment reactive encephalopathy in up to 10% of cases, with a mortality rate of 50%. Thus, the overall mortality from melarsoprol is 5% from arsenic encephalopathy. A lumbar puncture should be performed 1 day after a course of therapy for late-stage disease. All patients should be monitored for 2 years with lumbar punctures every 6 months. A relapse is suspected if the CSF cell count is more than 20 cells/μL. Reinfection is likely when CSF has more than 50 cells/μL, when the count has doubled since the previous count, or when there are 20 to 49 cells/μL in a symptomatic patient.25,39

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T A B L E 94–3. Treatment of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense Sleeping Sickness* Stage Early stage Endemic countries Other countries

Late stage Endemic countries Other countries

West African (T. b. gambiense)

East African (T. b. rhodesiense)

According to national legislation or guidelines Pentamidine isethionate, 4 mg/kg body weight daily or on alternate days for 7 to 10 days intravenously† or intramuscularly

According to national legislation or guidelines Suramin, test dose of 4-5 mg/kg body weight at day 1, followed by 5 injections of 20 mg/kg body weight every 7 days (e.g., days 3, 10, 17, 24, 31); the maximum dose per injection is 1 g

According to national legislation or guidelines If available: eflornithine, 100 mg/kg body weight at 6-hour intervals for 14 days (150 mg/kg body weight in children) by short infusions over a period of at least 30 minutes Alternative: melarsoprol,‡ 3 series of 3.6 mg/kg body weight at 24-hour intervals for 3 days; the series are spaced by intervals of 7 days

According to national legislation or guidelines Eflornithine not recommended (low efficacy38)

Melarsoprol,ठ1 series of 1.8, 2.16, 2.52 mg/kg body weight at 24-hour intervals; 1 series of 2.52, 2.88, 3.25 mg/kg body weight at 24-hour intervals; and 1 series of 3.6, 3.6, 3.6 mg/kg body weight at 24-hour intervals; the series are spaced by intervals of 7 days (the maximum dose is 5 mL)

*No firm recommendations exist for the use of the trypanocidal drugs; the schedules indicated are those most commonly used. A concise treatment schedule for treatment of T. b. gambiense sleeping sickness consisting of 10 days of melarsoprol, 2.2 mg/kg body weight daily, is under final evaluation.39,40 Note: This 10-day schedule must not be used for treatment of T. b. rhodesiense sleeping sickness, because there are no data available. † Very slow intravenous injection or short infusion, only under well-controlled circumstances. ‡ The concomitant application of 1 mg/kg body weight prednisolone has been shown to reduce the incidence of encephalopathic syndromes in one large-scale clinical trial.41 § A single dose of Suramin is often applied before the stage determining lumbar puncture. From Burri C, Brun R: Human African trypanosomiasis. In Cook GC, Zumla AI, eds: Manson’s Tropical Diseases, 21st ed. Edinburgh: Saunders, 2003, pp 1303-1323. Used with permission.

T A B L E 94–4. Causes of Cerebrospinal Fluid Eosinophilia Angiostrongylus cantonensis (most common) Ascaris (rare, anecdotal) Coccidioidomycosis Cysticercus Drug reactions Echinococcus Gnathostoma spinigerum (common) Meningeal lymphoma Paragonimus Schistosoma Strongyloides Syphilis Toxocara Trichinella spiralis Tuberculosis

Diagnosis Diagnosis requires microscopy. Eggs and larvae are found in tissue.

Treatment No drug has proved to be effective for the treatment of A. cantonensis. Most patients recover completely. Analgesics, corticosteroids, and removal of CSF at frequent intervals can relieve symptoms from increased intracranial pressure.42

Cysticercus of Taenia solium Epidemiology

Angiostrongylus cantonensis Epidemiology Angiostrongylus cantonensis is found mostly in southeast Asia and the Pacific Basin, but its distribution is spreading to Africa and the Caribbean. The infection is mainly acquired by eating raw or undercooked snails or slugs; it may also be acquired from eating crabs and freshwater shrimp.

Clinical Presentation This worm, more than Gnathostoma or Toxocara, is the main cause of eosinophilic meningitis worldwide (Table 94–4). Larvae in the brain cause headache, vomiting, neck stiffness, seizures, and focal neurological signs.

The pork tapeworm (Taenia solium) is prevalent in Latin America (there are many reports from Mexico and Peru), India, and southeast Asia. It is acquired from undercooked pork, in a life cycle involving humans, and directly from fecal contamination. Pigs are an inexpensive source of protein in povertystricken rural communities. Pigs eat human waste and rats that are alive or dead. Humans, pigs, and, by extension, rats enable cysticercosis. Humans are an accidental end-stage host of cysticerci, which die and degenerate in the brain, eye, and spinal cord, causing an inflammatory reaction. Cysticercosis is the most common cause of epilepsy in developing countries. T. solium intestinal carriers, releasing up to 200,000 eggs per day into their environment, are infective sources of cysticercosis, endangering all who come in contact with them. In 1993, the World Health Organization declared cysticercosis a potentially eradicable disease by tracing human carriers of T. solium. In the

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early 19th century, cysticercosis was diagnosed in 2% of autopsies in Berlin, roughly the same rate as found today in Mexico.11 The Commission on Tropical Diseases of the International League Against Epilepsy states that the prevalence of active epilepsy in tropical countries ranges from 1% to 1.5%, almost twice the level in Western countries. Regions and peoples with a religious aversion to pork are spared.24,43,44

Pathophysiology Taeniastatin covers the parasite surface; it is secreted by cysticerci and downregulates the host’s immune response, allowing the cysticerci to stay alive and dormant for 1 or 2 years, seldom up to 5 years, until it is recognized by the host’s immune system or until it is killed by medication, resulting in a brisk focal inflammatory response and seizures. Within 1 to 2 years after the first seizure, the untreated cysts are dead. They form 2- to 10-mm calcified deposits. The study of cytokine activation is complicated by the induction of certain cytokines by epilepsy itself.

Clinical Presentation With parenchymal disease, most children (80%) present with seizures. Episodic headaches and vomiting are featured in one third. Ventricular cysts may wander in the isodense CSF and cause hydrocephalus through an intermittent ballvalve effect. Subarachnoid cysts can result in meningeal signs, usually without fever. Rarely, cysticerci erode into large vessels. Arachnoiditis is another cause of hydrocephalus, as well as focal vasculitis, which may be responsible for lacunar strokes. Small space-occupying lesions are responsible for focal weakness. Cognitive and psychiatric impairments are common. In the eye, a scotoma may develop or vision may be lost.45 Solitary cysts seem to be more common in India. They must be distinguished from tuberculomas and hydatid cysts. Coenurosis is never common, but it is more likely in Africa and South America.

Diagnosis On the basis of autopsy findings in Mexico, most cases of neurocysticercosis remain undiagnosed despite the patient having cognitive and psychiatric problems throughout life. Subcutaneous cysts are palpable. In striated muscle, they rapidly calcify and may be noted on imaging studies. Stool examination is unrewarding. Peripheral eosinophilia is inconsistent and nonspecific. Blood and CSF serological analyses have improved. Many clinicians use the enzyme-linked immunoelectrotransfer blot (EITB) assay. It derives from coproantigens of adult T. solium and ignores nonspecific bands of antigen. EITB results may revert to negative after the cysticercus dies. The assay is not always readily available. In the blood, sensitivity is 92.5% and specificity is 100%. However, EITB sensitivity has been reported to be as low as 28% in subjects with a single parenchymal lesion, as is commonly seen in India.46 EITB sensitivity may be less in CSF.47 Enzyme-linked immunosorbent assay (ELISA) is based on crude antigen to cysticercal fluid. It is inexpensive and rapid. ELISA cross-reacts with other cestodes (other taeniae and

■

Figure 94–1. Inactive form (nodular stage) of cysticercosis. Axial computed tomography shows small calcification in the left occipital lobe. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

echinococci). It seems more sensitive in CSF (sensitivity, 62% to 90%; specificity 98% to 100%) than in blood. The diagnosis requires neuroimaging, with the goal of identifying the scolex (2 to 3 mm). Only since the frequent use of computed tomography in the 1980s has cysticercosis emerged as the most common cause of epilepsy in many areas. (Cerebral malaria is likely the most common cause of febrile seizures.) Magnetic resonance imaging may show a diagnostic invaginated scolex but not show the calcific stage, for which computed tomography is best. Magnetic resonance imaging can show ventricular cysts. In brain parenchyma, the cysts mature in 3 months to 10 mm in size (occasionally up to 20 mm); in the ventricles, they can exceed 5 cm. Therefore, serum EITB, CSF ELISA, and neuroimaging have become useful diagnostic tools48,49 (Figs. 94–1 through 94–7).

Treatment ■ Most children require anticonvulsants.50 ■ Individuals with cysticercosis have a higher incidence of

cutaneous reactions to phenytoin.51 ■ In the tropics, studies have shown that hypoproteinemia, malabsorption, and malnutrition affect drug kinetics. This has been shown with chloroquine, phenylbutazone, chloramphenicol, carbamazepine, and others. Higher doses of antiepileptics are sometimes required (Fig. 94–8). ■ Corticosteroids are indicated for cerebral edema and focal inflammation around a dead or dying cyst. They are used along with a cysticidal drug for multiple parenchymal brain

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Figure 94–2. Nodular stage of cysticercosis with residual contrast enhancement. A–C, Axial T2-weighted image shows multiple, hypointense (due to calcification) lesions in the cerebral parenchyma and cerebrospinal fluid spaces. D–F, Corresponding postcontrast T1-weighted images show persistent enhancement in most lesions. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

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Figure 94–2, cont’d.

cysts, giant (>5 cm) subarachnoid cysts, ventricular cysts, and spinal cysts. For arachnoiditis, the duration of corticosteroid therapy can be determined by repeat CSF examination.53,54 ■ Subarachnoid cysticercosis generally requires antiparasitic therapy. The dose and duration of therapy are controversial, and multiple courses of treatment may be required. An ophthalmological examination should precede the use of antiparasitic medication. Cysticercocidal drugs may cause irreparable damage, and when considering larvacidal medication, each case must be studied individually. Albendazole (15 mg/kg per day) may be given orally for 7 or more days. Simultaneously, dexamethasone (0.1 mg/kg per day) may be given. Enhancing lesions will degenerate regardless of therapy, but larvicidal medication may increase resolution and reduce recurrence of seizures.55,56 ■ Surgical excision is considered for extraparenchymal (ventricular and subarachnoid) cysts. CSF diversion is usually required for hydrocephalus.57,58 ■ Therapeutic options are discussed in several resources.25,59-61

Falciparum Malaria Epidemiology Travel or residence in an endemic area within the previous 3 months is sufficient to arouse suspicion of falciparum malaria. Mortality with cerebral malaria is 15% to 50%.

Pathophysiology ■ Cytoadherence and sequestration clog cerebral vessels with

parasitized red blood cells, which adhere to endothelial receptors. Ligands for adhesion are produced by the parasite and are expressed on knobs on the red blood cell surface. Cytokine excess in the capillaries, where sequestration occurs, appears to be more significant than obstruction of flow. To avoid passage through the spleen, which would eliminate the parasites, they travel inside red blood cells and adhere to endothelial cells and other red blood cells in the brain, lung, liver, placenta, and other organs. Massive infection may occur with low peripheral parasitemia.62,63 ■ Capillary permeability, including breakdown of the bloodbrain barrier, leads to perivascular edema. Pulmonary edema occurs in adults and is less common in children.64-67 ■ From 2% to 6% of the parasite genome codes for 50 to 150 variant antigens that switch parasite surface antigens and cytoadherence phenotype. ■ Plasmodium reduces oxygenation and competes for glucose. Systemic hypoglycemia is a poor prognostic factor.

Clinical Presentation Severe falciparum malaria is clearly defined and should be treated parenterally initially (Table 94–5). Patients with cerebral malaria present with coma, convulsions, dysconjugate gaze, pouting, and bruxism. Retinal hemorrhages are seen. CNS findings are symmetrical. The plantar reflexes are upgoing.68

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Figure 94–3. Active stage (vesicular stage) of cysticercosis. A, Coronal noncontrast T1-weighted image shows multiple well-defined cystic lesions containing a small area of intermediate signal intensity representing the scolex. B, In the same patient, axial T2weighted image shows similar findings. Note the absence of surrounding edema at this stage. C and D, Trace diffusion-weighted image and apparent diffusion coefficient map show the cystic lesion to have no restriction of diffusion and its signal to be isointense to that of cerebrospinal fluid. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

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Figure 94–4. Active (colloidal and granular stages) of cysticercosis. A, Axial computed tomography shows cystic lesion in the posterior left frontal region. B, Corresponding postcontrast T1-weighted image shows that the lesion enhances in a ring-like manner. The scolex is seen well in the center of the lesion. Because of the absence of edema, this lesion corresponds to one in the colloidal stage. C, In a different patient, coronal fluid-attenuated inversion recovery (FLAIR) image shows an area of high signal intensity (edema) in the right temporal lobe; thus, this lesion is in the granular stage. D, On an axial postcontrast T1-weighted image, the same patient has an enhancing lesion. The glomera of the choroid plexi are enhanced and should not be confused with cysticerci. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

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Figure 94–5. Intraventricular cysticercosis. A, Midsagittal T2-weighted image shows a cystic lesion in the anterior aspect of the lateral ventricles. There is hydrocephalus. B, In a different patient, axial fluid-attenuated inversion recovery (FLAIR) image shows a cysticercus in the anterior aspect of the third ventricle. The cyst is isointense to cerebrospinal fluid and difficult to visualize. C, In a third patient, midsagittal postcontrast T1-weighted image shows a lesion in the third ventricle. The lesion is isointense to the brain and shows peripheral enhancement. The lesion is “soft” and conforms to the space between the floor of the third ventricle and the massa intermedia. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

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Figure 94–6. Cisternal cysticercosis. A, Axial postcontrast T1-weighted image shows a conglomeration of cysticerci in the left sylvian fissure. There is peripheral enhancement suggesting active inflammation. B, Axial fluid-attenuated inversion recovery (FLAIR) image at nearly the same level shows that some lesions are isointense to cerebrospinal fluid whereas others are slightly hyperintense. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

T A B L E 94–5. Severe Falciparum Malaria Cerebral malaria, defined as unrousable coma (lasting >1 hour after a seizure) not attributable to any other cause in a patient with falciparum malaria Repeated generalized convulsions (>2 per 24 hours) Severe normocytic anemia (hemoglobin <5 g/dL) Hypoglycemia (<40 mg/dL) Metabolic acidosis (pH<7.25; HCO3− <15 mmol/L) Fluid and electrolyte disturbances Acute renal failure (<12 mL/kg urine in 24 hours; <400 mL urine in 24 hours; creatinine >3 mg/dL) Acute pulmonary edema or acute respiratory distress syndrome Circulatory collapse, shock, septicemia (algid malaria) (systolic blood pressure: adults, <70 mm Hg; children <5 years, <50 mm Hg) Abnormal bleeding Jaundice (bilirubin >3 mg/dL) Macroscopic hemoglobinuria High fever (axillary temperature >98.5°F) Hyperparasitemia (>10,000 trophozoites/μL or >5% of red blood cells infected) Modified from the World Health Organization: Management of Severe Malaria: A Practical Handbook, 2nd ed. Geneva: World Health Organization, 2000, p 5. Used with permission.

In children with febrile convulsions followed by coma, 30 to 60 minutes may have to pass before malaria is diagnosed, but treatment should not be delayed. Patients with malarial convulsions may present with only nystagmus, salivation, and twitching of the mouth or a digit. One third of seizures in children manifest only as eye deviation or salivation, or both. One in 10 children with severe malaria has sequelae: ataxia, hemiparesis (hemiconvulsion-hemiparesis syndrome), speech disor-

der, blindness, behavioral problems, cognitive difficulties (executive functions), and spasticity. Prolonged seizures, coma, hypoglycemia, and absence of hyperpyrexia are associated with neurological sequelae.69 Hypoglycemia not accompanied by sweating occurs in 20% of children and pregnant women but also in 8% of adults with severe malaria. It is caused by malaria itself (the parasite consumes glucose) or quinine-induced hyperinsulinemia. Hypoglycemia also results in coma, convulsions, extensor posturing, and shock. Acidosis and Kussmaul respiration are common. Respiratory distress is poorly understood and is the main cause of death in African children. Brainstem disturbance has been implicated.

Diagnosis Immunodiagnostics are used. If thick and thin smears are negative, repeated blood films should be examined every 8 to 12 hours for 12 to 48 hours. Treatment should not be delayed even if the initial slide is negative. The CSF is clear, the opening pressure is usually normal but is elevated in African children, there are less than 10 white blood cells/high-power field, the CSF protein concentration is slightly increased, and computed tomography of the brain is nondiagnostic.

Treatment Common errors in treating malaria are the following: ■ Delaying treatment ■ Omitting a travel history

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Figure 94–7. Spinal cysticercosis. A, Midsagittal T1-weighted image without contrast medium administration shows a well-defined cystic lesion in the distal thoracic spinal cord. B, Corresponding T2weighted image shows the lesion to be bright and the cord inferior and superior to the lesion to have edema (increased signal intensity). C, Axial T2-weighted image in a different patient shows a cystic lesion in the center of the thoracic spinal cord and multiple cystic lesions in the paraspinal muscles. (From Castillo M: Imaging of neurocysticercosis. Semin Roentgenol 2004; 39:465-473. Used with permission.)

chapter 94 parasitic and fungal infections Degenerative (transitional)* and/or active cysts

Only calcifications

Initiate AEM

Initiate AEM

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CT or MRI after 3–6 months Cyst(s) resolved and no seizure recurrence

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Cyst(s) not resolved with or without seizure recurrence

Cyst(s) resolved but seizure recurrence

Maintain AEM and CT or MRI at 3–6 months

Maintain AEM for 1–2 years after last seizure

No seizure recurrence for 1 year

Withdraw AEM

Seizure recurrence

Maintain AEM for 1–2 years after last seizure

Figure 94–8. Antiepileptic treatment for patients with first seizure due to neurocysticercosis.52 Asterisk indicates that “degenerative” includes a single enhancing lesion on computed tomography (computed tomography) after differential diagnosis has been established. AEM, antiepileptic medication; MRI, magnetic resonance imaging. (From Carpio A: Neurocysticercosis: an update. Lancet Infect Dis 2002; 2:751-762. Used with permission.)

■ Not realizing that patients with vivax malaria may have a ■ ■ ■ ■ ■ ■ ■

coinfection with falciparum malaria Not detecting hypoglycemia Not switching to oral therapy Using therapy too long Intubating unnecessarily Recognizing pulmonary edema late Forgetting a nasogastric tube, resulting in aspiration Omitting antibiotics if lumbar puncture is delayed

Treatment guidelines with quinine and quinidine for severe malaria are as follows:

■ Treatment is completed with oral medication for up to a

total of 7 days in most areas. ■ Side effects of quinine include cinchonism, hypoglycemia,

and a prolonged QT interval. A loading dose should be avoided if quinine, quinidine, or mefloquine were taken within 24 hours. ■ Doxycycline is added to quinine, quinidine, or mefloquine as 2.5 mg/kg daily (100 mg every 12 hours) for 7 days; if the patient is younger than 8 years or pregnant, use clindamycin instead. The artemisinins clear parasitemia faster than quinine:

■ Quinine dihydrochloride (salt), 20 mg/kg, is given as an

■ Artesunate (2.4 mg/kg) is given as an IV or intramuscular

intravenous (IV) load over 4 hours, in 5 to 10 mL/kg of 5% dextrose in saline; 8 to 12 hours after the start of the load, 10 mg/kg (salt) is given at the same dilution, over 4 hours, and repeated every 8 to 12 hours until oral medication is taken, for a total of 7 days. ■ Quinidine (base), 15 mg/kg, equivalent to 20 mg/kg of quinidine gluconate, is given as an IV load over 4 hours; then 7.5 mg/kg (base), equivalent to 10 mg/kg of IV quinidine gluconate, is given over 1 to 2 hours, every 8 hours until oral medication is taken, for a total of 7 days. ■ Because quinidine, the dextrorotatory isomer of quinine, is more effective and more cardiotoxic than quinine, the patient must be monitored electrocardiographically: the QRS complex should not exceed a 50% increase over the pretreatment complex and the QTc interval should not show more than a 25% increase. The IV dose may be reduced by one third after 48 hours.

(IM) load, followed by 1.2 mg/kg daily for a minimum of 3 days or until the patient can swallow quinine or mefloquine and doxycycline for a total of 7 days. ■ Artemether (3.2 mg/kg) is given as an IM load, followed by 1.6 mg/kg repeated every 12 to 24 hours for a minimum of 3 days or until the patient can swallow quinine or mefloquine and doxycycline for a total of 7 days. Artemether is formulated in peanut oil for injection. ■ Atovaquone and proguanil can be used instead of oral quinine. Corticosteroids are associated with an increased risk of adverse side effects and do not decrease mortality. The diagnosis and management of severe malaria70 and therapeutic options are discussed in other publications.25,70-76

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Gnathostoma spinigerum

Diagnosis

Epidemiology

Chest radiographic abnormalities are seen in 80% of patients. Oh83 reviewed 62 cases of cerebral paragonimiasis and found CSF eosinophilia in 8% and peripheral eosinophilia in 41%. If available, serology by enzyme-linked immunosorbent assay and complement fixation on CSF samples may be used for diagnosis and for monitoring therapy. Microscopic examination is performed on stool, gastric washings, sputum, or tissue.84 In chronic brain syndrome, magnetic resonance imaging shows multiple conglomerated, round, enhancing nodules (“soap bubbles”) with encephalomalacia in the temporal, parietal, and occipital lobes. Computed tomography scans show large calcified nodules or multiple cystic calcifications in the same region in 40% to 70% of cases.20,80,82,83

Gnathostoma spinigerum, a nematode larva, is acquired in Southeast Asia, Japan, and Latin America from eating undercooked fish, frogs, snakes, ducks, and chicken. Ceviche and sushi are known sources of infection.

Pathophysiology The adult worm migrates, carrying a row of spines and leaving a hemorrhagic tract in subcutaneous tissue, muscle, and the CNS.

Clinical Presentation One to 2 days after the larva is ingested, it causes epigastric pain as it penetrates the gastric mucosa. A retrospective study of 946 cases of gnathostomiasis in Mexico City identified nodular migratory panniculitis over the trunk as the most common skin sign.77 Migrating immature worms move through spinal foramina at all levels, causing sudden, severe radicular pain and nerve palsy. This resolves in a few days as the worm races to the brain, causing symptoms for as long as 15 years. Focal symptoms are present as well as eosinophilic meningitis with myeloencephalitis, and 25% of the CNS cases are fatal.

Treatment Praziquantel, 25 mg/kg 3 times a day for 2 days, is used for lung infections. Hydrocephalus is treated surgically.25

Schistosoma japonicum Epidemiology Schistosoma japonicum is found principally in China, Indonesia, and the Philippines. In CNS disease, this fluke locates in the brain, whereas Schistosoma mansoni and Schistosoma haematobium are more commonly found in the spinal cord.

Diagnosis Eosinophilia is prominent and serum levels of IgE are elevated. Diagnosis is by serology (ELISA when available: sensitivity, 93%; specificity, 96.7%) and magnetic resonance imaging (cervical cord enlargement and hemorrhagic tracts in the brain with scattered deep intracerebral hemorrhages). Microscopic examination is diagnostic.78

Pathophysiology Eggs embolize and obliterate pulmonary arterioles and embolize the brain.

Clinical Presentation

Paragonimus

Patients with S. japonicum in the CNS may present with an acute meningoencephalitis or a chronic, single granuloma or multiple granulomas. CNS symptoms (headache, fever, stiff neck, vomiting, or seizures) may be noted within days after the appearance of mucosanguineous stools in patients in the Philippines and within months in Japan and China. Partial seizures result from brain invasion by eggs or adult worms. There may be other focal signs.

Epidemiology

Diagnosis

Paragonimus is found in East Asia, West Africa, and Latin America. Disease is seen mainly in children and young adults. CNS disease is often fatal.

Stool microscopy is performed. Immunodiagnosis is similar to that of S. mansoni. On magnetic resonance imaging and computed tomography, there may be focal and asymmetrical findings, such as a dilated ventricle from massive egg embolization. CSF opening pressure is increased. The CSF cell count is increased (5 to 55 monocytes per high-power field), with increased protein and normal glucose concentrations. Partial seizures are more common in the Philippines and China, whereas generalized seizures are more common in Japan85 (Fig. 94–9).

Treatment Surgical removal or treatment with albendazole or ivermectin is recommended.25

Clinical Presentation The lung infection can be mistaken for bronchiectasis. It may be misdiagnosed as nocardiosis, tuberculosis, or metastatic lung cancer. Symptoms may be recognized for years before diagnosis.79 Epilepsy occurs in 65% to 95% of CNS cases before diagnosis. Chronic mild insidious eosinophilic meningitis (the majority of cases), or recurrent acute meningitis, as well as chronic decline in mental status persisting for as long as 20 years is described. Homonymous hemianopia is common.80,81 Flukes in the spinal cord cause spastic paraplegia.82

Treatment Praziquantel, an anticonvulsant, and occasionally corticosteroids are used. The dosage of praziquantel may vary with the worm burden.

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Figure 94–9. Abnormal computed tomographic scan of cerebral schistosomiasis in a 34-year-old patient. Right, The multiple low-density area is spread at the surface of the right hemisphere, and the right ventricle was remarkably more dilated than the left (normal) side. Left, Normal pattern in another 34-year-old patient. (From Hayashi M: Clinical features of cerebral schistosomiasis, especially in cerebral and hepatosplenomegalic type. Parasitol Int 2003; 52:375-383. Used with permission.)

Schistosoma mansoni and Schistosoma haematobium

monellae are carried on the surface or in the gut of the parasite.

Epidemiology

Clinical Presentation

Schistosomiasis affects 200 million people in the Middle East, Africa, Brazil, Suriname, Venezuela, and the Caribbean, wherever the freshwater snail vector is found. In CNS disease, S. haematobium can be found in the brain, but S. mansoni and S. haematobium are more commonly found in the spinal cord.

S. mansoni is the most common cause of schistosomal myeloradiculopathy. The second most common is S. haematobium. Radicular symptoms may occur at any stage of the infection but are more likely during early stages, or with mild chronic forms, than during later stages with severe forms of the disease, such as the hepatosplenic stage.86 In Brazil, Nascimento-Carvalho and Moreno-Carvalho87 reported that the most common CNS manifestations in pediatric neuroschistosomiasis due to S. mansoni are paraparesis (55%), urinary retention (53%), and paraplegia (20%).

Pathophysiology Radiculopathy may occur as soon as the adult female schistosome starts to lay eggs in the mesenteric veins. It is believed that the eggs enter the spinal cord through retrograde venous flow into the Batson plexus, which communicates with the portal system. Eggs of S. mansoni and S. haematobium have a spine on their shell, allowing them to stop their migration in the epidural venous system and cause the embolic eggs to accumulate in the lower spinal cord near the point of entry. Small asymptomatic eggs of S. japonicum are more often found in the brain at autopsy than the large-spined S. mansoni egg. Host immune response is a function of egg burden, which, in large accumulations, leads to large granulomas. Infection with Salmonella may be concomitant with schistosomiasis because sal-

Diagnosis CSF eosinophilia with increased concentrations of protein is common. Stool and urine microscopy and rectal biopsy are diagnostic (S. haematobium eggs are easily detected in the urine). S. mansoni is sometimes found in the urine. Multiple techniques allow schistosome antigens to be identified in the serum, urine, and CSF, mostly using ELISA and circulating anodic antigen. An ELISA of the CSF is helpful for suspected CNS infection.88 Magnetic resonance imaging shows an enlarged spinal cord.

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Treatment Prednisone (1.5 mg/kg per day) has been used, but its use remains controversial. Praziquantel is the drug of choice (60 mg/kg per day in two doses for 3 days). Treatment must be individualized. Decompressive laminectomy may be necessary.

Toxoplasma gondii Epidemiology Toxoplasma gondii is a protozoan found worldwide from Alaska to Australia. One third of the human population has been exposed. In one third of AIDS patients who are Toxoplasma seropositive, cerebral toxoplasmosis reactivates. Toxoplasmosis sickens fetuses and immunosuppressed hosts. Prophylactic medication has impacted the prevalence of postnatal infection. Nonfetal infection is acquired by ingesting tissue cysts in undercooked meat (pork, lamb, and rabbit) or oocysts in cat feces that have contaminated food, water, or hands (pregnant women should wear gloves when gardening). In British Columbia, a water reservoir became infected from use by cougars. Toxoplasmosis may be transmitted by blood transfusion and organ donation. Immunosuppressive therapy prescribed to transplant patients puts them at higher risk.89

T A B L E 94–6. Infectious Causes of Central Nervous System Calcifications After a pyogenic abscess After meningitis or arachnoiditis Cysticercosis (common) Echinococcus (rare) Fungal infections (including cryptococcosis) Human immunodeficiency virus/acquired immunodeficiency syndrome Paragonimus (multiple dense calcifications in the temporal and occipital lobes) Schistosomiasis (rare) TORCH syndrome (adult toxoplasmosis; rarely adult cytomegalovirus infection) Tuberculosis

Diagnosis

CD4 and CD8 cells and possibly astrocytes prevent reactivation in immune individuals. CD4 counts less than 100/μL are associated with more severe infections. TH1 helper T cells produce interleukin 2, interferon γ, and tumor necrosis factors α and β. Interferon γ has a preeminent role in the development of toxoplasmosis. Its synthesis results in chronic asymptomatic infection. When the CD4 cell count is less than 100/μL, interferon γ production decreases or stops. The imbalance between TH1 and TH2 responses allows interleukins 4 and 10 to further downregulate the secretion and activity of interferon γ. With progression of disease, multifocal necrotizing encephalitis develops, particularly in the thalamus, basal ganglia, and the intersection between white and gray matter in the frontal and temporal cortex.90 In dormant stages, bradyzoites are within pseudocysts in brain tissue and skeletal muscle. With reactivation, tachyzoites invade virtually any cell. The parasite favors neurons over microglial cells because they do not express major histocompatibility complex class 1 molecules and cannot be eliminated by sensitized CD8+ T cells.65

Toxoplasmosis can be diagnosed in several ways: isolation of the organism from the placenta in neonates, mouse inoculation or inoculation of tissue cell cultures; amplification of its DNA in blood or body fluids; demonstration of the organism in histological sections of tissue or in cytological preparations of body fluids; and characteristic serological test results. Serology has been the primary method of diagnosis of toxoplasmosis. IgG antibodies usually appear within 1 to 2 weeks after the infection is acquired, reach peak concentrations within 1 to 2 months, and usually persist for life. IgM antibodies may appear earlier and decline more rapidly than IgG antibodies, but they also can persist for years. CNS toxoplasmosis in general is a reactivation disease; therefore, the usefulness of serological testing is primarily to determine whether the patient has been previously exposed to the parasite. However, demonstration of intrathecal production of IgG or IgM antibodies against T. gondii is diagnostic of toxoplasma encephalitis. In patients with AIDS, the presence of toxoplasma IgG in association with multiple intracranial lesions, in the absence of prophylaxis against Toxoplasma, has a positive predictive value of approximately 80% for toxoplasma encephalitis and thus mandates empirical antitoxoplasmosis therapy. Polymerase chain reaction has been used successfully on samples of CSF and brain tissue. The sensitivity of polymerase chain reaction in CSF varies between 11% and 77%; the specificity approaches 100%. Therapy for toxoplasmosis decreases the sensitivity of polymerase chain reaction; sensitivity is higher in CSF or blood samples collected before or within the first week of therapy.

Clinical Presentation

Treatment

Acute toxoplasmosis induces a mononucleosis-like illness. Acute infection or reactivation in the immunosuppressed patient may result in encephalitis and devastating disease. Severe bilateral headache has little response to analgesics. Focal neurological signs are common (69% of cases). Seizures are observed in 15% to 30% as a presenting sign. Depression, bipolar disorder, altered mental status, ataxia, and dementia may follow. Blindness, with mental retardation and intracranial calcification (Table 94–6), and hydrocephalus occur in neonates.

Combination treatment is used for the treatment of toxoplasmosis, including CNS toxoplasmosis. Pyrimethamine, a folic acid antagonist, is the cornerstone of therapy, with either sulfadiazine or clindamycin added as second agents. Folinic acid should be administered concomitantly with pyrimethamine to avoid bone marrow suppression. Other drugs with activity against T. gondii include azithromycin, clarithromycin, atovaquone, dapsone, and trimethoprim-sulfamethoxazole. The duration of treatment of toxoplasmosis in immunodeficient patients can be as long as 6 months. The usual recom-

Pathophysiology

chapter 94 parasitic and fungal infections mendation is 4 to 6 weeks after the resolution of all signs and symptoms. Therapy for toxoplasmosis in AIDS patients has acute (primary or induction) and maintenance (secondary prophylaxis) treatment phases. Acute therapy should be continued for at least 6 weeks if there is clinical and radiological improvement. Lifelong suppressive therapy (secondary prophylaxis), with the same agents used for acute therapy but at a reduced dose, is necessary to prevent relapse. Secondary prophylaxis can be discontinued in those who have successfully completed initial therapy, remain asymptomatic with respect to signs and symptoms of toxoplasmosis, and have a sustained (i.e., >6 months) increase in their CD4+ T lymphocyte counts to more than 200 cells/μL on antiretroviral therapy.

FUNGAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM Although many fungal species can infect the CNS, most fungal CNS infections are caused by a relatively few important fungal organisms. In general, CNS infections caused by fungal organisms manifest either as meningitis or space-occupying lesions (including abscesses), or both. The following discussion describes the general characteristics of CNS infections caused by some of the leading fungal organisms, including Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, agents of mucormycosis, and Aspergillus species.

Central Nervous System Cryptococcosis C. neoformans is a round or oval yeast that has a worldwide distribution and is found particularly in bird excreta.91 Infection is acquired through inhalation of the organism. Most pulmonary infections are asymptomatic, but acute symptomatic pneumonia may occur. Infection can disseminate to distant sites either during this primary lung infection or later during reactivation, usually as a result of cell-mediated immune deficiency.92 The most likely site for dissemination is the CNS, but the reason is not entirely clear. Some investigators have hypothesized that there is a receptor in the CNS that binds a ligand on the organism, but this hypothesis has not been verified. Patients with CNS cryptococcosis usually present with a subacute meningitis, with signs and symptoms such as headache, fever, and focal neurological deficits occurring over several weeks.93,94 Symptoms may be subtle, waxing and waning. Classic meningeal symptoms (e.g., neck stiffness or photophobia) may not always be present. In particular, in human immunodeficiency virus infection, they are present in only one fourth to one third of patients. Brain imaging studies are also nonspecific; computed tomography scans may be normal in one half the cases. Cerebral atrophy and ventricular enlargement are the most common findings in human immunodeficiency virus–infected patients. Cryptococcomas (nodules in the brain parenchyma) can also be present occasionally, especially in patients with infection caused by C. neoformans var. gattii. CSF findings usually include an increased opening pressure, mild mononuclear pleocytosis, and increased protein concentration. India ink examination of the CSF is positive in 50% of non-AIDS

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patients with cryptococcal meningitis and in more than 80% of patients with AIDS. Similarly, cultures of CSF are usually positive. Both the serum and the CSF cryptococcal antigen tests are accurate for the diagnosis of cryptococcal meningitis, with sensitivity and specificity greater than 90%. The recommended treatment of cryptococcal meningitis has three stages, particularly in patients with HIV infection:95,96 1. Induction treatment is with amphotericin B, 0.7 mg/kg per day, plus flucytosine, 100 mg/kg per day, for at least 2 weeks. 2. The second stage is with fluconazole, 400 to 800 mg/day for 8 to 10 weeks. 3. The third stage consists of a chronic suppressive regimen with fluconazole, 200 mg once daily. Chronic suppression can be discontinued if patients remain asymptomatic and have a sustained increase in CD4 counts of more than 100 to 200/μL for at least 6 months after antiretroviral therapy.95 Patients without HIV infection either follow the same treatment algorithm as for HIV patients or are treated with a 6- to 10-week regimen of amphotericin B, with or without initial flucytosine.94 If the 6- to 10-week regimen is selected, the decision to discontinue treatment will depend on resolution of symptoms, negative CSF cultures on at least two occasions, and normal CSF values. Patients with ongoing immunosuppression that may have initially predisposed them to cryptococcal infection will require an additional 6 to 12 months of fluconazole therapy after these criteria are met. Increased intracranial pressure is a common feature of cryptococcal meningitis, particularly in patients with AIDS.97 It may result in a delayed clinical response and death; therefore, decompression may be required through drainage of the CSF by either serial lumbar punctures or placement of a shunt.

Central Nervous System Histoplasmosis H. capsulatum is a dimorphic fungus, which means that it occurs as a mold (mycelial form) in nature and as a yeast in tissue (and at temperatures less than 37°C in cultures).98 The yeast form is a small, thin-walled, oval structure measuring 2 to 4 mm in diameter. H. capsulatum is found in temperate zones around the world. In the United States, it is endemic in the Ohio and Mississippi river valleys.99 Its natural habitat is soil, especially soil with high organic content such as soil enriched with bird, chicken, or bat excrement. Infection is acquired by inhalation and deposition of mycelial fragments into the alveoli. The organism converts to its pathogenic yeast form and is phagocytosed by alveolar macrophages. Specific T cell–mediated immunity develops and inhibits the growth of the organisms. However, the persistence of the organisms within granulomas can lead to reactivation or dissemination (or both) of the disease during the immunosuppressed state.100 CNS involvement occurs either as an isolated infection or as part of a progressive disseminated disease.101,102 In disseminated disease, CNS involvement is noted in 5% to 10% of cases. Clinical presentation varies widely and includes meningitis, diffuse encephalitis, focal neurological deficits, and stroke syndromes. Unless the yeast is identified in different organs, the diagnosis of CNS infection itself may be problematic.101-103 CSF findings are nonspecific, usually with lymphocytic pleocytosis,

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decreased glucose levels, and increased protein levels. CSF cultures are often negative early in the disease, and they require multiple specimens, large volumes (greater than 10 mL), and an extended incubation period (longer than 35 days). Serological tests for anti-Histoplasma antibodies in the CSF may be positive in up to 80% of cases. Testing for Histoplasma polysaccharide antigen in the CSF can be useful in 38% to 67% of cases.104 The treatment of choice for CNS histoplasmosis is amphotericin B, 0.7 to 1 mg/kg per day for a total dose of 30 to 35 mg/kg, followed by fluconazole, 800 mg daily for 9 to 12 months.96,105 Itraconazole does not penetrate the blood-brain barrier well and therefore should not be used. Criteria for discontinuing treatment include a normal concentration of CSF glucose and an undetectable level of CSF Histoplasma polysaccharide antigen. If immunodeficiency cannot be reversed, lifelong maintenance therapy may be required. Some clinicians prefer lipid formulations of amphotericin B because they deliver higher doses with less toxicity. If lipid formulations are used, they should be administered at dosages of 3 to 5 mg/kg per day for a total of 100 to 150 mg/kg over 6 to 12 weeks.

Central Nervous System Blastomycosis B. dermatitidis is also a dimorphic fungus.98 The yeast cells are round and thick walled with daughter cells forming from a broad-based bud. It is an endemic fungus found primarily in the south central, southeastern, and midwestern United States, especially in the states along the Mississippi and Ohio rivers, as well as in the Canadian provinces bordering the Great Lakes.106 Occasionally, cases have also been reported in Africa, India, the Middle East, Central America, and South America. Outdoor activities near waterways and exposure to dust from construction and excavation sites are the major risk factors for acquiring infection. Infection begins with inhalation of the organism, which then enters the lungs and converts to its yeast phase. Infection at this stage is usually asymptomatic. Cellular immunity is the major host protective factor in preventing progression of disease. Symptomatic disease develops in about one half of infected individuals. In some, the infection spreads via the bloodstream and lymphatics to distant sites, most commonly skin, bone, and the genitourinary system.107 CNS involvement is uncommon (less than 5%) in immunecompetent patients with blastomycosis.108,109 In contrast, as many as 40% of AIDS patients with blastomycosis have been reported to have CNS disease, usually as a fulminant complication of widely disseminated blastomycosis.110 CNS blastomycosis manifests itself as either an abscess or meningitis. Both are difficult to diagnose in the absence of a diagnosis from another site in the body. CSF cultures are rarely positive, and culture of ventricular fluid may have a higher yield. Biopsy of cranial abscesses may be required for identification of the organism. For patients with CNS blastomycosis, amphotericin B deoxycholate remains the drug of choice.111 A total dose of at least 2 g is usually recommended. For patients unable to tolerate a full course of amphotericin B, fluconazole at a dosage of 800 mg/day can be substituted. Human immunodeficiency virus–infected or otherwise significantly immunocompromised

patients with CNS blastomycosis require long-term suppressive therapy with fluconazole.96

Central Nervous System Coccidioidomycosis C. immitis is a dimorphic fungus endemic to certain areas in the southwestern United States and parts of Mexico, Central America, and South America.112 The yeast form has a unique spherical structure known as a spherule, which is a large, round, thick-walled structure filled with daughter cells or endospores. As a spherule matures, its outer wall becomes thinner and eventually ruptures. This results in the release of endospores, which may propagate further in tissue. Infection is acquired by inhalation of the organism and the subsequent formation of a lung lesion is the consequence of an inflammatory response. Many of the infections are either asymptomatic or mild and self-limited.113 As with the other endemic fungi, control of the infection is dependent on cellmediated immunity. Coccidioidomycosis rarely spreads beyond the lungs. However, immunodeficiency conditions, such as in human immunodeficiency virus infection, immunosuppressive therapy, Hodgkin lymphoma, and transplant recipients, dramatically increase the risk of dissemination.114,115 Other conditions that increase the likelihood of dissemination include pregnancy and African or Filipino ancestry. Up to one third of disseminated cases present with meningitis. Infection predominantly affects the basilar meninges. However, intracerebral abscesses occasionally develop.116,117 The most common symptoms are headache, nausea, vomiting, and altered mental status. Hydrocephalus is a common complication of coccidioidal meningitis. CSF analysis shows mononuclear pleocytosis with decreased glucose and increased protein concentrations. CSF eosinophilia occurs in up to 70% of cases. Serological testing plays a more important role in the diagnosis and management of coccidioidomycosis than of other fungal infections.118 Tube precipitinreacting antibodies disappear and are not found in chronic infections, whereas complement-fixing antibodies are present as long as infection persists; they disappear when the infection resolves. Complement-fixing antibodies can also be detected in the CSF of patients with meningitis and similarly can be useful for monitoring disease. Culture of the CSF is often negative. The standard treatment for coccidioidal meningitis had been intrathecal amphotericin B, but this treatment is now reserved for patients who do not respond to oral azole therapy. The current preferred initial treatment for coccidioidal meningitis is oral fluconazole at 400 mg/day.119 Some patients may need higher doses of fluconazole. Treatment should be continued for at least 1 year and for 6 months after all evidence of further improvement has ceased. Relapses occur in approximately one third of patients when therapy is stopped, and some patients may require suppressive therapy indefinitely. In addition to antifungal therapy, a shunting procedure may be required to control hydrocephalus. If present, abscesses may require drainage or resection.

Central Nervous System Mucormycosis The term mucormycosis describes a group of diseases caused by fungi that belong to the order Mucorales.120 The genera

chapter 94 parasitic and fungal infections reported to cause invasive infection include Rhizopus, Absidia, Cunninghamella, Rhizomucor, Mucor, Apophysomyces, Saksenaea, Cokeromyces, and Syncephalastrum. These organisms are morphologically filamentous with broad, nonseptate hyphae with branches occurring at right angles. They are ubiquitous in nature and are common inhabitants of decaying matter and soil. Inhalation is the natural route of infection. However, traumatic inoculation has also been described. Undefined defects in immunity in immunocompromised patients and in diabetic patients permit the proliferation of the spores. The hallmark of mucormycosis is the direct invasion of blood vessels by these organisms and the subsequent thrombosis and tissue necrosis. The most common clinical presentation of mucormycosis is rhinocerebral mucormycosis.121,122 As the name implies, infection starts in the nose and paranasal sinuses and spreads to the orbit and the adjacent structures of the brain, commonly the frontal lobe and the cavernous sinus. The clinical manifestations of rhinocerebral mucormycosis reflect the involvement of the tissues and structures. Initial complaints are facial pain and headache. Fever may not be present. With further progression of the infection, additional complaints and findings include erythema and ulceration of the palate, periorbital cellulitis, proptosis, swelling of the conjunctiva, cranial nerve dysfunction, loss of vision, mental status changes, and coma. Isolated CNS mucormycosis has also been reported. The majority of these reports were in intravenous drug users.123 The most common clinical presentation includes mental status changes and focal neurological deficits. The infection appears to have a predilection for basal ganglia. The presence of tissue necrosis (e.g., black eschars and discharges) is suggestive of the disease; attempts at diagnosis and treatment should be prompt and aggressive. The diagnosis of mucormycosis requires the identification of the organisms in tissue. The agents of mucormycosis are usually difficult to grow in culture and blood cultures are rarely positive. Imaging studies (computed tomography and magnetic resonance imaging) of the sinuses and the brain are helpful in establishing the extent of involvement. Treatment of mucormycosis needs to be prompt and aggressive. Both surgical débridement of necrotic tissue and antifungal therapy are required. Repeated débridement is often necessary. The agents of mucormycosis are relatively refractory to antifungal therapy. They require high doses of amphotericin B deoxycholate, typically 1.0 to 1.5 mg/kg per day. Lipid preparations of amphotericin B are acceptable alternatives and may permit the delivery of high doses of amphotericin B with less toxicity. None of the currently available azoles or echinocandins are active against the organisms that cause mucormycosis. However, posaconazole, a new azole that is currently in phase III trials and is also available in compassionate use protocols, has been reported to have good activity against some of the agents that cause mucormycosis.124,125 The overall mortality rate of mucormycosis is approximately 50%.

Central Nervous System Aspergillosis Aspergillus is a mold that is ubiquitous in the environment worldwide, being found primarily in decaying vegetation but

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also in soil and water. Its hyphae (filaments) are thin and septated, branching off at acute angles. The most common species causing invasive infection include Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger.126 Infection is usually acquired by inhalation into the lungs. In persons without effective host defenses (e.g., neutropenic patients, patients receiving corticosteroid treatment, and transplant recipients), the inhaled organisms enlarge and germinate, invade tissue, and eventually cause disseminated infection. Tissue and vascular invasiveness is the hallmark of Aspergillus infections.127 The most common clinical manifestation of Aspergillus infection is invasive pulmonary infection. CNS aspergillosis may occur in up to 10% to 20% of all cases of invasive aspergillosis. Reports suggest that it is being encountered more frequently than in the past. Although it usually occurs as part of a disseminated infection with concomitant pulmonary infection, isolated CNS aspergillosis has been reported, particularly in intravenous drug users. Even though it has been reported among patients with HIV infection, CNS aspergillosis does not appear to be more common in HIV patients than in other immunocompromised patients. Its most common manifestation is a brain abscess causing headache, focal neurological signs, and altered mental status. The spectrum of CNS disease includes meningitis, hemorrhages, bland infarctions, myelitis, epidural abscesses, and mycotic aneurysms.128-134 The diagnosis of CNS aspergillosis requires the demonstration of the organism and its invasion in CNS tissue or isolation of the organism from a biopsy specimen or CSF. Blood cultures are rarely positive. Computed tomography or magnetic resonance imaging of the brain most commonly shows single or multiple ring-enhancing lesions with surrounding edema. Other radiographic appearances include hemorrhagic infarction pattern, parenchymal hemorrhage pattern, and diffuse necrotic encephalitis pattern.135 An enzyme immunoassay for detecting Aspergillus galactomannan, an Aspergillus antigen, has been licensed in the United States for the diagnosis of invasive aspergillosis.136 Although not extensively evaluated, at least one report suggests that detection of Aspergillus galactomannan in CSF may be of diagnostic value.137 Historically, invasive aspergillosis as a whole is refractory to treatment, with overall mortality rates of 50% or more. CNS aspergillosis carries the poorest prognosis, with mortality rates of more than 90% reported in most series.138 The following antifungal agents are active against Aspergillus species: amphotericin B deoxycholate, lipid forms of amphotericin B, itraconazole, voriconazole, and caspofungin. Voriconazole is considered by many as the agent of first choice for the treatment of invasive aspergillosis. This may also apply for the treatment of CNS aspergillosis. New drugs in development, such as posaconazole, ravuconazole, micafungin, and anidulafungin are also active against Aspergillus species and may offer new options for therapy. All drugs need to be given at high doses, and the optimal duration of therapy is unknown. Although it would be reasonable to continue to treat until clinical and radiographic abnormalities have resolved, it may be necessary to continue treatment as long as the underlying predisposition for invasive Aspergillus infection exists. Stereotactic drainage of abscesses may be required.139

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References

K E Y

P O I N T S

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The human immunodeficiency virus pandemic, immunosuppression, and global warming have resurrected the study of parasitology.

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Cysticercosis is the most common cause of epilepsy in developing countries.

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Prophylactic medication has impacted the prevalence of cerebral toxoplasmosis, a devastating disease.

●

Immunodiagnosis has made great strides in the diagnosis of the main parasitoses.

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Most fungal CNS infections are caused by a relatively few important fungal organisms.

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Most fungal CNS infections occur as part of a disseminated disease or as a disease in immunocompromised patients.

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C. neoformans has a predilection for the CNS.

●

Most patients with fungal CNS infections present with subacute to chronic meningitis. CNS aspergillosis is an exception.

●

With the exception of C. neoformans, demonstration or isolation of the causative organism in CSF is difficult.

Suggested Reading Benson CA, Kaplan JE, Masur H, et al: Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis 2005; 40:S131-S235. CDC Division of Parasitic Diseases: Parasitic disease information. Available at http://www.cdc.gov/ncidod/dpd/parasites/ listing.htm. Cook GC, Zumla AI, editors: Manson’s Tropical Diseases. Edinburgh: Saunders, 2003. Cortez KJ, Walsh TJ: Space-occupying fungal lesions. In Scheld WM, Whitley RJ, Marra CM, eds: Infections of the Central Nervous System, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 713-734. Drugs for parasitic infections. Med Lett Drugs Ther 2004. Available at http://www.medletter.com/freedocs/parasitic.pdf. Garcia HH, Del Brutto OH, Nash TE, et al: New concepts in the diagnosis and management of neurocysticercosis (Taenia solium). Am J Trop Med Hyg 2005; 72:3-9. Perfect JR: Fungal meningitis. In Scheld WM, Whitley RJ, Marra CM, eds: Infections of the Central Nervous System. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 691712. Scheld WM, Whitley RJ, Marra CM, editors. Infections of the central nervous system. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. Sobel JD, Mycoses Study Group: Guidelines from the Infectious Diseases Society of America: practice guidelines for the treatment of fungal infections. Clin Infect Dis 2000; 30: 652. Walker M, Zunt JR: Parasitic central nervous system infections in immunocompromised hosts. Clin Infect Dis 2005; 40:10051015.

1. Nevins A: Study In Power: John D. Rockefeller, Industrialist and Philanthropist. New York: Charles Scribner’s Sons, 1953. 2. Awasthi S, Bundy DA, Savioli L: Helminthic infections. BMJ 2003; 327:431-433. 3. Ing MB, Schantz PM, Turner JA: Human coneurosis in North America: case reports and review. Clin Infect Dis 1998; 27:519-523. 4. Ferreira MS, Nishioka Sde A, Silvestre MT, et al: Reactivation of Chagas’ disease in patients with AIDS: report of three new cases and review of the literature. Clin Infect Dis 1997; 25:1397-1400. 5. Breniere SF, Bosseno MF, Noireau F, et al: Integrate study of a Bolivian population infected by Trypanosoma cruzi, the agent of Chagas disease. Mem Inst Oswaldo Cruz 2002; 97:289-295. 6. Pinto NX, Torres-Hillera MA, Mendoza E, et al: Immune response, nitric oxide, autonomic dysfunction and stroke: a puzzling linkage on Trypanosoma cruzi infection. Med Hypotheses 2002; 58:374-377. 7. da Cunha AB: Chagas’ disease and the involvement of the autonomic nervous system. Rev Port Cardiol 2003; 22:813824. 8. Di Lorenzo GA, Pagano MA, Taratuto AL, et al: Chagasic granulomatous encephalitis in immunosuppressed patients: computed tomography and magnetic resonance imaging findings. J Neuroimaging 1996; 6:94-97. 9. Suiter TM, Schreiner-Suiter S, Glockner WM: Cerebral immune vasculitis as a complication of larva migrans infection caused by Toxocara canis [in German]. Med Klin (Munich) 1993; 88:445-448. 10. Osoegawa M: Diagnosis and treatment of central nervous system parasite infection with special reference to parasitic myelitis [in Japanese]. Rinsho Shinkeigaku 2004; 44:961-964. 11. Cook GC, Zumla AI, eds: Manson’s Tropical Diseases. Edinburgh: Saunders, 2003. 12. Scheld WM, Whitley RJ, Marra CM, eds: Infections of the Central Nervous System, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004. 13. Hashim FA, Ahmed AE, el Hassan M, et al: Neurologic changes in visceral leishmaniasis. Am J Trop Med Hyg 1995; 52:149-154. 14. Jin E, Ma D, Liang Y, et al: MRI findings of eosinophilic myelomeningoencephalitis due to Angiostrongylus cantonensis. Clin Radiol 2005; 60:242-250. 15. Gupta S, Desai K, Goel A: Intracranial hydatid cyst: a report of five cases and review of literature. Neurol India 1999; 47:214-217. 16. Altinors N, Bavbek M, Caner HH, et al: Central nervous system hydatidosis in Turkey: a cooperative study and literature survey analysis of 458 cases. J Neurosurg 2000; 93:1-8. 17. Tüzün M, Altinörs N, Arda IS, et al: Cerebral hydatid disease computed tomography and MR findings. Clin Imaging 2002; 26:353-357. 18. Sawanyawisuth K, Tiamkao S, Kanpittaya J, et al: MR imaging findings in cerebrospinal gnathostomiasis. AJNR Am J Neuroradiol 2004; 25:446-449. 19. Choo JD, Suh BS, Lee HS, et al: Chronic cerebral paragonimiasis combined with aneurysmal subarachnoid hemorrhage. Am J Trop Med Hyg 2003; 69:466-469. 20. Kaw GJ, Sitoh YY: Clinics in diagnostic imaging (58): chronic cerebral paragonimiasis. Singapore Med J 2001; 42:89-91. 21. Mao SC, Ye XC, Liu JX, et al: CT brain scanning in the diagnosis and localisation of cerebral schistosomiasis [in Chinese]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 1989; 7:115-118.

chapter 94 parasitic and fungal infections 22. Kirchhoff LV, Nash TE: A case of schistosomiasis japonica: resolution of CAT-scan detected cerebral abnormalities without specific therapy. Am J Trop Med Hyg 1984; 33:1155-1158. 23. Putman CE, Ravin CE, eds: Textbook of Diagnostic Imaging. Vols 1, 2, 2nd ed. Philadelphia: Saunders, 1994. 24. Commission on Tropical Diseases of the International League Against Epilepsy: Relationship between epilepsy and tropical diseases. Epilepsia 1994; 35:89-93. 25. Drugs for parasitic infections. Med Lett Drugs Ther 2004. Available at http://www.medletter.com/freedocs/parasitic.pdf. 26. CDC Division of Parasitic Diseases. Parasitic disease information. Available at http://www.cdc.gov/ncidod/dpd/parasites/ listing.htm. 27. Storey MV, Winiecka-Krusnell J, Ashbolt NJ, et al: The efficacy of heat and chlorine treatment against thermotolerant Acanthamoebae and Legionellae. Scand J Infect Dis 2004; 36:656-662. 28. Marciano-Cabral F, Cabral G: Acanthamoeba spp. as agents of disease in humans. Clin Microbiol Rev 2003; 16:273-307. 29. Velho V, Sharma GK, Palande DA: Cerebrospinal acanthamebic granulomas: case report. J Neurosurg 2003; 99:572-574. 30. Kilvington S, Price J: Survival of Legionella pneumophila within cysts of Acanthamoeba polyphaga following chlorine exposure. J Appl Bacteriol 1990; 68:519-525. 31. Alizadeh H, Apte S, El-Agha MS, et al: Tear IgA and serum IgG antibodies against Acanthamoeba in patients with Acanthamoeba keratitis. Cornea 2001; 20:622-627. 32. Bloch KC, Schuster FL: Inability to make a premortem diagnosis of Acanthamoeba species infection in a patient with fatal granulomatous amebic encephalitis. J Clin Microbiol 2005; 43:3003-3006. 33. Stanley SL Jr: Amoebiasis. Lancet 2003; 361:1025-1034. 34. Haque R, Ali IK, Akther S, et al: Comparison of PCR, isoenzyme analysis, and antigen detection for diagnosis of Entamoeba histolytica infection. J Clin Microbiol 1998; 36:449-452. 35. Furrows SJ, Moody AH, Chiodini PL: Comparison of PCR and antigen detection methods for diagnosis of Entamoeba histolytica infection. J Clin Pathol 2004; 57:1264-1266. 36. Delialioglu N, Aslan G, Sozen M, et al: Detection of Entamoeba histolytica/Entamoeba dispar in stool specimens by using enzyme-linked immunosorbent assay. Mem Inst Oswaldo Cruz 2004; 99:769-772. 37. Truc P, Lejon V, Magnus E, et al: Evaluation of the microCATT, CATT/Trypanosoma brucei gambiense, and LATEX/T b gambiense methods for serodiagnosis and surveillance of human African trypanosomiasis in west and central Africa. Bull World Health Organ 2002; 80:882-886. 38. Iten M, Mett H, Evans A, et al: Alterations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodesiense to D,L-α-difluoromethylornithine. Antimicrob Agents Chemother 1997; 41:1922-1925. 39. Burri C, Nkunku S, Merolle A, et al: Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. Lancet 2000; 355:1419-1425. 40. Schmid C, Nkunku S, Merolle A, et al: Efficacy of 10-day melarsoprol schedule 2 years after treatment for late-stage gambiense sleeping sickness. Lancet 2004; 364:789-790. 41. Pepin J, Milord F: The treatment of human African trypanosomiasis. Adv Parasitol 1994; 33:1-47. 42. Slom TJ, Cortese MM, Gerber SI, et al: An outbreak of eosinophilic meningitis caused by Angiostrongylus cantonensis in travelers returning from the Caribbean. N Engl J Med 2002; 346:668-675. 43. Roman G, Sotelo J, Del Brutto O, et al: A proposal to declare neurocysticercosis an international reportable disease. Bull World Health Organ 2000; 78:399-406.

1293

44. Mitchell WG: Neurocysticercosis and acquired cerebral toxoplasmosis in children. Semin Pediatr Neurol 1999; 6:267-277. 45. Hawk MW, Shahlaie K, Kim KD, et al: Neurocysticercosis: a review. Surg Neurol 2005; 63:123-132. 46. Narula G, Bawa KS: Neurocysticercosis: new millennium, ancient disease and unending debate. Indian J Pediatr 2003; 70:337-342. 47. Wilson M, Bryan RT, Fried JA, et al: Clinical evaluation of the cysticercosis enzyme-linked immunoelectrotransfer blot in patients with neurocysticercosis. J Infect Dis 1991; 164:10071009. 48. Villota GE, Gomez DI, Volcy M, et al: Similar diagnostic performance for neurocysticercosis of three glycoprotein preparations from Taenia solium metacestodes. Am J Trop Med Hyg 2003; 68:276-280. 49. Del Brutto OH, Rajshekhar V, White AC Jr, et al: Proposed diagnostic criteria for neurocysticercosis. Neurology 2001; 57:177-183. 50. Rajshekhar V, Jeyaseelan L: Seizure outcome in patients with a solitary cerebral cysticercus granuloma. Neurology 2004; 62:2236-2240. 51. Singh G, Kaushal S, Gupta M, et al: Cutaneous reactions in patients with solitary cysticercus granuloma on phenytoin sodium. J Neurol Neurosurg Psychiatry 2004; 75:331-333. 52. Carpio A, Hauser WA: Neurocysticercosis and epilepsy. In Singh G, Prabhakar S, eds: Taenia solium Cysticercosis: From Basic to Clinical Science. Chandigarh, India: CABI Publishing, 2002, pp 211-220. 53. Garcia HH, Pretell EJ, Gilman RH, et al: A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med 2004; 350:249-258. 54. Singhi P, Jain V, Khandelwal N: Corticosteroids versus albendazole for treatment of single small enhancing computed tomographic lesions in children with neurocysticercosis. J Child Neurol 2004; 19:323-327. 55. Kalra V, Dua T, Kumar V: Efficacy of albendazole and shortcourse dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial. J Pediatr 2003; 143:111-114. 56. Garcia HH, Evans CA, Nash TE, et al: Current consensus guidelines for treatment of neurocysticercosis. Clin Microbiol Rev 2002; 15:747-756. 57. Psarros TG, Zouros A, Coimbra C: Neurocysticercosis: a neurosurgical perspective. South Med J 2003; 96:10191022. 58. Garcia HH, Del Brutto OH, Nash TE, et al: New concepts in the diagnosis and management of neurocysticercosis (Taenia solium). Am J Trop Med Hyg 2005; 72:3-9. 59. Carpio A: Neurocysticercosis: an update. Lancet Infect Dis 2002; 2:751-762. 60. Garcia HH, Del Brutto OH: Taenia solium cysticercosis. Infect Dis Clin North Am 2000; 14:97-119. 61. White AC Jr: Neurocysticercosis: updates on epidemiology, pathogenesis, diagnosis, and management. Annu Rev Med 2000; 51:187-206. 62. Adams S, Brown H, Turner G: Breaking down the blood-brain barrier: signaling a path to cerebral malaria? Trends Parasitol 2002; 18:360-366. 63. de Souza JB, Riley EM: Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes Infect 2002; 4:291-300. 64. Mhlanga JD, Bentivoglio M, Kristensson K: Neurobiology of cerebral malaria and African sleeping sickness. Brain Res Bull 1997; 44:579-589. 65. Kristensson K, Mhlanga JD, Bentivoglio M: Parasites and the brain: neuroinvasion, immunopathogenesis and neuronal dysfunctions. Curr Top Microbiol Immunol 2002; 265:227257.

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66. Wassmer SC, Combes V, Grau GE: Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion. Ann N Y Acad Sci 2003; 992:30-38. 67. Baruch DI, Pasloske BL, Singh HB, et al: Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 1995; 82:77-87. 68. Beare NA, Southern C, Chalira C, et al: Prognostic significance and course of retinopathy in children with severe malaria. Arch Ophthalmol 2004; 122:1141-1147. 69. Holding PA, Stevenson J, Peshu N, et al: Cognitive sequelae of severe malaria with impaired consciousness. Trans R Soc Trop Med Hyg 1999; 93:529-534. 70. World Health Organization: Management of Severe Malaria: A Practical Handbook, 2nd ed. Geneva: World Health Organization, 2000. Available at http://www.who.int/malaria/docs/ hbsm.pdf. 71. Centers for Disease Control and Prevention: Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States). 2004. Available at http://www.cdc.gov/malaria/pdf/treatmenttable.pdf. 72. The Roll Back Malaria Partnership: RBM: a global partnership, 2005. Available at http://www.rbm.who.int/. 73. Ogutu BR, Newton CR: Management of seizures in children with falciparum malaria. Trop Doct 2004; 34:71-75. 74. Mturi N, Musumba CO, Wamola BM, et al: Cerebral malaria: optimising management. CNS Drugs 2003; 17:153-165. 75. Artemether-Quinine Meta-analysis Study Group: A metaanalysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 2001; 95:637-650. 76. Newton CR, Hien TT, White N: Cerebral malaria. J Neurol Neurosurg Psychiatry 2000; 69:433-441. 77. Magana M, Messina M, Bustamante F, et al: Gnathostomiasis: clinicopathologic study. Am J Dermatopathol 2004; 26:91-95. 78. Diaz Camacho SP, Zazueta Ramos M, Ponce Torrecillas E, et al: Clinical manifestations and immunodiagnosis of gnathostomiasis in Culiacan, Mexico. Am J Trop Med Hyg 1998; 59:908-915. 79. Miyazaki I: Cerebral paragonimiasis. Contemp Neurol Ser 1975; 12:109-132. 80. Kim SK: Cerebral paragonimiasis: a report of forty-seven cases. Arch Neurol 1959; 1:30-37. 81. Joo EY, Kim JH, Tae WS, et al: Simple partial status epilepticus localized by single-photon emission computed tomography subtraction in chronic cerebral paragonimiasis. J Neuroimaging 2004; 14:365-368. 82. Kusner DJ, King CH: Cerebral paragonimiasis. Semin Neurol 1993; 13:201-208. 83. Oh SJ: Cerebral paragonimiasis. Trans Am Neurol Assoc 1967; 92:275-277. 84. Maleewong W: Recent advances in diagnosis of paragonimiasis. Southeast Asian J Trop Med Public Health 1997; 28 Suppl 1:134-138. 85. Hayashi M: Clinical features of cerebral schistosomiasis, especially in cerebral and hepatosplenomegalic type. Parasitol Int 2003; 52:375-383. 86. Ferrari TC, Moreira PR, Cunha AS: Spinal-cord involvement in the hepato-splenic form of Schistosoma mansoni infection. Ann Trop Med Parasitol 2001; 95:633-635. 87. Nascimento-Carvalho CM, Moreno-Carvalho OA: Clinical and cerebrospinal fluid findings in patients less than 20 years old with a presumptive diagnosis of neuroschistosomiasis. J Trop Pediatr 2004; 50:98-100. 88. Mansour MM, Ali PO, Farid Z, et al: Serological differentiation of acute and chronic schistosomiasis mansoni by antibody responses to keyhole limpet hemocyanin. Am J Trop Med Hyg 1989; 41:338-344.

89. Hill D, Dubey JP: Toxoplasma gondii: transmission, diagnosis and prevention. Clin Microbiol Infect 2002; 8:634-640. 90. Sarciron ME, Gherardi A: Cytokines involved in toxoplasmic encephalitis. Scand J Immunol 2000; 52:534-543. 91. Levitz SM: The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. Rev Infect Dis 1991; 13:11631169. 92. Perfect JR, Casadevall A: Cryptococcosis. Infect Dis Clin North Am 2002; 16:837-874. 93. Pappas PG, Perfect JR, Cloud GA, et al: Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001; 33:690-699. 94. Powderly WG: Cryptococcal meningitis and AIDS. Clin Infect Dis 1993; 17:837-842. 95. Saag MS, Graybill RJ, Larsen RA, et al: Infectious Diseases Society of America. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000; 30:710-718. 96. Benson CA, Kaplan JE, Masur H, et al: Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis 2005; 40(Suppl 3):S131S235. 97. Graybill JR, Sobel J, Saag M, et al: The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000; 30:47-54. 98. Maresca B, Kobayashi GS: Dimorphism in Histoplasma capsulatum and Blastomyces dermatitidis. Contrib Microbiol 2000; 5:201-216. 99. Ajello L: Distribution of Histoplasma capsulatum in the United States. In Ajello L, Chick EW, Furcolow ML, eds: Histoplasmosis. Springfield, IL: Thomas, 1971, pp 103-122. 100. Wheat LJ, Kauffman CA: Histoplasmosis. Infect Dis Clin North Am 2003; 17:1-19. 101. Wheat LJ, Batteiger BE, Sathapatayavongs B: Histoplasma capsulatum infections of the central nervous system: a clinical review. Medicine (Baltimore) 1990; 69:244-260. 102. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al: Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990; 69:361-374. 103. Joseph Wheat L: Current diagnosis of histoplasmosis. Trends Microbiol 2003; 11:488-494. 104. Wheat LJ, Garringer T, Brizendine E, et al: Diagnosis of histoplasmosis by antigen detection based upon experience at the histoplasmosis reference laboratory. Diagn Microbiol Infect Dis 2002; 43:29-37. 105. Wheat J, Sarosi G, McKinsey D, et al: Infectious Diseases Society of America. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000; 30:688695. 106. Klein BS, Vergeront JM, Davis JP: Epidemiologic aspects of blastomycosis, the enigmatic systemic mycosis. Semin Respir Infect 1986; 1:29-39. 107. Bradsher RW, Chapman SW, Pappas PG: Blastomycosis. Infect Dis Clin North Am 2003; 17:21-40. 108. Kravitz GR, Davies SF, Eckman MR, et al: Chronic blastomycotic meningitis. Am J Med 1981; 71:501-505. 109. Gonyea EF: The spectrum of primary blastomycotic meningitis: a review of central nervous system blastomycosis. Ann Neurol 1978; 3:26-39. 110. Pappas PG, Pottage JC, Powderly WG, et al: Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1992; 116:847-853. 111. Chapman SW, Bradsher RW Jr, Campbell GD Jr, et al: Infectious Diseases Society of America. Practice guidelines for the

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112. 113. 114. 115. 116.

117. 118. 119. 120. 121. 122. 123. 124.

125.

management of patients with blastomycosis. Clin Infect Dis 2000; 30:679-683. Pappagianis D: Epidemiology of coccidioidomycosis. Curr Top Med Mycol 1988; 2:199-238. Stevens DA: Coccidioidomycosis. N Engl J Med 1995; 332:1077-1082. Deresinski SC, Stevens DA: Coccidioidomycosis in compromised hosts: experience at Stanford University Hospital. Medicine (Baltimore) 1975; 54:377-395. Logan JL, Blair JE, Galgiani JN: Coccidioidomycosis complicating solid organ transplantation. Semin Respir Infect 2001; 16:251-256. Mischel PS, Vinters HV: Coccidioidomycosis of the central nervous system: neuropathological and vasculopathic manifestations and clinical correlates. Clin Infect Dis 1995; 20:400-405. Banuelos AF, Williams PL, Johnson RH, et al: Central nervous system abscesses due to Coccidioides species. Clin Infect Dis 1996; 22:240-250. Pappagianis D, Zimmer BL: Serology of coccidioidomycosis. Clin Microbiol Rev 1990; 3:247-268. Galgiani JN, Ampel NM, Catanzaro A, et al: Infectious Diseases Society of America. Practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis 2000; 30:658-661. Eucker J, Sezer O, Graf B, Possinger K: Mucormycoses. Mycoses 2001; 44:253-260. Prabhu RM, Patel R: Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 2004; 10 Suppl 1:31-47. Peterson KL, Wang M, Canalis RF, et al: Rhinocerebral mucormycosis: evolution of the disease and treatment options. Laryngoscope 1997; 107:855-862. Pierce PF Jr, Solomon SL, Kaufman L, et al: Zygomycetes brain abscesses in narcotic addicts with serological diagnosis. JAMA 1982; 248:2881-2882. Tobon AM, Arango M, Fernandez D, et al: Mucormycosis (zygomycosis) in a heart-kidney transplant recipient: recovery after posaconazole therapy. Clin Infect Dis 2003; 36:14881491. Dannaoui E, Meis JF, Loebenberg D, et al: Activity of posaconazole in treatment of experimental disseminated zygomycosis. Antimicrob Agents Chemother 2003; 47:36473650.

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126. Sutton DA, Fothergill AW, Rinaldi MG: Guide to Clinically Significant Fungi. Baltimore: Williams & Wilkins, 1997. 127. Denning DW: Invasive aspergillosis. Clin Infect Dis 1998; 26:781-803. 128. Walsh TJ, Hier DB, Caplan LR: Aspergillosis of the central nervous system: clinicopathological analysis of 17 patients. Ann Neurol 1985; 18:574-582. 129. Kleinschmidt-DeMasters BK: Central nervous system aspergillosis: a 20-year retrospective series. Hum Pathol 2002; 33:116-124. 130. Torre-Cisneros J, Lopez OL, Kusne S, et al: CNS aspergillosis in organ transplantation: a clinicopathological study. J Neurol Neurosurg Psychiatry 1993; 56:188-193. 131. Boes B, Bashir R, Boes C, et al: Central nervous system aspergillosis: analysis of 26 patients. J Neuroimaging 1994; 4:123-129. 132. Boon AP, Adams DH, Buckels J, et al: Cerebral aspergillosis in liver transplantation. J Clin Pathol 1990; 43:114118. 133. Woods GL, Goldsmith JC: Aspergillus infection of the central nervous system in patients with acquired immunodeficiency syndrome. Arch Neurol 1990; 47:181-184. 134. Jantunen E, Volin L, Salonen O, et al: Central nervous system aspergillosis in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2003; 31:191-196. 135. Romero Vidal FJ, Ortega Aznar A, Ibarra de Grassa B: Central nervous system aspergillosis: computed tomographic patterns and radiopathological correlation. Int J Neuroradiol 1998; 4:320-323. 136. Stynen D, Goris A, Sarfati J, et al: A new sensitive sandwich enzyme-linked immunosorbent assay to detect galactofuran in patients with invasive aspergillosis. J Clin Microbiol 1995; 33:497-500. 137. Machetti M, Zotti M, Veroni L, et al: Antigen detection in the diagnosis and management of a patient with probable cerebral aspergillosis treated with voriconazole. Transpl Infect Dis 2000; 2:140-144. 138. Lin SJ, Schranz J, Teutsch SM: Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001; 32:358-366. 139. Stevens DA, Kan VL, Judson MA, et al: Infectious Diseases Society of America. Practice guidelines for diseases caused by aspergillus. Clin Infect Dis 2000; 30:696-709.

CHAPTER

95

PRION DISEASES ●

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●

●

Katherine Murray and Robert G. Will

Although the human forms of prion disease, including Creutzfeldt-Jakob disease (CJD), are rare, this group of fatal disorders of the central nervous system has become the subject of extensive scientific and public interest. Prion diseases affect both humans and animals (Table 95–1); are caused by infectious agents, which may consist only of a host-encoded protein; and share properties that pose a major challenge to animal and public health (Table 95–2). The critical difference between prion diseases and other neurodegenerative conditions is that they are transmissible experimentally and, sometimes, naturally. The hypothesis that bovine spongiform encephalopathy (BSE) has been transmitted from cattle to the human population as variant CJD (vCJD)1 and the possibility of secondary transmission through blood transfusion2,3 have increased the level of interest in and concern about these diseases.

this is explained by spontaneous conversion of the normal protein to the abnormal form in sporadic disease, by instability in protein structure in cases associated with mutations of the prion protein gene (PRNP), and by transmission of selfreplicating PrPSc in infectious forms. The absence of detectable PrPSc in some types of experimental prion disease has led to the hypothesis that it is intermediate forms of PrP, rather than the end-stage protein (PrPSc or PrP27-30), identified in postmortem brain samples, that are infectious. Whatever the structure of infectious PrP, these agents are remarkably resistant to normal sterilizing techniques,6 which adds to the concerns about onward transmission of infection.

ETIOLOGY AND PATHOGENESIS

Epidemiology

In all prion diseases, a post-translationally modified form of a normal membrane-associated protein, prion protein (PrP), is deposited in the brain and some other tissues. This is accompanied by neuropathological changes, including spongiform change, astrocytic gliosis, and neuronal loss, although, in addition, the abnormal form of prion protein (PrPSc) may be deposited in aggregates as amyloid plaques. The function of the normal host PrP has not been established. According to the prion hypothesis, PrPSc is the infectious agent and acts as a template for its own replication without additional informational material such as DNA or RNA.4 Evidence of the synthetic production of infectious PrP provides strong support to this hypothesis,5 although whether this theory adequately explains the existence of multiple strains of infectious agent remains controversial. After exposure to infection, there is a prolonged incubation period, extending to years or even decades in natural disease, during which there is no evidence of clinical disease, despite the accumulation of PrPSc and infection in peripheral tissues, mainly in the lymphoreticular system. There is no host immune response and no available serological test to identify the presence of infection; this implies that infected animals may enter the human food chain and infected humans may potentially act as blood donors. Prion diseases are unique in that they occur in sporadic, genetic, and infectious forms.4 According to the prion theory,

HUMAN PRION DISEASES

Sporadic Creutzfeldt-Jakob Disease This rare disease occurs worldwide with mortality rates of 1 to 2 cases per million population per year in systematic surveys.7 The cause of sporadic CJD (sCJD) is unknown, and there is no good evidence of clustering of cases to indicate an environmental source of infection and no consistent risk factors identified in case-control studies.8 sCJD occurs predominantly in the older age groups, with a mean age at death of about 66 years, but younger patients can be affected, and a handful of teenagers with sCJD have been described.

Genetic Human Prion Diseases Genetic Creutzfeldt-Jakob disease, Gerstmann-SträusslerScheinker disease, and fatal familial insomnia are all associated with, and perhaps caused by, mutations in PRNP, with variations in clinical and pathological phenotypes that are related to the specific mutation.9 Genetic human prion diseases have been found in most countries, but the frequency of these cases varies; some countries such as Slovakia, Israel, and Italy have high localized incidences.10 Overall, in genetic cases, age at death is approximately 10 years younger than that in sCJD.

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Iatrogenic Creutzfeldt-Jakob Disease This form of CJD is caused by the transmission of infection from person to person in the course of medical or surgical treatment.11 Numerically, the most frequent means of transmission have been through human dura mater grafts (168 cases worldwide) and human pituitary growth hormone (180 cases), although, in rare cases, other vectors have been implicated, including neurosurgical instruments, corneal grafts, and human pituitary gonadotrophin. Incubation periods range from 1.5 to more than 30 years and vary according to the route of inoculation.

Kuru This human prion disease occurred in the Fore region of Papua New Guinea and was caused by transmission of infection through ritual cannibalism.12 Kuru has now largely disappeared

since the cessation of cannibalism in the late 1950s, although there are still some new cases, with incubation periods exceeding 40 years.

Variant Creutzfeldt-Jakob Disease This new disease was identified in 1996, and there is now compelling evidence in support of the hypothesis that vCJD is caused by transmission of BSE to the human population, probably via the human food chain. There have been more than 150 cases of vCJD in the United Kingdom, but the annual mortality rate has dropped since 2000,13 and concerns about a massive epidemic have lessened. Small numbers of cases of vCJD have also been identified in other countries and may be related to export of bovine material from the United Kingdom, travel to the United Kingdom, or indigenous BSE (Fig. 95–1). The mean age at death in vCJD is only 30 years (range, 14 to 74 years). Possible explanations for the young age of patients with vCJD include age-related patterns of dietary exposure, age-related susceptibility, or a combination of these factors.

T A B L E 95–1. Prion Diseases Human

Animal

Codon 129 Polymorphism

Sporadic Sporadic CJD Genetic Genetic CJD Gerstmann-SträusslerScheinker disease

Infectious Scrapie in sheep and goats Transmissible mink encephalopathy BSE Spongiform encephalopathy* in the domestic cat, captive zoo species, including kudu, cheetah, tiger Chronic wasting disease of cervids

There is a variable region at codon 129 of human PRNP, which encodes either methionine or valine, leading to three possible genotypes: methionine homozygous (MM), methionine-valine

Fatal familial insomnia

T A B L E 95–2. Characteristics of Prion Diseases Uniformly fatal disorders of the central nervous system Causal agents relatively resistant to sterilization Prolonged asymptomatic incubation periods Infectivity in tissues, including the lymphoreticular system, during the incubation period No serological test for infectivity No practicable means of identifying carrier state

Infectious Kuru Iatrogenic CJD Variant CJD* *BSE related. BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease.

■

vCJD CASES WORLDWIDE NUMBER OF DEATHS PER ANNUM AND NUMBER ALIVE

variant Creutzfeldt-Jakob disease (vCJD) worldwide, analyzed as deaths per calendar year and patients currently living (as of 2005).

30

25

Number of cases

20

15

10

5

0 1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Figure 95–1. Total cases of

2005

Alive

chapter 95 prion diseases heterozygous (MV), or valine homozygous (VV). Variations in genotype at this locus have a profound effect on susceptibility to disease (Table 95–3) and to disease expression.14 In sCJD, there is an excess of individuals with an MM genotype and, to date, all tested clinical cases of vCJD have been MM. In iatrogenic CJD homozygosity, either MM or VV genotype is a relative risk factor, and in genetic human prion disease, the clinical and pathological phenotype may be influenced by the codon 129 genotype. One example is the codon 178 mutation of PRNP, in which a VV genotype is associated with a disease similar to sCJD, whereas with MM there is an illness (fatal familial insomnia), characterized by early profound autonomic disturbance, particularly affecting sleep.15

Clinical Features of Human Prion Disease Sporadic Creutzfeldt-Jakob Disease sCJD typically manifests with a rapidly progressive dementia and myoclonus, often with associated focal neurological features, including ataxia, dysphasia, and pyramidal signs (Table 95–4).16 The median duration of illness is only 5 months from first symptom to death, although a small minority of patients, usually in the younger age groups, survive for more than 1 year. Atypical forms include those with a pure cerebellar onset, with early cortical blindness or with a manifestation mimicking stroke. sCJD has been divided into six subtypes according to the three codon 129 genotypes and the two types of PrP deposited in the brain, as determined by Western blot.17 Patients with the MM type 1 protein and MV type 1 protein subtypes exhibit the

T A B L E 95–3. Polymorphism

Distribution of the Codon 129 Codon 129 Polymorphism (%)

Disease

MM

MV

VV

Sporadic CJD Variant CJD Genetic CJD Fatal familial insomnia Gerstmann-Sträussler-Scheinker disease Iatrogenic CJD Normal population

67 100 69 71 52 54 39

16 — 24 29 32 27 50

17 — 7 — 16 19 11

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typical features of sCJD, whereas the other four subtypes are often atypical in terms of age, clinical features, and neuropathology. Although the clinical diagnosis of sCJD is usually apparent in the typical forms, investigations are essential for ruling out other conditions, particularly those that are potentially treatable. The electroencephalogram shows pseudo-periodic triphasic complexes in about 60% of cases and, although cerebrospinal fluid (CSF) parameters are usually normal (except for a raised protein level in a minority of cases), the CSF 14-3-3 protein immunoassay has a high sensitivity and specificity for the diagnosis of sCJD in the appropriate clinical context.18 There is increasing evidence that the magnetic resonance imaging (MRI) brain scan may be diagnostically useful; highintensity signal in the caudate and putamen are evident in the majority of cases on T2-weighted imaging, fluid-attenuated inversion recovery imaging, and diffusion-weighted imaging sequences (Fig. 95–2). Brain biopsy can allow confirmation of the diagnosis during the patient’s life, but this procedure has risks and can yield negative findings as a result of sampling error.

Genetic Human Prion Disease The clinical features of genetic forms of human prion disease vary according to the mutation in PRNP, although there is also variability both within and between families.19 With some mutations, the clinical features are similar to those of sCJD—for example, with the codon 200 mutation—whereas other mutations are associated with atypical features for CJD, such as a progressive cerebellar syndrome and late cognitive impairment with the codon 102 mutation in Gerstmann-SträusslerScheinker disease. Overall, the duration of clinical illness is more protracted in genetic cases than in sCJD, and with some mutations, the illness can last for several years. Although these are dominantly inherited conditions, a significant proportion of patients with genetic cases do not have a family history of a similar disorder, perhaps because of premature death from other causes, nonpaternity, or de novo mutations. Screening of PRNP for mutations is essential for the diagnosis of these disorders, but fully informed consent for genetic screening is essential.

Iatrogenic Creutzfeldt-Jakob Disease This type of CJD manifests either with features similar to those of sCJD or with a progressive cerebellar syndrome and late cognitive impairment, if this develops at all.11 The factor

CJD, Creutzfeldt-Jakob disease; MM, methionine homozygous; MV, methioninevaline heterozygous; VV, valine homozygous.

T A B L E 95–4. Features of Human Prion Diseases

Mean age at death Median duration of illness (months) Positive electroencephalogram Positive CSF 14-3-3 protein immunoassay Positive MRI findings in caudate and putamen pulvinar area

Sporadic CJD

Variant CJD

gHPD

Iatrogenic CJD hGH

DM

67 5 60% 92% 60%

29 14 0% 47% 90%

55 14 45% 77% 21%

28 13 14% 64% 70%

44 6 50% 95% 31%

CJD, Creutzfeldt-Jakob disease; CSF, cerebrospinal fluid; DM, dura mater–related CJD; gHPD, genetic human prion disease, including genetic CJD, Gerstmann-SträusslerScheinker disease, and fatal familial insomnia; hGH, human growth hormone–related CJD; MRI, magnetic resonance imaging.

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L

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Figure 95–2. Magnetic resonance imaging brain scan in a patient with sporadic Creutzfeldt-Jakob disease, displaying symmetrical high-intensity signal (arrows) in the caudate and putamen in the left cerebral hemisphere. (Courtesy of Dr. D. A. Summers.)

determining the clinical manifestation is the route of exposure to infection. The sCJD phenotype occurs with effective exposure directly in the central nervous system—for example, with exposure to contaminated neurosurgical instruments— whereas a cerebellar syndrome occurs with a peripheral route of inoculation of infection in human pituitary hormone recipients. The duration of illness is similar to that of sCJD with central infection, but it averages about 12 months with peripheral exposure. The diagnosis of iatrogenic CJD rests on establishing a history of a relevant exposure, although investigations, including CSF 14-3-3 protein immunoassay and MRI brain scan, may show findings similar to those in sCJD.

Kuru It is of interest that kuru, a condition caused by peripheral infection either orally or through cuts and abrasions, also manifested with a progressive cerebellar syndrome, with little evidence of cognitive impairment. In contrast to other forms of human prion disease, kuru affected children, as well as adults, and many developed eye movement disorders, including strabismus, in addition to the cerebellar syndrome. The duration of illness varied, with a mean of about 12 months overall.

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Figure 95–3. Magnetic resonance imaging brain scan in a patient with variant Creutzfeldt-Jakob disease, displaying symmetrical high-intensity signal (arrows) in the posterior thalamic (pulvinar) region in both cerebral hemispheres. (Courtesy of Dr. D. A. Summers.)

Variant Creutzfeldt-Jakob Disease The clinical features of vCJD are relatively stereotyped, consistent with a single strain of infectious agent. The early stages are dominated by nonspecific psychiatric symptoms such as depression and anxiety, and in about one third of cases, there are early sensory symptoms, which are usually painful and persistent. This is followed after about 6 months by the development of cerebellar features, often affecting gait; involuntary movements, mainly myoclonus, chorea, or dystonia; and progressive cognitive impairment.20 The median survival length of 14 months is more prolonged than in sCJD. The diagnosis of vCJD is often suspected because of the development of a progressive neuropsychiatric syndrome in a relatively young individual. The electroencephalogram and CSF 14-3-3 protein immunoassay are not diagnostically helpful, but the MRI brain scan reveals a relatively specific abnormality in the form of high-intensity signal in the posterior thalamus (the pulvinar sign) in about 90% of cases (Fig. 95–3). These abnormalities are present on T2-weighted images but are more prominent in fluid-attenuated inversion recovery imaging and diffusion-weighted imaging sequences. Brain and tonsil biopsies can lead to a tissue diagnosis, but both procedures entail risks, and any surgical instruments used in these operations must be destroyed afterward.

chapter 95 prion diseases Secondary Transmission of Variant CreutzfeldtJakob Disease The level of infectivity in the lymphoreticular system in vCJD is greater than in sCJD, and there is evidence that there may be subclinical vCJD infection in a proportion of the U.K. population, some of whom may act as blood donors. In one case, vCJD was identified in a patient who received a blood donation from an individual who later developed vCJD2; in a second reported case, a recipient of a blood donation from a patient with vCJD was found at postmortem study to have positive PrP staining in the lymphoreticular system but not in the brain.3 This suggests that vCJD may be transmissible through blood transfusion, which is consistent with the demonstration in animal studies of transfusion transmission of experimental BSE in sheep. One of the cases linked to blood transfusion involved a person with heterozygous codon 129 polymorphism,3 which indicates that individuals with this genotype, who make up about 50% of the white population, may be at risk for infection. Numerous measures have been taken to minimize the risk from blood transfusion or blood products in the United Kingdom and many other countries. There is, as yet, no evidence of transmission of vCJD though contaminated surgical instruments.

TREATMENT Various medications have been used to treat CJD without benefit, including steroids, antiviral drugs, and anti-inflammatory agents. On the basis of efficacy in cell culture, quinacrine and chlorpromazine have been proposed as potential treatments for human prion disease, but anecdotal evidence suggests that these drugs may not be effective, and both have significant side effects. Formal trials of quinacrine are under way in the United Kingdom and the United States. Pentosan polysulfate has been studied in animal models for many years and clearly has an effect in extending the incubation period or allowing survival in some challenged animals. However, any benefit is dependent on applying the treatment either before or around the time of challenge, and pentosan polysulfate does not cross the blood-brain barrier. A small number of cases of human prion disease have been treated with intraventricular pentosan polysulfate. No systematic follow-up data are available, but one patient with vCJD has survived for a protracted period on treatment and remains alive as of this book’s publication, whereas another patient with vCJD died with no obvious benefit.

CONCLUSION Although human prion diseases are rare, these are devastating and fatal neurological disorders that usually manifest with a relentlessly progressive clinical course. Early diagnosis is an important objective, and this will be especially imperative if an effective treatment is developed. As with most neurological disorders, the clinical history and neurological examination are essential for diagnosis, and appropriate investigation can aid in the diagnosis. The popular perception of BSE and vCJD as “dread” diseases increases the importance of providing prompt and accurate information to the patients and their relatives, although it is probable that fear of CJD is currently more common than the disease itself.

K E Y

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P O I N T S

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Human prion diseases are rare, but they pose major challenges to public health because they are transmissible.

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Diagnosis of sporadic and variant CJD can usually be made on the basis of clinical features, but gene analysis is crucial for identifying genetic cases, and obtaining a history of relevant exposure is essential for identifying iatrogenic CJD.

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The codon 129 polymorphism of the prion protein gene influences susceptibility and disease expression.

●

Investigations such as electroencephalography, CSF 14-3-3 protein immunoassay, and MRI brain scan can aid in the diagnosis.

Suggested Reading Brown P, Preece M, Brandel J-P, et al: Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000; 55:1075-1081. Collinge J: Variant Creutzfeldt-Jakob disease [Review]. Lancet 1999; 354:317-323. Gajdusek DC: Le Kuru. Washington, DC: U.S. Department of Health and Human Services, 1981, pp 25-57. Prusiner SB: Prion diseases of humans and animals. J R Coll Physicians Lond 1994; 28(2, Suppl):1-30. Will RG, Alpers MP, Dormont D, et al: Infectious and sporadic prion diseases. In Prusiner SB, ed: Prion Biology and Diseases, 2nd ed. New York: Cold Spring Harbor Laboratory Press, 2004, pp 629-671.

References 1. Will RG, Ironside JW, Zeidler M, et al: A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347:921925. 2. Llewelyn CA, Hewitt PA, Knight RSG, et al: Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363:417-421. 3. Peden AH, Head MW, Ritchie DL, et al: Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364:527-529. 4. Prusiner SB: Prion Diseases of Humans and Animals. J R Coll Physicians Lond 1994; 28(2, Suppl):1-30. 5. Legname G, Baskakov IV, Nguyen H-OB, et al: Synthetic mammalian prions. Science 2004; 305:673-676. 6. Taylor DM, McConnell I, Brown DA, et al: New inactivation data for the agents of bovine spongiform encephalopathy (BSE) and scrapie. Neuropathol Appl Neurobiol 1994; 20:510. 7. Ladogana A, Puopolo M, Croes EA, et al: Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada. Neurology 2005; 64:1586-1591. 8. Wientjens DPWM, Davanipour Z, Hofman A, et al: Risk factors for Creutzfeldt-Jakob disease: a reanalysis of case-control studies. Neurology 1996; 46:1287-1291. 9. Pocchiari M: Prions and related neurological diseases. Mol Aspects Med 1994; 15:195-291. 10. Ladogana A, Puopolo M, Poleggi A, et al: High incidence of genetic human transmissible spongiform encephalopathies in Italy. Neurology 2005; 64:1592-1597. 11. Brown P, Preece M, Brandel J-P, et al: Iatrogenic CreutzfeldtJakob disease at the millennium. Neurology 2000; 55:10751081.

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12. Alpers M: Epidemiology and clinical aspects of kuru. In Prusiner SB, McKinley MP, eds: Prions. New York: Academic Press, 1987, pp 451-465. 13. Andrews NJ, Farrington CP, Ward HJT, et al: Deaths from variant Creutzfeldt-Jakob disease in the UK. Lancet 2003; 361:751-752. 14. Parchi P, Castellani R, Capellari S, et al: Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 1996; 39:767-778. 15. Montagna P, Cortelli P, Avoni P, et al: Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathol 1998; 8:515-520. 16. Knight R, Collins S: Human prion diseases: cause, clinical and diagnostic aspects. In Rabenau HF, Cinatl J, Doerr HW, eds:

17.

18. 19.

20.

Prions. A challenge for science, medicine and public health system. Basel, Switzerland: Karger, 2001, pp 6892. Parchi P, Giese A, Capellari S, et al: Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46:224233. Green AJE: Use of 14-3-3 in the diagnosis of Creutzfeldt-Jakob disease. Biochem Soc Trans 2002; 30:382-386. Gambetti P, Petersen RB, Parchi P, et al: Inherited prion diseases. In Prusiner SB, ed: Prion Biology and Diseases. New York: Cold Spring Harbor Laboratory Press, 1999, pp 509583. Will RG, Zeidler M, Stewart GE, et al: Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000; 47:575-582.

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NEUROSARCOIDOSIS AND NEURO-BEHÇET’S DISEASE ●

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Carlos A. Pardo-Villamizar

NEUROSARCOIDOSIS Neurosarcoidosis is a localized manifestation of sarcoidosis involving the central nervous system (CNS) or peripheral nervous system (PNS). Sarcoidosis, a multisystemic granulomatous inflammatory disorder of unknown cause, is manifested frequently as a pulmonary and lymph node disease that typically appears in young adults between 20 and 40 years of age. Neurosarcoidosis may occur in 5% to 10% of patients with sarcoidosis as part of multiorgan disease involvement or as the first localized manifestation of the disease.1 The pathological hallmark of sarcoidosis is the presence of noncaseating granulomatous tissue reactions and of inflammation dominated by macrophage activation, as well as mononuclear and lymphocytic infiltration. In the nervous system, noncaseating granulomas and inflammation may occur in any compartment of the CNS or PNS, producing focal or multifocal tissue damage that leads to neurological dysfunction.

Epidemiology and Etiopathogenesis The prevalence of sarcoidosis varies among different populations worldwide. In the United States, it appears to be more common in African Americans and white persons of northern European descent. In addition, foci of increased frequency of sarcoidosis have been described in some European countries. In developing countries in Latin America, Africa, and Asia, the prevalence of sarcoidosis remains uncertain because the high incidence of infectious granulomatous disorders such as tuberculosis, which closely resembles sarcoidosis, predominates as a clinical diagnosis. A multicenter case-control study of etiological factors in 736 patients with newly diagnosed sarcoidosis in the United States1 revealed neurological involvement in 4.6% of the patients. Interestingly, this study also revealed that women were more likely than men to have neurosarcoidosis and ocular involvement of the disease. The factors causing neurological involvement are still unknown, and it is still unclear whether racial or genetic factors play a role in determining the presence of CNS or PNS involvement. The etiological factors involved in the pathogenesis of sarcoidosis remain elusive, but several hypotheses have suggested a potential role of infection, exposure to environmental factors, and noninfectious factors. The occurrence of geographical clus-

ters and the increased risk among first- and second-degree relatives of patients with sarcoidosis are indicative of a role for an environmental or infectious etiological factor.2 Mycobacterium tuberculosis, Propionibacterium acnes, and Propionibacterium granulosum infections have emerged as potential agents in polymerase chain reaction studies of tissue biopsy specimens from patients with sarcoidosis; however, definitive studies to demonstrate a definite role for these or other infective agents have not been carried out.3 Genetic susceptibility, as determined by varying effects of several genes, has been proposed as an important factor determining the presence and variability of the clinical profile of sarcoidosis in different ethnic populations.4 Some major histocompatibility complex (MHC) alleles have been found to confer susceptibility to sarcoidosis (human leukocyte antigen [HLA]–DR11, -DR12, -DR14, -DR15, and -DR17) whereas others appear to be protective (HLA-DR1, HLADR4, and possibly HLA-DQ*0202). Polymorphisms in the angiotensin-converting enzyme, tumor necrosis factor α (TNFα) and vascular endothelial growth factor genes have also been postulated to be associated with the disease in some population-based studies.5,6

Clinical Features The clinical manifestations of neurosarcoidosis are heterogeneous, as noncaseating granulomas and inflammation may affect any compartment of the CNS and PNS (Table 96–1). The most frequent manifestations of neurosarcoidosis are associated with cranial neuropathy and the meningeal and encephalitic forms of the disease; clinical manifestations may overlap and produce complex neurological symptoms. The clinical course of neurosarcoidosis is variable and may exhibit a temporal profile consistent with a monophasic, relapsingremitting, or chronic pattern. The extent of the CNS or PNS involvement and the evolution of clinical problems determine the magnitude of the patient’s neurological disability. Some of the acute manifestations of neurosarcoidosis, such as cranial neuropathies, have a monophasic pattern that resolve quickly with steroid treatment; others, such as the meningeal, encephalitic, and myelopathic forms, frequently have a subacute course that may evolve into relapsing-remitting or chronic forms of the disease, necessitating more aggressive treatment approaches.

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T A B L E 96–1. Clinical Variants of Neurosarcoidosis Clinical Forms

Neurological Manifestation

Clinical Profile

Meningeal form

Aseptic meningitis Basal meningitis Chronic meningitis Pachymeningitis Dural tumor-like sarcoid lesions Facial paralysis Optic neuropathy Multiple cranial neuropathies

Headaches Increase intracranial pressure Hydrocephalus Single or multiple cranial nerve palsies

Cranial neuropathy form

Encephalitic form

Focal encephalitis Focal or multifocal leukoencephalitis Tumor-like sarcoid lesions

Neuroendocrine form

Panhypopituitarism

Myelopathic form

Subacute or progressive myelopathy

Neuropathic form

Multiple mononeuropathies Polyradiculoneuropathies Focal myositis Polymyositis

Myopathic form

Meningeal Forms Basal meningitis, chronic meningitis, and pachymeningitis are frequent manifestations among the meningeal forms of neurosarcoidosis (Fig. 96–1). A careful clinical assessment and contrast-enhanced magnetic brain imaging (MRI) studies, as well as a complete examination of the cerebrospinal fluid (CSF), are necessary to rule out the presence of other diseases that frequently involve the basal meningeal compartment, including tuberculous and fungal or neoplastic meningitis. Because the basal region of the brain is one of the areas most commonly affected by meningeal forms, cranial nerve palsies and hydrocephalus are the most frequent clinical manifestations of these forms of neurosarcoidosis. In patients with meningeal forms of neurosarcoidosis, granulomatous inflammatory reactions may impair the reabsortion of the CSF in the arachnoid villi and/or produce obstruction of CSF outflow. This accumulation of fluid leads to aggressive forms of hydrocephalus and increased intracranial pressure. Special precautions should be taken in patients with hydrocephalus associated with neurosarcoidosis, because lumbar puncture procedures may increase the risk of decompensation and cerebellar tonsillar herniation. Some of these patients may require ventriculostomy or ventriculoperitoneal shunts to avoid further complications from increased intracranial pressure, but the decision to use these neurosurgical approaches must be made carefully. Other variants of meningeal involvement in neurosarcoidosis include spinal arachnoiditis or dural tumor-like lesions that resemble meningiomas and produce focal symptoms in the intracranial or spinal compartments, with increased intracranial pressure or myelopathic symptoms, respectively. These tumor-like lesions are associated with extensive but localized noncaseating gran-

Single or multiple cranial nerve palsies Bilateral Bell’s palsy Diplopia Visual blurriness Vestibular symptoms Headaches Psychosis Seizures Focal neurological symptoms Increased intracranial pressure Diabetes insipidus Hypogonadism Hypothyroidism Gait disturbances Paraparesis/paraplegia Bladder dysfunction Paresthesias/dysesthesias Sensory level disturbances Multifocal or localized dysesthesias, paresthesias, weakness, monoradiculoneuropathies or polyradiculoneuropathies Weakness, muscle pain

ulomatous and inflammatory reactions of the dura mater and respond well to medical treatment without the need for surgical resection, except in situations in which there is a marked mass effect or increased intracranial pressure.

Cranial Neuropathy Forms Cranial neuropathies are frequent clinical manifestations of neurosarcoidosis and may manifest acutely after a monophasic or relapsing-remitting course. Bilateral facial paralysis is one of the classic manifestations of the disease. In the majority of affected patients, the presence of facial palsy or other cranial neuropathies is associated with basal meningitis and may be the result of perineural inflammation rather than intra-axial, axonal, or demyelinating nerve lesions. The optic, oculomotor, vestibular, and other lower cranial nerves may also be involved in neurosarcoidosis. Optic nerve involvement in neurosarcoidosis may generate diagnostic difficulties, particularly when there is also evidence of encephalitic forms that may mimic multiple sclerosis. A careful neuro-ophthalmological assessment is required in patients with visual pathway involvement in neurosarcoidosis to determine the presence of uveitis, iridocyclitis, or other forms of ocular involvement. In general, patients with cranial neuropathy forms usually respond well to treatment with steroids, but optic neuropathy or acousticvestibular involvement may evolve into relapsing-remitting or chronic forms in some patients.

Encephalitic Forms Focal encephalitis, leukoencephalitis, and multifocal white matter involvement are aggressive forms of neurosarcoidosis,

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Figure 96–1. T1-weighted brain magnetic resonance images with gadolinium enhancement in a patient with a meningeal form of neurosarcoidosis. Left, Leptomeningeal enhancement of the brainstem structures. Right, Dural enhancement in the supratentorial compartment.

inasmuch as these manifestations are frequently associated with subacute, relapsing-remitting or chronic patterns (Fig. 96–2). Symptoms associated with encephalitic forms include seizures, headache, signs of increased intracranial pressure, psychosis, motor dysfunction, cognitive decline, and other focal neurological manifestations. Focal or multifocal leukoencephalitic forms of neurosarcoidosis may mimic the clinical and MRI features of multiple sclerosis and/or neoplastic lesions. Patients with suspected demyelinating diseases should be evaluated to rule out the presence of sarcoidosis before the definitive diagnosis of such disorders is established. Some of the focal encephalitic forms of neurosarcoidosis represent aggressive forms of parenchymal CNS disease that become refractory to conventional treatment with steroids and may necessitate aggressive immunosuppressive therapy.

Neuroendocrine Forms Some patients with neurosarcoidosis exhibit a selective focal granulomatous meningeal inflammation of the infundibular, peri-infundibular, and suprasellar regions that may evolve into aggressive forms of hypothalamic dysfunction, focal encephalitis, and/or hypophysitis (Fig. 96–3). These localized manifestations of neurosarcoidosis manifest clinically with a variety of hormonal deficiencies but frequently with hypogonadism, central diabetes insipidus, and panhypopituitarism. In patients with this form of neuroendocrine involvement, the granulomatous inflammatory activity is often monophasic and subacute but produces important long-standing endocrine problems that necessitate life-long hormonal replacement and careful endocrinological follow-up.

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Figure 96–2. T1-weighted brain magnetic resonance image (MRI) with gadolinium enhancement in a patient with an encephalitic form of neurosarcoidosis. The brain MRI changes raised concerns for a glioblastoma multiform, but a brain biopsy revealed typical features of granulomatous reactions and multinucleated giant cell formation (see Fig. 96–5).

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Figure 96–3. T1-weighted brain magnetic resonance image with gadolinium enhancement, demonstrating the selective involvement of the hypothalamus–diencephalic structures and parahippocampal gyri in a patient with sarcoidosis who presented with panhypopituitarism. ■

Myelopathic Forms Although not as common as other forms of neurosarcoidosis, myelopathic forms may represent a diagnostic challenge if there is no previous history of systemic sarcoidosis. Myelopathic forms are frequently manifested as subacute or slowly progressive myelopathies associated with both motor and sensory symptoms. A presumptive or possible diagnosis of sarcoid myelopathy may be established if the patient has a previous history of systemic sarcoidosis, clinical evidence of myelopathy documented by clinical findings, and MRI findings of focal or multifocal intra-axial spinal cord lesions (Fig. 96–4). Because involvement of the spinal cord is frequently associated with slowly progressing tumor-like lesions, the diagnosis of sarcoid myelopathy is occasionally established after spinal cord biopsies are performed in patients with suspected spinal cord tumors.

Neuropathic and Myopathic Forms Peripheral nerve involvement in sarcoidosis occurs less frequently than other CNS variants of the disease and manifests clinically in the form of multiple mononeuropathies, mononeuritis multiplex, or polyradiculoneuropathies. Neuropathic forms of neurosarcoidosis follow subacute and relapsingremitting forms that produce a mixture of motor and sensory

Figure 96–4. T2-weighted image of the thoracolumbar spinal cord, demonstrating an extensive intra-axial lesion in a patient with sarcoidosis who presented with a subacute myelopathy.

symptoms. A definite diagnosis of peripheral nerve involvement in sarcoidosis is difficult to achieve. Biopsy of the sural nerve has a very low yield in establishing the diagnosis, and the presumptive diagnosis is generally based on indirect evidence of systemic disease activity, clinical evolution, and response to steroid treatment. Myopathic forms, in contrast, appear to be relatively easy to diagnose because the clinical manifestation involves primarily weakness and focal signs or polymyositis. However, patients with a history of systemic sarcoidosis and long-term use of steroids should be evaluated carefully because the potential presence of steroid myopathy may confuse the clinical situation. Pathological documentation of muscle involvement in sarcoidosis can be achieved by muscle biopsy, a procedure that has a better yield in demonstrating granulomatous inflammatory lesions than does nerve biopsy.

Diagnostic Approaches Clinical investigation of patients with suspected neurosarcoidosis requires a careful assessment of the systemic manifestations of the disease along with neurological evaluation. In the

chapter 96 neurosarcoidosis and neuro-behçet’s disease majority of patients with clinical manifestations of neurosarcoidosis, evidence of systemic disease is already established. However, in almost 50% of patients with suspected neurosarcoidosis, the neurological symptoms represent the first defining manifestation of sarcoidosis. In these patients, a more extensive and careful assessment of systemic involvement is necessary to establish a diagnosis of definite or probable neurosarcoidosis. Three categories have been established in the diagnostic assessment of neurological involvement in sarcoidosis:7 ■ A diagnosis of definite neurosarcoidosis may be established

in patients with symptoms consistent with any of the neurological forms of sarcoidosis and with pathological documentation of granulomatous inflammation obtained from CNS or PNS tissue biopsy. ■ A diagnosis of probable neurosarcoidosis may be established if the clinical profile is consistent with any of the neurological forms of the disease and is supported by CSF or imaging studies, proof of sarcoidosis in nonneural tissue biopsy, and ruling out of other potential causes of neurological dysfunction. ■ A diagnosis of possible neurosarcoidosis may be established if the clinical profile is consistent with any of the forms of neurosarcoidosis and if other possible causes of neurological dysfunction are ruled out.

Assessment of Systemic Sarcoidosis In patients with no known history of sarcoidosis and with neurological disease suspected to be associated with sarcoidosis, diagnostic strategies should focus on the evaluation of systemic disease, as well as the nature of the neurological involvement. Because pulmonary and lymphatic involvement is the most frequent systemic manifestation of sarcoidosis, a careful pulmonary assessment and the use of imaging techniques, such as chest computed tomographic scanning, gallium scanning, or fluorodeoxyglucose positron emission tomography are valuable diagnostic approaches for identifying areas of disease involvement and potential sites for biopsy. Tissue biopsy is highly recommended for establishing a definite pathological diagnosis in patients with identifiable parahilar lymphadenopathy or pulmonary lesions. Lymph nodes or lung biopsy specimens obtained by mediastinoscopy are frequently used for pathological studies in systemic sarcoidosis.

Assessment of Neurological Involvement in Sarcoidosis In patients with nonneural biopsy-proven systemic sarcoidosis, the diagnostic approach may be relatively uncomplicated, because the main focus of the assessment would be to establish the magnitude and extension of the nervous system involvement. The investigation of CNS and PNS involvement in neurosarcoidosis may entail the use of a variety of diagnostic strategies, including MRI, CSF studies, and CNS or PNS tissue biopsy. ■ MRI of the brain or spinal cord is a necessary step in evalu-

ating the magnitude and extent of the disease. Gadoliniumenhanced MRI studies are very helpful in establishing

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the patterns and topography of leptomeningeal or dural enhancement in meningeal forms and in facilitating the evaluation of the magnitude of active inflammation in encephalitic and myelopathic forms of the disease. ■ CSF analysis is necessary to investigate and rule out other potential etiologies, such as tuberculous, fungal or neoplastic meningitis, and other neurological disorders, and to determine the magnitude of the inflammatory activity. Mononuclear pleocytosis, an elevated protein concentration, an increased immunoglobulin G index, and the presence of oligoclonal bands are useful parameters in the evaluation of inflammatory activity. Unfortunately, the assessment of angiotensin-converting enzyme in CSF is rarely useful, because this test lacks sensitivity and specificity in the evaluation of patients with neurosarcoidosis. ■ CNS or PNS tissue biopsy is helpful in establishing a definitive diagnosis of neurosarcoidosis. However, as for all invasive brain procedures, the decision to obtain meningeal, brain, or spinal cord tissue biopsy specimens should be based on the need to establish a pathological diagnosis essential for treatment in the absence of other clinical or pathological data that support the diagnosis of probable neurosarcoidosis. In the majority of cases, a diagnosis of probable neurosarcoidosis is sufficient to justify initiating treatment. In patients with peripheral neuropathy suspected to be associated with sarcoidosis, sural nerve biopsy has a very low yield in establishing a definite pathological diagnosis. However, muscle biopsy may offer a better yield in establishing a definite diagnosis of inflammatory granulomatous myopathy.

Pathology The hallmark of pathological changes in sarcoidosis is the presence of a noncaseating granulomatous inflammatory reaction. Multinucleated giant cells, histiocytes, and lymphocytic infiltration are parts of the inflammatory tissue reaction (Fig. 96–5). In brain biopsy specimens, these changes are also characteristic, but a low frequency of giant cell or classic granuloma formation may be the main feature of some encephalitic forms in which marked mononuclear and lymphocyte infiltration predominate. Brain lesions associated with sarcoidosis frequently show a mixed inflammatory cellular profile with increased number of histiocytes, “foamy” macrophages, and both T and B lymphocytes.

Treatment Approaches The main goal of treatment for neurosarcoidosis focuses on the control of the granulomatous inflammatory activity within the CNS or PNS. Current therapies used in patients with neurosarcoidosis are the result of anecdotal experience and clinical case series rather than evidence from controlled clinical trials. Because neurosarcoidosis is a heterogeneous disorder, treatment approaches should be guided by the type, clinical course, and evolution of the disease. Clinical follow-up and coordination of treatment with other clinicians (e.g., pulmonologist, internist, ophthalmologist, and endocrinologist) are highly recommended because neurological problems in sarcoidosis are frequently associated with other systemic manifestations of the disease.

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Figure 96–5. Brain biopsy features of neurosarcoidosis. Left, Granulomatous reaction and marked mixed plasmolymphocytic infiltration. Right, Typical multinucleated giant cell formation surrounded by gliosis. (Hematoxylin and eosin stain.)

Treatment of Acute Manifestations or Early Stages of Neurosarcoidosis In a patient with newly diagnosed neurosarcoidosis who has not undergone steroid treatment or any other pharmacological intervention for sarcoidosis, treatment of monophasic forms or acute and subacute stages of meningeal, encephalitic, myelopathic, or neuromuscular forms should begin with steroid therapy. In the case of encephalitic and aggressive meningeal forms, an initial short course of intravenous methylprednisolone (1 g/day) for 3 to 5 days, followed by oral prednisone, may be helpful in controlling some of the acute symptoms associated with these forms of neurosarcoidosis. In mild forms of meningeal disease or cranial neuropathies, oral prednisone at a dosage of 1 mg/kg/day during the first and second weeks, followed by a tapering dosage over the next following weeks, may be effective in controlling acute symptoms. A decision about continuation of steroid treatment at lower dosages or use of other medications should be based on the patient’s clinical response, neurological assessment, brain or spinal cord imaging appearance, and/or laboratory studies. In patients who respond well to the initial steroid treatment, a lower maintenance dosage of prednisone (5 to 10 mg/day) may be beneficial to avoid relapses of the disease. In patients who continue to have marked neurological involvement despite steroid treatment or who have a relapse of symptoms, higher dosages of prednisone are sometimes necessary to maintain and control the clinical symptoms. In these patients, special consideration should be given to the potential long-term side effects associated with steroid therapy, and the use of other immunomodulatory and immunosuppressant medications should be considered.

Treatment of Refractory Disease and of RelapsingRemitting and Chronic Forms Treatment of relapsing-remitting and chronic forms of neurosarcoidosis may require the use of alternative treatments such as immunosuppressive or immunomodulatory medications. The decision to use these medications should be based on the patient’s response to steroid therapy, the adverse effects

of chronic use of steroids, and the clinical course of the disease. The major goal of therapy in relapsing-remitting and chronic forms of neurosarcoidosis is to limit the immune system reactivity that facilitates the development of granulomatous inflammatory lesions within the CNS or PNS. Immunosuppressant medications such as methotrexate, azathioprine, cyclophosphamide, and mycophenolate mofetil have been used as alternatives to the long-term use of prednisone or as adjuvants to chronic steroid therapy.8 The introduction of anti–TNF-α modulators has provided a new potential treatment approach for neurosarcoidosis. The selection of these medications should be based on the patient’s individual assessment, because some of these medications can have serious side effects.

Methotrexate In low doses (10 to 25 mg orally once a week), methotrexate has anti-inflammatory effects, and it has been widely used in sarcoidosis treatment to suppress proinflammatory cytokines such as TNF-α, interleukin-6, and interleukin-8. Methotrexate has potential hepatic, bone marrow, and pulmonary toxicity, and patients receiving this medication should be monitored closely with liver function and pulmonary function testing. Methotrexate affects the metabolism of folic acid and vitamin B12, and patients should receive supplemental vitamin B12 and folic acid (1 mg orally per day). One of the limitations of methotrexate use in neurosarcoidosis is its slowness in achieving therapeutic levels and effectiveness in the CNS.

Mycophenolate Mofetil Mycophenolate mofetil, a relatively new immunosuppressant, is beginning to replace methotrexate as the favorite medication in neurosarcoidosis. The safety profile of mycophenolate is comparatively better than those of other immunosuppressants, but this drug shares the same potential problems, including a risk of liver toxicity, marked leukopenia, or opportunistic infections. Dosages of 500 to 1000 mg orally twice a day appear to be sufficient to achieve control of refractory inflammatory activity within the CNS, but more controlled studies are necessary in the future to obtain meaningful conclusions about the effectiveness of this medication in neurosarcoidosis.

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NEURO-BEHÇET’S DISEASE

Azathioprine (1-2.5 mg/kg/day orally, as a single dose or twice daily) has been shown to be beneficial in some refractory cases, but its bone marrow, hepatic, and gastrointestinal toxicity, as well as potential oncogenic properties, limit its use to aggressive forms of sarcoidosis.

Neuro-Behçet’s disease is the neurological manifestation of Behçet’s disease, a systemic disorder characterized by an inflammatory vasculopathy and manifested clinically by mucocutaneous lesions, uveitis, large blood vessel vasculopathies, and gastrointestinal problems. Behçet’s disease occurs worldwide, but foci of high prevalence are well known in the Far East, Middle East, and Mediterranean countries. Epidemiological studies have shown that neurological involvement is more frequent among men (13%) than among women (5.6%).9 As in the case of sarcoidosis, the etiological factors associated with Behçet’s disease remain elusive. The frequency of neurological manifestations of Behçet’s disease is highly variable; authors of clinical and autopsy-based studies reported a prevalence of neurological involvement of between 5% and 20%.10,11

Cyclophosphamide Cyclophosphamide (50 to 200 mg orally per day) has also been used, but this drug has side effects associated with cystitis and neutropenia and has potential oncogenic properties.

Immunomodulatory and Anti–Tumor Necrosis Factor α Treatments Medications such as hydroxychloroquine, pentoxifylline, and, most recently, infliximab have been used in the management of neurosarcoidosis. Treatment with hydroxychloroquine (200-400 mg orally per day) requires careful ophthalmological follow-up, because of this drug’s association with retinopathy, and the drug may produce ototoxic, neuropsychiatric, and myopathic adverse effects. Infliximab, a humanized monoclonal antibody with an effect on TNF function, has proved useful in some cases of neurosarcoidosis; however, it is associated with an increased risk of infections, allergic reactions, or exacerbation of tuberculosis. This medication should be administered with methotrexate in order to achieve suppression of humoral responses. Other immunomodulatory medications such as pentoxifylline, thalidomide, and etanercept have been proposed as alternatives in the treatment of complicated forms of sarcoidosis, but their efficacy in cases of neurosarcoidosis is unknown.

Treatment of Secondary Neurological Manifestations Treatment of secondary problems associated with neurosarcoidosis is based on the patient’s individual clinical form of the disease and its manifestations. Seizures, increased intracranial pressure, pain, motor dysfunction, and spasticity may necessitate specific pharmacological interventions. Neuroendocrine forms of neurosarcoidosis require special attention because they are associated with multiple hormonal deficiencies, such as diabetes insipidus or other forms of hormonal dysfunction, that necessitate specific supplemental treatment and follow-up.

Nonpharmacological Therapeutic Approaches Management of secondary problems associated with neurosarcoidosis, such as increased intracranial pressure and hydrocephalus, require special attention, in view of the potential risk of life-threatening situations. Ventriculostomy or shunting procedures should be considered carefully in patients with evolving hydrocephalus and increased intracranial pressure. Surgical resection of tumor-like dural masses or focal encephalitic lesions that produce marked mass effect or increase intracranial pressure should be considered if medical treatment with steroids or other immunosuppressants is ineffective. In some cases refractory to pharmacological treatment and/or with difficult access to surgical resection, radiation therapy may be useful in controlling inflammatory tissue reactions and mass effect.

Clinical Features Patients with Behçet’s disease present with a variety of mucocutaneous, arthritic, ocular, and other systemic manifestations. Diagnostic criteria for the disease have been defined12 and include the presence of recurrent ulcerations that occur at least three times in one 12-month period, plus two of the following problems: recurrent genital ulceration, ophthalmic lesions (e.g., uveitis or retinal vasculitis), or dermatological lesions (e.g., erythema nodosum, papulopustular lesions, or acneiform nodules). The clinical manifestation of neuro-Behçet’s disease is highly variable and reflects the multifocal involvement of the CNS. Two major variants of neuro-Behçet’s disease are observed:13 a parenchymal (intra-axial) form, characterized by inflammation of small venous structures that produces focal or multifocal CNS involvement, and an extra-axial venous vasculopathy that produces venous sinus thrombosis. The parenchymal forms appears to be the most frequent manifestation (77% to 87% of cases) of neuro-Behçet’s disease,10,11 but both forms of the disease may overlap in some patients. PNS and myopathic forms of neuro-Behçet’s disease are relatively rare. PNS involvement manifests as acute or subacute polyradiculoneuropathies, including Guillain-Barré syndrome and sensorimotor and autonomic neuropathies. Myopathic forms manifest as necrotizing inflammatory myopathies. Like CNS involvement, PNS and myopathic involvement in in neuro-Behçet’s disease is associated with inflammatory vasculopathic changes.

Parenchymal (Intra-Axial) Forms of Neuro-Behçet’s Disease The parenchymal forms of neuro-Behçet’s disease are heterogeneous and manifested clinically by a variety of symptoms and signs that reflect the focal or multifocal involvement of the disease. Headaches, multiple cranial nerve involvement, cerebellar dysfunction, tumor-like lesions, white matter disease, encephalopathies, and myelopathies are frequent clinical manifestations of this form of the disease. Many patients with parenchymal forms of neuro-Behçet’s disease are young, have supratentorial white matter and cortex involvement that may mimic white matter disease, or have ischemic lesions that may lead to misdiagnoses of multiple sclerosis or stroke. However, one of the most frequent manifestations of this form is sub-

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acute brainstem involvement that manifests clinically with multiple cranial nerve involvement and corticospinal and cerebellar dysfunction. Myelopathic manifestations represent 10% to 30% of the parenchymal forms of neuro-Behçet’s disease.

completed in patients with suspected neuro-Behçet’s disease to rule out the potential presence of these disorders.

Treatment Approaches Nonparenchymal (Cerebrovascular) Forms of Neuro-Behçet’s Disease The extra-axial, or nonparenchymal, forms of neuro-Behçet’s disease manifest frequently as venous sinus thrombosis, but cases of arterial occlusion and aneurysmal formation are occasionally seen. These forms are less frequent than the parenchymal forms and occur in 13% to 23% of patients with neuro-Behçet’s disease.10,11 The venous vascular thrombosis form has a frequent subacute manifestation, it is strongly associated with systemic major vessel disease, and appears to manifest earlier in the course of the disease.14 Headaches, signs of increase intracranial pressure, cranial nerve involvement, and neurological signs associated with hemorrhagic venous infarction are frequently observed in the cerebrovascular forms of neuro-Behçet’s disease.

Diagnostic Approaches Patients with neurological manifestations who fit the diagnostic criteria for neuro-Behçet’s disease should undergo a careful assessment that includes neuroradiological assessment by MRI, CSF analysis, and other serological testing to rule out the potential presence of other disorders. Because neuro-Behçet’s disease may manifest with variable, multifocal, or relapsingremitting symptoms, it is sometimes misdiagnosed as multiple sclerosis. MRI of the brain and spinal cord is necessary to assess the magnitude and extension of the disease. MRI abnormalities include focal or multifocal lesions that frequently involve diencephalic and basal ganglia structures, the brainstem (pons and cerebellar peduncles), and subcortical white matter regions.15,16 Abnormalities observed in MRI studies reflect the ischemic, inflammatory, and vasculopathological nature of the disease and may exhibit varying degrees of contrast enhancement or ischemia-associated tissue changes. In contrast with multiple sclerosis, MRI abnormalities in periventricular white matter lesions are less frequent in neuro-Behçet’s disease. Diffusionweighted MRI and magnetic resonance venograms may be helpful in the assessment of patients with suspected cerebrovascular or extra-axial forms of the disease. CSF studies are important for determining the magnitude of inflammatory reactions within the CNS and may demonstrate presence of pleocytosis with neutrophilic or lymphocytic predominance and increase of protein concentration. As it happens in neuroinflammatory disorders of the CNS, increase in the immunoglobulin G index and presence of oligoclonal bands may be seen in some patients with neuro-Behçet’s disease10,11; thus, these parameters should be evaluated carefully as criteria for differentiation with multiple sclerosis. Other imaging approaches such as positron emission tomography and single photon emission computed tomography may be useful for assessing patterns of tissue perfusion and metabolism within the CNS. Serological testing to assess autoimmunity associated with rheumatological disorders (e.g., systemic lupus erythematous, vasculitis, or Wegener’s granulomatosis) should be

Treatment of neuro-Behçet’s disease is based on the use of immunosuppressant and immunomodulatory drugs. No prospective or controlled clinical trials have yet been performed to assess specific treatment protocols for neuro-Behçet’s disease. Methylprednisolone and prednisone are widely used in cases of neuro-Behçet’s disease, and treatment with these drugs may follow the same approach taken for patients with neurosarcoidosis. Treatment with immunosuppressants such as cyclophosphamide, methotrexate, and other immunomodulatory medications is also common, but, again, the efficacy of these drugs is known only on the basis of anecdotal reports.

CONCLUSIONS AND RECOMMENDATIONS Neurosarcoidosis and neuro-Behçet’s disease are multisystemic inflammatory disorders of unknown etiologies. Both disorders may follow acute, subacute, relapsing-remitting, and chronic courses. Because of the clinicopathological similarities to other neuroinflammatory disorders of the CNS, such as multiple sclerosis, patients suspected of having either neurosarcoidosis or neuro-Behçet’s disease require careful clinical assessment, brain and spinal cord imaging, and serological assessment. It is clear that patients with these disorders respond well to steroid therapy: methylprednisolone during early or acute phases of the disease, and prednisone during subacute or chronic stages of disease. However, it seems appropriate to consider the use of immunosuppressants (e.g., mycophenolate mofetil, methotrexate, and cyclophosphamide) or immunomodulatory medications (e.g., TNF-α modulators) when the course of disease shows chronicity or does not respond to steroid therapy. Coordinated care with other medical specialists (e.g., internists, pulmonologists, ophthalmologists, dermatologists, and endocrinologists) is highly recommended, because both neurosarcoidosis and neuro-Behçet’s disease are frequently associated with other organ involvement and systemic manifestations.

K E Y

P O I N T S

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Neurosarcoidosis is seen in 5% to 10% of patients with systemic sarcoidosis, and it may be the first localized manifestation of the disease.

●

Clinical manifestations of neurosarcoidosis are heterogeneous. Cranial neuropathies and meningeal, neuroendocrine, and encephalitic forms are frequent variants of neurosarcoidosis.

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The clinical course of neurosarcoidosis is variable and may exhibit monophasic, relapsing-remitting, or chronic patterns.

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Treatment with steroids is successful in the majority of patients with acute and subacute forms of neurosarcoidosis,

chapter 96 neurosarcoidosis and neuro-behçet’s disease but use of immunosuppressants or immunomodulatory medications is necessary in relapsing-remitting and chronic forms of the disease. ●

●

Neuro-Behçet’s disease is the neurological manifestation of Behçet’s disease that occurs in 5% to 20% of patients with this disease. Two major forms of disease are observed: a parenchymal form (e.g., white matter disease; brainstem or myelopathic involvement) and an extra-axial form (venous sinus thrombosis). Treatment of neuro-Behçet’s disease is based on the use of methylprednisolone and prednisone, but immunosuppressant drugs may be considered for long-term treatment.

3. 4. 5. 6.

7. 8. 9.

Suggested Reading Baughman RP, Lower EE, du Bois RM: Sarcoidosis. Lancet 2003; 361:1111-1118. Hoitsma E, Faber CG, Drent M, et al: Neurosarcoidosis: a clinical dilemma. Lancet Neurol 2004; 3:397-407. Siva A, Altintas A, Saip S: Behçet’s syndrome and the nervous system. Curr Opin Neurol 2004; 17:347-357. Smith JK, Matheus MG, Castillo M: Imaging manifestations of neurosarcoidosis. AJR Am J Roentgenol 2004; 182:289-295. Stern BJ: Neurological complications of sarcoidosis. Curr Opin Neurol 2004; 17:311-316.

10. 11.

12. 13. 14.

References 1. Baughman RP, Teirstein AS, Judson MA, et al: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 164:1885-1889. 2. Rybicki BA, Iannuzzi MC, Frederick MM, et al: Familial aggregation of sarcoidosis. A case-control etiologic study of sar-

15. 16.

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coidosis (ACCESS). Am J Respir Crit Care Med 2001; 164:20852091. Moller DR, Chen ES: What causes sarcoidosis? Curr Opin Pulm Med 2002; 8:429-434. Luisetti M, Beretta A, Casali L: Genetic aspects in sarcoidosis. Eur Respir J 2000; 16:768-780. Moller DR, Chen ES: Genetic basis of remitting sarcoidosis: triumph of the trimolecular complex? Am J Respir Cell Mol Biol 2002; 27:391-395. Schurmann M: Angiotensin-converting enzyme gene polymorphisms in patients with pulmonary sarcoidosis: impact on disease severity. Am J Pharmacogenomics 2003; 3:233243. Zajicek JP, Scolding NJ, Foster O, et al: Central nervous system sarcoidosis—diagnosis and management. QJM 1999; 92:103117. Moller DR: Treatment of sarcoidosis—from a basic science point of view. J Intern Med 2003; 253:31-40. Kural-Seyahi E, Fresko I, Seyahi N, et al: The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 2003; 82:60-76. Kidd D, Steuer A, Denman AM, et al: Neurological complications in Behçet’s syndrome. Brain 1999; 122(Pt 11):21832194. Akman-Demir G, Serdaroglu P, Tasci B: Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain 1999; 122(Pt 11):2171-2182. Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet 1990; 335:1078-1080. Borhani HA, Pourmand R, Nikseresht AR: Neuro-Behçet disease. A review. Neurologist 2005; 11:80-89. Tunc R, Saip S, Siva A, et al: Cerebral venous thrombosis is associated with major vessel disease in Behçet’s syndrome. Ann Rheum Dis 2004; 63:1693-1694. Lee SH, Yoon PH, Park SJ, et al: MRI findings in neuroBehçet’s disease. Clin Radiol 2001; 56:485-494. Akman-Demir G, Bahar S, Coban O, et al: Cranial MRI in Behçet’s disease: 134 examinations of 98 patients. Neuroradiology 2003; 45:851-859.

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97

THE NEUROLOGICAL VASCULITIDES ●

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Neil Scolding

Disorders caused by immunological or inflammatory disturbances affecting the nervous system account for a wide range of neurological diseases. They include primary or idiopathic neuroimmune disorders, which may affect any part of the neuraxis (e.g., multiple sclerosis, Guillain-Barré syndrome, myasthenia gravis) and which are common and familiar territories for the working neurologist. However, secondary disorders, in which the neurological disturbance reflects involvement of the nervous system in a (conventionally) systemic inflammatory process, although often no less common, infrequently manifest or behave in the ordered and predictable clinical manner of proper neurological diseases. Neurosarcoidosis, central nervous system (CNS) lupus, vasculitis, and neuro-Behçet’s disease all occasionally mimic one another, pursue erratic and unpredictable clinical courses, and confine themselves wholly to the nervous system, which renders diagnosis by tissue biopsy hazardous and unattractive; they evade the cautious diagnostician, and they confound the evidence-based therapist. This chapter provides a brief overview only of vasculitic diseases or vasculitides, which are more than capable of harboring most of these unsociable habits and so strike particular anxiety in the heart of the neurologist. (Table 97–1) The vasculitides are a heterogeneous group of disorders characterized by blood vessel inflammation, occasionally with additional, specific, and defining pathological features, together producing different but frequently overlapping clinical manifestations.1 The classic core histopathological change consists essentially of an inflammatory infiltrate within (not just around) the vessel wall, in association with destructive mural changes (fibrinoid necrosis), precipitating vascular occlusion and then infarction—microscopic or macroscopic—which in turn accounts for the clinical manifestations. Classification of the vasculitides is complex, with subdivisions into idiopathic vasculitic disorders—for example, giant cell arteritis, polyarteritis, and Wegener’s granulomatosis—and vasculitis secondary to collagen diseases, malignancy, viral infection, drugs, and so forth. The histological characteristics allow further classification, including the presence or absence of granulomas and/or the size of the vessel implicated (Table 97–2; Fig. 97–1). The CNS or peripheral nervous system (PNS) can be involved in virtually all of the systemic vasculitides, but “isolated angiitis,” affecting either the CNS or the PNS, is also rec-

ognized when there is little or no evidence of generalized inflammation.

MECHANISMS OF TISSUE DAMAGE In both primary and secondary CNS and PNS vasculitis, the neurological features arise principally through ischemia and infarction. These in turn result from three consequences of inflammation within the vascular wall: obstruction of the vessel lumen, increased coagulation from the effects of proinflammatory cytokines on the endothelial surface, and alterations in vasomotor tone. The development of a vasculitic process depends on interplay between cellular and humoral factors; most research interest has centered on the latter.2

Antibody-Dependent Mechanisms Direct Antibody Attack In some systemic vasculitides, a pathogenic role for anti–endothelial cell antibodies in injuring or, paradoxically, activating endothelial cells is proposed,3 although their lack of specificity and variable frequency of detection do raise questions about any truly causal role. In rare cases, antibodies against amyloid-β deposits may precipitate cerebral vasculitis.4

Immune Complex–Mediated Vasculitis Immune complex deposition in the blood vessel wall triggers complement activation, leading to polymorph and macrophage recruitment, amplification of inflammation, and the generation of lytic and injurious membrane attack complexes. Hepatitis B– and C–associated vasculitides are good examples of this process; the latter is found to underlie many cases of cryoglobulinemic vasculitis.5

Antineutrophil Cytoplasmic Antibody–Related Vasculitis Antineutrophil cytoplasmic antibodies (ANCAs) represent a family of antibodies directed against constituents of the

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neutrophil azurophil granules.6 Cytoplasmic ANCA (c-ANCA) targets proteinase-3 and is associated with nearly 95% specificity for Wegener’s granulomatosis. Perinuclear ANCA (pANCA), directed at myeloperoxidase, is less specifically found in patients with microscopic polyangiitis and Churg-Strauss syndrome.6 Such antibodies may play a significant role in generating and maintaining vascular inflammation.7,8

Cell-Mediated Damage Evidence for cell-mediated involvement in tissue injury in vasculitis9 comes in part from studies of microscopic polyarteritis nodosa and of Wegener’s granulomatosis. In both disorders, circulating T cells responsive to proteinase-3 are found, and vascular lesions contain activated T cells and antigen-presenting major histocompatibility complex class II–positive dendritic cells. In primary CNS and PNS vasculitic lesions, the predominant infiltrate is one of CD4+ and CD8+ T lymphocytes and monocytes.10

T A B L E 97–1. Immunological and Inflammatory Diseases of the Nervous System Site

Primary Disease

Brain (and spinal cord) Spinal cord

Multiple sclerosis

Peripheral nerve

Neuromuscular junction Muscle

Inflammatory myelitides Stiff-person syndrome Guillain-Barré syndrome and variants Chronic inflammatory demyelinating polyneuropathy Multifocal motor neuropathy Myasthenia gravis Polymyositis Dermatomyositis Secondary Disease Vasculitides Lupus, rheumatoid disease; other connective tissue diseases, anticardiolipin syndromes Behçet’s disease Sarcoidosis Paraneoplasia Organ-specific autoimmune disease (e.g., celiac disease, Hashimoto’s disease)

CAUSES OF NEUROLOGICAL VASCULITIS Primary (Isolated) Angiitis of the Nervous System In primary CNS vasculitis, there is no discernible recognized systemic vasculitic or, indeed, other disease, and vasculitis is confined to the brain and spinal cord. Although it is defined by this apparent exclusive distribution, autopsy studies have revealed subclinical extracranial involvement (e.g., of the pulmonary arteries and abdominal viscera11), which presumably helps explain the occasional features of fever, rigors, weight loss, raised plasma viscosity, and so forth. The angiitic process is focal and segmental in distribution and granulomatous, necrotizing, or lymphocytic in character, often with mixed morphological types in individual patients (therefore, the common term “granulomatous angiitis” is difficult to sustain). The clinical definition of cerebral vasculitis is not uniform, and this helps explain significant differences in the approach to diagnosis and therapy. Some authorities have defined the disorder by its angiographic appearances,11a which implies that tissue confirmation is not needed. (Indeed, some authors have suggested a more favorable monophasic clinical course in the so-called benign angiopathy of the CNS. This is a syndrome with normal or only mildly abnormal CSF and evidence of vasculitis on angiography alone.12 The concept has been questioned, in view of the recognized nonspecificity of angiography, the fact that cases not proceeding to biopsy are more likely to be less severe, and because pediatric cases satisfying “benign angiopathy” criteria often do not have a temperate, monophasic course and have required aggressive immunotherapy.13) Most authorities, however, including this author, believe that a certain diagnosis of primary CNS angiitis must depend on a positive biopsy. Two eponymous nonsystemic primary disorders may involve the CNS. Cogan’s syndrome is an unusual disorder, affecting mostly young adults and characterized by recurrent episodes of interstitial keratitis and/or scleritis with vestibulo-auditory symptoms, which may be complicated by CNS, PNS, or systemic vasculitis. In Eale’s disease, an isolated retinal vasculitis occurs, causing visual loss; again, neurological complications are well described. Primary PNS vasculitis closely parallels CNS disease. Otherwise termed nonsystemic vasculitic neuropathy, there is like-

T A B L E 97–2. Classification of the Vasculitides According to Size Dominant Vessel Involved

Primary

Secondary

Large arteries

Giant cell arteritis Takayasu’s arteritis Classic polyarteritis nodosa Kawasaki syndrome Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis Henoch-Schönlein purpura Essential cryoglobulinemia Cutaneous leukocytoclastic vasculitis

Aortitis with rheumatoid disease; infection (e.g., syphilis) Infection (e.g., hepatitis B)

Medium arteries Small vessels and medium arteries Small vessels

HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus.

Vasculitis with rheumatoid disease, SLE, Sjögren’s syndrome, drugs, infection (e.g., HIV) Drugs (e.g., sulfonamides) Infection (e.g., hepatitis C)

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Figure 97–1. Left, The typical angiographic appearances of multifocal areas of narrowing/stenosis and vascular occlusion are shown: these may, however, be seen in many nonvasculitic disorders. (Courtesy of Dr. Shelley Renowden, Bristol, United Kingdom.) Right, The histopathological characteristics of classic cerebral vasculitis include leukocytic infiltration and destruction of the vascular wall, with vascular occlusion and areas of microhemorrhage.

wise no overt evidence of any recognizable vasculitic disorder elsewhere; however, authorities have varied in their definitions and in whether cases that include mild constitutional symptoms or serological abnormalities should be excluded.14 As with primary CNS disease, the arguments are finely balanced as to whether nonsystemic vasculitic neuropathy is truly an exclusively neurological disease or a systemic vasculitis in which the overwhelming burden of disease falls on the PNS.15-18 This is not merely an academic question, because upon it hinges (at least partly) the justification for extrapolating therapeutic data from the systemic vasculitides.

Primary Systemic Vasculitides with Neurological Involvement Virtually all of the systemic vasculitides may be complicated by neurological involvement; many have their own defining characteristics. Constitutional disturbances—fever, night sweats, severe malaise, weight loss—are common and may be accompanied by a rash or arthropathy. Wegener’s granulomatosis predominantly affects the upper and lower respiratory tracts: the nose (often with destructive cartilaginous change that causes saddle nose deformity), sinuses, larynx, trachea, and lungs. Ocular involvement may occur, and renal disease occurs in 80% of affected patients. cANCA measurements are positive, with proteinase-3 specificity, and the biopsy findings are characteristic, with a necrotizing, granulomatous vasculitis. Neurological involvement occurs in up to 35% of affected patients19 but most commonly involves the PNS. Meningeal and middle ear disease may lead to significant cranial neuropathies (especially of nerves VII and VIII). Gadolinium-enhanced magnetic resonance imaging (MRI) is valuable in that it may reveal meningeal thickening and infiltration, which are ready targets for biopsy. Ocular involve-

ment may occur with orbital pseudotumor. Cerebral smallvessel vasculitis is rare but, when it does occur, is usually responsible for encephalopathies, seizures, and pituitary abnormalities; however, this manifestation may be indistinguishable from that of any other form of intracranial vasculitis. More likely is the unique contiguous extension of erosive granulomas from the sinuses or from remote metastatic granulomas to the CNS. Microscopic polyangiitis is a multisystem small-vessel vasculitis that has many similarities to Wegener’s granulomatosis, including pulmonary hemorrhage, but differs in that upper respiratory tract involvement is rare and granuloma formation is not seen. Affected patients usually have glomerulonephritis, and, indeed, this vasculitis is occasionally confined to the kidneys. In one study, mononeuritis multiplex was found in 55% of patients20; in this study, the brain was seldom affected (11%), and CNS disease did not contribute to mortality. There are, however, infrequent reports of p-ANCA–positive, rapidly progressive glomerulonephritis associated with cerebral vasculitis, necessitating aggressive therapy. Classic polyarteritis nodosa is now recognized as an unusual disorder that may cause medium- and small-sized muscular artery involvement in multiple organs, with the notable exception of the lungs and spleen. Eighty percent of affected patients present with renal failure and hypertension. Gastrointestinal involvement occurs in up to 50%, with abdominal pain caused by visceral infarcts. Heart failure and myocardial infarction reflect cardiac involvement. Neurological abnormalities are prominent (in 50% to 60%) but, again, are confined mostly to the PNS. It is believed that damage is initiated by immune complex deposition; fibrinoid necrosis is typical, although not diagnostic. Although there are no specific serological tests, about 20% to 30% of patients have hepatitis B antigen or antibody in serum. Visceral angiography displays aneurysms or occlusions of the visceral arteries.

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Churg-Strauss syndrome is characterized by hypereosinophilia with systemic vasculitis, occurring in individuals with recently developed atopic features. Asthma and mononeuritis multiplex are frequent manifestations of this disease. Rashes, with purpura, urticaria, and subcutaneous nodules, are common. Glomerulonephritis may develop; it may also affect coronary, splanchnic, and cerebral circulations. CNS involvement is evident in only about 7% of affected patients.21 About 50% of patients are seropositive for p-ANCA, 25% are seropositive for c-ANCA, and 25% have no antineutrophil cytoplasmic antibodies. Small-vessel vasculitis commonly affects postcapillary venules. The skin is most commonly involved, usually with purpura or urticaria; because of the common presence of an allergic precipitant, the term hypersensitivity vasculitis is often used synonymously; cutaneous leukocytoclastic vasculitis is the currently preferred epithet. In all these disorders, PNS involvement, usually with mononeuritis multiplex, is considerably more common than CNS disease, affecting from up to 70% of patients with classic polyarteritis nodosa and microscopic polyangiitis and 30% of patients with Wegener’s disease. Henoch-Schönlein purpura is an immunologically mediated small-vessel systemic vasculitis of children, affecting the skin, gastrointestinal tract, joints, and kidneys. Neurological involvement is well-described; hypertensive or uremic encephalopathy, steroid or cytotoxic drug therapy, or electrolyte imbalance can also cause severe CNS symptoms. Suspected cerebral vasculitis is reported as a complication, with supportive MRI changes but without tissue proof of the process. Kawasaki’s disease (mucocutaneous lymph node syndrome) usually affects children younger than 12 years. It has an incidence of fewer than 5 per 100,000 in the United Kingdom, but it is at least 20 times more common in Japan, where in 1967 it was first described. Coronary artery aneurysms occur in one fifth of untreated cases, which may result in myocardial infarction. Neurologically, aseptic meningitis is common, but hemiplegic strokes, encephalopathy, and facial palsy are also described. Pathologically, an acute systemic inflammatory vasculitis, with little or no fibrinoid necrosis, underlies the disease. There is a possible role for anti–endothelial cell antibodies in the pathogenesis.

Secondary Vasculitis: A Complication of “Nonvasculitic” Systemic Disorders Autoimmune and Inflammatory Disease Neurological or psychiatric symptoms in systemic lupus erythematosus (see Chapter 119) are common (40% to 50%),22 but the most frequent neuropathological finding is that of a noninflammatory vasculopathy of small arterioles and capillaries, with resulting microinfarcts and microhemorrhages. Histopathological studies have consistently demonstrated that vasculitis of the cerebral vessels is rare, with an incidence of 7% to 13%. Serological study naturally forms the mainstay of diagnosis. Sarcoidosis (see Chapter 96) affects the nervous system in only 5% of cases, commonly manifesting with optic and other cranial neuropathies (especially involving the facial nerve) and usually caused by granulomatous meningeal and brainstem

infiltration. Sarcoidosis may be complicated by systemic vasculitis affecting small- or large-caliber vessels in a manner similar to that of other vasculitides, with angiographic and, indeed, histological evidence of CNS vasculitis. Serum angiotensin-converting enzyme and calcium levels are not always raised. CSF abnormalities are seen in 80% of affected patients, usually with an elevated protein level and pleocytosis, and oligoclonal bands are present in about 45%. Cranial MRI exhibits nonspecific multiple white matter lesions or meningeal enhancement; whole-body gallium scanning can be more useful, demonstrating a characteristic pattern of uptake (affecting the parotid glands and lungs in particular). Pathological diagnosis by the Kveim test or, better still, by biopsy of cerebral or meningeal tissue provides the most reliable basis for treatment.23 Seropositive rheumatoid disease is a well-recognized precipitant of cerebral vasculitis, although skin involvement and mononeuritis multiplex are far more typical manifestations of rheumatoid vasculitis.22 There are unusual reports of CNS angiitis in the context of systemic sclerosis, Sjögren’s syndrome, and mixed connective tissue disease, even (although rarely) without a preceding history of systemic symptoms. Cryoglobulinemia can cause hyperviscosity and may trigger immune-complex deposition-triggered vasculitis (especially in association with hepatitis C infection), which is particularly common in mixed cryoglobulinemia. Renal, joint, and skin involvement with purpura progressing to necrotic ulceration is often present. Peripheral neuropathy occurs in 22% to 32% of affected patients, particularly as mononeuritis multiplex, and leukocytoclastic vasculitis is evident in biopsy specimens. The CNS is rarely affected. Behçet’s disease is caused predominantly by vasculitis affecting small- and medium-sized vessels (see Chapter 96).

Infections At least three mechanisms are implicated in vasculitis that is related to infection: direct invasion of the vessel wall, immune complex deposition, and secondary cryoglobulinemia. The association of hepatitis C infection with cryoglobulinemia and small-vessel vasculitis is mentioned previously; other infections, including hepatitis B, Epstein-Barr virus disease, cytomegalovirus disease, Lyme disease, syphilis, malaria, and coccidioidomycosis, have also been linked to mixed cryoglobulinemia. Numerous infectious agents have been implicated in primary invasion of the vascular wall, a more direct infectionassociated vasculitis.24 Aspergillus, Histoplasma, and Coccidioides species are among the fungal causes, usually confined to immunosuppressed patients and patients with diabetes mellitus. In human immunodeficiency virus (HIV) infection, cytomegalovirus and Toxoplasma infection may precipitate vasculitis, and syphilitic cerebral vasculitis has also reemerged in the context of HIV infection. Bacterial causes of meningoencephalitis—Mycobacteria, pneumococci, and Haemophilus influenzae—may also trigger intracranial vasculitis. One infection that merits particular attention in this context is herpes zoster ophthalmicus. This can cause secondary, localized CNS vasculitis that affects the ipsilateral hemisphere, probably by direct viral invasion of blood vessels,25 producing single or multiple smooth-tapered segmental narrowing on angiogra-

chapter 97 the neurological vasculitides phy. The characteristic clinical picture, seen in approximately 0.5% of cases, is that of an acute monophasic hemiparesis contralateral to the (usually by now resolving) ocular disease. The latent period may last from days to months but is usually approximately 3 to 4 weeks. The presence of mononuclear pleocytosis and raised varicella-zoster antibody titer aids the diagnosis. A more generalized necrotizing and granulomatous vasculitis can also occur. Complications of shingles may affect children similarly, although there have been less frequent reports of chickenpox triggering cerebral vasculitis. On occasional, only the spinal cord is involved in herpetic disease; in rare cases, more generalized vasculitis may occur with ophthalmic or remote zoster infection. Chronic viral infection with parvovirus B19 has been implicated in polyarteritis nodosa, Kawasaki syndrome, and Wegener’s granulomatosis, although causality is by no means proved.24 Tuberculosis-associated vasculitis may be driven by tuberculoprotein immune complexes. Cytomegalovirus, Epstein-Barr virus, and the viruses that cause hepatitis B, Lyme disease, syphilis, and malaria cause vasculitis by a similar mechanism, whereas in coccidioidomycosis, vascular inflammation occurs either directly or through cryoglobulinemia. Spores of the dimorphic fungus Coccidioides immitis, endemic to the southwestern United States and northern Mexico, can be inhaled with subsequent hematogenous spread, often to the meninges. Vasculitis involving the small penetrating branches of the major cerebral vessels, and consequent deep ischemic infarction, has been observed in up to 40% of these cases, but rarely has subarachnoid hemorrhage also been observed.

Malignancy, Lymphomatoid Granulomatosis, and Malignant Angioendothelioma Leukocytoclastic vasculitis may occur in association with a variety of cancers as a paraneoplastic phenomenon. CNS disease in the context of Hodgkin’s disease with a pathological picture indistinguishable from conventional isolated CNS angiitis has been reported.25a Lymphomatoid granulomatosis is a lymphomatous disorder centered on the vascular wall, with destructive change and secondary inflammatory infiltration lending the appearance of true vasculitis; the infiltrating neoplastic cell is of T lymphocyte derivation. Cutaneous and pulmonary involvement is common, with nodular cavitating lung infiltrates, and neurological manifestations occur in 25% to 30% of cases; they are the manifesting feature in approximately 20%. Neoplastic or malignant angioendotheliomatosis is also a rare, nosologically separate disorder, wherein the neoplastic process is intravascular (i.e., within the lumen) and the lymphomatous cells are B cell derived and characteristically do not invade the vascular wall. The neurological features of each disorder are similar, largely representing those of cerebral vasculitic disease; in malignant angioendotheliomatosis, lung involvement is not the rule; characteristic skin manifestations occur.

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multisystem necrotizing vasculitis.26 In humans, vasculitis may occur after only a single dose of amphetamine, but repeated exposure in young adults is the usual history. However, in many other reports of drug-induced vasculitis, there is no tissue confirmation, and the diagnosis of “vasculitis” is based on angiography, despite the fact that vasospasm can cause angiographic changes identical to those of vasculitis.26a In cocaine abuse, the significantly increased risk of ischemic stroke results from vasospasm (probably caused by increased catecholamine release) and very seldom from any form of vasculitis.27 In intravenous abuse, concomitantly injected contaminants such as hepatitis C virus may cause vasculitis. In rare cases, an immune reaction against (spontaneous) amyloid deposits within the cerebral vasculature appears to precipitate a true CNS vasculitis, a recently described disorder that has been termed Ab-related angiitis.4

CEREBRAL VASCULITIS The Clinical Features of Central Nervous System Vasculitis Focal or multifocal infarction or diffuse ischemia, affecting any part of the brain, explains the protean manifestations; the wide variations in disease activity, course, and severity; and the absence of a pathognomonic or even typical clinical picture. Most accounts of both primary and secondary intracranial vasculitides describe headaches, focal or generalized seizures, strokelike episodes with hemispherical or brainstem deficits, acute or subacute encephalopathies, progressive cognitive changes, chorea, myoclonus and other movement disorders, and optic and other cranial neuropathies.28-30 The course is commonly acute or subacute, but chronic progressive manifestations are also well described, as are spontaneous relapses and remissions. Systemic features such as fever, night sweats, livedo reticularis, or oligoarthropathy may also be present (often revealed only through direct questioning). Despite the diversity of neurological manifestation, three broad categories (not intended to carry either pathological or therapeutic differences) have been defined in one small study31; these may help to improve recognition of the condition: 1. Acute or subacute encephalopathy, commonly manifesting as an acute confusional state, progressing to drowsiness and coma. 2. A disorder superficially resembling atypical multiple sclerosis (“multiple sclerosis plus”) in phenotype, with a relapsing-remitting course and features such as optic neuropathy and brainstem episodes, but also accompanied by other features less common in multiple sclerosis, such as seizures, severe and persisting headaches, encephalopathic episodes, or hemispherical strokelike episodes. 3. Intracranial mass lesions with headache, drowsiness, focal signs, and often elevated intracranial pressure.

Diagnosis and Management Drug- and Toxin-Induced Cerebral Vasculitides The most compelling evidence of a direct association is related to amphetamines, with clinical and histological evidence of

Many other disorders, of course, may also cause a combination of headache, encephalopathy, strokes, seizures, and focal deficits of acute or subacute onset (Table 97–3). The diagnosis

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T A B L E 97–3. Some Neurological and Systemic Disorders That May Mimic Cerebral Vasculitis Vasculopathies Susac’s syndrome Homocystinuria Ehlers-Danlos syndrome Radiation vasculopathy Köhlmeier-Degos disease Fibromuscular dysplasia Fabry’s disease Moyamoya disease Amyloid angiopathy CADASIL Marfan syndrome Pseudoxanthoma elasticum Viral or fungal vasculitis Immune/Inflammatory Diseases Sarcoidosis Lupus and antiphospholipid disease Behçet’s disease Multiple sclerosis/ADEM Thyroid encephalopathy Infections Lyme disease AIDS Endocarditis Whipple’s disease Viral encephalitis Legionella/Mycoplasma pneumonia Tumors and Malignancies Atrial myxoma Multifocal glioma Cerebral lymphoma Paraneoplastic disease Other Diseases Multiple cholesterol emboli Thrombotic thrombocytopenic purpura Cerebral sinus thrombosis Mitochondrial disease ADEM, acute disseminated encephalomyelitis; AIDS, acquired immunodeficiency syndrome; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

of cerebral vasculitis therefore first involves the exclusion of alternative possibilities, before confirmation of intracranial vasculitis and followed by pursuit of the cause of the vasculitic process. No single simple investigation can confirm a diagnosis of cerebral vasculitis; some can rule it out.

Blood Tests and Serology Anemia is an infrequent finding, and a leukocytosis without eosinophilia is present in about 50% of affected patients. The erythrocyte sedimentation rate (ESR) and C-reactive protein levels are often abnormal, especially in cases secondary to systemic disease, but of course lack specificity. (Some authorities include a normal ESR as a defining feature of primary angiitis of the central nervous system [PACNS]; others report moderately elevated values in two thirds of patients.28-30) Serological testing (e.g., antinuclear antibody, ANCA) is vital for ruling out lupus or helping define any systemic origin of an established intracranial vasculitis, but it is of little value in confirming or

refuting isolated cerebral vasculitis. “False” ANCA positivity is sometimes seen in connective tissue disorders such as lupus and, rarely, in individuals with no apparent vasculitic disorder at all.

Spinal Fluid Examination Cerebrospinal fluid analysis is nonspecific but, again, useful in implying an inflammatory process within the CNS and ruling out infection and malignant diseases that may manifest similarly. Pooled case reviews suggest an elevation in cell count (mainly a lymphocytosis) and protein in 50% to 80% of affected patients.28-30 The CSF opening pressure is raised in almost one half of PACNS cases. Oligoclonal immunoglobulin bands in the CSF have been studied infrequently but are found frequently enough (perhaps in 40% to 50% of patients31) to warrant consideration of analysis. Oligoclonal band patterns that vary substantially, perhaps even disappearing altogether during the course of disease, do help point away from multiple sclerosis when this is part of the differential diagnosis.

Radiography MRI is a sensitive but not specific detector of vascular disease32; it discloses, of course, the results of vascular inflammation but not vasculitis itself. Ischemic areas, periventricular white matter lesions, hemorrhagic lesions, and parenchymal or meningeal enhancing areas can be seen. Correlation between MRI changes and blood vessel involvement may be poor: In one study, of 50 territories affected by vasculitis on contrastenhanced angiography, at least one third appeared normal on MRI.33 Other studies confirm this imperfect sensitivity, and there are (unfortunately) reported cases of proven cerebral vasculitis with normal-appearing MRI. Single photon emission computed tomography appears to be a useful but nonspecific imaging tool, again mirroring but not defining a vasculitic process.31 The value of positron emission tomographic scanning in this context has yet to be clarified. Magnetic resonance angiography has a niche in imaging of large-vessel vasculitides such as Takayasu’s arteritis and classic periarteritis nodosa, with potential to supplant contrastenhanced angiography,34 but does not have sufficient resolution to offer great value in evaluating medium- or small-vessel cranial vasculitis. Establishing the diagnostic value of contrast-enhanced angiography is complicated by the many studies in which investigators have used this as the “gold standard” for confirmation. Studies with pathological evidence indicate that angiography yields a false-negative rate of 30% to 40%,29,30 and there have been examples of patients with histologically proven PACNS who have completely normal-appearing angiograms. The explanation may be that the resolution of conventional imaging is not sufficient for the affected vessels. When abnormalities are present, they include segmental (often multifocal) narrowing with areas of localized dilatation or beading (see Fig. 97–1). Single stenotic areas in multiple vessels are more frequent than multiple stenotic areas along a single vessel segment in PACNS. Retrospective series30,35 suggest that the sensitivity is only 24% to 33%, and the specificity is of a similar order; an enormous number of inflammatory, metabolic, malignant, or other vasculopathies can closely

chapter 97 the neurological vasculitides mimic angiitis. Some authors have reported a risk of transient (in 10% of patients) or permanent neurological deficit (in 1%).36 Although its importance has been overemphasized, contrast-enhanced angiography remains a valuable investigational tool with a sensitivity comparable with that of biopsy. Indium-labeled white blood cell nuclear scanning has a limited role, particularly in disclosing areas of (sometimes unsuspected) systemic inflammation.31

Ophthalmological Examination Careful ocular examination, including slit-lamp study, forms a vital part of the assessment of patients with suspected cerebral vasculitis. On occasion, subclinical conjunctival, anterior, or posterior inflammation or retinal changes, through conjunctival biopsy, confirm ocular (and thereby imply neurological) sarcoidosis, Behçet’s syndrome, or other inflammatory disorders. Dynamic recording of erythrocyte flow, with video slit-lamp microscopic recording and low-dose fluorescein angiography to examine the vasculature of the anterior ocular chamber, can be a useful additional investigation.31

Histopathology Histopathological confirmation is important and may be made through biopsy of an abnormal area of the brain where possible or through “blind” biopsy, incorporating meninges and nondominant temporal white and gray matter. Biopsy may reveal an underlying process not otherwise suspected with profound therapeutic implications, such as infective or neoplastic (principally lymphomatous) vasculopathies; however, it is not a trivial procedure, inasmuch as it carries a risk of serious morbidity estimated at 0.5% to 2%. Sensitivity is limited to (at best) approximately 70%.29,30,35 Nevertheless, the significant risk means that up to 75% of reported cases are “diagnosed” without histopathological confirmation.11 A retrospective study of 61 patients undergoing biopsy for suspected cerebral vasculitis has usefully illuminated this topic.35 No patients suffered any significant morbidity as a result of the procedure. Thirty-six percent of patients were confirmed as having cerebral vasculitis, but, in an equally useful and important finding, 39% of biopsies revealed an alternative, unsuspected diagnosis: lymphoma (six cases), multiple sclerosis (two cases), and infection (seven cases, including toxoplasmosis and herpes and also, in two cases, cerebral abscess). Many of these nonvasculitic disorders are treatable, often indeed curable, but inappropriate treatment with steroids alone or with more potent immunosuppressive agents would have at best no useful effect and very often serious adverse consequences. Biopsy failed to yield a clear diagnosis in 25% of patients in this study; however, even in these cases, biopsy arguably might not be described as “noncontributory,” because it at least helped rule out the alternative diagnoses mentioned. The decision not to biopsy must be balanced against the harmful effects of immunosuppressive drugs used, potentially, unnecessarily. Once a vasculitic process has been confirmed, the specific defining characteristics of the primary and secondary vasculitides must be painstakingly sought.

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The Treatment of Cerebral Vasculitis Notwithstanding the problems in recognition and diagnosis, cerebral vasculitis is considered a highly treatable condition. Prospective controlled randomized trials are lacking because of the rarity of the condition and the absence of unifying diagnostic criteria. Retrospective analyses have been the main study tool, and they, together with lessons from systemic vasculitides,37 have provided significant support for the use of steroids with cyclophosphamide in confirmed cases.38 In biopsy-proven cerebral vasculitis, a reasonable induction regimen should comprise high dosages of steroids; probably best as intravenous methylprednisolone, 1 g/day for 3 days, followed by oral prednisolone, 60 mg/day, decreasing by 10 mg at weekly intervals to 10 mg/day if possible. This should be coupled from the outset with cyclophosphamide, 2.5 mg/kg (lower dosage of 2 mg/kg in elderly patients or in patients with renal failure) per day. This induction combination is suggested for 9 to 12 weeks. Pulsed weekly intravenous cyclophosphamide does not appear to differ significantly from daily oral treatment in efficacy, and it may have fewer side effects. The blood cell count should be carefully monitored for evidence of bone marrow suppression; the cyclophosphamide dosage should be reduced if there is leukopenia (total white blood cell count falling to below 4.0 × 109) or neutropenia (below 2.0 × 109). Cyclophosphamide is associated with hemorrhagic cystitis (a complication reduced by adequate hydration and mesna cover), a 33-fold increase in bladder cancer, other malignancies, infertility, cardiotoxicity, and pulmonary fibrosis. In a study of 145 patients treated with this agent for systemic Wegener’s disease and monitored for a total of 1333 patient-years, nonglomerular hematuria occurred in approximately 50%, the majority of whom had macroscopic changes consistent with cyclophosphamide-induced bladder injury evident on cystoscopy. Seven of these (and none without hematuria) developed transitional cell bladder carcinoma; six had had a total cumulative cyclophosphamide dose exceeding 100 g and a duration of oral treatment exceeding 2.7 years.39 A maintenance phase of treatment, converting to a regimen of alternate-day steroids (10 to 20 mg of prednisolone) and substituting azathioprine (2 mg/kg/day) for cyclophosphamide, is commenced after induction and continued for 10 months; it is then gradually withdrawn. Azathioprine is believed to be less toxic, but reversible bone marrow suppression can occur; hepatotoxicity, although rare, does occur; and there is a small increased risk of malignancies. Deterioration, failure to respond initially, or intolerance of this regimen may necessitate the use of alternative agents. Methotrexate at 10- to 25-mg doses on a weekly basis may be used in conjunction with steroids, during either induction or maintenance. Intravenous immunoglobulin (0.4 mg/kg/day for 5 days), with its good safety record, has been found useful in cases of systemic vasculitis, although it may induce only partial remission.40 Plasmapheresis may be valuable in cryoglobulinemia. It is also considered in severe life-threatening disease (e.g., pulmonary hemorrhage and severe glomerulonephritis), with 7 to 10 treatments over 14 days.41 Although there is little experience with its use in patients with intracranial disease, there is evidence of significant improvement when it is used in combination with steroids in cerebral disease associated with Henoch-Schönlein purpura.

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A number of monoclonal antibodies, directed against CD52 (present on most lymphocytes), CD20 (B cells), or tumor necrosis factor, are generating much excitement as novel therapies in various inflammatory diseases, including the vasculitides; paradoxically, however, the induction of vasculitis has also been reported with some of these agents.42-46 Interferon a can control not only hepatitis C–associated hepatitis but also cryoglobulinemia and vasculitis. Unfortunately, there frequently a relapse within months of treatment withdrawal.

GIANT CELL VASCULITIDES Giant cell vasculitis includes two histologically similar but clinically distinct diseases: temporal arteritis and Takayasu’s arteritis. Temporal arteritis, a chronic inflammatory disorder targeting large and medium-sized arteries, rarely affects individuals younger than 55 years and affects women twice as commonly as men, with an overall prevalence of 1 per 1000. It has an annual incidence of 17.4 per 100,000 in the population older than 50 years; therefore, new-onset unilateral or bilateral headache in a person in this age group should alert the physician. Classically, it manifests as temporal headache with tender, pulseless, nodular temporal arteries and, often described only after direct inquiry, symptoms of general malaise, jaw claudication, and features of polymyalgia rheumatica (stiffness and aching of the shoulder girdle, worse in the mornings, and occasionally general malaise). Neuro-ophthalmological symptoms are the most widely recognized; blindness occurs in one sixth of treated patients with the condition.47 This occurs as a consequence of anterior ischemic optic neuropathy after vasculitic involvement of the posterior ciliary arteries and/or the ophthalmic artery, from which they are derived. The typical picture comprises locally painless loss of acuity, commonly severe, often with an altitudinal field defect. The fundal appearances may be normal, although swelling, usually mild, may be present. Conventionally, the inflammatory process is believed to involve only the extracranial vessels and rarely to extend beyond the point of penetration of the dura. A large study of 166 patients with biopsy-proved temporal arteritis demonstrated neurological involvement in 31%, describing the usual comprehensive range of neurological manifestation: neuropsychiatric syndromes, peripheral neuropathies, mononeuropathies, spinal cord lesions, neuro-otological syndromes, various pain syndromes, transient ischemic attacks, and stroke. Most authorities, however, would find almost all these manifestations outside their common experience.47 Infarction of the vertebrobasilar territory is relatively uncommon, but there have been isolated reports of temporal arteritis manifesting as lateral medullary syndrome. The expected greater incidence of cerebrovascular disease in this older subgroup may, however, be confounding. Affected temporal arteries may be thickened and cordlike, are often nonpulsatile, and are tender. A raised ESR, often accompanied by normochromic normocytic anemia, must be followed up by temporal artery biopsy; a specimen of several centimeters’ length is recommended to help avoid false-negative results, which may occur because of the focal or multifocal nature of the disorder. Histopathological examination of the vessel reveals changes of vasculitis, with an inflammatory infiltrate comprising mononuclear and giant cells; the latter

phagocytose the elastic laminae, causing characteristic fragmentation. Immunoglobulin and complement deposits are apparent in lesions, but activated T cells predominate in the inflammatory infiltrate, which is suggestive of cell-mediated immune damage. Vasculitic changes may still be apparent in biopsy samples taken 14 days or more after the commencement of steroid treatment. The ESR may be used to monitor treatment response. However, it has been pointed out that a low ESR in active disease is not excessively rare and perhaps may be explained by an inability to mount an acute phase response or by very localized arteritis.48 Measuring serum interleukin-6 levels is a promising alternative to the ESR. Investigators have also emphasized that an elevated platelet count should be considered a risk factor for permanent visual loss in temporal arteritis and should accentuate the need for urgent treatment.49 Steroid resistance is extremely rare in temporal arteritis. Fear of permanent blindness encourages most physicians to prescribe an immediate starting dosage of 60 to 80 mg of oral prednisolone daily, although prospective studies have suggested lower dosages (20 mg) to be as effective. After 4 to 7 days on a high dosage, gradual reduction by perhaps 5 mg weekly should be attempted to reach a maintenance dose of approximately 10 mg/day, with the clinical response and ESR (or plasma viscosity) used as a guide. Most authorities recommend continuing steroids for a period of 12 to 24 months; some patients still require steroids 2 to 5 years later. The importance of preventing long-term consequences of corticosteroids, particularly bone protection from osteoporosis, must be stressed. Azathioprine is often used as a steroid-sparing agent. Takayasu’s arteritis, originally described in young Asian women, is now globally recognized. It is alternatively named pulseless disease, because in 98% of affected individuals, at least one major arterial pulse is absent, as a result of the characteristic involvement of the aorta and its large branches. The disease process is initially inflammatory and later occlusive; during the latter phase, most of the neurological abnormalities occur. Syncope is reported in at least 50% of patients, but also seen are strokes, transient ischemic attacks, and visual abnormalities, all exacerbated by hypertension. This illness should be suspected in a patient younger than 40 years who has symptoms of limb claudication, absence of one or more pulses, a difference in systolic blood pressure of more than 10 mm Hg between the arms, and the presence of arterial bruits. Early histological features of the disease include granulomatous changes in the media and adventitia of the aorta and its branches, later followed by intimal hyperplasia, medial degeneration, and sclerotic adventitial fibrosis.

VASCULITIS OF THE PERIPHERAL NERVOUS SYSTEM In comparison with the clinical picture and diagnosis of CNS disease, those of PNS vasculitis are relatively straightforward. Up to 50% of patients present with mononeuritis multiplex; the remainder present with a more diffuse asymmetrical or a distal symmetrical polyneuropathy. Usually there are mixed sensory and motor features, which are very commonly painful and progress rapidly.15-18 Other causes of multiple focal large-nerve palsies must not be forgotten; these range from common disorders, such as diabetes mellitus, to the less common, such as

chapter 97 the neurological vasculitides hereditary liability to pressure palsies, lead poisoning, sarcoidosis, HIV infection, and paraneoplasia. As outlined previously, involvement of the PNS is substantially commoner than that of the CNS in the systemic vasculitides. Electrophysiological investigation may confirm an axonal neuropathy, often revealing subclinical involvement (potentially converting an apparent mononeuropathy to mononeuritis multiplex). Conduction block from focal ischemic demyelination is not rare, and there may be changes resulting from denervation. Confirmation of the diagnosis is achieved by nerve biopsy; the ideal sample includes a clinically and electrophysiologically involved nerve, and a sample of muscle is also examined in a combined nerve-muscle biopsy. In secondary PNS vasculitis, treatment of the primary cause is, of course, mandatory—interferons, possibly with plasmapheresis, for hepatitis B– or C–related cryoglobulinemia, antiretroviral therapy for HIV infection, and so forth—together with high-dosage steroids as necessary for the neuropathic problems. When vasculitic neuropathy is part of a systemic vasculitis, cyclophosphamide and steroids (as for CNS vasculitis) should be administered. In isolated PNS vasculitis, there is no consensus regarding the preferred treatment. Some authorities suggest that this is a more benign disease than systemic vasculitis and can be managed, at least at first, with steroids alone. Others advocate conventional full-dosage cyclophosphamide therapy from the outset.

K E Y

P O I N T S

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In practice, vasculitic brain disease is not common.

●

Careful clinical history and examination are warranted when suspect signs and symptoms are present.

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Targeted investigations very often help rule out many alternative diseases.

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Angiography is nonspecific as an investigational tool.

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Biopsy is probably underused but is valuable in both diagnosing and ruling out other treatable disorders.

●

Cyclophosphamide, not steroids alone, are indicated for definite CNS vasculitis.

Suggested Reading Lie JT: Classification and histopathologic spectrum of central nervous system vasculitis. Neurol Clin 1997; 15:805-819. Schmidley JW: Central and Peripheral Nervous System Angiitis. Oxford, UK: Butterworth Heinemann, 2000. Scolding NJ: Immunological and Inflammatory Diseases of the Central Nervous System. Oxford, UK: Butterworth-Heinemann, 1999.

Reference List 1. Watts RA, Scott DG: Classification and epidemiology of the vasculitides. Baillieres Clin Rheumatol 1997; 11:191-217.

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2. Jennette JC, Falk RJ, Milling DM: Pathogenesis of vasculitis. Semin Neurol 1994; 14:291-299. 3. Salojin KV, Le TM, Nassovov EL, et al: Anti-endothelial cell antibodies in patients with various forms of vasculitis. Clin Exp Rheumatol 1996; 14:163-69. 4. Scolding NJ, Joseph F, Kirby PA, et al: Aβ-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 2005; 128(Pt 3):500-515. 5. Cacoub P, Maisonobe T, Thibault V, et al: Systemic vasculitis in patients with hepatitis C. J Rheumatol 2001; 28:109-118. 6. Mohan N, Kerr GS: Diagnosis of vasculitis. Best Pract Res Clin Rheumatol 2001; 15:203-223. 7. Harper L, Williams JM, Savage CO: The importance of resolution of inflammation in the pathogenesis of ANCA-associated vasculitis. Biochem Soc Trans 2004; 32:502-506. 8. Xiao H, Heeringa P, Hu P, et al: Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110:955963. 9. Mathieson PW, Oliveira DB: The role of cellular immunity in systemic vasculitis. Clin Exp Immunol 1995; 100:183-185. 10. Lie JT: Biopsy diagnosis of systemic vasculitis. Baillieres Clin Rheumatol 1997; 11:219-236. 11. Lie JT: Classification and histopathologic spectrum of central nervous system vasculitis. Neurol Clin 1997; 15:805-819. 11a. Scolding NJ, Wilson H, Hohlfeld R, et al: The recognition, diagnosis and management of cerebral vasculitis: a European survey. Eur J Neurol 2002; 9:343-347. 12. Calabrese LH, Gragg LA, Furlan AJ: Benign angiopathy: a subset of angiographically defined primary angiitis of the central nervous system. J Rheumatol 1993; 20:2046-2050. 13. Gallagher KT, Shaham B, Reiff A, et al: Primary angiitis of the central nervous system in children: 5 cases. J Rheumatol 2001; 28:616-623. 14. Collins MP, Periquet MI: Non-systemic vasculitic neuropathy. Curr Opin Neurol 2004; 17:587-598. 15. Collins MP, Periquet MI, Mendell JR, et al: Nonsystemic vasculitic neuropathy: insights from a clinical cohort. Neurology 2003; 61:623-630. 16. Davies L, Spies JM, Pollard JD, et al: Vasculitis confined to peripheral nerves. Brain 1996; 119:1441-1448. 17. Dyck PJ, Benstead TJ, Conn DL, et al: Nonsystemic vasculitic neuropathy. Brain 1987; 110:843-854. 18. Said G, Lacroix-Ciaudo C, Fujimura H, et al: The peripheral neuropathy of necrotizing arteritis: a clinicopathological study. Ann Neurol 1988; 23:461-465. 19. Nishino H, Rubino FA, DeRemee RA, et al: Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 1993; 33:4-9. 20. Guillevin L, Durand-Gasselin B, Cevallos R, et al: Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42:421-430. 21. Sehgal M, Swanson JW, DeRemee RA, et al: Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc 1995; 70:337-341. 22. Scolding NJ: Neurological complications of rheumatological and connective tissue disorders. In Scolding NJ, ed: Immunological and Inflammatory Diseases of the Central Nervous System. Oxford, UK: Butterworth-Heinemann, 1999, pp 147180. 23. Zajicek JP, Scolding NJ, Foster O, et al: Central nervous system sarcoidosis—diagnosis and management. QJM 1999; 92:103117. 24. Lie JT: Vasculitis associated with infectious agents. Curr Opin Rheumatol 1996; 8:26-29. 25. Hilt DC, Buchholz D, Krumholz A, et al: Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by

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cerebral angiitis: diagnosis and management approaches. Ann Neurol 1983; 14:543-553. 25a. Greco FA, Kolins J, Rajjoub RK, Brereton HD: Hodgkin’s disease and granulomatous angiitis of the central nervous system. Cancer 1976; 38:2027-2032. 26. Citron BP, Halpern M, McCarron M, et al: Necrotizing angiitis associated with drug abuse. N Engl J Med 1970; 283:10031011. 26a. Nolte KB, Brass LM, Fletterick CF: Intracranial hemorrhage associated with cocaine abuse: a prospective autopsy study. Neurology 1996; 46:1291-1296. 27. Aggarwal SK, Williams V, Levine SR, et al: Cocaine-associated intracranial hemorrhage: absence of vasculitis in 14 cases. Neurology 1996; 46:1741-1743. 28. Scolding NJ: Cerebral vasculitis. In Scolding NJ, ed: Immunological and Inflammatory Diseases of the Central Nervous System. Oxford, UK: Butterworth-Heinemann, 1999, pp 210258. 29. Calabrese LH, Mallek JA: Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine 1988; 67:2039. 30. Hankey G: Isolated angiitis/angiopathy of the CNS. Prospective diagnostic and therapeutic experience. Cerebrovasc Dis 1991; 1:2-15. 31. Scolding NJ, Jayne DR, Zajicek JP, et al: The syndrome of cerebral vasculitis: recognition, diagnosis and management. QJM 1997; 90:61-73. 32. Harris KG, Tran DD, Sickels WJ, et al: Diagnosing intracranial vasculitis: the roles of MR and angiography. Am J Neuroradiol 1994; 15:317-330. 33. Cloft HJ, Phillips CD, Dix JE, et al: Correlation of angiography and MR imaging in cerebral vasculitis. Acta Radiol 1999; 40:8387. 34. Atalay MK, Bluemke DA: Magnetic resonance imaging of large vessel vasculitis. Curr Opin Rheumatol 2001; 13:4147. 35. Alrawi A, Trobe J, Blaivas M, et al: Brain biopsy in primary angiitis of the central nervous system. Neurology 1999; 53:858860. 36. Hellmann DB, Roubenoff R, Healy RA, et al: Central nervous system angiography: safety and predictors of a positive result

37.

38. 39. 40. 41. 42.

43. 44. 45. 46. 47. 48. 49.

in 125 consecutive patients evaluated for possible vasculitis. J Rheumatol 1992; 19:568-572. Jayne D, Rasmussen N, Andrassy K, et al: A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36-44. Scolding NJ, Wilson H, Hohlfeld R, et al: The recognition, diagnosis and management of cerebral vasculitis: a European survey. Eur J Neurol 2002; 9:343-347. Talar-Williams C, Hijazi YM, Walther MM, et al: Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996; 124:477-484. Jayne DR, Chapel H, Adu D, et al: Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000; 93:433-439. Gaskin G, Pusey CD: Plasmapheresis in antineutrophil cytoplasmic antibody–associated systemic vasculitis. Ther Apher 2001; 5:176-181. Booth A, Harper L, Hammad T, et al: Prospective study of TNFα blockade with infliximab in anti-neutrophil cytoplasmic antibody–associated systemic vasculitis. J Am Soc Nephrol 2004; 15:717-721. Unger L, Kayser M, Nusslein HG: Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis 2003; 62:587-588. Mathieson PW, Cobbold SP, Hale G, et al: Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med 1990; 323:250254. Mohan N, Edwards ET, Cupps TR, et al: Leukocytoclastic vasculitis associated with tumor necrosis factor-α blocking agents. J Rheumatol 2004; 31:1955-1958. Sneller MC: Rituximab and Wegener’s granulomatosis: are B cells a target in vasculitis treatment? Arthritis Rheum 2005; 52:1-5. Caselli RJ, Hunder GG: Neurologic complications of giant cell (temporal) arteritis. Semin Neurol 1994; 14:349-353. Salvarani C, Hunder GG: Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurrence in a population-based study. Arthritis Rheum 2001; 45:140-145. Lincoff NS, Erlich PD, Brass LS: Thrombocytosis in temporal arteritis rising platelet counts: a red flag for giant cell arteritis. J Neuroophthalmol 2000; 20:67-72.

CHAPTER

TUMORS ●

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OF THE ●

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BRAIN

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Jeremy Rees

Tumors of the brain are regarded as one of the most devastating group of neurological diseases—they are associated with significant neurological morbidity, they lead to progressive physical, cognitive and emotional dysfunction and are frequently fatal. The term brain tumor is used to describe both primary tumors that originate from the brain, cranial nerves, pituitary gland. or meninges and secondary tumors (metastases) that arise from organs outside the nervous system. These tumors present in many different ways dependent on their location, their rate of growth, and their effect on healthy neural tissue. Diagnosis requires careful history and examination, imaging, and histological examination, and management is best determined in a multidisciplinary team environment comprising neurologists, neurosurgeons, oncologists, neuropathologists, neuroradiologists, and clinical nurse specialists. Despite the dramatic advances in neurosurgical technology, imaging, neuroanesthesia, radiotherapy techniques, and new drug development, the prognosis for many brain tumors, particularly malignant gliomas, remains bleak. The lack of a “cure” for the majority of these patients requires increasing emphasis on quality of life issues, and assessment of these is a standard feature of modern brain tumor trials. This chapter aims to cover the key points required to manage patients with brain tumors effectively and sensitively, with specific emphasis on diagnostic and treatment considerations.

EPIDEMIOLOGY Intracranial tumors are the eighth most common neoplasm in adults (approximately 5% of all primary neoplasms) and the most common solid tumor in children. They are the second leading cause of death from neurological disease in the United Kingdom (second only to stroke) and account for 2% of all cancer deaths in adults. The incidence of primary brain tumors is considerably higher than tumor registry figures suggest. Based on a study from the southwest of England ascertaining data mainly from radiology records, the crude annual incidence for primary tumors was found to be 21 in 100,000.1 The annual incidence in the United States as ascertained from the Central Brain Tumor Registry is lower at 6.7 in 100,000 persons.2 There is increasing evidence that the incidence of gliomas and lym-

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phomas is increasing, particularly in elderly patients, although this is more likely to be due to increased case ascertainment, with the increasing availability of modern imaging techniques.3 Brain tumors can present at any age. In children, they are the most common solid tumor and mainly occur in the posterior fossa, such as medulloblastoma, ependymoma, and juvenile pilocytic astrocytoma. In contrast, adults more commonly present with supratentorial tumors, particularly gliomas and meningiomas, accounting for over 75% of brain tumors. The most frequent tumors of middle life (third and fourth decades) are astrocytomas, meningiomas, pituitary adenomas, and vestibular schwannomas, whereas glioblastoma multiforme and metastases are more frequent in the fifth and six decades of life. There is a strong female preponderance of meningiomas, particularly in the spinal canal, whereas gliomas occur slightly more frequently in men. Germ cell tumors, particularly of the pineal region, occur frequently in adolescent males.

ETIOLOGY Numerous epidemiological studies have been carried out to investigate etiological factors, but no clear risk factors have emerged apart from therapeutic ionizing irradiation. Cranial radiotherapy, even at low doses, has been shown to increase the relative risk of meningiomas by a factor of 10 and gliomas by a factor of 3.4 Other radiotherapy-induced tumors include cranial osteosarcomas, soft tissue sarcomas, schwannomas, and peripheral nerve sheath tumors. They have been described following radiotherapy for tinea capitis, craniopharyngioma, and pituitary adenomas and prophylactic cranial irradiation for acute lymphoblastic leukemia. Second tumors tend to lie within the radiation field, usually in lower dose regions, and develop from a few years to many decades after irradiation. The reported median time to the development of gliomas is 7 years. Sarcomas develop with a longer lag time and meningiomas may be seen 30 or 40 years later. The histology is identical to spontaneous tumors, although meningiomas are more likely to contain atypical features and have a worse prognosis. No other environmental exposure has been clearly identified as a risk factor. There is widespread concern about the possible risks of cellular telephones, but case-control studies have not shown any increased risk in respect of any subtype of brain

chapter 98 t u m o r s o f t h e b r a i n

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tumor using measures of the type of telephone, duration and frequency of use, and cumulative hours of use.5 So far, the consensus of opinion based on four studies is that mobile telephone use does not increase the risk of developing a brain tumor. However, with the exponential increase in the ownership and duration of use of these hand-held devices, it is important to continue surveillance of brain tumor trends in order to detect a latent period of several decades for the development of a tumor. Genetic causes of brain tumors are rare but important. Occasionally, brain tumors occur in successive generations without any other tumor predisposition. More commonly, they are associated with neurocutaneous syndromes such as neurofibromatosis (optic nerve glioma, meningioma, vestibular schwannoma) and tuberose sclerosis (subependymal giant cell astrocytoma), von Hippel-Lindau syndrome (hemangioblastoma), and familial tumor syndromes such as Li-Fraumeni syndrome (glioma) and Cowden disease (dysplastic cerebellar gangliocytoma or Lhermitte-Duclos disease).

pathways involved in proliferation, growth control, apoptosis, DNA repair, and genomic stability may differ from one tumor to another, but the phenotypes of the resulting tumors are similar.

PATHOGENESIS

1. 2. 3. 4. 5.

Brain tumors arise from an accumulation of mutations in genes that normally regulate the pathways of cell proliferation and differentiation. As in all human cancers, oncogenes and tumor suppressor genes are involved in the pathogenesis of brain tumors. One of the more frequent aberrations in human cancers are deletions or mutations of the TP53 gene, located on chromosome 17p, which encodes a 53-kDa protein, p53. These are found in approximately 40% of astrocytic tumors. This protein influences multiple aspects of cell cycle control as well as DNA repair after radiation damage and the induction of apoptosis. Other important genetic aberrations seen in malignant gliomas include amplification and mutations of the epidermal growth factor receptor (EGFR) gene and deletions and mutations of PTEN (phosphatase and tensin homology). Studies of astrocytic tumors show that the accumulation of predictable genetic alterations is associated with increasing malignant progression. The mammalian cell cycle is divided into four phases: G1, S, G2, and M. Unrestricted cell multiplication is one of the hallmarks of cancer and is controlled in the normal cell by a complex series of positive and negative regulators that constitute the cell cycle checkpoints. Important proteins involved in these checkpoints include p53, MDM2, p14ARF, and p21, which regulate the progression of cells through the G1 cell cycle phase. Disruption of these protein complexes by gene deletions or mutations is found in varying proportions of gliomas, such as MDM2 gene amplification (in 10% to 15% of anaplastic astrocytomas) and glioblastoma multiformes lacking TP53 mutations. MDM2 is a cellular protein, which binds to and inactivates p53 and thus acts as an oncogene promoting glioma growth. Taken overall, the various gene mutations mentioned above can all lead to a slight growth advantage, which can be further amplified by a gradual accumulation of further mutations, particularly when associated with loss of heterozygosity of the other allele. Current theories of malignant transformation postulate that this process is a sequence of multiple genetic alterations, each of which contributes to some expression of the tumor’s malignant characteristics. The various cellular

CLINICAL FEATURES Brain tumors can present in many different ways, and with the increased accessibility to high quality neuroimaging, they are being detected at a much earlier stage of their natural history than was the case previously. In some respects, this has made management decisions more difficult, particularly when a tumor is found that is in an inoperable location and is causing very few symptoms. Asymptomatic tumors are sometimes detected when patients are scanned for unrelated conditions and in many cases may be left alone. The symptoms of brain tumors can be either focal or generalized and are most conveniently classified into five clinical syndromes that may coexist in the same patient or be present at different stages of the disease course: Raised intracranial pressure Progressive focal or cranial nerve deficit Seizure disorder Cognitive/behavioral changes Endocrine disorders (hypersecretion or hyposecretion of the hypothalamic-pituitary axis)

The precise combination of clinical features varies on the location, histology, and rate of growth of the tumor. For instance, a patient with a low-grade glioma typically presents with a seizure disorder that may remain static for many years, whereas a patient with a malignant glioma may present with a rapidly progressive neurological deficit and raised intracranial pressure and be dead within a few weeks.

Raised Intracranial Pressure As a brain tumor grows, there is displacement of cerebrospinal fluid into the spinal compartment and a reduction of blood volume. Eventually, the intracranial pressure rises because the skull behaves as a rigid box. Headache is the most common symptom of brain tumors, occurring in 23% of patients at initial presentation and 46% by the time of hospital admission. Headache alone, however, is an extremely rare presenting symptom, occurring in only 1.9% of patients.6 Because headache is such a common symptom in the population as a whole, it accounts for a disproportionate number of referrals of patients to neurology clinics concerned about the possibility of a brain tumor. Most brain tumor headaches are intermittent and nonspecific and may be indistinguishable from tension headaches.7 They may occasionally indicate the side of the tumor. Certain features of a headache are suggestive but not pathognomic of raised intracranial pressure. These include headaches that wake the patient at night or are worse on waking and improve shortly after rising, as well as headache associated with visual obscurations (transient fogging associated with changes in posture). Supratentorial tumors typically produce frontal headaches, whereas posterior fossa tumors usually result in occipital headache or neck pain. Nausea and vomiting may be a feature of raised pressure but may also occur as an early symptom of fourth ventricular tumors.

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Brain tumors cause increased intracranial pressure by a variety of different mechanisms. They may have grown so large in a relatively short space of time that they cause stretching of pain-sensitive intracranial structures by a direct mass effect or by an effect on the microvasculature leading to cerebral edema. Smaller tumors, particularly those located in the posterior fossa, may cause headaches by obstructing cerebrospinal fluid circulation and producing obstructive hydrocephalus. Tumors may also cause raised intracranial pressure by producing large cysts. Occasionally, meningeal-based tumors cause localized headache through stretching of overlying dura. As a general rule, headaches with migrainous features are rarely due to an underlying tumor, although occasionally occipital tumors produce occipital seizures that are similar in many respects to migraine. Untreated intracranial pressure leads to gradual deterioration in cognition, intermittent drowsiness, and eventually coma. Brainstem compression is the usual mode of death in patients with progressive brain herniation. The exact structures that are involved depend on the type of herniation—the most common types are uncal herniation, where the medial temporal lobe herniates across the tentorium, giving rise to an ipsilateral third nerve palsy, and tonsillar herniation, where the cerebellar tonsils are pushed down into the foramen magnum, leading to coma and death.

Progressive Neurological and Cranial Nerve Deficits Focal neurological symptoms due to brain tumor are typically subacute and progressive with over 50% of patients having focal signs by the time of diagnosis. However, they may present acutely with strokelike symptoms, particularly if there is intratumoral hemorrhage, or even as a reversible event similar to a transient ischemic attack. Cortical tumors produce contralateral weakness, sensory loss, dysphasia, dyspraxia, and visual field loss depending on their location. A progressive hemianopia is often not detected by the patient, who may simply complain of bumping into objects or having a number of unexplained scrapes with parked vehicles or other stationary objects. Nondominant parietal tumors may present with topographical disorientation. Posterior fossa tumors cause gait ataxia, usually associated with headache and vomiting, whereas tumors in the cerebellopontine angle present with progressive unilateral deafness followed by ipsilateral facial sensory loss. Tumors in the fourth ventricle may present with effortless vomiting without nausea, a symptom that may predate more classic “posterior fossa” symptoms by many months or even years. Pituitary tumors compressing the optic chiasm cause a bitemporal quadrantanopia progressing onto hemianopia or pituitary apoplexy if there is hemorrhage or infarction. Subfrontal meningiomas may present with anosmia due to compression of the olfactory nerves in the anterior cranial fossa but may grow to a large size before clinical symptoms become apparent.

to 60% of patients. Approximately one half the patients have focal seizures, and the other one half have secondarily generalized seizures. Seizures occur in over 90% of cases of lowgrade gliomas and frequently remain the only complaint for many years. Conversely, malignant gliomas have a lower frequency of seizures presumably because of their more rapid growth and destructive characteristics. Seizures are also common presenting symptoms for meningiomas (40% to 60%) and metastases (15% to 20%). Temporal and frontal tumors are more likely to cause seizures than are occipital or parietal tumors, particularly when cortically based. The characteristics of the seizure depend on the location of the tumor. Frontal lobe tumors cause typically brief, frequent, and nocturnal seizures, which tend to spread rapidly and may become generalized. Common manifestations of a frontal lobe seizure include bicycling movements of the legs at night, turning of the head and eyes to the side away from the tumor (frontal adversive seizure), speech arrest, and hemiclonic spasms with a jacksonian march (posterior frontal tumors) in clear consciousness. In contrast, mesial temporal tumors can begin with olfactory or gustatory hallucinations, an epigastric rising sensation, or psychic experiences such as déjà vu or depersonalization. Once the seizures progress to a loss of awareness, the patients may stare blankly, speak unintelligibly, or exhibit lip smacking, picking at clothing, or other automatisms. Secondary generalized tonic-clonic seizures may follow on from partial seizures, more frequently in untreated patients. The presence of seizures is a favorable prognostic factor for survival, possibly due to lead-time bias in diagnosis and possibly due to the slow growth of epileptogenic tumors compared with more high-grade destructive tumors. In a study of patients with low-grade astrocytomas, the 5-year survival for patients with epilepsy as the only sign of tumor was 63% compared with 27% among the whole group.8

Mental State Changes These are an uncommon presentation of brain tumors occurring in about 20% of patients at diagnosis. Personality changes may be quite subtle initially and may present as an inability to cope at work. In these cases, it is essential to obtain a collateral history from relatives or colleagues at work. Subfrontal meningiomas may present as loss of interest and motivation by virtue of their slow growth in a noneloquent region and may be mistaken for depression or early dementia. Often, personality changes are evident in retrospect and are more commonly noted by the patient’s family than by the patient.

Endocrine Syndromes A detailed review of endocrine syndromes associated with pituitary tumors is beyond the scope of this chapter. Tumors may present with hormonal disturbances due either to hypersecretion of pituitary hormones (e.g., amenorrhea, acromegaly, galactorrhea) or hyposecretion (e.g., hypopituitarism).

Seizure Disorder Brain tumors account for about 5% of epilepsy cases, although they are overrepresented in cases of intractable epilepsy. Seizures are the presenting symptom in 25% to 30% of patients with gliomas and are present at some stage of the illness in 40%

DIAGNOSIS The diagnosis of a brain tumor is made by a combination of contrast-enhanced computed tomography scanning/magnetic

chapter 98 t u m o r s o f t h e b r a i n resonance imaging and pathological classification of either a biopsy or resection specimen. Over the past decade or so, there have been a number of newer techniques introduced to complement conventional structural imaging, including proton magnetic resonance spectroscopy, functional metabolic imaging (single photon and positron emission tomography), and advanced magnetic resonance techniques, such as perfusion imaging (measuring blood flow and blood volume), diffusion weighted imaging (measuring cellularity), and diffusion tensor imaging (assessing integrity of white matter pathways). These are being gradually integrated into the routine preoperative evaluation of a brain tumor but add little to the conventional sequences in terms of refining diagnostic certainty.9 Just as there is clinicopathological correlation between World Health Organization (WHO) grade and prognosis, there is also a radiological/pathological correlation, specifically with respect to the degree of contrast enhancement seen within the tumor. Most grade II gliomas do not enhance, unlike grades III and IV, where there is usually irregular ring enhancement and, in the case of grade IV tumors, central necrosis. However, as mentioned, certain grade I gliomas, particularly juvenile pilocytic astrocytomas, also enhance, and this can occasionally give rise to diagnostic confusion, particularly in adults, in whom juvenile pilocytic astrocytomas are much less common than malignant gliomas. The key imaging characteristics of common types of tumors are summarized in Table 98–1; see also Figure 98–3 for radiological/pathological correlations.

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malignant phenotype is classified as grade IV. The peak of age of incidence is proportional to the most common histological grade; that is, grade I tumors usually present in childhood, grade II in young adulthood, grade III in middle age, and grade IV in older age. The exception to this rule is the grade IV primitive neuroectodermal tumors, which occur most frequently in childhood. Neuroepithelial tumors (predominantly gliomas) account for approximately 50% to 60% of all primary brain tumors. The other common types are meningiomas (20%) and pituitary adenomas (15%). Rarer tumors include primary central nervous system lymphomas, neuronal tumors, and germ cell tumors. Metastatic tumors are more common than primary brain tumors and usually originate from lung (50%), breast (15%), melanoma (10%), and unknown (15%). In children, the most common tumors are low-grade astrocytomas, ependymomas, suprasellar tumors, medulloblastomas, and other primitive neuroectodermal tumors. There is increasing use of molecular classification in addition to morphology, but at present, this is not an integral part of the standard neuropathological report. The grading system is based on a number of histological features including the degree of cellular atypia and pleomorphism, the presence of vascular proliferation and necrosis, and the cellular proliferation rate and correlates with the degree of malignancy, the likelihood of metastatic spread and recurrence, and ultimately survival.

Gliomas PATHOLOGY There are over 160 types of primary brain tumors arising from neuroepithelial tissue within the brain, the meninges covering the brain, the sellar region, and the cranial nerves. The WHO published a landmark classification in 1993 and, in 2000, further refined their classification system (Table 98–2).10 The key to the WHO classification is the stratification of tumors according to their biological activity so that the lower the WHO grade, the better the overall prognosis. As a general rule, the category of grade I tumors is reserved for neoplasms that have a stable histology and that are potentially curable by surgical removal alone. In contrast, tumors that appear histologically “benign,” yet are known to progressively transform over time into higher grade lesions, are categorized as grade II neoplasms. Those tumors with anaplastic histology are regarded as grade III high-grade neoplasms, and the most

Gliomas are the most common type of primary brain tumor and are so called because they share morphological and immunohistochemical features with astrocytes and oligodendroglial and ependymal cells. Astrocytic neoplasms are the most common of the three and include tumors of all WHO grades. Low-grade gliomas can be subdivided into WHO grade I tumors (e.g., pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and subependymal giant cell astrocytomas [usually but not invariably associated with tuberose sclerosis]) and WHO grade II tumors (e.g., diffuse and gemistocytic astrocytomas, oligodendrogliomas, and oligoastrocytomas [which contain elements of both astrocytic and oligodendroglial lineage, otherwise known as mixed gliomas]). These two grades should be regarded as distinctive groups in that grade I tumors never progress into grade II tumors, unlike grade II tumors, which frequently transform into grade III and grade IV tumors (as dis-

T A B L E 98–1. Imaging Characteristics of Common Brain Tumors Tumor

Enhancement

Calcification

Cyst

Necrosis

Edema

Glioma Pilocytic astrocytoma Diffuse astrocytoma Oligodendroglioma Anaplastic astrocytomas Glioblastoma multiforme Ependymoma Meningioma Lymphoma Germinoma Medulloblastoma Metastasis

Mural nodule Rare Patchy Patchy Irregular Yes Homogeneous Homogeneous Patchy Patchy Ring

No Yes (rarely) Yes No No No Yes No No No No

Yes Yes (rarely) Yes Yes Yes Yes Yes (rarely) No Yes Yes Yes

No No No Yes Yes Yes (rarely) Yes (rarely) No Yes Yes Yes

No No No Yes Yes Yes Yes Yes Yes Yes Yes

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T A B L E 98–2. World Health Organization Classification and Grading of Tumors of the Nervous System Tumors of Neuroepithelial Tissue Astrocytic tumors Pilocytic astrocytoma Pleomorphic xanthoastrocytoma Subependymal giant cell astrocytoma Desmoplastic infantile astrocytoma Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma multiforme Gliosarcoma Oligodendroglial tumors Oligodendroglioma Anaplastic oligodendroglioma Mixed astrocytic and oligodendroglial tumors Oligoastrocytoma Anaplastic oligoastrocytomas Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Anaplastic ependymoma Choroid plexus tumors Choroid plexus papilloma Choroid plexus carcinoma Neuronal and mixed neuronal-glial tumors Gangliocytoma Ganglioglioma Desmoplastic infantile ganglioglioma Dysembryoplastic neuroepithelial tumor Central neurocytoma Pineal parenchymal tumors Pineocytoma Pineoblastoma Embryonal tumors Primitive neuroectodermal tumors Medulloblastoma Meningeal tumors Meningioma Atypical meningioma Anaplastic meningioma Hemangiopericytoma Melanocytic tumor of the meninges Tumors of vascular origin Cavernous angioma Hemangioblastoma Germ cell tumors Germinoma Embryonal carcinoma Yolk sac tumor (endodermal sinus tumor) Choriocarcinoma Teratoma Tumors of the sellar region Pituitary adenoma Pituitary carcinoma Craniopharyngioma Primary central nervous system lymphomas Peripheral nerve sheath tumors Vestibular schwannoma Trigeminal schwannoma Facial nerve schwannoma Malignant peripheral nerve sheath tumor Metastatic tumors

WHO Grade I I, II I I II III IV IV II III II III I I II III I IV I I, II I I I I IV IV IV I II III

cussed later). Therefore, grade II tumors should be thought of as part of a biological continuum that extends through to grade IV tumors. Grade I gliomas are usually well circumscribed and potentially curable by surgical resection alone. The most common type is the juvenile pilocytic astrocytoma, so called because it presents in childhood and is characterized by the presence of astrocytes with hairlike (pilocytic) processes. The tumor has a narrow zone of microscopic infiltration and appears radiologically as an enhancing mural nodule, which is supplied by capillaries that lack a complete blood-brain barrier surrounded by a cyst. This leads to the contrast enhancement seen on computed tomography scans or magnetic resonance images (Fig. 98–1). Other grade I tumors may contain neuronal elements such as ganglioglioma and are known as mixed glioneuronal tumors. They can occur anywhere in the brain but have a predilection for the temporal lobes and may give rise to intractable temporal lobe epilepsy. Grade II astrocytomas also grow slowly and act in a “benign” manner, usually presenting with seizures but, in contrast to grade I tumors, they are diffusely infiltrative and recur after surgery, usually as a higher-grade glioma. The macroscopic and microscopic appearances are of diffuse spread into normal brain parenchyma, making it impossible for the surgeon to distinguish macroscopically between tumor and normal brain tissue. The astrocytic morphology may be fibrillary or protoplasmic, but these distinctions are not important in clinical practice. The gemistocytic variant, however, tends to behave in a more aggressive manner. Astrocytomas are hypercellular compared with normal white matter, and the tumor cells show hyperchromasia and pleomorphism, with striking irregularity of the nuclei. The normal architecture is commonly disrupted into a microcystic pattern. Mitoses are absent or solitary. The other main cellular type of low-grade glioma is the oligodendroglioma characterized by the presence of uniform round nuclei with small nucleoli and perinuclear halos. These tumors are often calcified and may have areas of focal increased cellularity. Some grade II gliomas have intermixtures of astrocytic and oligodendroglial cellular elements and are appropriately called oligoastrocytomas. All three types have a propensity to undergo anaplastic change and turn into a high-grade glioma. Time to malignant transformation is variable and at present cannot be predicted on the basis of histology or genetics alone, although it may be shorter in older patients. High-grade or malignant gliomas encompass grade III (anaplastic) tumors and grade IV gliomas. These tumors are characterized histologically by increasing cellular density and pleomorphism, mitotic activity, and proliferation indices. Grade III tumors are defined by the presence of frequent mitoses, whereas the presence of vascular proliferation and/or necrosis is the hallmark of a grade IV tumor (glioblastoma multiforme). Tumors with higher-grade histology behave in a more destructive manner and present more commonly with symptoms of raised intracranial pressure, focal neurological deficit, or mental state changes. These tumors are generally incurable.

GENETICS The molecular classification of gliomas has become increasingly important in therapeutic decision making, particularly

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A B

C ■

D Figure 98–1. (A) Juvenile cerebellar pilocytic astrocytoma. Sagittal Gd-enhanced T1-weighted magnetic resonance imaging showing contrast enhancing nodule within the cerebellar hemisphere of a child and surrounding cyst. (B) Diffuse astrocytomas. Coronal FLAIR sequence showing large intrinsic frontotemporal tumor. This tumor did not enhance following contrast injection. (C) Anaplastic astrocytoma. Coronal T1-weighted gadolinium showing large heterogeneously enhancing right frontal lobe tumor with mass effect. (D) Glioblastoma multiforme. Axial T1-weighted scans ring enhancing tumor with central necrosis in left occipital lobe.

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the distinction between tumors of astrocytic lineage and oligodendroglial lineage, with the latter being characterized by losses of part of chromosomes 1 and 19. The only molecular genetic alteration consistently observed in patients with low-grade astrocytomas is mutation of the TP53 gene, located on chromosome 17, which occurs in 50% to 60% of patients with astrocytomas. Loss of normal p53 function promotes growth and malignant transformation and is therefore believed to be one of the most important gene alterations associated with the development of malignant gliomas. Loss of p53 is also seen in anaplastic astrocytomas and glioblastomas arising from low-grade gliomas. In contrast, glioblastomas arising de novo more commonly have amplification of the EGFR gene, suggesting that they arise from different genetic pathways. In glioblastoma multiforme, there are gains of chromosome 7 and deletions of chromosomes 10 and 22, both of which contain multiple tumor suppressor genes, together with structural alterations of chromosomes 1p, 9p, 11p, 12q, and 13q. As a result of these various genetic aberrations, GBMs can be divided on the basis of molecular features into primary and secondary GBMs, which correlate with their clinical behavior. Primary GBMs arise de novo in older patients and are strongly associated with amplification and overexpression of the EGFR gene, increased MDM2 activity, and decreased PTEN. In contrast, secondary GBMs arise out of previous low-grade gliomas, occur in younger individuals, and are associated with early p53 loss and overexpression of PDGF. As with primary GBMs there is loss of PTEN. Astrocytomas can be distinguished from oligodendrogliomas on the basis of histological features, as described earlier. During the past decade, the specific association between tumors of oligodendroglial lineage, particularly tumors with classic histology, and loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) has been recognized. Loss of 1p/19q is found in 40% to 90% of oligodendrogliomas compared with less than 1% of astrocytomas. Nearly all tumors with 1p loss also have 19q loss, suggesting that inactivation of one or more genes on each of these arms is a fundamental event in oligodendroglioma oncogenesis. This chromosomal fingerprint is tightly associated with chemosensitivity and prolonged survival and has taken molecular classification out of the basic science laboratory and into the clinical arena.11 Candidate tumor suppressor genes have still not been identified. Other genetic alterations less frequently encountered in oligodendroglioma include losses of chromosomes 4, 6, 14, 11p, and 22q. Neuropathology laboratories are increasingly offering genotyping for 1p and 19q; the results will influence the prognosis, as 70% to 80% of long-term survivors have 1p/19q loss. The coincidence of these two genetic aberrations is unique to oligodendroglioma. They are not found in oligodendroglioma “mimics” such as dysembryoplastic neuroepithelial tumors or central neurocytomas and are therefore useful in cases with equivocal morphology. The correlation with chemosensitivity is particularly high in patients, with 75% of patients with anaplastic oligodendrogliomas responding to treatment with procarbazine, CCNU, and vincristine and 50% achieving a prolonged and durable survival.11 Similar but less dramatic responses have also been observed in patients with low-grade oligodendrogliomas.

TREATMENT The three conventional modalities of treatment for brain tumors are surgery, radiotherapy, and chemotherapy. In some patients, suc as those with unresectable low-grade gliomas, it is perfectly reasonable and safe to offer no specific treatment at all. In other patients, such as frail elderly patients with significant tumor-associated disability, any benefits of treatment in terms of prolongation of survival may be outweighed by the treatment-associated morbidity. The use of each therapeutic modality therefore should be dictated by the location of the tumor within the brain and within the skull, specifically, whether it is intra-axial (e.g., glioma) or extra-axial (e.g., meningioma), the likely histology, and the patient’s age and general condition. The distinction between intra- and extra-axial tumors is important, as the effect on surrounding brain tissue and the likely plane of dissection are critical to the success of radical surgery (Fig. 98–2). When considering surgery for intrinsic tumors, patient factors, particularly age and performance status, are far more important in terms of prognosis than any specific treatments used, and this needs to be borne in mind when evaluating the efficacy of any treatment and claims that survival is significantly improved.

Surgery There are three principal indications for surgery in the management of brain tumors: tissue diagnosis (via stereotactic or open biopsy), relief of raised intracranial pressure (via tumor debulking, lobectomy, aspiration of tumor-associated cysts, insertion of shunts for tumor-associated hydrocephalus), and prolongation of survival. The complete removal of an intracranial tumor is the goal of radical tumor surgery and is routinely achieved in the treatment of convexity meningiomas and other extra-axial tumors such as nonsecreting pituitary adenomas and vestibular schwannomas. Surgery may also be regarded as curative for a limited number of intrinsic tumors, particularly WHO grade I gliomas, such as juvenile pilocytic astrocytomas. In other malignant intrinsic tumors, such as medulloblastomas and solitary brain metastases, the extent of resection plays a vital prognostic role in determining the success of adjuvant treatment but is not in itself curative. The main complications of surgery are neurological deficit, postoperative hydrocephalus, cerebrospinal fluid leak, and seizures, as well as the general complications of any surgery, such as wound infection, deep vein thrombosis, and pulmonary embolism. The role of surgery in the management of the majority of primary intrinsic tumors, specifically gliomas, is more controversial as even radical removal is unlikely to be curative given the diffusely infiltrative nature of these tumors and their tendency to spread far beyond the core of the tumor along extracellular pathways and white matter tracts. Furthermore, as there are no prospective randomized studies correlating extent of resection with survival and it is highly unlikely that such studies will ever be carried out, controversy will continue to exist with regard to the impact that extent of resection has on outcome. There have been a number of recent advances in tumor neurosugery including computerized neuronavigation techniques,

chapter 98 t u m o r s o f t h e b r a i n Glioma: Diffuse infiltration

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Meningioma: Expansive growth Meningothelial cells Neurons

(Reactive) astrocytes Cortex Neoplastic astrocytes

White matter

■

Oligondendrocytes

Figure 98–2. Intra-axial versus extra-axial tumors. Illustration of the principal differences between intrinsic (intra-axial) and extrinsic (extra-axial) tumors. Intrinsic tumors, such as gliomas, are characterized by diffuse infiltration of neoplastic astrocytes that spread along white matter tracts as well as within cortical or subcortical gray matter. In contrast, extra-axial tumors, such as meningiomas, show expansive but well-demarcated growth. They compress gray and white matter structures and induce proliferation of astrocytes (gliosis) and edema. From a surgical viewpoint, gliomas are essentially incurable because of this diffusely invasive growth pattern. (Courtesy of Professor Sebastian Brandner.)

improved preoperative mapping of eloquent brain areas using functional magnetic resonance imaging, and assessment of white matter pathways by diffusion tractography. Frameless stereotaxy now enables the surgeon to delineate the tumor boundaries seen on preoperative magnetic resonance imaging with the surface markings of the brain in three dimensions. However, this may be affected by brain shift as the cranial cavity is opened and therefore becomes less accurate at deeper levels of the brain. In this respect, intraoperative magnetic resonance imaging now allows the surgeon to view the results of his or her resection while the patient is still on the table and remove further tissue as necessary according to the scan appearances of the tumor. These have all contributed to improving the morbidity and mortality of neurosurgery, but an effect on overall survival has yet to be demonstrated. Nevertheless, the ability to remove more and more abnormal tissue with less and less risk to the patient and eventually to resect almost an entire intrinsic tumor remains the Holy Grail of oncological neurosurgery.

Radiotherapy Radiotherapy has become the most commonly used tumorspecific therapy in neuro-oncology. Therapeutic radiation for brain tumors is most commonly produced from high-energy linear accelerators that generate x-rays and electrons, which have much higher energy than those used in diagnostic radiology. Protons, neutrons, and gamma rays from cobalt 60 decay are used particularly for extrinsic tumors. Radiotherapy may also be delivered directly into the tumor using radioisotopes such as iodine 125. Radiation can be either directly (e.g., protons and other charged particles) or indirectly (e.g., x-rays and gamma rays) ionizing. Indirect ionizing radiation targets DNA by producing short-lived fast-moving charged particles when absorbed into

water-rich tissue, leading to single- and double-strand breaks. Single-strand breaks are easily reparable, but double-strand breaks lead to difficulties with subsequent mitoses and chromosomal aberrations, some of which are lethal to the cell. Traditionally, external beam radiotherapy is delivered in multiple daily fractions over several weeks, in order to spare normal tissue, which has a greater capacity than tumor tissue to repair sublethal damage and to repopulate between fractions. Recent advances in the technology of diagnostic imaging and computerized treatment planning systems have allowed greater accuracy of radiotherapy delivery. The brain lends itself to high precision techniques due to the lack of internal motion within the skull and the ease of immobilization of the skull itself. Conformal radiotherapy allows the profile of the radiation beam to be shaped around the tumor (to conform to the tumor edges), and this reduces both the short- and long-term toxicity of the treatment. Highly focused radiation can be given either in a single high dose (stereotactic radiosurgery) or in smaller fractions (stereotactic radiotherapy) and is predominantly indicated for lesions less than 3 cm in diameter that are well circumscribed, extra-axial, and more than 5 mm from vital structures. This has led to more widespread use of stereotactic radiotherapy in the treatment of benign extra-axial tumors such as vestibular schwannomas, skull-based meningiomas, and small intrinsic tumors in eloquent locations. However, this approach is not appropriate for infiltrative tumors such as gliomas. The main side effects of radiotherapy include hair loss, which is usually permanent and tiredness, particularly toward the end of a long course of treatment. Early delayed radiation toxicity is characterized by severe lethargy and occasionally worsening of a preexisting neurological deficit, giving rise to concerns about the possibility of tumor recurrence. This usually responds to steroids. In contrast, late delayed radiation toxicity is irreversible and includes vasculopathy, dementia, brain necrosis, and secondary tumors.

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Neuro-Oncology Macroscopic pathology

Histology

Meningioma

Medulloblastoma

Oligodendroglioma

Glioblastoma

Low-grade astrocytoma

Imaging

Chemotherapy Chemotherapy has traditionally been the “poor relative” of brain tumor treatments, but over the past decade the role of chemotherapy has expanded and many options are now available to treat a wide variety of tumors. Tumors that had been previously regarded as chemoresistant are now being treated with new chemotherapy schedules and used in combination with other therapeutic modalities, particularly radiotherapy. There are a number of specific difficulties in evaluating new drugs for central nervous system tumors, specifically the determination of treatment response by magnetic resonance

imaging alone, particularly when patients have been heavily pretreated, and the problems of drug delivery into tumors that may be shielded from the systemic circulation by the bloodbrain barrier. Chemotherapy is usually administered as multimodality therapy, concurrently with radiotherapy, either as single agents or as combinations of drugs. Combining agents with different mechanisms of action and different toxicities has been found to be effective for many different tumor types. Cytotoxic chemotherapy impairs DNA synthesis and, as tumor cells divide more rapidly than most normal cells, achieve an acceptable therapeutic index.

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Figure 98–3. Radiological and pathological correlations of common central nervous system tumors. Each row of figures shows imaging appearances (magnetic resonance imaging or computed tomography) (left), macroscopic aspect on formalin fixed postmortem brains with a tumor at similar locations (center), and representative histological sections (right), stained with hematoxylin and eosin, which stains nuclei dark blue and cytoplasm and extracellular matrix pink. Low-grade astrocytoma: Magnetic resonance imaging (T1-weighted with contrast) shows involvement of the temporal and frontal lobes and considerable mass effect with midline shift. Gross section of a brain with a similar tumor shows effacement of cortical structures, basal ganglia, and midline shift. Histology shows a tumor with low density of tumor cells, ample fibrillary background, and thin vessels. Glioblastoma multiforme: magnetic resonance imaging (T1-weighted with contrast) shows ring enhancement indicating neovascularization and vascular permeability as well as central necrosis. The brain section shows a hemorrhagic tumor in the left temporal and frontal lobes. There is considerable midline shift and hemorrhage in the corpus callosum and fornix, indicating tumor extension over the midline. Histologically, the tumor is characterized by a very high density of cells (dark nuclei with sparse cytoplasm), and a typical feature is necrosis with pseudopallsading arrangement of tumor cells. Oligodendroglioma: magnetic resonance imaging (coronal FLAIR sequence) shows involvement of parietal cortex and subcortical white matter with expansion of the tumor outside of the brain and erosion of the inner skull table. A brain section of a similar tumor shows a relatively well-demarcated cystic, partially hemorrhagic space occupying lesion. Classic histological features of oligodendroglioma are cells with clear appearance (“fried-egg” cells), central nuclei, and a network of thin, branching vessels (not shown). Medulloblastoma: computed tomography scan with contrast shows an enhancing midline mass lesion arising from the cerebellar hemisphere. Note the hydrocephalus as a result from compression of the fourth ventricle. A sagittal section shows a large tumor in the posterior fossa that displaces the cerebellar vermis and compresses the brainstem. Typical histological features are wedge-shaped nuclei that are arranged to rosettes with neuropil-like matrix in their center. Meningioma: computed tomography scan with contrast shows a typical strongly enhancing tumor that is dural based. Meningiomas are often associated with considerable edema, and in this case, there is very significant displacement of brain tissue, which becomes symptomatic relatively late, due to the slow growth of these tumors. Postmortem finding of an asymptomatic meningioma impressing the temporal lobe in situ (upper section) and after (lower section) removal, leaving a cavity. Histologically, meningiomas show variable features. A typical feature shown here is the concentric arrangement of tumor cells, which can become calcified. (Courtesy of Professor Sebastian Brandner.)

Chemotherapy may be delivered before surgery or radiotherapy, known as neoadjuvant treatment, simultaneously with radiotherapy, known as concomitant treatment, or after surgery or radiotherapy, known as adjuvant treatment. It may given as part of the primary treatment or at progression, particularly for malignant gliomas. The main cytotoxic agents used in the treatment of brain tumors are temozolomide, procarbazine, lomustine (CCNU), carmustine (BCNU), vincristine, carboplatin, and cisplatin. Temozolomide, procarbazine, and lomustine are alkylating agents causing alkyl groups to bind to DNA, producing DNA cross-links or single- or double-strand breaks. In contrast, vincristine is a microtubule poison and disrupts the mitotic machinery, particularly in the G1 phase. Temozolomide is increasingly being used for brain tumor treatment. It is an imidazotetrazine derivative of dacarbazine with good oral bioavailablity and is rapidly metabolized to an active derivative. It works by methylating the O6 position on guanidine and depletes the drug resistance enzyme methylyguanine methyltransferase (MGMT) enzyme. It is relatively well tolerated and so has become the chemotherapeutic agent of choice for many patients with gliomas, although it has yet to be compared head-to-head with the conventional combination regimen of procarbazine, CCNU, and vincristine (PCV). There is extensive research interest in novel compounds known as small molecules that block signaling pathways mediated by various growth factors. In some cases, they produce tumor shrinkage when used as monotherapy, although in the majority of instances they are cytostatic rather than cytotoxic. Examples of compounds under investigation include EGFR antagonists such as OSI-7740–erlotinib and PDGFR antagonists such as STI-571. It is likely that these will find a place in the chemotherapy armamentarium in association with either radiotherapy or with more conventional cytotoxic drugs.

The main dose-limiting effects of chemotherapy are bone marrow suppression, which may be cumulative or noncumulative. This can be managed by either increasing the interval between cycles until bone marrow recovery has occurred or reducing the dosage in subsequent cycles. Other effects specific to brain tumor chemotherapy include constipation and headache (temozolomide), rash and jaundice (procarbazine), neuropathy (vincristine, cisplatin), and nephropathy (cisplatin, methotrexate). Most chemotherapy-induced toxicity is reversible on cessation of the drug. In order to avoid systemic administration and hence toxicity altogether, various new methods of drug delivery are under investigation. In particular, the implantation of drug directly into the tumor resection cavity using biodegradable wafers containing carmustine (Gliadel) has now been shown in phase 3 trials to prolong survival in malignant gliomas. Convectionenhanced delivery uses catheters placed into the brain parenchyma around the resection cavity to deliver intratumoral chemotherapy by infusion over several days. The use of convection rather than diffusion alone results in larger volumes of distribution, an important consideration when treating gliomas which are known to grow for many centimeters around the tumor cavity.

SUPPORTIVE TREATMENT Steroids are used extensively in neuro-oncology to reduce peritumoral edema, to improve symptoms and quality of life, and to reduce the morbidity of brain tumor surgery. Dexamethasone is the most frequently used steroid and is 10 times more potent than prednisolone. The main side effects include weight gain, fluid retention, impaired glucose tolerance, skin changes, proximal myopathy, and increased susceptibility to infections.

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Figure 98–4. The effects of corticosteroids used in neuro-oncology. Patient with glioblastoma multiforme who required high doses of steroids showing dramatic effects on facial appearance and body habitus. Note radiotherapy-induced alopecia.

Not uncommonly, the patient becomes cushingoid leading to dramatic changes in body habitus and facial appearance (Fig. 98–4). As with all steroids, the aim is to use the lowest dose possible that controls symptoms. Steroids have a lympholytic effect and are therefore cytotoxic to primary central nervous system lymphomas. If there is a clinical suspicion of lymphoma based on the results of a scan, then steroids should be avoided prior to biopsy as they may cause temporary disappearance of the tumor. Patients with brain tumors are prone to seizures and are frequently treated with anticonvulsants. The management of tumor-associated epilepsy is beyond the scope of this chapter but, as a general rule, the principles are similar to those for the treatment of patients with epilepsy patients, although seizures are more likely to be resistant to monotherapy with antiepileptic drugs. Specific prescribing considerations for these patients include interaction with anticancer drugs and steroids and the greater potential for cognitive impairment due to the underlying tumor. For this reason, many neuro-oncologists are using non–enzyme-inducing antiepileptic drugs in preference, such as lamotrigine and levetiracetam.

INTRA-AXIAL TUMORS Gliomas Gliomas are, by and large, incurable, with median survival ranging from 5 to 15 years for low-grade gliomas to less than 1 year for grade IV tumors. Treatment decisions have to be made taking into consideration quality of life issues, specifically

weighing potential benefits of prolongation of life against treatment-associated morbidity.

Low-Grade Gliomas The management of low-grade gliomas is one of the most controversial issues in neuro-oncology. These are typically diffusely infiltrating tumors, often invading but not destroying eloquent regions of the brain, and cannot be removed completely in the majority of cases by surgical resection alone. Although some patients may survive for decades, the majority of these tumors eventually become high-grade gliomas and these are usually fatal. There are a large number of surgical series advocating the benefits of complete resection over partial resection but these are all retrospective and include patients with a variety of tumor histologies, specifically pilocytic and non-pilocytic astrocytomas. They are by definition subject to selection bias, and therefore reports of better outcomes for patients with larger resections need to be interpreted in light of the known prognostic factors which include tumor size.12 Despite these reservations, surgery is the only certain way of removing a large volume of tumor tissue and is widely used in young, fit patients with tumors in noneloquent regions (e.g., nondominant frontal or temporal lobes). Some surgeons will resect tumors in dominant frontal temporal lobes, using the techniques of awake craniotomy to monitor language perioperatively, but there are no comparative data published comparing this approach with a more conservative policy. This lack of clear benefit is supported in part by a population-based study of nearly 1000 patients with low-grade glioma that showed a relatively small and nonsignif-

chapter 98 t u m o r s o f t h e b r a i n icant difference in overall survival between patients who had had a biopsy only (6.4 years), a subtotal tumor resection (6.8 years), or a gross-total tumor resection (7.6 years).13 The benefit of early radiation in low-grade gliomas is similarly unclear. The European Organisation for Research and Treatment of Cancer (EORTC) reported interim results from a trial comparing early radiotherapy (at diagnosis) with radiotherapy at progression. This was a prospective trial and followed patients for a median of 5 years. Patients who had early radiotherapy showed a significant improvement in time to progression compared with patients irradiated at tumor progression but there was no difference in overall survival. The 5-year estimate was 63% versus 66% (overall survival) and 44% versus 37% (time to progression) for the treated and control arms respectively.14 On the basis of these data, the majority of oncologists irradiate patients with low-grade glioma only at progression or rarely for control of intractable seizures. The standard dosage schedule is 54 Gy in 33 fractions over 6.5 weeks. Chemotherapy is being increasingly used for low-grade gliomas, particularly those with oligodendroglial elements. There are strong indications that a significant percentage of low-grade oligodendrogliomas respond favorably to PCV chemotherapy with improvements in seizure control and cognitive function more readily apparent than shrinkage of the tumors in magnetic resonance images.15 Temozolomide has also been found to be useful in oligodendrogliomas both as primary treatment and in recurrent disease after radiotherapy, particularly in those tumors with loss of chromosome 1p and 19q. Because of the relatively indolent growth of these tumors, combined with their comparatively long survivals and treatment associated morbidity, low-grade gliomas are often managed conservatively with symptomatic treatment (antiepileptic drugs) alone. Regular surveillance imaging is used to detect early signs of tumor progression, such as the development of new areas of gadolinium enhancement, which frequently predates clinical deterioration. Patients need to be carefully informed of the pros and cons of active treatment versus no treatment at all. Ultimately, this is a highly individualized decision process that depends on the age of the patient, the tumor type and location, and the philosophy of the treating clinicians. As a result, there is a wide discrepancy in the way that patients with low-grade gliomas are managed from center to center, giving rise to considerable uncertainty over the most appropriate form of intervention for that individual patient. At our center, we are in the process of developing magnetic resonance imaging parameters as surrogate markers for biological behavior in order to determine whether it is possible to select patients at high risk of tumor progression while the tumor is still in the “premalignant” phase of its natural history.

Malignant Gliomas In contrast to the situation with low-grade gliomas, the general principles of management of malignant gliomas are much more clear-cut. These are fast growing aggressive tumors, which, untreated, are associated with a median survival of 3 to 4 months. Initial management consists of dexamethasone to reduce vasogenic edema and to prepare the patient for surgery

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(biopsy or resection). Once surgery has been performed, the dose of dexamethasone should be rapidly reduced to the lowest dose possible to minimize the side effects of prolonged highdose steroids. Phenytoin is often given prophylactically around the time of surgery and should be weaned 1 week after operation in patients who have not had seizures. Surgery is the primary treatment modality for tumors where resection is believed to be technically feasible and in the best interest of the patient. Resection has the advantage over biopsy of providing more tissue for diagnosis as well as reduction of tumor bulk and possible prolongation of time to tumor progression. It also allows the surgeon to implant interstitial chemotherapy in the form of carmustine wafers and therefore start adjuvant tumor treatment immediately and hence slow down the inevitable regrowth, prior to radiotherapy. Despite these advantages, there is still wide variation in surgical practice with “aggressive” surgeons arguing the case for gross total resections as a means of achieving significant tumor “cytoreduction,” thereby improving the chances of successful treatment with adjuvant radiotherapy and chemotherapy and reducing the need for steroids. More conservative surgeons will often only perform a biopsy on a high-grade tumor, particularly tumors that are in the dominant hemisphere or deeply seated, arguing that there is limited evidence for the survival benefits of radical surgery in the absence of prospective randomized trials. A trial comparing resection with biopsy alone for patients in whom the surgeon is uncertain about the benefits of one over the other is unlikely ever to be carried out because of the perceived ethical problems and difficulties recruiting patients to a nontreatment arm. Relative contraindications to surgery include poor performance status, significant medical comorbidity, and tumors in eloquent or inaccessible locations. For these patients, the risks of surgery may be outweighed by the potential benefits. The overall morbidity rate for untreated malignant gliomas is 24% with a mortality rate of 1.5%. The chances of neurological improvement with surgery are just over 20% with less than 10% of patients deteriorating.16 In contrast, there is unanimity of opinion about the benefits of radiotherapy for malignant gliomas as it is the only treatment that has been proved to extend survival in this patient group. Radiotherapy is indicated for the treatment of grades III and IV astrocytomas and oligodendrogliomas, and treatment with radical intent is given to patients under the age of 70 years who have a good performance status, that is, a Karnofsky performance scale of at least 70, implying the ability to self-care. The radiation field encompasses the contrast-enhanced T1-weighted target with a margin of between 2 and 3 cm to sterilize “satellite” tumor cells. The total dose is usually 60 Gy, delivered over 6 weeks in 30 fractions. In a landmark study, the median survival of patients with malignant gliomas increased from 14 weeks with supportive treatment alone to 36 weeks with radical radiotherapy.17 Lower-dose schedules, such as 30 Gy in 10 fractions, are used mainly in the palliative setting, particularly for patients over the age of 70 in poor general condition.

Chemotherapy Chemotherapy for malignant gliomas has traditionally been used as adjuvant treatment following radiotherapy (mainly in the United States) or at recurrence. The common drugs used are nitrosoureas such as BCNU (as adjuvant treatment) and

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PCV or temozolomide at recurrence. There is no clear benefit for the use of adjuvant chemotherapy over radiotherapy alone, although a meta-analysis based on 12 randomized trials suggested a small benefit of chemotherapy compared with radiotherapy alone (a 5% increase in 2-year survival).18 A trial is under way comparing PCV with temozolomide in recurrent disease, and the results will not be available until 2008. A trial has shown that the use of concomitant temozolomide with radical radiotherapy followed by six cycles of adjuvant temozolomide in patients with glioblastoma multiforme offered a significant survival advantage over radiotherapy alone with minimal additional toxicity. Although the increase in median survival from 12.1 months with radiotherapy alone to 14.6 months in the concomitant temozolomide group was relatively modest, the 2-year survival rate increased from 10.4% to 26.5%.19 These results represent a significant improvement in the outlook of patients with glioblastoma multiforme, although it remains to be seen whether these data can be extrapolated to patients with anaplastic astrocytomas. Further trials to confirm these findings are unlikely to occur given that the sample size was large (573 patients from 85 centers), that prognostic factors were well matched between the two groups, and that 85% of patients in the concomitant arm completed both radiotherapy and temozolomide as planned. Furthermore, an exploratory subgroup analysis defined according to known prognostic factors demonstrated a survival benefit in nearly all subgroups. However, in a parallel study on the same patient group investigating the role of genetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation, there was a striking survival benefit in those patients who received temozolomide and whose tumors contained a methylated MGMT promoter compared with those who did not have a methylated MGMT promoter.20 Chemotherapy is being increasingly used for patients with anaplastic oligodendrogliomas following a landmark study from the National Cancer Institute of Canada study reporting a 75% response rate in patients with anaplastic oligodendrogliomas treated with PCV.11 Subsequently, temozolomide (TMZ) has also been found to have activity with high response rates and durable responses. Because of the increasing interest in chemotherapy for anaplastic oligodendrogliomas, trials are being carried out investigating the role of neoadjuvant and adjuvant chemotherapy. Rather surprisingly, a randomized controlled clinical trial of neoadjuvant intensive PCV chemotherapy followed by radiotherapy versus radiotherapy alone in patients with pure and mixed anaplastic oligodendrogliomas showed no benefit in terms of overall survival between the two groups. Although there was a slight prolongation of progression-free survival in the combined treatment group, this was at the expense of considerable acute toxicity in the PCV group. As predicted, patients with 1p and 19q loss lived longer than other patients irrespective of treatment.21 An abstract, just presented at the time of writing, has also failed to demonstrate a survival benefit for PCV therapy when used as adjuvant treatment to radiotherapy in patients with anaplastic oligodendrogliomas.

PROGNOSIS Neither earlier diagnosis of tumors nor advances in treatment over the last decade have significantly changed the overall prog-

nosis of primary brain tumors. The median survival of glioblastoma multiforme without treatment is 3 months, and with radiotherapy treatment, 9 months. Anaplastic astrocytomas are associated with a median survival of 18 months. Young age and good performance status are the most important prognostic factors. The outlook for patients with low-grade gliomas is considerably better with a median survival of 5 to 10 years depending on age, performance status, and histology. Oligodendrogliomas are more chemosensitive than astrocytomas, have a more indolent course, and so their prognosis is correspondingly better with patients surviving 10 to 15 years after diagnosis. As discussed, loss of chromosomes 1p/19q is an independent good prognostic factor in both newly diagnosed and recurrent oligodendrogliomal tumors. Similarly, hypermethylation of the MGMT promoter sequence seems to be a good prognostic factor for glioblastoma.

Primary Central Nervous System Lymphomas Primary central nervous system lymphomas are rarer tumors than gliomas, accounting for 4% of primary brain tumors in a recent survey. Their incidence has increased significantly over the last two decades since the advent of acquired immunodeficiency syndrome, but they are also becoming more common in immunocompetent patients, particularly in the sixth and seventh decades. Over 50% of cases occur in the cerebral hemispheres, and one third have multifocal disease. The tumor presents frequently with behavioral cognitive and focal neurological dysfunction, particularly visual field defects, reflecting a predilection for the peritrigonal area interrupting the posterior visual pathways. On magnetic resonance imaging, these tumors are typically periventricular with a diffuse and homogeneous pattern of enhancement and, unlike malignant gliomas, rarely show central necrosis. Almost all primary central nervous system lymphomas are high-grade B-cell lymphomas, predominantly of the diffuse large-cell subtype. Cerebrospinal fluid spread occurs in about 25% of patients and ocular spread in 20% so all patients should be screened with a slitlamp and cerebrospinal fluid examination prior to treatment. Human immunodeficiency virus testing should be a routine part of the screening work-up. Systemic staging with computed tomography scanning of the chest, thorax, pelvis, and bone marrow biopsy is of little use, as less than 4% of patients with primary central nervous system lymphomas have extracerebral disease. There is no benefit for surgical resection, and so where there is a high clinical and radiological index of suspicion, a stereotactic biopsy should be undertaken, preferably without steroid cover. There is some debate over the relative benefits of chemotherapy (based around high-dose systemic methotrexate), radiotherapy, and the two treatments combined. Standard combination chemotherapy for systemic lymphoma (e.g., CHOP) is ineffective in primary central nervous system lymphoma. Chemotherapy is associated with a complete response rate of between 50% and 80%, whereas radiotherapy alone is associated with a median survival of 12 to 18 months. The combination of the two increases median survival to 40 months, but there is a high risk of delayed neurotoxicity, particularly in older patients manifesting as a severe and rapidly progressive dementia.

chapter 98 t u m o r s o f t h e b r a i n Pineal Tumors These are rare but very interesting tumors and usually present in adolescents and young adults with hydrocephalus and Parinaud’s syndrome (upgaze palsy, convergence retraction nystagmus, light-near dissociation). Most tumors of the pineal region are either germinomas or pineal cell tumors. Diagnosis can sometimes be achieved non-invasively by tumor markers in blood and cerebrospinal fluid, obtained at shunting for hydrocephalus. The presence of tumor markers (α-fetoprotein, β-human chorionic gonadotrophin, and placental alkaline phosphatase) is indicative of a germ cell tumor that may be germinomatous or nongerminomatous. Pure germinomas can be cured by radiotherapy alone, which can be delivered to the pineal region and ventricular system unless there is evidence on cytology or imaging of cerebrospinal fluid spread, in which case the whole neuraxis should be irradiated. Nongerminomatous tumors are treated surgically followed by radiotherapy, and chemotherapy is used increasingly prior to irradiation for patients with malignant germ cell tumors.

Brain Metastases These are very common tumors; 10% to 15% of all patients with cancer develop brain metastases during the course of their disease. Most metastases arise from cancers of the lung, breast, kidney, or melanomas, and the majority will be multiple. Diagnosis is established by enhanced computed tomography or magnetic resonance imaging, the latter being mandatory for all patients with a solitary metastasis on computed tomography scanning, to determine whether there are other multiple tumors that are not seen on computed tomography. Initial management includes corticosteroids to reduce peritumoral edema and assessment of underlying tumor control. Metastases cause significant disruption of the blood-brain barrier and are often surrounded by considerable edema, frequently out of proportion to the size of the tumor. In patients with no known cancer, further investigations should be carried out to determine the site of a possible primary and should include chest x-ray, computed tomography scan of the thorax, abdomen, and pelvis, and mammography or, in certain centers, whole body positron emission tomography scanning that highlights areas of increased metabolic activity. If all these investigations are negative, biopsy of the brain lesion is necessary to rule out other potentially treatable causes. Subsequent treatment depends on the age and condition of the patient, the stage of the underlying tumor, and the number and location of metastases. Whole brain radiotherapy, at a dose of 30 Gy in 10 fractions, is used to treat patients with multiple metastases, although the benefit in terms of survival and quality of life compared with best supportive care has never been compared in a randomized controlled trial. These patients generally have a poor prognosis of between 3 and 7 months’ life expectancy depending on age, performance status, and presence of other metastatic disease. Patients who present with solitary metastases and controlled or overt systemic disease should be considered for either surgical resection or stereotactic radiotherapy/radiosurgery. Two of three trials have shown that surgery followed by radiotherapy is associated with a superior local control rate and a significant improvement in overall median survival compared with radiotherapy alone. For patients with tumors in eloquent

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locations, stereotactic radiosurgery is an alternative to surgery provided that the tumor is less than 3.5 cm in diameter. This technique delivers highly focused radiation to the tumor. The efficacy is similar to surgery in uncontrolled studies but no head-to-head studies have been carried out. Side effects include headache, seizures, and radiation necrosis. The role of whole brain radiotherapy following radiosurgery or complete resection of solitary metastases is unclear and is being investigated in a randomized controlled study. The definition of “multiple” varies from center to center. Some oncologists advocate stereotactic radiosurgery for as many as seven tumors—most will treat a maximum of three. In patients with multiple metastases who are relatively asymptomatic and who are about to undergo chemotherapy for their primary disease, it may be reasonable to defer whole brain radiotherapy and assess response after chemotherapy.

Medulloblastomas These tumors are the most common malignant central nervous system tumor in childhood presenting with gait ataxia and raised intracranial pressure. They are uncommon in adults accounting for less than 1% of all brain tumors, and therefore no adult-specific protocols have been formally tested in clinical trials. As with children, the primary treatment is maximal surgical resection followed by craniospinal irradiation. The usefulness of chemotherapy has not been established in adults. The 5-year progression-free survival rate is approximately 60%.

Extra-axial Tumors Meningiomas These are the second most common intracranial tumors, accounting for 15% to 20% of all primary brain tumors. They are more frequent in women, and some are hormonally sensitive, presenting in pregnancy. Risk factors include neurofibromatosis types I and II and prior cranial irradiation, particularly for childhood leukemia or brain tumors. They arise from the meningeal lining of the cerebral hemispheres (convexity meningiomas), the falx cerebri (parafalcine), the roof of the anterior cranial fossa (orbital prefrontal meningiomas), the sphenoid wing (sphenoid ridge meningiomas), the base of the skull, the cerebellopontine angle, and the foramen magnum. Rarely, they may grow out of the optic nerve sheath. They can also present in the spine, almost always in women. Increasingly they are picked up as an incidental finding discovered after a scan for an unrelated problem. The diagnosis is established by computed tomography scanning/magnetic resonance imaging that shows an extra-axial homogeneously enhancing tumor, often with a dural tail. There may be a central area of necrosis, which does not necessarily imply a worse prognosis. Brain invasion and perifocal edema are often seen in more aggressive tumors. The majority of tumors are histologically benign (90% are WHO grade I, 8% are WHO grade II [atypical], and 2% are WHO grade III [malignant or anaplastic]). Surgery is the only curative treatment, but for tumors around the base of the skull and foramen magnum, a policy of watch and wait or stereotactic radiotherapy may be more appropriate. The recurrence rate depends on the extent of tumor resection and the histological grade. In order to achieve complete excision, the whole tumor and associated dura must be

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exposed and removed or coagulated. Even for seemingly completely excised tumors, the recurrence rate is 3% at 5 years and 10% at 10 years. Tumors with atypical or malignant histology are associated with 5-year recurrence rates of 40% and 80%, respectively. For this reason, all malignant meningiomas should have adjuvant radiotherapy. For atypical meningiomas, the decision to irradiate postoperatively will depend on the completeness of resection, the accessibility of the tumor, and the age of the patient. Fractionated radiotherapy at doses of around 54 Gy offers control rates between 80% and 95%. Stereotactic radiotherapy can be given to small tumors where the meningioma is in an inaccessible location, such as the skull base, and close to vital structures, such as the optic nerve. Radiosurgery with doses of approximately 15 Gy is probably equally effective for tumors less than 3 cm in diameter. Stereotactic radiotherapy is now the treatment of choice for optic nerve sheath meningiomas. For recurrent tumors, a second resection followed by external beam radiotherapy is usually offered to delay the inevitable regrowth of the tumor. Some tumors continue to recur despite radiotherapy, and in these patients, chemotherapy with hydroxyurea or hormonal treatment with antiprogestogens is sometimes offered. The response rate, however, is generally poor. Malignant meningiomas have been treated with adjuvant combination therapy using cyclosphosphamide, adriamycin, and vincristine with limited success.

Acoustic Neuromas (Vestibular Schwannomas) These account for approximately 8% of primary tumors and usually arise from the superior part of the vestibulocochlear nerve. Bilateral tumors are the hallmark of neurofibromatosis type 2. They present with vertigo, dizziness, tinnitus, and progressive unilateral hearing loss. Progressive tumor growth is associated with facial sensory disturbance, facial twitching, facial palsy, cerebellar ataxia, and, finally, bulbar palsy due to brainstem compression. Treatment options include observation alone, particularly in elderly patients with small tumors, microneurosurgery, and stereotactic radiotherapy or radiosurgery. The latter is limited to small tumors (up to 2 to 3 cm in diameter) and leads to tumor reduction in up to 80% of patients, with a low facial nerve morbidity and preservation of hearing of greater than 50%. This is becoming the treatment of choice now for small tumors, particularly as the detection rate is increasing with improved access to magnetic resonance imaging for patients with unilateral hearing loss. Surgical resection is the only option for medium-size and large tumors.

CONCLUSIONS Brain tumors are a heterogeneous group of neoplasms with different biologies, clinical features, and management considerations. The outlook for most brain tumor patients is poor, and new therapies are desperately required. However, with the advent of improved neurosurgical and radiotherapeutic techniques, together with a growing understanding of the molecular events that underlie proliferation and invasion of tumor cells, new approaches to the treatment of these refractory tumors are opening up. Future strategies are likely to consist of a combination of treatment modalities and agents acting synergistically at different intracellular loci to stop tumor growth. Future basic research aims to exploit the specific genetic alter-

ations in a cancer cell by means of highly specific, effective, and nontoxic therapy. This Holy Grail has not been achieved in neuro-oncology, but the future is looking more hopeful now than it did even 5 years earlier.

ACKNOWLEDGMENTS The author would like to acknowledge the contribution of Professor Sebastian Brandner for Figures 98–2 and 98–3 and for the constructive suggestions about the pathology and genetics of brain tumors.

K E Y

P O I N T S

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Intracranial tumors are rare and account for 2% of all cancer deaths in adults. They are more common than previously believed and are increasing in incidence.

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Most tumors occur sporadically, but a minority are associated with neurocutaneous syndromes, particularly neurofibromatosis types 1 and 2, prior cranial irradiation, and other rare familial cancer syndromes.

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Molecular genetics are becoming increasingly relevant clinically, particularly the association between chromosomal loss of 1p/19q and the prognosis of oligodendrogliomas.

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Appropriate management is dictated by patient factors (age and performance status) and tumor histology.

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Surgical resection is indicated for tissue diagnosis, the relief of raised intracranial pressure, and prolongation of survival, although the latter is controversial. Extra-axial tumors are more likely to be cured than are intra-axial tumors.

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The role of surgery in the improvement of overall survival in the management of gliomas has not been conclusively established and therefore remains one of many practice options.

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The combination of various treatment modalities, specifically chemotherapy with radiotherapy, has resulted in a significant improvement in survival of patients with glioblastoma, although it remains to be seen whether this applies to other types of malignant glioma.

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It is appropriate to manage low-grade gliomas with a watchand-wait policy and intervene only if there is clinical and/or radiological evidence of progression. Gross total resection is indicated for pediatric low-grade gliomas.

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Advances in radiotherapy techniques have enabled higher doses to be delivered with increasing accuracy, resulting in reduced treatment-related toxicity to surrounding healthy tissue.

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Stereotactic radiosurgery is becoming widely accepted as an alternative to surgical resection for small extra-axial tumors (e.g., acoustic neuromas, optic nerve sheath meningiomas) and solitary or a limited number of (fewer than three) metastases.

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Surgical resection for solitary metastases offers improved local control and survival rates when used in conjunction with radiotherapy compared with radiotherapy alone.

chapter 98 t u m o r s o f t h e b r a i n Suggested Reading Grant R: Overview: brain tumor diagnosis and management/Royal College of Physicians guidelines. J Neurol Neurosurg Psychiatry 2004; 75(Suppl II):ii37-ii42. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352:997-1003. Ries LAG, Eisner MP, Kosary CL, et al, eds: SEER cancer statistics review 1975-2001. Bethesda: National Cancer Institute, 2004. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987-996.

References 1. Pobereskin LH, Chadduck JB: Incidence of brain tumors in two English counties: a population based study. J Neurol Neurosurg Psychiatry 2000; 69:464-471. 2. Ries LAG, Eisner MP, Kosary CL et al, eds: SEER cancer statistics review 1975-2001. Bethesda: National Cancer Institute, 2004. 3. Werner MH, Phuphanich S, Lyman GH: The increasing incidence of malignant gliomas and primary central nervous system lymphomas in the elderly. Cancer 1995; 76:1634-1642. 4. Ron E, Modan B, Boice J, et al: Tumors of the brain and nervous system following radiotherapy in childhood. N Engl J Med 1988; 319:1033-1039. 5. Inskip PD, Tarone RE, Hatch EE, et al: Cellular-telephone use and brain tumors. N Engl J Med 2001; 344:79-86. 6. Grant R: Overview: brain tumor diagnosis and management/Royal College of Physicians guidelines. J Neurol Neurosurg Psychiatry 2004; 75(Suppl II):ii37-ii42. 7. Forsyth PA, Posner JB: Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993; 43 16781683. 8. van Veelen MLC, Avezaat CJJ, Kros JM, et al: Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery. J Neurol Neurosurg Psychiatry 1998; 64:581-587. 9. Rees JH: Advances in MR imaging of brain tumors. Curr Opinion Neurol 2003; 16:643-650. 10. Kleihues P, Cavenee WK, eds: Pathology and genetics of tumors of the nervous system. In World Health Organisation Classification of Tumors. Lyon, France: IARC Press, 2000.

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11. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90:1473-1479. 12. Keles GE, Lamborn KR, Berger MS: Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurg 2001; 95:735745. 13. Johannesen TB, Langmark F, Lote K: Progress in long-term survival in adult patients with supratentorial low-grade gliomas: a population-based study of 993 patients in whom tumors were diagnosed between 1970 and 1993. J Neurosurg 2003; 99:854-862. 14. Karim ABMF, Afra D, Cornu P, et al: Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medial Research Council BR04: an interim analysis. Int J Radiat Oncol Biol Phys 2002; 52:316324. 15. Streffer J, Schabet M, Bamberg M, et al: A role for preirradiation PCV chemotherapy for oligodendroglial brain tumors. J Neurol 2000; 247:297-302. 16. Chang SM, Parney IF, McDermott M, et al: Perioperative complications and neurological outcomes of first and second craniotomies among patients enrolled in the Glioma Outcome Project. J Neurosurg 2003; 98:1175-1181. 17. Walker MD, Alexander E Jr, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a co-operative clinical trial. J Neurosurg 1978; 49:333-343. 18. Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002; 359:10111018. 19. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987-996. 20. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352:997-1003. 21. Cairncross G, Seiferheld W, Shaw E, et al: An Intergroup randomized controlled clinical trial of chemotherapy plus radiation (RT) versus RT alone for pure and mixed anaplastic oligodendrogliomas: Initial report of RTOG 94-02 [abstract]. Presented at the 2004 ASCO annual meeting, New Orleans, La.

CHAPTER

TUMORS

OF THE ●

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SPINAL CORD ●

April L. Fitzsimmons and Patrick Y. Wen

Tumors of the spinal cord are a rare but distinct group of central nervous system neoplasms that affect all ages. Often slow growing, they should be considered in any patient who presents with neck or back pain, radiculopathy, or myelopathy. Classification is based on location and cell of origin: Intramedullary tumors most often arise from glial cells; intradural extramedullary tumors may arise from Schwann cells of the nerve roots or meningeal cells covering the spinal cord; and extradural tumors commonly arise from the bony elements of the vertebral column. Magnetic resonance imaging (MRI) plays a central role in anatomical localization and diagnosis. Since the first resection of a spinal cord tumor by Victor Horsley in 1887, advances in microsurgical techniques have allowed physicians to more accurately diagnose and treat spinal cord tumors. However, much remains to be learned about optimal management for this rare but challenging group of neoplasms.

EPIDEMIOLOGY Spinal cord tumors are rare, accounting for only 4% to 10% of all primary central nervous system tumors. According to several population-based studies, their annual incidence is estimated to be 0.5 to 1.4 per 100,000.1,2 Spinal cord tumors are classified into three groups according to anatomical location: extradural, intradural extramedullary, and intramedullary (Fig. 99–1). Extradural tumors are the most common cause of spinal cord tumors and usually arise from elements of the vertebral column or from metastatic disease. Primary vertebral column tumors include chordoma, multiple myeloma, osteosarcoma, chondrosarcoma, and Ewing’s sarcoma. Breast, lung, and prostate cancers are the most common sources of metastatic extradural tumors. Intradural extramedullary tumors represent more than half of the nonextradural spinal cord tumors in adults. Approximately 80% of these tumors are either nerve sheath tumors (neurofibromas and schwannomas) or meningiomas; epidermoids, dermoids, teratomas, and metastases make up much of the remaining fraction (Table 99–1). Nerve sheath tumors most commonly manifest in the fourth decade and are evenly distributed among men and women. Multiple intraspinal neurofibromas are often found in patients with neurofibromatosis type

1. Malignant degeneration of a neurofibroma into a malignant peripheral nerve sheath tumor is a rare but highly lethal complication in patients with neurofibromatosis type 1. Spinal meningiomas most often manifest in the fifth to seventh decades and exhibit a striking female predilection (4 : 1). In women, 80% occur in the thoracic spine. This regional predominance does not hold true in men, in whom meningiomas are found throughout the cervical, thoracic, and, less commonly, lumbosacral cord. Ionizing radiation and trauma are known risk factors for the development of spinal meningiomas.3 Intramedullary tumors account for less than one third of all spinal tumors in adults, whereas the majority of spinal tumors in children are intramedullary.4 Glial tumors (ependymomas and astrocytomas) predominate in all age groups. Ependymomas are increasingly more common with age, reaching a peak incidence in the fourth decade. They occur more frequently in men than in women. The remainder of the category is composed of rare tumors such as hemangioblastoma, neurocytoma, ganglioglioma, lipoma, primitive neuroectodermal tumor, lymphoma, and metastatic disease. Hemangioblastomas also exhibit a male preponderance and may occur sporadically or in association with von Hippel–Lindau disease. Gangliogliomas, although rare in adults, have been recognized as among the most common intramedullary tumors in children.5

CLINICAL MANIFESTATIONS The clinical manifestations of intrinsic spinal cord tumors are similar across a variety of histopathological subtypes. Tumors tend to be indolent, with symptoms often present for 6 months to several years before diagnosis. Extradural metastases producing cord compression tend to have a more rapid course. The most common symptoms include pain, weakness, sensory disturbances, gait change, bowel and bladder dysfunction, and sexual dysfunction. Signs of cord compression or hydrocephalus may also be present at diagnosis. Pain from spinal cord tumors manifests in several different forms. Most commonly, patients experience midline or axial spinal pain. It is often worse at night and increased with recumbency, coughing, sneezing, straining, or other maneuvers that increase intrathoracic or intra-abdominal pressure. Paraspinal pain and tenderness may also be present as a result of local muscle spasm. Pain and dysesthesias that follow a radicular

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Extradural

A

Intradural extramedullary

B ■

Intramedullary

C

Figure 99–1. Anatomical location of spinal cord tumors. A, Extradural. B, Intradural extramedullary. C, Intramedullary.

T A B L E 99–1. Spinal Cord Tumors Intradural Intramedullary

Extramedullary

Extradural

Most Common

Less Common

Most Common

Less Common

Most Common

Less Common

Ependymoma Astrocytoma Hemangioblastoma

Oligodendroglioma Ganglioglioma PCNSL Metastatic disease Teratoma Neuroenteric cyst Dermoid tumor Epidermoid tumor Lipoma Cavernous angioma

Schwannoma Neurofibroma Meningioma Myxopapillary ependymoma

Paraganglioma Ganglioglioneuroma Drop metastases Neuroenteric cyst Dermoid tumor Epidermoid tumor Lipoma Cavernous angioma

Metastatic disease

Chordoma Multiple myeloma Osteosarcoma Chondrosarcoma Ewing’s sarcoma Soft tissue sarcoma Plasmacytoma Giant cell tumor Osteoblastoma

PCNSL, primary central nervous system lymphoma.

distribution are most common with extramedullary lesions that affect the dorsal roots or plexus; painful dysesthesias affecting an entire limb have also been described. A sensation of lancinating pain or electricity down the length of the spine, Lhermitte’s sign, can be caused by compressive cervical cord lesions. Thoracic tumors may cause a bandlike pain around the chest or abdomen, resembling the pain of herpetic neuralgia. Tumors in this location may also cause progressive kyphoscoliosis, particularly in children.6 Weakness, reflex change, sensory loss, and bowel or bladder dysfunction may be present early or late in the course of disease. Intramedullary lesions tend to produce dysfunction earlier than do extramedullary lesions, which often cause deficits by external compression rather than direct invasion of

tissue. In general, rapid progression or short duration of symptoms portends a higher grade tumor and a poorer prognosis.7,8 Weakness from spinal cord tumors may be secondary to (1) direct involvement of the anterior horn cells or descending motor tracts within the cord itself, as with intramedullary tumors; (2) compression or infiltration of the ventral roots as they exit the spinal cord, as with nerve sheath tumors; or (3) external compression of the corticospinal tracts, resulting in myelopathy and upper motor neuron weakness, as with many extramedullary tumors, particularly thoracic meningiomas or epidural metastases.9 Sensory loss is often patchy, involving one or more particular modalities more than others. For example, central cord lesions, such as ependymomas, can cause pain and loss of temperature sensation with preserved position and

chapter 99 tumors of the spinal cord Dorsal columns (deep touch, proprioception, and vibration) Dorsal Leg root Arm

T A B L E 99–2. Differential Diagnosis of Spinal Cord Tumor Dysembryonic lesions

Vascular malformations Lateral corticospinal tract (motor) Lateral spinothalamic tract (pain and temperature)

Leg Trunk Arm Sacral Leg Trunk Arm

Vascular disease Demyelinating disease Inflammatory disease Infectious disease

Degenerative joint disease Ventral root ■

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Figure 99–2. Spinal cord cross-section, showing major tracts and lamellation.

vibratory sensation by affecting the central crossing fibers in the cord. Because of lamellation of the spinothalamic tracts, there may be sacral sparing of pain and temperature sensation from central lesions as well (Fig. 99–2). Compressive lesions often manifest with pain and an ascending sensory level; accompanying signs may include spasticity, upper motor neuron weakness, and bladder dysfunction. In general, sensory loss from intramedullary cord lesions tends to be symmetrical, whereas sensory loss from extramedullary lesions is often asymmetrical as a result of involvement of nerve roots. Several well-recognized syndromes may be encountered from spinal cord tumors at various levels. Tumors in the lower lumbar region may produce a conus medullaris syndrome, characterized by early bowel, bladder, and sexual dysfunction; by a mixture of upper and lower motor neuron weakness; and by patchy numbness. Tumors in this region can also produce a cauda equina syndrome, characterized by urinary retention, saddle anesthesia, lower motor neuron weakness, and reflex loss. Brown-Séquard syndrome—with ipsilateral weakness; contralateral pain; and loss of proprioception, vibration sensation, and temperature sensation—can result from eccentric intramedullary or extramedullary lesions. Tumors at the foramen magnum can cause suboccipital pain, lower cranial nerve palsies, bilateral hand atrophy, and loss of position and vibration sensation in the upper extremities more than in the lower extremities. Finally, hydrocephalus can be present in association with spinal cord tumors, particularly those in the high cervical region, perhaps as a result of high cerebrospinal fluid (CSF) protein level, spinal block, or outflow obstruction of the fourth ventricle caused by leptomeningeal thickening.10 The differential diagnosis of spinal cord tumors includes (1) nonneoplastic or dysembryonic lesions, such as lipoma or syringomyelia; (2) vascular malformations, including arterial venous malformation and dural arteriovenous fistula; (3) vascular disease, such as spinal cord infarction or amyloid angiopathy11; (4) demyelinating disease; (5) inflammatory myelitis, as in transverse myelitis or sarcoidosis; (6) infectious disease, including syphilis, human T cell lymphotropic virus type 1, and schistosomiasis; (7) neurodegenerative disease, such as amyotrophic lateral sclerosis; and (8) extrinsic compression from

Neurodegenerative disease Miscellaneous

Lipoma Neuroenteric cyst Dermoid tumor Epidermoid tumor AVM Dural AVF Spinal cord stroke Amyloid angiopathy Multiple sclerosis Transverse myelitis Sarcoidosis Systemic lupus erythematosus Syphilis Tuberculosis HTLV-1 Schistosomiasis Cervical spondylosis Hypertrophic arthritis Herniated disc ALS Post-irradiation myelopathy Syringomyelia Epidural lipomatosis Extramedullary hematopoiesis

ALS, amyotrophic lateral sclerosis; AVF, arteriovenous fistula; AVM, arteriovenous malformation; HTLV-1, human T cell lymphotrophic virus type 1.

degenerative joint disease, as in spondylosis or hypertrophic arthritis, epidural metastatic disease, extramedullary hematopoiesis, and epidural lipomatosis (Table 99–2).

DIAGNOSTIC TESTS Plain Radiographs Since the advent of MRI, plain radiography has not been routinely used to diagnose spinal cord tumors because soft tissue is not adequately imaged. However, abnormalities are sometimes seen in the bony structures of the vertebral column as a consequence of the tumor itself, particularly in children. Nerve sheath tumors may cause widening of the neural foramina. Intramedullary tumors often cause diffuse widening of the spinal canal, localized erosion, or scalloping of the posterior vertebral bodies and flattening of pedicles. Scoliosis is a common early sign of intramedullary thoracic neoplasms in children.

Computed Tomography and Computed Tomographic Myelography Like the plain radiograph, computed tomography (CT) has largely been supplanted by MRI except in patients who cannot tolerate or who have a contraindication to MRI. CT does remain the study of choice for visualization of osseous structures and can demonstrate bony changes surrounding an extramedullary mass in the region of the neural foramen. CT is also useful during preoperative planning to evaluate spinal stability. Intravenous contrast material enhances the sensitivity of CT for detecting soft tissue pathology if MRI cannot be performed. For tumors in the cervical region, computed tomographic angiography may be

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employed to define the relationship of the tumor with the vertebral arteries. Computed tomographic myelography is superior to standard myelography for demonstrating the rounded filling defects of intradural extramedullary lesions or widening of the spinal cord caused by intramedullary lesions.

Magnetic Resonance Imaging MRI plays a central role in the imaging of spinal cord tumors and affords superior anatomical localization of soft tissue masses. The majority of tumors can easily be classified as extradural, intradural extramedullary, or intramedullary by MRI alone; this thereby greatly aids in characterization of the tumor. Both sagittal and axial T1- and T2-weighted images should be obtained, in addition to sagittal and axial T1-weighted images after the administration of gadolinium. Diffusionweighted imaging is occasionally useful for detecting cytotoxic edema and for differentiating tumors from abscesses.12 Astrocytomas usually manifest as focal enlargements of the spinal cord (Fig. 99–3). They are typically hypointense or isointense on T1-weighted images and hyperintense on T2-weighted images. Unlike their intracranial counterparts, nearly all spinal astrocytomas are enhanced after administration of contrast material, regardless of World Health Organization grade. Contrast material helps delineate tumor margins from surrounding edema, cyst, or syrinx. Although both cysts and syrines are hyperintense on T2-weighted images, cysts usually show enhancement along their borders, whereas syrinxes do not. Ependymomas share many imaging characteristics with astrocytomas, but there are several features that may help distinguish the two. Ependymomas typically are enhanced more intensely than are astrocytomas. They are more likely to have

A ■

B

heterogeneous signals because of hemorrhagic or cystic components. On T2-weighted images, dark caps, representing hemosiderin deposition, may be seen. Finally, ependymomas tend to be more central on axial cuts and have a greater predilection for the lower spinal cord. Unlike cellular ependymomas, myxopapillary ependymomas are often hyperintense on T1-weighted images, which probably reflects their mucinous nature (Fig. 99–4). Hemangioblastomas tend to have slightly different MRI characteristics according to size. Smaller lesions (10 mm or less) are isointense on T1-weighted images, hyperintense on T2-weighted images, and uniformly enhanced with gadolinium (Fig. 99–5). Larger lesions are often hypointense or isointense on T1-weighted images, heterogeneous on T2-weighted images, and heterogeneously enhanced after contrast material administration.13 Many hemangioblastomas have associated cysts, which can be quite large and may be hyperintense on T1weighted images as a result of high protein content. Most lesions have surrounding areas of hypointensity on T1weighted images and hyperintensity on T2-weighted images, which represent peritumoral edema.14 Intramedullary metastases are characterized by hyperintensity on T2-weighted images and homogenous enhancement after gadolinium administration (Fig. 99–6). Additional leptomeningeal deposits are often seen on postcontrast T1weighted images. Nerve sheath tumors are characterized by isointense signal on T1-weighted images and markedly strong signal on T2weighted images with occasional weak signal centrally (the socalled target appearance). Enhancement is variable: Some tumors show uniform enhancement, whereas others may be only peripherally enhanced or nonenhanced (Fig. 99–7). When multiple tumors are present, they are more likely to represent

C

Figure 99–3. Astrocytoma. A, Sagittal T2-weighted magnetic resonance imaging (MRI) reveals an expansile mass in the thoracic spinal cord, representing a World Health Organization grade II astrocytoma. Sagittal T1-weighted MRI before (B) and after (C) gadolinium administration demonstrates heterogeneous enhancement.

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A ■

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B Figure 99–4. Myxopapillary ependymoma. A, Sagittal T1-weighted magnetic resonance imaging (MRI) demonstrates a rounded, hyperintense lesion at the filum terminale, which represents a myxopapillary ependymoma. B, Sagittal T2-weighted MRI reveals the same lesion to be isointense with spinal cord.

neurofibromas than schwannomas. Malignant degeneration of a nerve sheath tumor can be difficult to recognize radiographically, although malignant lesions tend to be larger and have more irregular, infiltrating borders.15 Spinal meningiomas have an isointense or hypointense appearance on T1-weighted images and a slightly hyperintense appearance on T2-weighted images (Fig. 99–8). They are intensely and homogeneously enhanced after contrast material administration, except within areas of calcification. These areas are dark on all sequences and have little associated enhancement. Epidural metastatic lesions are most often isointense on T1weighted images, hyperintense on T2-weighted images, and enhanced after contrast material administration. In cases of suspected spinal cord compression, the entire spine must be imaged, because 30% of patients have multiple deposits at the time of diagnosis (Fig. 99–9).

Angiography Angiography is sometimes employed for operative planning in order to identify the location of important spinal penetrating arteries. It may also be used to rule out an arteriovenous malformation or a dural arteriovenous fistula, entities that can mimic a primary spinal cord neoplasm.

Cerebrospinal Fluid Studies CSF studies have little importance in the direct diagnosis of spinal cord tumors. Abnormalities in the basic constituents of spinal fluid, including glucose level, total protein level, and

lymphocyte count, may be present but are nonspecific. Some spinal cord tumors, particularly ependymomas, are associated with an increased protein level in the CSF. Meningiomas occasionally lead to a decrease in CSF glucose level. The cell count is usually normal, but a mild elevation (25 to 100 cells/mm3) may be seen. Cytologic study has low yield in diagnosing spinal cord tumors, even in the presence of leptomeningeal spread. Other studies, such as a search for oligoclonal bands and measurement of myelin basic protein, may be ordered if multiple sclerosis is a diagnostic consideration.

MANAGEMENT Surgery Surgery is the mainstay of treatment for most spinal cord tumors, particularly since the advent of the operating microscope, intraoperative ultrasonography, evoked potential monitoring, surgical lasers, and the ultrasonic aspirator. The objectives of surgery range from gross total resection to limited biopsy for pathological diagnosis. Unlike excision of intracranial neoplasms, surgery for spinal tumors must take into account spinal stability, particularly in pediatric patients, and implantation of hardware may be necessary to avoid postoperative deformity or instability. Most tumors are resected with a dorsal approach through a posterior midline incision, laminectomy, and durotomy. Intramedullary lesions, with the exception of pia-based hemangioblastomas, are often completely surrounded by normal tissue. They cannot be visualized from the surface, and a midline myelotomy is required for exposure. In such cases, intraoperative ultrasonography may be used to

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Figure 99–5. Hemangioblastoma. A, Sagittal T2weighted magnetic resonance imaging reveals multilevel (C4-T1) signal abnormality within the spinal cord, which represents a hemangioblastoma with peritumoral edema. Sagittal (B) and axial (C) T1-weighted postcontrast images clearly delineate the hemangioblastoma at C5-C6 from surrounding edema.

A

B

C

help delineate the location, length, and depth of the myelotomy.16 Intraoperative motor and/or somatosensory evoked potentials are routinely employed to assess the integrity of the spinal motor and/or sensory pathways during tumor resection and to prevent postoperative functional deterioration.17 The extent of resection is guided by lesion anatomy, surgical experience, results of intraoperative monitoring, and preliminary histological diagnosis obtained from frozen sections at the time of surgery.18 Patients with preoperative functional independence and few medical comorbid conditions and in whom frozen section exhibits low-grade histopathology are generally the best candidates for aggressive surgical resection. Radiation therapy was traditionally considered the initial treatment of choice for most patients with extradural spinal cord compression. The use of decompressive laminectomy in combination with radiation therapy did not improve outcome.19 Surgery was confined to patients presenting with extradural cord compression without a histological diagnosis, radioresis-

tant tumors, compression of the spinal cord by bone, and recurrent cord compression after radiation therapy. In a prospective, randomized, controlled trial, Patchell and colleagues compared anterior decompression followed by radiation therapy (30 Gy) with radiation therapy alone.20 The study was stopped after interim analysis at midpoint because of a significant benefit in the patients who received both surgery and radiation therapy. A total of 101 patients were enrolled. Patients treated with surgery retained the ability to walk significantly longer than did those treated with radiotherapy alone (median, 126 days versus 35 days; P = .006). Surgically treated patients also maintained continence and functional Frankel and American Spinal Injury Association scores significantly longer than did patients receiving radiation. The length of survival was not significantly different between the two groups, although there was a trend toward longer survival time in patients who underwent surgery (median, 129 days versus 100 days; P = .08). Of importance was that the median length of hospitalization

■

Figure 99–6. Intramedullary metastasis. A, Postcontrast T1-weighted magnetic resonance imaging (MRI) demonstrates a homogeneously enhanced lesion in the ventral aspect of the cord at T7. The patient had stage IV non–small cell lung carcinoma. B, Sagittal T2-weighted MRI reveals strong signal in the thoracic cord, extending from T7 to T10.

A

B

A

C

■

B

Figure 99–7. Schwannoma. A, Axial T1-weighted magnetic resonance image with contrast material demonstrates an extramedullary intradural lesion with homogeneous enhancement, representing a schwannoma. Axial (B) and sagittal (C) T2-weighted images show the C5-C6 lesion expanding the left neural foramen and exerting mass effect on the left side of the spinal cord.

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■

Figure 99–8. Meningioma. A, Sagittal T2-weighted magnetic resonance imaging (MRI) reveals an isointense lesion in the posterior intradural compartment, which causes anterior displacement of the cord and cord compression at T6. Strong signal within the cord itself can be seen adjacent to the lesion. B, Sagittal T1weighted MRI with contrast material reveals a dura-based lesion with homogeneous enhancement, which is consistent with meningioma.

A

B ■

Figure 99–9. Extradural spinal cord compression. A, Sagittal T1-weighted magnetic resonance imaging (MRI) with contrast material reveals extradural metastases in the thoracic spine, which compress the swollen spinal cord. B, Axial T1-weighted MRI with contrast material reveals the spinal cord encased in an extradural tumor.

A

B

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chapter 99 tumors of the spinal cord during which the cord compression was diagnosed and treated was 10 days for both treatment groups (P = .86). This study suggests that patients with extradural cord compression treated with radical direct decompressive surgery plus postoperative radiotherapy regained the ability to walk more often and maintained it longer than did patients treated with radiation alone. Surgery enabled most patients to remain ambulatory and continent for the remainder of their lives, whereas patients treated with radiation alone spent approximately two thirds of their remaining lives unable to walk and incontinent. Whether the findings of this study can be extrapolated to other institutions without the surgical resources to perform emergency anterior decompression in patients with epidural cord compression routinely, and whether the benefit of surgery applies to radiosensitive tumors such as breast cancer, remains to be seen. Nonetheless, this is an important study that could change the management of patients with extradural cord compression.

Radiation Because there have been no randomized prospective studies examining the efficacy of radiation for primary spinal cord tumors, significant controversy regarding its use remains. Many retrospective series exist, but their usefulness is limited by small sample size, limited follow-up, and lack of matched controls. In general, most practitioners agree that there is no role for radiation in patients with completely resected lowgrade gliomas who are monitored with serial surveillance scans. Complete resection is achieved more often with ependymomas than with astrocytomas, but the dominant pattern of failure is local for both. In most cases in which gross total resection has not been achieved, postoperative local radiation therapy is administered up to a dosage of 4000 to 5400 cGy. Dosages higher than 5500 cGy are associated with increased risk of radiation-induced myelopathy. Children’s tolerance may be lower.21,22 Image-guided frameless stereotactic radiosurgery has emerged as a treatment option for primary and metastatic spinal cord tumors.23,24 In this system, high-dose radiation can be delivered to a tumor volume with minimal damage to adjacent normal structures. For low-grade astrocytomas, surgery and postoperative radiation produce survival rates of 50% to 91% at 5 years and 40% to 91% at 10 years.25 For ependymomas, survival is slightly better: 60% to 100% at both 5 and 10 years. High-grade astrocytomas appear to respond to radiation in the short term, but overall survival rates are dismal. Craniospinal radiation may be employed for cases of ependymoma with central nervous system dissemination. Postoperative radiation therapy is rarely employed for hemangioblastomas, nerve sheath tumors, and spinal meningiomas, except in the case of malignant peripheral nerve sheath tumor15 or malignant meningioma. Radiation is the mainstay of therapy for patients with epidural spinal cord compression resulting from metastatic disease. Focal radiation therapy is usually administered at a dose of 3000 cGy (30 Gy) administered over 2 weeks.26

Chemotherapy Chemotherapy has a limited role in the treatment of primary spinal cord tumors, except in children, who are more susceptible to the deleterious effects of radiation than adults. Data

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are limited to small case series and case reports. Chemotherapy may have a role in the treatment of epidural cord compression from chemosensitive tumors such as lymphoma and myeloma.

OUTCOMES Postoperatively, patients frequently experience transient worsening of neurological function. The most important predictors of postoperative neurological deterioration are preoperative disability and malignant histology.27 Significant postoperative motor morbidity resulting in functional dependence is lowest in patients with normal preoperative examination findings. This fact argues for early surgery (before neurological deterioration) in patients with intramedullary tumors. Patients with severe or long-standing deficits rarely show improvement after surgery. Manipulation of the posterior columns during a standard dorsal myelotomy often results in transient or permanent proprioceptive impairment, even in patients with normal preoperative examination findings. Other surgical complications include CSF leak, meningitis, transient or permanent bowel or bladder dysfunction, and spinal instability that leads to kyphoscoliosis. In patients with ependymomas, gross total resection provides the best chance at long-term disease-free survival. Two groups have reported disease-free survival rates of 100% after radical resection without postoperative radiotherapy; seven of these patients were monitored for more than 10 years.28,29 Overall 10-year survival rates are better for spinal ependymomas than for astrocytomas, ranging from 50% to 95%.30,31 The most important prognostic factor is the ability to attain gross total resection; histological grade and preoperative neurological status are also important.32-34 For spinal cord astrocytomas, 5- and 10-year survival rates are 50% to 73% and 23% to 54%, respectively.30 As with ependymomas, important prognostic factors include histological grade (median length of survival, 98 months for World Health Organization grade I disease versus 15 months for grade IV disease); symptom duration before diagnosis (longer duration correlates with increased length of survival); preoperative performance status (5-year survival rate of 75% for Karnofsky Performance Status scores of 80 to 100 versus 51% for scores of <60); and postoperative performance status.7 Factors not shown to be relevant prognostically include sex, age, site and extension of tumor, extent of surgical resection, and dose of postoperative radiotherapy.7,30,35 Hemangioblastomas have the best long-term clinical outcome of the three most common intramedullary tumors. More than 90% of patients remain clinically stable or improve, and complete resection virtually eliminates the risk of recurrence for sporadic tumors.36,37 Poor prognostic factors include significant preoperative deficits, large tumor size, and anterior tumor location.36 For patients with von Hippel–Lindau disease, the risk of developing new hemangioblastomas or continued growth of existing ones warrants routine long-term follow-up with gadoliniumenhanced MRI. Results of surgery for extramedullary tumors tend to be very good; most patients exhibit significant improvement in neurological function postoperatively. Gross total resection of nerve sheath tumors is curative in most cases. For meningiomas, the recurrence risk is also quite low, except for en plaque lesions, lesions with significant extradural spread, or tumors with

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malignant histological processes. Patients with neurofibromatosis type 1 and spinal neurofibromas are at increased risk for developing recurrent tumors and therefore require close follow-up. In addition, they have a significantly higher longterm mortality rate than do patients without neurofibromatosis type 1 (10-year survival rates of 60% and >90%, respectively).38 For epidural spinal cord compression from metastatic disease, the prognosis depends primarily on pretreatment neurological function. In addition, radiosensitivity of the underlying tumor plays a role. Lymphoma, myeloma, and prostate cancer are the most radiosensitive, whereas renal cell and non–small cell lung cancer lesions tend to be relatively radioresistant. Of the patients who are ambulatory at diagnosis, almost all remain ambulatory after radiation therapy. In contrast, only 2% to 6% of patients who are paraplegic at the onset of radiotherapy regain the ability to walk.26

CONCLUSION Spinal cord tumors are a rare but important cause of back pain and neurological dysfunction in the pediatric and adult populations. MRI has markedly improved physicians’ ability to accurately localize and diagnose lesions early in the course of disease. Advances in microsurgical technique have paved the way for more aggressive surgical resection; however, many tumors remain either unresectable or only partially resectable. Treatment strategies for patients with residual disease continue to evolve, but more sophisticated therapies are clearly needed to improve outcomes.

K E Y

P O I N T S

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Spinal cord tumors are rare, accounting for only 4% to 10% of all primary central nervous system tumors.

●

The majority of tumors manifest with pain and signs of neurological dysfunction such as weakness, reflex change, sensory loss, and bowel or bladder dysfunction.

●

MRI is the most important modality for imaging spinal cord tumors, both at diagnosis and postoperatively as a screening tool for recurrence.

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Surgery is the mainstay of treatment for spinal cord tumors, although many patients receive radiotherapy if gross total resection cannot be achieved.

Suggested Reading Balmaceda C: Chemotherapy for intramedullary spinal cord tumors. J Neurooncol 2000; 47:293-307. Ferner RE, O’Doherty MJ: Neurofibroma and schwannoma. Curr Opin Neurol 2002; 15:679-684. Isaacson SR: Radiation therapy and the management of intramedullary spinal cord tumors. J Neurooncol 2000; 47:231238.

Parsa AT, Lee J, Parney IF, et al: Spinal cord and intradural-extraparenchymal spinal tumors: current best care practices and strategies. J Neurooncol 2004; 69:291-318. Prasad D, Schiff D: Malignant spinal-cord compression. Lancet Oncol 2005; 6:15-24. Van Goethem JW, van den Hauwe L, Ozsarlak O, et al: Spinal tumors. Eur J Radiol 2004; 50:159-176.

References 1. Sasanelli F, Beghi E, Kurland LT: Primary intraspinal neoplasms in Rochester, Minnesota, 1935-1981. Neuroepidemiology 1983; 2:156-163. 2. Helseth A, Mork SJ: Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients. J Neurosurg 1989; 71:842-845. 3. Harrison MJ, Wolfe DE, Lau TS, et al: Radiationinduced meningiomas: experience at the Mount Sinai hospital and review of the literature. J Neurosurg 1991; 75:564574. 4. Sloof JL, Minehan KJ, McCarty CS: Primary Intramedullary Tumors of the Spinal Cord and Filum Terminale. Philadelphia: WB Saunders, 1964. 5. Miller DC: Surgical pathology of intramedullary spinal cord neoplasms. J Neurooncol 2000; 47:189-194. 6. Rossitch E Jr, Zeidman SM, Burger PC, et al: Clinical and pathological analysis of spinal cord astrocytomas in children. Neurosurgery 1990; 27:193-196. 7. Innocenzi G, Salvati M, Cervoni L, et al: Prognostic factors in intramedullary astrocytomas. Clin Neurol Neurosurg 1997; 99:1-5. 8. Rodrigues GB, Waldron JN, Wong CS, et al: A retrospective analysis of 52 cases of spinal cord glioma managed with radiation therapy. Int J Radiat Oncol Biol Phys 2000; 48:837842. 9. Solero CL, Fornari M, Giombini S, et al: Spinal meningiomas: review of 174 operated cases. Neurosurgery 1989; 25:153160. 10. Rifkinson-Mann S, Wisoff JH, Epstein F: The association of hydrocephalus with intramedullary spinal cord tumors: a series of 25 patients. Neurosurgery 1990; 27:749-754; discussion, Neurosurgery 1990; 27:754. 11. Lee M, Epstein FJ, Rezai AR, et al: Nonneoplastic intramedullary spinal cord lesions mimicking tumors. Neurosurgery 1998; 43:788-794; discussion, Neurosurgery 1998; 43:794-795. 12. Van Goethem JW, van den Hauwe L, Ozsarlak O, et al: Spinal tumors. Eur J Radiol 2004; 50:159-176. 13. Chu BC, Terae S, Hida K, et al: MR findings in spinal hemangioblastoma: correlation with symptoms and with angiographic and surgical findings. AJNR Am J Neuroradiol 2001; 22:206-217. 14. Baker KB, Moran CJ, Wippold FJ 2nd, et al: MR imaging of spinal hemangioblastoma. AJR Am J Roentgenol 2000; 174:377-382. 15. Ferner RE, Gutmann DH: International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res 2002; 62:1573-1577. 16. Platt JF, Rubin JM, Chandler WF, et al: Intraoperative spinal sonography in the evaluation of intramedullary tumors. J Ultrasound Med 1988; 7:317-325. 17. Morota N, Deletis V, Constantini S, et al: The role of motor evoked potentials during surgery for intramedullary spinal cord tumors. Neurosurgery 1997; 41:1327-1336. 18. Parsa AT, Lee J, Parney IF, et al: Spinal cord and intraduralextraparenchymal spinal tumors: current best care practices and strategies. J Neurooncol 2004; 69:291-318.

chapter 99 tumors of the spinal cord 19. Young RF, Post EM, King GA: Treatment of spinal epidural metastases: randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 1980; 53:741748. 20. Patchell R, Tibbs PA, Regine O, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomized trial. Lancet 2005; 366:643-648. 21. Marcus RB Jr, Million RR: The incidence of myelitis after irradiation of the cervical spinal cord. Int J Radiat Oncol Biol Phys 1990; 19:3-8. 22. Sundaresan N, Gutierrez FA, Larsen MB: Radiation myelopathy in children. Ann Neurol 1978; 4:47-50. 23. Ryu SI, Chang SD, Kim DH, et al: Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions. Neurosurgery 2001; 49:838-846. 24. Gerszten PC, Ozhasoglu C, Burton SA, et al: CyberKnife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery 2004; 55:89-98; discussion, Neurosurgery 2004; 55:98-99. 25. Isaacson SR: Radiation therapy and the management of intramedullary spinal cord tumors. J Neurooncol 2000; 47:231-238. 26. Prasad D, Schiff D: Malignant spinal-cord compression. Lancet Oncol 2005; 6:15-24. 27. Constantini S, Allen JC, Epstein F: Pediatric and adult primary spinal cord tumors. In Black PM, Loeffler JS, eds: Cancer of the Nervous System, 1st ed. Cambridge, MA: Blackwell Scientific, 1997, pp 637-649. 28. Epstein FJ, Farmer JP, Freed D: Adult intramedullary spinal cord ependymomas: the result of surgery in 38 patients. J Neurosurg 1993; 79:204-209.

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29. McCormick PC, Torres R, Post KD, et al: Intramedullary ependymoma of the spinal cord. J Neurosurg 1990; 72:523532. 30. Abdel-Wahab M, Corn B, Wolfson A, et al: Prognostic factors and survival in patients with spinal cord gliomas after radiation therapy. Am J Clin Oncol 1999; 22:344-351. 31. Waldron JN, Laperriere NJ, Jaakkimainen L, et al: Spinal cord ependymomas: a retrospective analysis of 59 cases. Int J Radiat Oncol Biol Phys 1993; 27:223-229. 32. Hoshimaru M, Koyama T, Hashimoto N, et al: Results of microsurgical treatment for intramedullary spinal cord ependymomas: analysis of 36 cases. Neurosurgery 1999; 44:264-269. 33. Whitaker SJ, Bessell EM, Ashley SE, et al: Postoperative radiotherapy in the management of spinal cord ependymoma. J Neurosurg 1991; 74:720-728. 34. Cooper PR: Outcome after operative treatment of intramedullary spinal cord tumors in adults: intermediate and long-term results in 51 patients. Neurosurgery 1989; 25:855859. 35. Jyothirmayi R, Madhavan J, Nair MK, et al: Conservative surgery and radiotherapy in the treatment of spinal cord astrocytoma. J Neurooncol 1997; 33:205-211. 36. Lonser RR, Weil RJ, Wanebo JE, et al: Surgical management of spinal cord hemangioblastomas in patients with von HippelLindau disease. J Neurosurg 2003; 98:106-116. 37. Roonprapunt C, Silvera VM, Setton A, et al: Surgical management of isolated hemangioblastomas of the spinal cord. Neurosurgery 2001; 49:321-327; discussion, Neurosurgery 2001; 49:327-328. 38. Seppala MT, Haltia MJ, Sankila RJ, et al: Long-term outcome after removal of spinal neurofibroma. J Neurosurg 1995; 82:572-577.

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100

NEUROLOGICAL COMPLICATIONS CANCER TREATMENTS ●

●

●

OF

●

William Whiteley and Robin Grant

People with cancer frequently develop neurological symptoms. One of the dilemmas facing doctors is whether these symptoms are directly due to cancer affecting the nervous system, indirectly associated with cancer (e.g., paraneoplastic syndromes), due to causes other than cancer, or due to a complication of one of the treatments that the cancer patient has received (e.g., anticonvulsants, antidepressants, steroids, chemotherapy).

TIMING OF NEUROLOGICAL COMPLICATIONS ■ Neurological complications of surgery occur immediately or

commonest neurological side effect of anticancer drugs (Table 100–1). People with preexisting neuropathies, diabetes, or alcohol abuse are more prone to the chemotherapy-induced neuropathy. Drug-induced neuropathies develop during chemotherapy or within a few months (usually less than 4 months) after completion of chemotherapy. Neuropathies may progress after discontinuation of treatment for up to 2 to 3 months and then often stabilize or recover to some degree over the ensuing months or years. Acute severe neuropathies, leading to a Guillain-Barré–like syndrome, have been reported rarely after the administration of suramin and tacrolimus.

shortly after surgery. ■ Neurological complications of radiation therapy are rare

during radiation therapy (because of the concomitant use of steroids), are most common weeks to a few months after completion of treatment and then are relatively uncommon until years later when late neurological complications start developing in long-term survivors. ■ Complications of local cancer treatments (e.g., intra-carotid or intrathecal chemotherapy), commonly start 2 to 3 days after each treatment and are direct toxic complications. ■ Neurological complications of systemic cancer treatments (e.g., chemotherapy) can be as a direct effect (a neural toxic effect on a nerve) or an indirect effect (secondary to immunosuppression). ■ If chemotherapy is given systemically, neurological complications that start around the time of nadirs in blood counts are commonly due to indirect complications (bacterial, viral; e.g., shingles) or opportunistic infection. Neurological complications can start within a few weeks of completion of chemotherapy due to a direct cumulative drug toxic effect on the nerve.

NEUROLOGICAL COMPLICATIONS OF CHEMOTHERAPY Neuropathy Neuropathies in patients with systemic cancer may be associated with dietary deficiency or cachexia but are also the

Encephalopathy Confusion is a common occurence in cancer patients undergoing treatment. Treatable reversible causes of confusion, such as metabolic encephalopathy, infection, endocrine (hypothyroid, diabetes) deficiency states (vitamin B12/folate), and drugrelated causes (e.g., tricyclics, anxiolytics, analgesics), must be sought. Most chemotherapeutic agents in usual dosages have limited penetration across the blood-brain barrier. Symptoms of encephalopathy are more likely to occur when high doses of drugs are used (e.g., methotrexate, cytosine arabinoside, 5fluorouracil [5-FU]), when drugs are administered locally to brain tissue (e.g., Gliadel wafers, biological response modifiers, gene therapy), intrathecally (e.g., methotrexate, cytosine arabinoside, thiotepa) intra-arterially (e.g., nitrosourea or cisplatin), or if the blood-brain barrier is already damaged such as by a brain tumor (Table 100–2). Frequency of confusion is also associated with the mode of drug delivery (intratumoral > intrathecal > intracarotid > oral or intravenous) and the dose given. A more specific condition, reversible posterior leukoencephalopathy (RPLE), can be caused by immunosuppression or some chemotherapy agents (cyclosporin, tacrolimus, interferon α, L-asparginase, vincristine, and high-dose methotrexate). Patients develop confusion, visual disturbance, seizures, and hypertension, which may progress to blindness and coma. White matter changes in the posterior brain on magnetic resonance imaging are diagnostic of RPLE. Elimination of the offending drug and treatment of hypertension can result in recovery without residual neurological signs over a 2- to 3-week period.

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Neuro-Oncology accelerated atherosclerosis of intracranial or extracranial vessels, which can lead to embolic or ischemic stroke (see later).

T A B L E 100–1. Neurological Complications by Drug Agent

Drug

Plant alkaloids

Vincristine Paclitaxel/docetaxel Methotrexate 5-Fluorouracil Cytosine arabinoside Ifosfamide Carmustine (BCNU) Thiotepa Cisplatin

Antimetabolites

Alkylating agents

Brain Toxicity

Nerve Toxicity

+/− +/− ++ ++ ++

+++ +++ +/−

++ +/− +/− +/−

+/−

+/− +++

+++ = very common; ++ = common; + = occasional; +/− = depends on route of administration.

T A B L E 100–2. Clinical Neurological Syndrome by Drug Side Effect

Drug

Encephalopathy

High dose: methotrexate, cytosine arabinoside, 5-fluorouracil, ifosfamide, paclitaxel, tamoxifen Intra-arterial: BCNU/ACNU, platinum derivatives. Intra-thecal: methotrexate, cytosine arabinoside, thiotepa Rare: platinum derivatives, interleukin 2, interferon α, L-asparginase Other: anticonvulsants, antidepressants, antinauseants Cytosine arabinoside, 5-fluorouracil All the above (including anticonvulsants) Cisplatin, vincristine, tamoxifen, interferon α Intrathecal: methotrexate, cytosine arabinoside Cisplatin, bleomycin, L-asparginase, tamoxifen Common: platinum derviates, vinca alkaloids, taxols Rare: cytarabine, daunorubicin, 5fluorouracil, suramin, tacrolimus Platinum derivatives, taxols, vinca alkaloids Platinum derviatives, taxols

Cerebellar ataxia Seizures Cranial neuropathies Meningitis Stroke Neuropathy

Muscle cramps Lhermitte’s sign

Seizures Most patients with cancer who develop seizures have either a direct cause for it (e.g., metastasis, carcinomatous meningitis) or an encephalopathy. Drug-related seizures are rare but have been reported. Tonic-clonic seizures on the background of cognitive disturbance suggest a toxic encephalopathy.

Stroke Strokes are more common in people with cancer than in the general population. The most common cause in cancer patients is nonbacterial thrombotic endocarditis (especially in adenocarcinoma). Myelosuppression or coagulopathy contributes to the increased frequency of cerebral hemorrhage or infarction. Strokes can occur with cisplatin or with L-asparginase therapy. There is insufficient evidence to associate stroke strongly with other chemotherapeutic agents. Radiotherapy may induce

CHEMOTHERAPEUTIC AGENTS Cisplatin Cisplatin is an alkylating agent that damages rapidly dividing cells by inhibiting DNA synthesis and separation by formation of links within and between strands of DNA. It is used mainly to treat ovarian, testicular, bladder, and small cell lung cancers. The main neurological side effect of cisplatin is a dose-related sensory neuropathy that can affect up to 80% of patients who complete six courses of treatment. Symptoms start after a cumulative dose of 300 to 400 mg/m2. Platinum-containing drugs accumulate in the dorsal root ganglia, where they have a toxic effect, which causes an ataxic sensory neuropathy. They also affect large myelinated fibers in the peripheral nerves, causing axonal loss and demyelination. Patients complain of paraesthesia, numbness, and pain in the toes and fingers that subsequently spread proximally to affect the arms and legs. Proprioception is impaired and reflexes are lost. Strength, pain, and temperature sensation are usually spared. Nerve conduction studies demonstrate decreased amplitude of sensory action potentials. The neuropathy may become severe enough to stop treatment with cisplatin. In 30% of patients with neuropathy, symptoms progress for 2 to 6 months after stopping treatment. The neuropathy is irreversible in many cases. One fifth of patients given cisplatin develop symptomatic high tone deafness and tinnitus, due to damage to the cochlear hair cells. Deafness is rarely severe enough to interfere with speech perception, but tinnitus can seriously affect quality of life. Infrequently, cisplatin can produce vertigo and unsteadiness. About one third of patients develop Lhermitte’s phenomenon (electric shock–like sensations on neck flexion). Rarely, cisplatin causes a reversible posterior leukoencephalopathy. Intra-arterial cisplatin can cause optic neuropathy. Carboplatin and oxaliplatin have similar side effects but are less neurotoxic.

Vinca Alkaloids Vinca alkaloids bind to tubulin and prevent its depolymerization from microtubules to dimers, disrupting normal spindle function and thus preventing cell division. This tubular toxic effect is believed to inhibit fast axonal transport and leads to axonal degeneration. Vincristine causes the most severe neuropathy, is usually the dose-limiting side effect, and occurs to some degree in all patients. Vindesine, vinblastine, and vinorelbine usually only give rise to mild neuropathies. Vincristine is used in the treatment of hematological malignancies, sarcomas, and brain tumors. After the administration of vincristine, mild paraesthesias in the fingertips and feet and muscle cramps are experienced, followed by weakness. Sural nerve biopsy shows primary axonal degeneration accompanied by segmental demyelination and reduction in both large and small fiber densities. It is usually slowly reversible months to years after withdrawal. Vincristine can cause an autonomic neuropathy, with abdominal pain and constipation (30%), urinary retention, or postural hypotension. Life-threatening paralytic ileus may occur. Some patients develop cranial nerve palsies, bilateral foot drop, or wrist drop, which can be severe and incompletely

chapter 100 neurological complications of cancer treatments reversible. Vincristine administration intrathecally produces a fatal encephalopathy.

Methotrexate Methotrexate is used for hematological malignancies, breast cancer, and occasionally intrathecally for malignant meningitis. It is an antifolate agent, inhibiting dihydrofolate reductase, hence reducing purine and thymidine synthesis. Folinic acid after treatment reduces frequency of neurological toxicity. Oral methotrexate rarely causes neurotoxicity. When administered into the cerebrospinal fluid or given in high doses intravenously (>1 g/m2), it can lead to a rapid onset of confusion, headache, and fever. This chemical meningitis produces an encephalopathy a few hours after intrathecal administration and is associated with a cerebrospinal fluid pleiocytosis. This illness is severe enough to be confused with bacterial meningitis, although the temporal association with methotrexate injection usually makes the diagnosis obvious. Several days after the third or fourth weekly treatment with the drug, multiple fluctuating focal deficits (said to be “strokelike”) may occur. Recovery is usually full and the disorder does not usually recur. A delayed encephalopathy affects up to 25% of long-term adult survivors of primary cerebral lymphoma treated with methotrexate and radiotherapy. This may cause progressive dementia, gait disturbance, seizures, and focal neurological deficits. White matter changes are found on magnetic resonance imaging. A delayed reversible myelopathy can be seen after several intrathecal injections with methotrexate.

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and stabilize microtubular assembly, which seems to inhibit fast axonal transport leading to axonal dysfunction. Paclitaxel is used for the treatment of breast, ovarian, and lung cancers. About one half of patients treated with taxol in doses over 200 mg/m2 develop a sensory neuropathy involving all sensory modalities. Symptoms usually begin within 1 to 2 days of treatment. Patients develop paraesthesia and some unsteadiness on walking due to a mild sensory ataxia. A few patients may develop weakness. Examination reveals signs of a neuropathy with a mild ataxia from proprioceptive loss. Perioral numbness may also occur. Nerve conduction studies and sural nerve biopsy confirm an axonal neuropathy with some segmental demyelination. The neuropathy is usually partially reversible once the treatment is stopped. Taxol can cause Lhermitte’s phenomenon.

Ifosfamide Ifosfamide is used in the treatment of sarcoma, lymphoma, myeloma, and ovarian and testicular cancers. It is an alkylating agent that is hydroxylated in the liver to its active metabolite. It may lead to an acute encephalopathy with cerebellar and extrapyramidal symptoms with hallucinations and seizures possibly related to mitochondrial toxicity. This usually occurs in between 11% and 60% of patients and begins within 24 hours of treatment and resolves within a median of 3 to 4 days but can persist for 7 to 10 days. Severe encephalopathy occurs in less than 5%. Methylene blue can be used both as treatment and as prophylaxis for this encephalopathy. Thiamin infusions (100 mg diluted in 100 mL of normal saline every 4 hours) has also been found to reverse neurological symptoms.

Cytosine Arabinoside Cytosine arabinoside (Ara-C or cytarabine) is used for hematological malignancies, breast cancer, and occasionally is given intrathecally for leptomeningeal carcinomatosis. High-dose Ara-C causes a reversible cerebellar syndrome in 10% to 20% of patients. It usually starts a few days after treatment, peaks at 2 to 3 days, and then resolves within 2 weeks of treatment, although the resolution may be incomplete. Occasionally, a more diffuse encephalopathy occurs with seizures. Intrathecal therapy can lead to a chemical meningitis and myelopathy. Neuropathy is rarely reported, especially where Ara-C is used with other drugs.

5-Fluorouracil 5-FU is used for gastrointestinal, head and neck, and breast cancers. In people with reduced activity of the enzyme dihydropyrimidine dehydrogenase, it may cause confusion or coma. The most common neurological toxicity, however, is a subacute reversible cerebellar syndrome. If 5-FU is used in combination with levamisole, a more severe encephalopathy may develop with seizures. Magnetic resonance imaging scans in these patients may show multiple enhancing white matter lesions.

Taxol (Paclitaxel) and Taxotere (Docetaxel) Paclitaxel is extracted from the bark of the Pacific yew and docetaxel from the needles of the English yew. Taxenes promote

Intracarotid Therapies Intracarotid carmustine (BCNU) or cisplatin is usually associated with local eye pain and can lead to optic neuropathy with reduction in visual acuity, color vision, and occasionally complete unilateral blindness. A retinal vasculitis is reported in 10% of patients. Intra-arterial BCNU can cause cerebral parenchymal damage in the territory of the anterior choroidal artery and lead to an encephalopathy.

Intratumoral Therapies for Brain Tumors BCNU-impregnated wafers (Gliadel), biological response modifiers, immunotherapy, and gene therapy reduce the toxic systemic effects but are associated with an increased frequency of local effects (edema, cerebritis, raised intracranial pressure) that may manifest with seizures or focal deficits.

Tamoxifen Tamoxifen interferes with the activity of estrogen and slows or stops the growth of cancer cells that have estrogen receptors. Ocular toxicity develops in 12% of those on long-term tamoxifen in the form of blurred vision as a result of keratopathy or change in color vision as a pigmentary retinopathy or optic neuropathy. These visual symptoms are reversible on discontinuation of the drug.

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Corticosteroids Corticosteroids are used to reduce peritumoral edema in patients with brain and spinal tumors, as oncolytic agents, and with systemic chemotherapy to reduce nausea and vomiting. An acute myopathy can come on within a week of starting highdose corticosteroids and can involve respiratory muscles. Some patients develop myopathy after using low doses of steroids for a period as short as a month, but more commonly this occurs after prolonged use. They usually result in a painless weakness of the pelvic girdle leading to difficulty rising from a chair or climbing stairs. Occasionally, the pectoral girdle and neck muscles may also be involved. The only treatment is drug withdrawal. Steroids also cause changes in mood with occasional psychosis, insomnia, tremor, and disturbances in smell. Steroid withdrawal can produce headaches, lethargy, myalgia, arthralgia, or postural hypotension.

NEUROLOGICAL COMPLICATIONS OF CRANIAL IRRADIATION Different tissues have different susceptibilities to radiation therapy. The nerves, brain, and spinal cord seem to be quite resistant to radiation, whereas skin, mucosa, and eye tissues are more sensitive. The pituitary gland and hypothalamus may be included in the radiation field when treating frontotemporal gliomas and craniopharyngiomas; in those patients, hypopituitarism may develop years after radiation. Growth hormones are affected first, followed by gonadotropins, thyrotropin, and rarely corticotrophin. Hyperprolactinemia is common. The likelihood of developing a neurological complication of cranial radiation is directly related to the total radiation dose (more than 6000 cGy), the fractionation regimen (fractions more than 200 cGy), the field size (whole brain > partial brain), age of the patient (older than 60 years), and the concomitant use of chemotherapy. The frequency of these complications increases in survivors with time.

Early Radiation Side Effects Patients with aggressive large intracerebral tumors who have not been given adequate doses of steroids are at increased risk of acute encephalopathy. Symptoms usually develop within 1 or 2 days of radiotherapy treatment and are usually at their worst within the first 2 weeks. Patients develop headaches, nausea and vomiting, and worsening of existing neurological deficits. Magnetic resonance imaging may reveal localized peritumoral white matter edema and mass effect (Fig. 100–1). Symptoms usually resolve after the steroid dose is increased.

Early Delayed Radiation Side Effects This starts a few weeks to a few months after completion of cranial irradiation. Patients notice a slowly developing lethargy and problems with concentration and memory. Occasionally there may be worsening of existing focal neurological symptoms. Early delayed reaction is very common (greater than 50%) and is believed to represent the direct effects of radiation on the more radiation sensitive myelin and glial cells. In 15%, early delayed side effects may mimic tumor recurrence. A brain-

■

Figure 100–1. Magnetic resonance imaging of early delayed radiation-induced white matter in normal brain showing white matter edema and downward displacement of the ventricle 2 months after radiation therapy for a recurrent falcine atypical meningioma.

stem encephalopathy may develop after irradiation of the posterior fossa. Rarely, patients treated with concurrent chemotherapy or elderly patients develop an early severe leukoencephalopathy, which is sometimes permanent. Minor symptoms can be monitored, but if severe, treatment with small doses of dexamethasone for 1 to 2 months and then slowly tapering them over 2 to 4 weeks is usually sufficient. In almost all patients, symptoms have settled by 3 to 4 months after completion of radiation therapy.

Late Effects of Radiation Radiation-Induced Cranial Neuropathy The cranial nerves and retina are remarkably resistant to the effects of radiation, but after treatment for pituitary tumors, optic neuropathy or rarely retinopathy can occur. Painless visual loss begins 12 to 18 months after radiotherapy with a loss of acuity or visual field constriction. Ophthalmoscopy may reveal cotton-wool spots, hemorrhages, and optic nerve swelling. Steroids are ineffective in treating this complication. Optic neuropathy may also occur with radiation-related accelerated carotid atherosclerosis, producing carotid occlusion. Differential diagnosis for visual loss in cancer patients includes optic neuropathy due to intracarotid chemotherapy, high-dose tamoxifen, methotrexate, vincristine, or 5FU; paraneoplastic retinopathy; anterior ischemic optic neuropathy; glaucoma; and multiple sclerosis. Rarely, hypoglossal, accessory, vagal,

chapter 100 neurological complications of cancer treatments

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Figure 100–3. Histology of the brain showing changes of radiation necrosis with hyalinization of vessel walls.

■

Figure 100–2. Magnetic resonance imaging scan/histology of a case with radiation necrosis and mass effect with contrast enhancement and central necrosis consistent with tumor recurrence 3 years following 60 Gy in 30 fractions given to patient with anaplastic astrocytoma.

glossopharyngeal, and acoustic nerve palsies occur, usually with radiation treatment for head and neck cancers. Hearing loss after radiotherapy occurs years after treatment for acoustic neuroma and may be related to ischemic damage of the cochlea. Damage to the other cranial nerves is rare.

Radiation Necrosis Radiation necrosis occurs in patients treated with high focal doses of radiation. Patients present from several months to 10 years after cranial radiation. In 2.8% of patients treated for malignant glioma, focal radiation necrosis develops, but among those surviving a year as many as 9% develop the condition. The most important factor is the total dose of radiation given equal to or greater than 6000 cGy. The clinical and radiological presentation is similar to that of recurrent intracerebral tumor, with progressive focal neurological signs associated often with headaches, papilloedema, and seizures, usually close to the original tumor site. Computed tomography and magnetic resonance imaging can be indistinguishable from tumor progression (Fig. 100–2). Single-photon emission computed tomography with thallium or positron emission tomography with 18F-FDG can help distinguish tumor from radionecrosis. Increased uptake supports active tumor and low uptake suggests radionecrosis. Pathological examination shows white matter necrosis and, in more severe cases, necrosis of gray and white matter. There is often extensive vascular damage with endothelial proliferation, fibrosis/fibrinoid necrosis, and luminal occlusion (Fig. 100–3). Treatment of radiation necrosis

with high-dose oral steroids may produce an improvement in symptoms and imaging. Surgical debulking of the mass is justified in some patients, first, to confirm the diagnosis and, second, to reduce mass effect. The use of anticoagulants and hyperbaric oxygen is reported to be successful in case reports, although they are not routinely used in clinical practice.

Dementia Due to Radiation-Induced Leukoencephalopathy Up to one fifth of long-term survivors of cancer who have had cranial radiation therapy suffer from a slow or stepwise dementia with apraxia and ataxia, mimicking normal pressure hydrocephalus. This is one of the most common reasons for poor quality of life in long-term survivors of malignant glioma. It causes a subcortical dementia with slowness of thought, apathy, and unsteady walking (apraxia). It is sometimes severe enough to inhibit the patient initiating gait or even standing. Later, incontinence develops. Although it has been reported as occurring as early as 6 months after radiation, the more characteristic course is starting 2 to 3 years after radiation therapy and slowly deteriorates over the next 5 to 10 years, until the patient is totally dependent on caregivers. Imaging shows marked atrophy of the brain with enlargement of the ventricles or diffuse white matter changes, most marked on magnetic resonance imaging (Fig. 100–4). Later, there may be dystrophic calcification in the brain (Fig. 100–5). Pathology shows a disseminated necrotizing leukoencephalopathy with demyelination in the subcortical and periventricular white matter sparing the gray matter and the basal ganglia. There may also be a mineralizing microangiopathy with calcium deposition in and around vessels leading to occlusion and dystrophic calcification within the brain. There is no effective treatment.

Transient Ischemic Attacks and Stroke Stenosis of the carotid and vertebral arteries has been associated with radiotherapy to the head and neck and may manifest with stroke. Radiotherapy seems to result in an accelerated

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Neuro-Oncology atherosclerosis, which can affect both intracranial and extracranial blood vessels. The atherosclerosis is due to a combination of radiation-induced endothelial damage and conventional risk factors for arterial disease. Short lesions can be treated with endovascular techniques. Moyamoya disease can be found in patients after radiotherapy treatment, which may manifest with hemorrhagic or ischemic complications.

Radiation-Induced Tumors The most common radiation-induced tumors are meningiomas, gliomas, and sarcomas (see Fig. 100–5). The evidence is strongest for meningiomas (relative risk, 9.5) but gliomas (relative risk, 2.6) also have an increased frequency. The frequency is directly related to radiation dose and length of survival.

Cavernous Angiomas Cavernous angiomas are small capillary dilatations in the brain that may develop 4 to 8 years after cranial irradiation. They may manifest as asymptomatic abnormalities on imaging or may be associated with seizures or headache. They may be difficult to distinguish from tumor recurrence in some situations on computed tomography scanning, but magnetic resonance imaging demonstrates the lesion has no mass effect and there is a characteristic hemosiderin ring around them (Fig. 100–6). ■

Figure 100–4. Severe radiation-induced leukoencephalopathy following radiation for a left frontoparietal anaplastic astrocytoma.

B A

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Figure 100–5. Late radiation-induced diffuse calcific microangiopathy (A) and a radiation-induced meningioma in the falx (B), occurring 20 years after treatment with radiation therapy for medulloblastoma.

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Figure 100–6. Cavernous hemangiomas (dark circular areas) in the temporal lobe and pons years after radiation therapy for a craniopharyngioma.

chapter 100 neurological complications of cancer treatments

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NEUROLOGICAL COMPLICATIONS OF SPINAL CORD/PLEXUS IRRADIATION Radiation-induced spinal cord damage can follow radiation for spinal tumors or where the spinal cord is included in the radiation field for treatment of other tumors. The incidence is 0.5% with a total dose of 4500 cGy, 5% when the cord receives between 5700 and 6100 cGy, and 50% when the cord receives 6800 to 7300 cGy. Incidence also depends on the size of the area of nervous system irradiated.

Early Local Neurological Complications of Radiotherapy Positioning for radiation or insufficient padding can be associated with nerve trauma, either as a result of compression of the nerves (brachial plexus, radial nerve, ulnar nerve) or due to a brachial neuritis. Nerve compression is apparent immediately after the treatment session and is often confined to one nerve. Brachial neuritis can mimic an acute cervical disc. It is usually preceded by very severe “boring” scapular or shoulder pain, which then eases off over a number of days or weeks to leave muscle wasting proximally, often with winging of the scapula. Its onset and severity are too acute to mimic direct nerve invasion from cancer. The condition improves spontaneously with time.

Acute Radiation Myelopathy This can occur within days of starting radiation for a spinal cord or epidural tumor. Treatment is with steroids.

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Figure 100–7. T1-weighted gadolinium-enhanced magnetic resonance imaging of the cord showing contrast-enhanced area appearing some weeks after radiation therapy for a spinal metastatic deposit.

Early Delayed Radiation Myelopathy Subacute transient myelopathy is common after radiotherapy of the spine. It may occur in up to 5% to 15% of patients treated for Hodgkin’s disease where the cord is in the field. The only symptom experienced may be Lhermitte’s phenomenon. There are rarely findings on imaging, but some develop high signal in the cord with contrast enhancement (Fig. 100–7). The symptoms improve after 1 to 9 months. Steroids are rarely required.

Delayed Progressive Myelopathy This occurs in 1% to 12% of long-term survivors after radiation for esophageal, lung, lymphoma, and head and neck cancers, when the spinal cord is in the radiotherapy field. The peak incidence is between 1 and 2 years after treatment. It usually causes numbness in the legs and abdomen below the level of the radiation field, which may be asymmetrical at the beginning. Sometimes a Brown-Sequard syndrome is seen, and there may also be autonomic features. Slowly progressive sensory and motor symptoms may lead to paraparesis in about one half of patients. Magnetic resonance imaging shows low-intensity signal on T1-weighted images and highintensity signal on T2-weighted scans, occasionally with contrast enhancement. There may be some swelling of the cord, although later in the course of the illness the cord becomes atrophic. Paraparesis is usually irreversible when it occurs.

Lower Motor Neuron Syndrome This may occur between 4 months and many years after radiation therapy. It is slowly progressive; causes weakness, wasting, fasciculation, and reflex loss mainly in the legs; and may mimic motor neuron disease. There is no sensory loss or sphincter dysfunction. The condition progresses over several months, but stabilization may then occur. Magnetic resonance imaging is usually normal or shows some cord atrophy.

Brachial and Lumbosacral Plexopathies Radiation-induced plexopathies usually begin years after treatment and have a progressive course. They are usually associated with breast cancer or lymphoma. Brachial neuropathies usually manifest with numbness or paraesthesia of the fingers, followed by pain and sometimes weakness. The symptoms may stabilize, although they can progress. The condition is believed to be due to fibrosis of tissues surrounding the plexus and perhaps radiation-induced vascular occlusion of vessels supplying the plexus or nerves leading to nerve infarction. Distinguishing these plexopathies from tumor involvement or other causes of brachial plexopathy can be difficult, although Horner’s syndrome and early, severe pain are found more fre-

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quently in brachial plexus metastasis. Myokymia (spontaneous, semirhythmical bursts of electrical potentials) is found in about one half of patients with radiation-induced plexopathy. Lumbosacral plexopathy has similar clinical features but involves the lower limbs. Malignant nerve sheath tumors of the brachial plexus, Lumbosacral plexus, or peripheral nerves can rarely complicate radiotherapy.

K E Y

P O I N T S

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Complications of chemotherapy affect the central or peripheral nervous systems and are commonly dose related. They develop during or within months of completion of treatment.

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Encephalopathy may be due to chemotherapy; however, metabolic, infective, vascula, or other drug-related causes are more likely.

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Intratumoral, intrathecal, or intracarotid therapies are more frequently associated with focal neurological worsening or encephalopathy than is systemic treatment.

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Peripheral neuropathy may progress for weeks after discontinuation of chemotherapy (“coasting”) and up to 30% start after completion of treatment.

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Early delayed effects of radiation may mimic tumor progression but are reversible with short courses of corticosteroids.

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Late effects of radiation can produce focal brain necrosis or diffuse white matter damage.

Suggested Reading Belka C, Budach W, Kortmann RD, et al: Radiation induced CNS toxicity: molecular and cellular mechanisms. Br J Cancer 2001; 85:1233-1239. Crossen JR, Garwood D, Glastein E, et al: Neurobehavioural sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994; 12:627-642. Keime-Guibert F, Napolitano M, Delattre J-Y: Neurological complications of radiotherapy and chemotherapy, J Neurology 1998; 245:695-708. Verstappen CCP, Heimans JJ, Hoekman K, et al: Neurotoxic complications of chemotherapy in patients with cancer. Drugs 2003; 63:1549-1563.

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PARANEOPLASTIC DISORDERS THE NERVOUS SYSTEM ●

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Myrna R. Rosenfeld and Josep Dalmau

Paraneoplastic neurological disorders (PNDs) are an extensive group of syndromes that can affect any part of the nervous system by mechanisms that are mostly immune mediated (Table 101–1).1 PNDs are more frequent than previously considered, with an incidence that varies with each type of tumor. The tumors most frequently involved are small cell lung cancer (SCLC) (~3% of patients develop PND), thymoma (15%), and plasma cell dyscrasias associated with malignant monoclonal gammopathies (~5% to 15%). With other solid tumors, the incidence of PND is less than 1%.2 In 60% of patients with PND, symptoms develop before the presence of a tumor is known; the majority of these patients are seen by neurologists, who should be aware that prompt diagnosis and treatment of the tumor along with immunotherapy may stabilize or improve the PND. In 40% of patients, symptoms of PND develop after the tumor diagnosis or at tumor recurrence. In this group of patients, the differential diagnosis is extensive because PND may mimic many other neurological complications of cancer or its treatment. The diagnosis of PND has been facilitated by serological tests that are based on the detection of antineuronal antibodies in the patients’ serum or cerebrospinal fluid (CSF), but in at least 40% of patients, no antibodies are detected, and in some instances, the antibodies can be detected in patients who have cancer but not PND.3 Therefore, although testing for these antibodies is useful, it does not replace the importance of a comprehensive clinical assessment that should always rule out other complications of cancer. In addition to the immune-mediated PNDs, patients with cancer may develop neurological symptoms from a large and heterogeneous group of mechanisms unrelated to metastasis; these are not further discussed but are listed in Table 101–2.

IMMUNOPATHOGENESIS OF PARANEOPLASTIC NEUROLOGICAL DISORDERS AND EFFECTS ON THE TUMOR Paraneoplastic Neurological Disorders of the Central Nervous System Many of these disorders occur in association with immune responses against intraneuronal antigens expressed by the

underlying cancer (paraneoplastic or onconeuronal antigens). These immune responses are characterized by the presence of antibodies and cytotoxic T cell responses against the onconeuronal antigens. As far as the antibodies are concerned, there have been several attempts to reproduce PND by passive transfer of serum or immunoglobulin G (IgG) to animals or by immunization with recombinant antigens that prime B cell responses.4-6 These procedures did not result in neurological dysfunction, although immunization did result in high titers of serum antibodies.7 It has been argued that the antibodies cannot reach the intracellular antigens, but data from other immune-mediated disorders suggest that antibodies can enter cells and disrupt the function of the antigen.8 Prior studies may have failed in part because they did not reproduce the continuous intrathecal synthesis of antibodies that occurs in patients with PND. As far as the T cell response is concerned, a pathogenic role was initially suggested by the neuropathological findings in autopsy studies of patients with PND.9 These studies demonstrated prominent infiltrates of inflammatory cells, later characterized as CD4+ and CD8+ T cells that are usually accompanied by microglial activation and gliosis (Fig. 101–1).10,11 Analysis of the presence of antigen-specific T cells in the peripheral blood and brain infiltrates of patients and studies of antigen presentation by dendritic cells or fibroblasts modified to express the paraneoplastic antigens provide strong evidence of a role of cytotoxic T cells.12-15 An attempt to model the disease in animals by priming the T cell response resulted in minimal perivascular inflammatory infiltrates but did not reproduce the disease or result in interstitial T cell infiltrates with neuronophagia that occur in patients.16 Overall, these studies suggest that both antibody and cytotoxic T cell responses are probably necessary to cause neuronal injury. This concept is important not only for modeling the disease but also for the development of treatment strategies for PNDs of the central nervous system (CNS).

Paraneoplastic Neurological Disorders of the Peripheral Nervous System For many PNDs of the peripheral nerve and muscle, the evidence of immune-mediated mechanisms is also abundant, but the target antigens are less well defined than in PNDs of the

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T A B L E 101–1. Classification of Immune-Mediated Paraneoplastic Neurological Disorders Area Involved

Classical Syndromes

Nonclassical Syndromes

Central nervous system

Encephalomyelitis Limbic encephalitis Cerebellar degeneration Opsoclonus-myoclonus Subacute sensory neuronopathy Gastrointestinal paresis or pseudo-obstruction

Brainstem encephalitis Stiff-person syndrome Necrotizing myelopathy Motor neuron disease Acute sensorimotor neuropathy (Guillain-Barré syndrome, plexitis) Subacute and chronic sensorimotor neuropathies Neuropathy of plasma cell dyscrasias and lymphoma Vasculitis of the nerve and muscle Pure autonomic neuropathy Acute necrotizing myopathy Polymyositis Myasthenia gravis Acquired neuromyotonia Optic neuritis

Dorsal root ganglia or peripheral nerves

Muscle

Dermatomyositis

Neuromuscular junction

Lambert-Eaton myasthenic syndrome Cancer-associated retinopathy Melanoma-associated retinopathy

Eye and retina

T A B L E 101–2. Nonmetastatic Neurological Complications of Cancer Different from Immune-Mediated Paraneoplastic Neurological Disorders Syndrome

Proposed Mechanism

Cerebrovascular disease Wernicke-Korsakoff syndrome Myelopathy, sensory neuropathy Pellagra-like syndrome Diffuse metabolic encephalopathy Opportunistic CNS infections POEMS neuropathy

Coagulopathy Thiamine deficiency Cobalamin deficiency

Carcinoid myopathy Cachectic myopathy

Niacin deficiency in carcinoid tumors Hypoxia, organ failure, electrolyte imbalance, endocrine disorders Cancer- or treatment-related immunodeficiency Cytokines (IL-6, IL-1β, TNF-α), MMP, VEGF Increased serotonin secretion by carcinoid tumors Proteolytic tumor-derived “toxohormone”-like peptides, cytokines (TNF-α, IFN γ, IL-6, IL-1β)

CNS, central nervous system; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinases; POEMS, syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. ■

CNS. Evidence of immune mechanisms is found mainly by the detection of inflammatory infiltrates composed of T cells. A direct pathogenic role of antibodies has been demonstrated in only a few disorders that can occur with or without a cancer association, including (1) neuromyotonia and antibodies to voltage-gated potassium channels, (2) a subset of autonomic neuropathies and antibodies to the ganglionic acetylcholine receptor (AChR), and (3) disorders of the neuromuscular junction, such as myasthenia gravis in association with antibodies to the AChR of the neuromuscular junction and the Lambert-Eaton myasthenic syndrome (LEMS) in association with antibodies to P/Q-type voltage-gated calcium chan-

Figure 101–1. Activated cytotoxic T cells (dark brown staining) in the brain of a patient who died of anti-Hu–associated paraneoplastic encephalomyelitis. The T cells have been immunolabeled with TIA, a marker of activated cytotoxic T cells. Small arrows indicate T cells; arrowhead indicates a neuron undergoing degeneration.

nels. In contrast to PNDs of the CNS, in which the antigens are usually intraneuronal, the antigens of antibody-mediated PNDs are receptors or ion channels expressed on the surface of nerves, or at the preneuromuscular or postneuromuscular synapse.

chapter 101 paraneoplastic disorders of the nervous system Effects of Paraneoplastic Immunity on the Tumor It has been suggested that paraneoplastic immunity is clinically effective in controlling tumor growth, accounting for the small size and limited metastatic burden of tumors associated with PNDs. However, despite the demonstration that some patients with PNDs develop cytotoxic T cell responses to tumor antigens, the oncological outcomes in studies of hundreds of patients with antibody-associated PND do not significantly differ from those of patients without PNDs.17-23 In addition, investigators who examined whether immunotherapy favored tumor growth did not identify a change in tumor behavior.24,25 By and large, these studies suggest either that the efficacy of the antitumor immune response is minimal or that the cancer usually overcomes the antitumor immune effect.1

GENERAL APPROACH TO THE DIAGNOSIS OF PARANEOPLASTIC NEUROLOGICAL DISORDERS The diagnosis of PNDs is usually based on (1) the recognition of the neurological syndrome, (2) the demonstration of the associated cancer, and (3) the detection of serum and CSF paraneoplastic antibodies.3

Recognition of the Neurological Syndrome An extensive group of disorders similar to PNDs may occur in the absence of cancer (Table 101–3). However, some syndromes are associated with cancer much more frequently than others, or the clinical features are characteristic enough that they readily suggest a paraneoplastic etiology. These syndromes are

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considered “classical PNDs” (see Table 101–1). Other syndromes may result from paraneoplastic mechanisms but occur more frequently in the absence of cancer. These syndromes are considered “nonclassical” and necessitate a more extensive differential diagnosis. For example, a brainstem syndrome, chorea, or the Guillain-Barré syndrome may be paraneoplastic manifestations of cancer but are mostly not cancer related, or their development in a patient with cancer may simply be coincidental. Most PNDs develop and progress rapidly until stabilization in a few weeks or months, causing severe disability. Patients often become wheelchair bound or bedridden over a short period of time. PNDs that affect the CNS, dorsal root ganglia, or proximal nerve roots are often accompanied by lymphocytic pleocytosis, an elevated IgG index, the presence of oligoclonal bands, or intrathecal synthesis of paraneoplastic antibodies. However, similar CSF abnormalities can be encountered in any inflammatory or immune-mediated disorder of the CNS, and some patients with PNDs may have normal findings on CSF studies. In most instances, CSF studies are necessary to rule out other cancer complications, such as leptomeningeal metastasis.26 All patients with PNDs of the CNS and some peripheral nerve syndromes (e.g., plexopathies) should undergo neuroimaging evaluation of the involved area. Magnetic resonance imaging (MRI) is the best technique for ruling out metastatic lesions or other complications that may suggest a PND. In most PNDs of the CNS, the function of the blood-brain barrier is preserved, and therefore the affected brain regions are rarely enhanced with contrast material. The abnormalities are usually demonstrated with T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences. In syndromes such as limbic encephalitis with predominant hippocampal involvement

T A B L E 101–3. Differential Diagnosis of Paraneoplastic Neurological Disorders of the Central Nervous System Paraneoplastic Neurological Disorder Cerebellar degeneration

Limbic encephalitis

Sensory neuronopathy Opsoclonus-myoclonus

Differential Diagnosis

Additional Considerations in Patients Known to Have Cancer

Alcohol-related degeneration Vitamin deficiency (B1, E) Toxins (anticonvulsants, other) Infectious or postinfectious cerebellitis Miller-Fisher syndrome GAD-associated ataxia Gliadin-associated ataxia Idiopathic degeneration Viral encephalitis (HSV) Nonparaneoplastic (anti-VGKC) encephalitis Temporal lobe tumor Systemic lupus erythematosus Doxifluridine toxicity Toxic-metabolic encephalopathy Hashimoto’s encephalitis Sjögren’s syndrome Idiopathic encephalitis Sjögren’s syndrome Toxins (pyridoxine) Idiopathic neuronopathy Infectious, postinfectious encephalitis Metabolic encephalopathy Toxins Idiopathic encephalitis

Cerebellar metastasis Chemotherapy toxicity (5-FU, Ara-C)

Brain metastasis HHV 6 infection (particularly after bone marrow transplantation)

Chemotherapy (cisplatin, paclitaxel, docetaxel, vincristine) Brain metastasis

Ara-C, cytosine arabinoside; 5-FU, 5-fluorouracil; GAD, glutamic-acid decarboxylase; HHV, human herpesvirus; HSV, herpes simplex virus; VGKC, voltage-gated potassium channel.

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(short-term memory loss, seizures), the MRI findings are often suggestive of the syndrome, although the etiology could be nonparaneoplastic.27 There is also increasing evidence that brain [F18] fluorodeoxyglucose positron emission tomography (FDG-PET) has diagnostic usefulness in PNDs.28 In the early stages of PNDs, FDG-PET may show hypermetabolism in the abnormal brain regions identified by MRI, but in some patients, the MRI findings are normal.29 Biopsy of an abnormal brain region identified by MRI or FDG-PET may be considered if a neoplastic process is suspected or if the clinical, CSF, and MRI findings are unusual. Abnormalities supporting but not specific to PND include infiltrates of mononuclear cells, neuronophagic nodules, neuronal degeneration, microglial proliferation, and gliosis.30

antigen are helpful. All patients with a neuropathy of unclear etiology should be examined for the presence of a monoclonal gammopathy in the serum and urine and, if results are positive, undergo a skeletal survey and bone marrow biopsy; these studies may uncover a malignant plasma cell dyscrasia, amyloidosis, or B cell lymphoma.2 Close oncological surveillance should be undertaken in patients with classical PNDs with or without paraneoplastic antibodies and in patients with nonclassical PND and paraneoplastic antibodies. It is recommended that patients undergo periodic cancer screening for at least 5 years after diagnosis of PNDs; in 90% of patients, the underlying tumor is discovered within the first year of PND symptom manifestation. Patients whose cancer is in remission and who develop PNDs should be examined for tumor recurrence.

Demonstration of Associated Cancer PNDs usually develop at early stages of cancer, and therefore the tumor (or tumor recurrence) may be difficult to demonstrate. Modern imaging techniques are able to demonstrate small tumors that were often missed by techniques used previously. In most instances, the tumor is revealed by computed tomography of the chest, abdomen, and pelvis. The type of syndrome and paraneoplastic antibody may suggest a specific underlying tumor and the need for additional tests, such as mammography or ultrasonography of the pelvis or testes. Whole-body FDG-PET is very useful in demonstrating occult neoplasms or small metastatic lesions that may be more accessible for biopsy than the primary tumor is (Fig. 101–2).31 In addition to imaging studies, serum cancer markers such as carcinoembryonic antigen, CA-125, CA-15.3, or prostate-specific

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Detection of Paraneoplastic Antibodies Paraneoplastic antibodies are antibodies whose presence serves as a marker of the paraneoplastic origin of a neurological syndrome. Several concepts are important in testing for paraneoplastic antibodies (Table 101–4). First, antibodies are present in approximately 60% of patients with PNDs of the CNS; therefore, the absence of antibodies does not preclude a paraneoplastic syndrome. Second, paraneoplastic antibodies may be identified (usually at low titers) in the serum of a variable proportion of patients with cancer but without PND (i.e., anti-Hu and antiCV2/CRMP5 in 20% and 10% of patients with SCLC, respectively).32,33 Third, in PNDs of the CNS, the antibodies are found in serum and CSF; detection of CSF antibodies is a strong indicator that the associated neurological syndrome is paraneo-

Figure 101–2. A, Body fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrates the tumor in a patient with anti-Yo antibodies. Abnormal FDG uptake demonstrates right axillary adenopathy, revealed by biopsy to be an adenocarcinoma. The detection of serum and cerebrospinal fluid anti-Yo antibodies indicated that the patient had paraneoplastic cerebellar degeneration and that the primary tumor was likely to be in the breast. B, A section of rat cerebellum has been incubated with the serum of the patient; note that the anti-Yo antibody reacts predominantly with the cytoplasm of Purkinje cells and, to a lesser degree, with the cytoplasm of cells of the molecular layer.

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T A B L E 101–4. Paraneoplastic Antibodies Antibody

Associated Syndrome

Most Frequent Cancers

Well-Characterized Paraneoplastic Antibodies Hu (ANNA1) Paraneoplastic encephalomyelitis, PSN, PCD, limbic encephalitis Yo (PCA1) PCD CV2/CRMP5 Several Ri (ANNA2) Ataxia, opsoclonus-myoclonus, brainstem encephalitis Ma2* Limbic, diencephalic, brainstem encephalitis Amphiphysin Stiff-person syndrome, paraneoplastic encephalomyelitis

Small cell lung cancer Ovary, breast cancers Small cell lung cancer Breast, gynecological, small cell lung cancers Testicular, lung cancers Breast, small cell lung cancers

Partially Characterized Paraneoplastic Antibodies Tr PCD Zic4 PCD PCA2 Several ANNA3 Several

Hodgkin’s disease Small cell lung cancer Small cell lung cancer Small cell lung cancer

*Some patients harbor Ma1 and Ma2 antibodies; the presence of Ma1 is usually associated with predominant brainstem and cerebellar involvement and with tumors other than testicular neoplasms. The prognosis in patients with tumors other than testicular neoplasms is poorer than that of patients with Ma2 antibodies and testicular neoplasms. PCD, paraneoplastic cerebellar degeneration; PSN, paraneoplastic sensory neuronopathy.

plastic. Fourth, most PNDs of the peripheral nerve or muscle are not associated with paraneoplastic antibodies, except for anti-Hu (Fig. 101–3) and anti-CV2/CRMP5 antibodies. Fifth, not all paraneoplastic antibodies have the same sensitivity and specificity; on the basis of their clinical relevance, the paraneoplastic antibodies are classified in two categories: well-characterized paraneoplastic antibodies and partially characterized antibodies (see Table 101–4).3 Well-characterized paraneoplastic antibodies include antiHu, Yo, Ma2, Ri, CV2/CRMP5, and amphiphysin. These six antibodies and the corresponding antigens have been characterized by different laboratories and reported in large series of patients with PNDs. Detection of any of these antibodies strongly supports the diagnosis of PND even if no tumor is found at initial evaluation. Some antibodies are more syndrome specific than others; for example, anti-Yo antibodies are almost always accompanied by cerebellar degeneration, and anti-Ma2 antibodies are almost always accompanied by limbic or upper brainstem dysfunction, whereas anti-Hu or anti-CV2/CRMP5 antibodies are accompanied by a much wider spectrum of symptoms. Partially characterized antibodies are those with which clinical experience is limited or for which the target antigens are unknown. Until there is more experience, detection of any of these antibodies is of limited diagnostic value, and the management of affected patients should be similar to that of patients without paraneoplastic antibodies, including extensive clinical, CSF, and neuroimaging evaluations to rule out other, more frequent complications of cancer. Several antibodies, including P/Q-type voltage-gated calcium channels, voltage-gated potassium channels, and nicotinic or ganglionic AChR antibodies can be detected in both the paraneoplastic and nonparaneoplastic forms of the associated disorder (Table 101–5). These antibodies may assist in the diagnosis of the neurological disorder but are not predictive of the presence of a tumor. The same P/Q-type voltage-gated calcium channel antibodies that are associated with the paraneoplastic and nonparaneoplastic forms of LEMS have also been encountered in a subset of patients with paraneoplastic cerebellar degeneration (PCD) and SCLC; therefore, detection of these

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Figure 101–3. Expression of Hu proteins by human dorsal root ganglia neurons. Anti-Hu immunolabeling of a section of human dorsal root ganglia obtained from the autopsy study of a neurologically normal individual. Note that the Hu proteins are expressed specifically by the nuclei and, to a lesser degree, by the cytoplasm of neurons (brown staining). The surrounding satellite cells do not contain Hu proteins.

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T A B L E 101–5. Antibodies Associated with the Paraneoplastic and Nonparaneoplastic Forms of the Neurological Disorder Antibody

Syndrome

AChR (nicotinic, neuromuscular junction) AChR (ganglionic or neuronal) P/Q-type VGCC* VGKC

Myasthenia gravis

T A B L E 101–6. Diagnostic Criteria for Paraneoplastic Neurological Disorders Definite Paraneoplastic Neurological Disorders A classical syndrome and cancer A nonclassical syndrome that resolves or significantly improves after cancer treatment A nonclassical syndrome with paraneoplastic antibodies (well-characterized or not) and cancer A neurological syndrome (classical or not) with well-characterized antibodies and no detected cancer

Autonomic neuropathy Lambert-Eaton myasthenic syndrome Neuromyotonia, limbic encephalitis

Possible Paraneoplastic Neurological Disorders A classical syndrome with no paraneoplastic antibodies and no cancer but carrying high risk for an underlying tumor A neurological syndrome (classical or not) with partially characterized paraneoplastic antibodies and no detected cancer A nonclassical syndrome with cancer but without paraneoplastic antibodies

*In patients with cerebellar degeneration, with or without associated LambertEaton myasthenic syndrome, detection of these antibodies should prompt the search of a small cell lung cancer. AChR, acetylcholine receptor; VGCC, voltage-gated calcium channels; VGKC, voltage-gated potassium channels.

antibodies in patients with a subacute cerebellar syndrome should prompt the search for a SCLC.34

Diagnostic Criteria of Paraneoplastic Neurological Disorders Information obtained from the type of neurological syndrome, detection of the cancer, and presence or absence of paraneoplastic antibodies has been used to define general guidelines for the diagnosis of PNDs, with the caveat that both the diagnosis of the tumor and the development of the neurological syndrome should occur within 5 years (Table 101–6).3 Nowadays, the use of whole-body computed tomography and FDG-PET allows detection of the tumor at the time of neurological syndrome manifestation in 80% to 90% of the patients. The indicated guidelines are useful but not perfect, and patients with criteria of possible PND should be carefully considered for alternative diagnoses.

SPECIFIC PARANEOPLASTIC SYNDROMES Paraneoplastic Encephalomyelitis Paraneoplastic encephalomyelitis refers to an immune-mediated inflammatory disorder that can affect any part of the CNS, dorsal root ganglia, and autonomic nerves. The main areas involved include the hippocampus (limbic encephalitis), the Purkinje cells of the cerebellum (cerebellar degeneration), the lower brainstem (brainstem encephalitis), the dorsal root ganglia (sensory neuronopathy), the spinal cord (myelitis) (Fig. 101–4), and the sympathetic or parasympathetic ganglia and nerves (orthostatic hypotension, gastrointestinal paresis or pseudo-obstruction, cardiac arrhythmia, erectile dysfunction, and abnormal pupillary responses to light).17,19 Less frequently, patients may develop discrete focal cortical encephalitis, sometimes manifesting as epilepsia partialis continua. The diagnosis of paraneoplastic encephalomyelitis should be considered when the dominant symptoms result from involvement of two or more of the indicated areas. Symptoms of paraneoplastic encephalomyelitis develop rapidly and progress over weeks or months until stabilization or death. The CSF is almost always abnormal, with mild to moderate lymphocytic pleocytosis, increased protein concen-

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Figure 101–4. Lower motor neuron dysfunction and muscle atrophy secondary to paraneoplastic myelitis. Prominent atrophy involving the scapular region, trapezius, deltoid, and paraspinal muscles in a patient with SCLC and lower motor neuron dysfunction caused by anti-Hu–associated paraneoplastic myelitis.

tration, and oligoclonal bands or increased IgG index.18 Brain MRI findings are often abnormal; FLAIR or T2-weighted sequences reveal hyperintensities in involved areas and sometimes clinically silent regions; the abnormalities usually are not enhanced after administration of contrast material. For reasons that are unclear, contrast enhancement is more likely to occur in some forms of encephalitis (e.g., limbicdiencephalic encephalitis associated with anti-Ma2 antibodies) than in others (limbic encephalitis associated with anti-Hu antibodies).35,36 Several antibodies assist in the diagnosis of paraneoplastic encephalomyelitis and the underlying neoplasm (see Table 101–4). The management of paraneoplastic encephalomyelitis is based on prompt treatment of the tumor along with immunosuppression. Although the standard of care remains to be established, the use of corticosteroids and intravenous immunoglobulin (IVIg), combined with chemotherapy, may help stabilize or improve the neurological symptoms during the

chapter 101 paraneoplastic disorders of the nervous system time that the tumor is treated. Afterward, if the neurological symptoms have stabilized or improved, patients should be considered for prolonged treatment with immunosuppressants that target not only the antibodies but also the T cell immunity (e.g., cyclophosphamide combined with corticosteroids, among other strategies; see Fig. 101–1). Although this approach has not been useful for patients with advanced disease,37 there is evidence that at early stages of PNDs, it may be effective.1,24 Patients with brainstem symptoms have a much poorer prognosis than do patients with involvement of other areas of the CNS.

Limbic Encephalitis The dominant symptom of limbic encephalitis is short-term memory loss in association with confusion, confabulation, seizures, affective or mood disorders, and hypersomnia or insomnia.27 Patients may present with acute behavioral change, delusional thoughts, poor judgment, or status epilepticus, which lead to an initial diagnosis of psychosis, drug abuse, or malingering. FLAIR or T2-weighted MRI demonstrates abnormalities in the medial aspect of the temporal lobes, but sometimes the involvement is more extensive or affects areas outside the limbic system. FDG-PET may reveal hyperactivity in regions that are normal in MRI (Fig. 101–5).35 Electroencephalography usually demonstrates unilateral or bilateral temporal lobe epileptic discharges or slow background activity. Electroencephalographic monitoring is important in patients who appear confused or have a low level of consciousness; many of them are in nonconvulsive status epilepticus.

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The antibodies more frequently associated with paraneoplastic limbic encephalitis are anti-Hu, anti-CV2/CRMP5, and anti-Ma2.35,36,38 Patients with anti-Hu antibodies usually have SCLC, and those with anti-CV2/CRMP5 antibodies often have SCLC or thymoma. Anti-Ma2 antibodies in young men is usually associated with testicular neoplasms; in elderly men or women, the leading neoplasm is non–small cell lung cancer. The response of paraneoplastic limbic encephalitis to treatment is variable; some patients exhibit dramatic improvement if the tumor is treated promptly or sometimes with corticosteroids and IVIg, whereas others with similar symptoms and antibodies do not respond to therapy. However, improvement is unlikely if the tumor is not treated. There is some evidence that patients without paraneoplastic antibodies or young patients with anti-Ma2 antibodies are more likely to experience improvement than are patients with anti-Hu or CV2/CRMP5 antibodies.35,36 A subset of patients with limbic encephalitis harbors antibodies to voltage-gated potassium channels; most of these patients do not have cancer, but in a few instances a SCLC has been found.39 Although this type of limbic encephalitis usually responds to IVIg, plasma exchange, or corticosteroids, some patients develop life-threatening complications (e.g., status epilepticus and hyponatremia) that are difficult to control.

Paraneoplastic Cerebellar Degeneration Patients with PCD usually present with dizziness, vertigo, oscillopsia, or gait unsteadiness that rapidly evolves to frank gait

Figure 101–5. Limbic encephalitis. Brain magnetic resonance imaging (MRI) (A) and fluorodeoxyglucose positron emission tomography (FDG-PET) (B) in a patient with small cell lung cancer who developed subacute short-term memory deficits and mild numbness in the fingers of the right hand. The patient’s serum and cerebrospinal fluid contained anti-Hu antibodies, and the diagnosis was paraneoplastic limbic encephalitis and mild sensory neuronopathy. Brain MRI demonstrates fluid-attenuated inversion recovery asymmetrical hyperintensities, predominantly in the left medial temporal lobe (A, right), and the FDG-PET shows hyperactivity in the hippocampi (B). These neuroimaging findings are typical of limbic encephalitis.

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and limb ataxia. Other symptoms include dysarthria, dysphagia, diplopia (often without obvious oculoparesis), and predominant downbeat nystagmus. MRI of the brain usually yields normal findings at symptom presentation and reveals cerebellar atrophy as the disease evolves.40 Cerebellar symptoms may occur in association with any of the paraneoplastic antibodies listed in Table 101–4. The tumors more frequently associated with PCD are lung, ovary, and breast cancers and lymphoma. A few antibodies (anti-Yo, anti-Tr) are associated with dominant cerebellar symptoms without significant involvement of other areas of the nervous system (see Fig. 101–2B).41,42 Other antibodies are usually associated with additional neurological symptoms. Patients with PCD and SCLC should be evaluated for motor weakness, because some of these patients may have LEMS.40 PCD results from degeneration of the Purkinje cells of the cerebellum along with inflammatory infiltrates in the deep cerebellar nuclei and lower brainstem. As occurs with other PNDs, 30% to 40% of patients with PCD do not harbor antineuronal antibodies. In these patients, the differential diagnosis is extensive (see Table 101–3). Although PCD is refractory to most treatments, isolated case reports of response to plasma exchange, IVIg, and T cell immunosuppression (e.g., cyclophosphamide) have been reported. Prompt diagnosis and treatment of the tumor, along with immunosuppression, may stabilize the disorder or prevent involvement of other areas of the CNS.

G

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M

Figure 101–6. Reactivity of amphiphysin antibodies with cerebellum. Section of rat cerebellum reacted with the serum of a patient with paraneoplastic stiff-person syndrome and breast cancer. Note the intense and diffuse reactivity of the antibodies (brown staining) with the molecular (M) and granular layers (G) of the cerebellum; the Purkinje cells are spared. This pattern of reactivity is typical of amphiphysin antibodies that were confirmed with immunoblot (not shown).

Opsoclonus-Myoclonus

Stiff-Person Syndrome

Opsoclonus is a disorder of eye motility with involuntary, chaotic, conjugate saccades. It is almost always associated with myoclonus of the trunk and limbs and sometimes with truncal or limb ataxia. Some patients develop symptoms of diffuse encephalopathy that may lead to stupor, coma, and death. In adults, the tumors more frequently involved are SCLC and gynecological and breast cancers.43 In children, opsoclonusmyoclonus is usually accompanied by hypotonia, irritability, behavioral changes, and psychomotor retardation, and the underlying tumor is a neuroblastoma.44 MRI findings are usually normal, and the CSF is normal or exhibits lymphocytic pleocytosis, increased protein concentration, or oligoclonal bands. The pathological substrate of opsoclonus-myoclonus has not been established; autopsy findings can be normal or reveal encephalitis in the brainstem or cerebellum. Most patients with paraneoplastic opsoclonus-myoclonus do not have detectable paraneoplastic antibodies. An exception is the anti-Ri antibody that identifies a subgroup of patients with opsoclonus-myoclonus, ataxia, breast or gynecological cancers, and, less frequently, SCLC.45 Other antibodies (e.g., anti-Yo, anti-Ma2, anti-Hu) have been reported in a few patients with opsoclonus associated with cerebellar or brainstem encephalitis. Paraneoplastic opsoclonus-myoclonus may respond to IgGdepleting strategies (IVIg or plasma exchange and corticosteroids) along with treatment of the tumor; improvement is rare if the tumor is not treated. There is an idiopathic form of opsoclonus-myoclonus that tends to occur in younger patients and responds better to immunotherapy.43

In about 80% of patients with stiff-person syndrome, the disorder develops as a nonparaneoplastic phenomenon in association with diabetes, polyendocrinopathy, and antibodies to glutamic acid decarboxylase. Neurological symptoms include fluctuating rigidity of the axial musculature with superimposed spasms precipitated by emotional upset and auditory or somesthetic stimuli. Muscle stiffness affects primarily the lower trunk and legs, but it can extend to the arms. Electrophysiological studies show continuous activity of motor units in the stiffened muscles, which improves after treatment with diazepam. The rigidity lessens during sleep or general anesthesia.46 A similar syndrome, although with more frequent involvement of the arms, may occur as a paraneoplastic manifestation of cancers of the breast and lung and, less frequently, Hodgkin’s lymphoma. Paraneoplastic stiff-person syndrome is characterized by the presence of antibodies to amphiphysin (Fig. 101–6) and, in rare cases, with antibodies to glutamic acid decarboxylase.47 Muscle rigidity may also occur with less frequent syndromes: paraneoplastic encephalomyelitis with rigidity (usually with brainstem involvement) or spinal myoclonus with rigidity. Some of these patients harbor anti-Ri antibodies and have acute episodes of flushing and piloerection, which is suggestive of autonomic dysfunction. The pathological substrate of paraneoplastic stiff-person and similar syndromes is an immune-mediated dysfunction of the γ-amino butyric acid and glycinergic spinal cord neurons at the presynaptic level. Treatment of the tumor and the use of steroids are usually effective. IVIg is useful in patients with nonparaneoplastic stiff-person syndrome and probably effective in the paraneoplastic form of the disorder.

chapter 101 paraneoplastic disorders of the nervous system Paraneoplastic Sensory Neuronopathy Paraneoplastic sensory neuronopathy (PSN) is characterized by progressive numbness and often painful dysesthesias involving the limbs, trunk, and, less frequently, the cranial nerves, causing face numbness or sensorineural hearing loss. The symptom manifestation is frequently asymmetrical and is accompanied by decreased or abolished reflexes and relative preservation of strength. All types of sensation can be affected, but loss of proprioception is often predominant. As a result, patients develop sensory ataxia and pseudoathetoid movements of the extremities (predominantly the hands), demonstrated when the patient closes the eyes or is distracted during the examination.48 PSN results from inflammatory involvement of the dorsal root ganglia, usually accompanied by dorsal nerve root inflammation. For this reason, symptoms are often asymmetrical and the CSF exhibits inflammatory abnormalities. PSN is frequently associated with paraneoplastic encephalomyelitis, particularly in patients with SCLC. These patients almost always harbor anti-Hu antibodies (see Fig. 101–3).17 Electrophysiological studies demonstrate that patients with PSN have small-amplitude or no sensory nerve action potentials with relative preservation of motor conduction velocities. Because PSN often overlaps with paraneoplastic encephalomyelitis that may affect lower motor neurons and is sometimes associated with peripheral neuropathy, the electrophysiological studies may show motor abnormalities.49,50 Autopsy studies indicate that when anti-Hu antibodies are detected, the sensory symptoms result from involvement of the dorsal root ganglia and dorsal nerve roots.17 Some of these patients harbor additional antibodies to CV2/CRMP5 (Fig. 101–7).51

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Prompt treatment of patients with corticosteroids and IVIg (along with treatment of the tumor) may result in stabilization or mild improvement of the dorsal root ganglia dysfunction, sometimes confirmed with improvements in results of electrophysiological studies.52

Paraneoplastic Neuropathies Subacute paraneoplastic neuropathies that occur at early stages of cancer or tumor recurrence include PSN (that, as discussed previously, result from dorsal root ganglia involvement rather than peripheral nerve involvement) and a group of debilitating sensorimotor neuropathies whose appearance may precede the diagnosis of the tumor. The course of these neuropathies is usually rapid and progressive, rarely with relapsing and remitting episodes.53 The dominant symptoms are sensorimotor deficits, sometimes with pain as a major complaint (i.e., vasculitis of the nerve and muscle). In rare instances, the sympathetic or parasympathetic nerves are the main target of the paraneoplastic disorder, which results in acute pandysautonomia. Life-threatening symptoms include gastrointestinal dysmotility with intestinal pseudo-obstruction,54,55 orthostatic hypotension,56,57 and cardiac dysrhythmias.17,58,59 Other symptoms may include dry mouth, erectile dysfunction, anhidrosis, and sphincter dysfunction.60 At advanced stages of cancer, the paraneoplastic neuropathies are more frequent but milder than those that precede the cancer diagnosis. An extensive number of chemotherapeutic agents can cause a neuropathy, and these should be considered in the differential diagnosis.61

Figure 101–7. Reactivity of anti-CV2/CRMP5 antibodies with rat brain (A) and cerebellum (B). Antibodies to CRMP5 (collapsing response mediator protein) react with proteins expressed by subsets of neurons and glial cells; the pattern of reactivity varies with the fixatives used. Both specimens exhibit the reactivity of the serum from a patient with paraneoplastic encephalitis and cerebellar dysfunction; note the intense immunolabeling of the neuronal cell bodies and neuronal processes.

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Several malignancies involving plasma cells and B lymphocytes, such as myeloma or B cell lymphoma, are associated with sensorimotor neuropathies that often resemble chronic inflammatory demyelinating neuropathy. Patients with Waldenström’s macroglobulinemia develop distal symmetrical sensorimotor polyneuropathy with predominant involvement of large sensory fibers (vibration sense is particularly affected).62 In patients with paraneoplastic neuropathies, antibody markers are often not found except for anti-Hu antibodies, which usually indicate dorsal root ganglia involvement, and anti-CV2/CRMP5 antibodies, which may be associated with neuropathies with mixed axonal and demyelinating features. Antibodies against myelin-associated glycoprotein are often found in patients with Waldenström’s macroglobulinemia, but similar antibodies can be identified in patients with immunoglobulin M monoclonal gammopathies without an underlying malignancy. Several studies indicate that antiganglioside antibodies are absent in most paraneoplastic neuropathies,63 although a few isolated cases have been reported.64 Patients with autonomic neuropathy may harbor antibodies to the ganglionic AChR; similar antibodies are found in patients without cancer.65 In general, paraneoplastic neuropathies with predominant demyelinating features respond to immunotherapy (corticosteroids, IVIg, or plasma exchange), whereas those with axonal features are more difficult to treat.53 The neuropathy associated with vasculitis of the nerve and muscle may respond dramatically to corticosteroids and cyclophosphamide.66 Other treatment-responsive neuropathies include those associated with Waldenström’s macroglobulinemia (treatment of the malignancy, IVIg, plasma exchange, corticosteroids, or rituximab, among others); sclerotic myeloma (resection of the sclerotic lesion, focal radiation, or chemotherapy); and autonomic neuropathy with ganglionic AChR antibodies (IgG-depleting strategies).65 The neuropathy of multiple myeloma is refractory to most treatments (for a detailed review of paraneoplastic neuropathies, see Rudnicki and Dalmau, 20002).

Lambert-Eaton Myasthenic Syndrome LEMS results from an antibody-mediated attack against the P/Q-type voltage-gated calcium channels located at the presynaptic level of the neuromuscular junction. This interferes with the release of acetylcholine and results in muscle weakness and fatigability. LEMS should be suspected in patients with proximal weakness, dry mouth, and decreased or absent reflexes, particularly if the patient is known to have SCLC or a history of smoking.67 In general, the legs are more involved than the arms. Mild muscle aches and distal paresthesias are common.68 Cranial nerve involvement is frequent but mild and transient and is almost always accompanied by motor weakness in the extremities. The symptom presentation of isolated ocular weakness virtually excludes the diagnosis of LEMS.69 In addition to dry mouth, patients may have other signs of autonomic dysfunction (orthostatic hypotension, erectile dysfunction, blurred vision). Electrophysiological studies show smallamplitude compound muscle action potentials. At slow rates of repetitive nerve stimulation (2 to 5 Hz), there is a decremental response, whereas at fast rates (20 Hz or more) or after maximal voluntary muscle contraction, facilitation occurs with an incremental response of at least 100%.

Approximately 60% of patients with LEMS have an underlying neoplasm, usually SCLC or, in rare cases, other tumors such as lymphoma.67 Paraneoplastic LEMS may be associated with PCD or paraneoplastic encephalomyelitis.40 The nonparaneoplastic cases often have a slower symptom presentation and are associated with other autoimmune conditions such as thyroiditis or insulin-dependant diabetes mellitus.67 Treatment of the tumor and medications that enhance acetylcholine release (3,4-diaminopyridine or a combination of pyridostigmine and guanidine) are usually effective.70 IVIg and plasma exchange ameliorate symptoms within 2 to 4 weeks, but the benefit is transient. Long-term immunotherapy with prednisone or azathioprine is an alternative for patients who do not experience improvement with 3,4-diaminopyridine.71

Myasthenia Gravis Myasthenia gravis is a disorder of the postsynaptic neuromuscular junction, usually caused by anti-AChR antibodies. Patients without these antibodies may harbor antibodies against muscle-specific kinase. In contrast to LEMS, in which the motor weakness tends to progress in a caudocranial direction with decreased or absent reflexes, myasthenia gravis tends to progress in the opposite direction with early and prominent ocular paresis and preservation of the reflexes.69 Approximately 10% of patients with myasthenia gravis have thymoma. Thymoma-related myasthenia gravis is almost invariably accompanied by AChR antibodies but not by anti–musclespecific kinase antibodies. After resection of the thymoma, the treatment is similar to that in patients without thymoma and may include plasma exchange, IVIg, anticholinesterase inhibitors, and long-term immunosuppression.71

Paraneoplastic Dermatomyositis and Polymyositis These two disorders have similar clinical features, including proximal muscle weakness, myalgia, and muscle tenderness. Pharyngeal, esophageal, and neck flexor muscles are often involved. Reflexes and sensation are unaffected. Dermatomyositis is accompanied by purplish discoloration of the eyelids (heliotrope rash) and erythematous scaly lesions over the knuckles. Associated conditions may include arthralgias and contractures, myocarditis, and interstitial lung disease.72 The diagnoses of both inflammatory myopathies are based on clinical and electrophysiological findings, detection of elevated serum muscle enzyme levels (which can be normal in some patients), and demonstration of inflammatory infiltrates in the muscle biopsy. Dermatomyositis is probably caused by an immune-mediated intramuscular angiopathy, leading to ischemia, muscle fiber necrosis, and perifascicular atrophy. The inflammatory infiltrates are composed of macrophages, B cells, and CD4+ T cells.73,74 In contrast, polymyositis is mediated by a CD8+ T cell response. Although patients with polymyositis may have cancer, studies suggest that in most instances, the presence of both is coincidental.75 In contrast, many patients with dermatomyositis (particularly those older than 50 years) have cancer; the tumors more involved are ovarian and breast cancers in women and lung and gastrointestinal cancers in men. There are no serological tests indicative of paraneoplasia. Besides treatment of the tumor, the management of paraneoplastic dermato-

chapter 101 paraneoplastic disorders of the nervous system myositis and polymyositis is similar to that of the nonparaneoplastic form of these disorders and includes corticosteroids, azathioprine, and IVIg.76,77

Acute Necrotizing Myopathy This disorder is a rare paraneoplastic manifestation of cancer that manifests with acute and severe muscle weakness, markedly increased serum muscle enzyme levels, and extensive muscle necrosis with mild or no inflammatory infiltrates. Patients often die as a result of the extensive muscle involvement; a few patients respond to treatment of the tumor and corticosteroids.78 The disorder has been reported in association with other syndromes, including myasthenia gravis with thymoma and rhabdomyolysis.79,80

Paraneoplastic Visual Syndromes Paraneoplastic retinopathy is characterized by progressive loss of photoreceptor function that usually precedes the diagnosis of cancer.81 Symptoms include painless loss of visual acuity and color vision, light-induced glare, photosensitivity, and peripheral and ringlike scotomas. Funduscopic examination findings are normal or demonstrate arteriolar narrowing. The electroretinogram shows flat photopic responses. Paraneoplastic retinopathy associated with antirecoverin antibodies is known as cancer-associated retinopathy and is usually associated with SCLC (Fig. 101–8).82 There is evidence that antirecoverin antibodies can gain access to the aqueous humor and may cause apoptotic death of photoreceptor cells.83,84 Patients with metastatic melanoma may develop a syndrome known as melanoma-associated retinopathy. Symptoms include night blindness, relative preservation of visual acuity, shimmering or flickering sensations, midperipheral field defect, and prolonged dark adaptation. Retinal vessel attenuation and vitreous infiltrates are found in 30% of patients. The electroretinogram shows no or decreased adapted B wave response.

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Some patients with melanoma-associated retinopathy have antibodies against unknown antigens expressed by bipolar cells of the retina.85,86 The treatment of paraneoplastic retinopathies is based on controlling the tumor; there are a few reports of visual improvement after corticosteroids, IVIg, or plasma exchange, but the majority of patients do not experience improvement with immunotherapy.82,86 Optic neuritis is a very rare paraneoplastic manifestation of cancer that almost always occurs in association with encephalomyelitis and SCLC. Symptoms include painless bilateral visual loss, swollen optic discs, and field defects with tunnel vision. Several associated antibodies have been identified, including anti-Hu, anti-Tr, anti-Yo, and, more frequently, antiCV2/CRMP5.87 Patients may have concurrent retinitis, vitreal infiltrates, and abnormal electroretinographic patterns. The visual outcome is usually poor. Optic neuritis and myelitis resembling Devic’s disease has been reported in a patient with myasthenia gravis, thymoma, and necrotizing myopathy. An antibody against unknown antigens expressed by the CNS and thymoma was identified; all neurological symptoms except visual acuity were ameliorated by immunotherapy.79

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PNDs are more frequent than previously considered; the incidence varies with each type of tumor.

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Symptoms of PNDs develop before the presence of a tumor is known in more than 50% of cases.

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Prompt diagnosis and treatment of the tumor along with immunotherapy may stabilize or improve the PND.

Suggested Reading Bataller L, Dalmau JO: Paraneoplastic disorders of the central nervous system: update on diagnostic criteria and treatment. Semin Neurol 2004; 24:461-471. Darnell RB, Posner JB: Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003; 349:1543-1554. Graus F, Delattre JY, Antoine JC, et al: Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135-1140. Rosenfeld MR, Dalmau J: Current therapies for paraneoplastic neurologic syndromes. Curr Treat Options Neurol 2003; 5:6977. Rudnicki SA, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 2000; 23:1800-1818.

References ■

Figure 101–8. Antirecoverin antibodies in a patient with cancerassociated retinopathy. Section of bovine retina incubated with the serum of a patient with cancer-associated retinopathy. The brown staining at the level of the photoreceptor layer (arrow) corresponds to antibodies to recoverin, the main autoantigen of cancerassociated retinal degeneration.

1. Bataller L, Dalmau JO: Paraneoplastic disorders of the central nervous system: update on diagnostic criteria and treatment. Semin Neurol 2004; 24:461-471. 2. Rudnicki SA, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 2000; 23:18001818.

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3. Graus F, Delattre JY, Antoine JC, et al: Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135-1140. 4. Tanaka K, Tanaka M, Onodera O, et al: Passive transfer and active immunization with the recombinant leucine-zipper (Yo) protein as an attempt to establish an animal model of paraneoplastic cerebellar degeneration. J Neurol Sci 1994; 127:153158. 5. Tanaka K, Tanaka M, Igarashi S, et al: Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody. 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to paraneoplastic cerebellar degeneration lymphocytes in severe combined immunodeficiency mice. Clin Neurol Neurosurg 1995; 97:101105. 6. Graus F, Illa I, Agusti M, et al: Effect of intraventricular injection of an anti–Purkinje cell antibody (anti-Yo) in a guinea pig model. J Neurol Sci 1991; 106:82-87. 7. Sillevis Smitt PA, Manley GT, et al: Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 1995; 45:18731878. 8. Levin MC, Lee SM, Kalume F, et al: Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 2002; 8:509-513. 9. Henson RA, Hoffman HL, Urich H: Encephalomyelitis with carcinoma. Brain 1965; 88:449-464. 10. Graus F, Ribalta T, Campo E, et al: Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis. Neurology 1990; 40:219222. 11. Jean WC, Dalmau J, Ho A, et al: Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with antiHu–associated paraneoplastic encephalomyelitis. Neurology 1994; 44:140-147. 12. Benyahia B, Liblau R, Merle-Béral H, et al: Cell-mediated autoimmunity in paraneoplastic neurologic syndromes with antiHu antibodies. Ann Neurol 1999; 45:162-167. 13. Albert ML, Austin LM, Darnell RB: Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 2000; 47:9-17. 14. Tanaka M, Tanaka K, Shinozawa K, et al: Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1998; 161:88-90. 15. Tanaka K, Tanaka M, Inuzuka T, et al: Cytotoxic T lymphocyte– mediated cell death in paraneoplastic sensory neuronopathy with anti-Hu antibody. J Neurol Sci 1999; 163:159162. 16. Pellkofer H, Schubart AS, Hoftberger R, et al: Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 2004; 127:1822-1830. 17. Dalmau J, Graus F, Rosenblum MK, et al: Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 1992; 71:59-72. 18. Graus F, Keime-Guibert F, Rene R, et al: Anti-Hu–associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138-1148. 19. Sillevis SP, Grefkens J, De Leeuw B, et al: Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002; 249:745-753. 20. Hetzel DJ, Stanhope CR, O’Neill BP, et al: Gynecologic cancer in patients with subacute cerebellar degeneration predicted by anti–Purkinje cell antibodies and limited in metastatic volume. Mayo Clin Proc 1990; 65:1558-1563.

21. Rojas I, Graus F, Keime-Guibert F, et al: Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55:713-715. 22. Rojas-Marcos I, Rousseau A, Keime-Guibert F, et al: Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer. Medicine (Baltimore) 2003; 82:216223. 23. Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998; 50:652657. 24. Vernino S, O’Neill BP, Marks RS, et al: Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro-oncol 2004; 6:55-62. 25. Keime-Guibert F, Graus F, Broet P, et al: Clinical outcome of patients with anti-Hu–associated encephalomyelitis after treatment of the tumor. Neurology 1999; 53:1719-1723. 26. Posner JB: Neurologic Complications of Cancer. Philadelphia: FA Davis, 1995. 27. Gultekin SH, Rosenfeld MR, Voltz R, et al: Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000; 123:1481-1494. 28. Crotty E, Patz EF Jr: FDG-PET imaging in patients with paraneoplastic syndromes and suspected small cell lung cancer. J Thorac Imaging 2001; 16:89-93. 29. Dadparvar S, Anderson GS, Bhargava P, et al: Paraneoplastic encephalitis associated with cystic teratoma is detected by fluorodeoxyglucose positron emission tomography with negative magnetic resonance image findings. Clin Nucl Med 2003; 28:893-896. 30. Henson RA, Urich HE: Cancer and the Nervous System: The Neurological Manifestations of Systemic Malignant Disease. London: Blackwell Scientific, 1982. 31. Younes-Mhenni S, Janier MF, Cinotti L, et al: FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127:2331-2338. 32. Graus F, Dalmau J, Rene R, et al: Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997; 15:2866-2872. 33. Bataller L, Wade DF, Graus F, et al: Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62:778-782. 34. Graus F, Lang B, Pozo-Rosich P, et al: P/Q type calciumchannel antibodies in paraneoplastic cerebellar degeneration with lung cancer. Neurology 2002; 59:764-766. 35. Dalmau J, Graus F, Villarejo A, et al: Clinical analysis of antiMa2–associated encephalitis. Brain 2004; 127:1831-1844. 36. Alamowitch S, Graus F, Uchuya M, et al: Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain 1997; 120:923-928. 37. Keime-Guibert F, Graus F, Fleury A, et al: Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000; 68:479-482. 38. Lawn ND, Westmoreland BF, Kiely MJ, et al: Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 2003; 78:1363-1368. 39. Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody–associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127:701-712. 40. Mason WP, Graus F, Lang B, et al: Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain 1997; 120:1279-1300.

chapter 101 paraneoplastic disorders of the nervous system 41. Shams’ili S, Grefkens J, De Leeuw B, et al: Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003; 126:1409-1418. 42. Bernal F, Shams’ili S, Rojas I, et al: Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin’s disease. Neurology 2003; 60:230-234. 43. Bataller L, Graus F, Saiz A, et al: Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 2001; 124:437-443. 44. Russo C, Cohn SL, Petruzzi MJ, et al: Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 1997; 28:284-288. 45. Sutton IJ, Barnett MH, Watson JD, et al: Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol 2002; 249:1597-1598. 46. Brown P, Marsden CD: The stiff man and stiff man plus syndromes. J Neurol 1999; 246:648-652. 47. De Camilli P, Thomas A, Cofiell R, et al: The synaptic vesicleassociated protein amphiphysin is the 128-kD autoantigen of stiff-man syndrome with breast cancer. J Exp Med 1993; 178:2219-2223. 48. Chalk CH, Windebank AJ, Kimmel DW, et al: The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci 1992; 19:346-351. 49. Camdessanche JP, Antoine JC, Honnorat J, et al: Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 2002; 125:166-175. 50. Oh SJ, Gurtekin Y, Dropcho EJ, et al: Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study. Clin Neurophysiol 2005; 116:28-34. 51. Antoine JC, Honnorat J, Camdessanche JP, et al: Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann Neurol 2001; 49:214-221. 52. Oh SJ, Dropcho EJ, Claussen GC: Anti-Hu–associated paraneoplastic sensory neuropathy responding to early aggressive immunotherapy: report of two cases and review of literature. Muscle Nerve 1997; 20:1576-1582. 53. Antoine JC, Mosnier JF, Absi L, et al: Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 1999; 67:7-14. 54. Sodhi N, Camilleri M, Camoriano JK, et al: Autonomic function and motility in intestinal pseudoobstruction caused by paraneoplastic syndrome. Dig Dis Sci 1989; 34:19371942. 55. Chinn JS, Schuffler MD: Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction. Gastroenterology 1988; 95:1279-1286. 56. Gosney MA, Gosney JR, Lye M: Orthostatic hypotension and vasodilatory peptides in bronchial carcinoma. J Clin Pathol 1995; 48:1102-1105. 57. Ashraf W, Farrow LJ: Severe orthostatic hypotension in carcinoma of the pancreas. Br J Clin Pract 1992; 46:278-279. 58. Zacharias AS, Brashear HR, Munoz EL, et al: Paraneoplastic encephalomyeloneuritis obscured by coma. Neurology 1996; 46:1177-1179. 59. Angelini P, Holoye PY: Neurocardiogenic syncope and Prinzmetal’s angina associated with bronchogenic carcinoma. Chest 1997; 111:819-822. 60. Veilleux M, Bernier JP, Lamarche JB: Paraneoplastic encephalomyelitis and subacute dysautonomia due to an occult atypical carcinoid tumour of the lung. Can J Neurol Sci 1990; 17:324-328. 61. Dropcho EJ: Neurotoxicity of cancer chemotherapy. Semin Neurol 2004; 24:419-426.

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62. Ropper AH, Gorson KC: Neuropathies associated with paraproteinemia. N Engl J Med 1998; 338:1601-1607. 63. Antoine JC, Camdessanche JP, Ferraud K, et al: Antiganglioside antibodies in paraneoplastic peripheral neuropathies. J Neurol Neurosurg Psychiatry 2004; 75:1765-1767. 64. Kloos L, Sillevis SP, Ang CW, et al: Paraneoplastic ophthalmoplegia and subacute motor axonal neuropathy associated with anti-GQ1b antibodies in a patient with malignant melanoma. J Neurol Neurosurg Psychiatry 2003; 74:507-509. 65. Vernino S, Low PA, Fealey RD, et al: Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343:847-855. 66. Oh SJ: Paraneoplastic vasculitis of the peripheral nervous system. Neurol Clin 1997; 15:849-863. 67. Wirtz PW, Smallegange TM, Wintzen AR, et al: Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg 2002; 104:359-363. 68. O’Neill JH, Murray NM, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988; 111:577-596. 69. Wirtz PW, Sotodeh M, Nijnuis M, et al: Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2002; 73:766-768. 70. Sanders DB, Massey JM, Sanders LL, et al: A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 2000; 54:603-607. 71. Newsom-Davis J: Therapy in myasthenia gravis and LambertEaton myasthenic syndrome. Semin Neurol 2003; 23:191-198. 72. Dalakas MC: Polymyositis, dermatomyositis and inclusionbody myositis. N Engl J Med 1991; 325:1487-1498. 73. Kissel JT, Mendell JR, Rammohan KW: Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986; 314:329-334. 74. Engel AG, Hohlfeld R, Banker BQ: The polymyositis and dermatomyositis syndromes. In Engel AG, FranziniArmstrong C, eds: Myology. New York: McGraw-Hill, 1994, pp 1335-1383. 75. Sigurgeirsson B, Lindelof B, Edhag O, et al: Risk of cancer in patients with dermatomyositis or polymyositis. A populationbased study. N Engl J Med 1992; 326:363-367. 76. Amato AA, Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin 1997; 15:615-648. 77. Dalakas MC, Illa I, Dambrosia JM, et al: A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329:1993-2000. 78. Levin MI, Mozaffar T, Al-Lozi MT, et al: Paraneoplastic necrotizing myopathy: clinical and pathological features. Neurology 1998; 50:764-767. 79. Antoine JC, Camdessanche JP, Absi L, et al: Devic disease and thymoma with anti–central nervous system and antithymus antibodies. Neurology 2004; 62:978-980. 80. Petzold GC, Marcucci M, Butler MH, et al: Rhabdomyolysis and paraneoplastic stiff-man syndrome with amphiphysin autoimmunity. Ann Neurol 2004; 55:286-290. 81. Bataller L, Dalmau J: Neuro-ophthalmology and paraneoplastic syndromes. Curr Opin Neurol 2004; 17:3-8. 82. Keltner JL, Thirkill CE: Cancer-associated retinopathy vs recoverin-associated retinopathy. Am J Ophthalmol 1998; 126:296-302. 83. Shiraga S, Adamus G: Mechanism of CAR syndrome: antirecoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9– and caspase 3–dependent pathway. J Neuroimmunol 2002; 132:72-82. 84. Ohguro H, Maruyama I, Nakazawa M, et al: Antirecoverin antibody in the aqueous humor of a patient with cancer-associated retinopathy. Am J Ophthalmol 2002; 134:605-607.

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85. Milam AH, Saari JC, Jacobson SG, et al: Autoantibodies against retinal bipolar cells in cutaneous melanoma–associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:91-100. 86. Keltner JL, Thirkill CE, Yip PT: Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome:

eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 2001; 21:173-187. 87. Cross SA, Salomao DR, Parisi JE, et al: Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003; 54:38-50.

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102

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Rolfe Birch and Marco Sinisi

The peripheral nervous system is affected by neoplastic disease in the following ways: 1. In neuropathy secondary to malignant disease elsewhere, usually in the lung. 2. By infiltration with disseminated malignant disease, particularly from cancer of the breast. 3. By pressure, infiltration, or distortion from malignant tumors arising from related structures. 4. By tumors arising within a nerve from nonneural elements. 5. By tumors, benign or malignant, arising within the nerve from neural elements, which may be isolated or part of a generalized disease. Malignant transformation may occur in neurofibromas: this change is extremely rare in schwannomas. Tumors of the peripheral nerves (PNTs) are sufficiently common that they are encountered by surgeons or neurologists at regular intervals but infrequently enough to still cause perplexity in diagnosis and treatment. Too many cases of benign schwannoma are subjected to biopsy, which damages the parent nerve, inflicts pain, and increases the difficulties surrounding excision; too often the true nature of the swelling and of its anatomical relations is not appreciated, so that the nerve trunk is excised. Even worse, inadequate biopsy or incorrect interpretation of that biopsy in a malignant tumor of nerve leads to inadequate treatment.1 Nerve sheath tumors develop within tissues of neuroectodermal (neural crest) origin. A schwannoma is composed of Schwann cells, and so it develops a true capsule, the perineurium of the fascicle of origin. Malignant transformation within a solitary neurofibroma is a definable risk; malignant tumors are an important cause of morbidity and mortality in neurofibromatosis type 1 (NF1). In a number of the authors’ patients, the correct diagnosis of NF1 was made only when they presented with a PNT. For these patients, the involvement of other systems, the implications of transmission to children, and risks of malignant transformation require careful attention. The classification used in this chapter is displayed in Table 102–1. The true nature of PNT has been greatly clarified by electron microscopy, immunohistochemistry, and genetic studies. Perineurial cells arise from fibroblasts.2 Transmission electron microscopic studies have shown that schwannomas do indeed arise from Schwann cells; ultrastructural characteristics enable

the distinction among schwannoma, neurofibroma, and perineurioma.3 Folpe and Gowan4 emphasized the role of immunocytochemistry in the analysis of PNT, whereby specific antigens on cells of neural origin can be demonstrated by polyclonal or monoclonal antibodies. The strong expression of S-100 by Schwann cells is particularly important in distinguishing between the large schwannomas of the retroperitoneum and soft tissue sarcomas. The perineurial cell does not express S100 but does express the epithelial membrane antigen. Fibroblasts express vimentin and fibromentin. Immunoreactivity, cytogenetic, and molecular genetic analyses demonstrate that Ewing’s sarcoma, Askin’s tumor of the chest wall, the primitive neuroectodermal tumor of bone, and neuroepithelioma are variations from a common neural origin, distinct from neuroblastoma. The cells of Ewing’s sarcoma exhibit characteristic reciprocal translocation of the long arms of chromosomes 11 and 21, in common with other tumors of this group.5-8 The clinical diagnosis of most PNTs, whether benign or malignant, is usually fairly straightforward in cases in which the swelling is located within the limbs. Supplementary investigations are necessary to confirm that diagnosis and to clarify the location of the tumor, its size, and its relation to vital structures. The possibility of a second malignant peripheral nerve sheath tumor (MPNST) or of premalignant change within a benign lesion is a particular problem in NF1. A swelling of a nerve may masquerade as PNT and yet may, in fact, be an expression of generalized neuropathy (Figs. 102–1 and 102–2). Plain radiographs of the affected anatomy should always be obtained before any computed tomography or magnetic resonance imaging. For most PNTs, magnetic resonance imaging is particularly valuable in showing the relations of the tumor and in indicating the extent of spread into the skeleton or spinal canal.9 Magnetic resonance angiography is probably superior to digital subtraction angiography in demonstrating the relation of the tumor to adjacent great vessels. Computed tomography with contrast enhancement is required in the analysis of tumors extending within the spinal canal (Fig. 102–3).

BIOPSY Biopsy should not be performed when the clinical diagnosis of benign PNT is secure. There are some objections to biopsy in MPNST: The intervention must breach tissue planes; an inade-

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T A B L E 102–1. Classification of Peripheral Nerve Tumors Type

Benign

Malignant

Nerve sheath tumors

Schwannoma (neurilemmoma) Perineurioma Solitary neurofibroma Plexiform neurofibroma (pathognomonic of neurofibromatosis type 1) Ganglioneuroma

Malignant peripheral nerve sheath tumor (MPNST) (malignant schwannoma, neurofibrosarcoma, nerve sheath sarcoma) Malignant neurofibroma

Neural tumors

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Ganglio neuroblastoma, neuroblastoma Primitive neuroectodermal tumor (PNET); includes neuroepithelioma, extraskeletal Ewing’s tumor, PNET of bone

Figure 102–1. Massive intraspinal/extraspinal schwannoma in a 36-year-old man caused progressive tetraparesis over the course of 4 years. Plain radiographs of the neck were not performed until the condition was quite advanced.

quate sample or incorrect analysis may lead to a false diagnosis of benign lesion in MPNST or of malignancy within a benign lesion. A biopsy specimen in MPNST should be adequate for defining the cell of origin, and this is particularly relevant in primitive neuroectodermal tumors, for which adjuvant therapy is an essential element in treatment. The staging of sarcomas of bone or of other soft tissues is a well-established and accepted practice. However, the compartment for an MPNST is the trunk nerve itself, and the authors have found centripetal extension of up to 20 cm within an apparently normal nerve trunk in some cases. Conventional staging investigations do not detect early malignancies at other sites in NF1, nor are they particularly good in detecting the early stages of transformation from benign to malignant lesions. MPNSTs are best treated in units that have access to all essential modalities of diagnosis. The operating surgeon should be responsible for the planning of biopsy and also for examination of all and of any material with colleagues in a multidisciplinary team (Fig. 102–4).

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Figure 102–2. Schwannoma of the tibial nerve at the knee in a 58-year-old man. Magnetic resonance image reveals a well-formed capsule and no surrounding edema. The popliteal vein is displaced, but there is no narrowing of the popliteal artery. The tumor, which measured 6 cm in maximum diameter, lies eccentrically to the tibial nerve. There is a characteristic heterogenic signal.

The authors’ unit has treated more than 450 patients with PNTs (Table 102–2). Their experience and those of others in the management of these tumors are summarized as follows.

THE BENIGN SCHWANNOMA This is the most common of all true PNTs, and it can be removed without impairment for function of the nerve of origin. Eighty percent of affected patients were between 30 and 69 years of age; 55% were male. The upper limb was the site of the tumor in more than 70% of cases; the brachial plexus and

chapter 102 tumors of the peripheral nerves adjacent spinal nerves, in a little more than one third. Schwannomas can be found in bone, muscle, or viscera. Massive mediastinal or retroperitoneal tumors are not rare. The authors have found multiple schwannomas in 23 patients, and the tumor is common in NF1. Loss of function occurs when the tumor arises in an enclosed space. Most intraspinal/extraspinal tumors (dumbbell tumors) are schwannomas, and affected patients may present with quite advanced afflictions of the spinal cord. Bilateral vestibular tumors are pathognomonic of neurofibromatosis type 2 (NF2). Schwannomas arise from Schwann cells, which invest cranial nerves III to XII close to their origin. Malignant transformation of a benign schwannoma is rare.10

Pathology The perineurium, with condensed internal layers, forms a capsule about the tumor that, in turn, forms an eccentric oval

swelling, usually less than 3 cm in diameter, with nerve bundles stretched over it. It may be multinodular. The plexiform variation infiltrating the nerve of origin, so that enucleation is impossible, is rare. Larger tumors develop cysts and undergo degenerative changes of hemorrhage, calcification, and hyalinization. The appearance of the epineurial vessels coursing over the capsule of the tumor is quite characteristic; they are engorged and tortuous. The cut surface is yellowish. In larger tumors, it is cystic and it may be bloodstained. The diagnostic feature is the organization of Schwann cells into areas of compact bundles (Antoni-A tissue) or a less orderly arrangement of spindle or oval cells in a loose matrix (AntoniB tissue). There may be an abrupt change from one to the other. Palisades of compact parallel rows of cells forming Verocay bodies are a feature of Antoni-A tissue. In larger tumors, the nuclei may appear hyperchromatic, large, and multilobed (ancient schwannomas) and a misdiagnosis of malignancy may be made on the basis of these findings, as it may also be for schwannomas formed exclusively from Antoni-A tissue (the cellular variety). This error is prevented by consideration of the nature of the tumor as a whole and by immunohistochemistry. Strong expression of S-100 distinguishes the schwannoma from soft tissue sarcomas such as leiomyosarcoma (Figs. 102–5 and 102–6).11

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Figure 102–3. Malignant peripheral nerve sheath tumor arising from the seventh cervical nerve and eroding the intervertebral foramen in a 24-year-old man.

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Figure 102–4. Schwannoma arising from the upper trunk in a 38-year-old man. Incomplete excision biopsy had been performed 6 weeks previously. This provoked severe pain and also paralysis of nerves C5 and C6. Good function was restored by repair of the lesion.

T A B L E 102–2. Peripheral Nerve Tumors Operated 1976-2006, Peripheral Nerve Injury Unit, RNOH Benign

Malignant

Type

Number

Type

Number

Solitary schwannoma Multiple schwannoma

264 23

36 14

Benign tumors in neurofibromatosis types 1 and 2 Solitary neurofibroma Ganglioneuroma

63 (of which 38 were schwannomas)

MPNST MPNST in neurofibromatosis type 1 Solitary malignant neurofibroma

33 3

PNET Neuroblastoma

5 2

11

MPNST, second malignant peripheral nerve sheath tumor; PNET, primitive neuroectodermal tumor; RNOH, Royal National Orthopaedic Hospital

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Figure 102–5. Schwannoma showing Antoni-A and Antoni-B tissue, palisades, and Verocay bodies. Ancient change is evident. Hyalinization of the walls of the small blood vessels, hemorrhage, and hemosiderin pigment and cystic changes are present. Hematoxylin and eosin stain; magnification, ×250. (Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

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Figure 102–6. Cellular plexiform schwannoma showing strong S-100 staining. Magnification, ×100. (Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

Clinical Features The most frequent manifestation is a swelling that is painful in response to pressure. A mass was detectable in 90% of affected patients, and this was almost always painful on palpation. Progressive neurological deficit occurs only when the tumor arises in a contained space, as in intraspinal extension. Diagnosis in the limb is straightforward. The lump is mobile from side to side but not in the longitudinal axis of the limb. Percussion induces painful paresthesia in the territory of the nerve of origin, similar to Tinel’s sign. This sign is the most useful finding in the diagnosis of schwannomas. At times, the schwannoma causes severe spontaneous pain, particularly when it arises in the sole of the foot or in the buttock and is exposed to pressure on walking or sitting. Spontaneous persistent pain was noted in more than 25% of the authors’ patients, and a degree of motor weakness was recorded in 13%. Although 80% of the authors’ patients presented within 36 months of onset of symptoms, diagnosis was greatly delayed in

others, up to 30 years in one case of schwannoma arising within the sciatic nerve. This delay in diagnosis is particularly common for the deep-seated tibial division of the sciatic nerve and for extraspinal and intraspinal tumors. Treatment is by operation. The indications for operation are to confirm a clinical diagnosis, to remove a tumor that is causing pain, to prevent worsening of symptoms from continuing growth of the tumor, and to obviate the extremely low risk of malignant transformation. The aim of operation is to remove the tumor without damage to conducting tissue. The risk of worsening pain or leaving the patient with a permanent loss of function is less than 1% in a properly performed intervention. Earlier biopsy by incision or by needle led to fibrosis and distortion of the planes about and within the nerve trunk and increased the difficulty of excision. Exposure of massive schwannomas in the mediastinum, in the retroperitoneum, or in close relation to the spinal canal is a considerable undertaking, fraught with potential hazard, but in these cases, the untreated tumor poses a very serious threat to adjacent vital structures distorted or compressed by the enlarging mass. For tumors arising within the trunk nerves of the limbs, the exposure should be linear along the course of the nerve and long enough to enable display of the nerve trunk above and below the tumor of adjacent arteries, veins, and other tissues. Magnification with loupes or operating microscopes is helpful. With the tumor exposed and the nerve adequately mobilized, an incision is made in the epineurium, remote from intact bundles, which are seen coursing over the tumor and displayed around it. The plane of dissection lies between the true glistening capsule of the tumor and the bundles of the nerves lying within their epineurium. A nerve stimulator is an essential instrument during the operation, and it is particularly valuable in defining conducting elements within bundles that are so tightly splayed over the capsule of the tumor that they appear almost translucent. It is usual to find one slender bundle entering the proximal pole of the tumor and exiting at the distal pole, which is removed with the tumor. Conduction across this bundle is rare. A number of severe complications have been seen in patients referred to the authors after primary intervention. Among these are 24 cases of complete excision of a major nerve or nerves and another 18 in which there was partial excision of the nerve or nerves. Severe neuropathic pain complicated needle biopsy in 11 more patients (Figs. 102–7 and 102–8). The brachial plexus and the superior mediastinum are common sites for large schwannomas. The transclavicular exposure was designed to provide adequate exposure and control of the venous trifurcation, the first part of the subclavian artery, the vertebral artery, and the recurrent laryngeal nerve, and it has been safely applied in more than 50 cases.12 The posterior subscapular route is valuable for tumors that lie in the posterior mediastinum (Fig. 102–9).13

THE SOLITARY NEUROFIBROMA A typical neurofibroma arising in a major nerve trunk is easily recognizable. These tumors are significant for three reasons: They may grow to a very large size; they may extend along a spinal nerve into the spinal canal; and there is a slight but definite risk of malignant transformation.11 The neurofibroma of

chapter 102 tumors of the peripheral nerves

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Figure 102–9. Large schwannoma arising from cervical nerve VI, displayed by the transclavicular approach, in a 53-year-old woman. The subclavian and vertebral arteries and the internal jugular vein are shown mobilized away from the tumor. The phrenic nerve is seen passing obliquely over the anterior face of the tumor.

Figure 102–7. Schwannoma arising from the tibial nerve in a 48-year-old man. Note the intact, conducting bundles of the nerve splayed over the tumor, which is eccentric.

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Figure 102–10. Magnetic resonance imaging scan showing a massive neurofibroma arising from T2 in a 33-year-old woman. It was successfully excised through the transclavicular approach.

Figure 102–8. The conducting elements of the nerve are intact after enucleation of the tumor.

a trunk nerve is not easily separable from nerve bundles; therefore, enucleation is not always possible. Most of the large peripheral neurofibromas arise from slender trunks, and so their removal is relatively straightforward and causes little loss of function (Figs. 102–10 and 102–11). The tumors appear uniformly gray-white and translucent, and they are rubbery and fibrous in consistency. The tortuous epineurial vessels that are characteristic of the schwannoma are not seen in a neurofibroma. The recognition of malignancy in these tumors is particularly difficult. If the neurofibroma extends into adjacent viscus or if it recurs after adequate primary excision, then it must be treated as malignant, regardless of the pathological characteristics of the tissue removed. The slow but inexorable progression of some of these tumors is reminiscent of the behaviors of certain other soft tissue sarcomas. A large neurofibroma is always potentially malignant.

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Figure 102–11. Solitary benign neurofibroma. The matrix is fibrillary, and there are comma-shaped nuclei. Hematoxylin and eosin stain; magnification, ×960. (Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

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OTHER BENIGN TUMOR-LIKE CONDITIONS Two of these merit attention because they present difficulties in diagnosis.

Lipofibromatous Hamartoma This benign lesion most commonly involves the median nerve and usually manifests as a fluctuant, tender swelling extending from above the wrist into the palm of the hand. At surgery, the nerve is found entering a large, yellowish, fatty tumor. Individual nerve bundles are so closely involved that removal of the tumor is impossible without resection of the nerve. Biopsy carries risks of pain and loss of function. There is overgrowth of epineurium, perineurium, and endoneurium. Transmission electron microscopic studies reveal perineurial hyperplasia and excessive collagen.11

of their condition, and the complications of the disease for themselves and their families were known to only a few. The surgeon may be the first to make the diagnosis and should work closely with a clinical geneticist so that the patient and family are adequately advised and supported. Support groups such as LINK in the United Kingdom, have produced excellent fact sheets on NF1 and NF2, and patients have been much helped by contact with such groups. NF1 is a disorder of the central and peripheral nervous systems, the skeleton, and the blood vessels. It is progressive, and there are four major causes of premature death: massive plexiform neurofibroma in the mediastinum, involving the airways; astrocytoma of the optic chiasm, brain, or cerebellum; cervicoparaspinal neurofibroma; and MPNST. The risk of MPNST in a patient with NF1 is about 3%. These tumors are rare in the first decade, manifest during adolescence or early adulthood, and their prognosis is poor (Fig. 102–12).6,15

Malignant Peripheral Nerve Sheath Tumors The Intraneural Ganglion This tumor most commonly involves the common peroneal nerve at the knee. It is one of the few benign disorders of nerves that cause loss of function. Spinner and colleagues (2003)14 demonstrated that the cyst extends along the articular branch from the proximal tibiofibular joint into the deep division of the common peroneal nerve. Successful operation requires excision of the articular branch, in addition to decompression of the main nerve.

NEUROFIBROMATOSIS NF1 is much more common than NF2, with an incidence of about 1 per 3000 persons in comparison with 0.1 per 100,000 (Table 102–3). Only one half of the authors’ patients were aware

The most dangerous of these arise in patients with NF1 and account for about one third of all these tumors. The patients are younger, the incidence peaking between the ages of 20 and 30 years, and there is a tendency for tumors to arise more centrally. The prognosis is worse than it is for the solitary malignancy. MPNST develops in about 3% to 5% of patients with NF1. The rate of survival 5 years after the diagnosis ranges from 16% to 30% in published series (Figs. 102–13 and 102–14).16 The second group includes tumors caused by irradiation and accounts for about 10% of all MPNSTs.6 It is important to distinguish these tumors from recurrence of primary malignancy, because some of them can be treated successfully by resection. The prognosis for solitary MPNST is similar to that for soft tissue sarcomas in general, with a 5-year survival rate of about 50%. The incidence peaks in the fourth, fifth, and sixth decades of life, and the tumor tends to arise more peripherally.16

T A B L E 102–3. Diagnostic Features of Neurofibromatosis Types 1 and 2 Feature

Type 1 (Peripheral Neurofibromatosis)

Type 2 (Central Neurofibromatosis)

Incidence Inheritance Gene locus

1 to 3 per 4000 Autosomal dominant Proximal long arm of chromosome 17 New mutations account for one third to one half of new cases

0.1 per 100,000 Autosomal dominant Distal long arm of chromosome 22 New mutations account for up to two thirds of new cases

Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals One plexiform neurofibroma

Bilateral cranial nerve VIII masses seen with appropriate imaging techniques (e.g., CT or MRI)

Diagnostic criteria 1 2

3 4 5 6 7

Freckling in the axilla or inguinal region Optic gliomas A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis Two or more Lisch nodules (iris hamartoma) A first-degree relative (parent, sibling, or offspring) with type 1 by the previous criteria

CT, computed tomography; MRI, magnetic resonance imaging.

Or two or more neurofibromas of any type A first-degree relative with type 2 and either unilateral eighth nerve mass or two of the following: 1. Neurofibroma 2. Meningioma 3. Glioma 4. Schwannoma 5. Juvenile posterior subscapular lenticular opacity

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Figure 102–14. Massive malignant peripheral nerve sheath tumor arising from the medial cord of the brachial plexus in a 34year-old man with neurofibromatosis type 1. There was severe pain, resistant to opiates, and rapidly progressing palsy of the whole of the plexus. Forequarter amputation relieved pain. The patient died of intraspinal extension 22 months after operation.

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Figure 102–12. Neurofibromatosis type I in a 24-year-old man. There was no family history of this disease, and the diagnosis was made when he presented with a benign tumor arising within the axilla.

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Figure 102–13. Malignant peripheral nerve sheath tumor arising from the sciatic nerve in a 14-year-old boy with neurofibromatosis type 1. The tumor provoked intense pain and rapidly progressing sciatic paralysis. Excision of the tumor relieved pain, but the patient died of widespread pulmonary and visceral metastases 20 months after surgery.

The most important factors in the prognosis for all of these tumors are their size and manifestation. Tumors in NF1 tend to arise more centrally in deep-seated locations, and the rate of growth is faster. The cardinal clinical feature of MPNST is pain, and this is usually associated with progressive impairment of nerve function. Spontaneous neuropathic pain with loss of nerve conduction in association with a palpable mass is indicative of MPNST until proven otherwise. Errors in diagnosis are not uncommon; there are numerous descriptions of unnecessary laminectomy or excision of a cervical rib before correct diagnosis was made. Clinical features and findings at surgery are more important in diagnosis than are histological characteristics, most of all in the so-called low-grade malignant neurofibromas. Small tumors appear as fusiform swellings in the nerve trunk. They are hard, the nerve is surrounded by vascular adhesions, and edema of adjacent tissues is a particularly significant finding. In larger tumors, the diagnosis is all too evident. The mass may have burst out of the epineurium, extending into muscle or bone. Larger tumors develop as multilobular masses, and there may be cystic changes, hemorrhage, and, in the most malignant and rapidly growing tissue, extensive areas of necrosis. The most common histological appearance is reminiscent of fibrosarcoma with masses of spindle-shaped cells organized into wavy lamellae. Irregularity of the cells and a wavy or buckled appearance of the nuclei are often found. Metaplastic differentiation occurs in about 20% of patients. Bone, cartilage, and muscle are the most commonly affected tissues; epithelioid differentiation into glandular or squamous tissue is less common. The prognosis for the “triton” tumor, which shows differentiation into skeletal muscle, is particularly poor. Transmission electron microscopic studies suggest that about 25% of these tumors show features of Schwann cells; fibroblasts predominate in about another 25%. Many MPNSTs do not stain for the S-100 protein, and examination for multiple neural markers is advised (Figs. 102–15 to 102–17).16

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Management

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Figure 102–15. Malignant peripheral nerve sheath tumor. The tumor is densely cellular with moderate pleomorphism and high mitotic index. Hematoxylin and eosin stain; magnification, ×400. (Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

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These tumors do not respond to irradiation or to chemotherapy, and the correct treatment is adequate excision of the nerve trunk. Frozen examination of the proximal stump is essential for ruling out intraneural extension. The authors have seen such extension of up to 20 cm from the proximal pole of the tumor. This material should be reviewed by the operating surgeon before completion of the operation. The authors have found it necessary to section the spinal nerve at the foramen in six patients, and in two more, the spinal nerve proximal to the dorsal root ganglion was excised by means of hemilaminectomy. There is no case at all for attempting repair of the nerve. Local recurrence after “limb sparing” operations is much more common with MPNSTs than it is for nonneural soft tissue tumors. With sarcomas arising in the extremity, adequate excision of an MPNST will leave a gap, at the very least, of 20 cm, and attempts to restore function by grafting onto such a defect are futile. Amputation is necessary when the epineurium has been breached or with recurrence. Lusk and colleagues17 advised forequarter amputation in patients with MPNSTs arising within the brachial plexus. This is necessary for recurrence after an apparently adequate excision or when there is such involvement of the plexus that no function can be preserved. It may be necessary for palliation even if it cannot be cured. Of 15 patients with tumors in known NF1 in the authors’ experience, 13 died within 2 years of diagnosis, and only one patient remained apparently disease free at 3 years. Of the 35 patients with solitary tumors, six died within 2 years of diagnosis, and seven more are known to have disease. Of the 22 apparently disease free at a minimum of 5 years after surgery, 14 were treated by excision of the nerve, 5 by amputation of the limb, and 3 by forequarter amputation.

Figure 102–16. Malignant peripheral nerve sheath tumor in a patient with neurofibromatosis type 1, arising from the brachial plexus. A proportion of the tumor cells are expressing myoglobin (Triton tumor). Magnification, ×400. (Courtesy of Dr. Kim Suvarna.)

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Figure 102–17. Neuroepithelioma arising from the sciatic nerve in a 14-year-old boy with neurofibromatosis type 1. There are areas of rosette formation. Hematoxylin and eosin stain; magnification, ×400. (Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

K E Y

P O I N T S

●

Management of PNTs requires expert multidisciplinary care.

●

Biopsy of a PNT is not always required or appropriate.

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Careful surgical treatment can help maintain function, ensure full excision, and enable accurate histological diagnosis.

●

Seventy percent of schwannomas are in the upper limb.

●

Approximately 10% of schwannomas are multiple.

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Malignant transformation of schwannomas is rare.

●

Painful, tender swelling and a positive percussion sign are characteristic clinical features of schwannomas.

Suggested Reading Birch R, Bonney G: The peripheral nervous system and neoplastic disease. In Birch R, Bonney G, Wynn Parry CB, eds: Surgical Disorders of the Peripheral Nerves. London: Churchill Livingstone, 1998, pp 335-372.

chapter 102 tumors of the peripheral nerves Fletcher JA: Cytogenic analysis of soft tissue tumors. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 125-146. Meltzer PS: Molecular genetics of soft tissue tumors. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 103-124. Spinner RJ, Atkinson JLD, Teil RL, et al: Peroneal intraneural ganglia: the importance of the articular branch. A unifying theory. J Neurosurg 2003; 99:330-343.

References 1. Birch R, Bonney G: The peripheral nervous system and neoplastic disease. In Birch R, Bonney G, Wynn Parry CB, eds: Surgical Disorders of the Peripheral Nerves. London: Churchill Livingstone, 1998, pp 335-372. 2. Bunge MB, Wood PM, Tynan LB, et al: Perineurium originates from fibroblasts: demonstration in vitro wIth a retroviral marker. Science 1989; 243:229-231. 3. Henderson WH, Papadimitriou JM, Coleman M: Ultrastructural Appearances of Tumours: Diagnosis and Classification of Human Neoplasia by Electron Microscopy., 2nd ed. Edinburgh: Churchill Livingstone, 1986, Section Three: Neural Tumours. 4. Folpe AL, Gowan AM: Immunohistochemistry for analysis of soft tissue tumors. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 119-246. 5. Fletcher JA: Cytogenic analysis of soft tissue tumours. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 125-146. 6. Giannini C: Tumors and tumor-like conditions of peripheral nerves. In Dyck PJ, Thomas PK, eds: Peripheral Neuropathy, 4th ed. Philadelphia: Elsevier, 2005, pp 2585-2606.

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7. Meltzer PS: Molecular genetics of soft tissue tumors. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 103-124. 8. Weiss SW, Goldblum JR: Primitive neuroectodermal tumors and related lesions. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 1265-1322. 9. Kuntz C, Blake L, Britz G, et al: Magnetic resonance neurography of peripheral nerve lesions in the lower extremity. Neurosurgery 1996; 39:750-757. 10. Woodruff JM, Selig AM, Crowlely K, et al: Schwannoma with malignant transformation: a rare distinctive peripheral nerve tumor. Am J Surg Pathol 1994; 18:882. 11. Weiss SW, Goldblum JR: Benign tumors of the peripheral nerves. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, Chapter 2001, pp 1111-1208. 12. Birch R, Bonney G, Marshall RW: A surgical approach to the cervico-dorsal spine. J Bone Joint Surg Br 1990; 72:904-907. 13. Kline DG, Kott J, Barnes G, et al: Exploration of selected brachial plexus lesions by the posterior subscapular approach. J Neurosurg 1978; 49:872-879. 14. Spinner RJ, Atkinson JLD, Teil RL, et al: Peroneal intraneural ganglia: the importance of the articular branch. A unifying theory. J Neurosurg 2003; 99:330-343. 15. Riccardi VM: Neurofibromatosis. In Kennard C, ed: Recent Advances in Clinical Neurology, No. 6. Edinburgh: Churchill Livingstone, 1990, pp 186-208. 16. Weiss SW, Goldblum JR: Malignant tumors of peripheral nerves. In Weiss SW, Goldblum JR, eds: Enzinger and Weiss’ Soft Tissue Tumors, 4th ed. St. Louis: Mosby, 2001, pp 12091264. 17. Lusk MD, Kline DG, Garcia CA: Tumour of the brachial plexus. Neurosurgery 1987; 21:439-453.

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HEAD TRAUMA ●

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H. Gordon Deen

Traumatic brain injury (TBI) is a major cause of death and disability in the United States and many other parts of the world. An estimated 1.5 million people sustain a TBI each year in the United States. There are 50,000 deaths from TBI, which accounts for one third of all injury-related deaths. Among TBI survivors, more than 200,000 require hospitalization, and 80,000 to 90,000 experience the onset of a long-term or lifelong disability associated with a TBI. The social and economic costs related to TBI are enormous. Direct and indirect costs of TBI were estimated to be $56.3 billion in 1995. These statistics indicate that TBI is a major public health problem with significant socioeconomic implications. The leading causes of TBI are motor vehicle accidents, gunshot wounds and other types of physical assault, and falls. TBI also occurs in a wide variety of athletic activities. Approximately 300,000 sports-related TBIs occur each year in the United States. Boys and men are twice as likely as girls and women to sustain a TBI. Individuals 15 to 24 years of age and those older than 75 constitute the two age groups at highest risk for TBI.

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Firearms should be stored unloaded in a locked cabinet or safe, and bullets should be stored in a separate, secure location.

TRAUMA CARE SYSTEMS The development of organized trauma care systems has also played a role in improving the outcomes of patients with TBI and other injuries. These systems, which have been introduced in the United States since the late 1970s, have been shown to decrease mortality after major trauma.1 The most advanced of these is the level 1 trauma center, which maintains trauma surgeons and anesthesiologists in the hospital 24 hours per day and ready access to trauma surgical suites. Neurosurgeons and other specialists are immediately available as needed. The next echelon is the level 2 trauma center, which has immediate access to surgeons and anesthesiologists but does not maintain in-house physician staffing. A level 2 center is able to initiate definitive care for all injured patients but may have to refer some tertiary trauma care needs to a level 1 center. Some cities also have specialized pediatric trauma centers.

PREVENTION

TRAUMATIC BRAIN INJURY CLASSIFICATION

Any discussion of the management of TBI should start with injury prevention. When a person drives or rides in a motor vehicle, it is important to wear a seat belt, observe speed limits and other traffic regulations, and avoid driving while intoxicated or excessively fatigued. Since the mid-1990s, there have been public education initiatives on these matters and more aggressive enforcement of driving regulations by law enforcement officials. Automobile manufacturers continue to add new safety features to cars, including airbags, antilock brakes, crumple zones to protect the passenger compartment, and various stability control systems. All these factors have had a positive effect on rates of morbidity and mortality from TBI caused by motor vehicle accidents. (Popp, 1998) Helmets should be worn during participation in certain athletic activities, including riding a bicycle or motorcycle, playing a contact sport, using in-line skates, riding a skateboard, riding a horse, and skiing and snowboarding. (Popp, 1998) Falls in the home can be minimized by removing tripping hazards, such as loose electrical cords, and through the safe use of ladders.

TBI is a very common problem with a wide spectrum of severity. Both clinical examination and radiographic imaging are essential components of the optimal evaluation of these patients.

Glasgow Coma Scale and Glasgow Outcome Scale A simple and reliable clinical assessment tool is needed for evaluating acute TBI. An accurate baseline assessment is crucial, and serial assessments are also needed, because neurological status may change with time, sometimes rapidly. TBI care is provided by a wide range of physicians, nurses, and allied health personnel. Many classification schemes have been developed; however, the Glasgow Coma Scale (GCS) (Table 103–1), introduced by Teasdale and Jennett in 1974, is the most widely used.2 The GCS has proved to be accurate, capable of detecting clinically important changes in neurological status, and easy to use by a variety of health care professionals.

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T A B L E 103–1. The Glasgow Coma Scale

T A B L E 103–2. The Glasgow Outcome Scale

Activity

Outcome Category

Definition

Good recovery

Patient able to return to former occupation, although not necessarily at the same level; may have minor neurological or psychological impairments Patient unable to return to work but otherwise able to perform the activities of daily living independently Patient requires assistance to perform daily activities and cannot live independently Absence of speech or no evidence of mental function in a patient who appears awake with spontaneous eye opening

Score Performance

Eye opening 4 3 2 1

Spontaneously In response to voice In response to pain None

5 4 3 2 1

Oriented Confused Inappropriate words Incomprehensible sounds None

6 5 4 3 2 1

Follows commands Localizes to pain Withdraws in response to pain Abnormal flexion in response to pain Abnormal extension in response to pain None

Best verbal response

Moderate disability Severe disability Persistent vegetative

Best motor response

Total score ranges from 3 to 15.

Scores on the GCS range from 3 to 15. A GCS score of 3 to 8 is indicative of severe head injury, with a mortality rate of 35% to 40%. A GCS score of 9 to 12 is indicative of moderate head injury, with a mortality rate of 5% to 10%, and a score of 13 to 15 is indicative of mild head injury, with a mortality rate of less than 2%. Children older than 2 years and teenagers have a better prognosis than do adults. The postresuscitation GCS is one of the strongest predictors of ultimate outcome after TBI. For example, a patient who opens eyes only in response to pain, has a best motor response of abnormal flexion to pain, and a best verbal response of incomprehensible sounds would receive 2 points for eye opening, 3 points for motor response, and 2 points for verbal response. The GCS score would therefore be 7, in the severe TBI category. The GCS cannot be used reliably in patients younger than 2 years, because children in that age group are not able to carry out the normal motor and verbal responses required by the test. Various pediatric head injury scales have been proposed, but none has been widely adopted. A reliable scale is also needed to assess the long-term outcomes of patients as they recover from TBI. The Glasgow Outcome Scale (Table 103–2) is a commonly used system that has been developed for this purpose. Serial testing indicates that more than two thirds of patients reach their final outcome category on the Glasgow Outcome Scale within 3 months of injury.

Death

CT provides a very detailed look at the brain parenchyma, skull, and extracranial soft tissues and is very accurate in the diagnosis of important sequelae of TBI, including intracranial hematoma, midline shift, cerebral edema, pneumocephalus, and skull fracture. Magnetic resonance imaging (MRI) is less useful in evaluating acute head injury, because scanning times are longer and because it is more difficult to perform in patients who are agitated and combative and in patients on mechanical ventilation. For these reasons, MRI is generally not performed in the setting of acute TBI. MRI may be useful in selected cases, such as when the patient is unconscious but CT yields normal or unremarkable findings. In these situations, MRI may reveal evidence of diffuse axonal injury or a brainstem injury that was not seen on CT. The clinical severity of TBI is not always correlated with the magnitude of findings seen on CT. For example, in a patient with clinically mild TBI, an intracranial hematoma may be apparent on the admitting computed tomographic scan. With modern high-resolution scanning techniques, head CT displays abnormal findings in up to 50% of cases of mild TBI.3 Conversely, a patient, who is deeply unconscious with a severe TBI, may undergo initial head CT that yields completely normal findings. This underscores the fact that the clinician cannot rely solely on clinical findings or on results of CT when evaluating patients with TBI. The clinical and imaging examinations are complementary, and both are needed for the optimal evaluation of patients with TBI.

TYPES OF TRAUMATIC BRAIN INJURY Primary and Secondary Injury

IMAGING OF TRAUMATIC BRAIN INJURY Computed tomography (CT) has revolutionized the imaging of patients with acute TBI. Since its introduction in the 1970s, the procedure has become much faster, and image quality has improved dramatically. On a modern scanner, each image is acquired in less than a second, and an entire head examination can be completed in less than a minute. CT has replaced plain skull radiography and angiography as the primary imaging modality in acute TBI.

Brain injury in TBI can be viewed as having two components: primary and secondary (Greenberg, 2001). The damage caused by the direct forces of the injury is known as the primary injury. Since the 1980s, there has been increasing recognition that further damage may occur after the traumatic event, as the result of brain ischemia or herniation. This phenomenon has come to be known as the secondary injury. Hypotension, hypoxia, raised intracranial pressure (ICP), and seizures are risk factors for the development of secondary injury and should be treated aggressively.

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Diffuse and Focal Injury TBI is also classified according to the distribution of injury, which may be diffuse, focal, or a combination of the two. Concussion is the classic example of a mild, diffuse injury, whereas diffuse axonal injury represents a more severe, diffuse injury. Cerebral contusion is the classic example of focal brain injury.

SPECIFIC INJURIES Concussion The most common head injury is concussion, also known as mild traumatic brain injury. The hallmark of concussion is an alteration of consciousness as a result of nonpenetrating injury to the brain. There is often a period of amnesia for the event, and recovery is generally rapid. Aside from altered mental status, the neurological examination yields normal findings. Results of CT and MRI of the brain are normal. No specific treatment for concussion is required. Prognosis is excellent, and a full recovery may be expected in most cases. Patients are allowed to return to their usual activities as their symptoms resolve. Two complications of concussion warrant further discussion. First, it is now believed that the effects of repeated concussion are cumulative and can lead to the development of chronic dementia. The “punch drunk” syndrome that occurs in professional boxers exemplifies this phenomenon. Another serious complication of seemingly mild head injury is the second-impact syndrome, a rare condition that has been described in athletes who sustain a second head injury while still symptomatic from an earlier injury. Although the individual appears to have only minimal impairment from the first injury, malignant cerebral edema, which is refractory to all interventions, occurs soon after the second injury. The mortality rate with second-impact syndrome is 50% to 100%. Recognition and increasing understanding of this syndrome have led to the development of guidelines that allow for a safe return to athletic competition while avoiding the devastating complications of second-impact syndrome. In addition to neurological examination and imaging studies, neuropsychological testing is now an important part of the decision-making process for allowing athletes to return to competition after TBI (Bailes, Day, 2001).4

Thus, contusion was considered only in cases of severe TBI and was therefore thought to be pathognomonic for severe injury. Since the advent of CT, especially current high-resolution techniques, contusions have commonly been observed in patients with clinically mild and moderate TBI. It is now recognized that there is a wide range of severity associated with cerebral contusion. Tiny punctate contusions in patients with mild TBI have little or no clinical significance and carry the same prognosis as normal findings on CT.5 At the other end of the spectrum, large contusions with significant mass effect in patients with severe TBI can be life-threatening. Contusions can be classified as coup or contrecoup injuries. Coup contusions occur at the location of impact, whereas contrecoup contusions occur on the opposite side or at a point distant from the impact. Contusions may be present in any part of the brain but are most common in the frontal and temporal lobes. Figure 103–1 shows a typical hemorrhagic contusion in the left inferior frontal region, just above the roof of the orbit. Contusions often enlarge during the first week after injury. Repeated CT should be considered if the patient exhibits clinical deterioration. Surgery may be necessary to resect areas of contused brain if there is significant mass effect with raised ICP. Temporal lobe contusions are particularly ominous because of their proximity to the brainstem and risk of herniation.

Intracerebral Hematoma Intracerebral hemorrhage is bleeding within the brain parenchyma and generally occurs after severe head injury. As with contusion, the natural history of intracerebral hemorrhage is one of progressive enlargement during the first few days after injury. Intracerebral hemorrhage may develop on a delayed basis in areas of contusion. Individuals with coagulopathy from liver disease or anticoagulant medications are at increased risk for intracerebral hemorrhage. In these

Diffuse Axonal Injury A more severe form of diffuse TBI is diffuse axonal injury. This type of injury is the result of shear and tensile forces within the brain. Clinical examination often reveals severe deficits, including coma and decerebrate posturing, in contrast to CT, which yields generally unremarkable findings. Diffuse axonal injury is often present in fatal head injury. Survivors may remain in a vegetative state or have other long-term deficits.

Contusion Cerebral contusion is the classic example of focal TBI. In the pre-CT era, cerebral contusion could be diagnosed only in the operating room during craniotomy or at the autopsy table.

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Figure 103–1. Computed tomographic head scan shows a left frontal hemorrhagic contusion just above the orbital roof.

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individuals, intracerebral hemorrhage may occur after lowimpact injury. Small intracerebral hemorrhages can be observed, whereas larger intracerebral hemorrhages that cause significant mass effect should be resected.

Subdural Hematoma Subdural hematoma is the result of bleeding over the surface of the brain, beneath the dura. Subdural hematoma may be acute or chronic. Acute subdural hematoma usually occurs after severe, high-impact injuries and is often associated with contusions of the adjacent areas of the brain. If the subdural hematoma is small (<5 mm in thickness) and the patient is stable clinically, a period of observation may be reasonable. If conservative management is elected, careful clinical observation and follow-up imaging are needed, because there is potential for the subdural hematoma to enlarge. Craniotomy to remove the hematoma is necessary if there is significant mass effect with raised ICP. At surgery, the hematoma is found to have a solid, jelly-like consistency. Chronic subdural hematoma represents the gradual accumulation of liquefied hematoma in the subdural space, occurring over 2 or more weeks. Chronic subdural hematoma is usually present in elderly persons, who have more prominent subdural spaces as a result of cerebral atrophy. Chronic subdural hematoma, occurs most commonly after minor head injury. Sometimes the patient and family cannot even recall when the injury occurred. Over time, the hematoma gradually enlarges as a result of repeated episodes of minor bleeding and/or the drawing of fluid into the hematoma as a result of an osmotic effect. As in other forms of intracranial hemorrhage, risks of chronic subdural hematoma are elevated in individuals with coagulopathy caused by liver disease or anticoagulant medications. Surgery is often required and may involve either burr hole drainage or a craniotomy. At surgery, a chronic subdural hematoma is liquefied and is described as having a “crank case oil” appearance. The prognosis is guarded, and there is substantial risk of recurrent subdural hematoma that necessitates further surgery. Figure 103–2 shows bilateral chronic subdural hematomas. Subdural hematoma may have both acute and chronic components if there is ongoing bleeding in the subdural space. The presence of a mixed acute and chronic subdural hematoma is readily identified on CT (Figure 103–3).

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Figure 103–2. Computed tomographic head scan shows bilateral chronic subdural hematomas.

Epidural Hematoma Epidural hematoma represents acute bleeding into the epidural space. This bleeding may be either arterial or venous. The classic epidural hematoma is observed with a linear skull fracture of the temporal bone, which tears the middle meningeal artery, allowing blood to accumulate under pressure in the epidural space. However, sizable epidural hematoma of venous origin may also occur. Epidural hematoma is usually observed in children and young adults but is rare in elderly persons, because of the firm adherence of the dura to the inner table of the skull. A convexity epidural hematoma is usually readily identified on routine head CT; however, an epidural hematoma low in the middle cranial fossa may be missed on axial images as a result of artifact from the adjacent skull base. In such cases, coronal imaging may be helpful in demonstrating the

■

Figure 103–3. Computed tomographic head scan shows bilateral subdural hematomas with acute and chronic components.

hematoma. A right frontal epidural hematoma is shown in Figure 103–4. The typical clinical scenario of a patient developing an epidural hematoma is one in which the patient, often a child, sustains a blow to the head and is initially stunned but then rapidly regains awareness, only to deteriorate again over the next few minutes to hours. Typical clinical findings include dilation of a pupil, caused by a cranial nerve III palsy,

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Pneumocephalus The finding of intracranial air, or pneumocephalus, indicates a skull fracture of either the convexity or cranial base. Air is readily identified on CT and may be in the extracerebral, intracerebral, or intraventricular space. Small quantities of intracranial air are of no pathological significance and resolve within a few days. In rare cases, large quantities of air enter the intracranial space and lead to mass effect on the brain. This condition is known as tension pneumocephalus and is the result of a persistent cerebrospinal fluid (CSF) fistula. Emergency surgery may be necessary to evacuate air and decompress the brain through the placement of drainage tubes. A diligent search for a CSF fistula must be undertaken. Surgery may be needed to obliterate CSF fistulae and prevent further entry of air into the brain.

Skull Fracture

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Figure 103–4. Computed tomographic head scan shows a right frontal epidural hematoma. (Courtesy of Daniel F. Broderick, MD.)

ipsilateral to the injury, and progressive obtundation. Emergency craniotomy is usually required for an epidural hematoma. The lesion must be identified and evacuated as soon as possible in order to prevent brain herniation and to obtain a good outcome.

Traumatic Subarachnoid Hemorrhage Subarachnoid hemorrhage may occur after head trauma. It may be an isolated finding, or it may occur in association with other findings, such as contusion and intracerebral hemorrhage. Whenever subarachnoid hemorrhage is present after a lowimpact injury, or in cases in which the history of head trauma is vague or uncertain, the possibility of subarachnoid hemorrhage from an aneurysm must be considered. In these cases, magnetic resonance angiography, computed tomographic angiography, or conventional angiography should be performed. Vasospasm is much less common in traumatic subarachnoid hemorrhage than in aneurysmal subarachnoid hemorrhage. There is no specific treatment for traumatic subarachnoid hemorrhage. Patient management should be guided by the clinical examination and other findings on CT. There is a small risk of delayed hydrocephalus, so at least one follow-up computed tomographic scan is warranted. Intraventricular hemorrhage may also occur after head trauma. Bleeding into the ventricular system is usually associated with severe TBI and poor long-term outcome. The presence of intraventricular hemorrhage is thought to be a marker, but not the cause, of poor clinical outcome. Late hydrocephalus may also occur after traumatic intraventricular hemorrhage. As with subarachnoid hemorrhage, whenever intraventricular hemorrhage is present after mild or questionable head trauma, the possibility of aneurysmal hemorrhage must be considered and appropriate screening performed.

A variety of skull fractures may be observed in TBI. Skull fractures are classified as simple or compound, linear or stellate, and depressed or nondepressed. The physician should perform a careful examination of any scalp lacerations to look for evidence of depressed bone fragments, CSF leakage, or exposed brain tissue in the wound. Clinical signs of fracture of the skull base (basilar skull fracture) include CSF otorrhea or rhinorrhea, hemotympanum, retro-auricular ecchymosis (Battle’s sign), periorbital ecchymosis (“raccoon’s eyes”) in the absence of direct orbital trauma, and cranial nerve injury, particularly cranial nerves I, II, VI, VII, and VIII. Some of these findings may become apparent only after a delay. Most skull fractures are readily identified on CT. Fractures of the skull base may be harder to visualize with standard head CT protocols. In these cases, specialized CT techniques may be required, including coronal imaging, thin slices, and bone windows. Figure 103–5 depicts a linear skull fracture through the left lambdoid suture with a small amount of adjacent pneumocephalus. A simple, linear, nondepressed skull fracture requires no specific treatment but does have some prognostic significance. In one large study of minor TBI, 3% of patients with a skull fracture deteriorated to the point of needing a neurosurgical procedure, whereas the risk of significant deterioration in patients without a skull fracture was less than 1%.6 This indicates that in cases of clinically mild TBI, the prognosis is worse in patients with a skull fracture than in those whose head CT does not reveal a fracture. These data have led some investigators to recommend that a skull fracture be an indication for overnight admission to the hospital for patients with clinically mild TBI. Surgical repair is indicated for depressed skull fractures if there is a depression measuring more than 8 to 10 mm (or greater than the thickness of the skull) or for débridement of compound (open) fractures with dural laceration, CSF leakage, and parenchymal injury. Placement of a nasogastric tube is contraindicated in patients with basilar skull fractures involving the anterior cranial fossa, because it would be possible for a nasogastric tube to pass through the incompetent skull base into the brain. If gastric drainage is needed in such cases, an orogastric tube should be placed.

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B Figure 103–5. A, Computed tomographic head scan shows a linear skull fracture through the left lambdoid suture (arrow) with adjacent pneumocephalus. B, Close-up view of fracture.

Penetrating Cranial Trauma

Adverse Effects of Anticoagulant Medications

Gunshot wounds to the head account for the majority of penetrating cranial injuries. Examination should include description of visible entrance and exit wounds, in addition to the usual assessments with GCS and of neurological function and general physical examination. The prognosis is generally poor, especially in high-velocity wounds. Patients with little cerebral function (in the absence of shock, alcohol overdose, or drug overdose) are unlikely to benefit from surgical intervention, and supportive care is most appropriate in these situations. For patients who are believed to be capable of some recovery, the goals of surgery include débridement of devitalized tissue, evacuation of hematomas, removal of accessible bullet and bone fragments, obtaining hemostasis, and separation of the intracranial compartment from air sinuses that may have been traversed by the bullet. Any knives or other sharp objects protruding from the skull should not be removed in the field but, instead, should be left in place for extraction in the operating room under more controlled circumstances.

It is crucial to know whether the patient is taking anticoagulant medications, such as warfarin or clopidogrel, or antiplatelet medications, such as aspirin, because these medications increase the risk of intracranial hemorrhage. A complete blood cell count with measurements of platelet counts, international normalized ratio, and prothrombin time should be obtained. In patients taking warfarin, anticoagulation should be reversed with fresh-frozen plasma and phytonadione (AquaMEPHYTON). Depending on the level of anticoagulation, this reversal can take hours to days. Historically, this has presented a therapeutic dilemma in situations in which rapid reversal of anticoagulation is needed. A common example of this is the case of a patient with a large warfarin-related subdural hematoma causing cerebral herniation who needs an emergency craniotomy. If fresh-frozen plasma is given too rapidly, fluid overload and congestive heart failure may ensue. If the anticoagulation is not reversed fast enough, herniation may occur and the patient may die before surgery can safely be performed. A significant advance in the care of these patients has been the introduction of recombinant factor VIIa (NovoSeven). Administered intravenously in doses of 15 to 100 μg/kg, this product can reverse the anticoagulant effects of warfarin within a few minutes of administration. Rapid reversal of anticoagulant medications has two benefits: first, the risk of further enlargement of the hematoma is decreased, and, second, emergency surgery can be safely carried out in situations in which hematoma removal is warranted. Clotting parameters should be monitored, as additional doses of recombinant factor VIIa or fresh-frozen plasma may be required after initial reversal with the former.

CLINICAL ASSESSMENT Initial assessment of the patient with TBI includes obtaining a history of the circumstances of the injury and a pertinent medical history. If conscious, the patient may be able to supply this information; otherwise, this information must be obtained from other sources, including family members and bystanders who may have witnessed the traumatic event. Any history of seizure activity should be noted. If the patient is found unconscious and a history cannot be obtained, and if CT reveals a subarachnoid hemorrhage, the possibility of nontraumatic hemorrhage (e.g., aneurysmal subarachnoid hemorrhage) must be considered.

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There is a seemingly small risk of thrombotic complications related to the use of recombinant factor VIIa. The major drawback to this medication is its cost. A 1.2-mg vial costs about $1000. However, in cases of life-threatening intracranial hemorrhage, the benefits of this product clearly outweigh the expense and risks of its use. The clinician must also inquire about the use of alcohol or illicit drugs, which could impair consciousness. Appropriate drug screens of blood and urine should be obtained.

Physical Examination The physical examination should include assessment of vital signs, GCS assessment, neurological examination, and general examination for evidence of systemic injury and spinal column injury. The scalp should be inspected for evidence of scalp laceration and underlying skull fracture. It may be necessary to shave a portion of the scalp in order to perform an adequate evaluation. Careful examination of a scalp laceration may reveal a depressed skull fracture with dural laceration and exposed cerebral tissue, even in cases of clinically mild TBI. Tachycardia and hypotension are indicative of hypovolemic shock, which should prompt a search for systemic injury, such as intra-abdominal hemorrhage or pelvic fracture. Hypotension is not observed with TBI, with two exceptions: profound blood loss from a scalp laceration (which is uncommon) and in the agonal phase of severe TBI with brain death. Bradycardia and hypertension are known as Cushing’s response and are indicative of raised ICP. Bradycardia and hypotension are suggestive of a cervical spinal cord injury.

pneumocephalus, and cerebral edema. If results of CT are unremarkable, electrolytes, metabolic parameters, and arterial blood gases should be measured. Electroencephalography is useful in selected cases. A lumbar puncture with CSF examination is needed if meningitis is a strong consideration; however a lumbar puncture is contraindicated in the presence of raised ICP. Dissection of the carotid or vertebral arteries is a rare complication of trauma to the head and neck. Dissection should be considered if there is major neurological deterioration that cannot be explained by the testing described previously. This diagnosis can be established by ultrasonography or magnetic resonance angiography. Figure 103–6 illustrates the dramatic worsening that may occur with TBI. The case involved a 72-year-old woman who presented to the emergency department with a clinically mild TBI (GCS score, 15) after a fall at home. Figure 103–6A shows the initial computed tomographic head scan, which was unremarkable, aside from extracranial soft tissue swelling in the right parietal region. The patient was dismissed from the emergency department in the care of her family. Later that day, the patient exhibited marked deterioration and was brought back to the hospital by her family. She was deeply comatose, and the GCS score had decreased from 15 to 6. Figure 103–6B shows the follow-up computed tomographic head scan, obtained 10 hours after the initial scan, which reveals interval development of a large acute right subdural hematoma. Emergency craniotomy was required. This was an example of a “talk and deteriorate” injury.

TREATMENT

Coexisting Spinal Injury

Hospital Admission

The unconscious patient should be assumed to have a cervical spine injury until proven otherwise. A rigid cervical collar should remain in place until the cervical spine can be judged stable by appropriate clinical and radiographic assessment. Flaccid limbs and priapism are worrisome signs that suggest a high likelihood of spinal cord injury.

In cases of clinically mild TBI, one of the first decisions to be made is whether to admit the patient to the hospital for observation or to have the patient observed at home. There is no evidence that hospital admission improves the outcomes of patients with mild TBI. Two large clinical series in which investigators compared outcomes of observation of inpatients and outpatients with mild TBI failed to show a benefit of inpatient care.8,9 Nevertheless, large numbers of patients with mild TBI are admitted to the hospital for overnight observation, generally for medicolegal reasons. Dozens of guidelines have been published, but no consensus exists about which patients with minor TBI should be admitted for in-hospital observation, nor is there any consensus regarding the duration of hospital stay for admitted patients. Some guidelines specify 24- or 48-hour hospital admission. Others recommend “overnight admission,” but this vague and nonspecific. For example, a patient who is admitted to the hospital in the late evening or early morning hours and is then discharged on morning rounds may actually be in the hospital for only a few hours. The most important consideration is for the patient to be in an environment where he or she can be observed carefully for any evidence of neurological deterioration. The decision to admit or observe on an outpatient basis depends on clinical judgment, results of CT in selected patients, and consideration of a patient’s social situation. As a general rule, the patient with a GCS score of 15, no evidence of skull fracture on CT, and a responsible parent or other adult available to monitor the

“Talk and Die” Injuries It is now well known that patients with seemingly mild TBI can have a brief period of stability, or even improvement, followed by dramatic neurological deterioration. This ominous clinical scenario was first reported by Reilly and associates in 1975.7 This initial report focused on patients who talked at some point after the injury and then died. These injuries came to be known as “talk and die” injuries and, in their milder form, as “talk and deteriorate” injuries. Neurological worsening, as documented by a decline in the GCS score, immediately raises concern about an expanding intracranial hematoma; however, several other possibilities must be considered as well, including hydrocephalus, pneumocephalus, cerebral edema, metabolic abnormalities (hyponatremia, hypoglycemia, adrenal insufficiency), drug or alcohol withdrawal, seizures, meningitis, and carotid or vertebral artery dissection. In the event of neurological deterioration, head CT should be repeated, with a search for hematoma, hydrocephalus,

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Surgical Issues The initial computed tomographic scan should be carefully scrutinized for any acute surgical problems, including intracerebral hemorrhage, subdural hematoma, epidural hematoma, and depressed skull fracture. Any hematoma causing significant mass effect on the brain should be promptly evacuated. Smaller hematomas and small areas of contusion can be monitored but may necessitate surgery on a delayed basis if there is subsequent enlargement. There is no precise size threshold above which the hematoma must be evacuated and below which the lesion may be safely monitored. These decisions must be made on a caseby-case basis, guided by the patient’s clinical course and findings on CT.

Intracranial Pressure Monitoring A

B ■

Figure 103–6. A, Initial computed tomographic head scan is unremarkable. There is mild generalized cerebral atrophy, consistent with age. Right parietal extracranial soft tissue swelling is seen. B, Follow-up computed tomographic head scan 10 hours later shows a large acute subdural hematoma with midline shift. The black arrow indicates the component of the hematoma over the cerebral convexity. The white arrow indicates an interhemispheric component of the hematoma along the falx cerebri.

patient may be observed at home. In pediatric patients, the possibility of child abuse is an additional consideration. A child should not be discharged home if the clinical and radiographic findings are at all suggestive of nonaccidental injury. All patients with moderate and severe TBI require hospital admission. More severe injuries should be monitored in an intensive care unit or a dedicated neurosurgical unit. The majority of patients with severe TBI require endotracheal intubation for airway control and mechanical ventilation.

ICP monitoring should be considered for clinically severe TBI (GCS score, 3 to 8). There are various types of ICP monitors, including intraventricular, intraparenchymal, subdural, and epidural devices. Intraventricular monitors are more accurate and have the added advantage of allowing withdrawal of CSF to lower ICP. The main drawback to intraventricular monitoring is difficulty with catheter placement if the ventricles are severely compressed as a result of cerebral edema caused by severe TBI. In these cases, it may not be technically possible to cannulate the ventricles. Other concerns with the intraventricular technique include the risk of intraparenchymal hemorrhage associated with passing a catheter through brain tissue and the risk of infection. An intraventricular ICP monitor is visible in Figure 103–7. Subdural and epidural monitors are technically easier to place and have a lower risk of hemorrhage and infection, but they provide less accurate readings of ICP and do not enable CSF withdrawal. In view of all benefits and risks, intraventricular monitors are generally preferred. ICP monitors may be placed in the surgical suite or in the intensive care unit.

Management of Raised Intracranial Pressure The normal ICP is 10 to 15 mm Hg in adults and older children. Various threshold values are used at different centers, above which treatment measures are instituted. This threshold is usually 20 to 25 mm Hg. A related concept is that of cerebral perfusion pressure (CPP), which equals the mean arterial pressure (MAP) minus ICP; that is, CPP = MAP − ICP

Normal adult CPP is higher than 50 mm Hg. Because of cerebral autoregulation, large fluctuations in systemic blood pressure produce only small changes in cerebral blood flow. However, when CPP falls below 40 mm Hg, cerebral blood flow is impaired. Thus, a major goal of TBI care is to maintain CPP within a normal range through appropriate management of systemic blood pressure and ICP. After placement of the ICP monitor, efforts are made to keep ICP lower than 20 mm Hg and CPP higher than 50 mm Hg. General measures include elevating the head of the bed 30 to

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B Figure 103–7. A, Lateral scout view from a computed tomographic head scan in which an intraventricular intracranial pressure monitor is visible. B, Axial computed tomographic image showing catheter position in the ventricles.

45 degrees, avoidance of hypoxia, maintenance of normocapnia (carbon dioxide tension, 35 to 40 mm Hg), and light sedation. If raised ICP persists, the follow measures may be needed: heavy sedation with fentanyl and paralysis with vecuronium; drainage of CSF in 3- to 5-mL increments; mannitol, 0.25 to 1 g/kg, followed by 0.25 g/kg every 6 hours; and mild hyperventilation to a carbon dioxide tension of 30 to 35 mm Hg. If mannitol is used, serum electrolytes and osmolality must be monitored closely. Mannitol must be discontinued if serum osmolality exceeds 320 mOsm/L. Head CT should be repeated if there is a persistent problem with raised ICP. Finally, high-dose barbiturate therapy (barbiturate coma) should be considered as a last resort for raised ICP that is refractory to all other measures.

Anticonvulsant Therapy Post-traumatic seizures are a recognized complication of TBI. Post-traumatic seizures are classified as being early if they occur within 1 week of injury and late if the onset is more than 1 week after injury. There may be justification for a third category of “immediate” seizure, occurring minutes to hours after injury. Total prevention of seizures would obviously be of great benefit to the patient. Administration of an anticonvulsant medication to prevent a first seizure (prophylactic anticonvulsants) has been the subject of considerable investigation. Data indicate that in adults, prophylactic anticonvulsants lower the risk of early seizures but do not improve outcomes. Prophylactic anticonvulsants also do not lower the risk of late seizures.10 In Guidelines for the Management of Severe Head Injury, the American Association of Neurological Surgeons has rated various treatments as standards, guidelines, or options. Prophylactic anticonvulsants are considered by this organization to be an option of unclear benefit to the patient.11 This means that the clinician may choose to prescribe or withhold this

treatment, on the basis of clinical judgment. If prophylactic anticonvulsants are being considered, the decision to prescribe must be made in view of the known potential for serious complications associated with these medications. Prophylaxis, when prescribed, is usually phenytoin, and the usual duration of therapy is 1 week. If late seizures occur, long-term anticonvulsant therapy is needed, usually starting with phenytoin or carbamazepine and progressing to other agents in the event of therapeutic failure or toxicity. Immediate seizures may complicate an otherwise trivial injury, especially in children. In these cases, a period of observation, without initiation of anticonvulsant therapy, may be appropriate. Patients with clinically severe TBI (GCS score, 3 to 8), penetrating brain injury, and a history of alcohol abuse are at higher risk for developing post-traumatic seizures.

Steroids The use of glucocorticoids in severe TBI dates back to the 1960s. Early laboratory and clinical work suggested that glucocorticoids improved cerebral edema, lowered ICP, and had other beneficial effects. As a result, these agents became a standard part of the management of severe TBI. However, more recent investigation indicates that glucocorticoids do not lower ICP or improve outcome in patients with severe TBI. Therefore, the routine use of glucocorticoids is no longer recommended for any type of TBI.11

OUTCOMES Prognosis in TBI is well correlated with the admission GCS score, measured after resuscitation. As mentioned previously,

chapter 103 head trauma severe TBI (GCS score, 3 to 8) carries a mortality rate of 35% to 40%; moderate TBI (GCS score, 9 to 12) carries a mortality rate of 5% to 10%; and mild TBI (GCS score, 13 to 15) carries a mortality rate of less than 2%. Children older than 2 years and teenagers have a better prognosis than do adults in all categories. The presence of an intracranial hematoma that must be surgically removed, evidence of obliteration of basal cisterns on head CT, and the presence of raised ICP indicate a poor prognosis.

Post-traumatic Syndrome This is a well-known and yet poorly understood complication of mild or moderate TBI. Patients report somatic symptoms, including headache, dizziness, blurred vision, tinnitus, and balance difficulties; cognitive symptoms, including difficulty concentrating and impaired judgment; and psychosocial symptoms, including depression, emotional lability, personality changes, insomnia, and fatigue. Treatment for these symptoms is largely supportive. The clinical course is usually one of improvement, although progress is quite variable. In some cases, further evaluation is warranted. Head CT, MRI, and neuropsychological testing may be needed. Imaging studies occasionally identify a late complication of TBI, such as hydrocephalus, that can be helped with surgical intervention. Electroencephalography should be considered when there is a question of seizure activity. A more severe form of post-traumatic syndrome is chronic traumatic encephalopathy, also known as dementia pugilistica or punch drunk syndrome, which results from repeated concussions, as described previously.

CONCLUSIONS AND RECOMMENDATIONS TBI is a major cause of death and disability in many parts of the world. The leading causes of TBI are motor vehicle accidents, gunshot wounds and other types of assault, and falls. A key aspect of TBI management is injury prevention. The development of organized trauma care systems has improved outcomes for patients with TBI and other major injuries. TBI has a wide spectrum of severity from trivial to lifethreatening. Evaluation of a patient with TBI includes GCS testing, neurological examination, and a general physical examination to search for spinal and systemic injuries. CT is the imaging modality of choice. Optimal evaluation of the patient with TBI is dependent on both clinical assessment and imaging findings from head CT. The majority of TBIs are mild. Although no specific treatment is required, there is a small risk of deterioration from a delayed intracranial hemorrhage. For this reason, all patients with mild TBI should be observed for 24 hours after injury for any evidence of clinical deterioration. This observation may be carried out in the hospital or at home, depending on clinical and imaging findings and the patient’s social situation. When a patient with mild TBI deteriorates, this is known as a “talk and deteriorate” injury and, in its most extreme form, as a “talk and die” injury. All moderate and severe TBIs require hospital admission. Clinically significant intracranial hematomas should be

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promptly evacuated. ICP monitoring should be considered in patients with severe TBI (GCS score, 3 to 8), and ICP higher than 20 mm Hg should be treated aggressively. Seizures are controlled with either phenytoin or carbamazepine. Prophylactic anticonvulsants, administered in an effort to prevent a first seizure, are an option for patients with moderate and severe TBI. Steroids are no longer routinely recommended for TBI. Clinical deterioration should prompt consideration of followup head CT to look for development of new intracranial hemorrhage or progression of a known hemorrhage. Hypotension, hypoxia, seizures, raised ICP, and expanding hematomas are known to cause secondary brain injury, and all should be treated aggressively. Indicators of poor prognosis include low initial GCS score, the presence of an intracranial hematoma necessitating removal, raised ICP, obliteration of basal cisterns on CT, and advanced age.

K E Y

P O I N T S

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TBI is a major cause of death and disability in many parts of the world. The social and economic costs associated with TBI are enormous.

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The GCS is the most widely used clinical measure of TBI severity. The GCS is a straightforward, objective assessment that can be administered by physicians, nurses, and allied health staff.

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Head CT is the primary imaging modality for TBI. CT is very sensitive for surgically significant findings, such as intracranial hematoma and depressed skull fracture.

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ICP monitoring should be considered for patients with severe TBI, with GCS scores of 3 to 8.

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The possibility of cervical spine injury must be ruled out in all patients with TBI. In particular, the patient who is comatose with a severe TBI and/or acute intoxication with alcohol or drugs should be considered to have a cervical spine injury until proven otherwise.

Suggested Reading Bailes JE, Day AL, eds: Neurological Sports Medicine: A Guide for Physicians and Athletic Trainers. Rolling Meadows, IL: American Association of Neurological Surgeons, 2001. Brain Trauma Foundation: Guidelines for the Management of Severe Head Injury, 2nd ed. Park Ridge, IL: American Association of Neurological Surgeons, 2000. Greenberg MS: Handbook of Neurosurgery, 5th ed. New York: Thieme, 2001, pp 626-685. Popp AJ, ed: A Guide to the Primary Care of Neurological Disorders. Park Ridge, IL: American Association of Neurological Surgeons, 1998.

References 1. Mendeloff JM: Trauma systems and public policy. Annu Rev Publ Health 1991; 12:401-424. 2. Teasdale G, Jennett B: Assessment of coma and impaired consciousness: a practical scale. Lancet 1974; 2:81-84.

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3. Fay GC, Jaffe KM, Polissar NL, et al: Mild pediatric traumatic brain injury: a cohort study. Arch Phys Med Rehabil 1993; 74:895-901. 4. Broshek DK, Barth JT: Neuropsychological assessment of the amateur athlete. In Bailes JE, Day AL, eds: Neurological Sports Medicine: A Guide for Physicians and Athletic Trainers. Rolling Meadows, IL: American Association of Neurological Surgeons, 2001, pp 155-168. 5. Hahn YS, McLone DG: Risk factors in the outcome of children with minor head injury. Pediatr Neurosurg 1993; 19:135-142. 6. Dacey RG, Alves WM, Rimel RW, et al: Neurosurgical complications after apparently minor head injury: assessment of risk in a series of 610 patients. J Neurosurg 1986; 65:203-210.

7. Reilly PL, Graham DI, Adams JH, et al: Patients with head injury who talk and die. Lancet 1975; 2:375-377. 8. Lowdon IMR, Briggs M, Cockin J: Post-concussional symptoms following minor head injury. Injury 1989; 20:193-194. 9. Miller JD, Murray LS, Teasdale GM: Development of a traumatic intracranial hematoma after a “minor” head injury. Neurosurgery 1990; 27:669-673. 10. Temkin NR, Dikmen SS, Wilensky AJ: A randomized, doubleblind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990; 323:497-502. 11. Brain Trauma Foundation: Guidelines for the Management of Severe Head Injury, 2nd ed. Park Ridge, IL: American Association of Neurological Surgeons, 2000.

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SPINAL TRAUMA ●

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Thomas Kossmann, Ilan Freedman, and Cristina Morganti-Kossmann

Spinal cord injury (SCI) is a devastating event for patients and their families, with many severe medical, social, and economic sequelae. Patients may be permanently disabled and may ultimately have a lifelong dependence on support services. The neurological dysfunction after traumatic SCI results from a “primary” mechanical insult, followed by a downstream cascade of “secondary” processes that disrupt normal cord anatomy and function. The primary insult is determined by the mechanism of injury, energy applied to the cord, level of SCI, and patient factors such as medical comorbid conditions and the preinjury space available to the cord. Secondary injury mechanisms include, but are not limited to, disruption of the microcirculation, loss of autoregulation, edema, ischemia, calcium toxicity, glutamate excitotoxicity, lipid peroxidation, and free radical activation.1 Greater understanding of the pathophysiology of the secondary cascade and effective early resuscitation measures have improved the outcomes for these patients. Treatment of SCI is aimed at preserving residual neurological function, avoiding secondary injury to the cord, and restoring spinal alignment and stability. Currently, there is also burgeoning activity in basic research aimed at repair and regeneration of the injured spinal cord. This may facilitate higher levels of independence and productivity and may markedly improve the quality of life for patients with SCI.2,3

EPIDEMIOLOGY The incidence of SCI in developed nations is approximately 30 to 50 per million persons per year. Accordingly, 10,000 new cases of SCI are diagnosed in the United States each year. The most common mechanisms of SCI include motor vehicle accidents, falls from a height, violence, and sports-related injuries. Approximately 55% of these injuries occur in the cervical region, 15% in the thoracic region, 15% at the thoracolumbar junction, and 15% in the lumbosacral area. The incidence of SCI among boys and men is three to four times that among girls and women. The incidence peaks in adolescence and young adulthood; two thirds of all cases arise in patients younger than 30. With improvements in medical and surgical care, those who survive their initial injuries can now expect to live long lives, but the cost of caring for such patients over the course of a lifetime is substantial. The incidence of SCI is also

increased in the sixth and seventh decades of life. This is a result of aging and an associated increase in cervical spondylitic disease, which narrows the spinal canal and predisposes to spinal injury.

DEFINITIONS SCI can be categorized as incomplete paraplegia, complete paraplegia, incomplete tetraplegia, and complete tetraplegia. According to the classification of the American Spinal Injury Association,4 tetraplegia is the “impairment or loss of motor and/or sensory function in the cervical segments of the spinal cord.” Paraplegia refers to “impairment or loss of motor and/or sensory function in the thoracic, lumbar, or sacral segments of the spinal cord.” SCI is deemed an incomplete injury when motor sensory function is preserved below the level of injury. Sparing of sensation in the perianal region may be the only sign of residual function. Sacral sparing may be demonstrated by preservation of some sensory perception in the perianal region and/or by voluntary contraction of the rectal sphincter. The injury is deemed complete when all function, including rectal, motor, and sensory function, is lost. During the first few days after injury, this diagnosis cannot be made with certainty because of the possibility of spinal shock (described later). The dermatomes and myotomes caudal to the neurological levels that remain partially innervated are named the zone of partial preservation. The neurological injury level is determined primarily by clinical examination and is defined as the most caudal spinal cord segment with normal sensory and motor function on both sides of the body. The sensory level refers to the most caudal spinal cord segment with normal sensory function. The motor level is defined similarly with regard to motor function as the lowest key muscle that has a grade of at least 3/5 (Table 104–1). The bony level of injury is that at which the vertebrae are damaged, which causes injury to the spinal cord. As spinal nerves enter the spinal canal through the vertebral foramina and ascend or descend inside the spinal canal before entering the spinal cord, there is frequently a discrepancy between the bony and neurological levels. This discrepancy becomes more pronounced the further caudal the injury is.

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ANATOMY OF SPINAL CORD INJURY

Atlanto-Occipital Dislocation

Fractures of the spine are determined by the forces applied to the spinal column. Such forces include distraction and compression, flexion and extension, and combinations thereof. Fractures are also categorized by anatomical location: cervical, thoracic, and lumbar.

This is caused by traumatic hyperflexion and extension, in which the ligamentous connections between the skull and C1 and C2 are disrupted (Fig. 104–1). Because of the highly unstable nature of this injury, these patients often either die of brainstem destruction and apnea or are profoundly neurologically impaired (ventilator dependent and tetraplegic). On occasion, a patient may survive if prompt resuscitation is available at the injury scene. This injury may be identified in up to 20% of patients with fatal cervical spine injuries and is a common cause of death in cases of shaken baby syndrome in which the infant died immediately after being shaken.

Cervical Injury The cervical spine is the region most vulnerable to injury. These injuries can be classified as upper and lower cervical. Upper cervical injuries include those to the base of the skull, C1, and C2. Lower cervical injuries affect C3 to C7. Upper cervical spine injuries can be described as atlanto-occipital dislocation, C1 fractures, disruption of the transverse ligament of C1, C2 odontoid fractures, and traumatic C2 spondylosis fractures. Lower cervical spine injuries are generally classified into facet dislocations, compression fractures, burst fractures, and teardrop fractures.

Atlas Fracture (C1) This injur represents 10% of all cervical fractures and usually results from axial loading, such as when a large load falls vertically on the head or in a fall in which the patient lands on the head in a relatively neutral position. The most common C1 fracture is a burst fracture (Jefferson’s fracture), which involves disruption of both the anterior and posterior rings of C1 with lateral displacement of the lateral masses (Fig. 104–2). In patients who survive, these fractures are usually not associated with SCIs but may be accompanied with significant retropharyngeal swelling. The trauma team should be alert to this possibility and should consider prophylactic intubation. Approximately 40% of atlas fractures occur in combination with fractures of the axis (C2).

T A B L E 104–1. Muscle Strength Grading Score

Clinical Finding

0 1 2 3 4 5 NT

Total paralysis Palpable or visible contraction Full range of motion with gravity eliminated Full range of motion against gravity Full range of motion but less than normal strength Normal strength Not testable

A ■

Axis (C2) Fractures Because of its unusual shape, the C2 vertebra is susceptible to various fracture patterns, depending on the force and direction of impact. Acute C2 fractures represent approximately 18% of all cervical spine injuries.

B Figure 104–1. Atlanto-occipital dislocation. A, Computed tomographic scan reconstruction. The articular surface of the condyle is dislocated anteriorly. Note the space between the occipital condyle and C1. B, Three-dimensional reconstruction from computed tomographic scans.

chapter 104 spinal trauma Approximately 60% of C2 fractures involve the odontoid process. These are classified according to the scale of Anderson and D’Alonzo. Type 1 odontoid fractures involve the tip of the odontoid and are relatively uncommon. Type II odontoid fractures occur at the waist of the odontoid and C2 body and are the most common type (Fig. 104–3). Type III odontoid fractures occur at the base of the dens and extend obliquely into the body of C2.

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Posterior Element Fractures of C2 A hangman’s fracture involves the pars interarticularis, usually results from an extension injury, and represents approximately 20% of all C2 fractures. Variations of a hangman’s fracture include bilateral fractures through the lateral masses or pedicles. Approximately 20% of all axis fractures are nonodontoid, nonhangman’s fractures and include fractures through the body, pedicle, lateral mass, laminae, and spinous process.

Fractures and Dislocations (C3 to C7)

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Figure 104–2. Jefferson’s fracture: fracture of the anterior and posterior arc of C1 (two-part fracture).

Bony injury to the lower cervical area occurs in the form of compression fracture, burst fracture, or teardrop fracture. Compression fractures arise from a flexion injury, with no greater than 25% compression of the middle column and no injury to the posterior longitudinal ligament. Burst fractures are the result of compression and flexion. Teardrop fractures are caused by flexion with rotation and compression and are notably unstable injuries (Fig. 104–4). Fractures of C3 are relatively infrequent because this vertebra is positioned between the more vulnerable axis and the more mobile C5 and C6 vertebrae. C5 is the most commonly fractured cervical vertebra in adults, whereas subluxation more often occurs at the level of C5 on C6. Common injury patterns at these levels are vertebral body fractures with or without subluxation; subluxation of the articular processes; and fractures of the laminae, spinous processes, pedicles, or lateral masses. In rare cases, ligamentous disruption occurs without fractures or facet dislocations. The incidence of neurological injury increases dramatically with facet dislocations. After unilateral facet dislocation, 80% of patients develop a neurological injury (of which approximately 30% are root injuries only, 40% incomplete SCIs, and 30% complete SCIs). In the presence of bilateral locked facets, the morbidity is much worse, with 16% incomplete and 84% complete SCIs.

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Figure 104–3. Dens fracture before (A) and after (B) reduction.

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B

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Figure 104–4. Teardrop fracture of C7. Multiple-slice reconstruction with clearly visible teardrop fracture of C7. This may indicate additional discoligamentary injury. ■

Figure 104–6. Radiograph of the thoracolumbar junction, showing a T12 burst fracture.

from violent forces, they are associated with a high incidence of concomitant injuries, such as rib fractures, pneumothorax, hemothorax, pulmonary contusion, cardiac contusion, and sometimes aortic shearing injury.

The Thoracolumbar Junction

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Figure 104–5. Magnetic resonance image of multiple fractures of the thoracic spine. The fractured thoracic vertebrae appear smaller with irregular shape and white appearance in the magnetic resonance image.

The thoracic spine has a natural kyphosis (concave forward), whereas the lumbar spine has a lordosis (convex forward). Because of the change of curvature in the transition zone, the thoracolumbar junction acts like a fulcrum between the inflexible thoracic region and the stronger lumbar levels, which predisposes it to injury.5 Consequently, approximately 15% of spinal injuries are found in this region (Fig. 104–6). The three-column structural concept described by Dennis is integral to evaluation of the thoracolumbar spine. According to this concept, the spine is divided into anterior, middle, and posterior columns. The anterior column comprises the anterior longitudinal ligament, anterior half of the vertebral body, and anterior half of the disk. The middle column consists of the posterior longitudinal ligament with the posterior half of the vertebral body and disk. The posterior column is composed of all structures posterior to the middle column, back to the level of the supraspinous ligament. Disruption of two or three columns at one level generates spinal instability.

The Thoracic Spine

Lumbar Spine

The mobility of the thoracic spine is much more restricted than that of the cervical spine, because it has additional support from the rib cage. This region requires greater force to disrupt its integrity and thus has a much lower incidence of fractures (Fig. 104–5). However, because the thoracic canal is relatively narrow, a fracture dislocation here frequently results in a severe neurological deficit. Because thoracic spine fractures result

The Dennis classification also divides lumbar spine injuries into minor and major categories on the basis of radiographic criteria. Major injuries encompass compression fractures, burst fractures, flexion- and distraction-type injuries, and fracture dislocations. Minor injuries include transverse process fractures, articular process fractures, spinous process fractures, and pars interarticularis fractures.

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lar changes such as vasodilatation, congestion (hyperemia), and petechial hemorrhages. In many cases, no abnormalities are observed during this period (particularly in the absence of massive compression or laceration injury), inasmuch as much of the pathology of human SCI results from secondary phenomena mediated by cellular and molecular cascades. This suggests that there may be a window of opportunity during the immediate phase for downregulating the deleterious secondary events.

Acute Phase (Hours to 1 to 2 Days)

■

Figure 104–7. Magnetic resonance image of a Chance fracture at L3. Note the destruction of the posterior spine complex. A superior burst fracture of L3 is also evident.

Compression fractures usually result from failure of the anterior column with intact middle and posterior columns, frequently from an anterior flexion force accompanied by a posterior tensile force. These injuries are generally not associated with neurological deficit. With lumbar burst fractures, loss of height of the anterior and middle columns is characteristically shown on radiographs, with retropulsion of bone into the canal and widening of the interpedicle distance. These fractures are inherently unstable. Flexion and distraction injuries, frequently described as Chance fractures (Fig. 104–7), represent a failure of the middle and posterior columns in tension, with the anterior column acting like a hinge. Fracture dislocations are associated with failure of all three columns with a combination of forces, including flexion rotation, flexion distraction, or shearing. Because of their inherent instability these injuries are probably associated with a high incidence of severe SCI. Because the spinal cord ends at the L1 vertebral level, the cord itself may not necessarily be injured in lumbar fractures. Instead, insult to the cauda equina may occur. The neurological deficit here is less severe than in injuries to the spinal cord itself.

HISTOLOGY OF SPINAL CORD INJURY According to Belanger and Levi (2000) and Park and associates (2004), the histological changes in SCI can be categorized as immediate, acute, intermediate, and late phases.6,7

Immediate Phase (Initial 1 to 2 Hours) This phase involves the mechanical tissue disruption at the time of injury (e.g., tears, distortions, compression) and vascu-

This phase is characterized by vascular alterations, edema, hemorrhage, inflammation, and neuronal and myelin changes. The edema may be vasogenic: that is, secondary to breakdown of the endothelium at the blood-brain barrier, which leads to leakage of plasma fluid into the extracellular space. Diminished blood flow to the injured region and pressure effects may in turn cause ischemic damage. Cytotoxic edema (intracellular swelling), occurring mostly in astrocytes, is observed from 3 hours to 3 days after injury. This is probably caused by factors such as glutamate, lactate, K+, nitric oxide, arachidonate, reactive oxygen species, and ammonia, levels of which are elevated in the extracellular space shortly after injury, altering the osmotic balance of the cells. Hemorrhage in the acute phase occurs in the gray matter after contusion injury. This is primarily a result of rupture of postcapillary venules or sulcal arterioles, either from mechanical disruption or from intravascular coagulation that leads to venous stasis and distension. The larger caliber vessels are usually spared. The high metabolic requirements of neurons make the gray matter exquisitely sensitive to ischemic injury. This can be compounded by the loss of autoregulatory mechanisms that normally control the microvascular hemodynamics tightly within the spinal cord. The early inflammatory response is a complex process involving vascular changes, including the disruption of the blood-brain barrier and the upregulation of endothelial cell adhesion molecules that allow the activation and extravasation of cells from the bloodstream (neutrophils, macrophages, lymphocytes) into the injured tissue. These cells also release a large number of soluble immune mediators (cytokines, chemokines) that consequently activate resident glial cells.1,3 A mild influx of neutrophils has been described as beginning within 1 day after SCI, with a peak at 2 days and a decrease by 3 days. This is in sharp contrast to other tissues, in which the neutrophilic influx is often marked. The neutrophilic response in the central nervous system (CNS) is likely to be neurotoxic in nature, because once these cells are activated and accumulated at the lesion site, they release potent free radicals that attack the integrity of the lipid bilayer of the cellular membrane. The extent of neutrophil infiltration has been associated with blood-brain barrier dysfunction and tissue damage. The neuronal and axonal changes in the acute phase include marked axonal swelling and ultimately fiber disconnection. Microscopically, this is marked by the formation of typical retraction balls. Myelin breakdown is another feature of the early period after SCI. This is initially characterized by swelling of the myelin sheaths, and ultimately by fragmentation of myelin and its phagocytosis by macrophages. Myelin loss generally occurs in

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association with axonal pathology. Oligodendrocytes are also exquisitely sensitive to SCI. Much of the injury to these cells appears to be necrotic, but oligodendrocyte apoptosis has also been documented both in experimental animals and in humans.

Free Radicals Free radicals play a pivotal role in spinal trauma. These molecules hold unpaired electrons that make them highly reactive to lipids, proteins, and DNA. Molecular oxygen possesses two unpaired electrons. Addition of one electron to oxygen produces superoxide, whereas the addition of two electrons produces hydrogen peroxide, and the addition of three electrons produces the highly reactive hydroxyl radical. Generation of these free radicals can be catalyzed by free or protein-bound iron. After the initial period of local hypoperfusion and ischemia, the injured spinal cord may undergo a period of reperfusion. Ironically, this allows a significant inflow of free radicals, which then exacerbate the tissue damage.

Excitotoxicity In SCI, excitotoxicity has been demonstrated to be predominantly caused by glutamate, the most prevalent excitatory neurotransmitter in the CNS.6 Release and accumulation of glutamate occur rapidly after SCI, reaching toxic levels as early as 15 minutes after experimental injury. Glutamate activates N-methyl-D-aspartate (NMDA) receptors and thereby allows extracellular calcium (and sodium) to move down a massive concentration gradient into the cell. NMDA receptor activation may also trigger the release of calcium into the cytoplasmic compartment from intracellular stores. Elevated cytosolic and mitochondrial calcium concentrations can trigger a multitude of calcium-dependent processes that reduce energy available to the cell, potentially leading to apoptosis.

Intermediate Phase (Days to Weeks) Microglia and astrocytes play important roles in this phase of SCI, leading to either beneficial or detrimental effects on the damaged tissue.

Microglia Activation of these resident macrophages of the nervous system occurs as early as 1 day after injury. There has long been a debate regarding the role of these cells in CNS injury. For many years, it was believed that they were likely to be detrimental, because of secretion of potentially harmful molecules such as glutamate, proteases, cytokines, nitric oxide, and superoxide anions. This concept is changing as a result of the observation that microglia indirectly induce neurotrophic factors (e.g., nerve growth factor through the release of cytokines such as interleukin-1β and tumor necrosis factor α), thus also supporting regeneration of the injured tissue. It has been suggested that microglia are responsible for phagocytosis of lipids contained within necrotic debris. These lipids are potential sources of free radicals, which may expose the CNS to excessive oxidative stress if they are not removed rapidly.

Astrocytes Astrocytes are the primary source of growth factors (e.g., nerve growth factor, fibroblast growth factor 2, platelet-derived growth factor, ciliary neurotrophic factor, insulin-like growth factor), as well as neurotrophic and extracellular matrix components that may promote neuroprotection, repair, and regeneration, contributing to neurological recovery. However, reactive astrocytes localized at the edge of the lesion also undergo hypertrophy, at later times (2 to 3 weeks), and then send out long, thick cytoplasmic processes that ultimately form the so-called glial scar. This may isolate the lesion from the remaining viable tissue and is suggested to act as a barrier to axonal regrowth after injury.

Late Phase (Weeks to Months/Years) The later phases of SCI are characterized by wallerian degeneration, astroglial and mesenchymal scar formation, development of cysts/cavities and syrinx, and schwannosis.

Wallerian Degeneration Wallerian degeneration consists of the anterograde disintegration of axons and their transected myelin sheaths. The myelin sheaths are distorted and fragmented with absent, dense, or flocculent axoplasm. The astroglial scar eventually replaces the destroyed myelin sheath. In the CNS, wallerian degeneration is a more protracted process than in the peripheral nervous system and may take more than a year to complete. The bloodbrain barrier becomes leaky along pathways undergoing wallerian degeneration, most probably because of activation of microglia/macrophages in the degenerating tracts.

Astroglial Scar Formation of an astroglial scar marks the end stage of reactive astrocytosis. The scar comprises tightly interwoven astrocyte processes attached to one another by tight junctions and surrounded by extracellular matrix.

Mesenchymal Scar Not to be confused with astroglial scars, mesenchymal scars represent deposition of fibrous connective tissue and collagen and are well-recognized impediments to axonal growth.

Cysts/Cavities Single, multiple, or multiloculated cysts filled with extracellular fluid and surrounded by thin astrogliotic walls may form in the final “healing” phase of the necrotic process. These cavities create a gap for the regeneration of axonal fibers.

Syrinx This is a cavity with a denser gliotic wall that is under pressure. This is problematic, for as the pressure increases, the cavity enlarges, compressing the adjacent cord parenchyma and aggravating the neurological deficits. The mechanism of syrinx formation is not understood but may often be associated with

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cord tethering. Surgical drainage is the only available treatment.

Schwannosis This is a misnomer because it represents aberrant intramedullary and extramedullary proliferation of both Schwann cells (the myelinating cells of the cord) and associated axons. The incidence of schwannosis in human SCI is extremely high, particularly in patients who have survived at least 4 months. It is postulated that schwannosis may contribute to pain, spasticity, and other abnormal processes observed in long-term patients with SCI.

SPINAL CORD SYNDROMES Incomplete lesions may be classified into a number of neurologic syndromes that reflect the anatomical level of cord injury. Recognition of the type of lesion enables the clinician to gather information about the mechanism of injury and guides selection of appropriate treatment. The various syndromes also have different prognoses for recovery.8 ■

Central Cord Syndrome Because the motor fibers to the cervical segments are topographically arranged toward the center of the cord, damage to the central cord affects the arms and hands more severely than the lower extremities. The degree of sensory loss is variable. This syndrome is usually seen after a hyperextension injury in a patient with preexisting cervical canal stenosis (often resulting from degenerative osteoarthritic changes). The history is commonly that of a forward fall that resulted in a facial impact. The syndrome may occur with or without cervical spine fracture or dislocation. Central cord syndrome in young patients has a relatively good prognosis. Recovery usually follows a characteristic pattern. The lower extremities recover strength first, bladder function next, and the proximal upper extremities and hands last (Fig. 104–8).

Anterior Cord Syndrome Infarction in the territory supplied by the anterior spinal artery causes damage to the anterior two thirds of the cord. This syndrome is characterized by paraplegia and a dissociated sensory loss with loss of pain and temperature sensation. Posterior column function (position, vibration, and deep pressure sense) is preserved. This syndrome has the poorest prognosis of the incomplete injuries.

Figure 104–8. Magnetic resonance image showing a central cord syndrome. Note the bleeding within the spinal cord at the C6C7 level.

Neurogenic Shock versus Spinal Shock Neurogenic shock may occur after a cervical or high thoracic (T1-T5) injury that interrupts thoracic sympathetic outflow. This results in loss of vasomotor tone and loss of cardiac sympathetic innervation. The consequent hypotension and bradycardia may cause secondary neurological injury and pulmonary, renal, and cerebral insults. Under these conditions, it may not be possible to restore a patient’s blood pressure by fluid infusion alone, because massive fluid resuscitation may generate pulmonary edema. The blood pressure can instead be restored by supplementing moderate volume replacement with judicious use of inotropes, such as dobutamine, and pressors, such as dopamine, that increase vascular tone. Muscarinic antagonists, such as atropine, can be used to treat hemodynamically significant bradycardia. Spinal shock refers to the muscle flaccidity and loss of reflexes seen after SCI. The “shock” to the injured cord may make it initially appear completely functionless. However, because the cord is usually not completely destroyed in SCI, the duration of this state is variable; recovery usually occurs.

Penetrating Injuries Brown-Séquard Syndrome This disorder results from hemisection of the cord, and its pure form consists of ipsilateral motor paralysis (corticospinal tract) and loss of proprioception (posterior column), in association with contralateral loss of pain and temperature sensation beginning one to two levels below the level of injury (spinothalamic tract). The classic syndrome is rare, but variations are common. Some recovery is usually obtained, even if the syndrome is caused by a direct penetrating injury to the cord.

Penetrating SCIs are most commonly caused by gunshots or stabbings. A complete neurological deficit may result if the path of injury passes directly through the vertebral canal. Complete deficits can also be produced by energy transfer from a highvelocity missile (e.g., a rifle bullet) passing close to the spinal cord rather than through it. Spinal instability from penetrating injury is exceedingly rare. Associated injuries, however, should be highly suspected. Penetrating cervical injuries are combined with a high incidence of vascular lesions, whereas

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penetrating thoracic trauma is associated with pulmonary and cardiac injuries. Knife or gunshot trauma to the lumbar spine may be accompanied by damage to the abdominal viscera, genitourinary system, or major vascular structures, and severe infection may follow bullet injuries that traverse the colon. Penetrating injuries can be complicated by the formation of cerebrospinal fluid fistulae. All patients with penetrating spinal injuries should therefore receive treatment with tetanus prophylaxis and broad-spectrum antibiotics.

Spinal Cord Injury without Radiographic Abnormality (SCIWORA) Because of the relatively large size of the head and the greater inherent mobility in the skeletally immature spine, combined with ligamentous laxity or disruption, children’s spinal cords are vulnerable to damage in high-energy trauma. The pediatric spine, however, because of its unique anatomical and biomechanical characteristics, may have a normal radiographic appearance even in the presence of a high-energy injury with neurological impairment. This reflects the inherent elasticity of the soft tissues, which allows spontaneous reduction after intersegmental replacement. In a child with SCI without abnormal findings on plain radiographs, a hyperextension cervical SCIWORA should be considered. A high index of suspicion is required. Because the flexibility of the spine is reduced with increasing age, SCIWORA is rarer in the adult trauma population, but it should be suspected in all patients with a neurological deficit and apparently normal radiographs.9,10

MANAGEMENT OF SPINAL TRAUMA Victims of high-speed motor vehicle accidents, persons ejected from a vehicle, and patients with falls from a height are at particularly high risk of SCI. However, because severe SCI can also result from a seemingly minor insult, all trauma patients should be presumed to have a SCI until proved otherwise.7,11-13

Prehospital Management Initial management adheres to the guidelines of the American College of Surgeons Advanced Trauma Life Support protocol, which sequentially prescribes airway management, ventilation and oxygen, and circulatory support before neurological evaluation and resuscitation. The primary injury to the spinal cord is sustained at the time of impact and is irreversible. The caregivers’ role is to prevent and minimize secondary injury. This task begins in the field during initial resuscitation: ■ Patients should receive supplemental oxygen. ■ If the airway is compromised, a nasotracheal or orotracheal

intubation should be considered with simultaneous inline stabilization, whereby a second person manually maintains the patient’s head and the neck in neutral alignment with the torso. Cricothyroidotomy may be required if these techniques fail to secure the airway. ■ Large-bore intravenous access should be established, and mean arterial blood pressure should be maintained above 85 mm Hg to ensure adequate spinal cord perfusion.

Spine Immobilization This has become established as standard care in the management of multiple trauma and begins at the accident field. Such immobilization entails placement of a hard cervical collar, transportation on a rigid long spine board, and use of logrolling technique when the patient is turned. As prolonged spinal immobilization predisposes to decubitus ulceration and deep venous thrombosis and may compromise nursing care, the board should be removed promptly after arrival at the hospital. Log rolling is the standard maneuver to allow examination of the head and back and to transfer the patient onto and from a spine board. Ideally, five people participate in its use: one to hold the patient’s head and coordinate the roll; three to control the patient’s chest, pelvis, and lower limbs; and one to perform associated procedures. Inadequate mobilization may lead to fracture displacement, which can further compromise spinal cord function and convert a good prognosis into a devastating and life-threatening outcome.

Emergency Department Management On arrival at the emergency department, securing the patient’s airway, breathing, and circulation is again the priority. Simultaneous evaluation and treatment should proceed. The physical examination includes a complete neurological examination and an assessment of the head and back. An accurate knowledge of sensory dermatomes and muscle innervation is necessary to determine the level of SCI. Manual in-line stabilization of the patient’s head is maintained while the cervical collar is temporarily removed so that the neck can be palpated for deformity or pain. Prognostically, it is important to assess for any indication of preserved long tract function of the spinal cord. Signs of an incomplete injury may include any sensation (including position sense) or voluntary movement in the lower extremities and sacral sparing.

Imaging There is a risk that spinal column injuries may be missed when other potentially life-threatening injuries are present. Radiological imaging consequently plays a pivotal role in diagnosing injuries in multiple-trauma patients. There is, however, no consensus in the literature as to which investigations are necessary to detect a clinically significant SCI or how many and which radiographs are necessary to rule out such injury (“clear” the spine). The traditional standard three-view plain film series comprises the lateral, anteroposterior, and open-mouth peg views. There is evidence that primary helical computed tomography of the entire cervical spine (with sagittal and coronal reconstructions) is more sensitive than plain films for investigating osseous integrity and competency of the spinal canal. In addition, magnetic resonance imaging offers better evaluation of soft tissues such as the intervertebral disks, ligaments, and neural elements. Major trauma centers continue to update their spine clearance protocols to reflect these innovations; some centers now routinely perform full-neck computed tomographic scans on all unconscious trauma patients and also in conscious patients with neck pain or high-risk mechanism of injury.

chapter 104 spinal trauma

A ■

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B Figure 104–9. Pincer fracture of L3. A, Computed tomographic reconstruction with visible destruction of the L3 anterior column. The L2 and L4 vertebrae are acting like pincers. Because of the high flexibility of the ligaments in young patients, no further significant damage occurs in the posterior elements of the lumbar spine. B, Computed tomographic reconstruction of pincer fracture reduced with a cage. The defect of the vertebrae was replaced with an expandable cage filled with bone. With the minimally invasive surgical technique, minimal morbidity is caused by the surgical approach.

Surgical Treatment

Pharmacological Therapy

The short-term goal is to place the spinal cord and nerves in the optimal position for recovery. Strategies range from an external orthosis to surgical intervention. Factors such as mechanism of injury, degree of neurological deficit, level of injury, and fracture anatomy contribute to the selection of the preferred treatment for each individual patient. The timing, choice of surgical approach and extent of surgery in the acute management of spinal trauma are controversial. The time from injury to surgery and the degree of initial SCI appear to be important prognostic factors, but various authors have presented conflicting arguments. Some suggest that neurological recovery in patients with progressive deficits is greater if patients are treated within 8 hours of injury. Others argue that early surgery may predispose seriously injured patients to intraoperative and postoperative respiratory distress, additional bleeding, and infection and may increase the risk of adverse outcomes. Kossmann and colleagues (2004) recommended two-staged “damage control” approach for spine trauma.14 Relatively safe procedures, such as posterior internal stabilization of thoracic or lumbar fractures or temporary external fixation of cervical fractures in a halo thoracic brace, are performed early. Once the patient is medically stable, a second operation for reconstruction of the anterior column may be performed. This delay allows for general recovery of the patient and facilitates safer anesthesia. Eventually, the definitive surgery can be electively scheduled at a time when an experienced spine surgeon is available. This may enable use of new minimally invasive techniques that are now available for the reconstruction of the anterior column of the thoracic and lumbar spine (Fig. 104–9).15

Most traumatic injuries to the spinal cord do not involve actual transection of the cord but rather entail damage of the fibers from contusive, compressive, or stretch injury. Often, portions of the ascending and descending tracts remain intact. Although it is not currently known how much of the spinal cord needs to remain intact to mediate meaningful neurological function, the observation of anatomical continuity of the spinal cord has led to the notion that pharmacological treatments, if applied early, may be able to interrupt the secondary cascade and thereby improve the survival of damaged tissue.1 Cell membrane (plasma and organelle) lipid peroxidation has been demonstrated to be a key mechanism in the secondary cascade. Post-traumatic glutamate release, activation of the arachidonic acid cascade, and production of prostaglandins result in vasoconstriction and microembolism. This leads to formation of oxygen free radicals, which cause lipid peroxidation, more often involving neurons and endothelium, thus directly impairing neuronal and axonal membrane function, with consequent microvascular damage and secondary ischemia.

Methylprednisolone In experimental studies, the glucocorticoid methylprednisolone has been shown to reduce lipid peroxidation, lessen edema and inflammation, lower excitatory amino acid release, and inhibit tumor necrosis factor α expression and nuclear factor κB activation. The nonglucocorticoid 21-aminosteroid tirilazad has also been shown to have these antioxidant neuroprotective properties. Treatment with methylprednisolone

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quickly became the standard of care for acute SCI; clinical studies indicated that initiation of treatment within the first 3 hours is optimal. However, use of high-dose methylprednisolone is controversial. Some researchers argue that the risks associated with methylprednisolone, such as increased wound infection rates, pneumonia, and severe sepsis, outweigh what they believe are usually modest neurological benefits. Other researchers have criticized the interpretations and conclusions drawn from the National Acute Spinal Cord Injury Studies that supported administration of methylprednisolone. Currently, many centers administer methylprednisolone if it can be given within 8 hours of the injury. In addition to methylprednisolone and other steroids, there has also been interest in the tetracycline antibiotic minocycline and the immunosuppressants FK-506 and cyclosporine. In animal models of contusive SCI, preliminary results with minocycline suggest a promising reduction in apoptotic death at the injury site and improved locomotor function. Cyclosporine acts at the mitochondrial membrane to impede apoptosis and has been shown to promote tissue sparing and inhibit lipid peroxidation in models of brain injury and SCI. In experimental models, FK-506 has been shown to promote axonal regeneration within the CNS.

Opioid Antagonists The nonspecific opioid receptor antagonist naloxone was investigated extensively in the early 1980s in animal models of SCI; results indicated that it reversed spinal shock and improved spinal cord blood flow. However, this beneficial response, which was believed to be mediated by antagonizing the rise in endogenous opiates after SCI, was not reproduced by all researchers. Large clinical evaluations of naloxone or other opioid receptor antagonists have not been undertaken.

Glutamate Receptor Antagonists Recognition that NMDA and non-NMDA receptor activation plays a role in excitotoxic damage after SCI has stimulated interest in the development of pharmacological interventions. NMDA receptor antagonists, such as gacyclidine and MK-801, have demonstrated neuroprotective effects in animal studies. Development of these agents as clinical therapies has been hampered by the widespread distribution of glutamate (and its receptors) in neurotransmission throughout the human CNS. It is therefore difficult to avoid extensive side effects with systemically administered treatment. Gacyclidine trials have thus far not been able to demonstrate clinical benefit.

New Pharmacological Approaches Novel Scavengers of Reactive Oxygen Species Results of research suggest that peroxynitrite, which is formed from the combination of superoxide and nitric oxide radicals, may be the most critical reactive oxygen species in acute SCI. This compound is capable of causing widespread damage to lipids, proteins, and nucleic acids. Prototypical scavengers of peroxynitrite include penicillamine and tempol. These have been shown to be neuroprotective in cell culture and in vivo models of acute CNS injury.

Dual Inhibition of Lipid Peroxidation and Peroxynitrite Dual inhibition of lipid peroxidation and neuronal nitric oxide synthase (an enzyme that contributes to the production of peroxynitrite) has been reported to attenuate post-ischemic degeneration in in vivo models of SCI.

Combination Treatment Combining antioxidant therapy with agents offering complementary mechanisms of action has also been proposed. Candidates for combination with methylprednisolone or tirilazad include calpain inhibitors, antiapoptotic compounds, and antiinflammatory agents. Combining neuroprotective and neurorestorative molecules that enhance the plasticity of surviving neurons has also been suggested, and a number of agents have been identified. These include neuroimmunophilins that stimulate axonal sprouting and inhibitors of the myelin-derived Nogo protein, known to impair axonal growth.

Neutralizing the Effects of Myelin Inhibitors Identification of axon growth inhibitory components of myelin has led to development of strategies aimed at neutralizing these proteins to promote axon regeneration. These consist of extrinsic approaches to block the inhibitors or their receptor and of intrinsic approaches to modulate their intracellular pathways. Three major forms of Nogo (Nogo-A, Nogo-B, and Nogo-C) have been identified. Monoclonal antibody that recognizes Nogo-A and blocks the neurite growth inhibitory activity of myelin has been tested in vivo. To apply specific monoclonal antibodies for therapeutic use, an effective system for delivery to the CNS must be ensured. Effective strategies for delivering antibody treatment are currently under development. Alternatively, to bypass the need to inject antibodies, a vaccine to stimulate the patient’s own immune system to generate antibodies against inhibitors of myelin proteins is also being investigated.

Transplantation Strategies The isolation of embryonic stem cells from the inner cell mass at the blastocyst stage of development has revolutionized the field of biology. These cells can replicate indefinitely without aging, are pluripotent, and can easily be genetically manipulated. The ability to isolate a relatively pure population of stem cells, to maintain them in culture over multiple passages, and then to demonstrate that these cells can differentiate into neurons, astrocytes, and oligodendrocytes in vitro and in vivo represented a major breakthrough in the understanding of neural development. The possibility that stem cells could be used for neural regeneration and repair for replacement strategies has provided an impetus for intensive research. There is evidence that various neural stem cells and precursors have differing properties in terms of cytokine dependence and of antigen and receptor expression. Thus far, researchers have demonstrated that embryonic stem cell–derived oligodendrocytes can myelinate in the normal immature nervous system. Transplantation of embryonic stem cells and more mature cells by use of fragments of peripheral nerve, fetal tissue, or Schwann cell bridges is often assessed in conjunction with the administration of neurotrophins, such as brain-derived

chapter 104 spinal trauma neurotrophic factor or neurotrophin 3, which have been shown to promote the growth of regenerating axons from transplanted tissue into the injured spinal cord. However, to restore neurological function, replenishment of cells at the injury site with stem cells needs to be followed by successful differentiation and targeted formation of operational connections by the new fibers. The complexity of these multifactorial events makes successful transplantation a challenging task. Research in this area is being pursued. The utility of embryonic stem cells for clinical therapy has, so far, also been limited by their propensity to form teratocarcinomas when transplanted as undifferentiated cells. It is hoped that further research into the molecular mechanisms regulating stem cell differentiation will allow the full capacity of endogenous and transplanted stem cells to be harnessed for clinical use.

CONCLUSION Primary neurological injury at the time of spinal column trauma is mediated through dissipation of mechanical energy and is caused by compression, cord stress, tension, shear, or disruption. A secondary injury cascade is mediated through alteration in the biomechanical environment of the cord and/or ischemia. Proper treatment of patients sustaining spinal injuries involves a meticulously coordinated effort involving emergency response personnel, emergency department doctors, trauma and orthopedic surgeons, nurses, and rehabilitation physicians. Through improvements in medical and surgical care, patients who survive their initial injuries can now expect to live long lives. Burgeoning research into the mechanisms of secondary injury and greater attention given to preventative strategies and early resuscitation promise to facilitate further improvements in neurological outcomes in patients who sustain spinal injuries. This should enable higher levels of independence and productivity and thereby improve the outlook for these patients, most of whom are young and otherwise healthy.

K E Y ●

P O I N T S

Neurological dysfunction after spinal cord injury (SCI) results from a “primary” mechanical insult followed by “secondary” cascades that disrupt normal cord anatomy and function.

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Secondary injury mechanisms include disruption of microcirculation, loss of autoregulation, edema, ischemia, calcium toxicity, glutamate excitotoxicity, lipid peroxidation, inflammation, and release of free radicals.

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The histological changes in SCI are categorized in immediate (initial 1 to 2 hours), acute (hours to 1 to 2 days), intermediate (days to weeks), and late phases (weeks to months/years).

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A “three-column structural concept” divides the thoracolumbar spine into anterior, middle, and posterior columns; disruption of two or three columns at one level generates spinal instability.

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Disorders caused by incomplete spinal cord lesions are classified into a number of neurological syndromes that reflect the anatomical level of cord injury and have different prognoses for recovery.

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Although spinal instability from penetrating injury is exceedingly rare, a high index of suspicion should be maintained for associated injuries such as vascular lesions with cervical trauma and pulmonary and cardiac injuries with thoracic trauma.

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High-energy blunt trauma, such as that resulting from motor vehicle accidents, poses greatest risk for SCI, but all trauma patients should be presumed to have a SCI until proved otherwise, because severe SCI can also result from a seemingly minor insult.

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As the spinal cord ends at the L1 vertebral level, the cord is not injured in many lumbar fractures; instead, insult to the cauda equina may occur, causing less severe neurological deficit.

Suggested Reading Anderson LD, D’Alonzo RT: Fractures of the odontoid process of the axis. J Bone Joint Surg Am 1974; 56:1663-1674. Belanger E, Levi AD: The acute and chronic management of spinal cord injury. J Am Coll Surgeons 2000; 190:603-618. Denis F: The three column spine and its significance in the classification of acute thoracolumbar spinal injuries. Spine 1983; 8:817-831. Kossmann T, Trease L, Freedman I, et al: Damage control surgery for spine trauma. Injury 2004; 35:661-670. Kwon BK, Tetzlaff W, Grauer JN, et al: Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J 2004; 4:451-464. Maynard FM, Bracken MB, Creasey G: International standard for neurological and functional classification of spinal cord injury. Spinal Cord 1997; 35:266-274. Park E, Velumian AA, Fehlings MG: The role of excitoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 2004; 21:754-774.

References 1. Kwon BK, Tetzlaff W, Grauer JN, et al: Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J 2004; 4:451-464. 2. Mohta M, Sethi AK, Tyagi A, et al: Psychological care in trauma patients. Injury 2003; 34:17-25. 3. Lee TT, Green BA: Advances in the management of acute spinal cord injury. Orthop Clin North Am 2002; 33:311-315. 4. Maynard FM, Bracken MB, Creasey G: International standard for neurological and functional classification of spinal cord injury. Spinal Cord 1997; 35:266-274. 5. Hsu JM, Joseph T, Ellis AM: Thoracolumbar fracture in blunt trauma patients: guidelines for diagnosis and imaging. Injury 2003; 34:426-433. 6. Park E, Velumian AA, Fehlings MG: The role of excitoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 2004; 21:754-774.

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7. Belanger E, Levi AD: The acute and chronic management of spinal cord injury. J Am Coll Surgeons 2000; 190:603-618. 8. Vale F, Burns J, Jackson AB, et al: Combined medical and surgical treatment after spinal cord injury: result of a prospective pilot study to assess the merits of aggressive medical resuscitation and blood pressure management. J Neurosurg 1997; 87:129-146. 9. Kothari P, Freeman B, Grevitt M, et al: Injury to the spinal cord without radiological abnormality (SCIWORA) in adults. J Bone Joint Surg Br 2000; 82:1034-1037. 10. Pang D, Pollack I: Spinal cord injury without radiographic abnormality in children: the SCIWORA syndrome. J Trauma 1989; 29:654-664.

11. Guidelines for initial management and assessment of spinal injury. British Trauma Society. Injury 2003; 34:405-425. 12. Gilbert J: Critical care management of the patient with acute spinal cord injury. Crit Care Clin 1987; 3:549-567. 13. Patel RV, Delong W Jr, Vresilovic EJ: Evaluation and treatment of spinal injuries in the patient with polytrauma. Clin Orthop Relat Res 2004; (422):43-54. 14. Kossmann T, Trease L, Freedman I, et al: Damage control surgery for spine trauma. Injury 2004; 35:661-670. 15. Kossmann T, Jacobi D, Trentz O: The use of a retractor system (SynFrame) for open, minimal invasive reconstruction of the anterior column of the thoracic and lumbar spine. Eur Spine J 2001; 10:396-402.

chapter 105 peripheral nerve injury

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PERIPHERAL NERVE INJURY ●

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Devon I. Rubin and Robert C. Hermann

Peripheral nerve trauma is any injury to a nerve caused by an extrinsic agent; such injuries constitute a distinct category of peripheral nerve disorders. Peripheral nerve trauma is a commonly encountered problem in level I trauma centers after severe trauma, and residual manifestations of nerve dysfunction are a common reason for referral to a neuromuscular practice. In one population-based study, injury to the peripheral nerves was responsible for 2% of hospital admissions and 29% of surgical procedures after trauma.1 In the majority of cases, nerve dysfunction is the result of penetrating, stretch, or crush injury from violent accidents, although a variety of other extrinsic agents may also produce nerve injury. Appropriate early identification and evaluation of nerve trauma is important in guiding the treatment and the attempts to preserve or improve function of the nerve. The clinical features, pathophysiology, evaluation, and treatment of physical nerve injury are discussed in this chapter.

ANATOMY AND PHYSIOLOGY OF PERIPHERAL NERVE INJURY The foundation for understanding nerve injury begins with a brief discussion of nerve anatomy and physiology. This topic and its relation to nerve injury have been reviewed extensively.2,3 Through the classic work of Sunderland (1990), the details of the microstructure of nerve anatomy have been elucidated and have formed the foundation for the development of classification schemata of nerve injury.2 The peripheral nerve is composed of several components, each of which plays an integral role in nerve function (Fig. 105–1). The cell body, or cyton, is the metabolic center of the nerve and produces the structural elements and nutrients that are important for maintaining nerve function. The axon is the main transporting segment of the nerve and conducts action potentials and transports proteins from the cell body to the nerve terminal. Most nerves contain a myelin sheath that surrounds the axon and provides a mechanism for rapid conduction of the action potential along the axon. Several supporting structures are important in maintaining the integrity and form of the nerve but do not play a role in action potential propagation. Surrounding each myelinated axon, each group of unmyelinated axons, and their investing

Schwann cells and basal lamina is a framework of collagen fibrils formed by fibroblast. These longitudinally directed collagen fibers form a thin sheath immediately external to the Schwann cell basal lamina. This functional unit consisting of the axon or axons, their surrounding Schwann cells, and the basal lamina and collagen makes up the endoneurium, or endoneurial tube. The endoneurial tube makes up the simplest component of the connective tissue sheath of a peripheral nerve. Nerve axons and their endoneurium are grouped into fascicles within the nerve. Each fascicle within the nerve is surrounded by perineurium. The perineurium is composed of a lamellated arrangement of flattened sheaths cells formed from mesodermal, undifferentiated fibroblast-like cells with long cell processes. The perineurial sheath cells are surrounded by a basal lamina and separated and surrounded by layers of collagen fibers arranged in oblique, circular, and longitudinal arrays. The collagen fibers within the perineurium provide most of the elastic and tensile strength of peripheral nerve. The epineurium is the outermost layer of the nerve and is composed of loose areolar tissue and fat, collagen, elastin, and lymphatic and blood vessels. The collagen bundles within the epineurium and the elastic fibers are oriented primarily longitudinally. This arrangement holds the nerve fascicles together while separating the fascicles from one another and also protects the nerve fascicles by dissipating the stress on the nerve from external pressure. The number of fascicles of axons contained within the epineurium of a particular compound nerve varies in number from 1 to 100. In a compound nerve containing sensory, motor, and autonomic axons, a single fascicle usually contains many different types of axons. The arrangement of axons in a fascicle is actually very complex. Along the longitudinal course of the nerve. there is a continuous intermixing of axons from one fascicle to another. This interchange of axons between fascicles is most prominent in proximal portions of the nerves and is much less prominent in distal portions below the elbow and knee. The fascicular arrangement within nerves is important when the manifestations of nerve trauma are considered. Incomplete lesions of a peripheral nerve may involve individual fascicles to different degrees, and injury to a peripheral nerve at one site may therefore produce different symptoms, signs, and severity than does damage to the same nerve at different points along the course of a peripheral nerve.

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Figure 105–1. Anatomy of peripheral nerve.

Epineurium Perineurium Endoneurium

Myelin Axon Cell body

The primary function of a nerve is to conduct information from one site to another in the nervous system. In the peripheral nervous system, the motor nerves conduct impulses from the brainstem or spinal cord to a muscle, whereas the sensory nerves conduct sensory stimulus from a peripheral receptor back to the spinal cord or brainstem. An inability to conduct these impulses produces weakness, sensory loss or disturbance, or autonomic dysfunction. The physiology of propagation of these impulses begins with an action potential generated at the cell body of the motor neuron or peripheral sensory receptor. The action potential then rapidly spreads from the point of origin over the entire axon membrane to the nerve terminal at the neuromuscular junction, in the case of a motor axon, or to the central nervous system, in the case of a sensory axon. Rapid propagation of the action potential along the nerve relies on the integrity of the axon, the transmembrane channels, and the myelin sheath. When nerve injury occurs, interference with action potential development and propagation may occur, leading to neurological symptoms.

CLASSIFICATION OF PERIPHERAL NERVE INJURY Different classifications of stages of nerve injury have been developed.2,4 One scheme, proposed by Sunderland (1990), sep-

arates nerve injury into five stages on the basis of the extent of anatomical disruption of the nerve (Table 105–1).2 In this classification, the higher stages of nerve injury represent a greater degree of damage to the nerve and the surrounding structures, and therefore the potential for nerve regeneration and regrowth diminishes, leading to a poorer prognosis. The other classification scheme, developed by Seddon, consists of fewer stages that also reflect the degree of damage to the different components of the nerve and supporting structures. Seddon proposed three stages of nerve injury: neurapraxia, axonotmesis, and neurotmesis.4 Neurapraxia in Seddon’s classification scheme corresponds to Sunderland’s first-degree injury. In neurapraxia, there is a block of conduction of the action potential across the region of nerve injury. The axon and supporting structures remain structurally intact, but conduction of the action potential across the abnormal area of the axon is blocked. Conduction of action potentials and the structural integrity of the proximal and distal portions of the axon are maintained. When the inciting cause is removed, recovery occurs within hours to months, and the prognosis for recovery is good. Focal demyelination is the predominant pathological alteration of this stage, although alteration of the cell membrane or channels, such as that produced by local anesthetic, may also produce this type of injury.

T A B L E 105–1. Classification Schemata of Nerve Injury Seddon Stage

Sunderland Stage

Pathologic Change

Clinical Examples

Neurapraxia Axonotmesis

First degree Second degree

Alteration of the axonal membrane or myelin sheath Axon loss (intact endoneurium, perineurium, epineurium)

Neurotmesis

Third degree Fourth degree Fifth degree

Axon and endoneurium disruption Axon, endoneurium, and perineurium disruption Disruption of all nerve structures, including the epineurium

Mild compressive ulnar neuropathy Traumatic stretch injury (from motor vehicle accident) Same as for second degree Same as for second degree Complete nerve laceration

chapter 105 peripheral nerve injury Axonotmesis in Seddon’s classification scheme is a more severe stage of injury. In this stage, the continuity of the axon is disrupted and the portion of the axon separated from the anterior horn cell or dorsal root ganglia undergoes wallerian degeneration. For the first week after an axonotmetic injury, the distal portion of the axon that is separated from the cell body still has the ability to propagate an action potential when stimulated electrically. After 1 week, wallerian degeneration of the axon occurs, and the disconnected segment of the axon can no longer conduct an action potential when stimulated. Axonal regeneration and regrowth along the endoneurial tubes is possible. Sunderland divided axonotmetic lesions into three separate degrees, on the basis of the amount of damage to the connective tissue. In Sunderland’s stage 2 injuries, the axon is disrupted but the endoneurial tube, and remainder of the connective tissue is intact. In stage 3, the axon and endoneurial tube are disrupted, but the perineurium and epineurium are intact. In stage 4 lesions, the axon, endoneurial tube, and perineurium are damaged, and only the epineurium is preserved. The duration and extent of axonal regrowth and regeneration depend on the degree of disruption of the nerve and the distance required for the nerve to regrow. The amount and speed of recovery are worse with higher grades of injury in Sunderland’s classification. Neurotmesis, or Sunderland’s fifth-degree injury, is the most severe stage, in which the axon, myelin, and connective tissue sheath, including the epineurium, are disrupted and the two ends of the nerve are separated. In this stage, effective recovery is very unlikely or impossible, depending on the amount of separation of the two ends of the nerve. The axonal sprouts may grow between the separated ends and form a neuroma but are unlikely to find an endoneurial tube to grow down.

EVALUATION OF NERVE TRAUMA The evaluation of the patient with nerve trauma relies on a careful and thorough neuromuscular history and examination and is supplemented by electrophysiological studies, imaging studies, and, on occasion, intraoperative exploration.

Clinical Evaluation The type and cause of injury is an important historical point to determine, because stretch, blunt trauma, or crush injuries typically produce more diffuse nerve injury than do penetrating injuries. The timing from the trauma to the development of neurological deficits is important. In most cases, the onset of neurological deficits occurs at the time of trauma, and delayed deficits may indicate injury from other complications, such as hemorrhage or edema. The neurological examination is crucial for determining the degree and distribution of deficits. However, in many instances, such as with multiple fractures of the extremity or alteration of consciousness with concomitant closed-head injury, it may be difficult to perform a reliable neurological examination. When possible, the examination should include careful assessment of motor function, including distribution and severity of weakness and atrophy, and of sensory loss, as well as of injury to associated soft tissue and supportive structures.

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Electrophysiological Evaluation Electrophysiological evaluation is a useful adjunctive test, performed in conjunction with the neurological examination, to assess peripheral nerve trauma. Electrophysiological studies generally consist of a combination of nerve conduction studies (NCS) and needle electromyography and are helpful in 1. Identifying localization of nerve trauma (e.g., single nerve branch, single nerve, plexus, or root). 2. Ruling out subclinical injury to other adjacent nerves. 3. Determining the pathophysiology and stage of nerve injury. 4. Determining the severity of injury. 5. Determining prognosis for recovery. 6. Determining extent of ongoing recovery. 7. Assessing the need for intraoperative exploration. Basic NCS are designed to evaluate the function of peripheral sensory and motor axons, striated muscles and the neuromuscular junction. NCSs are performed in two ways: (1) by stimulating a motor or mixed motor-sensory nerve and recording the action potentials of the muscle fibers innervated by the nerve or (2) by stimulating a mixed or pure sensory nerve at one site and recording the sensory nerve action potential at a distal or proximal site along the nerve. The combination of abnormalities in motor and sensory NCS allows identification of the site and pathophysiology of nerve injury. Motor NCS are often more useful than sensory NCS in identifying the degree and stage of nerve injury. In a normal nerve, supramaximal electrical stimulation of a nerve depolarizes all of the motor axons within the nerve, which subsequently produce action potentials within all muscle fibers innervated by that nerve. This produces a summated compound muscle action potential (CMAP), or M wave, recorded from a muscle innervated by the nerve. When the nerve is stimulated at a proximal and distal site, the CMAP amplitudes and areas of the two sites are similar, inasmuch as all axons within the nerve are similar in size and conduct at a similar rate. In most motor nerves, there is never more than a 20% reduction in amplitude and area between the two sites of stimulation (Fig. 105–2). In nerve trauma characterized by neurapraxia or early axonotmesis, the evoked action potential initiated at a site proximal to the injury is unable to propagate through the lesion. Thus, the lesion produces a “conduction block” of the action potential. However, because the axonal segment and supporting structures distal to the injury remain intact, stimulation distal to the lesion produces a normal response. In the most severe cases in which all axons within a nerve are affected, such as with complete nerve transection or a neurapractic lesion involving all motor axons, no response is obtained with proximal stimulation (complete conduction block) (Fig. 105–3). Stimulation distal to the site of nerve injury produces a propagated action potential and a normal CMAP. In cases of incomplete nerve injury, only some axons are affected, and a partial conduction block may occur (Fig. 105–4). Stimulation proximal to the lesion produces action potentials in all the motor axons. Some percentage of these action potentials are propagated by motor axons that are damaged, and these action potentials do not spread through the lesion. There, action potential spread is blocked. Other motor axons in the nerve may be spared by the lesion, and these spread across the lesion to reach the muscle and produce a CMAP. The amplitude and area of the CMAP are a rough guide to the number of axons spared in an

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Figure 105–2. Normal result of a motor nerve conduction study of the median nerve.

Amplitude 12.4 mV Area 35.9 mVms

Elbow 100 mA 5 mV

Wrist 60.3 mA 5 mV Amplitude 13.1 mV Area 37.3 mVms

5 ms

Amp 7.4 mV 100 mA 5 mV Amp 7.3 mV 100 mA 5 mV Amp 3.0 mV 100 mA 5 mV

Amp 0.3 mV

100 mA 5 mV

acute to subacute lesion. In more superficial nerves, or with near-nerve stimulation with a monopolar needle, the precise site of the nerve injury can be localized to within 2 cm by shortsegment incremental stimulation (“inching”) studies. In neurapractic lesions, the conduction block persists until the underlying process is reversed. However, in lesions characterized by axonotmesis or neurotmesis, subsequent events produce further changes on NCS. Within the first 5 to 7 days

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Figure 105–3. Ulnar motor nerve conduction study with short segmental incremental stimulation technique demonstrates complete focal conduction block at the medial epicondyle.

after injury, the NCS simulates a focal conduction block that is indistinguishable from a neurapractic lesion, with normal conduction distal to the injury but block of conduction with stimulation proximal to the lesion. However, after 5 to 7 days, wallerian degeneration of the axons in the distal segment of the nerve occurs, leading to inexcitability of the distal nerve. This is manifest on NCS by a low or absent CMAP response with stimulation proximal and distal to the site of the lesion. There-

chapter 105 peripheral nerve injury ■

Ulnar motor NCS (ADM recording)

5 ms

Amplitude 3.7 mV Above elbow

55.7 mA 2 mV

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Figure 105–4. Ulnar nerve conduction study (NCS) demonstrating partial conduction block in the forearm. ADM, abductor digiti minimi.

Amplitude 4.1 mV 61.2 mA 2 mV

Below elbow

100 mA 2 mV

Wrist

Amplitude 6.2 mV

63.5 mA 2 mV

fore, within the first week after injury, NCS is useful in localizing the lesion but not in determining severity or prognosis. However, after approximately 2 weeks, NCS can help the clinician distinguish neurapractic from axonotmetic lesions and better determine severity, pathophysiology, and prognosis, but in the case of axonotmetic lesions, it may be less helpful in precisely localizing the injury. Sensory NCSs are less helpful in localizing nerve injury because of the wide variation of conduction velocities from different fiber sizes within sensory nerves. As a result, there is more dispersion of the response with distal to proximal stimulation. In nerve injuries, this normal dispersion in sensory nerve action potentials makes it difficult to identify conduction block in sensory axons. Sensory NCSs are useful in attempts to distinguish injury to the brachial plexus from root avulsion. In axonotmetic lesions localized distal to the dorsal root ganglion (e.g., brachial or lumbosacral plexus), sensory fibers undergo wallerian degeneration, which leads to low-amplitude or absence of sensory responses. However, in root lesions in which the dorsal root ganglia remain intact, the sensory NCS responses remain entirely normal despite profound sensory loss. Sensory NCSs are also very important in the study of injuries to pure sensory nerves. Needle electromyography is used in conjunction with NCS to determine the pathophysiology, localization, and severity of nerve injury. Needle electromyography assesses spontaneous electrical activity arising from muscle fibers and the firing characteristics and structure of voluntary motor unit potentials. Fibrillation potentials are spontaneous action potentials from individual muscle fibers that are separated from the nerve terminal. Fibrillation potentials arise within 2 to 4 weeks after nerve injury and occur in muscles that are nearest the site of nerve injury before more distal muscles.

Each limb motor axon innervates hundreds of muscle fibers, and each limb muscle is innervated by several hundred motor axons. A basic concept of reinnervation that is often not understood requires some explanation. After motor axonal loss and denervation, reinnervation of skeletal muscle may occur in two basic ways. The loss of motor axons to a muscle may be incomplete or complete. If the axonal loss or denervation to a skeletal muscle is incomplete with some intact motor axons remaining, the surviving motor axons give off collateral sprouts from the nerve terminals near the muscle fibers that have lost their innervation. These collateral axonal sprouts from the surviving motor axons begin to reinnervate muscle fibers within a matter of days to weeks. Therefore, after incomplete lesions, reinnervation by collateral sprouting begins quickly. On the other hand, if all of the motor axons to a muscle are severed, reinnervation must occur by regrowth of axonal sprouts from the distal end of the proximal stump down the nerve to the end organ. This form of reinnervation takes much longer. Axonal sprouts grow at 1 mm per day, or 1 inch per month. In the case of complete axonal loss, the time to the beginning of reinnervation is determined primarily by the distance that the axonal sprouts have to travel to reach the end organ, and this takes months to years. Electromyographic assessment of voluntary motor unit potentials is helpful in identifying whether reinnervation by regrowth or collateral spouting is occurring. In pure neurapractic lesions, the needle examination reveals a reduced number of voluntary motor unit potentials recruited when the patient attempts to produce a more forceful activation of the muscle under examination. There are no fibrillation potentials or change in the amplitude, duration, or structure of the motor unit potentials. In axonotmetic or neurotmetic lesions, the disintegration of the motor axons extends to the nerve terminal

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at the neuromuscular junction, and the muscle fiber is separated from its innervation. Immediately after the injury, the needle examination reveals reduced recruitment if the lesion is partial or no motor unit activity if the lesion is complete. In partial lesions, the structure of the motor unit potentials should be normal. Fibrillation potentials appear in the denervated muscles after 2 to 3 weeks. In partial or incomplete axonotmetic lesions, the nerve terminals of surviving motor axons begin to produce axonal sprouts 4 days after the injury. These effectively reinnervate some denervated muscle fibers after 3 weeks. At that time, the structure of the surviving motor unit potentials begins to change. There is an increased number of turns or phases on the motor unit potential. As more and more collateral sprouts from a motor neuron reinnervate muscle fibers, the motor unit potentials become more complex, larger in amplitude, and longer in duration. In the case of reinnervation by regrowth of axons, the earliest motor unit consists of only one or a few muscle fibers, and as a result, the motor unit potential of those motor units is very small. These potentials have been called nascent motor unit potentials. As the reinnervating axons give off more branches that reinnervate more motor fibers, the number of muscle fibers innervated by each motor unit increases, and the amplitude and duration of the motor unit potential increase. The needle examination is performed on different muscles innervated by different nerves, different components of the plexus, and different nerve roots and anterior horn cells. A systematic approach allows determination of the site of the lesion, the age and severity of the lesion, the type of pathology, and the prognosis for recovery. In cases with electromyographic evidence of reinnervation, surgical intervention is often delayed or postponed, as described later.

11 patients, reliable identification of the nerve was made with ultrasonography, and neuroma formation, scarring with compression of underlying nerve, and partial discontinuity of nerve fascicles could be identified.9 In cases of injury to the brachial plexus in which root avulsion may have occurred, myelography and computed tomographic myelography are the imaging modalities of choice.10 The myelogram may demonstrate several findings to indicate root avulsion, including pseudomeningocele, poor root sleeve filling, and spinal cord edema or atrophy (Fig. 105–5). Although magnetic resonance imaging may also demonstrate findings suggestive of root avulsion, the findings on computed tomographic myelogram were correlated better with such injury at surgery than were the findings on magnetic resonance imaging.11

CAUSES OF PERIPHERAL NERVE TRAUMA There are many different causes of nerve trauma, each of which presents distinct issues related to nerve function, recovery, and treatment (Table 105–2). Much of the early information related to nerve trauma was derived from wartime injuries during the American Civil War and the World Wars. Currently, the most commonly encountered cause is blunt or stretch injury related to high-speed motor vehicle accidents, followed by falls, pene-

T A B L E 105–2. Causes and Types of Nerve Trauma

Imaging of Peripheral Nerve Trauma Historically, the sensitivity of imaging studies for identifying the anatomy of the peripheral nerve in detail was low, and imaging studies had low utility in the evaluation of peripheral nerve trauma. However, as the quality of imaging has improved, these studies are becoming increasingly useful adjunctive measures for assessing peripheral nerve trauma. Imaging studies can provide important information regarding the continuity of a nerve after trauma. Magnetic resonance imaging with short-time inversion recovery sequences can demonstrate denervated skeletal muscle, which is high in extracellular water content and thereby produces increased signal on short-time inversion recovery and T2-weighted images.5 The distribution of muscle involvement can be extrapolated to determine which nerve or nerves are affected by trauma. More recently, magnetic resonance neurography has evolved to allow for visualization of large peripheral nerves.6,7 Indications for magnetic resonance neurography include the need to visualize roots and nerves for entrapments, adhesions, or the effects of trauma.8 In some cases, magnetic resonance neurography can identify discontinuity of the nerve and therefore is helpful in determining prognosis of recovery.8 Ultrasonography provides less detail of nerve anatomy than does magnetic resonance neurography, but it has been evaluated for its utility in monitoring patients who have undergone direct nerve repair after peripheral nerve injury.9 In a group of

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Type of Trauma

Examples

Acute transection Chronic compression Stretch injury (stretch, rupture, avulsion) Injection Ischemic Radiation Temperature (cold)

Glass or knife wound, surgically induced Carpal tunnel syndrome Traction from motor vehicle accidents Intraneural injections Compartment syndromes Post-irradiation plexopathy Frostbite, trench foot

Figure 105–5. Computed tomographic myelogram demonstrating pseudomeningocele after traumatic root avulsion.

chapter 105 peripheral nerve injury trating trauma, and industrial accidents.12 Population studies have estimated that 5% of patients admitted to level I trauma centers have sustained peripheral nerve injuries.13 In many instances of injury related to major trauma, the precise mechanism of nerve injury may not be identified, or several mechanisms may have contributed. For example, in a severe motor vehicle accident, compression, crush, and stretch injury may occur, as may ischemia from arterial damage related to the injury.

Acute Nerve Transection or Laceration Acute transection of the nerve is less common than blunt or compressive injury and occurs with clean, sharp lacerations, such as wounds inflicted by glass or knife injuries. Nerve transactions may also occur as a result of fracture of an adjacent bone or as an iatrogenic injury after inadvertent nerve transection during surgical procedures. In a study of 722 surgically treated cases of nerve trauma, approximately 17% were iatrogenic, the majority occurring during orthopedic procedures or minor surgery.14 The nerve most commonly affected was the spinal accessory nerve (after lymph node biopsy), followed by the common peroneal, radial, and genitofemoral nerves. In most cases of nerve laceration, neurotmesis or complete transection of the entire axon and surrounding connective tissue structures occurs, producing a distinct separation of the two ends of the nerve. Depending on the length of the nerve separation, potential for regrowth or reinnervation is low. After clean nerve laceration, early surgical repair is usually necessary to align the two ends of the nerve. With lacerations related to blunt injuries, such as chainsaw or propeller blades, a delay of several weeks before surgical intervention may allow for identification and resection of damaged nerve tissue before realignment.15 In iatrogenic surgically induced nerve lacerations, the outcome after surgical intervention was good in approximately half of the patients, with some improvement in sensory, motor, or pain.

Chronic Nerve Compression The most common type of focal nerve injury encountered in most clinical practices is focal nerve compression. Although this may occur acutely, such as when transient paresthesias are experienced after compression of the ulnar nerve (the “funny bone”), it more commonly occurs over an extended period of time. Chronic compression most commonly affects the median, ulnar, and peroneal nerves. Compression of the nerve may occur as the result of repeated external force against the nerve, such as repeated compression of the peroneal nerve from leg crossing, or as a result of compression of the nerve within a fixed or enclosed passage or compartment, such as that occurring in carpal tunnel syndrome or ulnar neuropathy in the cubital tunnel. Several factors predispose a nerve to compression injury, such as anatomical location of the nerve at a site that lies in direct contact with an unyielding surface, when the nerve lies in a fixed or fibrous canal or passes through fibrous tissue, or when the nerve crosses an extensor side of a joint. The pathological changes that occur with chronic or repeated compression include mechanical and vascular changes. One of the first changes is focal demyelination at the site of compression. Experimental studies with tourniquet

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compression have been performed to produce a model of compressive lesions.16 In these studies, compression of the myelin with invagination and intussusception of paranodal regions was identified most prominently at the edge of the tourniquet. Over time, focal demyelination is followed by reduction in the axon diameter and, ultimately, axonal degeneration. However, if the cause is removed, reinnervation and remodeling of myelin may lead to recovery of nerve function and resolution of symptoms within weeks to months. In addition to the mechanical changes in the nerve, mechanical compression produces increased intraneural pressure, which in turn produces intraneural venous obstruction and capillary congestion. The symptoms and findings of nerve compression depend on the severity and chronicity of the injury. Sensory nerves are more susceptible to compression than are motor nerves, and affected patients initially present with paresthesias or sensory loss in the distribution of the nerve. When motor fibers are affected, weakness in muscles distal to the site of compression becomes evident. With axonal loss, muscle atrophy may occur. As expected, when clinical and electrophysiological signs of axonal loss are present, the recovery, even if the inciting cause is removed, is more prolonged and may be less complete.

Stretch Injury Stretch or traction is the most common mechanism of peripheral nerve injury after trauma and most commonly occurs with severe, violent trauma, such as that occurring in high-speed motor vehicle accidents. Less severe stretch injuries may occur after falls or surgical procedures (such as that occurring in the sciatic nerve after hip arthroplasty). Stretch injury is the most common type of traumatic injury affecting the brachial plexus and is a major cause of increased morbidity after motor vehicle accidents. In contrast to focal compression or laceration of the nerve, stretch injury produces traction and more mechanical strain on the nerves. As discussed earlier, nerve fibers travel in a plexiform configuration within the fascicles, and supporting connective tissue structures, which assist in maintaining the structure and integrity of the nerve, surround the axons. Although the epineurium protects the nerve fibers from external compression, the perineurial tissue is most important in the protection against stretch injury, because it provides more of the elasticity and resistance than do other structures. Several features of nerves protect them from stretch injury: (1) the undulating course of the nerve fibers within the fascicle, (2) the anatomical course of nerves across flexor aspects of joints (with the exception of the ulnar nerve at the elbow and the sciatic nerve at the hip), and (3) the elasticity of the nerve trunks.17 When the nerve is stretched, stepwise alterations of nerve anatomy occur (Fig. 105–6). First, the undulations of the epineurial connective tissue disappear, although partial laxity of the nerve fibers remains unaffected. Next, with continued stretching, the nerve fibers become straightened, the crosssectional area of the nerve is reduced, and the intraneural pressure is increased. Finally, with continued stretch, the nerve fibers become stretched and ultimately may rupture if continued tension is present.2,17 Experimental studies with rabbit nerves have shown that with mild, gradual stretch to 30% of the initial nerve length, minimal macroscopic changes occurred and the epineurium, perineurium, and endoneurium

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Figure 105–6. Stages of stretch injury to peripheral nerve (see text for description).

remained intact; however, the cross-sectional area of the nerve was reduced, and the myelin became swollen. With more severe gradual stretch, epineurium rupture occurred. The mean elongation to the point of limit of elasticity was 56%. No significant difference was seen in the pattern of damage with gradual or sudden stretching.18 The structure of nerve roots differs slightly from that of distal nerves in that nerve roots lack perineurial tissue and are arranged in a nonplexiform manner, which makes roots more vulnerable to injury than nerves. Therefore, when significant traction is produced along the nerve, the root is the region of least resistance, and root avulsion is more common than avulsion of a distal nerve segment. The severity of clinical features depends on the degree of stretch injury. In mild cases, a mild degree of motor and sensory loss may be present. However, in severe traction injuries, especially with nerve or root avulsion, the neurological deficits are much more severe and often complete. In addition, in most cases, the injury is more extensive, involving multiple nerves or root. In this situation, rupture of fascicles may occur over several centimeters of the nerve, which makes regeneration of the nerve less likely.

Injection Injury Injection injury is nerve damage resulting from the injection of a pharmacological agent at or adjacent to a nerve. Injection injury is an uncommon cause of peripheral nerve trauma and has most commonly been described in the sciatic nerve after gluteal muscle injections. Injury to the sciatic nerve is most likely to occur in patients with wasting of the glutei muscles and may also be related to fixation of the nerve to the piriformis muscle. Injection injuries have been identified more commonly in infants than adults, probably because of the small size of the overlying musculature. Patients with injection nerve injury typically develop neurological symptoms immediately or within minutes after the injection.19 Sharp stabbing or radiating pain in the distribution of the nerve is the initial symptom. Motor and sensory loss is common and occurs to a variable degree, ranging from severe weakness and sensory loss in the distribution of the injured nerve to only mild deficits. Spontaneous recovery is variable. Early reviews suggested that residual deficits persist in the majority of cases, with recovery in only 14%.19 Experimental studies of injection injury have demonstrated that regeneration of the injured nerve does occur, beginning 2 to 3 weeks after injection.20 A number of mechanisms of nerve injury after injections have been proposed. The most supported mechanism is a direct

toxic affect of the offending agent on the nerve. Several factors may be important in the development of nerve injury after injection. First, the nature of the offending agent may affect the degree of nerve injury. When injected intraneurally, many different pharmacological agents, including antibiotics, paraldehyde, and magnesium sulfate, produce significant nerve damage. In one animal study, injections of nine different agents produced a variable degree of pathological changes within the nerve. Meperidine and cephalothin resulted in minimal loss of myelinated and unmyelinated fibers, whereas severe nerve injury occurred after injections of penicillin, diazepam, and chlorpromazine, even when administered in the extrafascicular region.20 Comparison of the degree of injury with dose of several medications indicated that higher doses resulted in more severe injury. Because most active components of medications are contained in a buffered mixture with other agents, it is difficult to determine whether the nerve response was a reaction to the active ingredient or to the buffering agent. Control studies with intrafascicular or extrafascicular saline injection produces no pathological change.20 Second, the site of injection in relation to the nerve anatomy plays an important role in the development of nerve injury. Early studies have shown that injection in the epineurial region produces little no pathological change, although some medications such as paraldehyde may produce circumferential fibrosis. On the other hand, intraneural injections consistently produce inflammatory cell infiltration.19-21 In addition to direct toxic effect of the infused agent, nerve ischemia caused by thrombosis or spasm of a nutrient artery may occur as a reaction to the toxic effect of the drug infused, or mechanical trauma from the needle may also injure the nerve.22,23 The effect of the length of the bevel tip on the degree of nerve injury has been studied in mechanical nerve “impalement” and has demonstrated that shorter bevel tips produce more severe damage than do long bevel tips.22 Treatment of injection injury is largely symptomatic. However, exploratory surgery with nerve irrigation or neurolysis has been proposed.20

Ischemic Nerve Injury Peripheral nerves are relatively resistant to ischemia, inasmuch as they are supplied by a network of longitudinally arranged arterioles and veins, with feeding arteries entering the nerve at several sites along the nerves. Therefore, pure ischemia of nerve after trauma is unlikely to occur without concomitant nerve compression, stretch, or crush. Experimental studies of ischemia in the nerve are sparse, because ligation of a feeding artery does not produce significant ischemia.24,25 In a study on rat sciatic nerve, conduction failure occurred after 30 minutes of ischemia and was reversible if the ischemia persisted for less than 1 hour.26 Dyck and associates found a patchy distribution of nerve fiber degeneration that began in a central fascicular location in watershed zones in the mid–upper arm and in the midthigh for the lower extremity after nerve ischemia in humans.27 In many cases of peripheral nerve trauma, direct injury to the nerve from laceration, crush, or stretch produces nerve dysfunction. However, with these mechanisms of injury, interruption of the vascular supply surrounding the nerve may also play a role in the mechanism of nerve injury. Ischemic nerve

chapter 105 peripheral nerve injury injuries may occur after thrombosis that follows soft tissue trauma or bone fractures. This seems typically to result from bone and arterial lesions around the distal humerus, distal femur, and proximal tibia, where the arterial blood supply to nerves is more vulnerable because long sections of these nerves are dependent on a single nutrient artery. Embolization or graft thrombosis after aortofemoral bypass or peripheral vascular surgeries may produce ischemic damage to the distal tibial, distal peroneal, sciatic, or femoral nerves.28 Similar complications have been reported after transfemoral intra-aortic balloon assist pumps.29 Therapeutic or accidental intra-arterial injection of drugs may result in severe arterial spasm and thrombosis with soft tissue and nerve damage.23,30 Upper limb ischemia associated with artificial arteriovenous shunts for dialysis has produced ischemic damage to nerves.31

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Figure 105–7. Myokymic discharge in radiation-induced plexopathy.

although cases of improvement have been reported.36,40,41 There is no treatment established to reverse or improve the nerve injury, although surgical intervention, such as neurolysis or neurolysis with omental grafting, has been performed in some patients with variable improvement in symptoms.42,43

Cold-Induced Nerve Injury Radiation Injury Radiation-induced nerve injury is a delayed manifestation of radiation therapy. This entity most commonly occurs in the brachial plexus in patients receiving radiation to the breast or axilla, but it may affect the lumbosacral plexus or individual distal nerves coursing through in other fields of radiation. The incidence of development of brachial plexus injury after radiation usually ranges from 1.8% to 5% but has been reported as high as 9%.32-34 Clinical manifestations of radiation neuropathy include gradually progressive paresthesias and sensory loss, weakness and atrophy, and pain in the distribution of the nerve or nerves affected. Symptom onset occurs 1 month to 18 years after radiation exposure.34,35 Several factors have been associated with an increased risk of development of brachial plexopathy, including a higher dose of radiation (greater than 5000 cGy), increased number of ports of radiation administration, the use of adjunctive chemotherapy, and the extent of axillary node dissection.32-34,36 Although some authors have reported more selective involvement of the upper trunk of the brachial plexus, others have shown that the upper, lower, or entire plexus may be involved.32,36-38 The underlying pathophysiology of radiation-induced injury has not been completely established. Pathological studies have demonstrated loss of myelin, the presence of fibrosis and thickening of the neurolemma sheath, and hyalinization and obliteration of the vasa nervorum to the brachial plexus, which are suggestive of either focal compression of the plexus by fibrosis or chronic nerve ischemia as possible underlying mechanisms.32 Electrophysiological studies demonstrate abnormal motor and sensory findings and large motor unit potentials with reduced recruitment in the majority of patients. Myokymia is the hallmark clinical feature of radiation neuropathy and is seen as an undulation, wormlike rippling of the muscle. Myokymic discharges, spontaneously recurring bursts of motor unit potentials, are the electrophysiological correlate of myokymia and are found in up to 63% of patients with radiation-induced brachial plexopathies35 (Fig. 105–7). The presence of myokymic discharges is helpful in distinguishing radiationinduced plexopathies from neoplastic plexopathies.35-37 Neuroimaging studies may show increased or decreased signal and fibrosis in the region of the brachial plexus.39 The course of radiation-induced neuropathy is usually one of steady progression or stabilization in 90% of patients,

Cold-induced peripheral nerve injuries are uncommon causes of peripheral nerve trauma in peacetime. However, during wartime, military personnel exposed to prolonged cold, including trench foot, frostbite, and immersion foot syndrome, suffered manifestations of peripheral nerve injury. Early reports of immersion foot syndrome occurring during World War II described military personnel who developed skin abnormalities and sensory disturbances after exposure to immersion in nonfreezing water for prolonged periods of time. Clinical manifestations of cold-induced peripheral nerve injury begin an average of 6 days after exposure and initially consist of hyperemia and skin edema. With more severe or prolonged exposure, vesicle and blister formation occurs, followed by skin necrosis and loss of tissue. Symptoms may persist for months to years after the initial injury.44 Blair and colleagues reviewed the manifestations of cold-induced injuries in 100 patients 4 years after exposure during the Korean War.45 The most commonly experienced residual symptoms included (1) neuropathic symptoms (recurrent pain, sensitivity to cold, numbness) and (2) signs of sympathetic overactivity (vascular changes, hyperhidrosis).44,45 Pain is a prominent symptom; it may be described as aching, sharp, or burning and is aggravated by prolonged standing and cold. Electrophysiological studies in cold-induced peripheral nerve injury have demonstrated decreased sensory nerve action potential with slowed conduction velocity in the affected foot 6 months to 1 year after exposure.46,47 Several mechanisms of cold-induced nerve injury have been proposed, including primary vascular constriction or venous stasis in the vasa nervorum, vascular occlusion caused by thrombus formation, and cellular changes produced directly by cold.44 Early studies in cold-induced peripheral nerve injury demonstrated abnormalities in large myelinated fibers after cold exposure.48 More recent experiments on rat sciatic nerves have also demonstrated degeneration of large myelinated fibers, occurring within 48 hours after exposure.49 Although the duration of exposure is important in the development of nerve injury, repeated exposure with rewarming plays a crucial role in extending the degree of nerve injury. Experimental studies on rat sciatic nerves demonstrated that the amplitudes of compound nerve fiber action potentials and recovery of nerve blood flow to nerves that were exposed to intermittent cooling and rewarming were significantly reduced in comparison with those of nerves exposed to continuous cold for the same duration.50

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Furthermore, pathological analysis demonstrated preservation of myelinated and unmyelinated fibers after continuous cold injury but axonal degeneration with intermitted cooling.50 These findings suggest that initial insult to the nerve after cold exposure results from factors such as prolonged vascular stasis, endoneurial anoxia, and direct injury. However, rewarming produces further nerve damage, possibly from free radical injury.50 Treatment of cold-induced nerve injury is largely symptomatic. Agents previously used include anticoagulants, sympathetic blocking agents, and sympathetic blocks but have not been systematically studied.44

Electrical Nerve Injury Electrical injuries to peripheral nerves are uncommon and usually occur in the context of more severe or diffuse electrical injury of an extremity. In an early study of electrical injuries in 64 patients, 13% of patients developed peripheral nerve complications.51 The site of nerve injury is correlated with the site of electrical contact. Extensive tissue destruction and burn are often present.51 The anatomical distribution of nerve injury follows the path that the electrical current takes. Factors that affect the extent of nerve injury include the duration of contact, the voltage of the exposure, and the current density within the tissue.52 Peripheral nerves are very sensitive to electrical forces and have a lower resistance to current flow than blood, muscle, skin, tendon, or bone.53 The pathway of electrical current typically follows the course of neurovascular bundles because of its lower resistance to electrical current. Several mechanisms have been implicated in the pathogenesis of electrical nerve injury. The immediate and acute injuries to motor and sensory fibers are the direct result of the electrical current.54 The mechanism of electrical nerve injury is related to the propagating electrical current through the skin and deeper tissues to the nerves. The electrical current results in heating of the tissue and the buildup of electrical charge along the nerve membrane. In most instances, only a few seconds of exposure are necessary for the high-energy electrical trauma to occur. The current is denser at the closer proximity to the contact point; however there is often nonuniform exposure along the electrical field, which makes the pattern of tissue involvement variable. Pathological studies have suggested that permanent changes in the nerve do not extend beyond the area of local destruction.53,54 Persistent or delayed damage results from thermal or mechanical injury, fibrosis of the perineural tissues, or thrombosis of nutrient blood vessels.53 The clinical manifestations of electrical nerve injury most commonly include sensory disturbances, such as paresthesias, dysesthesias, and sensory loss, which may resolve within hours or days. The nerves most commonly affected are the median and ulnar nerves.51,53 In addition, sympathetic dysfunction may begin within hours, producing pain, burning sensation, and allodynia in the distribution of the nerve. Months after the injury, other sudomotor autonomic signs may manifest, including muscle atrophy, hair loss, and osteoporosis. Weakness occurs in more severe exposure but may be related to direct skeletal muscle injury, as well as neurogenic injury. Muscle swelling, myonecrosis, and compartment syndromes may also occur. The evaluation of electrical nerve injury occurs after the patient has been medically stabilized from a cardiovascular and

respiratory standpoint. Careful neurological examination is necessary for documenting the degree of weakness and sensory loss. Electrophysiological studies (NCS and needle electromyography) can be a useful adjunct to determining nerve function. Treatment of electrical nerve injury is predominantly supportive, rehabilitative, and focused on pain management. Early surgical intervention with fasciotomy and escharotomies may be effective for reducing increasing pressure from compartment syndromes. Neurological manifestations may persist for years after exposure, and the degree of recovery is variable.55 In one study of more than 2000 patients with electrical injuries over a 20-year period, approximately 8% sustained long-term peripheral nerve manifestations, including pain, sensory loss, and weakness.56

TREATMENT OF NERVE TRAUMA Surgical Treatment The surgical treatment of traumatic nerve injury is dependent on the etiology, type, and pathophysiology of injury and the timing of evaluation in relationship to the injury. In many cases, surgical intervention provides an opportunity for more rapid and significant recovery of function, although one of the most difficult treatment decisions is the determination of the need for surgical intervention and the appropriate timing of surgery. Spinner and Kline (2000) reviewed the management of peripheral nerve injuries.10 When the decision to surgically intervene is being considered, electrodiagnostic studies can be helpful in the determining how many axons are injured and whether the lesion is neurapractic or axonotmetic. Neurapractic lesions are more likely to recover spontaneously and are generally treated nonsurgically unless they persist longer than expected. In contrast, minimal and protracted recovery is expected with axonotmetic lesions, and therefore surgical intervention may help improve the chance and rapidity of recovery. Early surgical intervention may be considered immediately after the injury as primary repair or after a short delay of 3 to 4 days as delayed primary repair. Immediate primary repair is usually recommended when there has been a clean laceration of the nerve by a sharp object and where the nerve endings are not injured by crush or stretch. When a clean division of the nerve has occurred, end-to-end suture repair within 72 hours is recommended.10 In most other situations, it is often necessary to delay surgery by weeks to months. Secondary repairs may be performed as early as 2 to 4 weeks after the injury or 3 to 6 months after the injury. In some cases, surgery may be performed as late secondary repairs 1 to 2 years after the injury. Secondary early surgical repair after 2 to 4 weeks is generally recommended for blunt injuries or injuries with extensive soft tissue damage in which the nerve injury appears to be complete or very severe. In this situation, neuroma and scarring may develop within several weeks after trauma. Delaying surgery by several weeks allows for better determination of neuroma formation and scarring, and resection of the neuroma and scarring may improve recovery. When these scarred nerve stumps are resected, the growth cones of the new nerve endings may grow more rapidly.57 However, in many cases, surgery is usually delayed between several weeks and 6 months in order to determine the degree of spontaneous improvement. If the nerves

chapter 105 peripheral nerve injury remain in continuity and nerve regeneration is evident clinically or electrophysiologically during this time, surgical intervention is unlikely to be more beneficial than physiological recovery and is not recommended, because approximately 90% of patients in these cases recover.10 In one series, secondary repair 3 weeks to 3 months after sciatic nerve injury resulted in useful motor recovery in the tibial nerve in 83% of patients and the peroneal nerve in 39%.58 Useful recovery was achieved in 71% with thigh lesions and in only 31% with buttock-level lesions. Late surgery 1 to 2 years after the injury has not generally resulted in good recovery of motor function but may be necessary for pain control or to resect a neuroma. A variety of operative methods can be used to attempt to improve nerve function after nerve trauma10,59 (Table 105–3). Details of each method are beyond the scope of this chapter, but the neurosurgical literature contains more extensive reviews of this subject.10,59 One of the simplest procedures is internal neurolysis, which consists of opening the epineurium and separating out the different fascicles under magnification. The surgeon then inspects the individual fascicles and stimulates and records from them to determine which fascicles are intact. After internal neurolysis, the surgeon separates the fascicles within the nerve, and if some fascicles are interrupted or not functional, the surgeon attempts to identify the distal and proximal stumps, match up the fascicles, and suture together the distal and proximal stumps of the matching fascicles. If there is no evidence of viable axons crossing the injured area of the fascicle, the injured segment is resected back to normalappearing nerve, and an end-to-end repair or graft repair is performed. These procedures risk damage to the blood supply of the nerve and damage to branches of the fascicles either leaving the nerve or passing from one fascicle to another, as well as scar and neuroma formation. Intraoperative electrophysiological monitoring can be useful to determine the precise borders of the nerve injury and determine whether nerve action potentials can be conducted through the injured segment.3 The prognosis after surgical intervention varies according to the procedure performed. Direct suture repair carries the best prognosis, with approximately 79% of patients demonstrating recovery, whereas only 50% experience improvement with graft repair.10 Furthermore, in brachial plexus injuries, there is a better chance of recovery with upper trunk/lateral cord lesions than with lower trunk/medial cord lesions. Contraindication to surgical intervention include delayed evaluation (more than 1 year), C8-T1 root avulsion, or other comorbid conditions.10 In more severe cases of nerve rupture, the retracted ends of the nerve are identified and the surgeon must then make an evaluation of the condition of the distal and proximal ends of

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the nerve to determine whether the two separated ends of the nerve can be approximated without subjecting the nerve to too much tension or stretch. The damaged portions of the nerves are trimmed, and the fascicles of the proximal stump are aligned with fascicles of the distal stump under magnification. Then the proximal and distal stumps are connected either by sutures in the outer epineurium (epineurial repair) or in the interfascicular epineurium (grouped fascicular or fascicular repair) or by using nonsuture techniques. Nonsuture techniques have included wrapping the nerve; gluing the ends together with plasma clot or fibrin glue; or use of the carbon dioxide laser to weld the nerve ends together. Suture line tension must be minimized by mobilization of the nerve, positioning, and postoperative immobilization. If the gap is too large and suture line tension would be too great, then nerve grafting must be considered. Spinner and Kline (2000) gave some general guidelines based on their experience.10 They found that injured nerves with a measurable nerve action potential transmitted across the lesion during intraoperative nerve stimulation have a good recovery of function in 90% of cases. Good functional results can be expected in about 70% of end-to-end repairs and in 50% of graft repairs. Characteristics with a better outcome include (1) shorter nerve grafts, (2) early surgical intervention, and (3) young age of patients. Proximal lesions do worse than distal lesions, and lesions in the lower trunk brachial plexus do worse than those in the upper trunk. If a long segment of nerve is damaged or a long gap is present between the two retracted ends of the nerve, it may not be possible to perform an end-to-end repair of the nerve, and a nerve graft may be necessary to bridge the gap. With this technique, the axonal sprouts must cross two gaps, which slows growth, increases the risk of neuroma formation, and increases the risk that the axonal sprouts will not reach the proper end organ. However, grafts up to 20 cm in length have been used successfully. The survival and success of the graft depend on the quality of the operative bed, the vascular supply of the graft, and the thickness of the graft. Nerve grafts may be autologous (from the same patient), allografts (from another human), xenografts (from another species), or artificial or synthetic.60 Autologous nerve grafts from a remote donor site are the most commonly used technique for bridging a nerve gap. Various nerve guides have been used to direct axonal sprouts toward the distal stump, including silicone tubes, collagen-based nerve conduits, and a biodegradable polyglycolic acid-collagen tube filled with laminin-coated collagen fibers.59,61 Vanderhooft62 and Frykman and Gramyk63 reviewed the results of nerve grafting. In combining results from multiple centers, grafting of digital nerves produced good or better results in 50%. Even with a

T A B L E 105–3. Operative Methods Used to Treat Nerve Injury Method

Technique

Indication

External neurolysis Internal neurolysis/ split repair End-to-end repair Graft repair

Removal of circumferential scar Resection of scar around a portion of the nerve fascicle

Lesion in continuity Asymmetrical nerve injury; lesion in continuity

Aligning two ends of transected nerve Grafting from sural nerve or antebrachial nerve

Nerve transfer

Transfer functioning nerve to denervated muscle

Transected nerve with short gap between ends Transected nerve with large gap between ends Retracted stumps of transected nerve Irreparable nerve injury (e.g., root avulsion)

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delay between injury and repair of up to 6 months, 90% of patients achieved useful recovery. MacKinnon and Dellon performed grafts by using polyglycolic tubes in carefully selected patients and reported good results in 86%.64 Other procedures, such as end-to-side nerve anastomosis have been used.65,66 The distal segment of the injured nerve is sutured in an end-to-side manner to an adjacent nerve trunk, usually after an epineurial window and sometimes a perineurial window are formed in the donor nerve. The distal degenerated nerve segment attracts collateral sprouts from the healthy intact axons. The collateral sprouts from the donor nerve theoretically reinnervate the distal segment of the injured nerve. In the future, peripheral nerve repair may employ tissue engineering, neurotrophic factors, immunosuppression, and bioimplants. In cases in which the nerve injury is so severe that primary repair or grafting is impossible, such as root avulsion or proximal nerve injuries, then neurotization or nerve-to-nerve anastomosis may be employed. They are also useful in cases of destruction of a very long segment of nerve or cases of a long time between the injury and repair.67 For example, if the musculocutaneous axons to the biceps are destroyed very proximally, a portion of the median nerve can be divided and connected to the musculocutaneous nerve near the point where the musculocutaneous nerve enters the biceps. Nath and MacKinnon reported excellent recovery of biceps strength with this technique in 20 of 22 patients.67 Various neural structures such as the cervical plexus, contralateral spinal nerves, or components of the brachial plexus, spinal accessory nerve, phrenic nerve, pectoral nerves, and intercostal nerves have been employed. These nerves are severed, and the ends are connected primarily or by graft to a distal nerve such as the musculocutaneous, radial, or median nerve. The interposing nerve graft is usually taken from the sural nerve. More recently, muscles such as the gracilis have been removed from the lower extremity with particular care to preserve the nerve and vascular supply to the muscle. Then the muscle is transferred to the upper extremity and the nerve connected, usually to one of the intercostal nerves. Such neurotization procedures have resulted in effective elbow flexion in 25% to 50% of cases. A clinically useful outcome of such reinnervation requires training to produce central motor reorganization. As knowledge of the neurotrophic and neurotropic effects of various growth factors expands, it is possible that systemic or local administration of these agents may be used to enhance neuronal survival and promote regeneration.

Neuropathic pain is a major cause of morbidity after nerve trauma and may be as disabling as loss of function. Pharmacological treatment of nerve pain may include anticonvulsants, tricyclic antidepressants, or opioid medications.

CONCLUSION AND RECOMMENDATIONS Peripheral nerve trauma from a variety of insults is a significant cause of morbidity related to neurological dysfunction. Recognition of the clinical features of nerve trauma and early evaluation are important for correctly diagnosing the condition and providing early treatment to improve the chance of recovery. Evaluation of nerve trauma with early electrodiagnostic and imaging studies is helpful for defining the severity of injury, assessing the prognosis for recovery, and guiding the need for surgical intervention.

K E Y

P O I N T S

●

Peripheral nerve trauma is a common cause of morbidity seen after accidents.

●

Early clinical evaluation to define the extent of weakness and sensory loss may be difficult in the context of soft tissue injury to the limb.

●

Electrodiagnostic studies, performed within weeks after trauma, are important adjunctive tests for defining stage and severity of nerve injury and assessing for early nerve recovery.

●

Many different causes of nerve injury, including laceration, crush, stretch, ischemia, cold, injection, and radiation, can produce similar clinical manifestations.

●

Treatment of nerve trauma depends on the underlying etiology, site and severity of injury, degree of spontaneous recovery, and time since injury. Surgical interventions, including neurolysis or nerve grafting, may improve recovery of function in some cases.

Symptomatic Treatment

Suggested Reading

In addition to potential surgical intervention, a multidisciplinary approach to therapy is necessary. Physical therapy should be instituted as early as possible after injury. Physical and occupational therapy are key in preventing contractures or overstretching of muscles and ankylosis of joints and directing rehabilitation. Other considerations include the optimal use of prostheses, splints, or slings. It is extremely important to protect skin, muscles, tendons, and joints from secondary complications while nerve regeneration or recovery is awaited. Splinting in the best physiological position helps prevent stretching or contractures. Active and passive range-of-motion exercises must be performed. There should be careful design and timing of exercise programs.

Filler AG, Maravilla KR, Tsuruda JS: MR neurography and muscle MR imaging for image diagnosis of disorders affecting the peripheral nerves and musculature. Neurol Clin 2004; 22:643682. Harper CM, Thomas JE, Cascino TL, et al: Distinction between neoplastic and radiation-induced brachial plexopathy with emphasis on the role of EMG. Neurology 1989; 39:502-506. Robinson LR: Traumatic injury to peripheral nerves. Muscle Nerve 2000; 23:863-873. Spinner RJ, Kline DG: Surgery for peripheral nerve and brachial plexus injuries or other nerve lesions. Muscle Nerve 2000; 23:680-695. Sunderland S: The anatomy and physiology of nerve injury. Muscle Nerve 1990; 13:771-784.

chapter 105 peripheral nerve injury References 1. Selecki BR, Ring IT, Simpson DA, et al: Trauma to the central and peripheral nervous systems: Part II, a statistical profile of surgical treatment in New South Wales. Aust N Z J Surg 1982; 52:111-116. 2. Sunderland S: The anatomy and physiology of nerve injury. Muscle Nerve 1990; 13:771-784. 3. Robinson LR: Traumatic injury to peripheral nerves. Muscle Nerve 2000; 23:863-873. 4. Seddon HJ: Surgical Disorders of the Peripheral Nerves, 2nd ed. Edinburgh: Churchill Livingstone, 1975. 5. West GA, Haynor DR, Goodkin R, et al: Magnetic resonance imaging signal changes in denervated muscles after peripheral nerve injury. Neurosurgery 1994; 35:1077-1086. 6. Filler AG, Kliot M, Howe FA, et al: Application of magnetic resonance neurography in the evaluation of patients with peripheral nerve injury. J Neurosurg 1996; 85:229-303. 7. Maravilla KR, Aagaard BD, Kliot M: MR neurography. MR imaging of peripheral nerve. Magn Reson Imaging Clin North Am 1998; 6:179-194. 8. Filler AG, Maravilla KR, Tsuruda JS: MR neurography and muscle MR imaging for image diagnosis of disorders affecting the peripheral nerves and musculature. Neurol Clin 2004; 22:643-682. 9. Peer S, Harpf C, Willeit J, et al: Sonographic evaluation of primary peripheral nerve repair. J Ultrasound Med 2003; 22:1317-1322. 10. Spinner RJ, Kline DG: Surgery for peripheral nerve and brachial plexus injuries or other nerve lesions. Muscle Nerve 2000; 23:680-695. 11. Carvalho GA, Nikkhah G, Matthis C, et al: Diagnosis of root avulsion in traumatic brachial plexus injuries. Value of computerized tomography, myelography, and magnetic resonance imaging. J Neurosurgery 1997; 86:69-76. 12. Hill C, Riaz M, Mozzam A, et al: A regional audit of hand and wrist injuries. A study of 4873 injuries. J Hand Surg [Br] 1998; 23:196-200. 13. Noble J, Munro CA, Prasad VSSV, et al: Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma 1998; 45:116122. 14. Kretschmer T, Antoniadis G, Braun V, et al: Evaluation of iatrogenic lesions in 722 surgically treated cases of peripheral nerve trauma. J Neurosurg 2001; 94:905-912. 15. Klein DG: Timing for exploration of nerve lesions and evaluation of the neuroma in continuity. Clin Orthop 1982; 163:4249. 16. Ochoa, J, Fowler, TJ, Gilliatt, RW: Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J Anat 1972; 113:433-455. 17. Sunderland S: Stretch-compression neuropathy. Clin Exp Neurol 1981; 18:1-13. 18. Haftek J: Stretch injury of peripheral nerve. Acute effects of stretching on rabbit nerve. J Bone Joint Surg Br 1970; 52:354365. 19. Clark K, Williams PE, Willis W, et al: Injection injury of the sciatic nerve. Clin Neurosurg 1970; 17:111-125. 20. Gentili F, Hudson A, Kline DG, et al: Peripheral nerve injection injury: an experimental study. Neurosurgery 1979; 4:244253. 21. Tarlov IM, Perlmutter I, Berman AJ: Paralysis caused by penicillin injection; mechanism of complication—a warning. J Neuropath Exp Neurol 1951; 10:158-176. 22. Rice ASC, McMahon SB: Peripheral nerve injury caused by injection needles used in regional anaesthesia: influence of bevel configuration, studied in a rat model. Br J Anaesth 1992; 69:433-438.

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23. Stohr M, Dichgans J, Dorstelmann D: Ischaemic neuropathy of the lumbosacral plexus following intragluteal injection. J Neurol Neurosurg Psychiatry 1980; 43:489-494. 24. Chalk CH, Dyck PJ: Ischemic neuropathy. In Dyck PJ, Thomas, PK, eds: Peripheral Neuropathy, 3rd ed. Philadelphia: WB Saunders, 1993, pp 980-989. 25. Hess, K, Eames, R, Darveniza, P, et al: Acute ischaemic neuropathy in the rabbit. J Neurol Sci 1979; 44:19-43. 26. Schmelzer JD, Zochodne D, Low PA: Ischemic and reperfusion injury of rat peripheral nerve. Proc Natl Acad Sci U S A 1989; 86:1639-1642. 27. Dyck PJ, Conn DL, Okazaki H: Necrotizing angiopathic neuropathy. Three-dimensional morphology of fiber degeneration related to sites of occluded vessels. Mayo Clin Proc 1972; 47:461-475. 28. Boontje AH, Haaxma R: Femoral neuropathy as a complication of aortic surgery. J Cardiovasc Surg (Torino) 1987; 28:286-289. 29. Honet JC, Wajszczuk WJ, Rubenfire M, et al: Neurologic abnormalities in the leg(s) after use of intraaortic balloon pump: report of 6 cases. Arch Phys Med Rehabil 1975; 56:346-352. 30. Castellanos AM, Glass JP, Yung WKA: Regional nerve injury after intra-arterial chemotherapy. Neurology 1987; 37:834-837. 31. Wilbourn AJ, Levin KH: Ischemic neuropathy. In Brown WF, Bolton CF, eds: Clinical Electromyography, 2nd ed. Boston: Butterworth-Heinemann, 1993, pp 369-390. 32. Pierce SM, Recht A, Lingos TI, et al: Long-term radiation complications following conservative surgery and radiation therapy in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1992; 23:915-923. 33. Olsen NK, Pfeiffer P, Johannsen L, et al: Radiation-induced brachial plexopathy: neurological follow-up in 116 recurrencefree breast cancer patients. J Radiat Oncol Biol Phys 1993; 26:43-49. 34. Stoll RA, Andrews JT: Radiation-induced peripheral neuropathy. BMJ 1966; 1:834-837. 35. Harper CM, Thomas JE, Cascino TL, et al: Distinction between neoplastic and radiation-induced brachial plexopathy with emphasis on the role of EMG. Neurology 1989; 39:502-506. 36. Mondrup K, Olsen NK, Pfeiffer P, et al: Clinical and electrodiagnostic findings in breast cancer patients with radiationinduced brachial plexus neuropathy. Acta Neurol Scand 1990; 81:153-158. 37. Kori AH, Foley KM, Posner JB: Brachial plexus lesions in patients with cancer: 100 cases. Neurology 1981; 31:45-50. 38. Killer HE, Hess K: Natural history of radiation-induced brachial plexopathy compared with surgically treated patients. J Neurol 1990; 237:247-250. 39. Mumenthaler M, Narakas A, Gilliat RW: Brachial plexus disorders. In Dyck JP, Thomas PK, Lambert EH, et al, eds: Peripheral Neuropathy, 2nd ed, vol 2. Philadelphia: WB Saunders, 1987, pp 1384-1424. 40. Salner AL, Botnick LE, Herzog AG, et al: Reversible brachial plexopathy following primary radiation therapy for breast cancer. Cancer Treatment Rep 1981; 65:797-802. 41. Bowen BC, Verma A, Brandon AH, et al: Radiation-induced brachial plexopathy: MR and clinical findings. AJNR Am J Neuroradiol 1996; 17:1932-1936. 42. Wouter van Es H, Engelen AM, Witkamp TD, et al: Radiationinduced brachial plexopathy: MR imaging. Skeletal Radiol 1997; 26:284-288. 43. Gerard JM, Franck N, Moussa Z, et al: Acute ischemic brachial plexus neuropathy following radiation therapy. Neurology 1989; 39:450-451. 44. Shafer JC, Thompson AW: Local cold injury: a report of sequelae. Arch Dermatol 1955; 72:335-347. 45. Blair JR, Schatzki R, Orr KD: Sequelae to cold injury in one hundred patients: followup study four years after occurrence of cold injury. JAMA 1957; 163:1203-1208.

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46. Hanifin JM, Cuetter AC: In patients with immersion foot type of cold injury diminished nerve conduction velocity. Electromyogr Clin Neurophysiol 1974; 14:173-178. 47. Carter JL, Shefner JM, Krarup C: Cold-induced peripheral nerve damage: involvement of touch receptors of the foot. Muscle Nerve 1988; 11:1065-1069. 48. Denny-Brown D, Adams RD, Brenner C, et al: The pathology of injury to the nerve induced by cold. J Neuropathol Exp Neurol 1945; 4:305-323. 49. Kennett RP, Gilliatt RW: Nerve conduction studies in experimental non-freezing cold injury: II. Generalized nerve cooling by limb immersion. Muscle Nerve 1991; 14:960-967. 50. Jia J, Pollock M: Cold nerve injury is enhanced by intermittent cooling. Muscle Nerve 1999; 22:1644-1652. 51. Solem L, Fischer RP, Strate RG: The natural history of electrical injury. J Trauma 1977; 17:487-492. 52. Danielson JR, Capelli-Schellpfeffer M, Lee RC: Upper extremity electrical injury. Hand Clin 2000; 16:225-234. 53. DiVincenti FC, Moncrief JA, Pruitt BA: Electrical injuries: a review of 65 cases. J Trauma 1969; 9:497-507. 54. Skoog T: Electrical injuries. J Trauma 1970; 10:816-830. 55. Silversides J: The neurologic sequelae of electrical injury. CMAJ 1964; 91:195-204. 56. Gourbiere E, Corbut J-P, Bazin Y: Functional consequences of electrical injury. N Y Acad Sci 1994; 720:259-271. 57. McQuarrie IG: Perpheral nerve surgery. Neurol Clin 1985; 3:453-466.

58. Taha A, Taha J: Results of suture of the sciatic nerve after missile injuries. J Trauma 1998; 45:340-344. 59. Ijkema-Paassen J, Jansen K, Gramsbergen A, et al: Transection of peripheral nerves, bridging strategies and effect evaluation. Biomaterials 2004; 25:1583-1592. 60. Millesi H: Techniques for nerve grafting. Hand Clin 2000; 16:73-91. 61. Matsumoto K, Ohnishi K, Kiyotani T, et al: Peripheral nerve regeneration across an 80-mm gap bridged by a polyglycolic acid (PGA)–collagen tube filled with laminin-coated collagen fibers: a histological and electrophysiological evaluation of regenerated nerves. Brain Res 2000; 868:315-328. 62. Vanderhooft E: Functional outcomes of nerve grafts for the upper and lower extremities. Hand Clin 2000; 16:93-103. 63. Frykman GK, Gramyk K: Results of nerve grafting. In Gelberman RH, ed: Operative Nerve Repair and Reconstruction. Philadelphia: JB Lippincott, 1991, pp 553-567. 64. MacKinnon SE, Dellon AL: Clinical nerve reconstruction with a bioabsorbable polyglycolic acid tube. Plast Reconstr Surg 1990; 85:419-424. 65. Giovanoli P, Koller R, Meuli-Simmen C, et al: Functional and morphometric evaluation of end-to-side neurorrhaphy for muscle reinnervation. Plast Reconstr Surg 2000; 106:383-392. 66. Rowan PR, Chen LE, Urbaniak JR: End-to-side nerve repair. A review. Hand Clin 2000; 16:151-159. 67. Nath RK, MacKinnon SE: Nerve transfer in the upper extremity. Hand Clin 2000; 16:131-139.

CHAPTER

106

NEUROREHABILITATION ●

●

●

●

Michael D. Osborne and Thomas D. Rizzo, Jr.

This chapter provides an overview of the rehabilitation principles used to improve function and facilitate recovery in patients with neurological injury. Numerous and varied neurological conditions manifest unique impairments. Neurorehabilitation is a diverse topic. This chapter presents a systematic approach to evaluation and implementation of general rehabilitation interventions for neurological injury. The paradigms for treatment presented focus on spinal cord injury (SCI) and brain injury models, although the treatment approaches can be applied to the rehabilitation of patients with other disorders with similar neurological sequelae. Rehabilitation programs typically consist of two parts: (1) skilled therapeutic exercise, to maximize function, and (2) prescription and incorporation of specific adaptive equipment, to facilitate optimal function, mobility, and independence.

ASSESSMENT Initial Evaluation Successful implementation of any rehabilitation program starts with a comprehensive initial assessment of the primary neurological impairment and also a systematic evaluation of any other medical and musculoskeletal conditions that may affect the development and implementation of a patient’s rehabilitation program. For example, shoulder arthritis or rotator cuff pathology can significantly affect the rehabilitation of a braininjured or spinal cord–injured patient with severe lower extremity weakness who requires good shoulder strength and mobility in order to transfer and use assistive devices. Likewise, advanced cardiopulmonary disease may impair a patient’s ability to engage in aggressive gait training, in view of the aerobic demands of this activity. The initial rehabilitation evaluation should include an assessment of alertness, cognitive function, speech and language, vision, swallowing difficulties, musculoskeletal limitations, motor impairments, apraxia, sensory deficits, bowel function, bladder function, balance, and coordination. Numerous disease states can cause injury to the spinal cord, including trauma, spondylosis, demyelinating diseases, tumor, neurodegenerative diseases, infection, vascular injury, and toxic metabolic disorders. There are approximately 11,000 new cases

of traumatic SCI per year in the United States.1 About 700,000 people suffer a stroke each year, and stroke is currently the leading cause of serious long-term disability in the United States.2 However, numerous other disorders of brain function cause significant disability, and these patients may also benefit from directed rehabilitation therapies. Examples include encephalopathies, neurodegenerative diseases, hydrocephalus, demyelinating disease, and primary and metastatic brain malignancies. Many different types of rehabilitation programs are available for patients and are stratified in Table 106–1 according to level of medical acuity (the need for close medical supervision or nursing services) and intensity.

Assessment Scales SCI assessment starts with a determination of the level and the completeness of the spinal injury. The American Spinal Injury Association has published standards for classification of SCI level (Fig. 106–1) and a grading system for completeness of neurological injury (Fig. 106–2).3 Incomplete injuries have a much better prognosis for motor recovery than do complete injuries. Since 2000, the most frequent SCI neurological category at rehabilitation hospital discharge of persons reported to the National Spinal Cord Injury database is incomplete tetraplegia (34.3%), followed by complete paraplegia (25.1%), complete tetraplegia (22.1%), and incomplete paraplegia (17.5%).1 A variety of scales and assessment tools exist for evaluation of function after neurological injury. The primary initial assessment scale administered in traumatic brain injury is the Glasgow Coma Scale. The Glasgow Coma Scale numerical score reflects the depth of unconsciousness and is one of the most significant initial predictors of outcome and recovery.4 Table 106–2 summarizes some of the more commonly used scales in rehabilitation medicine. The Functional Independence Measure instrument is probably the most widely used functional assessment tool in the inpatient rehabilitation setting and can be applied irrespective of diagnosis (Fig. 106–3).

ACUTE ILLNESS REHABILITION Rehabilitation protocols should begin immediately after neurological injury, even if the patient is critically ill. One of the

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T A B L E 106–1. Classification of Rehabilitation Programs Program

Medical Acuity*

Hours of Rehabilitation

Acute inpatient rehabilitation Day therapy (outpatient) Subacute rehabilitation Home therapy Outpatient therapy Extended care facility

High Low-moderate Moderate Low Low Moderate

3 (minimum/day) 3-5 (usually 5 days/week) 1-3 (usually 3-5 days/week) 1 (usually 2-3 times/week) 1-2 (usually 2-3 times/week) 1 (usually 2-3 times/week)

*The need for close medical supervision or nursing services.

■

Figure 106–1. American Spinal Injury Association’s (ASIA) classification of spinal cord injury.

chapter 106 neurorehabilitation

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T A B L E 106–2. Commonly Used Assessment Scales

ASIA IMPAIRMENT SCALE A = Complete: No motor or sensory function is preserved in the sacral segments S4-S5. B = Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-S5. C = Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3. D = Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more. E = Normal: motor and sensory function are normal

Scale Type

Scale Name

Spinal cord injury impairment Stroke deficit

ASIA Impairment Scale

Level of consciousness/ cognitive function Motor function Spasticity Basic ADLs and mobility Instrumental ADLs Depression Quality of life Health status

ADL, activity of daily living; ASIA, American Spinal Injury Association; NIH, National Institutes of Health.

T A B L E 106–3. Acute Illness Rehabilitation Principles Rehabilitation Measure Musculoskeletal Pulmonary Swallowing

CLINICAL SYNDROMES Central Cord Brown-Séquard Anterior Cord Conus Medullaris Cauda Equina

Skin Bowl Bladder DVT prophylaxis Confusion

■

Figure 106–2. American Spinal Injury Association’s (ASIA) spinal

NIH Stroke Scale Canadian Neurologic Scale Glasgow Coma Scale (Ranchos) Level of Cognitive Function Scale Galveston Orientation and Amnesia Test Fugl-Meyer Scale Modified Ashworth Scale Barthel Index Functional Independence Measure Lawton & Brody Instrumental ADL Scale Katz ADL Scale Beck Depression Scale Hamilton Depression Scale Sickness Impact Profile Short-Form 36

Principle Prevention of contractures with range-of-motion exercise, stretching, positioning, splints, and footboards Incentive spirometry, chest percussive therapy, pulmonary toilet Bedside or video swallowing evaluation to assess aspiration risk Frequent repositioning (every 2 hours), padding of bony prominences, pressure-reducing mattresses, and specialized beds Assessment of continence, constipation, neurogenic bowl Assessment of continence, check for infection, implementation of indwelling or intermittent catheterization Subcutaneous heparin, sequential leg compression devices, compression garments, encouraging mobility and active calf exercises Reducing sedating medications, installing restraints or net bed for patient safety

DVT, deep vein thrombosis.

cord injury impairment scale.

FUNDAMENTAL REHABILITATION INTERVENTIONS Flexibility main goals is to minimize the effects of prolonged immobility that can be associated with severe neurological injury. In addition, quick identification of other body systems that may have been adversely affected facilitates immediate implementation of treatment schemes and thus minimizes the potential for morbidity. Table 106–3 outlines the various areas that require assessment.

Flexibility is an integral component of most rehabilitation schemes. Flexibility exercises can reduce contractures, reduce muscle pain, and decrease spasticity. Prolonged gentle passive stretching is preferred over aggressive forced or ballistic stretching,5 which can tear myofibrils and supportive connective tissue, leading to increased pain. The pain and microscopic tearing associated with aggressive stretching techniques reduces the potential for progressive gains in flexibility. Heat

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FIMTM Instrument 7 6

L E V E L S

Complete independence (timely, safely) Modified independence (device)

NO HELPER

Modified dependence 5 Supervision (subject = 100%) 4 Minimal assistance (subject = 75%+) 3 Moderate assistance (subject = 50%+)

HELPER

Complete Dependence 2 Maximal assistance (subject = 25%+) 1 Total assistance (subjet = less than 25%)

Self-Care A. Eating B. Grooming C. Bathing D. Dressing-upper body E. Dressing-lower body F. Toileting

ADMISSION

DISCHARGE

FOLLOW-UP

Sphincter Control G. Bladder management H. Bowel management Transfers I. Bed, chair, wheelchair J. Toilet K. Tub, shower Locomotion L. Walk/wheelchair M. Stairs

W Walk C Wheelchair B Both

W Walk C Wheelchair B Both

W Walk C Wheelchair B Both

A V B

Auditory Visual Both

A Auditory V Visual B Both

A V B

Auditory Visual Both

A V B

Auditory Visual Both

A Auditory V Visual B Both

A V B

Auditory Visual Both

Motor subtotal score Communication N. Comprehension O. Expression Social Cognition P. Social interaction Q. Problem solving R. Memory Cognitive subtotal score TOTAL FIMTM SCORE

NOTE: Leave no blanks. Enter 1 if patient is not testable due to risk.

Copyright © 1997 Uniform Dala System for Medical Rehabilitation (UDSMR), a division of UB Foundation Acivities. Inc.. (UBFA) Reprinted with the permission of UDSMR. All marks associated with FIM and UDSMR are owned by UBFA. ■

Figure 106–3. Functional Independence Measure (FIM) instrument.

chapter 106 neurorehabilitation application before stretching or a gentle aerobic warmup (if the patient is able to perform this) improves blood flow to the muscle and improves tissue elasticity. Ideally, stretches should be held for at least 30 seconds6 and, for optimal results, repeated twice a day.

Strengthening Weakness is a common sequela of neurological injury. Institution of strengthening programs can typically start as soon as the patient has the ability to perform voluntary motor contractions. Often, neuromuscular reeducation techniques are used concomitantly with strengthening programs to facilitate more coordinated return of motor function (see later discussion). A general approach to strengthening starts with focus on core muscles that support the trunk, spine, pelvic girdle, and shoulder girdle. As core strength improves, greater focus is placed on extremity strength training and on coordination of motor control. In the profoundly debilitated patient who is unable to maintain trunk stability in an upright position, assisted range-ofmotion exercises and progressive resistance exercises, with the therapist providing the assistance or resistance, can be implemented for the upper and lower limbs. As mentioned, the only requirement is that the patient have some degree of voluntary contraction. These exercises can be performed in a supine position or in a supported sitting or standing position. A tilt table (a plinth that can rotate 90 degrees from horizontal to vertical) can allow a gradually more upright posture while the patient exercises the arms and legs. The benefit is not only strengthening the legs through weight bearing but also reconditioning the cardiovascular system. Cardiovascular “tone” may be lost with even short periods of bed rest, leading to orthostatism. For patients with profound motor impairment, neuromuscular electrical stimulation can be used to facilitate strengthening, and in patients with SCI, such stimulation has been demonstrated to reduce disuse-related atrophy.7 However, caution should be exercised with use of neuromuscular electrical stimulation in patients with myopathy because it may result in exhaustion of the myopathic muscle. The primary physiological processes by which normal muscles achieve greater strength are muscle hypertrophy and enhanced neuromuscular control. In the initial 2 weeks of any strengthening program, the improvements in strength are related less to muscle hypertrophy than to enhanced neuromuscular control8; thereafter, muscle hypertrophy is the predominant factor. In the patient with neurological injury as the cause of weakness, improvements in strength also depend greatly on the processes of neurological recovery. The mechanisms of recovery vary, depending on the precise nature and extent of neurological injury.9 For example, central reorganization of motor control (neural plasticity) occurs after stroke, and collateral sprouting of motor unit nerve endings occurs in peripheral neurological injury.

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as stroke, hydrocephalus, and vestibulopathy, as well as those causing motor weakness, sensory or proprioceptive loss, or extrapyramidal dysfunction. Rehabilitation schemes for the significantly impaired patient start with an assessment of postural control in a seated position. Patients are taught methods to improve trunk stability and correct transient perturbations of balance. Once sitting balance is sufficiently mastered, patients progress through more challenging exercises. Functional exercises such as mobility training, transfer training, and gait training all provide a challenge to postural control and help facilitate improved balance. Advanced proprioceptive exercises include single-leg standing, balance-training platforms, wobble boards, and hopping. Rehabilitation of an extremity where injury has significantly impaired voluntary motor control is likewise challenging. Selection of a rehabilitation strategy depends, in part, on whether the limb is flaccid or spastic. Treatment in the flaccid extremity focuses on exploiting synergy patterns of muscle activation to facilitate voluntary movement. In the spastic extremity, techniques such as the Bobath neurodevelopmental training method or proprioceptive neuromuscular facilitation are used along with gentle prolonged stretching to decrease spasticity and improve motor control by using specific tonereducing postures and movement patterns.10,11 Biofeedback with surface electromyography can be used to facilitate neuromuscular reeducation.11 Orthoses and adaptive equipment are commonly used thoroughout the rehabilitation process to facilitate improvements in extremity function. These are discussed in more detail in subsequent sections.

Gait and Mobility Many of the treatment principles outlined in the preceding sections are incorporated into the rehabilitation programs designed to improve mobility and gait. The mobility goals depend on the degree of neurological impairment. The ability to safely transfer independently is a critical factor determining a patient’s level of overall independence. Likewise, a safe method of household mobility (with or without assistive devices) is typically a principal goal of acute rehabilitation. Specific techniques taught to patients to facilitate transfers include sliding board transfers and standing pivot transfers. Good trunk stability and triceps strength are requirements for sliding board transfers when patients have significant lower extremity weakness. Standing pivot transfers require good trunk stability, hip girdle strength, and quadriceps strength. Parallel bars and hemibars (a single bar for stroke rehabilitation) are used for gait training. The focus is on trying to achieve a fluid reciprocal gait. Specialized harness and treadmill apparatuses have been developed for gait training, including that for patients with significant impairments such as hemiplegia, paraplegia, and gait abnormalities associated with Parkinson’s disease.12,13 Adaptive equipment and lower extremity orthoses are widely used throughout the rehabilitation process to facilitate improvements in mobility and ambulation.

Balance, Coordination, and Neuromuscular Reeducation

Activities of Daily Living

Impairment in balance and coordinated motor control can be a very challenging rehabilitation obstacle. Poor postural control may be a sequela of many neurological disorders such

Activities of daily living (ADLs) can be classified as basic ADLs and instrumental ADLs. Basic ADLs include such activities as feeding, grooming, bathing, dressing, and toilet use.

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T A B L E 106–4. Commonly Prescribed Orthoses and Their Primary Applications Orthoses Type

Primary Application

Wrist-hand orthosis Lumbrical bar

Prevents contracture and reduces tone in a spastic upper extremity Prevents hyperextension of metacarpophalangeal joints and improves grip in a hand with loss of intrinsic muscle function Short thumb shell For median nerve injury: improves pincer grip Wrist tenodesis Facilitates passive finger flexion and grasping splint when the wrist is placed in extension by the brace Universal cuff Assists with feeding and grooming by holding utensils Balanced forearm Improves active elbow motion by supporting orthosis the upper arm in an abducted position and thereby eliminating the effects of gravity Arm sling or tray Supports the elbow, thus reducing shoulder pain in patients with stroke Ankle-foot orthosis Prevents footdrop, improves gait mechanics Long leg brace Supports weak quadriceps and ankle to facilitate ambulation Reciprocating gait Supports weak hip girdle and leg muscles to orthosis facilitate ambulation Cane, crutch, or Improves balance, prevents falls, reduces walker (many arthritic hip and knee pain, reduces energy varieties) demands of walking

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Figure 106–4. Canes. Three different grip types are demonstrated with three single-point canes (left to right, C-handle, straight handle, and ergonomic grip) and a four-point cane (quad cane) (far right).

Instrumental ADLs include higher level functions such as housekeeping, bookkeeping, shopping, telephoning, and managing medications. Occupational therapists are specifically trained in ADL assessment and rehabilitation. The overall therapeutic goal is to use the fundamental rehabilitation schemes of flexibility, strengthening, and aforementioned methods of improving motor control as a means of acquiring independent ADLs. Specific ADL training and repeatedly practicing the skilled movements of daily activities, such as dressing and grooming, are also highly beneficial and are commonly incorporated into most rehabilitation programs. Adaptive equipment can be very helpful in allowing patients to achieve independence in ADLs as well.

Adaptive Equipment As previously mentioned, rehabilitation of the neurologically impaired patient consists of two parts: (1) skilled therapeutic exercise to maximize function (as detailed in the preceding sections) and (2) prescription and incorporation of specific adaptive equipment to facilitate optimal function, mobility, and independence. Table 106–4 outlines some of the more commonly prescribed orthoses and their primary rehabilitation applications. Figures 106–4 to 106–9 depict common ambulatory aids. It is important for the physician and physical therapist to ensure that the prescribed orthosis or ambulatory aid is properly fitted and has the desired effect on function. Proper training with the assistive device to promote maximal function is particularly important with the prescription of ambulatory aids. Before discharge from inpatient rehabilitation centers, patients should have their home environments thoroughly

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Figure 106–5. Crutches. Left to right, Platform crutch with arm tray and hand grip, Lofstrand crutch, and axillary crutch.

assessed. Some patients may require significant modification of their homes and need additional durable medical equipment to ensure a safe environment and provide the patient with maximal independence. Table 106–5 lists some of the more common equipment needs.

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Figure 106–6. Aluminum walkers with (left) and without (right) wheels.

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Figure 106–8. Three-wheeled walker with large castor-type wheels, hand breaks, and a basket. This is useful for the more active and mobile patient who does not require an extremely stable base to lean upon. The large wheels are useful for negotiating uneven terrain.

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Figure 106–7. Hemi Walker. This is useful for patients with hemiplegia who cannot use a standard walker because of unilateral upper extremity weakness or spasticity.

COMMON MEDICAL AND REHABILITATION ISSUES Spasticity Numerous therapeutic strategies exist for the management of spasticity in patients with upper motor neuron syndrome,

including rehabilitation strategies, oral medications, intrathecal medications, focal chemodenervation, and surgery. Rehabilitation treatment strategies are variably effective14 and are summarized in Table 106–6. Spasticity scales, such as the Modified Ashworth Scale (Table 106–7), are helpful in monitoring response to treatment. Before aggressive medical or interventional therapies for spasticity are initiated, the patient should undergo a detailed assessment to determine which functional limitations or possible functional benefits their hypertonicity creates. For example, Ashworth grade 3 tone in the lower extremities of a paraparetic patient with multiple sclerosis may impair lower extremity dressing and personal hygiene. However, the spasticity may make standing pivot transfers easier, particularly if the patient has very poor lower extremity strength. The patient and physician may desire to reduce the spasticity through treatment; however, if therapy is successful and tone is significantly reduced, the patient may lose the ability to perform standing pivot transfers. Thus, both positive and negative effects on function must be considered before treatment, particularly if irreversible treatments such as neurolysis and surgery are being considered.15 The evaluation of a patient with worsening spasticity starts with a thorough assessment of potential noxious stimuli that may create amplification of muscle tone. Common causes of worsening spasticity in patients with SCI include bowel impaction, urinary tract infection, decubitus ulceration, acute abdomen, and pathological fracture. Rapid identification and treatment of these problems can result in a quick return to baseline tone.15

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Tr a u m a T A B L E 106–7. The Modified Ashworth Scale 0 1 1+ 2 3 4

No increase in muscle tone Slight increase in tone with a catch and release or minimal resistance at end of range of motion Slight increase in tone with a catch, followed by minimal resistance throughout the remaining range of motion More marked increase in tone throughout range of motion Considerable increase in tone, difficulty with passive movement Rigidity of affected part

Neurogenic Bowel

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Figure 106–9. U-Step walker. This walker provides a very stable base of support. The wheels are released when hand levers are gripped and then lock again upon release. A laser light projects on the floor at the patient’s feet to assist with the freezing gait pattern of Parkinson’s disease.

T A B L E 106–5. Common Adaptive Equipment and Durable Medical Equipment Needs Environment

Equipment

Home entrance Living room Bedroom

Ramp, railing Lift chair, reaching device Electric hospital-type bed, bedside commode, urinal Toilet seat riser, bath bench or shower chair, grab bars, handheld shower Built-up utensils Scooter, power wheelchair

Bathroom Kitchen General

T A B L E 106–6. Rehabilitation Strategies for Spasticity Management Tone-reducing positioning Cryotherapy Stretching Bracing Serial casting Electrical stimulation

Neurogenic bowel associated with SCI and other upper motor neuron disorders typically results in constipation and difficulty with stool evacuation. Rehabilitation interventions are aimed at bowel retraining and establishment of a routine bowel regimen.16,17 The goals of a bowel program are to use either digital rectal stimulation or chemical stimulation (mini-enema or suppository) to trigger reflex evacuation of stool in the distal colon. For this to work appropriately, stools must be soft but well formed so that peristalsis can propagate the stool toward the rectum. Bulking agents such as fiber supplements and stool softeners aid in establishing optimal stool consistency. In a bowel program, patients typically evacuate daily or every other day. For patients with incomplete neurological injury in which some voluntary motor function is preserved in the sacral segments, a bowel retraining program can be pursued. The goal is to restore the coordinated activation and relaxation of the muscles necessary to have a bowel movement. Intrarectal balloon training can facilitate voluntary evacuation. Patients who have sustained lower motor neuron injury to the sacral segments face a more challenging task in maintaining stool continence.18 With partial nerve injuries, bowel retraining is focused predominantly on strengthening the pelvic floor, especially the puborectalis and the external anal sphincter. Persistent and significant fecal incontinence reduces patient dignity and may lead to avoidance of socialization. For severe persistent problems that jeopardize skin care, surgical sling procedures or colostomy are options.

Neurogenic Bladder Neurological injury can cause a variety of problems with bladder function. In the first few weeks after an acute SCI, the bladder is usually flaccid (as a result of spinal shock), and urinary retention occurs. Indwelling catheters are usually placed on initial hospitalization, but as soon as appropriate, patients should be transitioned to an intermittent catheterization schedule. Patients are typically taught to self-catheterize at a frequency of four to five times a day. Oral hydration schedules are created to balance the patient’s needs for hydration without making it necessary to self-catheterize every few hours. The aim is to prevent accumulation of more than 500 mL in the bladder at one time and prevent overdistention, as well as overflow incontinence.19 If the patient regains sacral segment sensorimotor function, bladder training ensues. Patients follow timed voiding

chapter 106 neurorehabilitation schedules and learn techniques to facilitate bladder emptying such as suprapubic compression or reflex-stimulated voiding. Patients can also undergo more intensive electromyographically assisted bladder retraining programs to improve coordinated activation and relaxation of the muscles necessary to evacuate the bladder.19 Postvoid residuals are monitored to ensure complete emptying. When patients can consistently achieve postvoid residuals of less than 100 mL, intermittent catheterization can be discontinued. Many patients with SCI are at risk for developing detrusor sphincter dyssynergia, which results in a high-pressure bladder. In dyssynergia, the detrusor muscle spontaneously contracts, and the urethral sphincter does not concomitantly relax to allow bladder emptying. This creates high pressures in the bladder that force urine up the ureters into the kidneys; serious renal injury can develop. Dyssynergic bladders can be diagnosed with voiding cystomyography.20 Patients with neurogenic bladder (especially high-pressure bladders) need to undergo periodic reevaluation with cystomyography and lifelong renal surveillance.21

Pressure Ulcers Pressure ulceration of the skin can be a devastating complication of immobility. Patients with neurological injury are particularly at risk for pressure ulcers because of immobility and insensate skin. The body areas at highest risk are, first, the sacrum and then bony prominences such as the greater trochanters and heels. Furthermore, bowel and bladder incontinence can increase the risk of skin maceration and secondary infection.22 Patients with the ability to reposition themselves should do so frequently. Paraplegic patients use triceps press-ups to provide transient pressure relief to their buttocks and legs. Dependent patients must be turned by a caregiver every 2 hours and have bony prominences padded. Wheelchairs should be fitted with pressure-reducing cushions, and patients who spend considerable time in bed need a pressure-reducing mattress.22

Dysphagia A clinical swallowing evaluation can be administered at the bedside to establish a basic understanding of a patient’s aspiration risk. A more extensive evaluation with video fluoroscopy can help determine how different food consistencies are handled at the oral, pharyngeal, and esophageal phases of swallowing.23 Patients are taught protective and compensatory techniques for swallowing, such as the supraglottic swallow and the Mendelsohn maneuver.24 Liquids may be particularly difficult to control during the oral phase and are easily aspirated. This risk can be minimized by using a flavorless gelatin to increase the consistency of the liquid without altering its taste. Avoiding foods with multiple consistencies (e.g., stews or soups) also decreases the risk of aspiration.

Communication Speech and language disorders can be generally classified into four categories: aphasias, dysarthrias, dysphonias, and apraxia

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of speech. Speech-language pathologists can further characterize these disorders and formulate appropriate speech therapy interventions. Rehabilitation approaches vary according to diagnosis and target the patient’s primary impairments.25 Other difficulties in communication may also result from confusion, ventilator dependency, and cognitive impairment, among other sequelae of significant neurological injury. Further discussion on evaluation and treatment of speech and language disorders can be found in Chapter 3.

Autonomic Hyperreflexia Autonomic hyperreflexia is a potentially life-threatening condition that can occur in patients with SCI above the T6 level. Autonomic hyperreflexia develops when a noxious stimuli creates a sudden surge in sympathetic outflow that is not appropriately modulated by descending supraspinal inhibitory signals as a result of the SCI. This results in severe hypertension, headache, facial flushing, and reflex bradycardia (caused by stimulation of carotid sinus receptors).26 Treatment consists of sitting the patient upright, quickly identifying and eliminating the noxious source, and, when necessary, administering antihypertensives such as nitrates or nifedipine.26

Heterotopic Ossification Heterotopic ossification is aberrant bone formation that can occur with a variety of neurological injuries, such as SCI, stroke, and traumatic brain injury. It most commonly occurs about the hips, knees, shoulders, and elbows. Early clinical manifestations are warmth and swelling of the affected area. If new bone formation is exuberant, loss of range of motion and even joint ankylosis can occur. Radiographs demonstrate new bone formation; however, the most specific test for early identification is the triple-phase bone scan. The blood flow and blood pooling phases show areas of angiogenesis and matrix formation even before ossification.27 Initial treatment is institution of an aggressive range-of-motion program to prevent ankylosis of the joint. Bisphosphonates can reduce the severity of heterotopic ossification when they are initiated soon after the diagnosis is made.28

SUMMARY Rehabilitation of the neurologically impaired patient should begin as soon as possible after initial injury and starts with a systematic assessment of neurological function, as well as medical and musculoskeletal comorbid conditions. Fundamental rehabilitation interventions include stretching, strengthening, neuromuscular reeducation, balance and coordination exercises, transfer training, gait training, and ADL training. Adaptive equipment such as splints, braces, and ambulatory aids also facilitate optimal function, mobility, and independence. Comprehensive neurorehabilitation includes appropriate evaluation and treatment of spasticity, neurogenic bowel, neurogenic bladder, pressure ulcers, swallowing dysfunction, and impaired communication, among other medical and musculoskeletal complications of neurological injury.

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P O I N T S

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Rehabilitation programs typically consist of two parts: (1) skilled therapeutic exercise to maximize function and (2) prescription and incorporation of specific adaptive equipment to facilitate optimal function, mobility, and independence.

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Rehabilitation protocols should begin immediately after neurological injury, even if the patient is critically ill.

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Impairment in balance and coordinated motor control can be a very challenging obstacle to rehabilitation.

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The ability to safely transfer independently is a critical factor determining a patient’s level of overall independence.

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Adaptive equipment can be very helpful, allowing patients to achieve independence in ADLs and mobility.

Suggested Reading Foti D, Pedretti LW, Lillie S: Activities of daily living. In Pedretti LW, ed: Occupational Therapy Practice Skills for Physical Dysfunction, 4th ed. St. Louis: CV Mosby, 1996, pp 463-506. Good DC: Stroke: Promising Neurorehabilitation Interventions and Steps Toward Testing Them. Am J Phys Med Rehabil 2003; 82S:50-57. Kirshblum S: Rehabilitation of spinal cord injury. In DeLisa JA, Gans BM, Walsh NE, et al, eds: Physical Medicine and Rehabilitation: Principles and Practice, 4th ed. New York: Lippincott Williams & Wilkins, 2004, pp 1715-1752. Roth EJ, Harvey RL: Rehabilitation of stroke syndromes. In Braddom RL, ed: Physical Medicine and Rehabilitation, 2nd ed. Philadelphia: WB Saunders, 2000, pp 1117-1160. Whyte J, Hart T, Laborde A, et al: Rehabilitation issues in traumatic brain injury. In DeLisa JA, Gans BM, Walsh NE, et al, eds: Physical Medicine and Rehabilitation: Principles and Practice, 4th ed. New York: Lippincott Williams & Wilkins, 2004, pp 16771714.

References 1. Spinal Cord Injury. Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, National Spinal Cord Injury Statistical Center, August 2004. J Spinal Cord Med 2004; 27(Suppl 1):S139-S140. 2. American Heart Association: Heart Disease and Stroke Statistics—2005 Update. Dallas: American Heart Association, 2004. 3. International Standards for Neurological Classification of SCI. Atlanta: American Spinal Injury Association, 2002. 4. Vollmer DG: Prognosis and outcome of severe head injury. In Cooper PR, ed: Head Injury, 3rd ed. Baltimore: Williams & Wilkins, 1993, pp 553-581. 5. Bandy WD, Irion JM, Briggler M: The effect of static stretch and dynamic range of motion training on the flexibility of the hamstring muscles. Phys Ther 1998; 27:295-300. 6. Bandy WD, Irion JM: The effect of time on static stretch on the flexibility of the hamstring muscles. Phys Ther 1994; 74:845852.

7. Yarkony GM, Roth EJ, Cybulski GR, et al: Neuromuscular stimulation in spinal cord injury II: prevention of secondary complications. Arch Phys Med Rehabil 1992; 73:195-200. 8. Moritani T, deVries HA: Neural factors versus hypertrophy in the time course of muscle strength gain. Am J Phys Med 1979; 58:115-130. 9. Bach-y-Rita P, Brown AW, Lazarus JC, et al: Neural aspects of motor function as a basis of early and postacute rehabilitation. In DeLisa JA, Gans BM, eds: Rehabilitation Medicine, 2nd ed. Philadelphia: JB Lippincott, 1993, pp 381-403. 10. Luke C, Dodd KJ, Brock K: Outcomes of the Bobath concept on upper limb recovery following stroke. Clin Rehabil 2004; 18:888-898. 11. Albert T, Yelnik A: [Physiotherapy for spasticity]. Neurochirurgie 2003; 49(2-3, Pt 2):239-246. 12. Hesse S, Bertelt C, Jahnke MT, et al: Treadmill training with partial body weight support compared with physiotherapy in nonambulatory hemiparetic patients. Stroke 1995; 26:976981. 13. Miyai I, Fujimoto Y, Yamamoto H, et al: Long-term effect of body weight–supported treadmill training in Parkinson’s disease: a randomized controlled trial. Arch Phys Med Rehabil 2002; 83:1370-1373. 14. Watanabe T: The role of therapy in spasticity management. Am J Phys Med Rehabil 2004; 83(10, Suppl):S45-S49. 15. Satkunam LE: Rehabilitation medicine: 3. Management of adult spasticity. CMAJ 2003; 169:1173-1179. 16. Chen D, Nussbaum SB: The gastrointestinal system and bowel management following spinal cord injury. Phys Med Rehabil Clin North Am 2000; 11:45-56. 17. Merenda L, Brown JP: Bladder and bowel management for the child with spinal cord dysfunction. J Spinal Cord Med 2004; 27(Suppl 1):S16-S23. 18. Yim SY, Yoon SH, Lee IY, et al: A comparison of bowel care patterns in patients with spinal cord injury: upper motor neuron bowel vs lower motor neuron bowel. Spinal Cord 2001; 39:204207. 19. Andrews KL, Opitz JL: Bladder retraining. In Sinaki M, ed: Basic Clinical Rehabilitation Medicine, 2nd ed. St. Louis: CV Mosby, 1993, pp 195-206. 20. Rendeli C, Ausili E, Salvaggio E: Neurogenic bladder dysfunction: urodynamic evaluation. Rays 2002; 27:127-130. 21. Fowler CJ, O’Malley KJ: Investigation and management of neurogenic bladder dysfunction. J Neurol Neurosurg Psychiatry 2003; 74(Suppl 4):iv27-iv31. 22. Edlich RF, Winters KL, Woodard CR, et al: Pressure ulcer prevention. J Long Term Eff Med Implants 2004; 14:285-304. 23. Finestone HM, Greene-Finestone LS: Rehabilitation medicine: 2. Diagnosis of dysphagia and its nutritional management for stroke patients. CMAJ 2003; 169:1041-1044. 24. Noll SF, Bender CE, Nelson MC, et al: Rehabilitation of patients with swallowing disorders. In Braddom RL, ed: Physical Medicine and Rehabilitation, 2nd ed. Philadelphia: WB Saunders, 2000, pp 535-560. 25. Miller RM, Groher ME, Yorkston KM, et al: Speech, language, swallowing and auditory rehabilitation. In DeLisa JA, Gans BM, Walsh NE, et al, eds: Physical Medicine and Rehabilitation: Principles and Practice, 4th ed. New York: Lippincott Williams & Wilkins, 2004, pp 1025-1050. 26. Erickson RP: Autonomic hyperreflexia: pathophysiology and medical management. Arch Phys Med Rehabil 1980; 61:431440. 27. Buschbacher R: Heterotopic ossification: a review. Crit Rev Phys Med Rehabil Med 1992; 4:199-213. 28. Finerman GA, Stover SL: Heterotopic ossification following hip replacement or spinal cord injury. Two clinical studies with EHDP. Metab Bone Dis Relat Res 1981; 3:337-342.

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ENCEPHALOPATHIES ●

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Juan M. Pascual

CONCEPT AND CONTEXT OF NEUROMETABOLIC DISEASES Metabolic disorders constitute an expanding group of diseases comprising such heterogeneous conditions that a uniform introductory definition becomes necessary. Strictly speaking, neurometabolic diseases arise from genetic deficiencies of intermediary metabolism enzymes. Thus, mutation of genes encoding cytostructural or regulatory proteins or proteins involved in cell division, immunity, excitability, cell-to-cell communication, secretion, or movement do not give rise to metabolic diseases sensu stricto. Nevertheless, careful reflection on the molecular mechanisms of these latter disease categories leads to the recognition of intermediary metabolism abnormalities virtually in all of them, allowing at least some of them to be included with neurometabolic diseases. Whether involving carbohydrate, lipid, or protein metabolism, the manifestations of neurometabolic diseases are pleomorphic and can manifest at any stage during a life span. Regardless of their time and mode of manifestation, the approach to the potential patient with a neurometabolic disease includes a customized but systematic series of evaluations as well as a thorough assessment of the ancestry and family structure aimed at identifying all relatives at risk for a heritable trait. At the conclusion of the clinical interview, it should be possible to suspect the pattern of inheritance of a familial disease or, alternatively, the probability of a de novo, that is, noninherited, mutation. In the case of a potentially heritable trait, apparently unaffected relatives should be questioned and examined for the presence of specific abnormalities indicative of an incompletely penetrant trait. Then, a series of analytical investigations are tailored to confirm the diagnosis or, at least, to circumscribe the metabolic abnormality as much as possible according to the patient’s clinical syndrome. The biochemical analysis of banked patient tissues, such as biopsied muscle, and cellular elements, such as cultured fibroblasts, is often necessary to confirm a specific enzyme deficiency and should be followed, whenever possible, by genotyping. A variety of genetic test batteries and panels are available to screen genes associated with diseases that share a similar phenotype. When successful, genotyping allows for fully informed genetic counseling, for screening of at-risk relatives, and, in an increasing number of instances, for prenatal diagnosis via amniocentesis.

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MANIFESTATIONS UNFOLD IN TIME The apparent age at onset of metabolic disorders is variable, as the manifestations of neurometabolic diseases are intimately linked to the development of the nervous system. During infancy and childhood, several genetic expression programs come into play and become quiescent as the organism grows and matures. Thus, the effects of a pathogenic mutation may not be noticeable until the mutant gene is activated, and this may occur well after birth. For example, the fetal brain consumes preferentially lipid byproducts such as ketone bodies. At birth, the cerebral metabolic rate for glucose is minimal; it increases gradually during childhood, when it exceeds the neonatal rate by three-fold. By early adolescence, glucose consumption decreases and reaches the adult level, which is about twice the newborn rate. It is not surprising, then, that fetal and neonatal brains tolerate hypoglycemia relatively well. This is exemplified by the manifestations of glucose transporter type 1 deficiency, caused by mutation of the glucose carrier of the blood-brain barrier, which is usually unnoticeable in the newborn and becomes most pronounced during childhood; furthermore, they can be circumvented, to some degree, by a diet rich in ketogenic substrates, as the brain always retains the capacity to metabolize ketone bodies. In some occasions, the converse phenomenon is true, allowing for the restoration of a normal phenotype as development progresses and new genes replace the function of abnormal ones. This is illustrated by a transient or reversible form of cytochrome c oxidase–deficient myopathy that manifests in infancy with hypotonia and profound weakness, followed by a return of enzyme activity in muscle and normal strength later in childhood. In disorders causing an accumulation of a metabolite, symptoms may remain latent until the stored metabolite interferes with cellular organelles or forms deleterious aggregates. Yet, in other occasions, a precipitant factor triggers the sudden decompensation of a precarious cellular machinery. For example, a nutritional excess of fat may aggravate a fatty acid oxidation defect, inducing severe hypoglycemia and coma, or a protein load may result in hyperammonemia and mental disturbances in urea cycle defects (see Chapter 110). In some cases, well exemplified by Leigh syndrome, a “free interval” of several years may lapse before a trivial intercurrent respiratory or infectious illness precipitates cerebral necrosis, leading to fulminant disability. In

chapter 107 encephalopathies such cases, meticulous questioning and review of developmental milestones often uncover a preceding history of subtle but lifelong neurological dysfunction.

STATIC, EPISODIC, OR PROGRESSIVE DISEASES? Generally speaking, metabolic diseases are lifelong, permanent diseases, like their causal genetic mutations. However, they follow any imaginable temporal course even in the absence of environmental or nutritional precipitating factors, with some conditions manifesting only periodically and others exhibiting a static or apparently immutable course, which is in contrast with the still common notion of metabolic diseases as unrelenting, continuously symptomatic processes. The basis for the apparently paradoxical static and episodic manifestations of neurometabolic diseases is provided by the compartmentalization of metabolism.1 Because all cellular functions are spatially limited and regulated by membranes, metabolic reactions occur at rates governed not only by the kinetics of their corresponding enzymes but also (and often mainly) by substrate availability and product abundance. The former process, dependent on enzyme structure, is dictated by the gene; the latter, by the ability of cells and organelles to distribute and clear substrates and products, a process that is inherently dependent on the function of the membranes and membrane compartments of the various cell types that carry out the reaction in question.2 Thus, for example, an enzymatic deficiency affecting a reaction that is constantly active may be associated with the accumulation of a substrate that interferes with other reactions, causing inhibition and resulting in abnormal cell function. Such a substrate may be eliminated from the cell after it reaches a certain threshold level at a rate that is dependent on its concentration. After the substrate accumulates for the first time, production and elimination proceed indefinitely, maintaining a constant (elevated) concentration in the cell. This may constitute the basis for the permanent, immutable clinical manifestations that are sometimes associated with a static metabolic abnormality. Episodic diseases can also be modeled using the same mechanistic framework: a compound may accumulate without causing any abnormalities until a threshold concentration is reached or until another slowly fluctuating cellular process becomes vulnerable to it, such that an additional reaction is triggered, causing a decompensation that may propagate into a clinical crisis, only later followed by the restoration of the original (unstable) equilibrium. In this case, rare fluctuations of cellular metabolism may coincide and compound one another to cause a crisis in the setting of a permanently abnormal enzyme function. Metabolic control analysis computations are accommodating and predictive of such fluctuations. Of course, these scenarios may be complemented with other, higher-complexity hypothetical mechanisms that need not act exclusively of one another.

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negative-feedback regulation of enzymes, and induction or repression of genes by excess metabolite are a few logical, and not mutually exclusive, possibilities, although they do not fully explain many of these diseases. Additional consideration must be given to intragenomic signaling effects, such that a point mutation in one gene may result in upregulation or downregulation of other, unrelated genes. Such gene expression changes are sometimes viewed as “compensatory,” but they may well be deleterious, contributing to pathogenesis. Last, extra diagnostic and pathophysiological challenges are posed by the abundance of genetic polymorphisms of uncertain function present in all individuals, together with difficulties in separating true phenotypical characteristics from mere epiphenomena that are only tangentially related to the fundamental disease mechanism. In fact, many diseases are diagnosed by assaying metabolites generated by processes far removed from the original enzyme defect, which are only empirically found to associate with the classic form of that particular disease. The risk of errors inherent to this diagnostic approach cannot be overemphasized, particularly when confronted with unusual or partial forms of otherwise frequent diseases or with diseases so rare that the collective experience available is too sparse or insufficiently documented. Genotyping is also subject to special considerations when applied to neurometabolic diseases. Several well-known clinical entities can be confused with phenocopies (i.e., conditions that manifest similar phenotypes but are due to mutations of different, unrelated genes). For example, mutation of the SCO2 gene can result in a phenotype that resembles spinal muscular atrophy, which is typically due to SMN1 gene mutations. In this instance, the correct diagnosis is reached by paying attention to a clinical feature (cardiomyopathy) and a biochemical marker (lactic acidosis) that would be atypical in spinal muscular atrophy, again illustrating the value of the initial clinical and analytical assessment of the patient. Genotyping is additionally dependent on the abundance of a particular mutation in the patient’s tissues. Thus, mosaicism for MECP2 mutations in the male and skewed X chromosome inactivation in the female may account for the disparate phenotypes of Rett syndrome, encompassing male neonatal death, male mental retardation, asymptomatic female carrier status, or classic female Rett syndrome. The abundance of mitochondrial DNA mutations also varies depending on the tissue chosen for genotyping (a phenomenon known as heteroplasmy; see Chapter 88) and, in some cases, several easily accessible tissues (blood, urinary sediment, buccal smear) must be examined to detect or to exclude a low-abundance mutation. Last, carrier status should be investigated in all genetically susceptible individuals related to a patient with a low (incomplete) penetrance disease. For example, asymptomatic mothers of hypotonic infants affected by myotonic dystrophy should be examined for subtle signs of myotonia and, if appropriate, offered genotyping.

A PLEOMORPHIC PHENOMENOLOGY A COMPLEX GENETIC LANDSCAPE The precise pathophysiological mechanism of most neurometabolic diseases remains unknown, despite the accelerating pace of gene discovery. Among the mechanisms of metabolic diseases, accumulation of metabolic products, deprivation of substrates downstream of a metabolic blockade,

The phenotypes of neurometabolic diseases are often, and sometimes predominantly, nonneurological. Thus, abnormal urine odor, hepatomegaly, cardiomyopathy, cardiac arrhythmia, facial and skeletal malformations, neutropenia or disordered coagulation, and hair and skin abnormalities, among others, are characteristic features of some diseases (Table 107–1).

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T A B L E 107–1. Extraneurological Manifestations of Metabolic Encephalopathies Organs and Systems

Manifestations

Examples

Somatic dysmorphism

Coarse facies

Mucopolysaccharidoses Mucolipidoses GM1 gangliosidosis Zellweger disease Pyruvate dehydrogenase deficiency Sulfite oxidase deficiency Cockayne disease Zellweger disease Pyruvate dehydrogenase deficiency Glutaric aciduria type I Galactosemia

Characteristic facies

Cerebral dysgenesis Ocular abnormalities Lens dislocation

Hair abnormalities Skin abnormalities Cardiopathy

Progeric appearance Abnormal neuronal migration Corpus callosum agenesis Perisylvian hypotrophy Nuclear cataracts Sulfite oxidase deficiency Cataracts Corneal opacification Several abnormalities Alopecia Rash Cardiomyopathy

Arrhythmia Hepatopathy

Cholestasis Hepatomegaly

Intestinal abnormalities Nephropathy

Cirrhosis Liver failure Abdominal pain Pseudo-obstruction Fanconi’s syndrome Renal tubular acidosis Nephrotic syndrome

Skeletal abnormalities

Hematological disturbances

Dysostosis Patellar calcifications Acanthocytosis Anemia Pancytopenia Vacuolated lymphocytes

Psychiatric disturbances

Various

Abnormal urine odor

‘Sweaty feet’ Maple syrup Musty

Neurometabolic diseases may mimic other disorders. In the presence of a seemingly nonspecific constellation of nonprogressive abnormalities, neurometabolic diseases can be misdiagnosed for other, more common entities (Table 107–2). Misconceptions to be avoided include that metabolic diseases necessarily have a progressive clinical course and

Cockayne disease Mucopolysaccharidoses Mucolipidoses Menkes disease Multiple carboxylase deficiency Biotinidase deficiency Respiratory chain disorders Fatty acid oxidation disorders Pompe’s disease Glucogenoses III and IV Kearns-Sayre syndrome MELAS Niemann-Pick disease type C Smith-Lemli-Opitz syndrome Mucopolysaccharidoses Mucolipidoses Zellweger disease Alpers disease Acute intermittent porphyria MELAS Galactosemia Mitochondrial DNA deletion Respiratory chain disorders Respiratory chain disorders Congenital glycosylation defects Mucopolysaccharidoses Mucolipidoses GM1 gangliosidosis Zellweger disease Abetalipoproteinemia Respiratory chain disorders Glycolytic defects Organic acidurias Pompe disease Mucolipidosis Sialidosis Urea cycle defects Porphyrias Metachromatic leukodystrophy Krabbe disease Sanfilippo disease Wilson disease MELAS Glutaric aciduria type II Maple syrup urine disease Phenylketonuria

that terms such as “cerebral palsy” identify diseases, rather than heterogeneous syndromes defined by relatively loose criteria. In these cases, the index of clinical suspicion should remain high and metabolic screening should be applied, as some of these covert metabolic disorders are treatable.

chapter 107 encephalopathies T A B L E 107–2. Manifestations of Occult Neurometabolic Disease Abortion Sudden infant death Sepsis Stroke Failure to thrive Mental retardation Cerebral palsy Dietary intolerance or dependence Intermittent neurological dysfunction Somatic dysmorphism Cerebral malformations Autistic spectrum and other behavioral disorders

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T A B L E 107–3. Modalities of Metabolic Therapy Rehydration and correction of acidosis Exchange transfusion Peritoneal dialysis Hemofiltration Hemodialysis Dietary modification Vitamin supplementation Enzyme administration Bone marrow transplantation Organ transplantation Gene therapy and stimulation

GROUNDWORK FOR FUTURE THERAPIES DIAGNOSIS AND ITS VALUE The possibility of prenatal diagnosis through sampling of fetal tissue obtained by chorionic biopsy is a reality for numerous metabolic diseases but is limited to instances where a particular disease has been identified in the family or a suspicious malformation detected in the fetus. Biochemical or molecular genetic assays of amniocytes are available for an increasing number of conditions. Yet, the most effective mode of detection is by voluntary screening of certain populations at risk. When both members of a clinically normal couple are carriers of a recessive trait or when a dominant disease afflicts just one member, or even when the mother carries a pathogenic mitochondrial DNA mutation, several reproductive options are available. Among these, testing of an early embryo after in vitro fertilization and before implantation, in vitro fertilization by a healthy donor, nuclear transfer, abortion, or, if available, early initiation of therapy of an affected newborn are all preventive interventions. All of them are variably applied depending on technological and cultural factors. Newborn screening is still an underdeveloped and underused methodology with the potential to detect many, if not most, metabolic disorders. Testing is usually performed between the first 24 and 48 hours of life and uses dry bloodspots obtained from the heel and placed onto a filter paper card that is sent to a referral laboratory.3 Examples of conditions universally screened for are phenylketonuria and congenital hypothyroidism. At the present time, over 50 diseases, including specific disorders of amino acid, organic acid, and fatty acid metabolism, can be commercially screened for by tandem mass spectroscopy alone. However, in the United States, for example, some states test for fewer than 10 disorders, whereas others test for more than 30.4 Diverse efforts are under way to make this testing uniformly regulated and available. It is also possible to diagnose a neurometabolic disease postmortem, and every effort should be made to offer an exhaustive biochemical investigation to each family in whom an unexpected neonatal or an infantile sudden death occurs.5 At a minimum, dry blood cards and skin punch biopsies can be obtained; the latter can be deferred for up to 18 hours after death and are used to establish live fibroblast cultures for use in biochemical and genetic assays. Other tissues may also be harvested under the guidance of the appropriate metabolic consultant. Photographs and a radiographic skeletal survey are important additional investigational tools.

The principles of metabolic therapy (Table 107–3) have changed little in recent years, but their mode of application is being improved continuously. In the emergency setting, the decompensation or first manifestation of a neurometabolic disease may be accompanied by poor feeding, tachypnea, and acidosis due to accumulation of organic acids. This situation is associated with intracellular dehydration and, if too rapidly corrected by administration of fluids and/or bicarbonate, may lead to cerebral edema. Thus, gradual replacement of estimated losses is mandatory. Exchange transfusion is effective for the transient removal of soluble toxic metabolites. Peritoneal dialysis is simple but not as effective as exchange transfusion or hemodialysis in the emergent clearance of organic compounds. Hemofiltration uses an extracorporeal membrane to replace a plasmatic ultrafiltrate with electrolytes and nutrients. Hemodialysis is the most effective and rapid method for the removal of small soluble compounds but requires a significant commitment of resources and is thus not routinely performed in the emergency setting. Diets that diminish the use of a deficient metabolic pathway can be administered enterally or infused parenterally. Diets containing low protein, low carbohydrate, or high glucose sometimes with extra fat supplementation, all meeting minimum caloric, protein, and essential amino acid requirements, are available for specific diseases. Cofactors and vitamins should be administered at high doses when suspecting a potential vitamin-responsive disorder and they may later be maintained at a lower dose if the clinical response is inconclusive. Parenteral enzyme infusions are used with some success in lysosomal storage diseases such as Fabry disease, Gaucher disease, mucopolysaccharidosis type I, and Pompe disease, for lack of better methods to deliver the missing enzymes to the most affected tissues. Bone marrow transplantation corrects the enzymatic deficiencies of cells of hematopoietic origin in some mucopolysaccharidoses, and in some cases, the enzyme is partially restored in the brain. Early transplantation may prevent progression of neurological disease, but its long-term benefits are obscured by residual problems such as progression of skeletal and joint disability. Maximum safety and effectiveness are realized when the disease is in the preclinical stage and an HLA-matched sibling donor is available. Hepatic and liver/kidney transplantation has been considered in a variety of disorders with mostly anecdotal, mixed success. Liver transplantation appears to benefit patients afflicted by Wilson’s disease (see Chapter 108). Gene therapy remains an elusive ideal, as difficulties relative to targeting, maintenance, and

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T A B L E 107–4. Metabolic Encephalopathies I.

Disorders of the cell membrane Transport disorders Disorders of glucose transport Glucose transporter type 1 deficiency Disorders of metal transport Menkes disease Wilson disease* Excitability disorders Neurotransmitter deficiencies Segawa disease Other disorders of amine synthesis II. Disorders of intracellular organelles Peroxysomal diseases* Disorders of peroxisome biogenesis Zellweger-spectrum diseases Rhizomelic chondrodysplasia punctata Disorders of paroxysmal enzymes X-linked adrenoleukodystrophy Refsum disease Mitochondrial diseases* Disorders of fatty acid oxidation Carnitine transporter deficiency* Carnitine palmitoyltransferase deficiencies* Acyl-CoA dehydrogenase deficiencies* Pyruvate metabolism disorders Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Respiratory chain disorders* Disorders of mitochondrial DNA maintenance and communication* Krebs cycle disorders Glycosylation disorders Defects of oligosaccharide synthesis Defects of oligosaccharide processing Lysosomal diseases* Gaucher disease Niemann-Pick diseases GM2 gangliosidoses Sulfatide lipidoses Krabbe disease Mucopolysaccharidoses Mucolipidoses Farber disease

Fabry disease Schindler disease Neuronal ceroid lipofuscinoses Disorders of vesicular transport* Disorders of filaments Alexander disease* III. Enzyme disorders Urea cycle disorders Galactosemia Phenylketonuria Nonketotic hyperglycemia Glycogen storage disorders* Lesch-Nyhan disease The porphirias Maple syrup urine disease Glutaric acidurias I and II Other organic acidurias Sulfite oxidase deficiency Canavan disease Pantothenate kinase deficiency Cofactor and vitamin disorders* Thiamin deficiency Pyridoxine dependency Cobalamine disorders Folate disorders Biotin disorders Biotinidase deficiency Lipid and lipoprotein diseases Abetalipoproteinemia Tangier disease Smith-Lemli-Opitz syndrome Wolman disease Cerebrotendinous xanthomatosis Pelizaeus-Merzbacher disease* IV. Disorders of the cell nucleus and protein synthesis Disorders of DNA repair Ataxia-telangiectasia Disorders of RNA Myotonic dystrophy* Friedreich ataxia* Disorders of protein synthesis Vanishing white matter disease*

*Indicates diseases covered in other sections of the text.

expression of the corrected gene construct are being solved. Approaches that are under active investigation include pharmacological stimulation of residual alleles or unrelated genes using histone deacetylation inhibitors and loosening of translational fidelity by aminoglycoside antibiotic derivatives applied to mutations that result in the generation of premature DNA termination codons.

CLASSIFICATION OF THE METABOLIC ENCEPHALOPATHIES The metabolic disorders of the nervous system can be classified according to several criteria such as age at onset (birth, infancy, childhood, adolescence, and adulthood), size of the predominant abnormal metabolite (large polypeptides or carbohydrates or small intermediary metabolism compounds), mechanism of inheritance (mendelian or mitochondrial, including the special varieties of imprinted, anticipated, polygenetic, and intergenomic signaling diseases), and loss or gain of protein function

or, as preferred here, from a cellular perspective (Table 107–4). Such a classification, based on cellular structure, reflects the increased understanding of disease as a perturbation of cellular function, as well as the improved comprehension of the relationships that exist between individual cellular functions and structures. Thus, just as the cell is the reference framework in which genome, proteome, molecular function, regulation, and phenotype converge constituting the fundamental living entity, diseases and their symptoms and treatments are better understood at the level of complexity provided by a cellular point of view. Disorders of cell membranes primarily impact cell communication and the exchange of substances with the environment by disrupting membrane proteins or their ligands. Transport disorders, caused by primary deficiency of proteins responsible for selective permeability, exert particularly widespread cellular abnormalities derived from secondary intracellular substrate or cofactor deficiency. Disorders that cause abnormal neurotransmission include, apart from specific membrane receptor diseases, neurotransmitter deficiencies that render

chapter 107 encephalopathies cell membranes inexcitable or abnormally modulated. Disorders of organelles predominantly include abnormalities in organelle production, the function of their membranes or their contents, or their abnormal movement, leading to their accumulation or malformation and to the buildup of nonmetabolized compounds or, in the case of mitochondrial diseases, to the deficit of energy production. Enzymatic disorders are due to mutation of soluble enzymes or to cofactor deficiencies caused by inadequate absorption, processing or binding affinity, all resulting in abnormal catalysis. The cellular abnormalities brought about by soluble enzyme deficiencies tend to be morphologically modest but functionally widespread, as the consequence of cellular substrate diffusion and the release (or deprivation) of circulating plasmatic compounds, including lipoproteins. Disorders of nuclear function (DNA and RNA synthesis, processing, and maintenance) and of the cellular protein synthesis machinery are associated with broad cellular abnormalities by virtue of the central mission for which the cell nucleus is responsible. In general, membrane disorders tend to be associated with milder disease phenotypes, organelle disorders with slowly accumulating abnormalities, enzyme disorders with marked biochemical abnormalities detectable in tissues and fluids, and nuclear disorders with a bewildering array of cellular alterations and phenotypes, providing a sort of apparent, gross correlation between cellular function and disease severity. Nevertheless, disease is not a good indicator when cataloging the importance of the various cellular functions: the more central a process or reaction, the less probable it is that its disease is compatible with life. Thus, human diseases are most likely to affect the least important functions: those that exhibit redundancy, can be, at least, partially compensated for and, ultimately, allow for the survival of the organism. When mutation affects essential, highly conserved genes, the minimal form of genetic alteration, a polymorphism, may serve to drive evolution but not disease. Any higher-impact mutations, such as those causing sequence variation in an important protein area, are probably not tolerable and incompatible with life.

Glucose Transporter Type 1 Deficiency Mutations in the GLUT1 gene, responsible for glucose transport through the blood-brain barrier and then through a series of further barriers provided by the membranes of the astrocytes in the cerebral neuropil, cause a variety of manifestations dominated by refractory infantile epilepsy and spastic ataxia in its more typical and better defined, classic form.6 The disease can be inherited as an autosomal dominant trait from oligosymptomatic adults, who sometimes experience only dyslexia or infrequent seizures, and can lead to particularly severe neurological disability when GLUT1 mutations (located in chromosome 1) compound in both alleles, a rare occurrence. Newly recognized phenotypes such as isolated ataxia or dystonia, both responsive to carbohydrate load or to ketogenic diet, are receiving increasing attention, as the full phenotypical spectrum of the disease remains unknown. The hallmark feature and main diagnostic parameter associated with the disease is hypoglychorrhachia (cerebrospinal fluid glucose usually below 40 mg/dL or 2.2 mM). Supportive evidence comes from a characteristic positron emission tomography pattern of globally diminished uptake of fluorodeoxyglucose with thalamocortical depression

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accentuating a relatively increased basal ganglia uptake. The disease may be further confirmed by assaying GLUT1-mediated glucose uptake directly in patient erythrocytes, followed by sequence analysis of GLUT1. New mutations continue to be identified at a constant pace and some mutational hotspots have been discovered; yet, genotype/phenotype correlations remain elusive.7 Treatment generally involves discontinuation of anticonvulsants, which are often either ineffective or detrimental, and supplementation with carbohydrate-rich compounds, lipoic acid (known to enhance the expression of GLUT1 in vitro) or, alternatively, the strict administration of a ketogenic diet to provide alternative substrates. It appears that the neurological abnormalities set in very early in infancy and, despite the responsiveness of epilepsy to the ketogenic diet, significant cognitive and motor disabilities persist as an invariant disabling feature.8

Menkes Disease Mutation of the copper ATPase ATP7A, located in the transGolgi network and encoded by the X chromosome, causes the progressive copper deficiency disorder Menkes disease.9 Also known as kinky hair disease, Menkes disease is associated with copper deficiency, in contrast with Wilson disease, which is characterized by copper excess (see Chapter 108). ATP7A allows cellular copper to cross intracellular membranes and to be translocated from the trans-Golgi network to the plasma membrane in the presence of extracellular copper. The fundamental abnormality in this disease is thus the maldistribution of copper, which is unavailable as a cofactor of several enzymes including mitochondrial cytochrome c oxidase (see Chapter 88), lysyl oxidase, superoxide dismutase, dopamine betahydroxylase, and tyrosinase. Thus, the main features of the disease include mitochondrial respiratory chain dysfunction (complex IV deficiency); deficiency of collagen cross-links resulting in hair (pili torti and trichorrhexis nodosa) and vascular abnormalities (elongated cerebral vessels and subdural effusions); neuronal degeneration (markedly affecting Purkinje cells); and deficient melanin production.10 Affected neonates present with hypothermia, feeding difficulties, and seizures. The infants are pale and exhibit kinky hair. Serum copper concentration is low, and the ratio of urinary homovanillic acid/vanillylmandelic acid is elevated.11 A variety of minimally symptomatic phenotypes, including ataxia or mental retardation, have been recognized. Intramuscular or subcutaneous administration of copper-histidine affords protection against intellectual deterioration but is less effective in preventing other somatic complications.12

Segawa Disease (Dopa-Responsive Dystonia) Autosomal dominant mutations of the guanosine triphosphate cyclohydrolase I (GCH-I) gene, located in chromosome 14, cause the treatable dystonic syndrome known as Segawa disease. The fundamental biochemical abnormality is a decrease of tetrahydrobiopterin (BH4) associated with reduced tyrosine hydroxylase activity, leading to deficient dopaminergic transmission and extrapyramidal dysfunction.13 Tyrosine hydroxylase synaptic activity fluctuates throughout the day and decreases after the third decade of life: this probably accounts for the marked diurnal progression of symptoms and for the

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clinical stabilization observed after the fourth decade. Initial symptoms are often gait difficulties due to foot equinovarus posturing. Postural dystonia and tremor and small stature dominate the clinical symptomatology and can be prevented by administration of levodopa. Marked intrafamilial symptom severity variability exists, and nondystonic family members may suffer from major depressive disorder or obsessive-compulsive disorder responsive to enhancers of serotonergic neurotransmission and to levodopa administration. Sleep disorders, including difficulty falling asleep, excessive sleepiness, and frequent disturbing nightmares, are also features of this patient population.14 Autosomal recessive Segawa syndrome is due to mutations in the TH gene and causes early-onset parkinsonism responsive to levodopa, a more severe phenotype.15 Measurement of both total biopterin (most of which exists as BH4) and neopterin (the byproduct of the GTPCH1 reaction) in cerebrospinal fluid reveals that both compounds are decreased, a useful diagnostic clue to GCH-I deficiency.16 Decreased activity of GCH-I in stimulated mononuclear blood cells and fibroblasts further supports the diagnosis. Oral phenylalanine load can reveal a subclinical defect in phenylalanine metabolism due to liver BH4 deficiency in patients with Segawa disease.

Pyruvate Dehydrogenase Deficiency Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of lactic acidosis. PDH is a large mitochondrial matrix enzyme complex that catalyzes the oxidative decarboxylation of pyruvate to form acetyl-coenzyme A (CoA), nicotinamide adenine dinucleotide (NADH), and CO2. Symptoms vary considerably in patients with PDH complex deficiencies, and almost equal numbers of affected males and females have been identified, despite the location of the PDH E1 alpha subunit gene (PDHA1) in the X chromosome, owing to selective female X-inactivation.17 Thus, the mechanisms for the clinical variation observed in E1 alpha deficiency patients and its resemblance to a recessive disease are mutation severity in males and the pattern of X-inactivation in females.18 Several dozen PDHA1 mutations have been identified. Patients harboring mutations in the E1 beta subunit, the E2 dihydrolipoyl transacetylase segment of the complex, the E3-binding protein, the lipoyl-containing protein X, and the PDH phosphatase have been reported.19 Neurodevelopmental abnormalities, microcephaly, epilepsy, and agenesis of the corpus callosum are characteristic features.20 Infants may exhibit facial features of fetal alcoholic syndrome, and older children can present with intermittent weakness or alternating hemiplegia. Diagnosis of these disorders requires measurements of lactate and pyruvate in plasma and cerebrospinal fluid, analyses of amino acids in plasma and organic acids in urine, as well as neuroradiological investigations, including magnetic resonance spectroscopy to detect lactate. Enzymatic analysis of fibroblast PDH activity can be performed and molecular diagnosis is available. A ketogenical diet is recommended together with thiamine supplementation, which can afford a substantial response in responsive cases.21

Pyruvate Carboxylase Deficiency Pyruvate carboxylase is an autosomal recessive disease due to mutation of the PC gene, located in chromosome 11. Pyruvate carboxylase catalizes the conversion of pyruvate to oxaloacetate

in the presence of abundant acetyl-CoA, replenishing Krebs cycle intermediates in the mitochondrial matrix. The enzyme is bound to biotin. PC is involved in gluconeogenesis, lipogenesis and neurotransmitter synthesis.22 PC deficiency can manifest with three degrees of phenotypical severity: an infantile form (A) with infantile moderate lactic acidosis, mental and motor deficiencies, hypotonia, pyramidal tract dysfunction, ataxia, and seizures leading to death in infancy. Episodes of vomiting, acidosis and tachypnea can be triggered by metabolic inbalance or infection. A severe neonatal form (B) manifests with severe lactic acidosis, hypoglycemia, hepatomegaly, depressed consciousness, and severely abnormal development. Abnormal limb and ocular movements are common findings. Brain magnetic resonance imaging reveals cystic periventricular leukomalacia. Hyperammonemia and depletion of intracellular aspartate and oxaloacetate are profound. Early death is common. A rare benign form (C) causes episodic acidosis and moderate mental impairment compatible with survival and near normal neurological performance. A variety of mutations have been identified, with mosaicism probably accounting for the less severe phenotypes.23 Enzymatic analysis of fibroblast PC activity can be performed, but molecular diagnosis can be complicated by mosaicism. Dietary modification with triheptanoin (a triglyceride) supplementation has been attempted as a means to increase acetyl-CoA and anaplerotic propionylCoA.24 Liver transplantation has also been performed.25

Glycosylation Disorders Congenital disorders of glycosylation (CDG) are a group of autosomal recessive diseases defined by abnormal glycosylation of N-linked oligosaccharides.26 Well over a dozen enzymes involved in the N-linked oligosaccharide synthetic pathway can be mutated, causing a variety of manifestations. In some cases, the phenotypes are incompletely known, as only a small number of patients have been studied whereas, in others, novel enzyme deficiencies are periodically reported.27 Thus, genotype: phenotype correlations are still preliminary. CDG-Ia, the most common type of CDG, is due to phosphomannomutase 2 deficiency. Salient manifestations include inverted nipples, abnormal subcutaneous fat distribution and cerebellar hypoplasia. The clinical course has been divided into an infantile multisystem stage in which all somatic organs can be affected, a lateinfantile and childhood ataxia/mental retardation stage, during which neuropathy, retinitis pigmentosa, and stroke-like episodes can manifest, and an adult stable disability stage. CDGIb is caused by mannose phosphate isomerase deficiency. Salient features include cyclical vomiting, hypoglycemia, hepatic fibrosis, and protein-losing enteropathy, occasionally associated with coagulation disturbances without neurological involvement. CDG-Ic is due to deficiency of man(9)GlcNAc(2)PP-dolichyl-alpha-1,3-glucosyltransferase and is associated with hypotonia, intellectual deficits, ataxia, strabismus, and epilepsy.28 The diagnosis of all types of CDG can be reached by analyzing serum transferrin glycoforms by isoelectric focusing to determine the number of sialylated N-linked oligosaccharide residues linked to the protein.29 In select cases, molecular genetic analysis is feasible, including prenatal diagnosis. CDGIb is the only treatable type of CDG: mannose supplementation normalizes hypoproteinemia and coagulation defects and reverses both protein-losing enteropathy and hypoglycemia.

chapter 107 encephalopathies Organic Acidurias The organic acidemias (or organic acidurias) are disorders characterized by the urinary excretion of nonamino organic acids, which result from the abnormal amino acid catabolism of branched chain amino acids or lysine. These disorders include, but are not limited to, maple syrup urine disease (MSUD), propionic acidemia, methylmalonic acidemia, isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, 3hydroxy-3-methylglutaryl-CoA lyase deficiency, ketothiolase deficiency, glutaric aciduria type I, and succinic semialdehyde dehydrogenase deficiency, among other less well understood types.30,31 Specific enzymatic defects are responsible for each disorder, but several acidurias are caused by more than one enzyme deficiency. They are all inherited in an autosomal recessive fashion and, not uncommonly, the first affected family member remains undiagnosed until a sibling experiences the same clinical symptoms. The most severe and common presentation is a toxic neonatal encephalopathy that necessitates prompt recognition and treatment. Newborns present with vomiting, poor feeding, and progressive neurological symptoms such as seizures, abnormal tone, and depressed consciousness, often leading to coma. Cerebral edema, leukoencephalopathy, perisylvian (opercular) hypotrophy, or basal ganglia necrosis are features frequently detectable in neuroimaging studies and may provide important diagnostic clues. Unrecognized children and adolescents can exhibit episodic ataxia, intellectual deficits, Reye syndrome, or psychiatric disturbances. Laboratory abnormalities include acidosis, ketosis, hyperammonemia, abnormal serum hepatic enzyme levels, hypoglycemia, and neutropenia. Secondary carnitine deficiency due to excessive excretion of acylcarnitine is common. The diagnosis is made by urine organic acid analysis, a method that is particularly sensitive when it is performed during clinical decompensation, as the pattern of urinary excretion may be normal during symptomfree intervening periods. Analysis of plasma amino acids may also help to distinguish among specific disorders, and direct enzyme activity measurements in lymphocytes or fibroblasts confirm the diagnosis. DNA sequence analysis is available for the most common disorders. Prenatal diagnosis relies on the analysis of amniotic fluid metabolites and it is simplified by DNA analysis in the context of a family in which a child has been previously diagnosed. Treatment relies on the replacement of enzyme substrates and precursors while meeting essential amino acid and caloric needs. Several special infant formulas are commercially available. Thiamine is used to treat thiamine-responsive MSUD and hydroxocobalamin to treat methylmalonic acidemia. Carnitine supplementation is used to correct secondary deficiency. In disorders of propionic acid metabolism, the periodic administration of antibiotics can reduce the production of propionate by intestinal flora.32 Hepatic or combined liver-renal transplantation has been attempted with moderate success in some of these disorders.

Urea Cycle Disorders The urea cycle disorders result from defects in the metabolism of nitrogen, which is predominantly produced during the breakdown of proteins and other nitrogen-containing molecules. The urea cycle is the only source of endogenous arginine and it is the main clearance mechanism for waste nitrogen. Hyperammonemia is the defining feature of these disorders, that include

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deficiencies in the urea cycle enzymes carbamyl phosphate synthase I, ornithine transcarbamylase, argininosuccinic acid synthetase, argininosuccinic acid lyase and arginase, and the cofactor producer N-acetyl glutamate synthetase. With the exception of X-linked ornithine transcarboxylase deficiency, urea cycle disorders are inherited in an autosomal recessive fashion.33 These disorders manifest in the neonatal period with cerebral edema, lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, abnormal tone, respiratory alkalosis, and coma. In milder (or partial) urea cycle defects, ammonia accumulation may be triggered by illness, protein load, fasting, valproate administration, or stress at any later stage of life, resulting in mild elevations of plasma ammonia accompanying cyclical vomiting, lethargy, sleep disturbances, delusions, hallucinations, and psychosis. Slowly progressive spastic paraparesis and growth retardation can be manifestations of arginase deficiency.34 A subset of carrier females manifest ornithine transcarboxylase deficiency owing to skewed X-inactivation, a state that may also lead to hyperammonemic crises during pregnancy or in the postpartum. A specific pattern of plasma amino acid abnormalities helps to arrive at the specific diagnosis. For example, glutamine, alanine, and asparagine are commonly elevated, whereas arginine may be reduced in all urea cycle disorders except in arginase deficiency, in which it is markedly elevated. Plasmatic citrulline and urinary orotic acid excretion also assist in dissecting the affected enzymatic pathway.35 Enzyme activity assays, usually performed in liver tissue, are reserved for confirmatory diagnosis, whereas DNA sequencing analysis is available for most of these disorders. The treatment during a crisis involves dialysis or other forms of plasma filtration aimed at reducing plasma ammonia concentration. Intravenous administration of arginine chloride and of the nitrogen scavengers sodium phenylacetate and sodium benzoate blocks the production of ammonia. Long-term administration of oral sodium phenylbutyrate and arginine increase the excretion of nitrogen by providing an alternative pathway.36 Nevertheless, dietary protein restriction constitutes the mainstay of maintenance therapy.

Galactosemia Galactosemia is caused by deficiency of the enzyme galactosephosphate uridyltransferase (GALT), which catalyzes the production of glucose-1-phosphate and uridyldiphosphate (UDP)-galactose from galactose-1-phosphate and UPD-glucose. The disorder is inherited in an autosomal recessive fashion and is always attributable to mutations in the GALT gene in chromosome 9. Within days of starting to feed milk or lactosecontaining formulas, affected infants experience feeding difficulties, hypoglycemia, hepatic dysfunction, bleeding diathesis, jaundice, and hyperammonemia. When untreated, sepsis and death may occur. Those infants who survive but continue to ingest galactose develop intellectual deficits and cortical and cerebellar tract signs. Despite early initiation of dietary therapy, the long-term outcome can include cataracts, poor growth, language dysfunction, extrapyramidal signs and ataxia, and ovarian failure.37 The diagnosis is established by measuring erythrocyte GALT activity and by isoelectric focusing of the enzyme. All newborn screening programs typically include galactosemia and, thus, the disease should be readily identified before becoming symptomatic.38 Biochemical and molecular genetic tests are

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widely used for heterozygote detection and prenatal diagnosis.39 Assay of erythrocyte galactose-1-phosphate concentration, measurement of urinary galactitol, and estimation of total body oxidation of 13C-galactose to 13CO2 are used to quantify residual enzyme function and to monitor the response to dietary adjustments over time. The mainstay of therapy is lactose restriction, which rapidly reverses liver disease in newborns. On diagnosis, infants are immediately offered a lactose-free, soy-based formula that contains sucrose, fructose, and other nongalactose complex carbohydrates.

Phenylketonuria Classic phenylketonuria (PKU) is caused by near-complete deficiency of phenylalanine hydroxylase activity leading to hyperphenylalaninemia. The phenylalanine hydroxylase gene, PAH, is located in chromosome 12 and mutations in PAH are inherited in an autosomal recessive fashion. PKU was the first metabolic cause of mental retardation to be identified and is routinely screened for in all newborns.40,41 It is also an example of a disorder fully treatable by dietary restriction. A small proportion of infants with hyperphenylalaninemia have an underlying impaired synthesis or recycling of tetrahydrobiopterin (BH4) in the presence of a normal PAH gene, a condition that is independently treatable.42 Classic untreated PKU leads to microcephaly, epilepsy, and severe intellectual and behavioral disabilities. The excretion of excessive phenylalanine and its metabolites can confer a musty odor to the skin, and the associated inhibition of tyrosinase causes decreased skin and hair pigmentation. Patients also exhibit decreased myelin formation and deficient production of dopamine, norepinephrine, and serotonin. Motor disability can be prominent later in life. Untreated maternal PKU can produce congenital heart disease, intrauterine and postnatal growth retardation, microcephaly, and mental retardation in the offspring. The diagnosis is based on plasma phenylalanine measurement and DNA sequence analysis. Prenatal diagnosis using amniocytes is available. PKU treatment consists of dietary restriction of phenylalanine.43 A fraction of patients with primary phenylalanine hydroxylase deficiency respond to the 6R-BH4 isomer, which may act by enhancing residual enzyme function.44

Lesch-Nyhan Disease Among the inherited disorders of purine and pyrimidine metabolism, Lesch-Nyhan disease, caused by hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is the most common. The enzyme, encoded by the HPRT1 gene in the X chromosome, catalyzes the conversion of hypoxanthine to inosinic acid (IMP) and of guanine to guanylic acid (GMP) in the presence of phosphoribosylpyrophosphate, recycling purines derived from DNA and RNA.45 HPRT1 mutations diminish enzyme function or abundance and lead to uric acid overproduction. In addition to having hyperuricemia, hyperuricuria, and renal stones, male patients manifest abnormal neurological development during infancy. Hypotonia and failure to accomplish early motor milestones such as sitting, crawling, or walking can be prominent features. Later in childhood, other symptoms emerge, including abnormal involuntary movements such as dystonia, choreoathetosis, opisthotonus, and ballismus. Pyramidal tract dysfunction includes

spasticity, hyperreflexia, and Babinski signs. Profound intellectual deficits and self-injurious behavior can be prominent as are other motor compulsions. Females are carriers of HPRT1 mutations and can manifest increased uric acid excretion. They may show symptoms of the disease when nonrandom Xchromosome inactivation or skewed inactivation of the normal HPRT1 allele occur.46 A urinary urate-to-creatinine ratio above 2 is characteristic of the disease, as is an excessive urinary excretion of urate. Defective HPRT enzyme activity can be measured in blood cells, fibroblasts, or lymphoblasts. DNA sequencing detects mutations in virtually all cases. Treatment aims to restrain uric acid overproduction with allopurinol, which inhibits the conversion of hypoxanthine and xanthine to uric acid mediated by xanthine oxidase. Bone marrow transplantation seem to be of only limited value in correcting hyperuricemia and improving neurobehavioral symptoms.47

Pantothenate Kinase Deficiency Also known as pantothenate kinase-associated neurodegeneration (PKAN) and formerly called Hallervorden-Spatz disease, pantothenate kinase deficiency causes neuronal degeneration associated with cerebral iron accumulation. This disorder is caused by the absence of pantothenate kinase 2, which is encoded by the PANK2 gene located in chromosome 20, and participates in CoA biosynthesis, catalyzing the phosphorylation of pantothenate (vitamin B5), N-pantothenoyl-cysteine, and pantetheine.48 Accumulation of N-pantothenoyl-cysteine and pantetheine may induce cell toxicity directly or via free radical damage by chelating iron. Deficient pantothenate kinase 2 may also be predicted to result in CoA depletion and defective membrane biosynthesis in vulnerable cells such as rod photoreceptors. Accumulation of iron is specific to the globus pallidus and substantia nigra. Axonal spheroids, believed to represent swollen axons secondary to defective axonal transport, appear in the pallidonigral system, in the subthalamic nucleus, and in peripheral nerves.49 Patients first present in early childhood with dystonia that interferes with ambulation, associated with dysarthria, rigidity, pigmentary retinopathy and pyramidal tract dysfunction with spasticity and Babinski signs. Intellectual development may be variably affected. Psychiatric symptoms, including personality changes with impulsivity, depression, and emotional lability, are common. A specific brain magnetic resonance imaging abnormality, the eye-of-the-tiger sign, is characteristic of the disease, with rare exceptions.50 Hypoprebetalipoproteinemia and acanthocytosis may be additional manifestations of PANK2 mutations.51 The diagnosis relies on clinical and magnetic resonance imaging features. When both are consistent with PKAN, there is a high likelihood of identifying a pathogenic mutation in PANK2 by DNA sequencing, although large chromosomal deletions affecting one allele are likely to remain undetected by this method. Treatment strategies, including pantothenate (or phosphopantothenate) administration, have been advanced but not tested.

Smith-Lemli-Opitz Syndrome Smith-Lemli-Opitz syndrome is a malformative autosomal recessive disorder caused by abnormal cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol reductase, which, in turn, is due to mutations of the DHCR7

chapter 107 encephalopathies gene, located in chromosome 11. Decreased activity of 7dehydrocholesterol reductase results in failure to convert 7-DHC to cholesterol, elevated serum concentration of 7dehydrocholesterol or elevated 7-dehydrocholesterol/cholesterol ratio. Patients show hypotonia and prenatal and postnatal growth retardation, microcephaly with intellectual deficiency and multiple malformations, including a characteristic facies (temporal narrowing, downslanting palpebral fissures, epicanthal folds, blepharoptosis, anteverted nares, cleft palate, and micrognathia), cardiac defects, underdeveloped external genitalia (hypospadias, bilateral cryptorchidism and undermasculinization resulting in female external genitalia), postaxial polydactyly, and two- or three-toe syndactyly. Holoprosencephaly can be an associated manifestation.52,53 Tandem mass spectrometry of dried blood card samples readily identifies patients and may be used for newborn screening. Direct analysis of the DHCR7 gene by DNA sequencing confirms the presence of a mutation in most cases.54 Indicative prenatal clues on ultrasound examination include cardiac defects, cleft palate, genital abnormalities, growth retardation, or apparent female phenotype with a known 46,XY karyotype.55,56 The combination of low concentrations of unconjugated estriol, HCG, and α-fetoprotein on routine maternal serum testing at 16 to 18 weeks’ gestation is also suggestive of maternal carrier status and thus places the fetus at risk for Smith-Lemli-Opitz syndrome. Measurement of 7-dehydrocholesterol levels in amniotic fluid is available for prenatal diagnosis. Treatment with cholesterol supplementation and bile acids improves growth. The addition of the HMG-CoA reductase inhibitor simvastatin helps reduce serum 7-dehydrocholesterol.

Ataxia-Teleangiectasia Ataxia-teleangiectasia (A-T) is due to mutation of the ATM (ataxia-telangiectasia mutated) gene located in chromosome 11 and is inherited in an autosomal recessive fashion. The ATM protein is a serine-protein kinase that is activated by doublestranded DNA breaks and coordinates cell cycle checkpoints prior to repair.57 Hundreds of unique (private) mutations have been identified, which diminish ATM RNA abundance and impart a dominant negative potential to ATM containing missense mutations. The manifestations are dominated by progressive cerebellar ataxia beginning between 1 and 4 years of age (A-T is the most common cause of progressive cerebellar ataxia in childhood), oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Children present with signs of cerebellar dysfunction shortly after learning to walk, including slurred speech and oculomotor apraxia. During early childhood, these deficits stabilize or improve for several years, until cerebellar degeneration occurs. Loss of Purkinje cells and depletion of granule cells are prominent, as is the enlargement of all cellular nuclei. Patients are typically confined to a wheelchair before the second decade of life, when tremor, chorea, myoclonus, and neuropathy with absent reflexes become apparent. Intelligence is generally preserved. The risk of malignancy is 38% and immune deficiency is common. Immunoglobulin subclass deficiency and thymic hypoplasia are also common, but the opportunistic infections typical of other immune defi-

1443

ciencies are rare.58 The diagnosis of A-T relies on several tests: (1) elevation of serum α-fetoprotein (of predominantly hepatic origin), (2) immunoassay of ATM abundance, (3) radiosensitivity assay of colony-forming lymphoblastoid cells obtained from blood, (4) measurement of ATM kinase activity, and (5) ATM DNA sequence analysis.59 Iron chelators and aminoglycoside antibiotics, which reduce translational fidelity in cells harboring missense ATM mutations, are therapies under investigation.60

Friedreich Ataxia Friedreich ataxia is characterized by slowly progressive ataxia with onset before the third decade of life, associated with depressed tendon reflexes, dysarthria, Babinski signs, and loss of propioception and vibration senses. Alternative manifestations include later onset or preserved tendon reflexes. Optic atrophy, cardiomyopathy and diabetes mellitus or glucose intolerance are associated manifestations. Loss of ambulation and severe disability occur before the third decade.61,62 Most patients harbor mutations in the FRDA gene, usually in the form of a GAA triplet repeat expansion in intron 1, although compound heterozygosity with other FRDA mutations may also occur. The disease is inherited in an autosomal recessive fashion and is caused by the expansion of the triplet repeat normally present in chromosome 9. Normal FRDA alleles contain 5 to 33 GAA repeats, whereas premutation alleles (mutable normal alleles) contain 34 to 65 repeats: these may expand during parental transmission, resulting in disease-causing alleles that span 66 to 1700 repeats. FRDA encodes frataxin, a participant in ironsulfur cluster biogenesis, and therefore in the synthesis of enzymes such as respiratory chain complexes I to III and aconitases.63 Frataxin also regulates mitochondrial iron, perhaps by mediating mitochondrial iron efflux, leading to abnormal iron deposition in Friedreich ataxia. Patients have low blood levels of antioxidant enzymes, exhibiting a redox shift from the free form of glutathione to the protein-bound form. They also excrete large amounts of urinary 8-hydroxy-2′-deoxyguanosine and have elevated serum malondialdehyde, which are indirect indicators of oxidative DNA damage and lipid peroxidation, respectively.64,65 Myocardial energy production is also defective and associates with excessive ventricular wall thickness, a phenomenon that can be ameliorated with the administration of the antioxidant idebenone.66 The diagnosis relies on the identification of excessive repeats by polymerase chain reaction or Southern blot. DNA sequencing is reserved for other compounded FRDA mutations.

Fulminant Metabolic Encephalopathies Several metabolic encephalopathies typically manifest abruptly after birth, as the newborn relies on his or her own immature metabolism to replace placental function. Others manifest later but unexpectedly or can be provoked by a small metabolic disturbance imposed on an apparently normal neurological substrate (Table 107–5). In all cases, a systematic examination and a basic metabolic screening must be urgently undertaken. Empirical intervention should commence while the results of more laborious assays are pending. The combination of some symptoms and the results of initial exploratory tests allows for the reasoned initiation of urgent therapy. In the newborn, the

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T A B L E 107–5. Acute Metabolic Encephalopathy Syndromes Sudden infant death Progressive neonatal encephalopathy Neonatal convulsions Leigh syndrome Reye syndrome Intermittent ataxia Alpers syndrome

predominant manifestation of neurometabolic diseases includes progressive depression of consciousness, feeding difficulties, vomiting, and intractable seizures. An enlarged fontanel indicates the development of cerebral edema and signifies the need for rapid plasma filtration to remove a toxic metabolite. Imaging should be performed, as specific cerebral structural abnormalities can be indicative of certain disorders, such as necrosis of the basal ganglia in organic acidurias, leukoencephalopathy in MSUD, elongated cerebral vessels in Menkes disease, and perisylvian atrophy in glutaric aciduria type I. Multiple cerebral necrotizing lesions (poliodystrophy) with hepatopathy and lactic acidosis are typical of Alpers syndrome. In some cases, cofactor or vitamin supplementation is initiated in the presence of a specific clinical syndrome. For example, neonatal convulsions can be due to pyridoxine dependency, folinic acid responsive encephalopathy, biotinidase deficiency, or molybdenum cofactor deficiency, the first three of which are treatable by supplementation. Original newborn screening results should be retrieved and verified for all neonates and repeated during metabolic crises. Commercially available comprehensive screening of dried blood cards by tandem mass spectroscopy constitutes a suitable method for the diagnosis of patients of all ages in whom a metabolic disease is suspected. Later in childhood, fulminant metabolic encephalopathies manifest with better defined manifestations. Leigh syndrome causes acute neurological disability due to striatal necrosis and rhombencephalopathy easily detectable by magnetic resonance imaging and often associated with more extensive cerebral abnormalities. Reye syndrome combines cerebral edema with acute hepatopathy that can be induced by drugs or represent the manifestation of an underlying fatty acid oxidation defect. Intermittent ataxia can also be the manifestation of a disorder of energy metabolism or of organic aciduria. In all cases, bedside measurement of blood glucose and urine ketones should be immediately peformed. Blood count, serum electrolytes, blood gases, lactate, pyruvate, ammonia, serum amino acids, blood carnitine and acylcarnitines, urine organic acids, and urinary ketone bodies should also be assayed and neuroimaging (magnetic resonance imaging and spectroscopy) performed. Cerebrospinal fluid analysis should always include determination of glucose, lactate, pyruvate, and amino acids.

ACKNOWLEDGMENTS I thank Dr. S. DiMauro for numerous comments. I also acknowledge the support of my colleagues at the Colleen Giblin Research Laboratories for Pediatric Neurology, Columbia University, and The Child Brain Foundation during the writing of this chapter.

K E Y

P O I N T S

●

Neurometabolic diseases include a variety of genetically determined conditions that affect all organs and can be detected by biochemical assays of select, accessible tissues.

●

Metabolic diseases manifest when specific gene expression programs or functions are activated or when environmental (nutritional) circumstances uncover an underlying biochemical maladaptation to otherwise normal metabolic fluctuations.

●

The manifestations of metabolic diseases need not be constant or progressive. Many of these disorders manifest only episodically or impose invariable, static abnormalities on neurological function.

●

Phenocopies, imcomplete penetrance, polymorphisms, mosaicism, and genetic heteroplasmy are widespread occurrences that complicate the clinical and laboratory studies of metabolic diseases.

●

A variety of manifestations and biochemical assays guide the precise diagnosis of most metabolic diseases during life and, in some cases, prenatally or postmortem, anticipating the clinical course and reducing the possibility of an affected relative being born unexpectedly.

●

Except for some notable exceptions, treatment remains largely unsatisfactory, owing to the inextricable compartmentalization of metabolism. Therefore, research efforts concentrate on corrective genetic approaches applicable after early detection by newborn screening or even before fertilization.

Suggested Reading Brady RO, Schiffmann R: Enzyme-replacement therapy for metabolic storage disorders. Lancet Neurol 2004; 3:752-756. Gupta R, Appleton RE: Cerebral palsy: not always what it seems. Arch Dis Child 2001; 85:356-360. Kooijman SA: Quantitative aspects of metabolic organization: a discussion of concepts. Philos Trans R Soc Lond B Biol Sci 2001; 356:331-349. Kirkham FJ: Non-traumatic coma in children. Arch Dis Child 2001; 85:303-312. van Karnebeek CD, Jansweijer MC, Leenders AG, et al: Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005; 13:6-25.

References 1. Hulbert AJ, Else PL: Membranes and the setting of energy demand. J Exp Biol 2005; 208:1593-1599. 2. Hofmeyr JH, Cornish-Bowden A: Quantitative assessment of regulation in metabolic systems. Eur J Biochem 1991; 200:223-236. 3. Chace DH, Kalas TA: A biochemical perspective on the use of tandem mass spectrometry for newborn screening and clinical testing. Clin Biochem 2005; 38:296-309. 4. Therrell BL, Panny SR, Davidson A, et al: U.S. newborn screening system guidelines: statement of the Council of Regional

chapter 107 encephalopathies

5. 6.

7. 8. 9.

10. 11. 12.

13. 14.

15. 16. 17.

18. 19.

20. 21. 22. 23. 24. 25.

Networks for Genetic Services (CORN). Screening 1992; 1:135147. Christodoulou J, Wilcken B: Perimortem laboratory investigation of genetic metabolic disorders. Semin Neonatol 2004; 9:275-280. De Vivo DC, Trifiletti RR, Jacobson RI, et al: Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991; 325:703-709. Wang D, Pascual JM, Yang H, et al: Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005; 57:111-118. Pascual JM, Wang D, Lecumberri B, et al: GLUT1 deficiency and other glucose transporter diseases. Eur J Endocrinol 2004; 150:627-633. Menkes JH, Alter M, Steigleder GK, et al: A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 1962; 29:764-779. Menkes JH: Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol 1999; 3:147-158. Matsuo M, Tasaki R, Kodama H, et al: Screening for Menkes disease using the urine HVA/VMA ratio. J Inherit Metab Dis 2005; 28:89-93. Christodoulou J, Danks DM, Sarkar B, et al: Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients. Am J Med Genet 1998; 76:154-164. Segawa M, Nomura Y, Nishiyama N: Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 2003; 54:S32-S45. Van Hove JL, Steyaert J, Matthijs G, et al: Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency. J Neurol Neurosurg Psychiatry 2006; 77:18-23. Ichinose H, Suzuki T, Inagaki H, et al: Molecular genetics of dopa-responsive dystonia. Biol Chem 1999; 380:13551364. Hyland K: The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 2003; 54: S13-S17. Lissens W, De Meirleir L, Seneca S, et al: Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 2000; 15:209-219. Nissenkorn A, Michelson M, Ben-Zeev B, et al: Inborn errors of metabolism: a cause of abnormal brain development. Neurology 2001; 56:1265-1272. Maj MC, MacKay N, Levandovskiy V, et al: Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. J Clin Endocrinol Metab 2005; 90:41014107. De Vivo DC: Complexities of the pyruvate dehydrogenase complex. Neurology 1998; 5:1247-1249. Duran M, Wadman SK: Thiamine-responsive inborn errors of metabolism. J Inherit Metab Dis 1985; 8:70-75. Robinson BH, MacKay N, Chun K, et al: Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex. J Inherit Metab Dis 1996; 19:452-462. Wang D, Pascual JM, Yang H, et al: The molecular basis of pyruvate carboxylase deficiency. In press. Mochel F, DeLonlay P, Touati G, et al: Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab 2005; 84:305-312. Nyhan WL, Khanna A, Barshop BA, et al: Pyruvate carboxylase deficiency: insights from liver transplantation. Mol Genet Metab 2002; 77:143-149.

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26. Freeze HH, Aebi M: Altered glycan structures: the molecular basis of congenital disorders of glycosylation. Curr Opin Struct Biol 2005; 15:490-498. 27. Jaeken J, Carchon H: Congenital disorders of glycosylation: a booming chapter of pediatrics. Curr Opin Pediatr 2004; 16:434-439. 28. Marquardt T, Denecke J: Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 2003; 162:359-379. 29. Krasnewich D, Gahl WA: Carbohydrate-deficient glycoprotein syndrome. Adv Pediatr 1997; 44:109-140. 30. Pearl PL, Novotny EJ, Acosta MT, et al: Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 2003; 54:S73-S80. 31. Ogier de Baulny H, Saudubray JM: Branched-chain organic acidurias. Semin Neonatol 2002; 7:65-74. 32. de Baulny HO, Benoist JF, Rigal O, et al: Methylmalonic and propionic acidaemias: management and outcome. J Inherit Metab Dis 2005; 28:415-423. 33. Leonard JV, Morris AA: Urea cycle disorders. Semin Neonatol 2002; 7:27-35. 34. Iyer R, Jenkinson CP, Vockley JG, et al: The human arginases and arginase deficiency. J Inherit Metab Dis 1998; 21:86-100. 35. Steiner RD, Cederbaum SD: Laboratory evaluation of urea cycle disorders. J Pediatr 2001; 138:S21-S29. 36. Batshaw ML, MacArthur RB, Tuchman M: Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001; 138:S46-54. 37. Ridel KR, Leslie ND, Gilbert DL: An updated review of the longterm neurological effects of galactosemia. Pediatr Neurol 2005; 33:153-161. 38. Leslie ND: Insights into the pathogenesis of galactosemia. Annu Rev Nutr 2003; 23:59-80. 39. Tyfield L, Reichardt J, Fridovich-Keil J, et al: Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat 1999; 13:417-430. 40. Seashore MR, Wappner R, Cho S, et al: Development of guidelines for treatment of children with phenylketonuria: report of a meeting at the National Institute of Child Health and Human Development held August 15, 1995, National Institutes of Health, Bethesda, Maryland. Pediatrics 1999; 104:e67. 41. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 2001; 108:972-982. 42. Blau N, Erlandsen H: The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 2004; 82:101-111. 43. Blau N, Scriver CR: New approaches to treat PKU: how far are we? Mol Genet Metab 2004; 81:1-2. 44. Kim W, Erlandsen H, Surendran S, et al: Trends in enzyme therapy for phenylketonuria. Mol Ther 2004; 10:220-224. 45. Nyhan WL: The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metab Dis 1997; 20:171-178. 46. Jinnah HA, De Gregorio L, Harris JC, et al: The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 2000; 463:309-326. 47. Deliliers GL, Annaloro C: Hyperuricemia and bone marrow transplantation. Contrib Nephrol 2005; 147:105-114. 48. Hayflick SJ: Unraveling the Hallervorden-Spatz syndrome: pantothenate kinase-associated neurodegeneration is the name. Curr Opin Pediatr 2003; 15:572-577. 49. Johnson MA, Kuo YM, Westaway SK, et al: Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci 2004; 1012:282-298.

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50. Pellecchia MT, Valente EM, Cif L, et al: The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology 2005; 64:1810-1812. 51. Ching KH, Westaway SK, Gitschier J, et al: HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 2002; 58:1673-1674. 52. Shinawi M, Szabo S, Popek E, et al: Recognition of SmithLemli-Opitz syndrome (RSH) in the fetus: utility of ultrasonography and biochemical analysis in pregnancies with low maternal serum estriol. Am J Med Genet A 2005; 138:5660. 53. Hennekam RC: Congenital brain anomalies in distal cholesterol biosynthesis defects. J Inherit Metab Dis 2005; 28:385392. 54. Jira PE, Waterham HR, Wanders RJ, et al: Smith-Lemli-Opitz syndrome and the DHCR7 gene. Ann Hum Genet 2003; 67:269280. 55. Opitz JM, Gilbert-Barness E, Ackerman J, et al: Cholesterol and development: the RSH (“Smith-Lemli-Opitz”) syndrome and related conditions. Pediatr Pathol Mol Med 2002; 21:153-181. 56. Neri G, Opitz J: Syndromal (and nonsyndromal) forms of male pseudohermaphroditism. Am J Med Genet 1999; 89:201-209. 57. Perlman S, Becker-Catania S, Gatti RA: Ataxia-telangiectasia: diagnosis and treatment. Semin Pediatr Neurol 2003; 10:173182.

58. Becker-Catania SG, Chen G, Hwang MJ, et al: Ataxiatelangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity. Mol Genet Metab 2000; 70:122-133. 59. Gatti RA, Peterson KL, Novak J, et al: Prenatal genotyping of ataxia-telangiectasia. Lancet 1993; 342:376. 60. Lai CH, Chun HH, Nahas SA, et al: Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc Natl Acad Sci USA 2004; 101:15676-15681. 61. Taroni F, DiDonato S: Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci 2004; 5:641-655. 62. Gatchel JR, Zoghbi HY: Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 2005; 6:743-755. 63. Pandolfo M: Friedreich’s ataxia: clinical aspects and pathogenesis. Semin Neurol 1999; 19:311-321. 64. Rouault TA, Tong WH: Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol 2005; 6:345-351. 65. Zecca L, Youdim MB, Riederer P, et al: Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 2004; 5:863873. 66. Schols L, Meyer Ch, Schmid G, et al: Therapeutic strategies in Friedreich’s ataxia. J Neural Transm Suppl 2004; 68:135-145.

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WILSON DISEASE ●

●

●

●

John H. Menkes

Wilson Disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. The gene product, a P-type adenosine triphosphatase (ATPase), is necessary for both the incorporation of copper into ceruloplasmin and its excretion into bile. The disease is associated with increased hepatic copper storage which leads to a clinically heterogeneous illness marked by cirrhosis of the liver and degenerative changes in the basal ganglia. During the second half of the 19th century, a condition termed pseudosclerosis was distinguished from multiple sclerosis by the lack of ocular signs. In 1902, Kayser observed green corneal pigmentation in one such patient.1 Fleischer, who had also noted the green pigmentation of the cornea in 1903, commented on the association of the corneal rings with pseudosclerosis.2 In 1912, Wilson provided the classic description of the disease and its pathological anatomy but failed to mention the abnormal corneal pigmentation.3

EPIDEMIOLOGY The worldwide prevalence of Wilson disease is 1 per 30,000, with a carrier frequency of 1 per 90. In the United States, the frequency is about 1 per 55,000. The condition occurs in all races and ethnic groups, with a particularly high incidence in Eastern European Jews, in Italians from southern Italy and Sicily, and in people from some of the smaller islands of Japan—groups with high rates of inbreeding.

CLINICAL FEATURES Wilson disease is a progressive condition with a tendency toward temporary clinical improvement and arrest of symptoms.4 The presenting symptoms can be neurological, hepatic, psychiatric, or, less frequently, hematological. Symptoms at onset are listed in Table 108–1. In the experience of Gow and colleagues,5 of symptomatic patients aged 7 to 58 years, 22% presented with fulminant hepatic failure, 54% presented with liver abnormalities, 10% with neurological features, and 4% with hemolysis. In 10% of patients, hepatic and neurological symptoms were concurrent. In a fair number of cases, primarily in young children, initial symptoms are hepatic, such as jaundice or portal hypertension, and the disease can assume a rapidly fatal course without any

detectable neurological abnormalities.6,7 In many of these patients, an attack of what appears to be acute viral hepatitis heralds the onset of Wilson disease.8 The manifestation with hepatic symptoms is common among affected children in the United States. In the series of Werlin and associates,9 who surveyed patients in the Boston area, the primary mode of manifestation was hepatic in 61% of patients younger than 21 years. In about 10% of affected children in the United States, Wilson disease manifests as an acute or intermittent, Coombs’ test–negative, nonspherocytic anemia that is accompanied by leukopenia and thrombocytopenia.9 When neurological symptoms predominate, the manifestations are so varied that it is impossible to describe a characteristic clinical picture. As a rule, the appearance of neurological symptoms is delayed until 10 to 20 years of age, and the disease progresses at a slower rate than in the hepatic form. Symptoms of basal ganglia damage usually predominate, but cerebellar symptoms are occasionally in the foreground. Tremors and rigidity are the most common early signs. The tremor may be of the intention type, or it may be the alternating resting tremor of parkinsonism. More commonly, especially when the disease is in its more advanced stages, the tremor is localized to the arms and is best described by the term wing beating. The tremor is often absent when the arms are at rest; it develops after a short latent period when the arms are extended. The beating movements may be confined to the muscles of the wrist, but it is more common for the arm to be thrown up and down in a wide arc. The movements increase in severity; at times, they reach a point at which the patient is thrown off balance. The tremor may affect both arms but is usually more severe in one. Rigidity and spasms of the muscles are often present. In some instances, typical parkinsonian rigidity involves all muscles. Torticollis, tortipelvis, and other dystonic postures are not uncommon. Many patients have a fixed open-mouth smile with drooping of the lower jaw and excess salivation. Spasticity of the laryngeal and pharyngeal muscles can lead to dysarthria and dysphagia. A nearly pure Parkinson-like syndrome with progressive choreoathetosis or hemiplegia has also been described.10 Tendon reflexes are increased, but extensor plantar responses are exceptional. In essence, Wilson disease is a disorder of motor function; despite often widespread cerebral atrophy, there are no sensory symptoms or reflex alterations.

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T A B L E 108–1. Clinical Manifestations at Onset of Wilson’s Disease Symptoms Hepatic or Hematologic Abnormalities Behavioral Abnormalities Neurological Abnormalities “Pseudosclerotic” form: one or more of the following: Resting or intentional tremor Dysarthria or scanning speech Diminished dexterity or mild clumsiness Unsteady gait Tremor alone Dysarthria alone “Dystonic” form: One or more of the following: Hypophonic speech or mutism Drooling Rigid mouth, arms, or legs Seizures Chorea or small-amplitude twitches

Percentage* 35 25 40 40

33 5 60

1 <1

Table prepared with the assistance of Drs. I. H. Scheinberg and I. Sternlieb, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. *Percentages are approximate. ■

When Wilson disease manifests during childhood, the first signs are usually bulbar; these can include indistinct speech and difficulty in swallowing. A rapidly progressive dystonic syndrome is not unusual. Such patients can present with acute dystonia, rigidity, and fever, with an occasional elevation of serum creatine phosphokinase level.11 Behavioral and personality disorders were noted in Wilson’s original description of the disease.3 These are almost invariable and predominate in about one third of patients.12,13 They include impaired school or work performance, depression, mood swings, and frank psychosis. Of patients who show primarily neurological symptoms, about two thirds have had psychiatric problems before the diagnosis of Wilson disease is made. Minor intellectual impairment can also be observed, but seizures and mental deterioration are not prominent features of the disease. The intracorneal ring-shaped pigmentation, first noted by Kayser and Fleischer,1,2 might be evident to the naked eye or might appear only on slit-lamp examination. The color of the Kayser-Fleischer ring varies from yellow to green to brown. It is the consequence of copper deposition close to the endothelial surface of Descemet’s membrane. The ring can be complete or incomplete. It occurs in 79% of patients who present with hepatic symptoms and in all patients who present with cerebral or a combination of cerebral and hepatic symptoms.5,7 “Sunflower” cataracts are less commonly encountered, as are azure lunulae of the fingernails.14 Hypercalciuria and nephrocalcinosis are not uncommon and can be presenting signs of Wilson disease.15 Without treatment, death ensues within 1 to 3 years after the onset of neurological symptoms and is usually a result of hepatic insufficiency.

NEUROIMAGING Computed tomographic scans usually reveal ventricular dilatation and diffuse atrophy of the cortex, cerebellum, and brain-

Figure 108–1. Wilson disease. Coronal T2-weighted magnetic resonance images of a 22-year-old man with Wilson disease who presented with tremor and Kayser-Fleischer rings. There are bilateral hyperintense thalamic lesions. Spin-echo sequences with Siemens MAGNETOM Sonata at 1.5 tesla were used. (Courtesy of Dr. Franklin Moser, Division of Neuroradiology, Cedars Sinai Medical Center, Los Angeles.)

stem. About half the patients have symmetrical hypointensities in the head of the caudate, pallidum, substantia nigra, and red nuclei. The histopathology of Wilson disease suggests that these hypointensities are secondary to the presence of proteinbound copper in the thalamus and basal ganglia. Cortical atrophy and focal lesions in cortical white matter are also noted. Increased CT density resulting from copper deposition is not observed. T2-weighted magnetic resonance imaging demonstrates symmetrical areas of increased signal intensity in the putamen, particularly in its outer rim; in the thalami; in the head of the caudate nucleus; and in the globus pallidus (Fig. 108–1). In the series of King and coworkers, the midbrain was abnormal in 77% of patients with Wilson disease.16 Involvement included primarily the tegmentum but also included the substantia nigra and the mesencephalic tectum. Abnormalities are also seen in the pons and the cerebellum. These areas are hypointense on T1-weighted images.17 Correlation with the clinical picture is not good in that magnetic resonance imaging can produce normal findings in patients with neurological symptoms and abnormal findings in patients with no neurological symptoms.16,18 Positron emission tomography demonstrates a widespread depression of glucose metabolism; the greatest focal hypometabolism is observed in the lenticular nucleus. This abnormality precedes any alteration visible on computed tomography19 and improves with chelation therapy.20 In addition, a reduction in dopamine D2 receptor binding and loss of striatal dopamine transporters have been documented.21,22

chapter 108 wilson disease DIAGNOSIS When Wilson disease manifests with neurological manifestations, the diagnostic features include progressive extrapyramidal symptoms, which commence after the first decade of life; abnormal liver function; aminoaciduria; cupriuria; and absence or decreased serum levels of ceruloplasmin. In the experience of Gow and colleagues5 and of Steindl and coworkers,23 the diagnosis is more difficult to establish in patients who present with hepatic symptoms, particularly those who present in fulminant hepatic failure. The presence of a Kayser-Fleischer ring is the single most important diagnostic feature; its absence in a patient with neurological symptoms virtually rules out the diagnosis of Wilson disease. The ring is not seen in the majority of presymptomatic patients, nor is it seen in 33% of patients who present with hepatic symptoms.5 Absence or low serum level of ceruloplasmin is of lesser diagnostic importance; approximately 5% to 20% of patients with Wilson disease have normal levels of the copper protein. Ceruloplasmin levels are abnormally low in about 10% of persons heterozygous for the Wilson disease gene. Because gene carriers constitute about 1% of the population, there are 40 times more gene carriers with low ceruloplasmin values than patients with Wilson disease and low ceruloplasmin values. In affected families, the differential diagnosis between heterozygous and presymptomatic homozygous patients is of utmost importance, inasmuch as it is generally accepted that presymptomatic homozygous patients should be treated preventively.24 Several workers have stressed the diagnostic value of measuring 24-hour urine copper concentrations.25 In the experience of Gow and colleagues,5 however, 41% of patients who had a nonfulminant manifestation of Wilson disease, including all those with a neurological manifestation, had normal urinary copper excretion (<100 μg/24 hours). The “gold standard” study for the diagnosis of Wilson disease is liver biopsy.25 When this procedure is undertaken, it is advisable to perform histological studies with stains for copper and copper-associated proteins and chemical quantitation for copper. In all confirmed cases of Wilson disease, hepatic copper levels are greater than 3.9 μmol/g dry weight (237.6 μg/g), in comparison with a normal range of 0.2 to 0.6 μmol/g (20 to 50 μg/g dry tissue). Therefore, when low ceruloplasmin levels are found on routine screening and are unaccompanied by any abnormality of hepatic function or copper excretion, the patient is much more likely to be heterozygous for the Wilson disease gene than is a presymptomatic patient with Wilson disease.4 However, this supposition should be confirmed by liver biopsy.

ETIOLOGY AND PATHOPHYSIOLOGY Pathological Anatomy The abnormalities in copper metabolism result in a deposition of the metal in several tissues. Anatomically, the liver exhibits focal necrosis that leads to a coarsely nodular, postnecrotic cirrhosis. The nodules vary in size and are separated by bands of fibrous tissues of different widths. Some hepatic cells are enlarged and contain fat droplets, intranuclear glycogen, and

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clumped pigment granules; other cells are necrotic, with regenerative changes in the surrounding parenchyma.26 Electron microscopic studies indicate that copper is initially spread diffusely within the cytoplasm, probably as the monomeric metallothioneine complex. Later in the course of the disease, the metal is sequestered within lysosomes, which become increasingly sensitive to rupture.4 Copper probably initiates and catalyzes oxidation of the lysosomal membrane lipids, which results in lipofuscin accumulation. Within the kidneys, the tubular epithelial cells can degenerate, and their cytoplasm can contain copper deposits. In the brain, particularly in patients whose symptoms commenced before the onset of puberty, the basal ganglia have a brick-red pigmentation; spongy degeneration of the putamen frequently leads to the formation of small cavities.3 Lesser degenerative changes are seen in the brainstem, the dentate nucleus, the substantia nigra, and the convolutional white matter. Microscopic studies reveal loss of neurons, axonal degeneration, and large numbers of protoplasmic astrocytes, including giant forms termed Alzheimer cells. These cells are not specific for Wilson disease; they can also be seen in the brains of patients dying in hepatic coma or as a result of argininosuccinic aciduria or other disorders of the urea cycle. Opalski cells, also seen in Wilson disease, are generally found in gray matter. They are large cells with a rounded contour and finely granular cytoplasm. They probably represent degenerating astrocytes.

Molecular Genetics and Biochemical Pathology Cellular copper transport consists of three processes: copper uptake, intracellular distribution and use, and copper excretion.27 The site of copper absorption is probably in the proximal portion of the gastrointestinal tract. The metallothioneins, a family of low-molecular-weight metal-binding proteins containing large amounts of reduced cysteine, are involved in regulating copper absorption at high copper intakes. In addition to playing a role in the intestinal transport of copper, metallothioneins are probably also involved in the initial hepatic uptake of copper. After its intestinal uptake, copper enters the plasma, where it is bound to albumin in the form of cupric ion. Within 2 hours, the absorbed copper is incorporated into a liver protein. Cellular copper uptake is facilitated by Ctr1, a membrane protein that transports the metal in a high-affinity, metal-specific manner. The concentration of copper in normal liver ranges from 20 to 50 μg/g dry weight. Once within the hepatocyte, copper is bound to metallochaperones, a family of proteins that deliver it to various specific sites. The chaperone Atox1, through direct interaction with the P-type ATPase (ATP7B) of Wilson disease, delivers copper to the hepatic secretory pathway for excretion into bile. Within the hepatocyte cytoplasm, copper is complexed to what is probably a polymeric form of metallothionein. Last, copper can combine with apoceruloplasmin to form ceruloplasmin, which then reenters the circulation.28 More than 95% of serum copper is in this form.27 The gene for Wilson disease has been mapped to chromosome 13q14.3-q21.1. It has been cloned and encodes a coppertransporting P-type ATPase that is expressed in many tissues,

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including the brain.29 The ATPase is present in two forms: one form is probably localized to the late endosomes, in which it is involved in the delivery of copper to apoceruloplasmin.30 The other form, believed to represent a cleavage product, is found in mitochondria.31,32 More than 300 gene mutations have been described. Some mutations are population-specific; others are common in many nationalities. The majority are missense mutations, small insertions, or deletions.33 Most patients with Wilson disease have compound heterozygosity.34 A complete list of mutations is maintained at http://www.medicalgenetics.med. ualberta.ca/wilson/index.php. Although several workers have attempted to correlate genotype and phenotype, the same mutation can present vastly different clinical pictures.35 The genetic mutation induces extensive changes in copper homeostasis. Normally, the amount of copper in the body is kept constant through excretion from the liver into the bile. The two fundamental defects in Wilson disease are (1) reduced biliary transport and excretion of copper and (2) impaired formation of plasma ceruloplasmin.27 Biliary excretion of copper is between 20% and 40% of normal, and fecal output of copper is also reduced.36 Apoceruloplasmin is present in the livers of patients with Wilson disease, but because of a lack of copper available for incorporation, apoceruloplasmin is rapidly degraded. Of most importance, copper accumulates within liver. At first, it is firmly bound to copper proteins, such as ceruloplasmin and superoxide dismutase, or is complexed with metallothionein in the cupric form. When the copper load overwhelms the binding capacity of metallothionein, cytotoxic cupric copper is released, which causes damage to hepatocyte mitochondria and peroxisomes.37,38 Ultimately, copper leaks from the liver into blood, where it is taken up by other tissues, including the brain, which in turn are damaged by copper. More than 95% of serum copper is in the form of ceruloplasmin. Ceruloplasmin is a ferroxidase with multiple functions. It is involved principally in peroxidation of ferrous to ferric transferrin. In addition, it is believed to control the release of iron into plasma from cells in which the metal is stored in the form of ferritin. Although it is not involved in copper transport from the intestine, it is considered to be the major vehicle for the transport of copper from the liver and to function as a copper donor in the formation of a variety of copper-containing enzymes. The concentration of ceruloplasmin in plasma is normally between 20 and 40 mg/dL. Two other biochemical abnormalities are consistently found in patients with Wilson disease: 1. Low to low-normal plasma levels of iron-binding globulin can be demonstrated in the asymptomatic carrier and suggests that Wilson disease may also encompass a disorder of iron metabolism. This may result from the deficiency of hephaestin, a ceruloplasmin homolog that has been implicated in intestinal iron transport and may be involved in the transfer of iron from tissue cells to plasma transferrin.39 Iron deposition in the liver is increased,40 and an increase in cerebral iron uptake can be demonstrated by positron emission tomography.41 2. Persistent aminoaciduria is most marked during the later stages but may be noted in some asymptomatic patients. The presence of other tubular defects (e.g., impaired phosphate resorption in patients without aminoaciduria) suggests that a toxic action of the metal on renal tubules causes the aminoaciduria.

TREATMENT Even though it is clear that all patients with Wilson disease, whether symptomatic or asymptomatic, require treatment, there is no current consensus as to the optimal means of treating Wilson disease. The aims of treatment are initially to remove the toxic amounts of copper and secondarily to prevent tissue reaccumulation of the metal.25,42 Treatment can be divided into two phases: the initial phase, when toxic copper levels are brought under control, and maintenance therapy. There is no currently agreed-upon regimen for treatment of the new patient with neurological or psychiatric symptoms. In the past, most centers recommended starting patients on D-penicillamine (600 to 3000 mg/day). Although this drug is effective in promoting urinary excretion of copper, adverse reactions during the initial and maintenance phases of treatment are seen in approximately 25% of patients. These include worsening of neurological symptoms during the initial phases of treatment, which frequently are irreversible. Skin rashes, gastrointestinal discomfort, and hair loss are also encountered. During maintenance therapy, polyneuropathy, polymyositis, and nephropathy may occur. Some of these adverse effects can be prevented with pyridoxine (25 mg/day). Because of these side effects, many institutions now advocate initial therapy with ammonium tetrathiomolybdate (60 to 300 mg/day, administered in six divided doses, three with meals and three between meals). Tetrathiomolybdate forms a complex with protein and copper and, when given with food, blocks the absorption of copper. The major drawback to using this drug is that it still has not been approved for general use in the United States. Triethylene tetramine dihydrochloride (trientine) (500 mg twice a day, given at least 1 hour before or 2 hours after meals) is another chelator that increases urinary excretion of copper. It is less effective than penicillamine or ammonium tetrathiomolybdate, but the incidence of toxicity and hypersensitivity reactions is lower than in the former.42a Zinc acetate (50 mg of elemental zinc acetate three times a day) acts by inducing intestinal metallothionein, which has a high affinity for copper and prevents its entrance into blood. Zinc is far less toxic than penicillamine but is much slower acting. Diet does not play an important role in the management of Wilson disease, although Brewer recommended restriction of liver and shellfish during the first year of treatment.42 Zinc is the optimal drug for maintenance therapy and for the treatment of the presymptomatic patient. Trientine in combination with zinc acetate has been suggested for patients who present in hepatic failure. Liver transplantation can be helpful in the patient who presents in end-stage liver disease. The procedure appears to correct the metabolic defect and can reverse neurological symptoms.43 Schumacher and colleagues44 also recommended its use for patients with normal liver function but whose neurological symptoms have not responded to the various chelating agents. With these regimens, gradual improvement in neurological symptoms occurs. As a rule, brainstem auditory evoked potentials improve within 1 month of the onset of therapy; the somatosensory evoked responses return to normal somewhat more slowly.45 The Kayser-Fleischer ring begins to fade within 6 to 10 weeks after the onset of therapy and disappears completely in a couple of years.46 Neurological symptoms start improving 5 to 6 months after therapy begins and are generally gone in 24 months. As shown by serial neuroimaging

chapter 108 wilson disease

A ■

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B Figure 108–2. Wilson disease. A, Coronal T2-weighted magnetic resonance images in a 22-year-old woman with Wilson disease, 3 months after the disease had been diagnosed and at the start of penicillamine therapy. There are bilateral hyperintense thalamic lesions that are hypointense on T1-weighted images. B, Images in the same patient after 13 months of penicillamine therapy. There has been a significant regression of the thalamic lesions. Spin-echo sequences (recovery time, 2.5 milliseconds; echo time, 90 milliseconds) with Siemens MAGNETOM 6.3, operating at 1.5 tesla, were used. (Courtesy of Dr. I. Prayer, Zentral Institut für Radiodiagnose und Ludwig Boltzmann Institut, University of Vienna, Austria.)

studies, a significant regression of lesions occurs within thalamus and basal ganglia (Fig. 108–2A and B).18 Successive biopsies reveal a reduction in the amount of hepatic copper. Total serum copper and ceruloplasmin levels decrease, and the aminoaciduria and phosphaturia diminish. As a rule, patients who begin therapy before the evolution of symptoms remain healthy. Patients who have had exclusively hepatic disease do well, and in 80%, hepatic functions return to normal. Approximately 40% of children who present with neurological symptoms become completely asymptomatic and remain so for 10 or more years. Patients with the mixed hepatocerebral picture do poorly. Fewer than 25% recover completely, and approximately 25% continue to deteriorate, often with the appearance of seizures. In all forms of the disease, the earlier therapy begins, the better the outlook is.7 When symptom-free patients with Wilson disease discontinue chelation therapy, their hepatic function deteriorates in 9 months to 3 years, a rate that is far more rapid than deterioration after birth.47 There is accumulating evidence that oxidative damage caused by free radical formation can play a significant role in producing cell damage in Wilson disease. Gu and coworkers37 have noted severe mitochondrial dysfunction in the livers of patients with Wilson disease, with significant reduction in the activities of all enzyme complexes involved in oxidative phosphorylation. Other findings pointing to oxidative stress are the reduction in the plasma levels of various antioxidants, such as ascorbate and urate, and the increase of allantoin, a possible marker of free radical generation.48 These findings provide experimental support for the addition of antioxidants such as ascorbate or vitamin E to the therapeutic regimen of all patients with Wilson disease.

K E Y

P O I N T S

●

Wilson disease is a progressive condition with a tendency toward temporary clinical improvement and arrest of symptoms.

●

The gene for Wilson disease has been mapped to chromosome 13q14.3-q21.1. It encodes a coppertransporting P-type ATPase that is expressed in many tissues, including the brain.

●

The two fundamental defects in Wilson disease are (1) reduced biliary transport and excretion of copper and (2) impaired formation of plasma ceruloplasmin.

●

Presenting symptoms can be neurological, hepatic, psychiatric, or, less frequently, hematological.

●

Behavioral or personality disorders are almost invariable and predominate in about one third of patients.

●

The Kayser-Fleischer ring is present in all patients who present with cerebral or a combination of cerebral and hepatic symptoms. Its presence is the most important diagnostic feature.

●

Aims of treatment are initially to remove the toxic amounts of copper and secondarily to prevent tissue reaccumulation of the metal.

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Suggested Reading Akil M, Brewer GJ: Psychiatric and behavioral abnormalities in Wilson disease. In Weiner WJ, Lang AE, eds: Advances in Neurology, vol 65: Behavioral Neurology of Movement Disorders. New York: Raven Press, 1995, pp 171-178. Arima M, Takeshita K, Yoshino K, et al: Prognosis of Wilson disease in childhood. Eur J Pediatr 1977; 126:147-154. Gitlin JD: Wilson disease. Gastroenterology 2003; 125:18681877. Gow PJ, Smallwood RA, Angus PW, et al: Diagnosis of Wilson disease: an experience over three decades. Gut 2000; 46:415419. His G, Cox DW: A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet 2004; 114:165-172.

References 1. Kayser B: Ueber einen Fall von angeborener grünlicher Verfärbung der Cornea. Klin Monatsbl Augenheilkd 1902; 40:2225. 2. Fleischer B: Über einer der “Pseudosklerose” nahestehende bisher unbekannte Krankheit (gekennzeichnet durch Tremor, psychische Störungen, bräunliche Pigmentierung bestimmter Gewebe, insbesondere auch der Hornhautperipherie, Lebercirrhose). Deutsch Z Nervenheilk 1912; 44:179-201. 3. Wilson SAK: Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912; 34:295-509. 4. Scheinberg IH, Sternlieb I: Wilson’s Disease, 2nd ed. Philadelphia: WB Saunders, 1999. 5. Gow PJ, Smallwood RA, Angus PW, et al: Diagnosis of Wilson disease: an experience over three decades. Gut 2000; 46:415419. 6. Ferlan-Marolt V, Stepec S: Fulminant wilsonian hepatitis unmasked by disease progression: report of a case and review of the literature. Dig Dis Sci 1999; 44:1054-1058. 7. Arima M, Takeshita K, Yoshino K, et al: Prognosis of Wilson disease in childhood. Eur J Pediatr 1977; 126:147-154. 8. Scott J, Golan JL, Samourian S, et al: Wilson disease presenting as chronic active hepatitis. Gastroenterology 1978; 74:645651. 9. Werlin SL, Grand RJ, Perman JA, et al: Diagnostic dilemmas of Wilson disease: diagnosis and treatment. Pediatrics 1978; 62:47-51. 10. Lingan S, Wilson J, Nazer H, et al: Neurological abnormalities in Wilson disease are reversible. Neuropediatrics 1987; 18:1112. 11. Kontaxakis V, Stefanis C, Markidis M, et al: Neuroleptic malignant syndrome in a patient with Wilson disease [Letter]. J Neurol Neurosurg Psychiatr 1988; 51:1001-1002. 12. Akil M, Brewer GJ: Psychiatric and behavioral abnormalities in Wilson disease. In Weiner WJ, Lang AE, eds: Advances in Neurology, vol 65: Behavioral Neurology of Movement Disorders. New York: Raven Press, 1995, pp 171-178. 13. Portala K, Westermark K, Ekselius L, et al: Personality traits in treated Wilson disease determined by means of the Karolinska Scales of Personality (KSP). Eur Psychiatry 2001; 16:362371. 14. Cairns JE, Williams HP, Walshe JM: “Sunflower cataract” in Wilson disease. BMJ 1969; 3:95-96. 15. Azizi E, Eshel G, Aladjem M. Hypercalciuria and nephrolithiasis as a presenting sign in Wilson disease. Eur J Pediatr 1989; 148:548-549. 16. King AD, Walshe JM, Kendall BE, et al: Cranial MR imaging in Wilson disease. AJR Am J Roentgenol 1996; 167:15791584.

17. Van Wassenaer–van Hall HN, van den Heuvel AG, Algra A, et al: Wilson disease: findings at MR imaging and CT of the brain: clinical correlation. Radiology 1996; 198:531-536. 18. Prayer L, Wimberger D, Kramer J, et al: Cranial MRI in Wilson disease. Neuroradiology 1990; 32:211-214. 19. Hawkins RA, Mazziotta JC, Phelps ME: Wilson disease studied with FDG and positron emission tomography. Neurology 1987; 37:1707-1711. 20. Schlaug G, Hefter H, Engelbrecht V, et al: Neurological impairment and recovery in Wilson disease: evidence from PET and MRI. J Neurol Sci 1996; 136:129-139. 21. Oder W, Brucke T, Kollegger H, et al: Dopamine D2 receptor binding is reduced in Wilson disease: a correlation of neurological deficits with striatal 123I-iodobenzamide binding. J Neural Transm 1996; 103:1093-1103. 22. Jeon B, Kim JM, Jeong JM, et al: Dopamine transporter imaging with [123I]-β-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson disease. J Neurol Neurosurg Psychiatry 1998; 65:60-64. 23. Steindl P, Ferenci P, Dienes HP, et al: Wilson disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113:212-218. 24. Walshe JM: Diagnosis and treatment of presymptomatic Wilson disease. Lancet 1988; 2:435-437. 25. Brewer GJ, Yusbasiyan-Gurkan V: Wilson disease. Medicine 1992; 71:139-164. 26. Strohmeyer FW, Ishak KG: Histology of the liver in Wilson disease: a study of 34 cases. Am J Clin Pathol 1980; 73:12-24. 27. Gitlin JD: Wilson disease. Gastroenterology 2003; 125:18681877. 28. Tapia L, Gonzalez-Aguerre M, Cisternas MF, et al: Metallothionein is crucial for safe intracellular copper storage and cell survival at normal and supra-physiological exposure levels. Biochem J 2004; 378:617-624. 29. Tanzi RE, Petrukhin K, Chernov I, et al: The Wilson disease gene is a copper-transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993; 5:344-350. 30. Harada M, Kawaguchi T, Kumemura H, et al: The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein. Am J Pathol 2005; 166:499510. 31. Lutsenko S, Cooper MJ: Localization of the Wilson disease protein product to mitochondria. Proc Natl Acad Sci U S A 1998; 95:6004-6009. 32. Schaefer M, Hopkins RG, Failla ML, et al: Hepatocyte-specific localization and copper-dependent trafficking of the Wilson disease protein in the liver. Am J Physiol 1999; 276:G639G646. 33. His G, Cox DW: A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet 2004; 114:165172. 34. Thomas GR, Forbes JR, Roberts EA, et al: The Wilson disease gene: spectrum of mutations and their consequence. Nat Genet 1995; 9:210-217. 35. Palsson R, Jonasson JG, Kristjansson M, et al: Genotypephenotype interactions in Wilson disease: insights from an Icelandic mutation. Eur J Gastroenterol Hepatol 2001; 13:433436. 36. Frommer DJ: Defective biliary excretion of copper in Wilson disease. Gut 1974; 15:125-129. 37. Gu M, Cooper JM, Butler P, et al: Oxidative-phosphorylation defects in liver of patients with Wilson disease. Lancet 2000; 356:469-474. 38. Sheline CT, Choi DW: Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo. Ann Neurol 2004; 55:645-653. 39. Vulpe CD, Packman S: Cellular copper transport. Annu Rev Nutr 1995; 15:293-322.

chapter 108 wilson disease 40. Shiono Y, Hayashi H, Wakusawa S, et al: Ultrastructural identification of iron and copper accumulation in the liver of a male patient with Wilson disease. Med Electron Microsc 2001; 34:54-60. 41. Bruehlmeier M, Leenders KL, Vontobel P, et al: Increased cerebral iron uptake in Wilson disease: a 52Fe-citrate PET study. J Nucl Med 2000; 41:781-787. 42. Brewer GJ: Practical recommendations and new therapies for Wilson disease. Drugs 1995; 50:240-249. 42a. Brewer GJ, Askari F, Lorincz MT, et al: Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006; 63:521-527 43. Emre S, Atillasoy EO, Ozdemir S, et al: Orthotopic liver transplantation for Wilson disease: a single-center experience. Transplantation 2001; 72:1232-1236.

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44. Schumacher G, Platz KP, Mueller AR, et al: Liver transplantation: treatment of choice for hepatic and neurological manifestations of Wilson disease. Clin Transplant 1997; 11:217-224. 45. Grimm G, Oder W, Prayer L, et al: Evoked potentials in assessment and follow-up of patients with Wilson disease. Lancet 1990; 336:963-964. 46. Mitchell AM, Heller GL: Changes in Kayser-Fleischer ring during treatment of hepatolenticular degeneration. Arch Ophthalmol 1968; 80:622-631. 47. Walshe JM, Dixon AK: Dangers of non-compliance in Wilson disease. Lancet 1986; 1:845-847. 48. Ogihara H, Ogihara T, Miki M, et al: Plasma copper and antioxidant status in Wilson disease. Pediatr Res 1995; 37:219226.

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109

VITAMIN DEFICIENCIES OTHER NUTRITIONAL DISORDERS OF THE NERVOUS SYSTEM ●

●

●

●

Laurence J. Kinsella A vitamin is a substance that serves as a cofactor for a biochemical reaction and whose absence causes some derangement of function (Fig. 109–1). Thiamine is a classic example, required by three enzyme systems that are essential for glucose metabolism. However, the term vitamin deficiency is too restrictive to account for all disorders of nutrition with neurological consequences. A number of syndromes are associated with megadoses of vitamins (pyridoxine, zinc) and dietary supplements (Chinese herbal remedies, St. John’s Wort, ephedra) (Table 109–1). The recognition of mineral deficiencies such as copper myeloneuropathy, mineral excess disorders such as zinc-induced copper deficiency, and polynutritional disturbances such as postgastroplasty neuropathy requires that a discussion of “vitamin deficiency” be broadened to include other nutritional syndromes of the nervous system. The diagnosis of a nutritional disorder of the nervous system may be challenging for a number of reasons. First, multiple deficiencies may coexist in the same patient, as in dietary malnutrition, postgastroplasty neuropathy, and malabsorption states. Some syndromes that manifest acutely may not be interpreted as nutritional (Tables 109–2 and 109–3). Instead of evolving in a slowly progressive manner, some deficiency states may have an explosive onset triggered by an environmental stressor or by a sudden increase in metabolic demands for the deficient nutrient. The underrecognition of nutritional disorders in industrialized countries has led to difficulties in diagnosis, and these deficiencies may be more common than has been clinically appreciated. Thiamine deficiency has been reported in up to 17% of hospitalized elderly individuals1 and is documented in 3% of autopsy series.2,3 One study of thiamine-deficient alcoholic subjects demonstrated that more than 50% were also riboflavin deficient, and 2% had a concomitant deficiency of pyridoxine.4 With the increasing popularity of obesity-related surgery, new neurological syndromes have emerged as a result of postoperative polynutritional deficiency states (such as acute post–gastric reduction surgery neuropathy, described later). Cobalamin deficiency occurs in 5% to 14% of ambulatory elderly persons,5,6 and up to 27% of hospitalized elderly people develop protein-energy malnutrition during their hospital stay.7 Finally, several inherited enzyme deficiency disorders, although not accompanied by a vitamin deficiency, may nonetheless be vitamin responsive (Table 109–4). Homo-

cystinemia responds to pharmacological doses of folate, cobalamin, and pyridoxine, whereas methylmalonic acidemia responds to cobalamin. Patients with mitochondrial cytopathology may respond to large doses of thiamine (300 mg/day).

VITAMIN DEFICIENCIES Thiamine Pathogenesis and Pathophysiology The metabolically active form of thiamine, thiamine pyrophosphate (TPP), is crucial in the intermediary metabolism of carbohydrate. TPP is involved in three enzyme systems: (1) pyruvate dehydrogenase, which converts pyruvate to acetyl coenzyme A; (2) α-ketoglutarate dehydrogenase, which catalyzes the conversion of α-ketoglutarate to succinate in the Krebs cycle; and (3) transketolase, which catalyzes the pentose monophosphate shunt (see Fig. 109–1). A deficiency of TPP leads to elevated levels of serum pyruvate and lactate, reduced red blood cell transketolase activity, and a corresponding increase in transketolase activity in response to added TPP (“TPP effect”).8 Pathologically, patients with Wernicke-Korsakoff syndrome show capillary proliferation and petechiae. Spongy degeneration of astrocytes with neuronal preservation occurs in midline structures of the brain, such as the medial thalamic nuclei, the mammillary bodies, the periaqueductal gray area of the mesencephalon, and the pontine tegmentum (Fig. 109–2). Degeneration of the superior cerebellar vermis is frequent. The lesions in the thalami and mammillary bodies probably account for the confusion, memory loss, and confabulation. The pontine tegmental lesions may cause the oculomotor palsies, and the truncal ataxia may result from the midline cerebellar degeneration.9 Cellular injury in these regions may be caused by inhibition of adenosine triphosphate synthesis and induction of abnormal carbohydrate metabolism. In thiamine deficiency polyneuropathy, nerves show axonal degeneration with secondary demyelination. The neuropathy of dry beriberi may be related to TPP deficiency–induced impairment of nerve excitability and conduction.10,11

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M e ta b o l i c D i s e as e s Nicotinic acid

NADP

NADP

Glucose6-PO4

Glucose

6-Phosphogluconate

Pyruvate TPP

Thiamine

Alanine

Transketolase Fructose6-PO4

TPP

TPP-CHOH-CH3 CoA

Pantothenic acid

Citrate

Oxaloacetate

Isovaleryl CoA α-Ketoisocaproic

acid

Aconitate

NAD Malate

Isocitrate

Fumarate

Thiamine

Pyridoxine

Acetyl CoA

Nicotinic acid

Ribose-5-PO4

TPP

α-Ketoglutarate

Leucine

Pyridoxine

Thiamine

Succinate Succinyl CoA

Vitamin B12 folate

Vitamin B12 Methylmalonyl CoA

α-Ketobutyric acid ■

Methionine

Homocysteine

Figure 109–1. Major metabolic pathways involving coenzymes formed from water-soluble vitamins. CoA, coenzyme A; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; TPP, thiamine pyrophosphate. (Modified from Marcus R, Coulston AM: Water soluble vitamins. In Gilman AG, Goodman LS, Gilman A, eds: The Pharmacologic Basis of Therapeutics, 7th ed. New York: Macmillan, 1985, p 1556.)

T A B L E 109–1. Toxins Associated with Nutritional Syndromes Alcohol Zinc Pyridoxine Nitrous oxide Vitamin A

Wernicke-Korsakoff syndrome, painful polyneuropathy Copper deficiency myelopathy Large-fiber sensory neuropathy Cobalamin deficiency myelopathy Methyltetrahydrofolate reductase (MTHFR) deficiency encephalopathy Optic neuropathy, pseudotumor cerebri

of their carbohydrate from white rice, and infants breastfed by malnourished mothers. Other potential causes of thiamine deficiency include prolonged total parenteral nutrition,13 defective baby formula,14 hyperemesis gravidarum,15 anorexia nervosa, gastric or jejunoileal bypass,16,17 intractable vomiting after gastric stapling for morbid obesity,18 and severe malabsorption. Thiamine deficiency is also found among prisoners of war19 and persons engaged in hunger strikes. In addition, thiamine deficiency has been reported after long-standing peritoneal or hemodialysis.20,21

Epidemiology and Risk Factors

Clinical Features and Associated Disorders

Thiamine is most abundant in yeast, pork, legumes, cereal grains, and unpolished rice, and the recommended daily allowance of this vitamin is 0.5 mg/1000 kcal.12 The total body store is 30 to 100 mg, and thiamine is present in heart, skeletal muscle, liver, kidney, and brain tissue. Because the quantity stored is limited, the supply must be constantly replenished. The half-life of thiamine is approximately 2 weeks, and patients may suffer severe neurological complications and even death after 6 weeks of total thiamine depletion. Patients at high risk for deficiency include alcoholic persons, adults who derive most

Wernicke-Korsakoff syndrome and polyneuropathy (dry beriberi) are the two neurological disorders resulting from thiamine deficiency. The classic triad of confusion, ataxia, and oculomotor palsies is uncommon in clinical practice. In Harper and colleagues’ autopsy series of 131 patients, only 16% had all three features premorbidly.3 The frequency of Wernicke-Korsakoff syndrome in autopsy series ranges from 0.8% to 2.8%. The disorder is probably underdiagnosed during life. Wernicke-Korsakoff syndrome is most common in alcoholic persons as a result of a combination

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T A B L E 109–2. Acute and Subacute Manifestations of Nutritional Disorders Neurological Syndrome

Mechanism

Time Course

Acute post–gastric reduction surgery neuropathy Wernicke-Korsakoff syndrome

Excessive and prolonged vomiting, severe weight loss

Weeks to months after surgery Hours

Wernicke-Korsakoff syndrome Nitrous oxide–associated myeloneuropathy Pyridoxine neuropathy

IV glucose administration in a thiamine-deficient patient, inducing sudden demand for thiamine-dependent glycolytic enzymes Excessive and prolonged vomiting, severe weight loss (gastric surgery, hyperemesis gravidarum) N2O oxidizes cobalt core of cobalamin, affects vitamin B12–deficient patients acutely or vitamin B12–replete patients with multiple exposures Unknown, but probably multiple redox reactions

Weeks Hours Hours to days

IV, intravenous.

T A B L E 109–3. Nutritional Syndromes by Symptom Complex Encephalopathy

Movement Disorders

Myeloneuropathy

Neuropathy

Myopathy

Optic Neuropathy

Thiamine Niacin Folate Cobalamin Marchiafava-Bignami Acute post–gastric reduction surgery neuropathy MTHFR

Thiamine/chorea Cobalamin/hemiballismus

Cobalamin Vitamin E Copper Cuban neuropathy Acute post–gastric reduction surgery neuropathy Strachan’s Nitrous oxide–induced vitamin B12 deficiency

Acute post–gastric reduction surgery neuropathy Thiamine Alcohol Pyridoxine

Critical illness Vitamin D Protein-energy malnutrition

Vitamin A toxicity Deficiency amblyopia Cobalamin

MTHFR, methyltetrahydrofolate reductase.

T A B L E 109–4. Hereditary Disorders Responsive to Vitamin Therapy Thiamine

Cobalamin, folate, pyridoxine Biotin Niacin

Thiamine-responsive megaloblastic anemia Mitochondrial disorders MELAS MERRF Leigh’s disease Pyruvate dehydrogenase deficiency Maple syrup urine disease Methylmalonic acidemia Homocystinemia β-Methylcrotonyl glycinemia Propionic acidemia Hartnup’s disease (tryptophan metabolism)

MELAS, mitochondrial encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy associated with ragged-red fibers.

of poor diet, inadequate intake, impaired absorption of thiamine, and overdependence on alcohol as a source of calories. Certain individuals may also have a genetic predisposition toward the development of this syndrome because of an abnormality of thiamine-dependent enzymes.22,23 Polyneuropathy is present in more than 80% of patients with Wernicke-Korsakoff syndrome, but most cases are probably caused by alcoholism. Koike and associates demonstrated that thiamine deficiency and alcohol-induced neuropathy are distinct entities.11 Thiamine deficiency may manifest acutely with prominent motor weakness and large-fiber sensory loss. In contrast, alcoholic neuropathy manifests with slowly progressive muscular weakness and with sensory and reflex loss, accompanied by burning sensation in the feet and lancinating pains. Calf

tenderness is a prominent feature. Bilateral footdrop and even wristdrop may be present (Fig. 109–3). Half of Koike and associates’ patients had evidence of autonomic neuropathy with orthostatic hypotension.

Evaluation Serum thiamine levels lack sufficient sensitivity and specificity to be used alone. Red blood cell transketolase activity, with or without TPP challenge, is the most accurate assessment tool,8 but the test has become commercially unavailable. Magnetic resonance imaging may reveal abnormal signal in the midline nuclei corresponding to the pathological lesions described (Fig. 109–4).24

Management Treatment of suspected Wernicke-Korsakoff syndrome begins with the immediate intravenous administration of 100 mg of thiamine, followed by 100 mg/day intramuscularly or orally for 3 to 5 days. Patients should then be maintained on 50 mg of oral thiamine and daily multivitamins.

Niacin and Nicotinic Acid Niacin includes both nicotinic acid and nicotinamide, which form the metabolically active nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), an end product of tryptophan metabolism. More than 200 enzymes are dependent on NAD and NADP to carry out oxidation and reduction reactions, and these enzymes are involved in the synthesis and breakdown of carbohydrates, lipids, and amino acids. Although

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M e ta b o l i c D i s e as e s niacin is endogenously produced in humans, exogenous intake is necessary to prevent deficiency. Pellagra, or rough skin, continues to occur in parts of Africa and Asia, especially in populations dependent on corn as the principle source of carbohydrate. When corn is first soaked in lime water, as is done in Mexico when tortillas are prepared, niacin is liberated, and deficiency occurs less commonly. In the United States, niacin deficiency is seen in alcoholic persons and

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Figure 109–2. Wernicke’s encephalopathy. Gross appearance characterized by petechial hemorrhages in the typical locations. (Reprinted with permission from Okazaki H: Fundamentals of Neuropathology, 2nd ed. New York: Igaku Shoin, 1989, p 192.)

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Figure 109–3. Bilateral wristdrop and footdrop in a 40-year-old woman with Wernicke-Korsakoff syndrome and polyneuropathy. (From Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syndrome. Philadelphia: FA Davis, 1971.)

Figure 109–4. Brain T2-weighted magnetic resonance imaging in a patient with Wernicke-Korsakoff syndrome, demonstrating symmetrically increased signal intensity in the periaqueductal gray and midline structures. (From Yamashita M, Yamamoto T: Wernicke encephalopathy with symmetric pericentral involvement: MR findings. J Comput Assist Tomogr 1995; 19:307.)

chapter 109 vitamin deficiencies ■

Plasma Myelin sheath protein

Nucleus Purines

Homocysteine

Methionine

Pyrimidines

MB12 MTHF B12Tcll

MTHF

DNA

THF

THF

Figure 109–5. Intracellular vitamin B12 (B12) interactions. See the text for description. CoA, coenzyme A; B12TcII, transcobalamin II–bound cobalamin; DB12, deoxyadenosylcobalamin; MB12, methylcobalamin; MTHF, methyltetrahydrofolate; TcII, transcobalamin II; THF, tetrahydrofolate. (From Flippo TS, Holder WD Jr: Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch Surg 1993; 128:1391-1395. Copyright 1993 American Medical Association. All rights reserved.)

Mitochondria

B12

Tcll

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L-Methylmalonyl CoA

DB12 Succinyl CoA

DB12

Krebs cycle Cell cytoplasm

Carbohydrate synthesis

Lipid synthesis

in patients taking isoniazid. Pregnant women are protected from niacin deficiency because of their enhanced ability to convert tryptophan to niacin endogenously, particularly in the third trimester. Pellagra affects the skin, the gastrointestinal system, and the central nervous system; hence, the classic triad of the “three Ds”: dermatitis, diarrhea, and dementia. In industrialized countries, particularly among alcoholic persons, niacin deficiency may manifest only with encephalopathy.25-27 Patients may have altered sensorium, diffuse rigidity of the limbs, and grasping and sucking reflexes. Dementia and confusion are the most constant findings, followed by diarrhea (50%), and dermatitis (30%).27 Spinal cord and peripheral nerve defects have also been reported, particularly in prisoners of war.19 Coexisting deficiencies of thiamine and pyridoxine are common, especially in alcoholic persons. ■

Cobalamin (Vitamin B12) Pathogenesis and Pathophysiology Vitamin B12 deficiency produces neurological and hematological symptoms by impairing two enzyme systems (Fig. 109–5).5,28 Methylcobalamin is a cofactor of methionine synthase, a cytosolic enzyme that catalyzes the conversion of homocysteine and methyltetrahydrofolate to produce methionine and tetrahydrofolate. Methionine is further metabolized to S-adenosylmethionine, which is necessary for the methylation of myelin sheath phospholipids and proteins. Tetrahydrofolate is the required precursor for purine and pyrimidine synthesis. In the mitochondria, adenosylcobalamin catalyzes the conversion of L-methylmalonyl–coenzyme A to succinyl–coenzyme A. In deficiency states, serum levels of homocysteine and methylmalonic acid rise. Although the mechanism of megaloblastic changes in both folate and cobalamin deficiency is reasonably well understood, the biochemical basis of the neurological damage that occurs in cobalamin deficiency remains uncertain. Of the two reactions that require cobalamin, the methionine synthase reaction is considered more

Figure 109–6. Subacute combined degeneration of the spinal cord. A thoracic cord segment showing spongy degeneration of the white matter in a typical distribution (Weil’s stain). (From Okazaki H: Fundamentals of Neuropathology, 2nd ed. New York: Igaku Shoin, 1989, p 195.)

likely to play a critical role in nervous system function. In rare cases, neurological complications have also been reported in folate deficiency, because methionine synthase also requires this cosubstrate.29 It has been proposed that the accumulation of methylmalonate and propionate provides abnormal substrates for fatty acid synthesis, resulting in abnormal oddcarbon and branched-chain fatty acids, so-called funny fatty acids, which may be incorporated into the myelin sheath and interfere with impulse conduction. Vitamin B12 deficiency results in demyelination of the posterior columns, corticospinal tracts, and white matter of the cerebral hemispheres (Fig. 109–6).30 Less commonly, a sensorimotor and autonomic neuropathy that is axonal and demyelinating in nature may also be present.31,32 These lesions lead to a constellation of symptoms, including cognitive and affective disorders, ataxia, spasticity, and paresthesias.

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Epidemiology and Risk Factors The total body store of cobalamin is 2000 to 5000 μg, half of which is stored in the liver. The recommended daily allowance is 2.5 to 3 μg/day, and the average diet provides 20 μg/day. Because the vitamin is tightly conserved through the enterohepatic circulation, 2 to 5 years elapse before a subject develops cobalamin deficiency from malabsorption, and as long as 10 to 20 years must pass to induce a dietary deficiency from a strict vegetarian diet. In the Framingham Heart Study, 5% of elderly subjects had serum vitamin B12 levels less than 148 pmol/L, 40.5% had values less than 258 pmol/L, and 15% had serum methylmalonic acid levels greater than 376 nmol/L.33 Therefore, 15% of the elderly population demonstrate biochemical evidence of vitamin B12 deficiency. Folate deficiency is far more common in alcoholism than is cobalamin deficiency. Of all cases of folate deficiency, 87% occur in alcoholic persons, whereas only 11% to 13% of cobalamindeficient patients are alcoholic.34,35 For unclear reasons, vitamin B12 deficiency is uncommon in alcoholics. Anemia and macrocytosis (mean cell volume >100 fL) occur in 72% and 83%, respectively, of patients with vitamin B12 deficiency and in 100% and 75%, respectively, of those with folate deficiency.35 Approximately 50% to 78% of patients with vitamin B12 deficiency have autoimmune parietal cell dysfunction (pernicious anemia).36 Another 10% to 40% have food-bound cobalamin malabsorption, caused by achlorhydria.37 The rest have a variety of causes, mainly malabsorption from medical, surgical, or pharmacological impairments of gastric acid or intrinsic factor secretion. These include patients after gastric surgery38 and after bypass procedures for weight reduction,39 as well as those taking long-term H2 blocker therapy, as a result of inhibition of acid secretion.40 Nitrous oxide administration may precipitate acute vitamin B12 deficiency in patients with asymptomatic low cobalamin levels.28,41 Other causes of vitamin B12 deficiency include ileal resection, parasitic infestations from Diphyllobothrium latum, Crohn’s disease and other malabsorption states, short gut syndrome, a vegan diet, chronic alcoholism with poor diet, and rare congenital enzyme deficiencies.

Clinical Features and Associated Disorders Subacute combined degeneration of the spinal cord, peripheral nerve dysfunction, and cerebral dysfunction are classic features of the disorder. Many patients present without accompanying anemia or macrocytosis. Healton and associates reviewed 143 patients who had 153 episodes of cobalamin deficiency.42 On examination, 25% of patients demonstrated neuropathy; 12%, isolated myelopathy; and 41%, combined neuropathy and myelopathy. In 65% of patients, peripheral neuropathic symptoms and signs were combined with other manifestations such as myelopathy, cortical dysfunction, and autonomic dysfunction. In only 3% was neuropathy the only abnormality. In approximately 2% of all patients with peripheral neuropathies seen at referral centers, vitamin B12 deficiency was a primary cause.32 Memory dysfunction and affective and behavioral changes were seen in 8%. Cognitive deficits included psychosis, affective disturbances, and memory disturbances, as well as changes in personality. Orthostatic hypotension has been reported and may result from a disordered release of norepinephrine.43,44 Fourteen percent of patients with cobalamin deficiency had normal examination findings.

T A B L E 109–5. Differential Diagnosis for a Myeloneuropathy (“Absent Ankle Jerks and Upgoing Toes”) Cobalamin deficiency Vitamin E deficiency Copper deficiency Cervical spondylitic myelopathy with lumbar stenosis Amyotrophic lateral sclerosis Friedreich’s ataxia Syphilis Metachromatic leukodystrophy Adrenomyeloneuropathy Mitochondrial cytopathology Ceroid lipofuscinosis

Patients may develop a myeloneuropathy after exposure to nitrous oxide (Table 109–5).28,41,45 This occurs in two populations: those who have normal cobalamin levels but chronically abuse the anesthetic gas for recreational purposes, and those with a subclinical vitamin B12 deficiency who, after a short exposure to nitrous oxide for a dental or surgical procedure, develop paresthesias, burning sensation in the feet, and ataxia. Nitrous oxide is a potent oxidizing agent, which irreversibly oxidizes the cobalt core of cobalamin from a 1+ to 3+ valence state, rendering methylcobalamin inactive. This effectively inhibits the conversion of homocysteine to methionine, thus blocking the supply of S-adenosylmethionine. Low cobalamin levels have also been found in occasional patients with multiple sclerosis46 and human immunodeficiency virus infection47; however, no pathogenic relationship or treatment response has been established in either disorder.

Differential Diagnosis Twenty-five percent of patients with vitamin B12 deficiency have no anemia or macrocystosis.42 The most characteristic manifestations are gait dysfunction and paresthesias in an elderly individual. The hallmark findings of myeloneuropathy, absence of ankle reflexes, and extensor plantar responses, are present in only 41% of patients.42 Vitamin B12 deficiency must be differentiated from other causes of myelopathy and neuropathy.

Evaluation An algorithm for the diagnosis and treatment of cobalamin deficiency (Fig. 109–7) is based on two assumptions: (1) Normal results of a cobalamin assay do not fully rule out cobalamin deficiency, and (2) the normal range may vary, depending on the assay type. Many laboratories have switched from radioassay to chemiluminescence assay, which may have a higher normal reference range (250 to 1100 pg/mL). When cobalamin deficiency is suspected, it is practical to measure methylmalonic acid at the same time as cobalamin. Methylmalonic acid has greater specificity for vitamin B12 deficiency than does homocysteine. If the vitamin B12 level is low and the methylmalonic acid level is elevated, the patient is likely to have true vitamin B12 deficiency. False-positive elevations of the methylmalonic acid level are most commonly caused by renal insufficiency.48 A diagnosis of pernicious anemia (autoimmune parietal cell destruction) can be made by

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Figure 109–7. Algorithm for cobalamin deficiency diagnosis and treatment.* A higher normal reference range should be applied if chemiluminescence or other nonradioisotopic ligand-binding assays are used.† If the clinical picture is suggestive of possible cobalamin deficiency, patients with serum vitamin B12 levels higher than 300 pg/mL should be investigated similarly. IM, intramuscularly. (From Green R, Kinsella LF: Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995; 45:1435-1440.)

finding intrinsic factor antibodies. Unfortunately, this test has low sensitivity (40% to 60%). An elevated serum gastrin level may indicate achlorhydria, pernicious anemia, or food-bound cobalamin malabsorption. A Schilling test helps distinguish the condition as pernicious anemia, food-bound cobalamin malabsorption, or an ileal malabsorption problem.59

taining normal serum vitamin B12 level and for correcting elevation in serum methylmalonic acid level, with a comparable onset of action.50 It may be practical to replenish cobalamin stores first by using injections of cyanocobalamin for 1 week and then shifting to maintenance with 1000-μg daily oral supplements.

Management

Prognosis and Future Perspectives

Treatment may begin with intramuscular injections of cobalamin, 1000 μg/day for 5 days and then 500 to 1000 μg intramuscularly every month. Oral replacement is an alternative for patients who cannot tolerate intramuscular injections or for whom they are impractical. Kuzminski and colleagues (1998) demonstrated that 2000 μg of oral vitamin B12 is as effective as or more so than intramuscular shots given monthly for main-

The earlier intervention begins, the more likely the patient is to have a complete recovery.42,51

Folate (Vitamin B9) Although folic acid deficiency has long been recognized as an important contributor to neural tube defects, less well

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appreciated is its role in cognition and depression. Although both folate and vitamin B12 deficiencies may cause megaloblastic anemia, the neuropsychiatric disturbances may differ. Whereas vitamin B12 deficiency is more likely to result in subacute combined degeneration and neuropathy, folate deficiency is more likely to cause depression and dementia. Folate deficiency may result more frequently in elderly persons from a combination of factors, including poor diet, malabsorption, medications, and increased demand. Of the patients admitted to a geriatric unit, 16% showed evidence of folate deficiency, and this was correlated with both depression and cognitive decline.52 In 1998, folate supplementation of the food supply became mandatory in order to prevent neural tube defects. An unexpected benefit has been a 50% decline in the prevalence of homocysteine elevations in the United States.53 What effect this may have on the incidence of atherosclerosis, cerebrovascular events, and dementia remains to be seen. The link between folate deficiency and elevated homocysteine levels and vascular disease is well established. Less clear is whether aggressive suppression of homocysteine levels by folate supplementation reduces cardiovascular and cerebrovascular events. The Vitamin Intervention in Stroke Prevention (VISP) trial demonstrated that moderate reduction of total homocysteine through the use of folate, cobalamin, and pyridoxine supplements in patients with nondisabling cerebral infarction had no effect on vascular outcomes after 2 years.54

Pyridoxine (Vitamin B6) Pyridoxal phosphate is the active biochemical form of pyridoxine. It is a coenzyme of amino acid metabolism, particularly tryptophan and methionine. Inhibition of methionine metabolism as a result of pyridoxine deficiency results in excessive Sadenosylmethionine accumulation, which in turn inhibits nerve lipid and myelin synthesis.12 The recommended daily allowance of pyridoxine is 2 mg. It is found most abundantly in enriched breads, cereals and grains, chicken, orange and tomato juice, bananas, and avocados. Patients at risk for pyridoxine deficiency include those with general malnutrition, prisoners of war, refugees, alcoholic persons, infants of vitamin B6–deficient mothers, and patients taking isoniazid and hydralazine. Pyridoxine is unique in that both the deficiency and toxic states result in a peripheral neuropathy (described later). The deficiency affects the blood, skin, and nervous system. The skin changes are indistinguishable from those of pellagra, probably because of the close interaction of niacin and pyridoxine. Pyridoxine improves the microcytic anemia of alcoholic persons, as well as the anemia associated with pyridoxine-responsive seizures in infants. Pyridoxine-deficient peripheral neuropathy is seen primarily in patients taking isoniazid or hydralazine, and it is characterized by small-fiber sensory loss in distal limbs, weakness, and reflex changes. Patients describe burning sensation in the feet and painful paresthesias. Central nervous system manifestations include depression, irritability, and confusion.55 Up to 10% of patients taking isoniazid may develop a peripheral sensory neuropathy. Isoniazid promotes increased pyridoxine excretion in the urine, which results in a deficiency state. Daily intake of vitamin B6 (10-50 mg) prevents the neuropathy induced by isoniazid treatment, and thus vitamin B6

should be taken by patients receiving isoniazid. Once established, the neuropathy does not entirely resolve but may improve with replacement vitamin B6.

Vitamin E α-Tocopherol is the most active form of vitamin E present in humans. Tocopherol is absorbed and incorporated into chylomicrons in the small intestine. It is carried in portal blood to the liver, and α-tocopherol transfer protein binds and recycles vitamin E in the liver for incorporation into low-density lipoproteins and very-low-density lipoproteins.56 Once it is delivered to the cells, α-tocopherol serves as an antioxidant, preventing free radical peroxidation and injury to cell membranes. It is stored in adipose tissue, the liver, and muscles. Deficiency can occur at any stage of tocopherol metabolism: reduced intake, fat malabsorption, inhibition of enterohepatic circulation, mutation of α-tocopherol transport protein, and abetalipoproteinemia. Vitamin E deficiency leads to axonal membrane injury, with resultant axonal degeneration of peripheral nerves, dorsal root ganglia, and posterior columns (Figs. 109–8 and 109–9).57 Superficially, the spinal cord abnormalities bear a striking resemblance to those found with subacute combined degeneration of vitamin B12 deficiency. However, the lesions of vitamin B12 deficiency are caused by spongy demyelination of the posterior columns and lateral tracts, whereas those of vitamin E deficiency are the result of swollen and dystrophic axons, or spheroids, and astrocytosis in the posterior columns, dorsal root ganglia, and Clarke’s column. Vitamin E is fat-soluble and found in abundance in vegetable oils and wheat germ. The recommended daily allowance is 15 mg (22.5 IU) for adults. Patients at risk for the development of vitamin E deficiency include those who have the clinical conditions listed in Table 109–6.

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Figure 109–8. Vitamin E deficiency myelopathy. Cross-section of cervical spinal cord. The triple arrowheads denote light-staining symmetrical areas of degeneration involving the posterior columns. The two single arrowheads indicate involvement of the dorsal and ventral spinocerebellar tracts. In the posterior columns, the fasciculus cuneatus is affected to a greater extent than is the gracilis muscle. On microscopic study, numerous swollen and dystrophic axons (spheroids) and astrocytosis are visible in the posterior columns, and nerve cell loss is observed in the dorsal root ganglia. Luxol-fast blue–periodic acid–Schiff stain. (From Rosenblum JL, Keating JP, Prensky AL, et al: A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med 1981; 304:506. Copyright 1981 Massachusetts Medical Society. All rights reserved.)

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Figure 109–9. Teased nerve preparation in a patient with vitamin E deficiency, demonstrating axonal degeneration (arrows) in the sural nerve and osmium impregnation. N, nerve tissue. (From Rosenblum JL, Keating JP, Prensky AL, et al: A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med 1981; 304:507. Copyright 1981 Massachusetts Medical Society. All rights reserved.)

T A B L E 109–6. Disorders Associated with Vitamin E Deficiency Abetalipoproteinemia (Bassen-Kornzweig disease) Celiac disease Chronic pancreatitis Chronic cholestatic liver disease Cystic fibrosis Familial vitamin E deficiency (α-tocopherol transfer protein mutation) Homozygous hypobetalipoproteinemia Inflammatory bowel disease Intestinal lymphangiectasia Malnutrition Postgastrectomy Short bowel syndrome Total parenteral nutrition Tropical sprue Whipple’s disease From Jackson CE, Amato AA, Barohn RJ: Isolated vitamin E deficiency. Muscle Nerve 1996; 19:1162.

T A B L E 109–7. Neurologic Findings in Vitamin E deficiency Truncal and appendicular ataxia Areflexia Abnormal vibration sense and proprioception Ophthalmoplegia Retinitis pigmentosa and acanthocytosis (in patients with abetalipoproteinemia) Dysarthria Generalized weakness Extensor plantar responses From Jackson CE, Amato AA, Barohn RJ: Isolated vitamin E deficiency. Muscle Nerve 1996; 19:1162.

Patients develop areflexia, cerebellar ataxia, cutaneous sensory impairment, position and vibratory sense abnormalities, and, less commonly, ophthalmoplegia, muscle weakness, nystagmus, extensor plantar responses, ptosis, and dysarthria (Table 109–7).58 Acanthocytosis and pigmentary retinopathy is seen primarily in patients with abetalipoproteinemia. Patients with abetalipoproteinemia and congenital malabsorption develop symptoms in childhood and adolescence. On occasion,

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Figure 109–10. Patient with isolated vitamin E deficiency, demonstrating gait characterized by pseudodystonic extension of the knees, as well as prominent lordosis, and genu recurvatum. (From Jackson CE, Amato AA, Barohn RJ: Isolated vitamin E deficiency. Muscle Nerve 1996; 19:1163.)

adults with acquired malabsorption present with progressive ataxia. The clinical phenotype that accompanies familial vitamin E deficiency phenotype is indistinguishable from that of Friedreich’s ataxia (Fig. 109–10). Autosomal recessive familial vitamin E deficiency has been studied extensively and found to be caused by a frameshift mutation within the α-tocopherol transfer protein gene on chromosome 8. Defective α-tocopherol transfer protein prevents incorporation of vitamin E into very-low-density lipoproteins.59,60 Friedreich’s ataxia, Machado-Joseph disease, and other familial spinocerebellar ataxias61 should be considered in the differential diagnosis of patients presenting with this constellation of signs and symptoms. Approximately 90% or more of vitamin E is α-tocopherol, which can be measured directly in serum. Occasional patients with hyperlipidemia may have a falsely low α-tocopherol level. Vitamin E deficiency may result in electrophysiological abnormalities, including low-amplitude sensory nerve action potentials, slowed conductions, and abnormal somatosensory evoked potentials.62 Administration of α-tocopherol (400 mg twice a day) may prevent or reverse the effects of a deficiency state. Dosages of up to 100 mg/kg/day may be required in patients with abetalipoproteinemia and the familial vitamin E deficiency syndrome. The prognosis for recovery depends on the duration of symptoms before the initiation of treatment. Vitamin E is fat soluble and found in abundance in vegetable oils and wheat germ. It is carried in portal blood to the liver, where α-tocopherol transfer protein binds it and recycles vitamin E for incorporation into low-density and very-low-density lipoproteins. The patients at risk for development of vitamin E deficiency include those with hypobetalipoproteinemia or

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abetalipoproteinemia; other disorders of the pancreas and liver, such as cystic fibrosis; protein-calorie malnutrition; familial vitamin E deficiency; and other malabsorption states.63 Symptoms include areflexia, cerebellar ataxia, cutaneous sensory impairment, position and vibratory sense abnormalities, and, less commonly, ophthalmoplegia, muscle weakness, nystagmus, extensor plantar responses, ptosis, and dysarthria. The peripheral neuropathy is usually limited to the legs and is mild, axonal, and sensorimotor in nature.62 Vitamin E supplementation has been found to be protective from chemotherapy-induced neuropathy when administered before a patient receives cisplatin or paclitaxel.64

show confusion, memory loss, and affective disturbances. Many patients have been mistakenly diagnosed early in their course as having a conversion disorder.18 The polyneuropathy is axonal and demyelinating in type, acute in onset, and slow to resolve. Pathological studies have demonstrated axonal degeneration. One study demonstrating lipid-laden neurons and Schwann cells surrounding demyelinating and degenerating axons has not been replicated.66 The pathophysiology of this disorder is unknown but is probably polynutritional. The degree of disability appears to depend on the duration and severity of symptoms before diagnosis and treatment. Most patients have some residual weakness and sensory loss.

OTHER NUTRITIONAL SYNDROMES

Copper Deficiency Myeloneuropathy

Postgastroplasty Polyneuropathy Acute post–gastric restriction surgery neuropathy may affect up to 7% of patients after weight-reduction surgery.65 Some patients undergoing bariatric, or weight-reduction, surgery develop a syndrome of acute or subacute sensory loss, weakness, and areflexia, usually after a period of dramatic weight loss and repeated bouts of protracted vomiting.66 Some have also developed a type of encephalopathy that is clinically and pathologically identical to Wernicke-Korsakoff syndrome, with or without an associated polyneuropathy.18 Indeed, Wernicke and Korsakoff each described young women with intractable vomiting in their original reports: One woman had attempted suicide by drinking sulfuric acid, whereas the other had hyperemesis gravidarum.15 Thaisetthawatkul and colleagues (2004) compared 435 patients who underwent bariatric surgery with 126 control subjects who underwent gallbladder surgery. They found that 71 (16% of) those undergoing bariatric surgery developed some form of neuropathy, in comparison with 3% who underwent gallbladder surgery. Of the 71, more than half had entrapment neuropathy, mostly carpal tunnel syndrome. Twenty-seven had a polyneuropathy, and 5 had a radiculoplexus neuropathy. Sural nerve biopsies in five patients (four with polyneuropathy, one with radiculoplexus neuropathy) revealed prominent axonal degeneration with variable degrees of perivascular mononuclear cell infiltration. No definite vasculitis was seen. Risk factors identified for neuropathic complications of bariatric surgery were acute weight loss, excessive vomiting, postoperative complications, poor vitamin supplementation, and jejunoileal bypass procedure.65 Intractable vomiting is a constant feature. The syndrome may manifest suddenly several months after surgical procedures that include gastrojejunostomy, gastric stapling, vertical banding gastroplasty, and gastrectomy with Roux-en-Y anastomosis.67 After a period of recurrent vomiting and precipitous weight loss, patients develop numbness and tingling in the soles of the feet, calves, and thighs. Distal or proximal weakness may develop, and the patient may have difficulty arising from a chair or climbing stairs. Examination reveals symmetrical sensory loss in the legs more than in the arms, muscle weakness, and areflexia. Patients may develop quadriparesis and prolonged or permanent disability. Autonomic disturbances and orthostatic hypotension have also been recognized. When the condition is accompanied by encephalopathy, patients may

Subacute combined degeneration has been reported in patients with copper deficiency.68 In several instances, the cause was excessive zinc consumption in the form of remedies for prevention of colds and upper respiratory infections. Other patients have acquired the disorder as the result of malabsorption from gastric bypass or gastric reduction surgery. In a series of 25 patients, Kumar and associates found that all had gait dysfunction, probably as a result of sensory ataxia caused by posterior column dysfunction.68 Corticospinal signs and evidence of peripheral neuropathy were present in many. Seventeen had elevated serum zinc levels. Ten of 25 had a history of prior gastric surgery. Copper supplementation did not appear to reverse the clinical findings. Copper may now be added to other nutrient deficiencies, those of vitamin B12 and vitamin E, that may result in a myeloneuropathy.

Pyridoxine Toxicity Neuropathy Excess pyridoxine also results in a peripheral neuropathy. Megadoses of pyridoxine (generally in excess of 2 g/day) produce large-fiber sensory neuropathy,69 which, however, has also been reported with long-standing use of as little as 200 mg/day.70,71 Paresthesias, ataxia, and burning sensation in the feet may occur abruptly after megadoses or from 1 month to 3 years after lower doses. Sural nerve biopsies reveal reduced myelin fiber density and myelin debris, suggestive of axonal degeneration. After they stop taking pyridoxine, all patients improve, but the condition resolves entirely in only a few. Contrary to common misconceptions, such cases demonstrate that a water-soluble B vitamin may be toxic when taken in megadoses.

Strachan’s Syndrome The term Strachan’s syndrome was coined by M. Fisher, honoring Henry Strachan, a British medical officer stationed in Jamaica, who in 1888 described a syndrome of painful peripheral neuropathy, ataxia, optic neuropathy, and stomatitis among sugar cane workers.72 Symptoms included sensorineural deafness, dizziness, confusion, spastic leg weakness, footdrop, Wernicke’s encephalopathy, and rare cases of neck extensor weakness and myasthenic bulbar weakness. Poor nutrition, hard physical labor, and concurrent infection were thought to be exacerbating factors. In Fisher’s autopsy series of Canadian prisoners of war, the most prominent pathological finding was demyelination of the posterior columns of the thoracic and cer-

chapter 109 vitamin deficiencies vical spinal cord.73 This demyelination accounted for the loss of vibratory and position sense and sensory ataxia. Pathologically, the optic and auditory nerves showed moderate to severe demyelination. An outbreak of optic and peripheral neuropathy closely resembling Strachan’s syndrome occurred in Cuba from 1992 to 1993.74 Fifty thousand people developed variable degrees of optic neuropathy, painful sensory neuropathy, dorsolateral myelopathy, sensorineural deafness, spastic paraparesis, dysphonia, and dysautonomia. Almost half (45%) developed only centrocecal scotoma and optic neuropathy, often after a period of weight loss. Optic neuropathy and myeloneuropathy were seen in 24%, optic neuropathy and sensorineural hearing loss in 14%, and peripheral and optic neuropathies with hearing loss in 7%.74 Proposed mechanisms included deficiencies of vitamin B complex and thiamine, cyanide intoxication, viral infection, and mitochondrial DNA mutations. Infections appeared to precipitate or exacerbate symptoms. Almost all patients responded to early supplementation with B complex vitamins. Evidence of peripheral nerve involvement has been inconsistent. Clinical evidence of neuropathy is often lacking despite severe symptoms. Treatment consists of reestablishing a balanced diet with B-complex vitamin and vitamin A supplementation. In the Cuban experience, long-term sequelae were rare, because most patients underwent early treatment with nutritional supplements, including B-complex vitamin and vitamin A. In prisoners of war with long-standing symptoms, persistent ataxia, burning sensation in the feet, and visual defects often persisted despite adequate supplementation.

K E Y

P O I N T S

●

The rising popularity of gastric bypass surgery for morbid obesity, the use and misuse of dietary supplements, and widespread use of acid-suppressive therapy may lead to an increase in nutritional disorders of the nervous system.

●

New syndromes of nutritional deficiency—such as copper deficiency myeloneuropathy, post–gastric reduction surgery neuropathy, pyridoxine toxicity, and genetic disorders of folate and cobalamin metabolism—are being recognized.

●

Cobalamin (vitamin B12) deficiency should be considered in nonanemic patients with symptoms of gait dysfunction and paresthesias.

●

In up to 10% of patients with low normal vitamin B12 levels, true deficiency may be confirmed with metabolite assays for methylmalonic acid and homocysteine.

Suggested Reading Carmel R, Green R, Rosenblatt DS, et al: Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program) 2003; 62-81. Kuzminski AM, Del Giacco EJ, Allen RH, et al: Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1191-1198.

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Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, et al: A controlled study of peripheral neuropathy after bariatric surgery. Neurology 2004; 63:1462-1470.

References 1. O’Keefe ST, Tormey WP, Glasgow R, et al: Thiamin deficiency in hospitalized elderly patients. Gerontology 1994; 40:18-24. 2. Harper C: The incidence of Wernicke’s encephalopathy in Australia—a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 1983; 46:593-598. 3. Harper C, Giles M, Finlay-Jones R. Clinical signs of the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 1986; 49:341-345. 4. Langohr HD, Petruch F, Schroth J: Vitamin B1, B2, and B6 deficiency and neurological disorders. J Neurol 1981; 225:95-108. 5. Joosten E, Van Den Berg A, Riezler R, et al: Metabolic evidence of deficiencies of vitamin B12, folate, and vitamin B6 occur commonly in elderly people. Am J Nutr 1993; 58:468-476. 6. Green R, Kinsella LJ: Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995; 45:1435-1430. 7. Incalzi RA, Gemma A, Capparella O, et al: Energy intake and in-hospital starvation, a clinically relevant relationship. Arch Intern Med 1996; 156:425-429. 8. Leigh D, McBurney A, McIlwain H: Erythrocyte transketolase activity in the Wernicke-Korsakoff syndrome. Br J Psychol 1981; 138:153-156. 9. Rueler JB, Girard DE, Cooney TG: Wernicke’s encephalopathy. N Engl J Med 1985; 312:1035-1039. 10. Haas RH: Thiamine and the brain. Annu Rev Nutr 1988; 8:483515. 11. Koike H, Iijima M, Sugiura M, et al: Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann Neurol 2003; 54:19-29. 12. Marcus R, Coulston AM: Water soluble vitamin, the vitamin Bcomplex and ascorbic acid. In Shils ME, Olson JA, Shike M, eds: Modern Nutrition in Health and Disease, 8th ed. Philadelphia: Lea & Febiger, 1994, pp 1547-1590. 13. Vortmeyer AO, Hagel C, Laas R: Hemorrhagic thiamine deficient encephalopathy following prolonged parenteral nutrition. J Neurol Neurosurg Psychiatry 1992; 55:826-829. 14. Fattal-Valevski A, Kessler A, Sela BA, et al: Outbreak of lifethreatening thiamine deficiency in infants in Israel caused by a defective soy-based formula. Pediatrics 2005; 115:e233-e238. 15. Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syndrome. Philadelphia: FA Davis, 1971. 16. Seehra H, Macdermott N, Lascelles RG, et al: Wernicke’s encephalopathy after vertical banded gastroplasty for morbid obesity. BMJ 1996; 312:434. 17. Haid RW, Gutman L, Crosby TN: Wernicke Korsakoff encephalopathy after gastric plication. JAMA 1992; 247:25662577. 18. Paulson GW, Martin EW, Mojzisik C, et al: Neurologic complications of gastric partitioning. Arch Neurol 1985; 42:675-677. 19. Denny-Brown D: Neurological conditions resulting from prolonged and severe dietary restriction. Case reports in prisoners of war, and general review. Medicine 1947; 26:41-113. 20. Jagadha V, Deck JHN, Halliday WC, et al: Wernicke’s encephalopathy in patients on peritoneal dialysis or hemodialysis. Ann Neurol 1987; 21:78-84. 21. Descombes E, Dessibourg CA, Felly G: Acute encephalopathy due to thiamine deficiency (Wernicke’s encephalopathy) in a chronic hemodialyzed patient: a case report. Clin Nephrol 1991; 35:171-175. 22. Martin PR, McCool BA, Singleton CK: Molecular genetics of transketolase in the pathogenesis of the Wernicke-Korsakoff syndrome. Metab Brain Dis 1995; 10:45-55.

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23. Nixon PF: Is there a genetic component to the pathogenesis of the Wernicke-Korsakoff syndrome? Alcohol Alcohol 1984; 19:219-221. 24. Yamashita M, Yamamoto T: Wernicke’s encephalopathy with symmetric pericentral involvement: MR findings. J Comput Assist Tomogr 1995; 19:306-308. 25. Jollife N, Bowman KN, Rosenblum LA, et al: Nicotinic acid deficiency encephalopathy. JAMA 1940; 114:307-312. 26. Teare JP, Hyamas G, Pollock S: Acute encephalopathy due to co-existent nicotinic acid and thiamine deficiency. Br J Clin Pract 1993; 47:343-344. 27. Ishii N, Nishihara Y: Pellagra among chronic alcoholics: clinical and pathologic study of 20 necropsy cases. J Neurol Neurosurg Psychiatry 1981; 44:209-215. 28. Flippo TS, Holder WD Jr: Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch Surg 1993; 128:1391-1395. 29. Lever EG, Elwes RDC, Williams A, et al: Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry 1986; 49:1203-1207. 30. Pant SS, Ashbury AK, Richardson EP: The myelopathy of pernicious anemia: a neuropathological reappraisal. Acta Neurol Scand 1968; 44(Suppl 35):1-36. 31. McCombe PA, McLeod JC: The peripheral neuropathy of vitamin B12 deficiency. J Neurol Sci 1984; 66:117-126. 32. Saperstein DS, Wofe GI, Gronseth GS, et al: Challenges in the identification of cobalamin deficiency polyneuropathy. Arch Neurol 2003; 60:1296-1301. 33. Lindenbaum J, Rosenberg IH, Wilson PW, et al: Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994;60:2-11. 34. Savage DG, Lindenbaum J, Stabler SP, et al: Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994; 96:239-246. 35. Fernando OV, Grimsley EW: Prevalence of folate deficiency and macrocytosis in patients with and without alcohol-related illness. South Med J 1999; 92:841. 36. Lindenbaum J, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318:17201728. 37. Carmel R: Cobalamin, the stomach, and aging. Am J Clin Nutr 1997; 66:750-759. 38. Sumner AE, Chin MM, Abrahm JL, et al: Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med 1996; 124:469-476. 39. Halverson JD: Micronutrient deficiencies after gastric bypass for morbid obesity. Am Surg 1986; 52:594-598. 40. Marcuard SP, Albernaz L, Khazanie PG: Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994; 120:211-215. 41. Kinsella LJ, Green R: Anesthesia paresthetica: nitrous oxide–induced cobalamin deficiency. Neurology 1995; 45:16081610. 42. Healton EV, Savage DG, Brust JCN, et al: Neurologic aspects of cobalamin deficiency. Medicine 1991; 70:229-244. 43. Eisenhofer G, Lambie DG, Johnson RH, et al: Deficient catecholamine release as the basis of orthostatic hypotension in pernicious anemia. J Neurol Neurosurg Psychiatry 1982; 45:1053-1055. 44. White WB, Reik L Jr, Cutlip DE: Pernicious anemia seen initially as orthostatic hypotension. Arch Intern Med 1991; 141:1543-1544. 45. Layzer RB: Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 1988; 2:1227-1230.

46. Reynolds EH, Bottiglieri T, Laundy M, et al: Vitamin B12 metabolism in multiple sclerosis. Arch Neurol 1992; 49:649. 47. Herbert V: Vitamin B12 deficiency neuropsychiatric damage in acquired immunodeficiency syndrome. Arch Neurol 1993; 50:569. 48. Hvas AM, Juul S, Gerdes LU, et al: The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine. J Intern Med 2000; 247:507-512. 49. Carmel R, Green R, Rosenblatt DS, et al: Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program) 2003; 62-81. 50. Kuzminski AM, Del Giacco EJ, Allen RH, et al: Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1191-1198. 51. Savage DG, Lindenbaum J: Neurological complications of acquired cobalamin deficiency: clinical aspects. Ballieres Clin Haematol 1995; 8:657-678. 52. Reynolds EH: Folic acid, ageing, depression and dementia. BMJ 2002; 324:1512-1515. 53. Rader JI: Folic acid fortification, folate status and plasma homocysteine. J Nutr 2002; 132(Suppl):2466S-2470S. 54. Toole JF, Malinow MR, Chambless LE, et al: Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) trial. JAMA 2004; 291:565-575. 55. Brent J, Vo N: Reversal of prolonged isoniazid-induced coma by pyridoxine. Arch Intern Med 1990; 150:1751-1753. 56. Bieri JG, Corash L, Hubbard VS: Medical uses of vitamin E. N Engl J Med 1983; 308:1063-1071. 57. Rosenblum JL, Keating JP, Prensky AL, et al: A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med 1981; 304:503-508. 58. Muller DPR, Lloyd JK, Wolff OH: Vitamin E and neurological function. Lancet 1983; 1:225-227. 59. Gotoda T, Arita M, Arai H, et al: Adult onset spinocerebellar dysfunction caused by a mutation in the gene for the alphatocopherol transfer protein. N Engl J Med 1995; 333:13131318. 60. Harding AE, Matthews S, Jones S, et al: Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med 1985; 313:32-35. 61. Rosenberg RN: Spinocerebellar ataxias and ataxins. N Engl J Med 1995; 333:1351-1352. 62. Brin MF, Pedley TA, Lovelace RE, et al: Electrophysiologic features of abetalipoproteinemia: functional consequences of vitamin E deficiency. Neurology 1986; 36:669-673. 63. Jackson CE, Amato AA, Barohn RJ: Isolated vitamin E deficiency. Muscle Nerve 1996; 19:1161-1165. 64. Argyriou AA, Chroni E, Koutras A, et al: Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 2005; 64:2631. 65. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, et al: A controlled study of peripheral neuropathy after bariatric surgery. Neurology 2004; 63:1462-1470. 66. Feit H, Glasberg MR, Ireton C, et al: Peripheral neuropathy and starvation after gastric partitioning for morbid obesity. Ann Intern Med 1982; 96:453-455. 67. Peltier G, Hermreck AS, Moffat RE, et al: Complications following gastric bypass procedure for morbid obesity. Surgery 1979; 86:648-654. 68. Kumar N, Gross JB, Ahlskog JE: Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004; 63:33-39. 69. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 1983; 309:445-448.

chapter 109 vitamin deficiencies 70. Dalton K, Dalton MJT: Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 1987; 76:8-11. 71. Parry GJ, Bredesen DE: Sensory neuropathy with low-dose pyridoxine. Neurology 1985; 35:1466-1468. 72. Strachan H: On a form of multiple neuritis prevalent in the West Indies. Practitioner 1897; 59:477-484.

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73. Fisher M: Residual neuropathological changes in Canadians held prisoner of war by the Japanese (Strachan’s disease). Can Serv Med J 1955; 11:157-199. 74. Roman GC: An epidemic in Cuba of optic neuropathy, sensorineural deafness, peripheral sensory neuropathy and dorsal lateral myeloneuropathy. J Neurol Sci 1994; 127:11-28.

CHAPTER

110

UREA CYCLE DISORDERS ●

●

●

●

E. A. Crombez and S. D. Cederbaum

The urea cycle is a sequence of six enzymatic and two transport steps necessary to metabolize and excrete the nitrogen generated by the breakdown of amino acids in protein and other nitrogen-containing molecules (Fig. 110–1). The diet and the breakdown of endogenous tissues, particularly of skeletal muscle, are important sources of protein. Endogenous protein breakdown during episodes of acute catabolism presents the deficient ureagenic system with an overwhelming burden and results in the hyperammonemia that occurs in acute infections, after parturition, or during the menstrual cycle.1 The complete urea cycle is found only in the liver, although individual enzymes are present at lesser levels in other organs and may have additional metabolic roles. Severe liver disease with biosynthetic failure may also result in a deficient urea cycle and hyperammonemia. The first three enzymes in this cycle, Nacetylglutamate synthase (NAGS), carbamoyl phosphate synthase I (CPSI), and ornithine transcarbamylase (OTC) function inside mitochondria, and the latter three, argininosuccinic acid synthase, argininosuccinic acid lyase (ASL), and arginase, act in the cytosol. The two transporters are for ornithine and aspartate. Defects in citrin, the transporter for aspartate, causes citrin deficiency, also called citrullinemia type II. Defects in ornithine translocase, the transporter for ornithine, causes ornithine translocase deficiency (ORNT1), also called hyperammonemia, hyperornithinemia, and homocitrullinuria syndrome. Defects in all six steps of the urea cycle and in the transporters are known. Any deficiency of these proteins may result in the accumulation of excess ammonia in the body. Ammonia is toxic to the central nervous system, and any continuous or intermittent elevation of ammonia can result in encephalopathy and neurological damage. This damage can lead to seizures, psychosis, mental retardation, and death. The essential genetic characteristics of the eight disorders are summarized in Table 110–1.

or in a child with decreased appetite, vomiting, lethargy, behavioral abnormalities, and an altered finding on neurological examination. In the affected older child or adult, blood ammonia determination should be part of the evaluation of any acute encephalopathy or recurrent late-onset psychosis or somnolence.2 The diagnosis is supported by an elevated plasma ammonia concentration with a normal anion gap and a normal serum glucose concentration (Fig. 110–2). An encephalopathic electroencephalographic pattern during an episode of hyperammonemia and evidence of brain atrophy on magnetic resonance imaging, although nonspecific, provide further support for the diagnosis of a urea cycle defect. Plasma quantitative amino acid analysis can be used to aid in the delineation of the specific urea cycle disorder. Plasma amino acid analysis reveals reduced levels of arginine in all urea cycle disorders except arginase deficiency, in which arginine levels are elevated. Citrulline levels can also aid in discriminating the various urea cycle defects. Citrulline is produced by the first three enzymes, NAGS, CPSI, and OTC, and decreased levels are found when the level of any of these enzymes is deficient. In contrast, citrulline levels are increased with deficiencies of argininosuccinic acid synthase and ASL, because citrulline serves as a substrate for these more distal reactions. Urinary orotic acid levels are also used to differentiate CPSI and NAGS deficiency from OTC deficiencies. In the former, orotic acid levels are normal or reduced, whereas in the latter, they are elevated. A definitive diagnosis is made through measurement of enzyme activity, often from a liver tissue sample. If liver biopsy is not possible, diagnosis can be based on family history, clinical presentation, amino acid and orotic acid testing, and molecular genetic testing. These laboratory studies are carried out in highly specialized laboratories, which can be found on the GeneTests website (www.genetests.org).

EPIDEMIOLOGY DEFINITION The diagnosis of a urea cycle disorder is based on clinical examination and on biochemical, enzymatic, and molecular analyses. A urea cycle defect is first suspected in an infant with anorexia, alterations in respiratory function and thermoregulation, lethargy, seizures, and deteriorating neurological status

Seven of the eight urea cycle disorders—NAGS, CPSI, argininosuccinic acid synthase, ASL, arginase, ORNT1, and citrin deficiencies—are inherited as autosomal recessive traits. OTC deficiency is an X-linked disorder. Because of the absence of nationwide neonatal screening for these disorders, the true incidence of the individual urea cycle defects is not known. The estimated combined incidence for all urea cycle defects is 1 per

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■

HCO3⫺ ⫹ NH4⫹ UREA

Ornithine

Ornithine

OTC

Arginine

MITOCHONDRION NAGS

CPS-1

NAG

ARG1 CITR

Diet and Catabolism

NH4⫹

HCO3⫺

ORNT

Glutamate ⫹ Acetyl Co-A

CP Glutamate ⫹ Acetate

Arginine NOS

ASL

Citrulline

Aspartate

NO Orotic Acid

Citrulline

Figure 110–1. The six primary enzymatic steps of the urea cycle are shown in bold capital letters. Function of ornithine transporter (ORNT) and aspartate transporter (CITR) is necessary for the movement of substrates in and out of the mitochondrion. ARG1, arginase; ASL, argininosuccinic acid lyase; ASS, argininosuccinic acid synthase; Co-A, coenzyme A; CP, carbamoyl phosphate; CPS1, carbamoyl phosphate synthase; NAG, Nacetylglutamate; NAGS, Nacetylglutamate synthase; NO, nitric oxide; NOS, nitric oxide synthase; OTC, ornithine transcarbamylase.

Ornithine

ASS Aspartate Argininosuccinate

CYTOPLASM

T A B L E 110–1. Disorders of the Urea Cycle* Disorder and Protein Defect

Locus

Inheritance

N-acetylglutamate synthase deficiency Carbamoyl phosphate synthase I deficiency Ornithine transcarbamylase deficiency Argininosuccinic acid synthase deficiency Argininosuccinic acid lyase deficiency Arginase deficiency Citrin deficiency (also called citrullinemia II deficiency) Ornithine translocase deficiency (also called hyperammonemia, hyperornithinemia, and homocitrullinuria syndrome)

17q21.3 2q35 Xp21.1 9q34 7q11.2 6q23 7q21.3 13q14

Autosomal recessive Autosomal recessive X-linked Autosomal recessive Autosomal recessive Autosomal recessive Autosomal recessive Autosomal recessive

Heterozygote Detection

Prenatal Diagnosis

+ +\− + +\− + + +\− +\−

+ + + + + + +\− +

+, Testing is available by enzyme analysis, biochemical testing, linkage analysis, or mutation testing. +/−, Testing is available if mutation is known or if biochemical and enzymatic testing is definitive. *Similar to the table developed by W. R. Wilcox and S. D. Cederbaum and published in Rimoin D, Connor M, Pyeritz R, et al, eds: Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th ed. New York: Churchill Livingstone, 2001.

8200. OTC deficiency has the highest incidence, and arginase and NAGS deficiencies, the lowest.

CLINICAL FEATURES Severity of symptoms and age at onset are related, at least partially, to the position of the deficient enzyme in the pathway and to the degree of the enzymatic defect. Urea cycle disorders usually manifest either in the neonatal period or later in childhood. Manifestation in the neonatal period results from severe deficiency one of the first five enzymes in the cycle: NAGS, CPSI, OTC, argininosuccinic acid synthase, or ASL. Clinical manifestation after the neonatal period usually results from milder or partial defects of these enzymes, from arginase deficiency, or from disorders of one of the two transporters. Severe deficiency of any of the urea cycle enzymes except arginase results in the accumulation of ammonia and other

intermediate metabolites during the first few days of life. Unlike these disorders, arginase, ORNT1, and citrin deficiencies infrequently result in symptomatic elevation of plasma ammonia in the neonatal period and are the mildest of the eight urea cycle disorders. In patients with partial defects of these enzymes, a metabolic crisis with ammonia accumulation may be triggered by intercurrent illnesses or by stress at almost any time in life. Although these disorders share common symptoms, the severity and age at first manifestation can vary a great deal between and within the specific disorders. Many newborns with a severe enzyme deficiency initially appear well but rapidly develop hyperammonemia and lethargy, anorexia, abnormal respiratory patterns, hypothermia, seizures, abnormal posturing, and deterioration into coma. This process is accompanied by cerebral edema. Severe deficiency of NAGS, CPSI, OTC, argininosuccinic acid synthase, or ASL, the first five enzymes in the cycle, almost invariably manifests within the first few days after birth and has a high

chapter 110 urea cycle disorders ■

Elevated plasma ammonia concentration

Normal pH

Obtain: Urinary organic acids to evaluate inborn error of organic acid metabolism Primary urea cycle problem Obtain: Plasma amino acids

Low citrulline and arginine plasma concentration

Elevated citrulline plasma concentration

Obtain: Urine orotic acid

CPSI deficiency or NAGS deficiency: low or normal urinary orotic acid Obtain: Liver biopsy

Figure 110–2. Sequence of tests used in the differential diagnosis of hyperammonemia and urea cycle disorders. ASL, argininosuccinic acid lyase; ASS, argininosuccinic acid synthase; CPSI, carbamoyl phosphate synthase I; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase. (Modified from Summar ML, Tuchman M: Urea Cycle Disorders Overview. In GeneReviews at GeneTests. Seattle: University of Washington, Seattle, April 2003.)

Obtain: Blood pH

Low pH

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Markedly elevated plasma arginine concentration Confirm arginase deficiency with red cell enzyme assay

OTC deficienty: elevated urinary orotic acid Obtain: Liver biopsy or OTC molecular genetic testing

ASS deficiency: absent arginosuccinate

ASL deficiency: elevated arginosuccinate

Obtain: Fibroblast enzyme assay

Obtain: Red cell or fibroblast enzyme assay

mortality rate. Children with arginase, ORNT1 and citrin deficiencies can present in childhood, but episodes of symptomatic hyperammonemia are uncommon. In partial urea cycle enzyme deficiencies, individuals do well until an intercurrent illness or other stress results in a metabolic crisis with ammonia accumulation. In these individuals, the first recognized clinical episode may be delayed for months or years, and these patients typically have serial and milder elevations of plasma ammonia concentration throughout their lives. These individuals may have only recurrent abdominal pain, and the first indication of an inborn error may be developmental delay resulting from ammonia intoxication. Although the clinical signs and symptoms of the specific urea cycle disorders vary to a degree, a typical hyperammonemic episode is marked by loss of appetite, vomiting, lethargy, and behavioral abnormalities. The episode can be quite subtle and nonspecific. These initial symptoms progress to coma if there is no therapeutic intervention. Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brainstem. Seizures are common with severe hyperammonemia and are present in about half of affected patients. Respiratory alkalosis secondary to the hyperventilation caused by cerebral edema is

a common early finding. Hypoventilation and respiratory arrest can occur as pressure on the brainstem increases. Deficiency of the sixth enzyme, arginase, typically manifests in childhood with growth failure, developmental delay, and/or school failure and affects primarily the central nervous system. Episodic hyperammonemia of variable degree can occur but is rarely severe enough to be life-threatening. Typically, birth and early childhood are normal. At the age of 1 to 3 years, there is growth failure, and spasticity begins to develop. Soon, development, previously normal, slows or stops, and the child begins to lose previously achieved developmental milestones. If untreated, arginase deficiency progresses to severe spasticity with joint contractures, loss of ambulation, and severe mental retardation. Seizures are common and can usually be well controlled.

Neurotoxicity A common manifestation of all urea cycle disorders is episodic encephalopathy associated with hyperammonemia. Although ammonia is a well-recognized neurotoxin, the nature and specific effect that hyperammonemia may have on the central

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nervous system is not well understood. During a crisis, hyperammonemia causes increased blood-brain barrier permeability, depletion of intermediates of energy metabolism, and disaggregation of microtubules. Ammonia is toxic to the central nervous system even when levels are only mildly elevated, as during long-term therapy. Mildly elevated ammonia levels may cause alterations of axonal development and alterations in brain amino acid and neurotransmitter levels. Glutamine, an amino acid usually in equilibrium with ammonia and present in much higher levels in the blood, is also a likely proximate toxin. The elevated levels of glutamine in blood are mirrored in the cerebrospinal fluid and have been associated with astrocyte swelling and cerebral hypercirculation. Although cerebrospinal fluid glutamine is not usually monitored, instances of patients with neurological symptoms disproportionate to plasma ammonia levels have been associated with higher elevations of cerebrospinal fluid glutamine levels. Elevated glutamine levels may also cause neurotransmitter abnormalities. Chronically elevated glutamine levels stimulate the transport of large neutral amino acids, including tryptophan. Elevated amounts of tryptophan are converted to serotonin and quinolinic acid, both levels of which are elevated in the brains of OTC-deficient patients. These changes in serotonin metabolism may contribute to the behavioral, sleep and feeding problems seen in patients with urea cycle disorders. Clinicians’ ability to measure brain glutamine by magnetic resonance spectroscopy is improving, and these studies may become an essential part of the evaluation of any patient suspected of having a urea cycle disorder. Therapy could then focus on lowering the brain glutamine levels as an endpoint.

later ages are also accompanied by cerebral edema, which becomes even more dangerous once cranial sutures have fused. After hyperammonemic coma, magnetic resonance imaging and computed tomography also demonstrate increased sulcal markings, bilateral symmetrical low-density white matter lesions, and diffuse atrophy, sparing the cerebellum. In patients who have died during a hyperammonemic crisis, neuropathological changes have included intracerebral hemorrhage, prominent cerebral edema, swelling of type II astrocytes, and generalized neuronal cell loss (Fig. 110–4). Neuropathology in older children has included ulegyria, cortical atrophy with ventriculomegaly, and prominent cortical neuronal loss.

Cognitive Deficits Nearly all infants with a complete enzymatic deficiency who survive their initial hyperammonemic coma are left with mental retardation and other developmental disabilities. There is a documented inverse correlation between duration, and not peak level, of hyperammonemia and neurocognitive outcome. Neonates in stage III coma longer than 72 hours invariably have mental retardation. Cognitive outcome is better in children with complete defects who were treated prospectively. Patients with partial enzyme deficiencies also have a significant risk of developmental disabilities, and even asymptomatic OTCheterozygous women have cognitive deficits and are at risk for learning disabilities and attention deficit/hyperactivity disorder.

ETIOLOGY AND PATHOPHYSIOLOGY Neuroimaging Abnormalities and Neuropathology Head ultrasonography performed on neonates during initial presentations has revealed cerebral edema with largely obliterated ventricles. In surviving patients, the edema recedes with normalization of ammonia level, and the ventricles often become enlarged, as one manifestation of the cerebral atrophy that has occurred (Fig. 110–3). Hyperammonemic episodes at

A ■

B

The eight urea cycle disorders result from the inability to metabolize nitrogen produced from the breakdown of protein and other nitrogen-containing molecules. This waste nitrogen is converted into ammonia (NH4+) and transported to the liver, where it is normally processed through the urea cycle. Ammonia is toxic to the nervous system and is normally converted to urea, which is nontoxic, before being excreted in the urine.

C

Figure 110–3. Serial ultrasonograms of the head in a newborn with hyperammonemia caused by ornithine transcarbamylase deficiency. A, Study at presentation, demonstrating narrow ventricles secondary to brain edema. B, Study performed 4 days later, with ammonia level under control and remitting edema. The ventricles are of near-normal size. C, Study performed 6 days after presentation, demonstrating enlargement of ventricles secondary to brain atrophy caused by hyperammonemia and cerebral edema.

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N-Acetylglutamate Synthase Deficiency NAGS, the first enzyme in the urea cycle, serves to produce a cofactor necessary for the normal function of the enzyme CPSI. Because CPSI is rendered inactive in the absence of NAGS, the clinical pictures of these two disorders are very similar and are described in detail in the next section. Affected patients may present with neonatal hyperammonemia or with milder and intermittent episodes. Because there have been few cases, a clear description of the presentation and course is not available. The enzyme is confined to the liver, and cloning of the gene now allows diagnosis, which was most often made on liver biopsy by mutation analysis of the NAGS gene.

Carbamoyl Phosphate Synthase I Deficiency

A

B ■

Figure 110–4. Neuropathology of hyperammonemic syndromes. Chronic hyperammonemia resulting from urea cycle enzymopathies. A, Alzheimer type II cells (left, arrow) have enlarged nuclei and margination of chromatin in this hematoxylin and eosin–stained section. Doublets suggestive of a proliferative response are frequently seen (right, arrowhead). B, Electron micrograph revealing swelling of a perivascular astrocyte (Ast) from a patient with acute liver failure, who died of brain herniation. (From Felipo V, Butterworth RF: Neurobiology of ammonia. Prog Neurobiol 2002; 67:259-279.)

The enzymes, in order of their role in the pathway from the entry of ammonia, are 1. NAGS 2. CPSI 3. OTC 4. Argininosuccinic acid synthase 5. ASL 6. Arginase 7 and 8. Two transporters: citrin and ornithine translocase

CPSI deficiency, together with OTC deficiency in boys, is the most severe of the urea cycle disorders. Individuals with complete deficiency of this enzyme develop very high levels of ammonia in the neonatal period. CPSI deficiency can be lethal in newborns, and children rescued from their initial event are at high risk for chronic, recurrent, and extreme episodes of hyperammonemia. CPSI and other specific urea cycle disorders occur in milder forms when some enzymatic activity is preserved. Individuals with partial CPSI deficiency can develop the first symptoms at almost any time during life. Often an intercurrent illness or other stressful event triggers a crisis in these patients. In addition to ammonia levels that rise to 2000 μmol/L or greater, plasma amino acid levels may be greatly altered. There is a generalized increase in all amino acids with a particular increase in the transaminating amino acids: alanine, glutamate, and glutamine. The gene for CPSI deficiency has been cloned, and the specific mutations for any patient can, in principle, be determined. If the specific mutations are known, prenatal diagnosis becomes possible. If they are not known, prenatal diagnosis may nonetheless be accomplished by haplotype analysis both of the parents and of the fetus. Heterozygous gene carriers are not thought to be at risk for acute hyperammonemia in this disorder. However, subtle effects of the carrier status for this and other urea cycle disorders may exist. Diagnosis in low-risk newborns by screening is not possible with the technology currently available.

Ornithine Transcarbamylase Deficiency OTC deficiency is an X-linked recessive disorder resulting in severe disease in affected boys. As in CPSI deficiency, boys with complete OTC deficiency rapidly develop high levels of ammonia soon after birth. Patients who recover from their first crisis are at risk for repeated bouts of hyperammonemia. Girls with a disease-causing mutation on one of the X chromosomes can be either asymptomatic or have partial enzymatic deficiency. Female patients with partial disease may develop hyperammonemia throughout their lives and may require treatment. Infrequently, female patients may be affected severely enough to develop fatal neonatal hyperammonemia or to suffer from a fatal or damaging episode during childhood. Some female carriers are protein intolerant and adopt a low-protein diet because it makes them feel better. Female carriers are at risk for hyperammonemia when faced with the metabolic

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demands of pregnancy, and particular caution is warranted in this situation. Female carriers have, on average, lower IQ scores than do their noncarrier female relatives. The OTC gene has been cloned, and sequencing of all exons reveals mutations in 75% of affected male patients and 50% of affected female patients who present with hyperammonemia. As automated sequencing of DNA evolves, mutations in a larger proportion of patients will be ascertained. The clinical biochemical findings are similar to those found in NAGS and CPSI deficiencies, with one prominent and diagnostically important exception. The carbamyl phosphate that accumulates behind the enzyme block leaks from the mitochondrion into the cytoplasm and is channeled into pyrimidine biosynthesis. Two intermediates in this pathway, orotic acid and orotidine, accumulate; this allows OTC deficiency to be distinguished from NAGS and CPSI deficiency without the need for any enzymatic or molecular testing.

Argininosuccinic Acid Synthase Deficiency (Citrullinemia Type I Deficiency) Citrullinemia type I deficiency is caused by a deficiency of the enzyme argininosuccinate synthase, which converts citrulline and aspartate into argininosuccinate. Complete defects in this enzyme result in extremely elevated levels of citrulline. Severe defects cause neonatal hyperammonemia, and a fatal outcome results. Partial defects of this distal enzyme in the cycle result in milder clinical phenotypes; some patients are asymptomatic, and others have repeated but attenuated episodes of hyperammonemia. Chronic mild or even subclinical hyperammonemia may impair intellectual development. In contrast to the first three disorders in the cycle, citrulline levels are elevated in argininosuccinic acid synthase deficiency. In the mildest cases, citrulline levels may be normal or near normal except during acute episodes. Changes in other amino acids resemble those seen in OTC deficiency. The argininosuccinic acid synthase gene has been cloned, and numerous mutations are known. The condition is inherited as an autosomal recessive trait and carriers are not known to be symptomatic. Prenatal diagnosis is feasible either through genetic testing or by measuring citrulline levels and enzymatic activity in amniotic fluid cells. Neonatal screening is effective when blood levels of citrulline are measured by tandem mass spectrometry.

blood cells or in skin fibroblasts. The gene has been cloned, and prenatal diagnosis can be made reliably from the argininosuccinic acid levels in amniotic fluid. Neonatal screening based on elevated citrulline levels ought to be possible.

Arginase Deficiency (Hyperargininemia) Arginase is the sixth and final enzyme of the urea cycle and converts arginine to urea and ornithine. Urea is excreted from the body, and ornithine is recycled. A block in this enzyme activity results in high levels of arginine. However, arginase deficiency is the least likely of the urea cycle disorders to cause neonatal hyperammonemia. The clinical presentation and progression were described previously. In most patients, arginine level alone is elevated in plasma, although glutamine level may also rise when ammonia levels are elevated. Ammonia levels are often normal between acute episodes. In contrast to other urea cycle disorders, the proximate toxin may be arginine and not ammonia or glutamine, and this may account for the different symptoms. The liver form of arginase (ARGI) is absent in red blood cells. A second arginase (ARGII) is present at lower levels in the mitochondria of many tissues and may in part be responsible for the milder clinical expression of arginase deficiency. The ARGI gene has been cloned, and a number of mutations are known. Prenatal diagnosis is possible by mutation analysis and by measuring arginase levels in red blood cells obtained by percutaneous umbilical blood sampling. Diagnosis in the newborn should be possible by tandem mass spectrometric analysis of arginine levels in blood.

Transporter Deficiencies: Citrin Deficiency and Ornithine Translocase Deficiency Defects in the ornithine transporte ornithine translocase and in the aspartate transporter citrin result in hyperammonemia and can produce a severe and often subacute illness after the neonatal period. Defects in the ornithine transporter cause hyperammonemia, hyperornithinemia, and excess amounts of urinary homocitrulline. Citrin deficiency causes elevations in citrulline and ammonia levels and was formerly referred to as citrullinemia type II.

Argininosuccinic Aciduria Deficiency

TREATMENT

Although most known cases of ASL deficiency are clinically mild, complete deficiency of this enzyme can result in neonatal hyperammonemia and death. Affected patients present with developmental delay and a variety of neurological symptoms. ASL deficiency is characterized by extremely high levels of argininosuccinic acid in blood and all tissues, even in asymptomatic cases, which suggests that argininosuccinic acid may not be toxic and that all symptoms may be caused by elevations in ammonia level alone. However, because successful treatment of hyperammonemia from birth has been followed by developmental and neurological problems, doubt has been cast on this belief. In addition, elevated levels of argininosuccinic acid may contribute to the liver disease seen with this disorder, which can cause liver failure and necessitate transplantation. The diagnosis can be established by measuring the enzyme in red

The diagnosis, treatment, and management of a patient with a urea cycle defect should be provided by a team of specialists working in concert with the primary medical providers who will provide care locally during minor catabolic episodes and provide routine care for minor illness and health maintenance. Treatment involves acute management of hyperammonemic episodes and long-term management to optimize nutrition, growth, and development. During an acute episode of hyperammonemia, the goals of treatment are (1) to rapidly reduce the plasma ammonia level, (2) to enhance the excretion of nitrogen through alternative pathways by pharmacological intervention, (3) to reduce the amount of exogenous nitrogen, (4) to minimize catabolism of body protein by maximizing nutritional support, and (5) to reduce the risk of neurological damage. This chapter can provide only general guidelines for

chapter 110 urea cycle disorders care and cannot be used as a step-by-step protocol. Contact with a metabolic specialist should be established as quickly as possible.3

benzoate

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phenylacetate glycine 1 NH4⫹

NH4⫹

glutamine 2 NH4⫹

Acute Management Each of the inborn errors of the urea cycle can be associated with episodes of hyperammonemia. Most interventions apply to all of these, although each has its unique characteristics. Vomiting and altered mental status usually indicate a plasma ammonia concentration greater than 150 μmol/L and demand acute intervention. In this situation, the patient should be hospitalized, protein should be completely eliminated from the diet for at least 24 to 48 hours, intravenous sodium benzoate/sodium phenylacetate should be started, and dialysis should be considered. Any elevation of ammonia carries the risk of permanent brain damage and should be treated aggressively. There is a direct correlation between the extent of neurological damage and the duration and severity of the hyperammonemic episode. It is important to reduce the level of ammonia as quickly as possible, and the most effective way to accomplish this is through dialysis and pharmacological intervention.

Dialysis Severe hyperammonemia with ammonia concentrations greater than 250 μmol/L is nearly uniformly associated with altered mental status and stupor. Ammonia concentrations higher than 500 μmol/L are associated with severe brain edema and irreversible brain damage and can be life-threatening. In this situation, dialysis is the most efficient means of lowering ammonia levels. The form of dialysis to be used depends on the patient’s age, access to a treatment center, and clinical status and on available resources. Hemodialysis or hemoperitoneal dialysis is most effective, but an expert team is required. If ammonia continues to accumulate at a slower rate, peritoneal dialysis may be effective in maintaining a normal ammonia concentration. Exchange transfusion appears to be the least effective approach and is not recommended. Dialysis can be stopped when plasma ammonia falls below 200 μmol/L. If the concentration of plasma ammonia rebounds after dialysis is discontinued, further dialysis may be required.

Alternative Pathway Therapy To lower ammonia levels, dialysis may be complemented by medications that enhance the metabolism and excretion of nitrogen through alternative metabolic pathways. These medications include arginine, sodium phenylacetate, and sodium benzoate.4 The choice of medications depends on the specific enzymatic deficiency. Patients with NAGS, CPSI, or OTC deficiency have impaired biosynthesis of arginine in the liver and other tissues and should receive maintenance doses of arginine or arginine hydrochloride. The starting dosage is 250 mg/kg/day in younger patients, which should be adjusted depending on plasma levels 4 hours or more after administration. Citrulline, whose conversion to arginine “absorbs” one ammonia nitrogen, may be substituted for the arginine. Arginine supplementation is also needed in ASL deficiency, but in this instance, it cannot be substituted with citrulline. In the liver, arginine is converted

benzoylglycine (hippurate) ■

urea

phenylacetylglutamine

Figure 110–5. Reactions diverting ammonia from the urea cycle. Benzoate is conjugated to glycine to form benzoylglycine. The resynthesis of glycine diverts one molecule of ammonia, which otherwise would have had to be detoxified by the urea cycle. Similarly, phenylacetate combines with glutamine to form phenylacetylglutamine. In this instance, two molecules of ammonia are diverted to glutamine resynthesis.

into ornithine (see Fig. 110–1), which may drive ammonia into citrulline, a less toxic metabolite. Argininosuccinate is actively secreted by the kidneys, and excess arginine drives ammonia into argininosuccinate, a far less toxic compound. There is now some concern that argininosuccinate may have liver toxicity, and current emphasis with this disorder revolves around multimodal therapy. Arginase deficiency requires that no arginine or precursor amino acid be given. An important step forward was made in the early 1980s, when Brusilow and Horwich (2001) and Batshaw and collaborators (1987) documented that benzoate and phenylacetate anions divert ammonia from a defective (or normal) urea cycle to apparently harmless byproducts, benzoylglycine and phenylacetylglutamine.5 The reactions are shown in Figure 110–5. Benzoate is conjugated with glycine to form benzoylglycine (hippuric acid), and one molecule of ammonia is diverted to replace the glycine. Similarly, when the glutamines are replaced, two molecules of ammonia are consumed. The reactions are stoichiometric, and large quantities of the anions are given. Because excessive amounts of these anions are toxic, they need to be administered under the supervision of specialists in metabolic disorders. When administered with arginine, these nitrogen-scavenging compounds may control moderate episodes of hyperammonemia, in which the trigger of catabolism is not great. With defects in distal enzymes of the urea cycle, arginine alone is often adequate for clearing elevated ammonia levels, whereas defects of proximal enzymes usually necessitate sodium phenylacetate and sodium benzoate in addition to arginine. A loading dose of all three medications is given first, followed by constant infusion until oral administration can be started, usually when ammonia levels fall below 100 μmol/L. In patients with hepatic failure and bleeding esophageal varices, lactulose, in doses high enough to induce osmotic diarrhea, mitigates elevated ammonia levels by removing blood, which serves as an ammonia precursor, and by favoring the loss of amino nitrogen. Patients with urea cycle disorders have no protein substrate in the bowel and low levels of urea nitrogen. The amount of amino nitrogen lost with the osmotic diarrhea is much smaller than that removed by benzoate and phenylacetate. Elevated ammonia levels in severe liver disease are also probably treated more effectively by scavenging agents than by lactulose if no blood is present in the bowel.

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Dietary Management During any episode of hyperammonemia, nutrition must be optimized to reduce the amount of dietary nitrogen and to minimize production of nitrogen through the catabolism of body protein. During the first 24 to 48 hours of treatment of a patient in metabolic crisis, calories should be provided as carbohydrate and fat, either intravenously (as glucose plus insulin and intralipid) or orally (as protein-free oral formula). It is important, however, that this complete restriction of protein not exceed the initial 2-day period of treatment, because depletion of essential amino acids triggers protein catabolism and further nitrogen release. Affected individuals should be transitioned from parenteral to enteral feeds as soon as possible. In newborns and older infants, the eventual protein intake may need to be as high as 1.0 to 1.5 g/kg body weight per day, but this should be optimized under the guidance of a specialist. During the acute management, it is also important to avoid overhydration, which can exacerbate cerebral edema. The use of intravenous fluids with 10% dextrose and cardiac pressors, if necessary, is important, but it should be remembered that overhydration can result in cerebral edema and poor neurological outcome.

K E Y

P O I N T S

●

The urea cycle is made up of six enzymes and two transporters. Deficiency of each component results in a specific disorder with chronic or intermittent elevations of ammonia.

●

Diagnosis is suggested by clinical manifestation and elevated ammonia concentration and is confirmed by biochemical, enzymatic, and molecular testing.

●

Ammonia is toxic to the brain and results in both permanent and reversible damage.

●

Treatment is directed toward lowering and controlling ammonia levels and involves nutritional, pharmacological, and medical management by a team of specialists.

●

Although there is variable severity between and within specific disorders, they share common signs and symptoms, and their treatment and management are similar.

growth and development through diet, medications, and supportive care by a team of specialists.

Long-Term Management Nutritional support, pharmacological management, supportive care, and restriction of dietary protein are all necessary for maximizing growth and development and for minimizing neurological damage. These measures are best carried out by a metabolic team in a large medical center. Specialized formulas are used to provide adequate nutrition for growth and development while restricting protein intake. These special supplements consist of essential amino acids and are used to increase the biological value of the obligatory nitrogen intake. Oral nitrogen-scavenging medications for the metabolism and excretion of waste nitrogen are used on a long-term basis. Gastrostomy tubes are often required for nutrition and administration of medications. A team that includes physicians, nurses, dieticians, and social workers is required for the management of diet, seizure disorders, developmental delay, learning disabilities, and other clinical manifestations of urea cycle defects.

CONCLUSION AND RECOMMENDATIONS The metabolism of ammonia to urea requires the function of six enzymes and two transporters, defects in which result in the eight primary disorders of the urea cycle. Four of the six enzymes—OTC, argininosuccinic acid synthase, ASL, and arginase—make up the urea cycle. A deficiency of any of the eight proteins results in a block in the urea cycle and hyperammonemia. These disorders vary in severity but share clinical signs and symptoms, and diagnostic testing, treatment, and management are similar. Common symptoms include growth failure, developmental delay, mental retardation, seizures, episodic vomiting, anorexia, lethargy, altered mental status, and coma. The diagnosis is based on measurements of plasma ammonia and amino acids, urinary orotic acid, and enzyme levels and on molecular test results. Treatment is aimed at controlling ammonia levels while providing adequate nutrition for

Suggested Reading Brusilow SW, Horwich AL: Urea cycle enzymes. In Scriver CR, Beaudet AL, Valle D, et al, eds: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill, 2001, pp 1909-1963. Leonard JV: Disorders of the urea cycle. In Fernandes J, Saudubray JM, Van den Berghe G, eds: Inborn Metabolic Diseases. Diagnosis and Treatment, 2nd ed. Heidelberg: Springer-Verlag, 2000, pp 213-222. New developments in urea cycle disorders. Proceedings of a satellite workshop at the IX International Congress on Inborn Errors of Metabolism. August 31-September 1, 2003. Sydney, Australia. Mol Genet Metab 2004; 81(Suppl 1):S3-S91. Summar M, Tuchman M: Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr 2001; 138:S1-S10.

References 1. Brusilow SW, Horwich AL: Urea cycle enzymes. In Scriver CR, Beaudet AL, Valle D, et al, eds: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill, 2001, pp 1909-1963. 2. Leonard JV: Disorders of the urea cycle. In Fernandes J, Saudubray JM, Van den Berghe G, eds: Inborn Metabolic Diseases. Diagnosis and Treatment, 2nd ed. Heidelberg: SpringerVerlag, 2000, pp 213-222. 3. Summar M, Tuchman M: Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr 2001; 138:S1-S10. 4. New developments in urea cycle disorders. Proceedings of a satellite workshop at the IX International Congress on Inborn Errors of Metabolism. August 31-September 1, 2003. Sydney, Australia. Mol Genet Metab 2004; 81(Suppl 1):S3-S91. 5. Batshaw ML, Monahan PS: Treatment of urea cycle disorders. Enzyme 1987; 38:242-250.

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ENVIRONMENTAL TOXINS AND DISORDERS OF THE NERVOUS SYSTEM ●

●

●

●

Jean Lud Cadet and Karen I. Bolla

Individual cases of lead poisoning were reported as early as 200 B.C. Nevertheless, the need for the evaluation and treatment of the medical effects caused by exposure to chemicals was not recognized until the 20th century. Many of the offending chemicals affect both the central nervous system (CNS) and peripheral nervous system (PNS), and high-level exposure often results in delirium, seizures, or coma.1-4 Although residual effects can include mood and cognitive disorders, they are often not attributed to exposure to these chemicals. Because the diagnosis of toxin-mediated neurological deficits is one of exclusion, it is important to substantiate a history of significant exposure. Neurological examination and neuroimaging techniques are not very helpful in making a specific diagnosis of toxic encephalopathy but might rule out other causes for the patient’s clinical presentation.5,6 Neuropsychological assessment is essential in the evaluation of these patients. However, decrements in performance on these tests may be erroneously interpreted by clinicians who are not versed in neurobehavioral toxicology. In addition, evaluation of toxic effects on the brain must be considered in the context of each patient’s personality because psychiatric changes can be primary or secondary to chemical exposure. The clinical manifestations that result from exposure to distinct classes of agents (e.g., metals, organic solvents) are described in this chapter. However, a patient exposed to a certain chemical might not necessarily suffer from all of the symptoms associated with that substance. As with any diagnostic process, the differential diagnosis of neurotoxic exposure, neurological disorders, psychiatric diathesis, or malingering is based on the combined evidence derived from occupational and medical histories; from neurological, psychiatric, and neuropsychological examination findings; and from results of appropriate ancillary studies.

METAL INTOXICATION Arsenic Cause and Pathogenesis The National Institute for Occupational Safety and Health estimates that about 900,000 workers have potential daily exposure to arsenic. Arsenic poisoning occurs mainly via the oral route.

The metal is stored in the liver, kidneys, intestines, spleen, lymph nodes, and bones. After a few days, arsenic is also deposited in hair, where it can stay for many years. Arsenic is excreted slowly in the urine and in the feces, and it takes as long as 2 weeks for a single large dose of the toxin to be excreted. Arsenic affects oxidative metabolism and prevents the transformation of thiamine into acetyl–coenzyme A, rendering patients thiamine deficient. Organic arsenicals release the poison slowly and are therefore less likely to produce acute symptoms than is the elemental metal. Brains of patients who die of arsenic encephalopathy exhibit congestion, hemorrhagic lesions throughout the white matter, and areas of necrosis. Peripheral nerves exhibit decreased numbers of myelinated fibers and degenerative changes, including swelling, granularity, and a reduction in the number of axons.

Clinical Features and Diagnosis Acute toxicity is characterized by fever, headaches, anxiety, and vertigo. Seizures are common. Neurological examination reveals nystagmus, increased tendon reflexes, neck stiffness, and sometimes paralysis.7 Mees’ lines (white lines in the nails) usually appear 2 to 3 weeks after acute exposure to arsenic. Encephalopathy with marked excitement followed by lethargy and signs of acute peripheral neuropathy can develop within a few hours. In patients with fatal acute poisoning, coma and death ensue within a few days. Patients with subacute or chronic arsenic encephalitis can suffer from relentless headaches, physical and mental fatigue, vertigo, restlessness, and focal pareses. Spinal cord involvement is associated with weakness, sphincter disturbances, and motor and sensory impairments. Optic neuritis, manifested by cloudy vision and visual field defects, can also occur subacutely or be delayed for years. In general, a mixed sensory and motor neuropathy develops within 7 to 10 days after ingestion of toxic amounts of arsenic, and patients often complain of severe burning sensation in the soles of the feet. Long-standing cognitive changes have been reported. Arsenic intoxication should be considered in a patient with severe abdominal pain, dermatitis, painful peripheral neuropathy, and seizures. A history of arsenic exposure and toxic arsenic levels in hair, urine, or nails confirm the diagnosis. Arsenic is poorly tolerated in the presence of alcohol. Therefore, patients with alcohol-related disease have a greater risk of developing

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T A B L E 111–1. Overview of Central and Peripheral Complications of Heavy Metal Exposure Metals

Central Nervous System

Peripheral Nervous System

Management

Aluminum Arsenic Lead

Cognitive changes, ataxia, speech difficulties Myelopathy, vertigo, seizure, cognitive changes

No adverse effects Painful sensorimotor PNP

Children

Lethargy, cognitive deficits, ataxia, seizures, learning difficulties

No adverse effects

Adults

Delirium, seizures, cognitive decline, sleep disturbances Apathy, depression, psychosis, parkinsonism

Fasciculations Sensorimotor PNP No adverse effects

Deferoxamine Chelation with IV BAL, D-penicillamine, or DMSA Removal from exposure Chelation with IV calcium disodium– EDTA Oral penicillamine —

Irritability, delirium, psychosis, cognitive deficits, Parkinsonism Cognitive decline Intention tremor Depression, confusion, movement disorders

Axonal PNP

Manganese Mercury Inorganic Organic Thallium

Painful PNP Motor neuron disease Sensory neuropathy Guillain-Barré–like syndromes

Removal from exposure Anti-parkinsonism drug Removal from exposure Chelation Chelation with D-penicillamine BAL or DMSA BAL

BAL, British antilewisite (dimercaprol); DMSA, dimercaptosuccinic acid; EDTA, ethylenediamine tetra-acetic acid; IV, intravenous; PNP, peripheral neuropathy.

arsenic neuropathy. Although hair and nail samples may be useful, measurement of urinary arsenic levels is the test of choice. A level of arsenic in urine (24-hour measurement) greater than 50 μg/g creatinine is considered elevated. Because urinary level may be high after ingestion of seafood, a dietary history should be obtained. More reliable values can be obtained by measuring urinary inorganic arsenic metabolites: monomethylarsonic acid and dimethylarsinic acid.

Management In patients with acute oral ingestion of arsenic, gastric lavage with electrolyte replacement is recommended. Excretion of absorbed arsenic can be enhanced by chelation with dimercaprol (British antilewisite), D-penicillamine, or dimercaptosuccinic acid. Chelating agents can reverse or prevent the attachment of heavy metals to various essential body chemicals (Table 111–1). Although chelating agents may alleviate the acute symptoms, they might not improve chronic symptoms such as peripheral neuropathy or encephalopathy. Dimercaprol treatment is not considered effective after the appearance of neuropathy. Intravenous fluids for dehydration and morphine for abdominal pain are also recommended. Prognosis with severe arsenic poisoning is poor, with a mortality rate of 50% to 75%, usually within the first 48 hours.

Lead Inorganic Lead Cause and Pathogenesis Lead poisoning has a very long history. Although it was identified as early as 200 B.C., it remains a common occurrence even today. More than 1 million workers in more than 100 occupations are exposed to lead. In lead-related industries, workers not only inhale lead dust and lead fumes but may eat, drink, and smoke in or near contaminated areas, increasing the probability of lead ingestion. Family members can also be

exposed to lead dust by workers who do not wash thoroughly before returning to their homes. Other sources of lead exposure include surface dust and oils. The de-leading of gasoline has significantly decreased that source of lead exposure. The current major sources of lead in the environment are lead paint in homes built before 1950 and lead used in plumbing, which was restricted in 1986. In 1991, median blood levels of lead in adults in the United States were estimated at 6 μg/dL.8 Children 5 years old or younger are especially vulnerable to the toxic effects of lead. Elevated lead levels in children are caused by pica (compulsive eating of nonfood items) or by the mouthing of items contaminated with lead from paint dust. Children also absorb and retain more lead than do adults. For example, approximately 10% of ingested lead is absorbed by adults whereas 40% to 50% of ingested lead is absorbed by children. Young children with iron deficiency have increased lead absorption. The risk of in utero exposure is high because lead readily crosses the placenta.9 After inorganic lead is absorbed, it binds to erythrocytes and is excreted unchanged in humans. The rate of absorption depends on age and nutritional status. For example, iron and calcium deficiencies cause significant increases in lead absorption. Once absorbed, lead is also distributed to soft tissues (kidney, bone marrow, liver, and brain) and mineralized tissues (bones and teeth); 95% of the total body burden of lead is found in teeth and bones. Pregnancy, menopause, and chronic diseases are associated with mobilization of lead from bones and increased levels in blood. The turnover rate of lead in cortical and trabecular bone is slow, its half-life ranging from years to decades. Lead excretion is through the kidneys or the biliary system into the gastrointestinal tract. Although a person’s blood levels may begin to return to normal after a single exposure, the total body burden of lead may still be elevated. For lead poisoning to occur, significant acute exposures are not necessary because the body accumulates lead over time and releases it slowly. Lead encephalopathy has been associated with softening and flattening of convolutions in the brain. On occasion, there are punctate hemorrhages, dilation of the vessels, and dilation of

chapter 111 environmental toxins and disorders of the nervous system the ventricular system, especially in the frontal lobes. Histologically, extensive involvement of the ganglion cells is evident. The developing brain appears to be vulnerable to levels of lead that were once thought to cause no harmful effects.

Clinical Features and Diagnosis In children, exposure to toxic doses of lead can cause listlessness, drowsiness with clumsiness, and ataxia. Very high levels can cause convulsions, respiratory arrest, and coma. A diagnosis of lead toxicity should be considered in a child who shows changes in mental status, gait disorder, or seizures. Chronic low-level exposure in children can result in attention and learning disabilities or in cognitive decline. Children chronically exposed to lead have been reported to show a drop in mean verbal IQ score of 4.5 points. Primary school children with high lead levels in teeth, but without a history of lead exposure, had larger deficits in speech and language processing, psychometric intelligence scores, and classroom performance than did children with lower levels of lead. Children with high lead levels in their teeth are sevenfold more likely not to graduate from high school. They have a greater prevalence of poor eye-hand coordination, reading disabilities, poor fine motor skills, and poor reaction time.9-11 At present, acute lead encephalopathy resulting from industrial exposure is not common. Signs and symptoms generally include delirium, combative irrational behavior, sleep disturbances, decreased libido, increased distractibility, increased irritability, and mental status changes marked by psychomotor slowing, memory dysfunction, and seizures.12 Involvement of both sensory and motor peripheral nerves can be seen in adults with chronic lead intoxication. Sensory complaints include paresthesias and pain. Motor signs include fasciculations, atrophy, and weakness. Severe cases can manifest with wristdrop and footdrop. Extensive bilateral neuropathy involving the fingers, the hands, and the biceps, triceps, and deltoid muscles has also been reported. In individuals with predominantly motor findings, nerve conduction velocity may not be altered even after significant occupational exposure, but mild slowing in nerve conduction velocity has been reported. Anemia, abnormal kidney function, hypertension, and gout can also occur. Miscarriage and stillbirths are common among women who work with lead. Men may suffer from reduced sperm motility and/or counts. Patients with lead intoxication show increased levels of whole blood lead, free erythrocyte protoporphyrins (FEP), and urinary coproporphyrins. Blood lead levels reflect recent exposure to lead, whereas free erythrocyte protoporphyrin levels reflect chronic exposure. Free erythrocyte protoporphyrin levels begin to rise in adults once blood lead levels reach 30 to 40 μg/dL. These levels may remain elevated for several months even after exposure has ceased. The body burden of lead is measured through diagnostic chelation. Urinary lead excretion is measured after infusion of 1 g of calcium ethylenediamine tetra-acetic acid (EDTA). More than 600 g of lead excreted in the urine over a period of 72 hours is considered an elevated level. A noninvasive method of measuring body lead burden in bone is x-ray fluorescence. Computed tomography and magnetic resonance imaging are not useful in making a diagnosis of lead exposure. In some studies, neuropsychological evaluation of workers with lead blood levels below 30 μg/dL has revealed decrements in visuomotor integration, psychomotor

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speed, short-term visual and verbal memory, and problemsolving skills.

Management Immediate removal from the sources of exposure and administration of chelating agents are the main lines of defense against lead intoxication. Intravenous infusion of calcium disodium–EDTA, oral administration of succimer (dimercaptosuccinic acid), and chelation with oral D-penicillamine can be used (up to 2 g/day). Multiple chelation cycles might be necessary, and 24 hours of rest between cycles is recommended. Adequate hydration should be maintained because chelating agents can cause renal toxicity and because they can increase circulating levels of lead as a result of their ability to unbind lead from bones. Dimercaptosuccinic acid is reportedly safer than EDTA and D-penicillamine. Common side effects include hypertension and renal problems. Chelation therapy is recommended for children with blood lead levels above 45 μg/dL. Although chelation therapy may reduce symptoms of acute lead poisoning, it might not affect neurological and renal sequelae of acute or chronic lead intoxication. Prevention of lead toxicity in children includes removal of young children from contaminated environments such as houses with peeling paint. Individuals who are occupationally exposed to lead should use mandatory personal protective equipment. Complete recovery of higher cognitive functions may not occur in children with early childhood exposure to lead.

Organic Lead Organic lead (tetraethyl lead) is used as an antiknock agent in gasoline and jet fuels. Tetraethyl lead is absorbed rapidly by the skin, the lungs, and the gastrointestinal tract. It is converted to triethyl lead, which might be responsible for its toxicity. Because of its highly lipophilic nature, tetraethyl lead passes the blood-brain barrier readily and accumulates in the limbic forebrain, frontal cortex, and hippocampus. Symptoms of acute high-level exposure include delirium, nightmares, irritability, and hallucinations. Chronic effects of tetraethyl lead include poor neurobehavioral scores in tests of manual dexterity, executive ability, and verbal memory. Treatment is mainly supportive.

Manganese Cause and Pathogenesis Manganese is found in mining dusts and as an antiknock additive in gasoline. Hospitalized patients receiving total parenteral nutrition therapy that includes manganese can develop distinctive T1weighted hyperintense signals in the region of the globus pallidus on magnetic resonance images. Although these changes tend to disappear after cessation of total parenteral nutrition, their presence is correlated with high blood manganese levels and with clinical signs of parkinsonism. Inhalation is the primary source of manganese exposure. Neuropathologically, affected cells, including neurons in the pallidus, show histopathological changes. Neuronal death has been reported in the substantia nigra, the frontal and parietal cortices, cerebellum, and the hypothalamus.

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Clinical Features and Diagnosis

Clinical Features and Diagnosis

The onset of manganese toxicity depends on the intensity of exposure and on individual susceptibility. Symptoms may appear as soon as 1 or 2 months or as late as 20 years after exposure. The earliest symptoms of manganism include anorexia, apathy, hypersomnolence, and headaches. Neurobehavioral changes include irritability, emotional lability, and, after continued exposure, psychosis and speech abnormalities that sometimes lead to mutism. Other signs and symptoms include masklike facies, bradykinesia, micrographia, retropulsion and propulsion, fine or coarse tremor of the hands, and gross rhythmical movements of the trunk and head.13 A diagnosis of manganism requires a history of exposure to the toxin. Forty three percent of manganese body burden is in the bone. Excretion is biphasic, and consists of a rapid phase with a half-life of 4 days and a slower phase with a half-life of about a month. Individual manganese levels in blood and urine might not necessarily be correlated with the degree of current or past exposure.

Acute mercury poisoning can be caused by accidental ingestion of an antiseptic found in a medicine cabinet. Affected patients suffer from irritable, hyperactive, psychotic behaviors. Patients might develop acute weakness in the lower extremities. Chronic mercury toxicity is also associated with progressive personality changes, together with tremor and weakness of the limbs. Mercury-induced tremors, also known as “hatter’s shakes” or “Danbury shakes,” consist of fine tremors that occur at rest and are interrupted by myoclonic jerks. Patients might also develop gait and balance difficulties. Parkinsonism, dyskinetic movements, and seizures have been reported. Mercury poisoning may also be accompanied by peripheral polyneuropathy (sensorimotor axonopathy) that affects mainly the lower extremities. These are characterized by painful paresthesias and muscle atrophy. Blurred vision, narrowing of the visual fields, optic neuritis, optic atrophy, nystagmus, vertigo, and sensory ataxia have also been observed. Personality and cognitive changes might become manifest before the appearance of other neurological signs. “Mercurial neurasthenia,” which consists of extreme fatigue, hyperirritability, insomnia, pathological shyness, and depression, may develop weeks or months before the patient seeks treatment. In addition, violence and homicidal behaviors have been reported. Acrodynia, as chronic mercury toxicity in children used to be called, is a syndrome characterized by painful neuropathy and autonomic changes. This syndrome includes redness and coldness of hands and feet, painful limbs, profuse sweating of the trunk, severe constipation, and weakness. Affected children may also suffer from personality and cognitive changes and from tremors similar to those found in adults. Serum concentrations of mercury are not reliable indicators of inorganic or organic mercury toxicity because blood levels vary greatly between individuals. The threshold biological exposure indexes are 15 μg/L for blood and 35 μg/g of creatine for urine. Urinary excretion is not a good measure of toxicity because there is no correlation between symptoms and amount of mercury excreted in the urine. Because the signs of mercury intoxication mimic those of common neurological syndromes such as parkinsonism, the correct diagnosis depends on occupational history and documentation of mercury in the patient’s blood, urine, or hair.

Management and Prognosis The patient must be removed from the source of exposure. Manganese-induced movement disorders may or may not respond to levodopa. Patients may respond to levodopa doses of more than 3 g/day, with the best effects on rigidity. Chelation therapy may be useful. The neurological syndrome is usually progressive. In the very early stages, signs and symptoms may improve over a period of months after removal of the patient from the source of exposure, but the improvement is not necessarily correlated with a reduction in manganese concentration.

Mercury Inorganic Mercury Cause and Pathogenesis Inorganic mercury compounds have been used as antiseptics, disinfectants, and purgatives. Mercury was also used formerly in the form of cinnabar, a red pigment used for painting and coloring. Metallic mercury becomes volatile at room temperature and enters the body via inhalation. Mercury is a pollutant in air and water. Between 1953 and 1956, an epidemic of methyl mercury poisoning occurred in Japan when a large number of villagers developed chronic mercurialism (Minamata disease) from ingesting fish contaminated with methyl mercury from industrial waste. Individual susceptibility to the toxic effects of mercury varies, depending on the form of mercury involved, hygiene, diet (including vitamin deficiency), and intrinsic differences in mercury metabolism. Elemental mercury in the plasma is bound to hemoglobin and proteins and is taken up into the brain. Mercury has been detected in the urine as long as 6 years after initial exposure. Although the kidneys are the organs most affected by mercury, the effect on the CNS is substantial, and the highest concentrations are in the brainstem, cerebellum, cerebral cortex, and the hippocampus. Inorganic mercury alters cell membranes, but postmortem studies have revealed no or only slight neuronal damage in the presence of intracellular mercury.

Management and Prognosis Removal of the patient from the sources of exposure and chelation with N-acetyl-D-penicillamine are recommended. Long-term computed tomographic follow-up of survivors of Minamata disease revealed decreased bilateral attenuation in the visual cortex and diffuse atrophy of the cerebellum, especially the vermis.13a

Organic Mercury Cause and Pathogenesis Intoxications can be caused by ingestion of fish containing methyl mercury, homemade bread prepared from seed treated with methyl mercury–containing fungicide, or meat from livestock fed grain treated with mercury-containing fungicides. Organic mercury is absorbed via the gastrointestinal tract and is slowly excreted through the kidneys; the half-life ranges from

chapter 111 environmental toxins and disorders of the nervous system 40 to 105 days. Mercury readily crosses the placenta, and the blood concentrations in the fetus are equal to or greater than those in the maternal blood. Fetal methyl mercury poisoning can occur in asymptomatic mothers. Because methyl mercury can also be secreted in breast milk, mercury poisoning can also occur in breastfed children. Organic mercury readily crosses the blood-brain barrier, and its turnover in the brain is slow. In cases of chronic exposure, approximately 10% of the body burden localizes in the brain. Less than 3% is degraded into inorganic mercury. Excretion occurs primarily through the gastrointestinal tract, mostly through biliary secretion, and the mercury then undergoes immediate gastrointestinal reabsorption into the blood stream. Neuropathological changes included damage to peripheral neurons in the myelin sheath accompanied by glial proliferation and phagocytosis. In the brain, the most severe damage was found in the primary visual cortex, followed by the cerebellar cortex, the precentral and postcentral gyri, the transverse gyrus, and the putamen.

Clinical Features and Diagnosis Organic mercury toxicity manifests as a triad of peripheral neuropathy, ataxia, and cortical blindness. There may be a delay of 2 weeks to several months before the appearance of symptoms after exposure to the toxin. These begin with paresthesias of the extremities, which extends to a glove-stocking distribution. Touch and pain sensations are impaired, and there is often constriction of the visual fields. Infants of intoxicated mothers may develop mental retardation and cerebral palsy. Motor neuron disease resembling amyotrophic lateral sclerosis can also occur. In these patients, gradual weakness develops with features of both upper motor neuron disease (increased reflexes and prominent jaw jerk) and lower motor neuron disease (fasciculations and atrophy). Diagnostic approaches should include measurements of mercury in blood and hair because these values are less variable than urinary levels. Hair samples must be taken close to the scalp and then washed to remove contaminants such as hair dyes. Hair samples provide information about mercury exposure during the previous year.

Management and Prognosis The patient should be removed from the source of exposure. Chelating agents such as D-penicillamine, dimercaprol, or dimercaptosuccinic acid, which accelerate the excretion of

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mercury, are also useful. Because chelation mobilizes mercury from bones, it may exacerbate clinical symptoms and cause deposits of mercury in the brain. D-Penicillamine is effective in improving the CNS effects of mercury. However, D-penicillamine can cause hematopoietic suppression, alterations in cognitive and renal function, symptoms of myasthenia gravis, hepatitis, and allergic reactions. Blood concentrations of mercury usually begin to decline 3 days after initiation of chelation therapy. Administration of selenium and vitamin E may prevent the development of symptoms in asymptomatic subjects with high levels of blood mercury. Most patients with severe mercury poisoning die within a few weeks of the appearance of clinical manifestations. Those who survive may have major neurological disability. Patients with mild or moderate neurological signs and symptoms may experience improvement within the first 6 months. In a few cases, bedridden individuals have been reported to regain their ability to walk. Some affected children have regained vision.

ORGANIC SOLVENTS

(Table 111–2)

Ethylene Glycol Antifreeze is the most common source of ethylene glycol. Ingestion of ethylene glycol can be fatal and accounts for about 40 to 60 deaths per year. The toxicity of ethylene glycol is caused by its metabolic products: oxalate and aldehydes. Death results from renal or cardiopulmonary failure. After ingestion, signs and symptoms usually occur rapidly and include restlessness and agitation, increased somnolence, and convulsions. Stupor and coma can also occur. Milder cases are associated with fatigue, personality changes, and depression. The possibility of ethylene glycol poisoning is suggested by apparent inebriation in a patient whose breath does not smell of alcohol. Neuropathological abnormalities include cerebral edema and hemorrhage. Treatment consists of correcting the acidosis and using early dialysis to remove ethylene glycol, oxalate, and aldehydes.

n-Hexane and Methyl-N-Butyl Ketone Exposure to n-hexane occurs from recreational use. Acute exposure to n-hexane causes euphoria, but chronic intoxication is

T A B L E 111–2. Overview of Neurotoxic Complications of Organic Solvent Exposure Solvents

Central Nervous System

Peripheral Nervous System

Management

Ethylene glycol n-Hexane Methanol Methyl-N-butyl ketone Mixed solvents

Rare PNP No adverse effects Sensorimotor PNP PNP myopathy

Dialysis to correct acidosis Removal from exposure — Removal from exposure Removal from exposure

Toluene

Restlessness, agitation, seizures Euphoria, mania-like symptoms Delirium, psychosis, seizure, parkinsonism Euphoria Irritability, depression, cognitive deficits, sleep difficulties Euphoria, cognitive decline, delirium, seizures

Removal from exposure

Trichloroethylene

Headaches, insomnia, anxiety, cognitive deficits

PNP Sensorimotor PNP Trigeminal nerve damage PNP

PNP, peripheral neuropathy.

Removal from exposure

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associated with peripheral neuropathy. n-Hexane is metabolized to 2,5-hexanedione, which is responsible for much of the neurotoxicity of the parent compound. n-Hexane does not produce significant CNS symptoms. Lightheadedness, headache, decreased appetite, mild euphoria, and occasional hallucinations may occur acutely, but n-hexane does not cause seizures or delirium. The predominant neurological consequence of n-hexane exposure is peripheral neuropathy. Symmetrical sensory dysfunction in the hands and feet is the usual presenting complaint. There is decreased sensation to pinprick, vibration, and thermal stimulation. Persons who sniff glue (“huffers”) may develop proximal weakness. The most prominent electrophysiological feature is slowing of motor and nerve conduction velocities, which is proportional to the severity of clinical disease. Methyl-N-butyl ketone is used as a paint thinner, cleaning agent, and solvent for dye printing. Exposure to this solvent is associated with sensorimotor polyneuropathy, which may begin several months after a period of continued exposure. In the later stages, axonal degeneration occurs distally. Treatment for n-hexane and methyl-N-butyl ketone neuropathy consists of removal from the source of exposure. Recovery (regeneration of peripheral nerve axons) may then occur over a period of weeks.

Methyl Alcohol Methyl alcohol (methanol, wood alcohol) is used as a solvent and is a component of antifreeze fluids. Although only mildly toxic, methanol is oxidized to formaldehyde and formic acid, which can produce severe acidosis and are responsible for the clinical symptoms associated with its abuse. The oxidation and excretion of methyl alcohol are slow; toxic symptoms develop over 12 to 48 hours. Methanol toxicity involves the gastrointestinal and respiratory tracts, the visual system, and the CNS. Toxicity is manifested by nausea, vomiting, abdominal pain, headache, and vertigo. Patients may also become restless, uncoordinated, weak, or delirious. More severe cases can manifest with visual loss, parkinsonism, convulsions, stupor, or coma. Death can also occur as a result of respiratory failure. Methanol-induced neuropathological abnormalities include neuronal degeneration, primarily in the parietal cortex.14 Treatment involves frequent measurements of blood methanol and correction of acid-base imbalance. Administration of ethyl alcohol may be used to retard the conversion of methanol into formaldehyde and formic acid. Folic acid may be used to accelerate the metabolism of formic acid to carbon dioxide. Peritoneal dialysis or hemodialysis is recommended for patients with methanol blood levels greater than 50 mg.

Mixed Solvents Cause and Pathogenesis The National Institute for Occupational Safety and Health estimates that 9.8 million workers were exposed to solvents in the United States in 1970. The respiratory system is the primary mode of solvent absorption because of their volatility. The amount absorbed is influenced by respiratory rate, use of gas masks, and adequacy of workplace ventilation. At present, it appears that the number of workers suffering adverse effects

from exposure to organic solvents has decreased because of closer adherence to rules establishing appropriate levels of safe airborne concentrations and because of the mandatory use of personal protective equipment. However, recreational solvent huffing remains a major public health problem. In these cases, substances such as paint, glue, and gasoline in plastic bags are placed over the face and inhaled in order to generate euphoria or a “high.” Organic solvents are volatile and lipophilic and are eliminated through the kidneys after osmotic conversions that render them more water soluble. However, the metabolites that result from these reactions may be more toxic than the original compounds. Paint huffers can suffer from acute peripheral neuropathy. They can also suffer from frontal lobe atrophy. Although solvents may act like anesthetics (e.g., trichloroethylene), convulsants (e.g., flurothyl), anticonvulsants (e.g., toluene), anxiolytics (e.g., toluene), antidepressants (e.g., benzyl chloride), and narcotics (e.g., trichloroethylene), the cellular and molecular bases of their toxic effects remain to be determined. It has been suggested that their adverse effects may be mediated through their actions on neurotransmitters, such as dopamine and γ-aminobutyric acid; on receptors; or on ion channels.

Clinical Features and Diagnosis Symptoms of acute high-level exposure include euphoria, dysphoria, excitation, exhilaration, headache, and dizziness. Very high levels of exposure that occur during paint huffing may induce somnolence and coma, followed by death. Chronic lowlevel exposure occurs in industrial settings. In these cases, symptoms develop insidiously. Headaches are the most commonly reported problem. These begin shortly after patients arrive at work and disappear outside work hours and during vacations, when patients are not in the vicinity of the organic solvents. Other complaints include irritability, depression, poor attention or concentration, memory loss, sleep difficulties, decreased libido, and pain and numbness starting in the feet and progressing to the hands. Activities mandating manual dexterity, executive functioning, or motor functioning can be severely affected. The presence of a positive exposure history, objective findings on neuropsychological tests, and neurological examination findings suggestive of polyneuropathy are indicators of a solvent-induced neurological syndrome. The diagnosis is often one of exclusion because there are no specific biomarkers of solvent exposure. The differential diagnosis includes other neurological conditions, heavy alcohol abuse, and primary neuropsychiatric disorders with similar manifestations. A rating scale was developed in 1985 to classify patients who had been exposed to solvents: ■ Type I: subjective nonspecific symptoms only. Patients com-

plain of fatigue, attention and memory difficulties, and changes in mood and sleep patterns without any objective evidence of neurobehavioral dysfunctions. After discontinuation of exposure, symptoms completely disappear within 6 months to 1 year. ■ Type IIa: sustained personality and mood changes. Affective changes including depression, fatigue, poor impulse control, and aggressiveness. There is no evidence of neurobehavioral abnormalities.

chapter 111 environmental toxins and disorders of the nervous system ■ Type IIb: impairment of intellectual function, documented

by objective neurobehavioral tests, with possible mild neurological abnormalities. Difficulty in concentration, memory loss, and a decline in learning capacity may be present. After the patient’s removal from exposure, these symptoms may remain stable or improve but should not become worse. ■ Type III: dementia, with neurological signs and/or neuroradiological findings. Results of neurobehavioral tests reveal abnormalities related to repeated severe exposure (e.g., paint huffing). Symptoms are rarely reversible but do not generally progress once exposure is stopped. Nerve conduction studies can be extremely useful because many organic solvents affect the PNS before the CNS. Sensory polyneuropathy, more pronounced in the feet than in the hands, is characteristic of exposure to chronic organic solvents.

Management and Prognosis Management consists of removal from the source of exposure. In addition, anxiety and depression can be treated with psychotherapy or pharmacological interventions. Once the patient is removed from the source of exposure, signs and symptoms remain stable or improve with time. Deterioration may be seen in patients who suffer psychological disorders as a result of their exposure to these organic solvents.

Toluene (Methyl Benzene) Toluene is a used as paint, lacquer thinner, or a dyeing agent. It is also found in fuels. Because toluene is also part of the glue used by paint huffers, it has been suggested as a potential cause of the neurotoxic syndrome observed in these individuals. Although similar to the neurobehavioral changes of benzeneinduced toxic effects, those of toluene toxicity are more severe. Acute exposure causes fatigue, mild confusion, ataxia, and dizziness. Chronic use is associated with euphoria, disinhibition, and tremor. Neurobehavioral effects include decreases in performance IQ, memory abnormalities, poor motor control, decreased visuospatial functioning, and dementia.15 Treatment consists of removal from the source of toluene exposure.

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induced bronchial constriction, pulmonary edema, and myocardial irritation can result in fatalities. Trichloroethylene exposure can also cause cranial and peripheral neuropathies. Mixed sensory and motor involvements of the trigeminal and facial nerves are observed after high-level trichloroethylene exposure. Exposed individuals can suffer from retrobulbar neuropathy, optic atrophy, and oculomotor disturbances. Peripheral neuropathy is also common and characterized by extensive myelin and axonal degeneration. A history of possible trichloroethylene exposure should be sought in any patient who presents with trigeminal neuralgia or dysfunction. Other symptoms include anxiety, fatigue, headaches, and dizziness, in association with alcohol intolerance. Neurobehavioral effects include poor concentration and memory, decreased manual dexterity and visuospatial accuracy, and slowed reaction times. Treatment involves removal from exposure.

GASES

(Table 111–3)

Carbon Monoxide Cause and Pathogenesis Carbon monoxide is an odorless, nonirritating gas that is responsible for more than 3000 accidental or suicidal deaths and 10,000 episodes of illness each year. Sources of exposure include portable kerosene heaters, hot water heaters, furnaces, and inadequately vented fireplaces. Automobile exhaust fumes have carbon monoxide concentrations of approximately 50,000 ppm. The threshold limit value of carbon monoxide is 50 ppm, which causes a carboxyhemoglobin saturation level of 8% to 10% after an 8-hour exposure. Carboxyhemoglobin saturation levels of more than 50% cause substantial morbidity, and levels of 70% to 75% are usually fatal. Saturation may be reached because of acute high-level exposure or prolonged exposure to lower concentrations. Carbon monoxide enters the blood stream via the lungs and then binds reversibly to hemoglobin. Because the affinity of hemoglobin for carbon monoxide is about 225 times greater than that for oxygen, exposure to carbon monoxide results in decreased capacity of red blood cells to carry oxygen.

Trichloroethylene

Clinical Features and Diagnosis

Trichloroethylene is used in dry cleaning. It is also used to degrease metal parts and extract oils and fats from vegetable products. Addiction to the fumes has been reported in workers who experience euphoria upon exposure. Trichloroethylene-

Neurological signs of mild carbon monoxide poisoning include headache, dizziness, and impaired vision, which can progress to convulsions and coma. Persistent chronic exposure from inadequately vented heaters in the home can cause blindness,

T A B L E 111–3. Neurotoxic Complications of Gases and Pesticides Toxins

Central Nervous System

Peripheral Nervous System

Management

Carbon monoxide

Irritability, dizziness, cognitive dysfunction, seizures, parkinsonism Drowsiness, cognitive decline, hyperreflexia, spastic paraparesis Dizziness, decreased consciousness, sleep disturbances, cognitive dysfunction

No adverse effects

Removal from exposure

Rare Cramps, weakness, paresthesias Muscular fasciculations, PNP

Removal from exposure

Organochlorines Organophosphates

PNP, peripheral neuropathy.

—

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deafness, pyramidal signs, extrapyramidal signs, and convulsive disorders. Mild neurological effects may be transient or persistent and may appear immediately or days to weeks after exposure. Neuropsychiatric changes include irritability, violent behavior, euphoria, confusion, and impaired judgment. Cognitive symptoms include difficulties with visual and verbal memory, spatial deficits, and decline in cognitive efficiency and flexibility.16 Parkinsonism has also been reported after acute and chronic exposure. Imaging studies reveal lucency in the globus pallidus and atrophy. A history of exposure to carbon monoxide is necessary to make the diagnosis. In suspected cases, blood levels of carboxyhemoglobin should be determined, even though the current level of carbon monoxide in the blood may not be indicative of the severity of poisoning because carboxyhemoglobin declines rapidly after removal from exposure. If a patient dies of carbon monoxide poisoning, the level of carboxyhemoglobin determined in postmortem study represents the actual level of carbon monoxide at the moment of death, inasmuch as carbon monoxide cannot be excreted without active respiration.

Management and Prognosis Treatment involves removal of the patient from the contaminated environment and administration of 100% oxygen. Hyperbaric oxygen reduces the half-life of carboxyhemoglobin to less than 25 minutes and is considered the treatment of choice for all patients with severe carbon monoxide intoxication, although CNS oxygen toxicity is a potential risk. Hypothermia has also been advocated to decrease the tissue demands of oxygen. Neurological sequelae, including cortical blindness, seizures, cognitive impairment with amnesia, polyneuropathy, and a parkinsonian syndrome have been reported. Prognosis after intoxication can vary. For example, a follow-up study performed 3 years after carbon monoxide poisoning revealed that 43% of patients had impaired memory, 33% evinced a deterioration of personality, and 13% had neuropsychiatric abnormalities.

PESTICIDES

(See Table 111–3)

Organochlorine Insecticides Cause and Pathogenesis Chlorinated hydrocarbon insecticides are fat soluble. They can last for a long time in the environment and contribute to longterm clinical toxicity. These organochlorine insecticides include aldrin, chlordane, dichlorodiphenyltrichloroethane (DDT), endrin, heptachlor, chlordecone (Kepone), and lindane.17 Most of them have been banned or restricted in the United States because of their deleterious effects on wildlife. However, some are still used in less industrialized countries. Absorption may occur through oral, respiratory, or dermal routes. Although the mechanisms responsible for the neurotoxic effects of DDT and other organochlorine insecticides remain to be fully clarified, they are thought to involve excessive acetylcholine release. In contrast, organophosphates block the extracellular metabolism of acetylcholine. Because expo-

sure to both organochlorines and organophosphates results in cholinergic overactivation, they often cause similar clinical pictures.

Clinical Features and Diagnosis Acute DDT toxicity is associated with variable hyperesthesias in the mouth, tongue, and lower part of the face. Patients complain of dryness of the mouth, a gritty sensation in the eyelids, and marked drowsiness. Other signs and symptoms include night blindness, stiffness and pain in the jaw, aching of the limbs, spasms, and tremors. Neurological examination reveals that patients can suffer from nystagmus, variable disturbances to touch and heat in the distribution of the trigeminal nerve, upper extremity weakness that can progress to wristdrop, and inability to stand on one leg for any length of time. Electroencephalographic abnormalities include bitemporal sharp-wave activity and shifting lateralization. The diagnosis is one of exclusion, which depends mainly on the history of exposure.

Management and Prognosis Care is supportive. Patients with intractable seizures are treated accordingly. Pentobarbital may accelerate the metabolism of organochlorines. There are no specific antidotes to DDT poisoning.

Organophosphate Insecticides Cause and Pathogenesis Organophosphates are absorbed through the dermal and respiratory routes, but small amounts may also be ingested with foods that have been sprayed. Organophosphate insecticides are highly toxic to insects but less so to humans and domestic animals.18 Organophosphates such as triorthocresyl phosphate, mipafox, and trichlorfon compounds can be neurotoxic. Persons at high risk for organophosphate poisoning include factory workers involved in the production of these compounds and agricultural workers who use them to spray crops. Epidemics of organophosphate poisoning have been reported in some developing countries. In 1987, there were reports of 1754 pesticide-related cases in California. Organophosphates inhibit acetylcholinesterase and pseudocholinesterase. They include chlorpyrifos (Dursban), diazinon, malathion, ethyl and methyl parathion, and trichlorfon. The neurotoxicity of these compounds is related to their ability to inhibit acetylcholinesterase, which is found in the brain, spinal cord, myoneural junctions, and parasympathetic and sympathetic synapses. The resulting increase in acetylcholine overstimulates cholinergic receptors located in various anatomical sites.

Clinical Features and Diagnosis Affected patients often complain of a vague sense of fatigue, increased salivation, nausea and vomiting, diaphoresis, abdominal cramps, headaches, and dizziness. Symptoms develop within 24 hours of exposure. Difficulty with speaking or swallowing, shortness of breath, and muscle fasciculations can be seen in patients with moderate levels of exposure. More severely

chapter 111 environmental toxins and disorders of the nervous system affected patients have depressed levels of consciousness and marked myosis with no pupillary response. After initial recovery from acute intoxication, a delayed polyneuropathy (organophosphate insecticide delayed polyneuropathy [OPIDP]) may develop. OPIDP is a distal dying-back axonopathy characterized by cramping muscle pain in the legs, paresthesias, and motor weakness beginning 10 days to 3 weeks after the initial exposure. OPIDP-associated signs include footdrop, weakness of intrinsic hand muscles, absence of ankle jerk reflexes, and weakness of hip and knee flexors. Chronic lowlevel exposure is associated with weakness, malaise, headache, and lightheadedness. Anxiety, irritability, altered sleep, tremor, numbness and tingling of the extremities, and miosis may also be observed.19 Cognitive abnormalities include decreased capacity for information processing, decreased memory and learning abilities, and poor visuoconstructional skills. Diagnosis depends on exposure history, clinical symptoms, and abnormally low cholinesterase activity in the blood (biological exposure index, 70% of baseline level). A rise in serial cholinesterase levels after removal from exposure is diagnostic. Fasciculations with miosis are also diagnostic of organophosphate poisoning.

Management and Prognosis At the time of ingestion, vomiting should be induced. The primary treatment for mild to moderate organophosphate poisoning is the administration of atropine sulfate, 1 mg intravenously or intramuscularly, and pralidoxime (Protopam, 2PAM), 1 g intravenously. Potential complications of atropine toxicity include flushed, hot, and dry skin; fever; and delirium. Pralidoxime may cause marked increases in blood pressure. In patients with very severe organophosphate poisoning, intravenous administration of pralidoxime restores consciousness within 40 minutes. Prolonged high exposure and the appearance of CNS and PNS symptoms may be associated with an incomplete recovery. However, recovery is complete within weeks to months after lower levels of exposure.

ANIMAL TOXINS Snake, Scorpion, and Spider Venoms Cause and Pathogenesis Poisonous snakes include vipers, rattlesnakes, cobras, kraits, mambas, and the American coral snake.20,21 The black widow probably accounts for most of the neurotoxic syndromes that occur after spider bites. Fatalities associated with spider bites occur in approximately 2.5% to 6% of cases. Animal neurotoxins can either enhance or block cholinergic function. Snake venoms are toxic to cardiac muscles, coagulant pathways, and the nervous system. Snake venom acts presynaptically to inhibit the release of acetylcholine from presynaptic terminals in the neuromuscular junction and cause nondepolarizing neuromuscular block postsynaptically. These actions result in depression of cholinergic function at the neuromuscular junction. In contrast, spider venom causes excessive release of acetylcholine, with resulting tetanic spasms followed by paralysis.

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Clinical Features and Diagnosis Affected patients can present with retinal hemorrhages, localized pain and swelling, headache, vomiting, loss of consciousness, paresthesias, ptosis, and loss of vision secondary to coagulation disturbances. These signs and symptoms develop between 1 and 10 hours after a bite. Signs of paralysis begin with difficulty swallowing and opening the mouth. Effects of scorpion stings may include both local and systemic complications. Early problems include pain, swelling, excessive salivation, sweating, and abdominal pain. Death may result from hypertension, peripheral circulatory collapse, or cardiac failure. Neurological symptoms are more common in children than in adults and include overexcitement, muscle rigidity, convulsions, and altered mental status, probably secondary to hypoxia. Spider bites can cause paresthesias, fasciculations, tremor, and hyperreflexia. In patients with snake bites, it is especially important to identify the specific snake involved because there are specific antivenins.

Management and Prognosis Treatment of snake bites involves administration of anticholinesterases and specific antivenin as early as possible after the bite. If these are administered before the development of major weakness, both presynaptic and postsynaptic toxic effects can be aborted. Mechanical respiration may also be necessary. Gradual recovery might occur over the next 2 days. Treatment of scorpion bites depends primarily on supportive respiratory and cardiac measures and treatment of coagulation abnormalities.

Tick Paralysis Tick paralysis is a flaccid ascending paralysis caused by the bite of certain female ticks—namely, Dermacentor andersoni, Dermacentor variabilis, Dermacentor occidentalis, Amblyomma americanum, and Amblyomma maculatum—that are found commonly in areas west of the Rocky Mountains. The causative toxin is excreted in the saliva of the mature female tick during engorgement. Small children who are bitten are particularly likely to become paralyzed. The head and neck are the most common sites of tick attachment, although any part of the body may be involved. Proximity of the site of attachment to the brain appears to influence the severity of the disease. The toxin acts by inhibiting acetylcholine release at the neuromuscular junction, including neurons of the spinal cord and brainstem. The course of tick paralysis depends on the interval between identification and removal of the tick. If removal occurs before bulbar symptoms begin, improvement appears within hours, and complete recovery occurs by 1 week. If bulbar symptoms have appeared, patients usually die despite intensive treatment.

PLANT TOXINS Chickpea (Lathyrism) Lathyrism is related to a neurotoxin that acts on glutaminergic system. Spastic paraplegia has been observed in Europe and

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India after consumption of different varieties of chickpea.22 Development of human lathyrism is associated with two potent neurotoxins found in the peas: α-amino-β-oxalylaminopropionic acid and α-amino-γ-oxalylaminobutyric acid. Toxic neurological signs are seen when 30% or more of the diet consists of chickpeas. Men tend to be affected more than are women. The onset is subtle, with pain in the lumbar region and with stiffness and weakness of the lower extremities on awakening in the morning. The legs may become spastic and exhibit clonic tremor. Other patients complain of tremulousness, numbness, paresthesias, formication, and sphincteric spasms. Some patients complain of pain and cramps in the calf muscles. The upper extremities may also be involved in patients with severe disease. The pain and paresthesias usually disappear within 1 to 2 weeks after chickpeas are removed from the diet, but relapses may occur. Lathyrism has been classified on a 4-point scale: no-stick (mild), one-stick (moderate), two-stick (severe), and crawler-stage (very severe) cases. In the latter cases, victims are unable to move their legs and depend on their arms to move the body on their rumps. Neurological examination reveals no involvement of the cranial nerves, the sensory system, or the cerebellum.

Mushrooms Amanita mushrooms have strong anticholinergic effects. They contain high concentrations of ibotenic acid, muscazone, and muscimol. Intoxication is associated with mydriasis, agitation, ataxia, muscle spasms, and seizures. Indole compounds may be responsible for mushroom-induced hallucinations. The genera Inocybe and Clitocybe contain muscarine and cause cholinergic excitation at all parasympathetic nerve endings except those of the neuromuscular junctions and nicotinic sites. Coprinus atramentarius, or Inky Cap, is a common mushroom often considered edible. Its consumption in combination with alcohol, however, results in a severe toxic reaction similar to that seen with disulfiram. The syndrome includes facial flushing, paresthesias, and severe nausea and vomiting. The responsible toxin is coprine, which increases acetaldehyde blood levels.

BACTERIAL TOXINS

C. botulinum is a potent inhibitor of acetylcholine release. Three distinct forms of botulism exist. Foodborne botulism occurs after the ingestion of contaminated home-canned fruits and vegetables, which contain already-formed spores. This syndrome appears rapidly, usually between 8 and 36 hours after ingestion. Neurological signs appear within hours or, at most, 1 week after ingestion of the toxin. Wound-induced botulism results from the entry of the organism into the blood stream through the wound site. Spores may germinate locally in the tissues and cause a toxic syndrome. Infantile botulism usually occurs in the first 6 months after birth.24,25 It is caused by the absorption of C. botulinum from the gastrointestinal tract.

Clinical Features and Diagnosis Early signs of toxicity include nausea, vomiting with abdominal pain, and diarrhea. The presence of ptosis, extraocular paresis, and progressive weakness is suggestive of the diagnosis of myasthenia gravis. In addition, patients may suffer from dryness of the mucous membranes, dysphasia, swallowing difficulties, speech impairment, absence of or decreased gag reflex, and absence of or decreased deep tendon reflexes. By the second to fourth day of illness, greater muscular weakness develops. Progressive muscular weakness of neck muscles can result in inability of patients to raise their heads. Breathing difficulty may also lead to respiratory failure. Infants suffer from weakness with loss of muscle tone. Botulism is distinguishable from the Guillain-Barré syndrome because it is associated with descending weakness of the limbs, in that proximal muscles are affected before distal ones. Pupillary dilation observed in botulism helps differentiate it from myasthenia gravis. The diagnosis is confirmed by detecting the toxin either in the patient (blood) or in the implicated food products.26 A stool culture is also recommended.

Management and Prognosis Trivalent botulism equine antitoxin (ABE) is recommended, and the patient’s respiratory status should be monitored closely. In severe cases, a rapid deteriorating course often ends in death. Death occurs in 70% of untreated cases. If the patient survives, recovery begins within a few weeks.

Botulism

Diphtheria

Cause and Pathogenesis

Cause and Pathogenesis

There are approximately 20 cases of foodborne botulism in adults and 250 cases of infantile botulism reported each year. Botulism is thought to be involved in some cases of sudden infant death syndrome because of similar age distribution and because 10 infants who died from sudden infant death syndrome in California in 1977 also had evidence of intestinal infection with Clostridium botulinum. Sudden infant death syndrome might result from infection with C. botulinum because of toxin-induced flaccidity of the upper airway or tongue muscles, which leads to airway obstruction during sleep. Botulism results from the ingestion of one of the most potent poisons in existence.23 The toxin made by the spores of

Diphtheria is rare in many parts of the world as a result of immunization. Potential risk factors for this disease are lack of immunization, crowding, and poor hygiene. In the United States, only five cases of diphtheria were reported in 1991. The bacterium Corynebacterium diphtheriae is the causative agent of diphtheria. It is acquired through respiratory droplets from infected persons or asymptomatic carriers. There are two forms, oropharyngeal and cutaneous, with incubation periods lasting 1 to 4 days. The bacterium affects the respiratory tract, heart, kidneys, and nervous system through a toxin that causes tissue damage in the vicinity of affected areas and is transported to other organs via the blood stream. Muscle and myelin are preferentially affected by this powerful toxin. Neu-

chapter 111 environmental toxins and disorders of the nervous system rological symptoms result either from direct damage to muscle and peripheral nerve or from indirect damage caused by hypoxia and airway obstruction. The CNS is not directly affected because the toxin does not cross the blood-brain barrier.

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choline at cholinergic synapses. The nervous system is affected by tetanus through retrograde axonal transport. The incubation period varies from a few hours to several days. If the illness lasts for more than 5 days, demyelination and gliosis may occur, and hemorrhages are evident in the most severe cases.

Clinical Features and Diagnosis The initial symptoms of the disorder include fever, a gray to black throat membrane that is sore, nasal voice, dysphasia, and regurgitation. Subsequently, trigeminal, facial, vagus, and hypoglossal cranial nerves may become affected. Half of the patients with diphtheria-associated neurological dysfunction suffer from ocular involvement and paralysis of accommodation during the second or third week of disease. Two forms of neuropathy are usually recognized after infections: a localized pharyngeal-extraocular neuropathy secondary to local spread of the bacterial toxin and a generalized polyneuropathy caused by systemic spread of the toxin. Sometimes, patients may also suffer from changes in mental status, from drowsiness, and possibly from convulsions. The diagnosis is based on clinical history and manifestation. Physical examination reveals a characteristic gray to black membrane in the throat, enlarged lymph glands, and swelling of the neck and larynx. Diphtheric polyneuropathy can be distinguished from other polyneuropathies because of the early bulbar involvement, ciliary paralysis, and subacute evolution of a delayed symmetrical sensorimotor peripheral polyneuropathy. Diagnostic testing includes Gram stain of the infected membrane, throat culture, and electrocardiography, which reveals evidence of myocarditis.

Management and Prognosis Treatment generally involves administration of antitoxin within 48 hours of the earliest signs of infection; rest; and maintenance of proper airway and cardiac function. Everybody who has had contact of the infected person should be immunized, because protective immunity is not present longer than 10 years after the last vaccination. Diphtheria is preventable through immunization at the age of 3 months. Booster doses at 1 year and before entrance in school are recommended. The rate of death from the disease is 10%. Patients who do not die of respiratory distress or cardiac failure usually stabilize and recover completely over time.

Tetanus

Clinical Features and Diagnosis Patients usually present with headaches, restlessness, and pain at the site of injury. Tightness in the jaw and mild stiffness and soreness in the neck are usually noticed within a few hours. As time progresses, the jaw becomes stiffer and tighter (lockjaw). There is subsequent involvement of throat and facial muscles. Muscle rigidity then becomes generalized and may include the trunk and extremities. Rigidity in the abdominal muscles causes forward arching of the back. Tetanic contractions occur periodically and cause severe pain. In the most severe cases, convulsions and marked dyspnea with cyanosis can occur, terminating in asphyxia and death. Patients may also suffer from anxiety as well as mental and physical agony. The diagnosis depends on a history of a prior wound, a high C. tetani titer, and a history of partial immunization. Tetanus must be differentiated from the stiff-person syndrome, which does not involve trismus.

Management and Prognosis Patients should be hospitalized. The infected wound should undergo débridement. Barbiturates and diazepam may be used to initiate muscle relaxation. Tetanus immunoglobulin should be given. One dose of 3000 to 6000 U given intramuscularly into three sites simultaneously is recommended. If human antitoxin is unavailable, equine antiserum can be given. Tetanus is prevented by immunization. Children should be immunized at 2 months to 6 years of age. In adults, tetanus boosters last approximately 10 years. The rate of fatality from the disease is about 65%. Death generally occurs rapidly between the third and fifth day of illness. This is caused by exhaustion, spasminduced asphyxia, or circulatory failure. On occasion, tetanus antitoxin can cause adverse reaction involving primarily the PNS. This is followed by complete recovery after 6 months.

ACKNOWLEDGMENT The authors thanks Maryann Carrigan for her assistance in the preparation of this chapter.

Cause and Pathogenesis Tetanus is still an important cause of morbidity and mortality in underdeveloped countries. The bacteria can be transmitted in the anaerobic environment of soil-contaminated wounds. Tetanus is seen only in adults who have not been immunized. About 50 to 100 cases are reported in the United States each year, and about 60% of these occur in elderly individuals. The tetanus toxin is synthesized by the bacillus Clostridium tetani. Spores can remain dormant in the soil or in animal excrements for years until they enter the body and synthesize the neurotoxin. The tetanus toxoid can affect the CNS, the PNS, and the musculature. At high concentrations, the tetanus toxin acts like botulinum toxin in that it inhibits the release of acetyl-

K E Y

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Exposure to environmental toxins can result in signs and symptoms that mimic classical neurological syndromes.

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Environmental toxicants are significant causes of neurological and psychiatric morbidity.

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Solvent abuse is highly prevalent among adolescents.

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Suggested Reading Branchi I, Capone F, Alleva E, et al: Polybrominated dephenyl ethers: neurobehavioral effects following developmental exposure. Neurotoxicology 2003; 24:449-462. Davidson PW, Weiss B, Myers GJ, et al: Evaluation of techniques for assessing neurobehavioral development in children. Neurotoxicology 2000; 21:957-972. Josko D: Botulin toxin: a weapon in terrorism. Clin Lab Sci 2004; 17:30-34. Levy BS, Nassetts WJ: Neurologic effects of manganese in humans: a review. Int J Occup Environ Health 2003; 9:153-163. Rhee P, Nunley MK, Demetriades D, et al: Tetanus and trauma: a review and recommendations. J Trauma 2005; 58:1082-1088.

References 1. Goetz CG: Neurotoxins in Clinical Practice. New York: Spectrum, 1985. 2. Carpenter DO: Effects of metal on the nervous system of humans and animals. Int J Occup Med Environ Health 2001; 14:209-218. 3. Chang LW, Dyer RS, eds: Handbook of Neurotoxicology. New York: Marcel Dekker, 1995. 4. Krantz A, Dorevitch S: Metal exposure and common chronic diseases: a guide for the clinician. Dis Mon 2004; 50:220262. 5. Hartman DE: Neuropsychological Toxicology: Identification and Assessment of Human Neurotoxic Syndromes. New York: Pergamon, 1988. 6. Bolla KI: Use of neuropsychological resting in idiopathic environmental testing. Occup Med 2000; 15:617-625. 7. Graeme KA, Pollack CV Jr: Heavy metals toxicity, part I: arsenic and mercury. J Emerg Med 1998; 16:45-56. 8. National Advisory Council for Environmental Policy and Technology Report of Environmental Protection Agency. Washington, DC: U.S. Government Printing Office, 1993. 9. Bellinger D, Levinton A, Waternaux C, et al: Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med 1987; 316:10371043. 10. Bolla K, Rignani J: Clinical course of neuropsychological functioning after chronic exposure to organic and inorganic lead. Arch Clin Neuropsychol 1997; 12:123-131. 11. Schwartz BS, Bolla KI, Stewart W, et al: Decrements in neurobehavioral performance associated with mixed exposure to

organic and inorganic lead. Am J Epidemiol 1993; 137:10061021. 12. Schwartz BS, Lee, BBK, Bandeen-Roche K, et al: Occupational lead exposure and longitudinal decline in neurobehavioral test scores. Epidemiology 2005; 16:106-113. 13. Cotzias GC, Horiuchi K, Fuenzalida S, et al: Chronic manganese poisoning: clearance of tissue manganese concentrations with persistence of the neurological picture. Neurology 1968; 18:376-382. 13a. Tokuomi H, Uchimo M, Imamura S, et al: Minamata disease (organic mercury poisoning): neuroradiologic and electrophysiologic studies. Neurology 1982; 32:1369-1375. 14. Mittal BV, Desai AP, Khade KR: Methyl alcohol poisoning: an autopsy study of 28 cases. J Postgrad Med 1991; 37:9-13. 15. Benignus VA: Neurobehavioral effects of toluene: a review. Neurobehav Toxicol Teratol 1981; 3:408-415. 16. Gordon MF, Mercandetti M: Carbon monoxide poisoning producing purely cognitive and behavioral sequelae. Neuropsychiatry Neuropsychol Behav Neurol 1989; 2:145-152. 17. Baker SR, Williamson CF: The Effects of Pesticides on Human Health. Advances in Modern Environmental Toxicology. Princeton, NJ: Princeton Scientific Co., 1990. 18. Wesseling C, KeiferM, Ahlbom A, et al: Long-term neurobehavioral effects of mild poisoning with organophosphate and N-methyl carbamate pesticides among banana workers. Int J Occup Environ Health 2002; 8:27-34. 19. Kamel F, Hoppin JA: Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect 2004; 112:950-958. 20. Seneviratne U, Dissanayake S: Neurological manifestations of snake bite in Sri Lanka. J Postgrad Med 2002; 48:275-227. 21. Gold BS, Barish RA, Dart RC: North American snake envenomation: diagnosis, treatment, and management. Emerg Med Clin North Am 2004; 2:423-443. 22. Getahun H, Lambein F, Vanhoorne M, et al: Neurolathyrism risk depends on type of grass pea preparation and on mixing with cereals and antioxidants. Trop Med Int Health 2005; 10:169-178. 23. Erbguth FJ: Hostorical notes on botulism, clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord 2004; 8:S2-S6. 24. Krishna S, Puri V: Infant botulism: case reports and review. J Ky Med Assoc 2001; 99:143-146. 25. Cox N, Hinkle R: Infant botulism. Am Fam Physician 2002; 65:1388-1392. 26. Sharma SK, Whiting RC: Methods for detection of Clostridium botulinum toxin in foods. J Food Prot 2005; 68:1256-1263.

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NEUROLOGY OF PREGNANCY AND THE PUERPERIUM ●

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Steven Feske and Autumn Klein

The hormonal changes of pregnancy mediate a multitude of physiological effects that promote successful gestation and birth and influence disease states. These physiological changes interact with many common neurological disorders. In addition, neurological injury and dysfunction constitute the most threatening aspect of preeclampsia-eclampsia, a condition unique to pregnancy. Here, we first review those aspects of the physiology of pregnancy that influence neurological disease and discuss selected important neurological disorders, focusing on their clinical recognition and available therapies.

PHYSIOLOGY OF PREGNANCY Hormonal Changes Human chorionic gonadotropin (HCG) is a glycoprotein composed of two subunits designated α and β. α-HCG, produced by cytotrophoblasts, structurally resembles follicle-stimulating hormone, leutinizing hormone, and thyroid-stimulating hormone, whereas β-HCG, made by syncitiotrophoblasts, has a unique structure, making it the earliest characteristic clinical marker of pregnancy. β-HCG can be detected in the maternal serum or urine within days after implantation. The serum level of β-HCG doubles about every 2 to 3 days and can be followed as a marker of the health of the placenta and the pregnancy. Lower than expected levels of β-HCG, as seen in ectopic pregnancies and spontaneous abortions, indicate failure of proper placental development. Higher than expected levels of β-HCG suggest multiple gestations or trophoblastic disease, such as choriocarcinoma or hydatiform mole. HCG stimulates production of progesterone from the corpus luteum, supporting the placenta during the early stages of pregnancy. It acts as an immunosuppressant and, because of its resemblance to thyroid-stimulating hormone, has some thyrotropic activity. β-HCG production peaks at 10 to 12 weeks of gestation, falls to 10% of peak at about 16 weeks, remains stable until 22 weeks, and then slightly increases to term. α-Fetoprotein is a glycoprotein produced in the yolk sac and fetal liver. It may act as a fetal osmoregulator and an immunomodulator. It enters the fetal urine and is released into amniotic fluid. Because it is highly concentrated in the fetal central nervous system, elevation of its level in the maternal

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blood or in the amniotic fluid may indicate fetal central nervous system disease, such as a neural tube defect, or multiple gestations. A decrease in its level may suggest Down syndrome. In conjunction with β-HCG and estriol, its serum level is used in a “triple screen” to determine the overall health and development of the fetus and placenta. The three estrogens that are essential for the maintenance and growth of the fetus and the placenta are estradiol, estrone, and estriol. These hormones increase most dramatically in the first 16 weeks of pregnancy and then continue to increase at a slower rate until term. Estrogens, primarily estriol, increase uterine blood flow and are believed to be the trigger for parturition. Estrogens enhance myometrial irritability and contractility. They play a role in the preparation of the breast for lactation and of the cervix for labor and delivery. Through actions on the fetal pituitary, they may play a role in triggering the onset of labor. Estrogens increase neuronal excitability and lower the seizure threshold. This effect occurs through several mechanisms that inhibit the inhibitory action of γ-aminobutyric acid (GABA), including negative allosteric modulation of GABA transmission by binding to the GABA receptor, transcription regulation causing decreased synthesis of messenger RNA encoding the GABA precursor GABA-amino-decarboxylase, and decreased synthesis of GABA receptor subunits.1 Estrogens also have immunomodulatory effects (see Immune Changes). Progesterone and 17α-hydroxyprogesterone are the two progestational steroid hormones most important in pregnancy. Progesterones act in many ways in opposition to estrogens. They relax myometrial musculature and decrease uterine irritability. They maintain the endometrium supporting the developing fetus, and they decrease uterine blood flow. Progesterones have immunosuppressive effects locally at the site of implantation, allowing placentation to occur without immunological rejection (see Immune Changes). The pathway for fetal steroid production is fed completely by progesterone. Near delivery, progesterone inhibits initiation of uterine contractions by stabilizing cell membranes and preventing prostaglandin formation. In contrast to estrogens, progesterones have an anticonvulsant effect, through positive allosteric modulation of GABA.1 After delivery, the levels of all estrogens, progesterones, α-fetoprotein, and β-HCG return to normal within about 6 to 8 weeks. Normal ovulatory cycles return in approximately 10 weeks in a nonlactating woman and in about 17 weeks in a

chapter 112 neurology of pregnancy and the puerperium ■

500

Figure 112–1. Major hormonal changes during pregnancy and the puerperium.

Estradiol Estradiol Progesterone Estrone 16 ␣OH Progesterone 17 ␣OH Progesterone

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lactating woman. Normal menses returns in 12 weeks in women who are not breastfeeding. In lactating women, the timing of return is more variable. Return of menses does not always signal return of ovulation. Figure 112–1 summarizes some of the major hormonal changes of pregnancy and the puerperium.

Fluid, Hemodynamic, Cardiovascular, and Endothelial Changes Pregnancy is a chronic state of hypervolemia. From placentation until 10 weeks of gestation, the aldosterone levels and renin activity increase, and the hypothalamic “osmostat” is reset to a lower threshold, resulting in renal retention of sodium and water and slight decrease in serum osmolality. The volume of total body water then remains stable until 1 or 2 weeks after delivery, at which time volume begins its gradual return to normal. At term, total body water is increased by almost 50% above the prepregnancy state. Plasma volume increases from 6 to 8 weeks of gestation and peaks at 32 weeks. The increase in plasma volume is far greater than the increase in red blood cell volume, leading to a physiological dilutional anemia of pregnancy. After delivery, plasma volume is lost at a faster rate than red blood cell volume as the hematocrit increases to that of the nonpregnancy state.

Albumin production is increased during pregnancy under the influence of estrogen. Therefore, overall total protein increases, but serum albumin concentration decreases as a result of the greater plasma volume. After delivery, albumin production and concentration return to normal within 3 weeks. Attention to albumin levels is very important in dosing and monitoring drugs that are highly protein bound. Cardiac output, stroke volume, and heart rate increase 30% to 50% during pregnancy as a result of the increasing circulatory demands of the fetus and placenta and of the chronic hypervolemia of the pregnant mother. Half of this change occurs in the first 8 weeks of pregnancy. These measures of cardiac function then reach a peak at 25 to 30 weeks and remain stable until delivery. During labor and delivery, cardiac output increases to 50% above prepregnancy levels in the context of pain and apprehension. It increases another 20% to 30% within the 10 to 30 minutes after delivery. The increasing fluid mobilization after delivery maintains this high cardiac output for about 2 days. Cardiac output gradually decreases to about 25% above prepregnancy levels within 2 weeks after delivery and then normalizes in 6 to 12 weeks. Blood pressure is decreased during pregnancy as a result of a decrease in systemic vascular resistance. Decreases in blood pressure, more so in diastolic than in systolic pressure, are first noted in the seventh week of pregnancy. The blood pressure reaches its nadir at 24 to 32 weeks and then increases

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progressively to prepregnancy levels at term. Venous compliance increases throughout pregnancy, leading to decreased blood flow, increased stasis, and a dampened ability to react to orthostatic changes. The mechanisms underlying the decrease in systemic vascular resistance have not been well established, but it is presumed that the effects of prostaglandins, progesterone, and nitric oxide lead to vasodilation via both arterial and venous relaxation. There is also evidence that pregnant women are refractory to the hypertensive effects of angiotensin II. Women with preeclampsia-eclampsia do not show this decreased response to angiotensin II, and it has been hypothesized that this dysregulation plays a primary role in the pathogenesis of this disorder. Figure 112–2 summarizes the hemodynamic changes of pregnancy and the puerperium.

Changes in Coagulability Several effects converge to make pregnancy a state of hypercoagulability. Compression of the inferior vena cava, the aorta, and the arteries and veins that supply and drain the gravid

Percentage increase above non-pregnant state

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Figure 112–2. Hemodynamic changes during pregnancy and the puerperium.

uterus causes vascular injury. Muscular relaxation and decreased venous compliance allow venous pooling and congestion. Levels of clotting factors, coagulation inhibitors, and other blood constituents that mediate clot formation and lysis are changed during pregnancy, leading to an increase in hypercoagulability close to term. These effects may be augmented by the acute phase response to acute blood loss and iron deficiency anemia immediately after delivery and for several weeks postpartum. This response includes elevation of fibrinogen. Levels of the procoagulant factors I, VII, VIII, IX, X, XII, and XIII increase throughout pregnancy, while there is little or no increase in levels of factors II, V, and XI. These changes are probably mediated by estrogen. Increases in factor levels are most pronounced during the third trimester. In contrast to the elevation of procoagulant factors, the levels of some coagulation inhibitors fall during pregnancy, contributing to an overall state of hypercoagulability. The coagulation inhibitor antithrombin III is significantly decreased, with the lowest levels in the third trimester.2 Total and free levels of protein S are significantly decreased during the first and second trimesters. Although levels of protein C are largely unchanged, by the third trimester almost one third of women have functional activated protein C resistance.3 A study demonstrated that compared with pregnant controls, at all stages of gestation, protein C and activated protein C levels are lower in pregnant women with hypertension or a history of miscarriages.4 It has been postulated that these effects on protein C levels may contribute to the pathogenesis of preeclampsia-eclampsia. Coexisting with the hypercoagulability caused by changes in the levels and function of clotting proteins, there is a low level of disseminated intravascular coagulation during pregnancy. By term, the erythrocyte sedimentation rate increases to 50 to 60 Westergren units, and there is an increase in platelet activation and in the levels of fibrinogen and fibrin degradation products. Platelets are also consumed in the uteroplacental unit near term, creating a benign thrombocytopenia of pregnancy with platelet counts decreasing to 80,000 to 150,000/μL. Near term, fibrin polymerization is faster leading to faster clot formation, and there is a significant decrease in fibrinolysis due to placental activator inhibitors 1 and 2. Coagulation factors, coagulation inhibitors, platelets, and the regulation of fibrinolysis return to prepregnancy levels within a few weeks after delivery, with the exception of levels of protein S, antithrombin III, and von Willebrand factor. von Willebrand factor initially increases after delivery, while protein S and antithrombin III decrease even further.2 By 8 weeks, almost all factors have normalized.

Immune Changes Once the blastocyst contacts the uterine wall, the developing placenta acts to create an antigenically neutral barrier between the mother and the developing fetus. Controversy continues over whether there is systemic or localized immunosuppression that allows development of the fetus to proceed uninterrupted. The syncytiotrophoblasts, which make up the placenta closest to the mother, lack identifying major histocompatibility complex class I molecules, creating functional immunological blindness to the developing fetus. In addition, the synciotiotrophoblasts elaborate humoral factors, such as trans-

chapter 112 neurology of pregnancy and the puerperium forming growth factor β-2, that contribute to the immunosuppressed state by inhibiting cytotoxic T cells and natural killer cells. Progesterone has local immunosuppressive effects, inhibits T lymphocytes, and is found in higher concentrations in trophoblastic tissues. Estrogen decreases T cell proliferation and T helper cells. T helper type 1 (Th1) and T helper type 2 (Th2) cytokines are balanced during pregnancy. Th1 cytokines make interleukin 2, interferon α, and lymphotoxin, all of which promote cell-mediated immunity. Th2 cytokines make interleukins 4, 5, 6, and 10, which play roles in antibody-mediated and allergic responses. Overall, it is believed that pregnancy favors a state dominated by Th2 over Th1.

CLINICAL TOPICS

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breastfed had a lower rate of early headache recurrence after delivery. Women with menstrual migraine, defined strictly7 as headache that occurs on the first day of menses, have the greatest improvement in headaches during pregnancy. Pregnancy appears to affect the pattern of migraine with and without aura differently. In a self-reporting study comparing 88 women with migraine with aura and 180 women with migraine without aura, women with aura were more likely to have premenstrual syndrome and headaches exacerbated by oral contraceptive agents, and they were more likely to get relief from headaches during pregnancy.8 Women with migraine without aura had more menstrual migraine.

Pathophysiology

After puberty, migraine affects women three times more often than men and occurs in almost 20% of women across their lifetime. Headache during pregnancy is usually the result of a benign condition, most commonly migraine, but pregnancy predisposes women to several disorders that must be considered in the diagnostic evaluation. In addition, pregnant women are, of course, subject to the many uncommon disorders that may present with headache. Table 112−1 lists some common causes of headache during pregnancy and the puerperium.

There is little precise information about the etiology and triggers of headaches during pregnancy. Although it has always been postulated that a change in the estrogen levels plays a role in the pattern of migraines in pregnancy, experimental studies have not made this relationship clear. It has been shown that estradiol leads to a decrease in excitatory neurotransmitters such as dopamine and norepinephrine and an increase in inhibitory neurotransmitters such as serotonin, GABA, and endorphins.9 Estradiol increases during the course of pregnancy. This increase is physiologically advantageous in preparation for the pain of childbirth, and it may underlie the lessening of headaches through the course of pregnancy.

Epidemiology

Evaluation

Several studies have looked at the pattern of migraine in pregnancy with consistent findings. The effect of pregnancy does not parallel that of oral contraceptive agents. In a case-control study of 100 women with migraine with aura and 200 agematched controls, whereas oral contraceptives worsened headaches in 25% of women, pregnancy lessened migraine in 77%.5 In a prospective study of 49 women, migraine frequency decreased by about 50% in the first trimester, with 10.6% of patients experiencing complete remittance.6 In the second trimester, 87% of women reported a decrease in migraine frequency with 53% remission, and in the third trimester, 87% of women reported a decrease in migraine frequency with 79% remission. Migraine returned in 4% of women by day 2 postpartum, 34% by 1 week, and 36% by 1 month. Women who

The decision to perform neuroimaging at any time during pregnancy must be based on a weighing of the risks to the unborn fetus and benefits to the mother. If computed tomography scanning is done, it should be done with proper shielding to minimize radiation exposure. Computed tomography contrast dye poses a risk of fetal hypothyroidism and should be avoided. Noncontrast magnetic resonance imaging is very sensitive and safe. Gadolinium crosses the placenta, and its effects on the fetus are unknown, so it should be avoided. Lumbar puncture has no adverse effect on pregnancy, and pregnancy should not limit its use to test for hemorrhage, infection, or intracranial hypertension when the clinical situation warrants it.

Migraine

T A B L E 112–1. Some Causes of Headache Related to Pregnancy and Puerperium Migraine Low-intracranial pressure from cerebrospinal fluid leak after epidural anesthesia Intracranial hemorrhage Aneurysmal hemorrhage Arteriovenous malformation Other vascular anomalies Hemorrhagic venous infarction from cerebral venous sinus thrombosis Ischemic stroke Cerebral venous sinus thrombosis Arterial infarction Hypertensive encephalopathy from eclampsia Benign intracranial hypertension

Treatment Counseling about preventive interventions and safe medications is important in all women with headaches. The importance of nonpharmacological interventions, such as regular sleep and meals, avoidance of dehydration, avoidance of known headache triggers, regular exercise, meditation, and biofeedback, should be stressed as the first line of treatment during pregnancy. In some studies, these interventions have been shown to be as efficacious as medications.10 However, in many women with significant migraine, help from medications will be desirable. The choice of medications for migraines in pregnant women is dictated mainly by the potential for adverse side effects. Acute medications are given at the start of a headache to ameliorate or abort the headache pain. In most cases, women are motivated to minimize medication use during pregnancy, and intermittent dosing of safe agents provides adequate relief. If medication is needed for acute pain, acetaminophen should be

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the first-line of treatment. Combinations of acetaminophen with caffeine and butalbital may also be safely used, if they are not taken so frequently that they promote the transformed migraine of caffeine dependence or excessive barbiturate intake. If these agents are ineffective, then opiates and antiemetics are third-line agents. Opiates (category B) should not be used more than a few times a week, because if used to excess they can cause constipation and dependence in the mother and withdrawal in the baby at the time of birth. The antiemetics metoclopromide and prochloperazine (category B) can be as effective as analgesics in alleviating acute migraine symptoms. Potent inhibitors of prostaglandin synthesis and strong vasoconstrictors should be avoided in pregnancy. Aspirin in analgesic doses should be avoided. Aspirin interferes with implantation during conception, it increases the risk of bleeding throughout pregnancy, and it promotes premature closure of the ductus arteriosus in late pregnancy. Nonsteroidal antiinflammatory agents should be avoided. They also may prevent implantation, and they promote early closure of the ductus arteriosus. Although some authors recommend them as acceptable during the first and second trimesters, other choices are preferred. There have been some reports of cleft palate associated with codeine use in the first trimester, and although a causal link is not well supported, it is best to avoid it during pregnancy. Ergots should be strictly avoided due to their potent vasoconstricting effects and long half-lives. Serotonin agonists, “triptan” agents, should be avoided in pregnancy based on their potent vasoconstrictive effects and the lack of sufficiently powered data to argue for their safety. Registry data offer no clear evidence of an increased rate of congenital malformations in women who have taken these agents during pregnancy, but these data are not controlled and numbers of patients are too small to draw clear conclusions. A Danish study found an increased rate of preterm delivery and lower birth weight among users of sumatriptan.11 A Swedish registry study found only statistically insignificant trends of preterm delivery and low birth weight and no increase in the rate of congenital malformations.12 If headaches occur too frequently or they are too intense, prophylactic medications may be used to prevent them. The degree and frequency of headaches that represent a personal threshold for tolerance vary, and many women prefer to tolerate pain in order to avoid regular medication while they are pregnant. The physician should consider teratogenesis as well as long-term behavioral side effects when prescribing prophylactic medications for daily use. Because major fetal organs and facial structures have formed by the tenth week, if one can temporize until this time, teratogenic toxicity is of much less concern. β-Blockers, calcium channel blockers, and tricyclic agents have all been safely used for headache prophylaxis during pregnancy, although they all have potential harmful effects. β-Blockers may cause fetal growth retardation, and near term they may cause fetal hypoglycemia, bradycardia, respiratory depression, and hyperbilirubinemia. Calcium channel blockers may cause uterine relaxation prolonging labor and fetal cardiac depression if used near term. Tricyclic agents may cause fetal anomalies, neonatal withdrawal, and neonatal urinary retention if given near term. Serotonin reuptake inhibitors may cause jitteriness in newborns. To avoid adverse effects in the newborn, it is best to discontinue these drugs near term.

Valproic acid and carbamazepine can cause neural tube and other major fetal malformations, and they should not be used for headache prevention during pregnancy.13-15 Gabapentin is contraindicated given its effects on bony development and overall growth in laboratory animal studies. Experience with newer antiepileptic agents is limited, and they, too, are best avoided as migraine prophylactic agents. Commonly used supplements that are regarded as benign should be reconsidered in pregnancy. Magnesium can be an effective preventive medication for some women, but it may delay the onset and progression of labor. Riboflavin is regarded as relatively safe in pregnancy. A short course of corticosteroids can be used safely in mid to late pregnancy to break a persistent headache without undue exposure to the fetus. Prednisone is the preferred choice, because it crosses the placenta less than other corticosteroid preparations. Migraines that might have been relieved by late pregnancy tend to return after delivery, and treatment during breastfeeding warrants special considerations. The American Association of Pediatrics recommends nonsteroidal anti-inflammatory agents as generally safe for breastfeeding. Highly lipophilic medications, such as sumatriptan, cross readily into breast milk. For women taken sumatriptan, a safe recommendation is to pump breast milk 6 hours after an oral dose and 4 hours after an injected dose. Caution should be used with β-blockers, because they may cause newborn bradycardia or heart block.

Cerebrovascular Issues Epidemiology There have been no well-designed, long-term prospective studies evaluating the incidence of stroke in pregnancy and the puerperium. Comparisons of available retrospective data are limited because authors have defined the patient groups differently, sometimes including all or only late pregnancy, all or part of the postpartum period, or including or excluding women with spontaneous or therapeutic abortions, and they have defined stroke differently, including or excluding venous sinus thrombosis, subarachnoid hemorrhage, and transient ischemic attack. Estimates of incidence of stroke in pregnancy range from a low of 4.3 to a high of 210 cases per 100,000. In recent years, several retrospective studies have examined stroke in pregnancy shedding some new light on its epidemiology. These studies agree with older ones that there is an increased risk of stroke in pregnancy and the puerperium compared with the nonpregnant state and that the distribution between ischemic and hemorrhagic stroke is roughly equal. In public hospitals in the Ile de France studied from 1989 to 1992, there were 4.3 ischemic strokes per 100,000 women and 4.6 hemorrhagic strokes per 100,000 women.16 This study included only 2 postpartum weeks, and it excluded cerebral venous sinus thrombosis, subarachnoid hemorrhage, and transient ischemic attacks from the definition of stroke. A population-based retrospective study of hospitals in the Baltimore-Washington, DC, area from 1988 through 1991 was able to compare the rate of stroke in pregnant and nonpregnant women aged 15 to 44 years to assess the risk attributable to pregnancy. This study found 11 cerebral infarctions and 9 intracerebral hemorrhages per 100,000 deliveries. There was no increased risk of ischemic stroke during

chapter 112 neurology of pregnancy and the puerperium pregnancy (relative risk [RR], 0.7) and only a small trend of increase in the risk of intracerebral hemorrhage (RR, 2.5; confidence interval, 1.0 to 6.4) but a significantly increased risk of stroke of both types in the 6 weeks postpartum (ischemic stroke RR, 8.7; confidence interval, 4.6 to 16.7; hemorrhagic stroke RR, 28.3; confidence interval, 13.0 to 61.4).17 The study population was almost 40% African American. It included women having abortions and stillbirths, and it considered venous sinus thrombosis in the ischemic stroke category. Another study looked at women aged 15 to 44 years from a single hospital in Taiwan during the period from 1984 to 2002 identifying firstever cerebral infarct (including both cerebral venous thrombosis and arterial infarcts), cerebral hemorrhage, and subarachnoid hemorrhage. This study found a higher rate of strokes of 46.2 per 100,000 pregnancies (26 per 100,000 ischemic and 20.1 per 100,000 hemorrhagic), with the highest rate in the postpartum period.18 The high rate of rheumatic heart disease in the Taiwanese population likely accounts for the higher rate of ischemic strokes and emphasizes the difference in populations across these studies. Together, these studies suggest that the overall risk of stroke during pregnancy is low and determined mainly by the risk of background risk factors and that although there is likely a very small increase in hemorrhagic risk during pregnancy, there is a large increase in risk of ischemic and more so of hemorrhagic strokes during the postpartum period.

Pathophysiology of Ischemic Stroke in Pregnancy Strokes during pregnancy can be divided into those with mechanisms unique to pregnancy and those with more common mechanisms that are influenced by the pregnant state. The categories used in analyses differ among the available studies and missing categories and possible overlap of general and more specific categories make judgments tentative. However, it appears that the most common causes of ischemic stroke in pregnant and postpartum women are eclampsia and cerebral venous thrombosis, followed by cardioembolism and a variety of other mechanisms that are found in large studies of nonpregnant young patients with ischemic stroke. The French study mentioned earlier looked retrospectively at 348,295 deliveries from 1989 to 1992 in 63 public maternity wards in the Ile de France region for strokes that occurred through the second postpartum week.16 Cases of venous sinus thrombosis were excluded. The etiologies of the 15 ischemic strokes were found to be preeclampsia-eclampsia (7), unknown (5), dissection (1), amniotic fluid embolism (1), and protein S deficiency (1). The Baltimore-Washington, DC, study looked at all women aged 15 to 44 years who were discharged from 46 area hospitals during the period 1988 through 1991 and found 17 cerebral infarctions, of which they reported the cause in 16.17 Ischemic strokes were due to undetermined causes (6), preeclampsia-eclampsia (4), primary central nervous system vasculopathy (2), carotid dissection (1), thrombotic thrombocytopenic purpura (1), cortical vein thrombosis (1), and postherpetic vasculitis (1). If “primary central nervous system vasculopathy” represents eclampsia, which is likely (see later), then 6 of the 16 were related to eclampsia. A review of all deliveries at a Toronto hospital from January 1980 through June 1997 found 21 infarctions in pregnant and postpartum women among 50,711 deliveries.19 Eight of the 21 infarctions were venous. Of 13 arterial infarctions, 6 had unknown causes, and 4 were attributed

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to cardioembolism. Of the infarctions with unknown causes reported, two of six arterial infarctions and two of five venous infarctions occurred in women with preeclampsia. The study from Taiwan for first-ever cerebral infarction reported strokes among all women aged 15 to 44 years from a single hospital from 1984 through 2002.18 Among 49,796 pregnancies, 27 ischemic strokes (16 arterial, 11 venous) were related to pregnancy and the 6 weeks postpartum. The identified causes of the 16 arterial strokes were cardioembolism (9 [7 rheumatic and 2 nonrheumatic]), protein S deficiency (3), unknown (2), preeclampsia-eclampsia (1), and aneurysm (1). Of 11 patients identified with cerebral venous sinus thrombosis, identified causes were protein S deficiency (4), undetermined (4), and other coagulopathies (3) (systemic lupus erythematosus, protein C deficiency, and antiphospholipid syndrome). Although case identification and reporting are different across studies, the data consistently indicate an increase in the risk of cerebral venous sinus thrombosis likely related to the mechanisms of hypercoagulability in effect in late pregnancy and the postpartum period, a unique risk of stroke related to preeclampsia-eclampsia also in late pregnancy and postpartum, and a small number of cases of stroke from causes seen in nonpregnant populations. The emergence of cardioembolism as the commonest cause in the Taiwanese study probably reflects the higher risk of rheumatic heart disease in that population. Amniotic fluid embolism is a very rare cause of stroke specific to pregnancy. It occurs during labor or immediately after childbirth. Affected women are usually multiparous and older than 30 years. Amniotic fluid enters the circulation to embolize simultaneously the lungs and, via a patent foramen ovale or other right-to-left shunt, the cerebral circulation. Thus, it presents with cyanosis, dyspnea, hypotension, rarely seizures, and stroke. It may rapidly progress to cardiopulmonary collapse. Metastatic choriocarcinoma is a rare cause of either hemorrhagic or ischemic stroke that may be seen after pregnancy, abortion, or molar pregnancy. Angioinvasive cells of the choriocarcinoma can cause vascular obstruction directly, or they may invade the arterial wall to cause thrombosis and aneurysm with subsequent hemorrhage. Peripartum cardiomyopathy may lead to ischemic stroke. This condition is most commonly seen in multiparous African American women over the age of 30. It is usually diagnosed between the last 2 months of pregnancy and the sixth postpartum month when a woman presents with dyspnea due to congestive heart failure. Through mechanisms that remain unclear, all four chambers of the heart become dilated, and stroke occurs from cardioembolism of mural thrombi. The incidence of stroke in women attributable to peripartum cardiomyopathy is not known. There is a risk of recurrence in future pregnancies. Peripartum cerebral angiopathy or “angiitis” has been reported as an entity in the clinical literature. The diagnosis is typically based on the presence of headache, visual symptoms, confusion, seizures, or focal neurological signs in a peripartum woman with a cerebral angiogram showing multiple segmental narrowings. Cases have not been reported with biopsyproved angiitis, and the description just given is consistent with eclampsia, suggesting that most reported cases are, in fact, cases of eclampsia. Some cases have been associated temporally with the use of sympathomimetic agents or bromocriptine. Unless there is clear evidence of angiitis, the best treatment is removal of any potentially offending agents, the administration

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of magnesium sulfate, and control of blood pressure and seizures as for other cases of eclampsia.

Pathophysiology of Hemorrhagic Stroke in Pregnancy Subarachnoid hemorrhage has been cited as the third most common cause of nonobstetrical death in pregnancy.20 Different classification of intracerebral hemorrhage including or excluding subarachnoid hemorrhage as an etiology of stroke makes comparison of studies of intracranial hemorrhage tentative.16 Sharshar and colleagues’ 1995 study of women in the Ile de France found 16 hemorrhagic strokes among 348,295 deliveries. The identified causes were eclampsia (7), unknown (3), arteriovenous malformations (2), aneurysm (2), and cavernous angioma (2).16 Kittner and colleagues’ 1996 study of women in the Baltimore-Washington, DC, area found 14 intracerebral hemorrhages among 234,023 pregnancies (including 140,167 live births, 1076 stillbirths, and 92,780 spontaneous or induced abortions). They reported the cause in 13. The identified causes were indeterminate (4), arteriovenous malformations (3), preeclampsia-eclampsia (2), cocaine use (2), primary central nervous system vasculopathy (1), and sarcoid vasculopathy (1).17 The Baltimore-Washington, DC, population-based study of risk supports the suggestion that risk of hemorrhage is increased in the postpartum period, but no hemorrhages in this study were attributed to aneurysm. There remains some controversy about whether or not there is an increased risk of hemorrhage from aneurysms and arteriovenous malformations in the peripartum period. Although studies of total rates do not find such an increase, an analysis of the risk of rupture per day suggests a several-fold increase on the day of delivery.21,22 The increased blood volume during the second trimester and the increase in blood pressure and mobilization of fluids at the time of delivery likely lead to a slightly increased likelihood of rupture of arteriovenous malformation and aneurysms at these times.23 For both arteriovenous malformations and aneurysms, the increasing levels of estrogen as pregnancy progresses and their vasodilating effects may also contribute to an increased susceptibility to blood vessel rupture.

Clinical Presentation The presentation of strokes is similar in pregnant and nonpregnant patients, and the specific symptoms may provide insight into the mechanism. Headaches and seizures are common symptoms of the hypertensive encephalopathy of eclampsia, venous sinus thrombosis, and intracranial hemorrhage, and focal neurological deficits are common to all types of strokes. Although not specific to it, visual changes should raise suspicion of the hypertensive encephalopathy of preeclampsia-eclampsia.

Management of Stroke During Pregnancy Treatment of stroke in pregnancy should proceed as it does in the nonpregnant state with some consideration to the trimester of pregnancy. If it is thought that aspirin is needed in women with ischemic strokes, then low-dose aspirin can be given. Aspirin (pregnancy category D) inhibits placentation and may promote early closure of the ductus arteriosus, so it is best to

avoid it during the first and third trimesters, but it has been used safely in women with pregnancy-induced hypertension and in those with a history of recurrent loss of pregnancy. Because it may delay onset of labor, prolong labor, and increase bleeding during delivery, it is best to stop it approximately 2 weeks before expected delivery. Warfarin (category X) crosses the placenta and can cause fatal fetal hemorrhage and developmental malformations, so it is contraindicated during pregnancy. In women who require full anticoagulation for mechanical heart valves, cerebral venous sinus thrombosis, a hypercoagulable syndrome, or other indications, heparins are the preferred treatment, because these large molecules do not cross the placenta. Both unfractionated heparin (category C) and low-molecular-weight heparin (category B) can be administered subcutaneously throughout pregnancy, and unfractionated heparin can be given intravenously as well. Intravenous heparin can be stopped around the time of delivery and restarted immediately afterward to minimized bleeding risks. Fondaparinux, an antithrombin III–mediated factor Xa inhibitor, is classified as category B. Because there is limited experience with its use in pregnancy, its use should be reserved for women who cannot tolerate heparins. Ginsberg and colleagues reviewed the use of antithrombotic agents during pregnancy in detail.24 Based on theoretical considerations, tissue plasminogen activator (tPA) is contraindicated in pregnancy, unless it is thought that the benefits largely outweigh the risks in the setting of a major stroke. In fact, a few pregnant women have received tPA with no apparent adverse outcome.25,26 Hemorrhagic strokes should be treated according to accepted neurological and neurosurgical principles based on the clinical circumstances. For large (≥7 mm) asymptomatic or symptomatic aneurysms, neurosurgical guidelines recommend clipping or coiling before delivery, whenever possible. If the aneurysm cannot be clipped, cesarean delivery is generally advised even though this has not been shown to improve outcome. Treatment of aneurysmal rupture during pregnancy depends on the stage of pregnancy. The preferred option is cesarean section followed immediately by aneurysmal clipping if the woman is close to term. If rupture occurs earlier, then treatment proceeds as in nonpregnant patients. Where possible, mannitol use should be avoided or minimized to avoid fetal dehydration. Nimodipine (category C) can be used to prevent vasospasm after a significant subarachnoid hemmorhage with acceptable risk. Treatment of arteriovenous malformations without hemorrhage during pregnancy is less clear. Based on a series reported in 1974, Robinson and colleagues27 argue for a high likelihood of bleeding during pregnancy.27 Later series dispute this increase risk. Horton and colleagues21 found a hemorrhage rate of 3.5% per year during pregnancy and the puerperium, a rate similar to that of nonpregnant women with arteriovenous malformation and no history of prior hemorrhage. Robinson reported on arteriovenous malformations discovered after hemorrhage, whereas Horton and colleagues population included all arteriovenous malformations. This may account for some of the differences in their findings. Weir and Macdonald22 have argued that pregnancy increases the bleeding rate of arteriovenous malformations more than of aneurysms based on the relatively low ratio of aneurysms to arteriovenous malformations found as the cause of intracranial hemorrhage during pregnancy (1.3 in pregnancy versus 8.4 in all patients with intracra-

chapter 112 neurology of pregnancy and the puerperium nial hemorrhage). Both Horton and colleagues21 and Dias and Sekhar28 found that vaginal delivery added no risk of hemorrhage in patients with arteriovenous malformations. Based on these findings, vaginal delivery with epidural anesthesia is a reasonable choice for women with arteriovenous malformations.

Prognosis The risk of maternal death from ischemic stroke is low and less than that from hemorrhagic stroke. Combining the French and Toronto studies mentioned, there were no maternal deaths among 36 women with ischemic stroke.16 Hemorrhagic stroke is the third most common cause of nonobstetrical death in pregnant women, and 7 of the 29 women with hemorrhage in these two studies died.20 Among 20 women with ischemic stroke before delivery and known outcomes, there were 4 premature deliveries, 2 stillbirths, 1 miscarriage, and 1 termination. Of 26 women with intracerebral hemorrhage before delivery, there were 7 premature deliveries, 3 fetal deaths due to maternal death, 2 stillbirths, and 1 termination. The risk of recurrent stroke has been investigated in two recent studies.29,30 In these studies of young women with a history of stroke, the risk of recurrent stroke in subsequent pregnancies was very low (0% to 1.8%), with the greatest risk during the postpartum period in one study. Yet, in one study, more than 75% of young women who had had a stroke did not have subsequent pregnancy due to fear of having another stroke in pregnancy, to medical advice against another pregnancy, or to physical limitations resulting from the stroke.29

Preeclampsia-Eclampsia Preeclampsia-eclampsia is a systemic disorder of mid to late pregnancy characterized by hypertension and proteinuria. The criteria for diagnosis recommended by the National High Blood Pressure Program Working Group on High Blood Pressure in Pregnancy are given in Table 112–2. Endothelial cell dysfunction plays a major role in the pathogenesis of preeclampsia and likely accounts for many of the additional clinical features that may be a part of the full syndrome, including thrombocytopenia, microangiopathic hemolytic anemia, and hepatic and renal dysfunction. The acronym HELLP has been applied to the combination of hemolytic anemia, elevated liver function tests, and low platelets in the setting of preeclampsia-eclampsia.31 Eclampsia is defined as preeclampsia complicated by seizures. More recent definitions accept preeclampsia with encephalopathy but without seizures as defining eclampsia. Which terminological convention is chosen does not affect our understanding of the pathophysiology.

Epidemiology Preeclampsia affects 3% to 5% of pregnant women.32 It is a major cause of maternal and infant mortality and morbidity. Approximately 1 in 2000 pregnancies in the United States is complicated by eclamptic seizures, and the incidence is much higher in developing countries.33,34 Risk factors include obesity and poor nutrition, nulliparity, multiple gestations, age greater than 35 years, extrauterine and molar pregnancies, preexisting hypertension, diabetes mellitus, and thrombophilia.

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T A B L E 112–2. Criteria for the Diagnosis of Preeclampsia and Eclampsia Preeclampsia Gestational hypertension: systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg in a woman who was normotensive before 20 weeks’ gestation. Onset of hypertension is typically after 20 weeks’ gestation (or earlier in trophoblastic diseases such as hydatidiform mole or hydrops), and Proteinuria: ≥300 g protein/24 hr (usually ≥30 mg/dL; ≥1+ on dipstick)* Eclampsia Preeclampsia accompanied by seizures that are not attributable to other causes.† *In the absence of proteinuria, preeclampsia should be strongly considered when gestational hypertension is accompanied by headache, blurred vision, abdominal pain low platelet counts, or elevated liver enzyme values. † In the absence of seizures, coma or other features suggesting severe encephalopathy are sometimes termed eclampsia, although this extension of the definition remains non-standard. From Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183: S1-S22.

Pathophysiology Although the pathophysiology of preeclampsia-eclampsia is still not clear, abnormal placentation leading to impaired placental perfusion is likely to be the event that triggers downstream events in the disease process. Remodeling of the spiral arteries creates the low-resistance system that perfuses the intervillous space. This process is abnormal in preeclampsia leading to placental hypoperfusion. Women with preeclampsia have increased systemic vascular tone and heightened sensitivity to mediators of vasoconstriction. This increased vascular tone underlies the systemic hypertension, vasospasm, and decreased organ perfusion. There is also much evidence for a disorder of endothelial dysfunction. This endothelial cell dysfunction promotes the instability of vasomotor tone and hypertension as well as the increased vascular permeability, edema, and proteinuria characteristic of preeclampsia. The mechanism by which the placental insufficiency leads to vasomotor hyperreactivity and endothelial dysfunction is not well established. Proposed mechanisms include autoantibodies and oxidative stress, prompting activation of neutrophils and monocytes and release of inflammatory mediators. There is also clinical evidence for genetic predisposition.32 Population data argue for maternal susceptibility, yet some findings, such as a lack of concordance between monozygotic twins, an increased risk with changed paternity, and an increased risk in partners of fathers whose mothers had preeclampsia, point to a fetal contribution to susceptibility as well.35-37 Almost all women with preeclampsia have absolute hypertension. Although the degree of hypertension may be mild, there is usually a significant elevation of blood pressure compared with the premorbid blood pressure during pregnancy.38 If systemic hypertension and endothelial cell dysfunction reach a threshold of adequate severity, then there is a breakdown of cerebral autoregulatory vasoconstriction resulting in cerebral hyperperfusion and vasogenic edema of the brain. The endothelial dysfunction probably allows for edema to form at lower

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absolute perfusion pressures than in other forms of hypertensive encephalopathy. The nature and distribution of the brain lesions, as defined by computed tomography, magnetic resonance imaging, and single-photon emission computed tomography, are the same as in patients with hypertensive encephalopathy.38 Hyperperfusion is most pronounced posteriorly, and edema is most prominent in the subcortical white matter of the occipital lobes and other structures fed by the posterior circulation (Fig. 112–3).39,40 This pattern of hyperperfusion and edema is believed to reflect the relative low density of vasoconstricting sympathetic receptors in the posterior circulation.41 Yet, gray matter and anterior circulation structures are often involved, especially in severe cases. If limited to vasogenic edema, the lesions are reversible, but intraparenchymal hemorrhage and, less commonly, infarctions due to vasospasm and thrombosis may occur. Seizures may occur as a result of the subcortical and cortical edema. Hence, the defining seizures of eclampsia appear to be the severe end of the spectrum of dysfunction caused by hyperperfusion and brain edema.

Clinical Presentation Headache and visual phenomena consistent with occipital lobe edema are the most common symptoms of eclamptic encephalopathy. Seizures may be focal or secondarily generalized. Some women have encephalopathic features without seizures, such as confusion, aphasia, cognitive deficits, and depressed level of consciousness. Although hypertensive encephalopathy and seizure are most commonly preceded by typical features of preeclampsia, it is not uncommon for women to present with seizures in late pregnancy and in the early postpartum period with only mild hypertension.42

should be avoided during pregnancy. Angiotensin-converting enzyme inhibitors are also contraindicated during pregnancy (category D).43 Most eclamptic women have intravascular volume contraction and will benefit from volume replacement, but invasive hemodynamic monitoring may be useful to guide fluid therapy in severely ill women with refractory hypertension, oliguria, or pulmonary edema.44,45 Magnesium sulfate therapy now has strong support from clinical trials both to prevent further seizures in women with eclampsia and to prevent seizures in women with preeclampsia.46,47 Therapy can start with a loading dose of 4 to 6 g of magnesium sulfate followed by a 2 g/hr infusion. A supplemental loading dose of 2 g may be given if seizures recur shortly after the initial load. Tendon reflexes, respiratory function, and urine output should be followed closely. It is common practice to follow serum levels of magnesium, although it has not been established that this helps to guide therapy. It is most important to follow women for signs of neurological depression and to adjust magnesium sulfate doses accordingly. At levels of 8 to 10 mEq/L, tendon reflexes are typically depressed. At levels above 10 to 12 mEq/L, there is a high risk of respiratory depression. When patellar reflexes are lost, magnesium sulfate should be discontinued. If respirations are depressed, calcium gluconate should be given. Doses of magnesium sulfate should be adjusted for renal insufficiency, for example, by reducing the loading dose to 4 g and halving the maintenance dose. Although recent data argue that magnesium sulfate is better than phenytoin or diazepam for eclamptic seizures, refractory seizures should be treated aggressively with traditional antiepileptic drugs in addition to magnesium sulfate.

Epilepsy Diagnostic Evaluation and Differential Diagnosis The diagnosis of preeclampsia is based on the fulfillment of the clinical criteria of hypertension and proteinuria. The diagnosis of eclampsia is based on the finding of encephalopathy or seizures in late pregnancy or the postpartum period with computed tomography scanning or magnetic resonance imaging that shows evidence of characteristic edema and that rules out alternative brain lesions. Magnetic resonance imaging is more sensitive for detection of edema than computed tomography, and diffusion-weighted imaging is useful to distinguish reversible edema from ischemic stroke. Technetium singlephoton emission computed tomography imaging may demonstrate hyperperfusion characteristic of hypertensive encephalopathy, but this is not usually necessary for diagnosis. Patients with intracerebral or cerebellar hemorrhage should have vascular imaging to rule out an underlying vascular anomaly. Almost all women with eclampsia have hypertension, although the elevation may be mild or only relatively raised from a low baseline blood pressure of pregnancy.38

Management The mainstays of management are the rapid control of hypertension and the administration of magnesium sulfate. Mean arterial blood pressure should usually be lowered by 15% to 20%. This is best achieved rapidly with intravenous medications such as labetalol, hydralazine, or nicardipine. Nitroprusside and nitroglycerin can cause fetal cyanide toxicity, so they

In past years, women with epilepsy were discouraged from having children, and in some states laws required sterilization or prohibited marriage of women with epilepsy. A more scientific understanding of the true medical issues has corrected this discriminatory practice. Although the vast majority of epileptic women have normal pregnancies and deliveries, there is still a need for careful neurological care and monitoring during preconception, pregnancy, and the postpartum period.

Effect of Pregnancy on Seizure Frequency Epilepsy affects approximately 1% of the population, and about 1 million women in their reproductive years have epilepsy. It is estimated that 0.3% to 0.5% of all births occur in epileptic women. Seizure frequency seems to increase by approximately 25% to 33% during pregnancy.48 Older data suggest that the greatest increase occurs in the first trimester, but more recent data suggest a similar effect throughout pregnancy.49,50 Approximately 1% to 2% of women have a seizure during labor and delivery, and another 1% to 2% have a seizure within 24 hours after delivery. There are many possible explanations for this high rate of seizures. Many of these women do not have epilepsy but rather eclampsia or other symptomatic seizures. Among epileptics, the proconvulsant effect of the increased estrogen levels, third trimester and postpartum sleep deprivation, and decreasing levels of antiepileptic drugs due to more rapid metabolic inactivation and increased total body water may account for some of the increase in seizure frequency. Noncompliance

chapter 112 neurology of pregnancy and the puerperium

A

B

C

D

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F Figure 112–3. Magnetic resonance image in a woman with eclampsia. A 23-year-old primigravida woman at 30.5 weeks’ gestation awoke with a headache, nausea and vomiting, followed by a generalized tonic-clonic seizure. On presentation to the hospital, her blood pressure was 160/100. She was obtunded with mild right arm and leg weakness, hyperreflexia, and a right Babinski sign. She was treated with magnesium sulfate, labetalol, and hydralazine and emergency cesarean section. One month later, her blood pressure and neurological examination were normal. A-C, Axial fluid-attenuated inversion recovery (FLAIR) images done on presentation show the high intensity lesions involving the white and gray matter of both occipital lobes. There are no associated hyperintensities on diffusion-weighted images, consistent with cerebral edema. These lesions are typical for eclampsia in quality and location. D and E, Axial FLAIR images done on presentation show similar lesions in both basal ganglia and most prominently in the external and Internal capsules bilaterally and in both frontal lobes. Most of these lesions are not seen on diffusion-weighted imaging, consistent with cerebral edema, but there is a small focus of bright signal on diffusion-weighted imaging (with corresponding low apparent diffusion coefficient [not shown]) consistent with a small focus of infarction. F, Axial FLAIR images at 5 days after onset show resolution of the occipital lesions and partial resolution of the lesions of the left external capsule and basal ganglia, consistent with resolving edema.

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with medication due to fear of side effects or an inability to tolerate oral medications during early pregnancy and the delivery period may also contribute.

Consequences of Seizures During Pregnancy Prolonged generalized tonic-clonic activity during pregnancy has been shown to lead to maternal acidosis, hypoxia, and decreased fetal heart rate.51 Trauma from a seizure can lead to poor fetal and maternal outcomes, including premature rupture of membranes, infection, placenta abruption, placenta previa, and miscarriage. Most reports of poor outcome are from literature dating from the mid-twentieth century. More recent studies have found that complications of seizures are rare.52 Abruptio placenta was seen in 1% to 5% women after minor injury and in 20% to 50% after major seizure-induced injury. The effects of nonconvulsive status epilepticus during pregnancy are not well known.

Management Pregnant patients should be warned about the effects of trauma during pregnancy and should be counseled about safety measures to prevent harm. If antiepileptic drugs are indicated, then it should be emphasized that compliance will minimize risk of undue harm from a seizure. Treatment of women with epilepsy was outlined in the American Academy of Neurology Consensus Guidelines in 1998.53 Counseling and treatment should be undertaken long before planned conception. It is recommended that women be treated with an antiepileptic drug most appropriate to their seizure type and that they be maintained on a single agent whenever possible. If antiepileptic drug withdrawal before conception is planned, then it is best accomplished six months before the planned date. Folic acid, 0.36 to 5 mg daily, is recommended, because it is safe, and, although not conclusive, studies suggest that folate supplementation lowers the risk of teratogenicity attributable to antiepileptic drugs. The effects of pregnancy on drug distribution, pharmacokinetics, and metabolism are complex due to the simultaneous and interdependent changes in total body water, estrogen and progesterone levels, albumin levels, and transaminase activity. Estrogens increase hepatic enzyme activity, which leads to an increased rate of metabolic inactivation of most antiepileptic drugs throughout pregnancy and the early postpartum period. Total body water begins to increase in early pregnancy and returns to baseline by about 2 to 3 months postpartum. This increase in total body water results in a decrease in serum albumin concentration despite the increase in total protein synthesis that is stimulated by estrogens. Absolute drug levels decline as pregnancy progresses, but much of this decline is compensated by an increase in the ratio of free (active): total drug. It is usually necessary to increase antiepileptic drug doses to maintain therapeutic levels in late pregnancy. After delivery, doses should be lowered gradually to coincide with the return of total body water volume and albumin levels to prepregnancy values over the 2 to 3 months postpartum. Antiepileptic drug levels are best checked at least every month throughout pregnancy and then every 2 weeks in the third trimester. During the postpartum period, levels should be monitored every 1 to 2 weeks to keep pace with the rapid fluid

shifts. Because the complex relationships of changes in volume of distribution, induction of metabolism, decline in albumin, and redistribution of the free to total ratio are not predictable, it is important to measure both total and free levels when highly protein-bound agents such as phenytoin and valproate are used. If a drug is minimally protein bound, then the relationship is usually not clinically significant, and total levels provide adequate guidance. Selection of the proper antiepileptic drug is determined largely by standard considerations based on seizure type and individualized experience with effectiveness and tolerance. Development of congenital anomalies, fetal loss, and stillbirth all occur at an increased rate in women with epilepsy. A huge volume of data addresses the risk of fetal malformations induced by early exposure to antiepileptic drugs. Epileptic women taking antiepileptic drugs have a rate of major congenital malformations of about 4% to 6%. This is higher than the rate of 2% to 3% in the normal population. The baseline rate of major congenital malformations in epileptic women not taking antiepileptic drugs also may be elevated, but studies have not consistently found this increased background rate.54 Lack of controlled data greatly limits conclusions about the risk of particular antiepileptic drugs. The risk of an adverse outcome increases with increasing number of antiepileptic drugs; therefore, the recommendation to minimize polypharmacy is strong. Although there may be little difference in the risk conferred by the commonly used agents, certain risks are notable. The developing fetus is most sensitive to induction of malformations by exogenous agents between days 21 and 56 of gestation. A 1982 French study documented an increase in neural tube defects in women on antiepileptic drugs, especially valproate and carbamazepine.55 Women taking carbamazepine and valproate were noted to have an increased rate of spina bifida aperta.13-15 These congenital malformations are thought to be associated with the low serum and red blood cell folate levels that lead to hyperhomocystinemia. A family history of neural tube defects further increases the risk, so these drugs should be especially avoided in women with a positive family history. From the small population evaluated so far, the Gabapentin Pregnancy Registry has found a rate of malformations fetal similar to the rate in the general population.56 A review of the International Lamotrigine Pregnancy Registry, again with a small sample, found a 2.9% risk of major congenital malformations, also comparable to that of the general population and to registries of other drugs.57,58 Valproic acid alone may confer a greater risk of malformations than other agents, and the combination of valproic acid, carbamazepine, and phenobarbital may confer a particularly high risk.54 Older enzyme-inducing antiepileptic drugs cause vitamin K deficiency in the newborn by decreasing the transport of vitamin K across the placenta. This is most common after exposure to phenobarbital, primidone, and phenytoin, but it can also occur with other antiepileptic drugs, including carbamazepine, benzodiazepines, and ethosuximide. A woman who has been maintained on one of these antiepileptic drugs throughout pregnancy should receive 10 mg/d of oral vitamin K during the last month of pregnancy. At birth, the baby should be given 1 mg of intramuscular vitamin K. During labor and delivery, antiepileptic drugs should be given in oral or intravenous form. Many newer antiepileptic

chapter 112 neurology of pregnancy and the puerperium drugs that are not available in intravenous form are long acting and may sustain the mother throughout delivery. If a woman taking an exclusively oral agent has labor extending beyond the duration of action of the oral agent, then she may be given intravenous lorazepam in doses of 1 mg every 8 hours during delivery. In such a case, the pediatrician should be notified to prepare for the possible delivery of a sluggish baby. Breastfeeding is generally safe for mothers taking antiepileptic drugs. The secretion of antiepileptic drugs into breast milk depends on the molecular size and charge and the degree of protein binding. Drugs that are highly protein bound have much lower levels in the breast milk than in plasma. The ultimate level of the antiepileptic drug achieved in the blood of the infant also depends on the half-life of the drug. Most drugs achieve a low enough level in the infant to allow their safe use during breastfeeding. Due to their long half-lives, phenobarbital and many benzodiazepines may accumulate in the infant causing sedation and withdrawal. This is especially true of phenobarbital, which has a longer half-life in infants than in adults, up to 300 hours. There is so far little information about the safety of breastfeeding using newer agents.

Multiple Sclerosis and Myasthenia Gravis Data concerning the course of multiple sclerosis during pregnancy are conflicting. Women with multiple sclerosis usually remain stable during pregnancy. They may even improve on average. It has been reported that the risk of multiple sclerosis attacks increases by two- to three-fold during the postpartum period.59 However, a prospective study did not confirm this, finding a decreased risk of attacks during the third trimester and no increase in the postpartum period.60 It has been suggested that remissions of multiple sclerosis during late pregnancy result from the physiological immune permissive state that allows implantation and maintenance of the pregnancy.61,62 This effect is consistent with the known suppression of T-cell immunity during pregnancy discussed above. There are no clear guidelines for therapy and prevention of attacks during pregnancy. Although short-term courses of low or moderate doses of corticosteroids are safe in mid to late pregnancy, use during the first trimester may increase the risk of fetal malformations, virilization, and adrenal suppression. Therefore, if corticosteroids are to be given during pregnancy, therapy should be delayed until after the first trimester, and low doses and short courses should be used. Stronger immunosuppressive agents, such as mitoxantrone, azathioprine, and cyclophosphamide, should be reserved for after the pregnancy, and women should be advised that these agents may cause infertility. Although experience with the use of interferons (category C) during pregnancy is still limited, these agents are abortifacients in animals, and interferon β has been associated with fetal loss and low birth weight in humans.63 The manufacturers of interferon β1b (Betaseron) and interferon β1a (Avonex, Rebif) recommend that patients avoid them when planning and during pregnancy. A review of the known experience with glatiramer acetate (Copaxone) (category B) during pregnancy suggested no added risk of congenital malformations or spontaneous abortions.64 This agent may be recommended to women with multiple sclerosis who require disease modifying treatment while planning pregnancies.

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Pregnancy has many physiological effects, including hormonal, hemodynamic, coagulation, and immune adaptations, that have an impact on the expression of neurological disease.

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Pregnancy carries the risk of certain unique neurological disorders, including eclampsia.

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The hormonal changes of pregnancy affect migraine, most commonly lessening it, but many women require careful adjustment or addition of medications during pregnancy.

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Although stroke is uncommon in pregnancy, the hemodynamic and coagulation changes of late pregnancy and the postpartum period increase the risk of hemorrhagic stroke and ischemic stroke, this latter mainly as postpartum cerebral venous sinus thrombosis.

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Preeclampsia results from a maladaptation of the hemodynamic system to pregnancy. Eclampsia is a form of hypertensive encephalopathy that responds to prompt treatment with antihypertensive agents and magnesium sulfate.

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Estrogens have a proconvulsant effect, and this and other factors may complicate control of epilepsy during pregnancy. Special care must be given to the management of seizures during pregnancy to minimize maternal and fetal morbidity.

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A mildly immunosuppressive state supports normal pregnancy, sometimes resulting in a temporary improvement in autoimmune disorders such as multiple sclerosis. Special care must be given to the selection of medications in women with symptomatic multiple sclerosis during pregnancy.

Suggested Reading Beyenburg S, Stoffel-Wagner B, Bauer J, et al: Neuroactive steroids and seizure susceptibility. Epilepsy Res 2001; 44:141-153. Birk K, Rudick R: Pregnancy and multiple sclerosis. Arch Neurol 1986; 43:719-726. Ed Mancall EL, Munset TH: Neurologic Disorders and Pregnancy. Continuum: Lifelong Learning in Neurology. 2000; 6:8-63. Kittner SJ, Stern BJ, Feeser BR, et al: Pregnancy and the risk of stroke. N Engl J Med 1996; 335:768-774. Roberts JM, Cooper DW: Pathogenesis and genetics of preeclampsia. Lancet 2001; 357:53-56. Yerby MS, Kaplan P: Risks and management of pregnancy in women with epilepsy. Cleve Clin J Med 2004; 71:S25-S37.

References 1. Beyenburg S, Stoffel-Wagner B, Bauer J, et al: Neuroactive steroids and seizure susceptibility. Epilepsy Res 2001; 44:141153. 2. Wickstrom K, Edelstam G, Lowbeer C, et al: Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein S and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest 2004; 64:31-40.

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3. Clark P, Brennand J, Conkie JA, et al: Activated protein C sensitivity, protein C, protein S, and coagulation in normal pregnancy. Thromb Haemost 1998; 79:1166-1170. 4. Vodnik T, Ignjatovic S, Majkic-Singh N: Changes in the plasma levels of protein C system parameters in pregnancy. Scand J Clin Lab Invest 2003; 63:481-488. 5. Granella F, Sances G, Pucci E, et al: Migraine with aura and reproductive life events: a case control study. Cephalalgia 2000; 20:701-707. 6. Sances G, Granella F, Nappi RE, et al: Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia 2003; 23:197-205. 7. MacGregor EA: “Menstrual” migraine: towards a definition. Cephalalgia 1996; 16:11-21. 8. Cupini LM, Matteis M, Troisi E, et al: Sex-hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia 1995; 15:140-144. 9. Lagrange AH, Ronnekleiv OK, Kelly MJ: The potency of μopioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17-estradiol. J Neurosci 1994; 14:61966204. 10. Marcus DA: Nonpharmacologic treatment of migraine. TEN 2001; 3:50-55. 11. Olesen C, Steffensen FH, Sorensen HT, et al: Pregnancy outcome following prescription for sumatriptan. Headache 2000; 40:20-24. 12. Kallen B, Lygner PE: Delivery outcome in women who used drugs for migraine during pregnancy with special reference to sumatriptan. Headache 2001; 41:351-356. 13. Lindhout D, Meinardi H: Spina bifida and in-utero exposure to valproate. Lancet 1984; 2:396. 14. Lindhout D, Schmidt D: In-utero exposure to valproate and neural tube defects. Lancet 1986; 1:1392-1393. 15. Rosa FW: Spinal bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324:674677. 16. Sharshar T, Lamy C, Mas JL, for the Stroke in Pregnancy Study Group: Incidence and causes of stroke associated with pregnancy and puerperium: a study in public hospitals of Ile de France. Stroke 1995; 26:930-936. 17. Kittner SJ, Stern BJ, Feeser BR, et al: Pregnancy and the risk of stroke. N Engl J Med 1996; 335:768-774. 18. Jeng JS, Tang SC, Yip PK: Incidence and etiologies of stroke during pregnancy and puerperium as evidenced in Taiwanese women. Cerebrovasc Dis 2004; 18:290-295. 19. Jaigobin C, Silver FL: Stroke and pregnancy. Stroke 2000; 31:2948-2951. 20. Barno A, Freeman DW: Maternal deaths due to spontaneous subarachnoid hemorrhage. Am J Obstet Gynecol 1976; 125:384-392. 21. Horton JC, Chambers WA, Lyons SL, et al: Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1990; 27:867-872. 22. Weir B, Macdonald RL: Management of intracranial aneurysms and arteriovenous malformations during pregnancy. In: Wilkins RH, Rengachary SS, eds. Neurosurgery. New York: McGraw-Hill, 1996, pp 2421-2427. 23. Maymon R, Fejgin M: Intracranial hemorrhage during pregnancy and puerperium. Obstet Gynecol Surv 1990; 45:157159. 24. Ginsberg JS, Greer I, Hirsh J: Use of antithrombotic agents during pregnancy. Chest 2001; 119:122S-131S. 25. Ahearn GS, Hadjiliadis D, Govert JA, et al: Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options. Arch Intern Med 2002; 162:12211227.

26. Nassar AH, Abdallah ME, Moukarbel GV, et al: Sequential use of thrombotic agents for thrombosed mitral valve prosthesis during pregnancy. J Perinatal Med 2003; 31:257-260. 27. Robinson JL, Hall CS, Sedzimir CB: Arteriovenous malformations, aneurysms, and pregnancy. J Neurosurg 1974; 41:63-70. 28. Dias MS, Sekhar LN: Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium. Neurosurgery 1990; 27:855-865. 29. Lamy C, Hamon JB, Coste J, et al: Ischemic stroke in young women: risk of recurrence during subsequent pregnancies. French Study Group on Stroke in Pregnancy. Neurology 2000; 55:269-274. 30. Coppage KH, Hinton AC, Moldenhauer J, et al: Maternal and perinatal outcome in women with a history of stroke. Am J Obstet Gynecol 2004; 190:1331-1334. 31. Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982; 142:159-167. 32. Roberts JM, Cooper DW: Pathogenesis and genetics of preeclampsia. Lancet 2001; 357:53-56. 33. Saftlas AF, Olson DR, Franks AL, et al: Epidemiology of preeclampsia and eclampsia in the United States, 1979-1986. Am J Obstet Gynecol 1990; 163:460-465. 34. Aagaard-Tillery KM, Belfort MA: Eclampsia: morbidity, mortality, and management. Clin Obstet Gynecol 2005; 48:12-33. 35. Thornton JG, Macdonald AM: Twin mothers, pregnancy, hypertension and pre-eclampsia. Br J Obstet Gynaecol 1999; 106:570-575. 36. Lachmeijer AM, Aarnoudse JG, ten Kate LP, et al: Concordance for pre-eclampsia in monozygous twins. Br J Obstet Gynaecol 1998; 105:1315-1317. 37. Esplin MS, Fausett MB, Fraser A, et al: Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001; 344:867-872. 38. Schwartz RB, Feske SK, Polak JF, et al: Clinical and neuroradiolgraphic correlates in preeclampsia-eclampsia: insights into the pathogenesis of hypertensive encephalopathy. Radiology 2000; 217:371-376. 39. Mantello MT, Schwartz RB, Jones KM, et al: Imaging of neurologic complications associated with pregnancy. AJR Am J Roentgenol 1993; 160:843-847. 40. Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494500. 41. Beausang Linder M, Bill A: Cerebral circulation in acute arterial hypertension: protective effects of sympathetic nervous activity. Acta Physiol Scand 1981; 111:193-199. 42. Higgins JR, de Swiet M: Blood-pressure measurement and classification in pregnancy. Lancet 2001; 357:131-135. 43. Cunningham FG, MacDonald PC, Grant NF, et al: Hypertensive Disorders of Pregnancy. Williams Obstetrics, 20th edition. Stamford, Connecticut: Appleton and Lange, 1997:715. 44. Clark SL, Cotton DB: Clinical indications for pulmonary artery catheterization in the patient with severe preeclampsia. Am J Obstet Gynecol 1988; 158:453-458. 45. Cotton DB, Lee W, Huhta JC, et al: Hemodynamic profile of severe pregnancy-induced hypertension. Am J Obstet Gynecol 1988; 158:523-529. 46. Eclampsia Trial Collaborative Group: Which anticonvulsant for women with eclampsia? Evidence from the collaborative trial. Lancet 1995; 345:1455-1463. 47. Lucas MJ, Leveno KJ, Cunningham FG: A comparison of magnesium sulfate and phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333:201-205. 48. Yerby MS, Kaplan P: Risks and management of pregnancy in women with epilepsy. Cleve Clin J Med 2004; 71:S25-S37. 49. Knight AH, Rhind EG: Epilepsy and pregnancy: a study of 153 pregnancies in 59 patients. Epilepsia 1975; 16:99-110.

chapter 112 neurology of pregnancy and the puerperium 50. Costa ACL, Lopes-Cendes I, Guerreiro CAM: Seizure frequency during pregnancy and the puerperium. Int J Gynecol Obstret 2005; 88:148-149. 51. Hiilesmaa VK: Pregnancy and birth in women with epilepsy. Neurology 1992; 42(Suppl):8-11. 52. Bardy AH: Seizure frequency in epileptic women during pregnancy and puerperium: a prospective study. In: Janz D, Bossi L, Dam M, et al (eds): Epilepsy, Pregnancy, and the Child. New York, Raven Press, 1982, pp 27-31. 53. The Quality Standards Subcommittee of the American Academy of Neurology: Practice parameter: Management issues for women with epilepsy (summary statement): Report of the Quality Standards Committee of the American Academy of Neurology. Epilepsia 1998; 39:1226-1231. 54. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344:1132-1138. 55. Robert E, Guibaud P: Maternal valproic acid and congenital neural tube defects. Lancet 1982; 2:937. 56. Montouris G: Gabapentin exposure in pregnancy: results from Gabapentin Pregnancy Registry. Epilepsy Behav 2003; 4:310317. 57. Cunnington MC: International Lamotrigine Pregnancy Registry update for the Epilepsy Foundation. Epilepsia 2004; 45:1468.

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58. Cunnington MC, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee: Lamotrigine and the risk of malformations in pregnancy. Neurology 2005; 64:955-960. 59. Birk K, Ford C, Smeltzer S, et al: The clinical course of multiple sclerosis during pregnancy and the puerperium. Arch Neurol 1990; 47:738-742. 60. Sadovnick AD, Eisen K, Hashimoto SA, et al: Pregnancy and multiple sclerosis: a prospective study. Arch Neurol 1994; 51:1120-1124. 61. Birk K, Rudick R: Pregnancy and multiple sclerosis. Arch Neurol 1986; 43:719-726. 62. Davis RK, Maslow AS: Multiple sclerosis in pregnancy: a review. Obstet Gynecol Surv 1992; 47:290-296. 63. Boskovic R, Wide R, Wolpin J, et al: The reproductive effects of beta-interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005; 65:807-811. 64. Coyle PK, Johnson K, Pardo L, Stark Y: Pregnancy outcomes in patients with multiple sclerosis treated with glatiramer acetate (Copaxone). Mult Scler 2003; 9(suppl 1):564.

CHAPTER

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CARDIOLOGY

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113

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Martin A. Samuels

The neurology of cardiology may be divided into three categories: (1) the cardiac complications of neurological disease; (2) the neurological complications of cardiac disease (e.g., cardiacsource embolic stroke, neurological complications of cardiac surgery); and (3) neurocardiac syndromes (mitochondrial diseases; Friedreich’s ataxia; muscular dystrophies affecting the heart). The latter two categories are covered in other chapters of this book. This chapter deals with the cardiac manifestations of neuropsychiatric illnesses. In 1942, Walter Cannon reported several incidents of “voodoo” death,1 by which he meant death from fright. These events had several features in common. They were all induced by an absolute belief that an external force could cause demise and that the victim had no power to alter this course. Cannon postulated that death was caused by intense action of the sympathetic adrenal system. Evidence has accumulated to support the concept that voodoo death is a real phenomenon and is not limited to ancient peoples. Rather, it may be a basic biological principle that provides an important clue to understanding the phenomenon of sudden death in modern society, as well as opening a window into the world of neurovisceral disease. George Engel collected 160 accounts from the lay press of sudden death that was attributed to disruptive life events2 and concluded that such events could be divided into eight categories (Fig. 113–1), the common feature of which is lifethreatening stress without escape or control. Richter reported a series of experiments aimed at elucidating the mechanism of “voodoo” death.3 He found that domesticated rats could swim for about an hour in 93°F water, but if the animals’ whiskers were trimmed, they would invariably drown within a few minutes. When similar experiments were performed with wild rats, restraint contributed significantly to the tendency for demise, whereas, in the case of the calm, domesticated animals in which restraint and confinement were apparently not significant stressors, shaving the whiskers rendered these animals as fearful as wild rats, with a corresponding tendency for sudden death. Adrenalectomy did not protect the animals. In humans, one of the easily accessible windows into autonomic activity is the electrocardiogram (ECG). Byer and associates reported six patients with neurological disease in whom ECGs showed large upright T waves and long Q-T intervals.4 On the basis of experimental results of cooling or warming the endocardial surface of the dog’s left ventricle, they concluded

that these electrocardiographic changes resulted from subendocardial ischemia. Levine reported a patient with a subarachnoid hemorrhage who had electrocardiographic changes reminiscent of coronary disease.5 Burch and colleagues reported 17 patients with various types of stroke who had long Q-T intervals, large and usually inverted T waves, and frequent U waves.6 Cropp and Manning reported the abnormalities on ECGs in 29 patients with subarachnoid hemorrhage; in five of these patients, autopsy study verified the absence of coronary artery disease and myocardial infarction, which suggested that the abnormalities on ECGs were neurogenic.7 Selye described electrolyte-steroid cardiopathy with necrosis and argued that this lesion was distinct from the coagulation necrosis that occurred as a result of ischemic disease.8 Certain steroids and other hormones created a predisposition for the development of electrolyte-steroid cardiopathy with necrosis, but other factors were necessary for its development, including stress. Raab and associates found that cardiac lesions may be produced in rats by pretreatment with fluorocortisol, calciferol, or thyroxine, followed by restraint or cold stress, and that pharmacological blockade of sympathetic activity was cardioprotective.9 Intracoronary infusions of adrenaline reproduce the characteristic electrocardiographic pattern of neurocardiac disease, which is reminiscent of subendocardial ischemia, although no ischemic lesion could be found in the hearts of dogs sacrificed after several months of infusions.10 Melville and coworkers produced changes on ECG and myocardial necrosis by stimulating the hypothalamus of cats; autopsy studies revealed evidence of open coronary arteries.11 The cardiac lesion was characterized by intense cytoplasmic eosinophilia with loss of cross-striations and some hemorrhage, a condition now most commonly known as contraction band necrosis. Oppenheimer and Cechetto mapped the chronotropic organizational structure in the rat insular cortex, demonstrating that sympathetic innervation arises from a more rostral part of the posterior insula than does parasympathetic innervation.12 Despite the fact that myocardial damage had been produced in animals, it was not until Koskelo and associates reported on three patients with electrocardiographic changes caused by subarachnoid hemorrhage13 that contraction band necrosis was demonstrated in humans with neurological disease. Connor reported focal myocytolysis in 8% of 231 autopsy studies; the incidence was highest in patients who had died of intracranial

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hemorrhages.14 Connor pointed out that prior pathological reports probably overlooked the lesion because of the fact that it was multifocal, each individual focus being quite small, necessitating extensive tissue sampling. It is clear now that even Connor underestimated the prevalence of the lesion and that serial sections are required to rigorously rule out its presence. Greenshoot and Reichenbach reported nine patients with subarachnoid hemorrhage, all of whom had cardiac lesions, and demonstrated that the cardiac pathology could be reproduced in cats given mesencephalic reticular formation stimulation.15 Adrenalectomy did not protect the hearts. This finding supported the contention that the electrocardiographic changes and cardiac lesions result from direct intracardiac release of catecholamines. Hawkins and Clower injected blood intracranially into mice, thereby producing the characteristic myocardial lesions, which could be ameliorated but not prevented by pretreatment with adrenalectomy.16 This finding indicated that humorally delivered catecholamines had some role in the genesis of neurocardiac necrosis. Jacob and colleagues produced subarachnoid hemorrhage experimentally in dogs and carefully studied the sequential hemodynamic and ultrastructural changes that occurred.17 The

Situations that Predispose to Sudden Death The impact of the collapse or death of a close person During acute grief On threat of loss of a close person During mourning or on an anniversary of a significant event On loss of status or self-esteem Personal danger or threat of injury After danger is over Reunion, triumph, ecstasy ■

Figure 113–1. Situations that predispose to sudden death.

hemodynamic changes occurred in four stages, directly corresponding to the effects seen with intravenous noradrenaline injections: hypertension, tachycardia, rise in left ventricular pressure, and increased coronary blood flow. Ultrastructurally, a series of three stereotyped events, which could be imitated exactly with noradrenaline injections, occurred: migration of calcium-containing granules to the periphery of mitochondria, disappearance of these granules, and myofilament disintegration at the I bands. Partially successful efforts to modify the developments of neurocardiac lesions were made by McNair and coworkers, using reserpine pretreatment in mice subjected to simulated intracranial hemorrhage,18 and by Hunt and Gore, who pre-treated a group of rats with propranolol and then attempted to produce cardiac lesions with intracranial blood injections.19 The phenomena of the various types of myocardial cell death were clarified by Baroldi,20 who described three patterns: coagulation necrosis, the fundamental lesion of infarction; colliquative myocytolysis, the fundamental lesion of low output syndromes; and coagulative myocytolysis (now known as contraction band necrosis), the fundamental lesion of catecholamine-induced necrosis. Contraction band necrosis may be seen in reperfused areas around regions of coagulation necrosis, in sudden unexpected and accidental death, and in hearts exposed to high levels of catecholamines, as in people with pheochromocytoma. This is probably the major lesion described by Selye as electrolytesteroid cardiopathy with necrosis8 and is clearly the lesion seen in animals and people suffering acute neurological or psychiatric catastrophes (Fig. 113–2). It is likely that the subcellular mechanisms underlying the development of contraction band necrosis involve calcium entry. Zimmerman and Hulsmann reported that the perfusion of rat hearts with calcium-free media for short periods creates a situation such that upon readmission of calcium, there is a

■

Figure 113–2. The neurocardiac lesion: contraction band necrosis, also known as myofibrillar degeneration or coagulative myocytolysis. Arrows indicate contraction bands.

chapter 113 neurology of cardiology massive contracture, followed by necrosis and enzyme release.21 This phenomenon, known as the calcium paradox, can be imitated almost exactly with reoxygenation after hypoxemia and reperfusion after ischemia. The latter, called the oxygen paradox, has been linked to the calcium paradox by pathological calcium entry.22 This major ionic shift is probably the cause of the dramatic changes seen on ECG in the context of neurological catastrophe, a fact that could explain the phenomenon of sudden unexpected death in many contexts: for example, sudden death in middle-aged men; sudden infant death syndrome; sudden unexpected nocturnal death syndrome; frightened to death (“voodoo” death); sudden death in epilepsy; sudden death during natural catastrophe; sudden death associated with drug abuse; sudden death in wild and domestic animals; sudden death during asthma attacks; sudden death during the alcohol withdrawal syndrome; sudden death during grief after a major loss; sudden death during panic attacks; sudden death from mental stress; and sudden death during war. The connection between the nervous system and the cardiopulmonary system provides the unifying link that allows a coherent explanation for most, if not all, of the forms of sudden unexpected death. Powerful evidence from multiple disparate disciplines allows for a neurological explanation of sudden unexpected death.23 A wide variety of changes in the ECG is seen in the context of neurological disease. Two major categories of change are arrhythmias and repolarization changes. It is likely that the increased tendency for life-threatening arrhythmias found in patients with acute neurological disease arises from the repolarization change, which increases the vulnerable period during which an extrasystole would be likely to result in ventricular tachycardia and/or ventricular fibrillation. Thus, the essential and potentially most lethal electrocardiographic features, which are known to change in the context of neurological disease, are changes in the ST segment and T wave, reflecting abnormalities in repolarization. Most often, the changes are observed best in the anterolateral or inferolateral leads (Fig. 113–3). The electrocardiographic abnormalities usually improve, often dramatically, with brain death. The major unifying hypothesis for the generation of the electrocardiographic and cardiac morphological abnormalities seen in the context of neuropsychiatric illnesses follows from the fact that both phenomena occur in four circumstances: (1) catecholamine excess; (2) psychological stress; (3) electrical brain stimulation (iatrogenic or spontaneous); and (4) cardiac reperfusion (iatrogenic or spontaneous). Josué first showed in 1907 that adrenaline infusions could cause cardiac hypertrophy.24 This observation has been reproduced on many occasions, which documents the fact that systemically administered catecholamines are associated not only with electrocardiographic changes reminiscent of widespread ischemia but also with a characteristic pathological picture in the cardiac muscle (contraction band necrosis) that is distinct from myocardial infarction. An identical situation may be found in humans with chronically elevated catecholamines, as with pheochromocytoma. An identical cardiac lesion can be produced in various models of stress. A few autopsy studies on patients who experienced sudden death have shown myofibrillar degeneration. Cebelin and Hirsch reported a careful retrospective analysis of the hearts of 15 victims of physical assault who died as a direct result of the assault but without sustaining internal injuries.25

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Figure 113–3. The typical electrocardiogram in patients with neurogenic heart disease, showing a deeply inverted T wave in the inferolateral leads.

In 11 of the 15 individuals, contraction band necrosis was present. Wittstein and colleagues reported a stunned myocardium in people who suffered a severely stressful event.26 This is the human stress cardiomyopathy. As the contraction band necrosis is predominantly subendocardial, it may involve the cardiac conducting system, thus predisposing to cardiac arrhythmias. This lesion, combined with the propensity of catecholamines to produce arrhythmias even in a normal heart, may well raise the risk of a serious arrhythmia. This may be the major immediate mechanism of sudden death in many neurological circumstances, such as subarachnoid hemorrhage, stroke, epilepsy, head trauma, psychological stress, and increased intracranial pressure. Stress-induced myocardial lesions may be prevented by sympathetic blockade with many different classes of antiadrenergic agents (e.g., ganglionic blockers, catecholamine-depleting agents such as reserpine, and β-blockers). This suggests that catecholamines, either released directly into the heart by sympathetic nerve terminals or reaching the heart through the bloodstream after release from the adrenal medulla, may be excitotoxic to myocardial cells. Nervous system stimulation also produces contraction band necrosis. Stimulation of the lateral hypothalamus produces hypertension and electrocardiographic changes reminiscent of those seen in patients with central nervous system disorders. Furthermore, this effect on the blood pressure and ECG can be

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completely prevented by C2 spinal section and stellate ganglionectomy, but not by vagotomy, which suggests that the mechanism of the electrocardiographic changes is sympathetic rather than parasympathetic or humoral. Prolonged bilateral hypothalamic stimulation produces contraction band necrosis indistinguishable from that produced by catecholamines and stress. Stimulation of the left insula (as occurs in some seizures) or ablation of the right (as occurs with some strokes) may produce neurogenic electrocardiographic changes and contraction band necrosis. Other methods of producing cardiac lesions of this type include stimulation of the limbic cortex, the mesencephalic reticular formation, the stellate ganglion, and regions known to elicit cardiac reflexes such as the aortic arch. High levels of circulating catecholamines exaggerate the electrocardiographic findings and myocardial lesions, but high circulating catecholamine levels are not required for the production of pathological changes. Contraction band necrosis also occurs with cardiac reperfusion, as is commonly seen in patients who die after a period of time on a left ventricular assist pump for cardiac surgery. Similar lesions are seen in hearts that were reperfused by angioplasty or fibrinolytic therapy. The mechanism whereby reperfusion of ischemic cardiac muscle produces contraction band necrosis involves entry of calcium after a period of relative deprivation.27 Sudden calcium influx by one of several possible mechanisms (e.g., a period of calcium deficiency with loss of intracellular calcium; a period of anoxia followed by reoxygenation of the electron transport system; a period of ischemia followed by reperfusion, or opening of the receptor-operated calcium channels by excessive amounts of locally released noradrenaline) may be the final common pathway whereby the irreversible contractures occur, leading to contraction band necrosis. Thus, reperfusion-induced myocardial cell death may be a form of apoptosis (programmed cell death) analogous to that seen in the central nervous system wherein excitotoxicity with glutamate results in a similar, if not identical, series of events.28 The precise cellular mechanism for the electrocardiographic change and the histological lesion may well reflect the effects of large volumes of norepinephrine released into the myocardium from sympathetic nerve terminals.29 The fact that the cardiac necrosis is greatest near the nerve terminals in the endocardium and is progressively less severe closer to the epicardium provides further evidence that catecholamine toxicity produces the lesion. This locally released norepinephrine is known to stimulate synthesis of adenosine 3′,5′-cyclic phosphate, which in turn results in the opening of the calcium channel with influx of calcium and efflux of potassium. The actin and myosin filaments interact under the influence of calcium but do not relax unless the calcium channel closes. Continuously high levels of norepinephrine in the region may result in failure of the calcium channel to close, which leads to cell death and, finally, to leakage of enzymes (troponin, creatine kinase) out of the myocardial cell. Free radicals released as a result of reperfusion after ischemia or by the metabolism of catecholamines to the known toxic metabolite adrenochrome may contribute to cell membrane destruction, leading to leakage of cardiac enzymes into the blood.30,31 Thus, the cardiac toxicity of locally released norepinephrine represents a continuum ranging from a brief reversible burst of abnormalities on ECG to an irreversible failure of the muscle cell with enzyme leak and permanent repolarization abnormalities.

Histological changes would also represent a continuum ranging from complete reversibility in a normal heart through mild changes seen best with electron microscopy to severe myocardial cell necrosis with mononuclear cell infiltration and even hemorrhages. The level of cardiac enzymes released and the electrocardiographic changes would be correlated approximately with the severity and extent of the pathological process. In the most severe circumstance, neurogenic myocardial dysfunction may be sufficiently severe to substantially reduce cardiac output, producing acute heart failure with or without chest pain. The pattern of cardiac dysfunction corresponds to the density of catecholamines, producing the characteristic finding of left ventricular apical ballooning, which on echocardiogram or ventriculogram resembles the Japanese octopus trapping pot, the takotsubo, leading to the term takotsubo-like cardiomyopathy (broken heart syndrome).32,33 There is powerful evidence that overactivity of the sympathetic limb of the autonomic nervous system is the common phenomenon that explains the major cardiac abnormalities seen in neurological disorders. These profound effects on the heart may contribute in a major way to the mortality rates of many primarily neurological conditions such as subarachnoid hemorrhage, status epilepticus, ischemic and hemorrhagic stroke, and head trauma. These phenomena may also be important in the pathogenesis of sudden unexpected death in many clinical settings.

K E Y

P O I N T S

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The nervous system has a profound influence over the heart.

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Catecholamines mediate most neurocardiac phenomena.

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Neurocardiac damage is distinct from myocardial infarction.

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Neurocardiac lesions are arrhythmogenic and may mediate sudden death.

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Neurocardiac damage is an example of excitotoxicity.

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Neurogenic cardiac problems may be ameliorated with catecholamine blockers.

Suggested Reading Armour JA, Ardell JL: Neurocardiology. Oxford, UK: Oxford University Press, 1994. Brillman J: Neurocardiology in Neurologic Clinics, vol 11, no. 2. Philadelphia: WB Saunders, 1993. Johnson RH, Lambie DG, Spalding JMK: Neurocardiology. Philadelphia: WB Saunders, 1984. Kulbertus HE, Franck G: Neurocardiology. Mt. Kisco, NY: Futura, 1988. Meerson FZ: Adaptation, Stress and Prophylaxis. Berlin: SpringerVerlag, 1984. Samuels MA: “Voodoo” death revisited: the modern lessons of neurocardiology. Neurologist 1997; 3:293-304.

References 1. Cannon WB: “Voodoo” death. Am Anthropol 1942; 44:169-181. 2. Engel G: Sudden and rapid death during psychological stress. Ann Intern Med 1971; 74:771-782.

chapter 113 neurology of cardiology 3. Richter CP: On the phenomenon of sudden death in animals and man. Psychosom Med 1957; 19:191-198. 4. Byer E, Ashman R, Toth LA: Electrocardiogram with large upright T wave and long Q-T intervals. Am Heart J 1947; 33:796-801. 5. Levine HD: Non-specificity of the electrocardiogram associated with coronary heart disease. Am J Med 1953; 15:344-350. 6. Burch GE, Myers R, Adildskov JA: A new electrocardiographic pattern observed in cerebrovascular accidents. Circulation 1954; 9:719-726. 7. Cropp CF, Manning GW: Electrocardiographic change simulating myocardial ischaemia and infarction associated with spontaneous intracranial haemorrhage. Circulation 1960; 22:24-27. 8. Selye H: The Chemical Prevention of Cardiac Necrosis. New York: Ronald Press, 1958. 9. Raab W, Stark E, MacMillan WH, et al: Sympathogenic origin and anti-adrenergic prevention of stress-induced myocardial lesions. Am J Cardiol 1961; 1958:8:203-211. 10. Barger AC, Herd JA, Liebowitz MR: Chronic catheterization of coronary artery induction of ECG pattern of myocardial ischaemia by intracoronary epinephrine. Proc Soc Exp Biol Med 1961; 107:474-477. 11. Melville KI, Blum B, Shister HE, et al: Cardiac ischemic changes and arrhythmias induced by hypothalamic stimulation. Am J Cardiol 1963; 12:781-791. 12. Oppenheimer SM, Cechetto DF: Cardiac chronotropic organization of the rat insular cortex. Brain Res 1990; 533:66-72. 13. Koskelo P, Punsar SO, Sipila W: Subendocardial haemorrhage and ECG changes in intracranial bleeding. BMJ 1964; 1:14791483. 14. Connor RCR: Myocardial damage secondary to brain lesions. Am Heart J 1969; 78:145-148. 15. Greenshoot JH, Reichenbach DD: Cardiac injury and subarachnoid haemorrhage. J Neurosurg 1969; 30:521-531. 16. Hawkins WE, Clower BR: Myocardial damage after head trauma and simulated intracranial haemorrhage in mice: the role of the autonomic nervous system. Cardiovasc Res 1971; 5:524-529. 17. Jacob WA, Van Bogaert A, DeGroot-Lasseel MHA: Myocardial ultrastructural and haemodynamic reactions during experimental subarachnoid haemorrhage. J Mol Cell Cardiol 1972; 4:287-298. 18. McNair JL, Clower BR, Sanford RA: The effect of reserpine pretreatment on myocardial damage associated with stimulated

19. 20.

21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

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intracranial haemorrhage in mice. Eur J Pharmacol 1970; 9:1-6. Hunt D, Gore I: Myocardial lesions following experimental intracranial hemorrhage: prevention with propranolol. Am Heart J 1972; 83:232-236. Baroldi F: Different morphological types of myocardial cell death in man. In Fleckstein A, Rona G, eds: Recent Advances in Studies in Cardiac Structure and Metabolism: Pathophysiology and Morphology of Myocardial Cell Alteration, vol 6. Baltimore: University Park Press, 1975, pp 385-397. Zimmerman ANA, Hulsmann WC: Paradoxical influence of calcium ions on the permeability of the cell membranes of the isolated rat heart. Nature 1966; 211:616-647. Hearse DJ, Humphrey SM, Bullock GR: The oxygen paradox and the calcium paradox: two facets of the same problem? J Mol Cell Cardiol 1978; 10:641-668. Samuels MA: Neurally induced cardiac damage. Neurol Clin 1993; 11:273-292. Josué O: Hypertrophie cardiaque causee par l’adrenaline et la toxine typhique. C R Soc Biol (Paris) 1907; 63:285287. Cebelin M, Hirsch CS: Human stress cardiomyopathy. Hum Pathol 1980; 11:123-132. Wittstein IS, Thiemann DR, Lima JA, et al: Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005; 352:539-548. Braunwald E, Kloner RA: Myocardial reperfusion: a doubleedged sword? J Clin Invest 1985; 76:1713-1719. Gottlieb R, Burleson KO, Kloner RA, et al: Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994; 94:1621-1628. Eliot RS, Todd GL, Pieper GM, et al: Pathophysiology of catecholamine-mediated myocardial damage. J S Carolina Med Assoc 1979; 75:513-518. Singal PK, Kapur N, Dhillon KS, et al: Role of free radicals in catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol 1982; 60:1390-1397. Meerson FZ: Pathogenesis and prophylaxis of cardiac lesions in stress. Adv Myocardiol 1983; 4:3-21. Kawai S, Suzuki H, Yamaguchi H, et al: Ampulla cardiomypathy (“Takotsubo” cardiomyopathy)—reversible left ventricular dysfunction. Jpn Circ J 2000; 64:156-159. Gianni M, Dentali F, Grandi AM, et al: Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27:1523-1529.

CHAPTER

114

NEUROLOGY

OF GASTROENTEROLOGY AND HEPATOLOGY ●

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Ronald F. Pfeiffer

The enteric nervous system within the gut wall, replete with its neuronal networks and numerous neurotransmitters, mirrors many aspects of the central nervous system (CNS) and intimately interfaces with the CNS via the autonomic nervous system. Although seldom recognized, the number of neurons in the enteric nervous system is actually comparable to the number of neurons in the spinal cord, leading some authorities to refer to the enteric nervous system as the “little brain.”1,2 The striking similarities and intricate interaction between the neurological and gastrointestinal systems have been highlighted by the emergence of “neurogastroenterology” as a field of growing research and clinical interest.3 The boulevard connecting the two disciplines is a two-way street. Gastrointestinal manifestations of some neurological diseases are well known; the sometimes prominent gastrointestinal manifestations of Parkinson’s disease serve as a ready example.4 However, the potential presence of neurological dysfunction in the setting of gastrointestinal disease is often overlooked. Although neurological dysfunction in the setting of hepatic failure is very well known to both neurologists and gastroenterologists, the potential for neurological dysfunction in other gastrointestinal disease processes often eludes recognition. This chapter highlights several of these disease processes and also addresses some neurological aspects of hepatic failure.

GASTROINTESTINAL DISEASE Celiac Disease Celiac disease, also known as nontropical sprue, celiac sprue, or gluten-sensitive enteropathy, has historically been conceptualized as a disorder of the small intestine that in its adult-onset form is characterized clinically by steatorrhea, intermittent diarrhea, abdominal bloating, flatulence, malabsorption, weight loss, and aphthous stomatitis. Pathological features include villous atrophy and crypt hyperplasia. The proximal small intestine, especially the jejunum, is most prominently involved. Exposure to gluten, the protein fraction of wheat, appears to trigger an autoimmune response that in turn produces the intestinal mucosal damage characteristic of celiac disease. There are two distinct proteins in gluten

(glutenin and gliadin), and it is the production of immunoglobulin A antibodies to gliadin that has been traditionally held to be the vehicle for the mucosal damage, although it has also been suggested that these antibodies, although diagnostic markers of the disease, are not crucial to its pathogenesis.5 Other similar proteins, called prolamins, present in barley, rye, and oats, may induce a similar response. Most reports have estimated the prevalence of celiac disease at approximately 1% of the white population; one study indicated that 1 per every 120 to 300 persons in the United States and Europe is affected.6 Celiac disease appears to be most prevalent in northwestern Europe. Two peaks of clinical appearance have been identified: the first during infancy and the second between the ages of 30 and 50. A genetic component is presumably present, inasmuch as approximately 90% of individuals with diagnosed celiac disease carry the human leukocyte antigen DQ2 haplotype.7,8 Possible susceptibility loci have also been identified on chromosomes 2 and 5,9 but specific genetic mutations have not been delineated. Not all individuals with celiac disease manifest clinical symptoms. Serological tests and even intestinal biopsy may demonstrate the presence of the pathological process in completely asymptomatic individuals. Clinicians have also realized that celiac disease is not merely a gastrointestinal disease but is, in fact, a multisystemic disorder. Dermatitis herpetiformis is characterized primarily by a blistering skin rash, but patients with this disorder also demonstrate evidence of gluten-induced intestinal pathology, the presence of gluten-induced antibodies, and a response to dietary gluten restriction, which suggests that the two disorders may be part of a pathological spectrum.10 Osteoporosis and infertility have been reported as complications of celiac disease,6 as has psychiatric dysfunction.11 Individuals with celiac disease are also at increased risk for developing certain types of cancer, including lymphoma and carcinomas of the small intestine, esophagus, and pharynx.12 A particular variety of T cell lymphoma, now designated enteropathy-associated T cell lymphoma, has been specifically associated with celiac disease. Associations with other autoimmune diseases, such as autoimmune thyroid disease, type I diabetes mellitus, Sjögren’s syndrome, and primary biliary cirrhosis have also been described.13 Neurological dysfunction has also been identified in the context of celiac disease (Table 114–1). Neurological complications may, in fact, develop in 6% to 12% of persons with celiac

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T A B L E 114–1. Neurological Dysfunction in Celiac Disease

T A B L E 114–2.

Reported and Reasonably Well-Documented Ataxia Epilepsy Migraine Learning disabilities Peripheral neuropathy Myopathy

Nonbloody, less than urgent diarrhea Weight loss Abdominal pain (prominent feature) Anal and perianal lesions and fistulae Intestinal stricture formation

Reported but Less Clearly Documented Myoclonic ataxia Progressive multifocal leukoencephalopathy Chorea Autonomic neuropathy Neuromyelitis optica Central nervous system lymphoma

disease.14-16 CNS disorders have undergone the most intense investigation, but peripheral nervous system dysfunction has also been recognized.

Ataxia Ataxia is the neurological complication that has received the most interest and attention in the setting of celiac disease. In 1966, Cooke and Smith described 16 patients with celiac disease who had also developed progressive ataxia (along with other neurological abnormalities) that was unresponsive to gluten restriction.17 It was not until 1996, however, that the idea that ataxia might be a direct consequence of gluten sensitivity was proposed by Hadjivassiliou and colleagues when they published the first of a series of reports that delineated the presence of antigliadin antibodies in individuals with sporadic adult-onset ataxia of unknown etiology and subsequently created the term gluten ataxia for the condition.7,8,18,19 They later documented the presence of antigliadin antibodies (immunoglobulin G and/or immunoglobulin A) in 41% (54) of 132 individuals with sporadic idiopathic ataxia, in comparison with only 15% (5) of 33 persons with clinically probable multiple system atrophy, 14% (8) of 59 patients with familial ataxia, and 12% (149) of 1200 normal controls.19 In the same report, a second group of 44 patients with sporadic idiopathic ataxia from another clinic was also studied; antigliadin antibodies were present in 32% (14) of this group. Other investigators have also reported elevations of antigliadin antibodies in patients with sporadic idiopathic ataxia but with lower frequencies, ranging from 11% to 27%.14,20-22 This finding has not been universal, however. Some investigators have not encountered this elevation in their study populations.23,24 Gluten ataxia, as currently recognized by its proponents, has no particularly distinguishing clinical characteristics. Gait ataxia is, by definition, present in all individuals with gluten ataxia. Limb ataxia, dysarthria and ocular signs are present in the vast majority. Cerebellar atrophy is evident on magnetic resonance imaging (MRI) in 79% of patients, whereas white matter hyperintensities are evident in only 19%.19 Evidence of classical celiac disease was found in only 24% (12) of 51 individuals with gluten ataxia who underwent gastroscopy and duodenal biopsy. In another report by the same group of investigators, 26 of 43 patients placed on a gluten-free diet were able to maintain the diet for 1 year; all 26 experienced improve-

Gastrointestinal Features of Crohn’s Disease

ment in the ataxia, regardless of whether an enteropathy was present.25 Some investigators are not convinced that gluten ataxia exists as a distinct entity.5,23 They point to the nonspecificity of antigliadin antibodies, as reflected in the fact that antigliadin antibodies are present in significant numbers of normal controls. Moreover, antigliadin antibodies have been noted to be present in 44% (23) of a group of 52 patients with Huntington’s disease, which prompted speculation that antigliadin antibodies might simply be an epiphenomenon in certain neurodegenerative diseases and that gluten ataxia may not be a distinct clinical entity.26 The absence of any clearly defined pathophysiological mechanism that might account for the cerebellar dysfunction in affected individuals has been another criticism of the concept of gluten ataxia as a distinct clinical entity. However, a chronic, immune-mediated inflammatory process has been proposed to be responsible for the cerebellar damage,27 and autopsy examination in several affected individuals has demonstrated Purkinje cell loss and lymphocytic infiltration within the cerebellum and posterior columns of the spinal cord.8 Hadjivassiliou and colleagues (2003) suggested that screening for gluten sensitivity be undertaken in all individuals who present with adult-onset ataxia without any other obvious cause.19 There is, however, no universal agreement regarding the specific screening test that should be employed. Antireticulin, antiendomysial and antitissue transglutaminase antibodies may actually be identical,5 and their presence is quite specific for celiac disease. In contrast, antigliadin antibody, especially the immunoglobulin G isotype, is nonspecific and actually present in more than 10% of healthy blood donors. This diminishes the usefulness of antigliadin antibody testing as a screening test for celiac disease, but Hadjivassiliou and colleagues believed that immunoglobulin G antigliadin antibodies are the best diagnostic marker for gluten ataxia in that they mark the whole spectrum of gluten sensitivity and not just gluten enteropathy alone.19 It thus appears that research on gluten ataxia is currently unfinished.

Epilepsy Some investigators have suggested that the prevalence of epilepsy is increased among individuals with celiac disease. Epilepsy has been reported to be present in 3.5% to 5.5% of individuals with celiac disease.28,29 Examining the converse, Cronin and associates studied a group of patients with epilepsy and found the frequency of celiac disease, diagnosed from the presence of endomysial antibody, to be 2.3%, in comparison with 0.4% in a control group.30 A specific syndrome of epilepsy, bilateral occipital calcification, and celiac disease has also been described.31 These reports have been largely from Italian investigators, but reports from other parts of the globe have also been published.32 The mechanism for such an association is

chapter 114 neurology of gastroenterology and hepatology obscure. It also is not entirely clear whether a gluten-free diet improves seizure control in patients with celiac disease and epilepsy, although some investigators have reported that it does.32 An association between celiac disease and epilepsy has not been found by all investigators.33,34 Moreover, in one study, the presence of celiac disease–associated antibodies (antigliadin, antiendomysial, and antitissue transglutaminase) did not differ between 968 patients with epilepsy and a reference group of 584 individuals.35

Migraine An association between celiac disease and migraine has also been proposed. In a report by Gabrielli and colleagues, 4.4% (4) of 90 patients with migraine were found to have serological evidence of celiac disease; subsequent jejunal biopsy confirmed the presence of celiac disease in all four of these.36 Migraine severity improved in all individuals on a gluten-free diet. Abnormalities of regional cerebral blood flow, which were noted on single photon emission computed tomographic scanning in all patients with the combination of celiac disease and migraine, also improved in all individuals. Additional case reports have described resolution of migraine with treatment of celiac disease.37 Low serotonin levels have been proposed to be a common link between the two disorders.38

Learning Disabilities Learning disabilities, such as attention deficit/hyperactivity disorder, have been shown to occur with increased frequency in the setting of celiac disease.27 The co-occurrence of dyslexia and celiac disease has also been reported.39

Peripheral Neuropathy and Myopathy Both peripheral nerve involvement and myopathy have been described in celiac disease. In a retrospective chart review, Vaknin and associates found that peripheral neuropathy accounted for 17% of the neurological abnormalities present in a group of patients with celiac disease.16 Another group of investigators identified chronic axonal sensorimotor neuropathy in 23% (6) of 26 patients with celiac disease and abnormalities on neurophysiological testing in 31% (8).40 These findings were present despite the fact that all 26 individuals studied had been on gluten-free diets for a median of 3 years (range, 2 to 28 years). Sural nerve biopsy, when performed, has also demonstrated the presence of axonal injury.41 Inflammatory myopathy has also been described in the setting of celiac disease and in at least one instance has been associated with vitamin E deficiency; reversal of both clinical symptoms and muscle biopsy abnormalities was documented in that individual after treatment with vitamin E and institution of a gluten-free diet.42

Other Processes A number of other neurological manifestations of celiac disease have also been reported but less extensively evaluated. Examples include myoclonic ataxia,43 progressive multifocal leukoencephalopathy,44 chorea,45 autonomic neuropathy,46 and neuromyelitis optica.47 The significance of these reported associations is uncertain. Lymphoma within the CNS, with the

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immunophenotype of enteropathy-associated T cell lymphoma, has also been reported in celiac disease.12

Inflammatory Bowel Disease Two similar but distinct disease entities, ulcerative colitis and Crohn’s disease (regional enteritis, granulomatous colitis), are the most widely recognized members of a group of conditions collectively labeled inflammatory bowel disease (IBD). An autoimmune etiology, characterized by a dysregulated mucosal immune response to antigens normally present within the intestinal lumen, is suspected in both.48,49 During the latter half of the 20th century, a significant rise in the incidence of Crohn’s disease, but not ulcerative colitis, was noted, especially in North America and northern Europe.50 The explanation for this increased incidence, which has appeared to stabilize since about 1980, is uncertain, but suspicion has fallen on a variety of environmental factors. Genetic factors also appear to play a role in the generation of the inappropriate immune response. This has been most clearly identified in Crohn’s disease, in which the NOD2/CARD15 gene, which is involved in the immune detection of bacterial products, has been identified as a susceptibility gene for Crohn’s disease.51,52 Despite many similarities, the clinical features and pathological profiles of the two conditions also demonstrate decided differences (Tables 114–2, 114–3, and 114–4). Neurological dysfunction has been described in both. Ulcerative colitis is characterized clinically by urgent, bloody diarrhea (see Table 114–4). Its course is typically marked by exacerbations and remissions. The pathological hallmark of ulcerative colitis is diffuse inflammation of the mucosa and superficial submucosa of the colon, extending a variable distance proximally from the rectum but not beyond the colon.53 The primary clinical characteristics of Crohn’s disease, in contrast, consist of abdominal pain and nonbloody, less urgent diarrhea (see Table 114–2). Weight loss is also common. Scarring and stricture formation can lead to partial intestinal obstruction, and fistula formation is also frequent. As with ulcerative colitis, the clinical course of Crohn’s disease often entails exacerbations and remissions. Although Crohn’s disease T A B L E 114–3. Peripheral Nervous System Dysfunction in Inflammatory Bowel Disease Axonal sensorimotor neuropathy Acute inflammatory demyelinating neuropathy Mononeuropathy Brachial plexopathy Mononeuritis multiplex Multiple compressive neuropathies Cranial neuropathies Acute sensorineural hearing loss Melkersson-Rosenthal syndrome

T A B L E 114–4. Gastrointestinal Features of Ulcerative Colitis Urgent, bloody diarrhea Nausea and anorexia Weight loss Abdominal pain (usually not prominent)

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may involve virtually all levels of the gastrointestinal tract, it demonstrates a distinct predilection for the distal small intestine and proximal colon. In contrast to ulcerative colitis, gastrointestinal tract involvement in Crohn’s disease is patchy or segmental and extends deeply, often transmurally. Noncaseating granulomas may form but are not invariably present. Extraintestinal manifestations of both Crohn’s disease and ulcerative colitis are surprisingly common, with reported frequencies ranging from approximately 25% to more than 50% of affected individuals.54-57 Some of the extraintestinal manifestations, such as involvement of joints, skin, mouth, and eyes, seem to be correlated with the presence of active colonic inflammation and are observed in both Crohn’s disease and ulcerative colitis. Other clinical processes, such as gallstones and renal calculi, are correlated more directly with small intestinal involvement and are observed primarily in Crohn’s disease.58 Primary sclerosing cholangitis is a particularly important extraintestinal complication of ulcerative colitis that may progress to hepatic failure, independent of the severity of the ulcerative colitis itself. In comparison with many of the systemic manifestations of IBD, neurological involvement (myopathy and myasthenia gravis) occurs less frequently in both ulcerative colitis and Crohn’s disease. Lossos and colleagues (1995) reported the presence of neurological involvement in 3% (19) of 638 persons they studied with either ulcerative colitis or Crohn’s disease.59 In their comprehensive review, they described four categories of neurological involvement in Crohn’s disease and ulcerative colitis: peripheral neuropathy, myopathy or myoneural junction dysfunction, cerebrovascular disease, and myelopathy. Other groups of investigators have also documented seizures and encephalopathy in patients with IBD. Treatment for both Crohn’s disease and ulcerative colitis involves potent medications; thus, a number of neurological complications of treatment for these diseases have also been reported. Although neurological impairment often becomes evident during periods of disease activity, it can also emerge when the disease process is quiescent.

Peripheral Nervous System Involvement in Inflammatory Bowel Disease Within the peripheral nervous system, both nerve and muscle involvement may become evident in inflammatory bowel disease. Myoneural junction dysfunction has also been described.

Peripheral Neuropathic Disease The peripheral nervous system is the dominant site of neurological dysfunction in ulcerative colitis and Crohn’s disease, accounting for 31.5% of neurologically affected patients in the experience of Lossos and colleagues.59 A rather extensive array of peripheral neuropathic processes has received recognition (see Table 114–3). Acute inflammatory demyelinating neuropathy (Guillain-Barré syndrome), axonal sensorimotor neuropathy, mononeuropathy, brachial plexopathy, mononeuritis multiplex, multiple compressive neuropathies, and cranial neuropathies have all been described in the setting of Crohn’s disease and ulcerative colitis.59-62 Gondim and associates performed a retrospective study of 18 patients with Crohn’s disease and 15 with ulcerative colitis who had developed peripheral neuropathy with no other iden-

tifiable etiology.63 The neuropathy was demyelinating in nature in slightly fewer than 30% of the patients, small- or large-fiber axonal sensory in about 30%, and large-fiber axonal sensorimotor in approximately 40%. Small-fiber axonal sensory neuropathy was more frequently present in younger patients, whereas large-fiber axonal neuropathy tended to be present in older patients. Although both axonal and demyelinating neuropathies often responded to immunotherapy, the response was more consistent and robust in patients with demyelinating neuropathy. The actual pathological process inciting the peripheral neuropathy in individuals with IBD is uncertain. In some instances, nutritional factors—folate or vitamin B12 deficiency—have been responsible, but in other cases, the explanation is not so clear. A response to immunosuppressive therapy is suggestive of an autoimmune basis in some instances, but not all patients have been immunoresponsive. Infection with Campylobacter jejuni has been linked to both acute inflammatory demyelinating neuropathy and exacerbations of inflammatory bowel disease, but it has not been reported in concomitant cases. Two specific and unusual processes consisting of cranial nerve involvement have been noted in individuals with IBD. Melkersson-Rosenthal syndrome is characterized by the clinical constellation of recurrent facial nerve palsy, intermittent orofacial swelling, and fissuring of the tongue (lingua plicata). Not only has this syndrome been noted in the presence of Crohn’s disease, but also its pathological hallmark—noncaseating granuloma formation—is observed in Crohn’s disease. This has led some to suggest that Crohn’s disease and Melkersson-Rosenthal syndrome are actually part of the same pathological spectrum.64 Acute sensorineural hearing loss has been described, primarily in persons with ulcerative colitis.65-68 The presumption of an autoimmune basis for the hearing loss is based in part on reported responses to steroid administration. Chronic, subclinical hearing loss, discovered on audiometric screening, has also been documented in ulcerative colitis.69

Muscle and Myoneural Junction Disease Myopathy has been described in the setting of both ulcerative colitis and Crohn’s disease, but it is present more frequently in Crohn’s disease. It accounted for 16% of the cases of neurological dysfunction in the series compiled by Lossos and colleagues.59 Dermatomyositis, polymyositis, rimmed vacuole myopathy, and granulomatous myositis have all been noted in this setting. As with peripheral nerve involvement, an autoimmune basis is presumed to be present. Localized myositis involving the gastrocnemius muscles has also been reported in Crohn’s disease and is known as gastrocnemius myalgia syndrome.70 In approximately 50% of cases, the appearance of myopathic pathology seems to be correlated with disease activity in the bowel. Myasthenia gravis, another autoimmune disorder, has also been reported in the setting of both Crohn’s disease and ulcerative colitis, although reports of this association are quite sparse.

Central Nervous System Involvement in Inflammatory Bowel Disease CNS involvement in inflammatory bowel disease can assume many guises. Cerebrum, brainstem, and spinal cord can all be involved (Table 114–5).

chapter 114 neurology of gastroenterology and hepatology T A B L E 114–5. Central Nervous System Involvement in Inflammatory Bowel Disease Cerebrovascular disease Arterial thromboembolic infarction Dural and cortical venous thrombosis Vasculitis Myelopathic disease Seizures Diffuse encephalopathy Cerebral vasculitis Nutritional deficiency

Myelopathic and Motor Neuron Disease Chronic, slowly progressive myelopathy is yet another neurological manifestation of inflammatory bowel disease, accounting for 26% of the patients with neurological involvement in the series of Lossos and colleagues.59 Most of these individuals were suffering from Crohn’s disease rather than ulcerative colitis. An inflammatory basis was suspected, and oligoclonal banding was noted in one patient. Other investigators have suggested a possible association between ulcerative colitis and multiple sclerosis,71,72 and it has been reported that the incidence of multiple sclerosis is threefold greater in persons with ulcerative colitis than in the general population.71 Transverse myelitis has been reported in an individual with ulcerative colitis who also was found to have anti–Jo-1 antibody (antisynthetase) syndrome.73 Whether cases such as these are causal or coincidental is uncertain. A more definite causal relationship can be drawn with the occurrence of spinal empyema in the setting of Crohn’s disease secondary to fistula formation.74 There has been one case report of the coexistence of ulcerative colitis with motor neuron disease, although the issue of cause versus coincidence cannot be escaped in this instance either.75

Cerebrovascular Disease Vascular complications are well-documented extraintestinal manifestations of inflammatory bowel disease. In a massive undertaking, Talbot and coworkers reviewed the records of 7199 patients with either Crohn’s disease or ulcerative colitis and noted the presence of vascular complications in 1.3%.76 Deep venous thrombosis and pulmonary embolus were the most common sites of involvement, whereas cerebrovascular events accounted for only 9.8% of the total vascular complications (in 9 of 92 patients). Vascular complications occur more frequently in ulcerative colitis than in Crohn’s disease; the reason for this difference is uncertain.77 Hypercoagulability has been presumed to be responsible for the thromboembolic events, and elevations of factors V and VIII and fibrinogen levels, along with decreased antithrombin III levels, have been noted.78 Anticardiolipin antibodies, thrombopoietin, and homocysteine levels have also been shown to be elevated in individuals with ulcerative colitis and Crohn’s disease, but the elevations are not correlated with increased risk of thromboembolic events.79-81 In fact, no single or specific abnormality has been identified as the hypercoagulable culprit, and no consistent abnormality of the routinely recognized coagulopathy susceptibility factors has been discovered.82

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A variety of cerebrovascular events has been reported in ulcerative colitis and Crohn’s disease. Both large artery and lacunar infarcts have been described.83,84 Cerebral vasculitis has been identified in both Crohn’s disease and ulcerative colitis, which led to the proposal that an autoimmune basis is responsible for the cerebrovascular events. However, responses to both immunosuppressive therapy (corticosteroids and azathioprine) and anticoagulation have been reported, which suggests that a single explanation is improbable and that both hypercoagulable and autoimmune processes may have roles in different individuals.85-87 Both dural and cortical venous sinus thrombosis have been the subjects of numerous case reports in individuals with inflammatory bowel disease, predominantly but not exclusively in ulcerative colitis.77,88 Such events have occurred both during active exacerbations and during periods of disease quiescence. As with other cerebrovascular events, the mechanism of the coagulopathy is not entirely clear.

Seizures and Encephalopathy Seizures are an infrequently reported neurological complication of inflammatory bowel disease. They may occur as a complication of the surgical management of these diseases, presumably precipitated by factors such as fluid overload, electrolyte imbalance, hypoxia, and steroid administration or withdrawal.89 Seizures have also been reported as a complication of cyclosporine treatment in an individual with Crohn’s disease.90 Status epilepticus, with long-term sequelae, has been described in the setting of ulcerative colitis; the genesis for this has not been clearly delineated.91 Diffuse encephalopathy with altered consciousness may also develop in individuals with ulcerative colitis or Crohn’s disease. This may occur in the context of cerebral vasculitis85 but also as a consequence of nutritional deficiencies. Both Wernicke’s encephalopathy and possible selenium-induced encephalopathy have been described in individuals with Crohn’s disease receiving total parenteral nutrition.92,93 Wernicke’s encephalopathy has also been reported in an individual with clinically inactive Crohn’s disease.94

Whipple’s Disease Although originally described as a gastrointestinal disease, it has become abundantly clear that Whipple’s disease is a multisystem disorder (Table 114–6) that may also demonstrate joint, dermatological, lymphatic, cardiac, pulmonary, ocular, and neurological dysfunction.95 Thus, in addition to diarrhea, weight loss, and abdominal pain, individuals with Whipple’s disease may display migratory polyarthritis, generalized lymphadenopathy, anemia, fever, generalized malaise, chronic cough, pseudo-addisonian skin pigmentation, congestive heart failure, hypotension, pericardial friction rub, splenomegaly, focal glomerulitis, visual changes, uveitis, retinitis and a variety of neurological manifestations.95,96 Whipple’s disease affects primarily middle-aged men of European heritage, with an average age at symptom onset of approximately 50; the male-to-female ratio appears to have diminished since the 1990s from 8 : 1 to 4-5 : 1.95 By all accounts, Whipple’s disease is a very rare condition, even though it may be more prevalent than commonly recognized. There is some evidence that farmers have an increased risk for

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T A B L E 114–6. Systemic Features of Whipple’s Disease

T A B L E 114–7. Neurological Features of Whipple’s Disease

Cardiac Endocarditis Myocardial fibrosis Myocarditis Pericarditis

Cognitive impairment Psychiatric dysfunction Hypothalamic manifestations Insomnia Hypersomnia Hyperphagia Polydipsia and polyuria Oculomasticatory myorhythmia Oculo-facial-skeletal myorhythmia Seizures Ataxia

Dermatologic Skin hyperpigmentation Gastrointestinal Abdominal pain Diarrhea Weight loss Hematologic Anemia Musculoskeletal Arthralgias Arthritis Sacroiliitis Spondylitis Ocular Papilledema Retinitis Retrobulbar neuritis Uveitis Vitritis Pulmonary Chronic, nonproductive cough Dyspnea Pleural effusion Pleuritic chest pain Pulmonary infiltrates

developing Whipple’s disease.96 Although the presence of rod-shaped organisms was already described by Whipple in his 1907 report, it was only as recently as 2001 that the organism responsible for Whipple’s disease, Tropheryma whippelii, was identified and characterized as a member of the actinomycete family.95 The natural habitat of the organism and the route of infection remain obscure, although it has been suggested that T. whippelii may be a soil-dwelling organism, which might explain the increased incidence of infection in farmers. Because Whipple’s disease is so rare, no extensive literature covering the CNS manifestations of the condition exists. In fact, in a review of 12 patients from their own clinical practice, Gerard and associates were able to gather information from the literature on only an additional 122 individuals with CNS manifestations of Whipple’s disease.97 Clinical CNS involvement develops in 10% to 43% of patients with Whipple’s disease, but postmortem examinations demonstrate CNS lesions in over 90% of both symptomatic and asymptomatic individuals.95,98 Neurological dysfunction may be the presenting feature in approximately 5% of persons with Whipple’s disease (Table 114–7).98 Cognitive changes are the most frequently observed neurological manifestation of Whipple’s disease, appearing in 71% of individuals; psychiatric symptoms such as depression and personality or behavioral changes often accompany the cognitive dysfunction.99,100 Symptoms indicative of hypothalamic involvement, such as insomnia, hypersomnia, hyperphagia, polyuria, and polydipsia are less common.95,99,101 Cerebellar dysfunction with gait and balance impairment is said to develop in approximately 20% of persons with Whipple’s disease; pyrami-

dal tract abnormalities may occur.99,100 Peripheral neuropathy, ostensibly caused by malabsorption with consequent nutritional deficiency, has also been reported.100,102 Vertical gaze impairment develops in approximately 50% of patients and may lead to diagnostic confusion with progressive supranuclear palsy.100 Abnormalities of cranial nerves III, IV, and VI; internuclear ophthalmoplegia; ptosis; and pupillary abnormalities do occur but are unusual in Whipple’s disease.100,103 Approximately 20% of individuals with CNS manifestations of Whipple’s disease develop a unique type of involuntary movement, oculomasticatory myorhythmia.99,104 These movements consist of the combination of pendular convergence nystagmus and concurrent slow, rhythmic synchronous contractions of the masticatory muscles, and they are invariably accompanied by a supranuclear vertical gaze paresis. Sometimes the muscle contractions also involve the extremities, hence the term oculo-facial-skeletal myorhythmia. These movements (oculomasticatory myorhythmia and oculo-facial-skeletal myorhythmia) have been held to be pathognomonic for Whipple’s disease. Confirmation of the diagnosis of Whipple’s disease has typically depended on identification of periodic acid–Schiff stain–positive inclusions in macrophages present in duodenal biopsy specimens. However, both false-negative and false-positive errors may occur. Polymerase chain reaction analysis appears to be a more sensitive method of diagnosis, but there is some evidence that T. whippelii DNA may be present in healthy individuals without Whipple’s disease.95,98 In individuals with CNS symptoms, brain biopsy, when performed, yields positive results in more than 80%.99 Cerebrospinal fluid analysis may also be useful, often demonstrating an inflammatory cell response that sometimes contains periodic acid–Schiff stain–positive macrophages.101 Polymerase chain reaction analysis of the cerebrospinal fluid may also be positive in 80% of patients with Whipple’s disease and neurological symptoms.105 Prompt diagnosis of Whipple’s disease is important because effective treatment is available. The rarity of Whipple’s disease has precluded formal clinical trials, but empirical evidence suggests that an initial 2-week course of parenteral therapy with either a combination of penicillin G and streptomycin or with a third-generation cephalosporin (e.g., ceftriaxone), followed by a 1-year course of oral trimethoprim-sulfamethoxazole, is an effective treatment approach.95 The prolonged course of trimethoprim-sulfamethoxazole, which crosses the blood-brain barrier, is intended to treat potential or identified CNS involvement. This is especially important because CNS relapses carry a poor prognosis and a high mortality rate.

chapter 114 neurology of gastroenterology and hepatology HEPATIC DISEASE When hepatic disease, regardless of its cause, progresses to a point that the liver becomes incapable of effectively eliminating toxic substances, whether endogenously generated or exogenously derived, neurological dysfunction can ensue as the toxins breech the blood-brain barrier and invade the CNS. Hepatic failure most often evolves slowly, over a period of many months. However, fulminant hepatic failure (FHF) may erupt over a period of days to weeks. The neurological picture that develops in the former is vastly different than that in FHF. The mechanism of CNS injury is also different.

Minimal Hepatic Encephalopathy A change in nomenclature has evolved for the stage of hepatic encephalopathy in which routine clinical neurological and mental status examination findings are normal but subtle deficits can be documented on detailed neuropsychological testing. Earlier terms, such as subclinical hepatic encephalopathy or latent hepatic encephalopathy, have now yielded to the label minimal hepatic encephalopathy (MHE). Despite superficially normal neurological and neuropsychological functioning, individuals with MHE have identifiable deficits in occupational and psychosocial functioning, activities of daily living, and overall quality of life.106 Complex activities, such as planning a trip or handling family finances, may be affected.107 One study has also confirmed that individuals with MHE have impaired ability to drive an automobile.108 Estimates of the prevalence of MHE in individuals with cirrhosis range from 30% to 84%.109 In addition to the severity of hepatic functional impairment, other risk factors for the development of MHE include age, alcohol as the etiology of the liver failure, prior episodes of overt hepatic encephalopathy, presence of esophageal varices, and transjugular intrahepatic or surgical portosystemic shunts.107 MHE may also develop in individuals with congenital portosystemic shunts or shunts that develop as a result of portal thrombosis.110 A diagnosis of MHE has traditionally been based on formal neuropsychological testing, but a multimodal approach employing spectral electroencephalography and determination of partial pressure of ammonia has also been advocated.111 Although the functional deficits present in MHE often improve with treatment of the underlying hepatic disease, the long-term treatment benefits are uncertain. There is some evidence that, even after liver transplantation, some subtle impairment may persist.112

Chronic Hepatic Encephalopathy In individuals with chronic liver disease and cirrhosis, portal hypertension results in shunting of blood flow around the diseased liver and consequent delivery to the general circulation— and thus to the CNS—of blood that has not passed through the liver for detoxification. This toxin-laden blood is then capable of producing neurological dysfunction that initially is intermittent but occurs with increasing frequency, severity, and persistence as hepatic dysfunction progresses. Subtle changes in attention span, memory, personality, concentration, and reaction time typically constitute the earliest indications of insidiously emerging encephalopathy. With time and disease progression, these subtle features may evolve into

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T A B L E 114–8. Hepatic Encephalopathy: Clinical Stages, West Haven Criteria Stage 0 No detectable changes in personality or behavior Asterixis absent Stage 1 Trivial lack of awareness Shortened attention span Impaired addition or subtraction Hypersomnia, insomnia, or inversion of sleep pattern Euphoria or depression Asterixis can be detected Stage 2 Lethargy or apathy Disorientation Inappropriate behavior Slurred speech Obvious asterixis Stage 3 Gross disorientation Bizarre behavior Semistupor to stupor Asterixis generally absent Stage 4 Coma

stages of more overt cognitive impairment, characterized by increasing degrees of drowsiness, confusion, and disorientation, with the eventual evolution of stupor and coma. These levels of increasing neurological and cognitive dysfunction are traditionally divided into four stages and are known as the West Haven Criteria (Table 114–8).113 Signs of focal neurological impairment (such as cranial neuropathies, hemiparesis, and hemisensory deficit) are not usually present in chronic hepatic encephalopathy (CHE), although evidence of corticospinal tract dysfunction in the form of hyperreflexia or a Babinski response may emerge. Asterixis, a form of negative myoclonus characterized by sudden lapse of motor tone, is frequently present in individuals with CHE. However, asterixis is not pathognomonic for CHE and can be present in other toxic/metabolic encephalopathies. Although the diagnosis of CHE is ultimately based on clinical examination findings, both neurophysiological and neuroimaging procedures can provide useful information. Although neither specific for nor universally present in CHE, the classic electroencephalographic finding in CHE is the presence of triphasic waves. MRI may also demonstrate distinctive changes in individuals with hepatic failure. Hyperintensity within the globus pallidus on T1-weighted images can be prominent, but these changes are not limited to patients with overt CHE and are present in more than 75%,114 and perhaps up to 95%,115 of persons with cirrhosis, regardless of whether neurological symptoms are present. These pallidal abnormalities on MRI have been attributed to manganese deposition.114,116 Abnormalities on diffusion-weighted MRI, magnetic resonance spectroscopy, and on fluorine 18–fluorodeoxyglucose positron emission tomography have also been reported in CHE115,117 but are not employed in the diagnosis of CHE in routine clinical practice. The etiology of CHE has been the subject of long-running controversy. In particular, the role of ammonia in the

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generation of the CNS dysfunction has been the subject of much discussion and dispute.118 Oral protein loading and gastrointestinal bleeding are well-recognized precipitants of CHE that produce elevations of blood ammonia levels. Electrolyte imbalance, infection, and deteriorating liver function may also precipitate CHE. Although elevated blood ammonia levels are not universal, they are present in most individuals with CHE. Moreover, considerable overlap has been documented in ammonia levels between different grades of CHE severity, and this overlap has diluted and rendered controversial any correlation between the two.118 Thus, the usefulness of single blood ammonia determinations is severely limited in diagnosing CHE.119,120 Kundra and colleagues reported that plasma ammonia elevations mirrored the severity of encephalopathy in individuals with acute liver failure but not in persons with CHE.118 It has been suggested that venous ammonia levels, in particular, are unreliable and that arterial sampling is necessary for accurate assessment, but this was not borne out in one study.119 Proper handling of the blood specimen, however, is important, because failure to keep the sample on ice, delay in getting the sample to the laboratory, and use of tourniquets before blood sampling can all produce false elevations of ammonia level.120 Current evidence suggests that elevated blood ammonia level alone is not the sole determinant of CHE; rather, a multifactorial pathogenesis is more likely.121,122 It has been suggested that hyperammonemia leads to increased production of glutamine within astrocytes and that this, in turn, produces osmotic stress and astrocytic edema that culminates in altered neuropsychological function.123,124 “Untimely” activation of N-methyl-D-aspartate receptors within the CNS may also be involved in the evolution of CHE,125 as may increased oxidative/nitrosative stress.122 In a cell culture experiment, the combination of ammonia and manganese was lethal to a high percentage of cultured astrocytes, although neither substance alone was toxic; moreover, both the antioxidant superoxide dismutase and a nitric oxide inhibitor blocked the cell death.126 The genesis of CHE may also involve alterations in various neurotransmitter systems within the brain. Involvement of the γ-amino butyric acid receptor complex in CHE, particularly the benzodiazepine receptor site, has been the object of particular scrutiny. In an animal model of hepatic encephalopathy, increased messenger RNA expression levels of γ-amino butyric acid–A receptor subunits in the basal ganglia and hippocampus were described.127 Evidence for the presence of endogenous benzodiazepine receptor ligands, perhaps produced by gut bacteria, has been documented in CHE, and the plasma concentration of these ligands is correlated approximately with the degree of CHE.128 Ahboucha and associates documented increases up to 13fold in concentrations of the inhibitory neurosteroid allopregnanolone in the brains of 11 patients who died in hepatic coma, in comparison with 11 controls without hepatic, renal, or neurological diseases.129 Many neurosteroids possess potent sedative-hypnotic properties, and the authors suggested that the elevations present may be of pathophysiological significance.129 Activation of the serotonergic system and increased serotonin turnover has also been suggested to play a role in the pathogenesis of CHE, particularly its later stages.130,131 Standard treatment of CHE has traditionally consisted of measures to reduce ammonia levels. Identification and appro-

priate treatment of precipitating causes, restriction of dietary protein, and removal of sources of ammonia production within the gastrointestinal tract have been the bastions of treatment for CHE.128 Protein restriction is employed to reduce protein intake, and nonabsorbable disaccharides, such as lactulose and lactilol, are administered to acidify colonic contents and thus diminish absorption of both ammonia and endogenous benzodiazepine receptor ligands. Antibiotics, such as neomycin, ampicillin, and rifaximin, may also be employed to eliminate ammonia-producing bacteria from the gut, although they are not considered to be first-line treatment approaches, at least partly because of tolerability issues.132 Furthermore, the importance of colonic bacteria in the production of ammonia in the setting of CHE has been questioned, and the role of the small intestine as a generator of ammonia via glutamine uptake has been emphasized instead by some investigators.133 Controversy regarding the use of nonabsorbable disaccharides in CHE has surfaced in a Cochrane database review that questioned their beneficial effects in CHE and concluded that there currently is insufficient evidence to support their use.134,135 Some investigators have concurred with this assessment133,136; others have cautioned that the deficiencies in prior clinical trials of these substances should not be equated with dismissal of their use in clinical practice.137,138 The benzodiazepine receptor antagonist flumazenil produces short-term improvement in CHE but has not yet been shown to improve recovery or survival.139,140 The use of flumazenil in the treatment of CHE remains quite limited, primarily to situations of suspected pharmacological intoxication.141 Other modalities that have been proposed for the treatment of CHE include L-carnitine,142 branched-chain amino acids,143 and L-ornithine–L-aspartate.133 Artificial support systems are being investigated in CHE but have been targeted primarily toward individuals with more acute hepatic decompensation.

Fulminant Hepatic Failure Rapidly progressive fulminant hepatic failure (FHF), evolving over a period of days to weeks in individuals without any history of liver dysfunction, is a dreaded and often dramatic manifestation of liver disease. A variety of processes can trigger FHF, but drug reactions and viral hepatitis appear to be the most frequent culprits. In one report, acetaminophen overdose was the cause of FHF in 39% of 308 patients, idiosyncratic drug reactions were responsible in 13%, and viral hepatitis (hepatitis A and B combined) in 12%.144 More rare reported causes of FHF include senna laxative toxicity,145 carbamazepine toxicity,146 parvovirus infection,147 and dengue hemorrhagic fever.148 In many cases, however, the cause of the FHF remains unknown. The clinical course of FHF is characterized not only by rapid deterioration of liver function with development of jaundice but also by the development of coagulopathy, metabolic acidosis, and even hypoglycemia. In tandem with these systemic changes, encephalopathy emerges, with drowsiness often progressing to confusion and eventually coma. The hallmark and defining characteristic of the encephalopathy that develops in FHF is cerebral edema. The cerebral edema, with consequent increased intracranial pressure, can develop so rapidly in FHF that papilledema may not have time to even develop, and the increased intracranial pressure eventually may reach levels that compromise cerebral per-

chapter 114 neurology of gastroenterology and hepatology fusion. The pathogenesis of the cerebral edema is not entirely understood. Suspicion has focused primarily on increased astrocytic glutamine concentrations, with consequent cytotoxic edema, as the primary driver of cerebral edema in FHF, but some investigators propose that reductions in other brain osmolytes, specifically myoinositol and taurine, and increased lactate production may also be important.149 Alterations in cerebral blood flow with cerebral hyperemia may also be a contributing factor to the malignant cerebral edema that characterizes FHF.149,150 Reported mortality rates of FHF demonstrate considerable variability. Before the emergence of liver transplantation as a treatment option, mortality rates ranged from 80% to 85%. In a more recent large study of 295 patients with FHF, however, the rate of overall mortality at 1 year was 43%.151 Of the 295 patients, 25% survived with medical management, 41% underwent liver transplantation, and 34% died without transplantation. The rate of 1-year survival among the patients who received transplants was 76%. Numerous difficult issues complicate the management of FHF. Coagulopathy, hypoglycemia, and multiple organ failure present dauntingly difficult and complex treatment challenges for the hepatologist. For the neurologist, the management of cerebral edema and the recognition and treatment of seizures are equally difficult problems. Electroencephalographic monitoring, if available, provides invaluable assistance in the early recognition of subclinical seizure activity, especially in comatose or sedated patients. Intracranial pressure monitoring provides the most accurate assessment of cerebral edema but may also precipitate significant complications, such as intracranial hemorrhage, in 4% to 22% of patients.152 Mannitol or hypertonic saline administration may provide short-term reduction in intracranial pressure.153 The use of mild to moderate hypothermia is also undergoing evaluation as a means of treatment for cerebral edema in FHF.150,154 However, survival for most patients with FHF is ultimately dependent on liver transplantation. Artificial and bioartificial extracorporeal liver support devices are currently undergoing evaluation as bridging measures to sustain patients awaiting liver transplantation.155 One of these devices, the Molecular Adsorbent Recirculating System, has been used clinically since 1993 in more than 4000 patients.156 However, these systems are still considered experimental, and their efficacy in FHF has not yet been generally accepted.

Chronic Acquired Hepatocerebral Degeneration Although van Woerkom, in 1914, was probably the first to describe what is now recognized as chronic acquired (nonwilsonian) hepatocerebral degeneration (CAHD),157-160 it was the report in 1965 by Victor and colleagues, in which they described 27 patients with the disorder, that clearly established CAHD as a distinct clinical entity.158 CAHD is generally considered rare, although Victor and colleagues maintained that it is “much more frequent” than Wilson’s disease.158 Nevertheless, Chen and associates, in a case report and review of the literature that covered the years 1981 to 2003, were able to identify only 36 additional cases.161 It is possible that many cases of CAHD go unrecognized in individuals with chronic liver disease, in whom neurological features, especially if mild, might simply be overlooked or attributed to hepatic encephalopathy. The obser-

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T A B L E 114–9. Neurological Features of Chronic Acquired Hepatocerebral Degeneration Cognitive Impairment Executive dysfunction Apathy Slowness in responding Reduced attention and concentration Abnormalities of Movement Basal ganglia dysfunction Parkinsonism Tremor Chorea Myoclonus Asterixis Dystonia Cerebellar dysfunction Dysarthria Ataxia

vations of parkinsonism in 11 (21.6%) of 52 study subjects with cirrhosis by one group of investigators114 and of extrapyramidal features in over 50% of individuals with MHE by another group106 could conceivably reflect this lack of recognition. The clinical picture of CAHD typically emerges in individuals with advanced liver disease who have experienced repeated episodes of hepatic encephalopathy. However, this is not invariably the case, and CAHD has been documented in individuals who have never displayed any evidence of hepatic encephalopathy.159 It can also develop in persons who have not actual liver disease but rather other processes, such as portal vein thrombosis, that result in shunting of blood around the liver.158,162 In the series of Victor and colleagues, hepatic disease preceded the appearance of neurological disease in 81% of patients,158 but the severity and frequency of episodes of hepatic encephalopathy are not necessarily predictive of the ultimate neurological deficit.159 In general, CAHD is characterized by the combination of cognitive impairment and abnormalities of movement, but the clinical presentation can encompass considerable variability (Table 114–9). The cognitive features typically consist of executive dysfunction, apathy, slowness in responding, and reduced attention and concentration. Cortical findings, such as aphasia or apraxia, are generally not part of the clinical picture.158,159,163 Victor and colleagues reported cognitive impairment to be present in 80% of the patients they studied.158 Abnormalities of movement in CAHD reflect a combination of basal ganglia and cerebellar dysfunction. Dysarthria, ataxia, tremor, parkinsonism, chorea, myoclonus, asterixis, and dystonia all may appear, although dystonia is uncommon.158,159 Action, typically postural, tremor is the most frequently observed type of tremor, whereas rest tremor is distinctly less common.158,159 Mild pyramidal tract findings may be evident in a minority of individuals, but frank myelopathy is rare.158,159 Although the clinical setting and neurological features of CAHD are very similar to those of Wilson’s disease, the two can be distinguished by the absence of family history, the absence of Kayser-Fleischer rings, and the absence of abnormalities of copper metabolism in CAHD.158,159 The hallmark MRI feature of CAHD consists of bilaterally symmetrical hyperintense signal changes on T1-weighted images, most prominently in the globus pallidus, although involvement of the putamen, mesencephalon, and even cerebellum has been reported.159,160,164,165

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Manganese deposition is believed to be responsible for these changes.164 Victor and colleagues believed that the course and clinical features of CAHD were progressive and largely irreversible.158 However, both responsiveness to levodopa and resolution of dysfunction after liver transplantation have been reported.114,163

2.

3.

CONCLUSION The disease processes covered in this chapter are only a sampling of the extensive and intricate interface between the gastrointestinal and neurological systems. Nevertheless, it is hoped that increased awareness of this interface will lead to both more prompt recognition and more effective treatment of the neurological complications of gastrointestinal disease.

4. 5. 6. 7.

K E Y ●

●

●

P O I N T S

Celiac disease is a multisystem disorder that may include neurological dysfunction in the form of ataxia, seizures, migraine, learning disabilities, peripheral neuropathy, and myopathy. Neurological dysfunction in IBD may include peripheral neuropathy, myopathy, myelopathy, cerebrovascular events, and seizures. Cognitive impairment and behavioral changes are the most frequent nervous system manifestations of Whipple’s disease, but hypothalamic and cerebellar dysfunction, a variety of eye movement abnormalities, and peripheral neuropathy may also develop, and oculomasticatory myorhythmia, although present in only approximately 20% of individuals, may be pathognomonic for the condition.

●

The most frequent precipitating factors for FHF are acetaminophen overdose, idiosyncratic drug reactions, and viral hepatitis.

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Chronic acquired hepatocerebral degeneration is characterized by cognitive impairment and abnormalities of movement that may include both basal ganglia and cerebellar features.

8.

9.

10. 11.

12.

13. 14.

15.

Suggested Reading Dutly F, Altwegg M: Whipple’s disease and “Tropheryma whippelii.” Clin Microbiol Rev 2001; 14:561-583. Hadjivassiliou M, Grünewald R, Sharrack B, et al: Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain 2003; 126:685-691. Lewis M, Howdle PD: The neurology of liver failure. Q J Med 2003; 96:623-633. Lossos A, River Y, Eliakim A, et al: Neurologic aspects of inflammatory bowel disease. Neurology 1995; 45:416-421. Quigley EMM, Pfeiffer RF, eds: Neurogastroenterology. Philadelphia: Butterworth Heinemann, 2004.

16. 17. 18. 19. 20.

References 1. Camilleri M, Bharucha AE: An overview of gastrointestinal dysfunction in diseases of central and peripheral nervous

21.

systems. In Quigley EMM, Pfeiffer RF, eds: Neurogastroenterology. Philadelphia: Butterworth-Heinemann, 2004, pp 3557. Quigley EMM, Conklin JL: The “big” brain and the “little” brain: interactions between the enteric and central nervous systems in the regulation of gut function. In Quigley EMM, Pfeiffer RF, eds: Neurogastroenterology. Philadelphia: Butterworth-Heinemann, 2004, pp 3-14. Quigley EMM, Pfeiffer RF, eds: Neurogastroenterology. Philadelphia: Butterworth-Heinemann, 2004. Pfeiffer RF: Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2003; 2:107-116. Wills AJ, Unsworth DJ: The neurology of gluten sensitivity: separating the wheat from the chaff. Curr Opin Neurol 2002; 15:519-523. Farrel RJ, Kelly CP: Celiac sprue. N Engl J Med 2002; 346:180188. Hadjivassiliou M, Boscolo S, Davies-Jones GAB, et al: The humoral response in the pathogenesis of gluten ataxia. Neurology 2002; 58:1221-1226. Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, et al: Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998; 352:1582-1585. Ryan AW, Thornton JM, Brophy K, et al: Chromosome 5q candidate genes in coeliac disease: genetic variation at IL4, IL5, IL9, IL13, IL17 and NR3C1. Tissue Antigens 2005; 65:150-155. Wills AJ, Turner B, Lock RJ, et al: Dermatitis herpetiformis and neurological dysfunction. J Neurol Neurosurg Psychiatry 2002; 72:259-261. De Santis A, Addolorato G, Romito A, et al: Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med 1997; 242:421-423. Tutt ANJ, Brada M, Sampson SA: Enteropathy associated T cell lymphoma presenting as an isolated CNS lymphoma three years after diagnosis of coeliac disease: T cell receptor polymerase chain reaction studies failed to show the original enteropathy to be a clonal disorder. Gut 1997; 40:801-803. Pengiran Tengah DSNA, Wills AJ, Holmes GKT: Neurological complications of coeliac disease. Postgrad Med J 2002; 78:393-398. Pellecchia MT, Scala R, Filla A, et al: Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 1999; 66:32-35. Lagerqvist C, Ivarsson A, Juto P, et al: Screening for adult coeliac disease—which serological markers to use? J Intern Med 2001; 250:241-248. Vaknin A, Eliakim R, Ackerman Z, et al: Neurological abnormalities associated with celiac disease. J Neurol 2004; 251:1393-1397. Cooke WT, Smith WT: Neurological disorders associated with adult coeliac disease. Brain 1966; 89:683-722. Hadjivassiliou M, Gibson A, Davies-Jones GA, et al: Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347:369-371. Hadjivassiliou M, Grünewald R, Sharrack B, et al: Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain 2003; 126:685-691. Bürk K, Bösch S, Müller CA, et al: Sporadic cerebellar ataxia associated with gluten sensitivity. Brain 2001; 124:10131019. Bushara KO, Goebel SU, Shill H, et al: Gluten sensitivity in sporadic and hereditary cerebellar ataxia. Ann Neurol 2001; 49:540-543.

chapter 114 neurology of gastroenterology and hepatology 22. Luostarinen LK, Collin PO, Peraaho MJ, et al: Coeliac disease in patients with cerebellar ataxia of unknown origin. Ann Med 2001; 33:445-449. 23. Abele M, Schöls L, Schwartz S, et al: Prevalence of antigliadin antibodies in ataxia patients. Neurology 2003; 60:16741675. 24. Combarros O, Infante J, Lopez-Hoyos M, et al: Celiac disease and idiopathic cerebellar ataxia. Neurology 2000; 54: 2346. 25. Hadjivassiliou M, Davies-Jones GA, Sanders DS, et al: Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry 2003; 74:1221-1224. 26. Bushara KO, Nance M, Gomez CM: Antigliadin antibodies in Huntington’s disease. Neurology 2004; 62:132-133. 27. Zelnick N, Pacht A, Obeid R, et al: Range of neurologic disorders in patients with celiac disease. Pediatrics 2004; 113:1672-1676. 28. Chapman RWG, Laidlow JM, Colin-Jones D, et al: Increased prevalence of epilepsy in coeliac disease. BMJ 1978; 2:250251. 29. Holmes GK: Non-malignant complications of coeliac disease. Act Paediatr Suppl 1996; 412:68-75. 30. Cronin CC, Jackson LM, Feighery C, et al: Coeliac disease and epilepsy. Q J Med 1998; 91:303-308. 31. Magaudda A, Dalla Bernardina B, De Marco P, et al: Bilateral occipital calcification, epilepsy and coeliac disease: clinical and neuroimaging features of a new syndrome. J Neurol Neurosurg Psychiatry 1993; 56:885-889. 32. Pfaender M, D’Souza WJ, Trost N, et al: Visual disturbances representing occipital lobe epilepsy in patients with cerebral calcifications and coeliac disease: a case series. J Neurol Neurosurg Psychiatry 2004; 75:1623-1625. 33. Hanly JG, Stassen W, Whelton M, et al: Epilepsy and coeliac disease. J Neurol Neurosurg Psychiatry 1982; 45:729-730. 34. Pengiran Tengah DS, Holmes GK, Wills AJ. The prevalence of epilepsy in patients with celiac disease. Epilepsia 2004; 45:1291-1293. 35. Ranua J, Luoma K, Auvinen A, et al: Celiac disease-related antibodies in an epilepsy cohort and matched reference population. Epilepsy Behav 2005; 6:388-392. 36. Gabrielli M, Cremonini F, Fiore G, et al: Association between migraine and celiac disease: results from a preliminary casecontrol and therapeutic study. Am J Gastroenterol 2003; 98:625-629. 37. Serratrice J, Disdier P, de Roux C, et al: Migraine and coeliac disease. Headache 1998; 38:627-628. 38. Roche Herrero MC, Arcas Martinez J, Martinez-Bermejo A, et al: [The prevalence of headache in a population of patients with coeliac disease]. Rev Neurol 2001; 32:301-309. 39. Knivsberg AM: Urine patterns, peptide levels and IgA/IgG antibodies to food proteins in children with dyslexia. Pediatr Rehabil 1997; 1:25-33. 40. Luostarinen L, Himanen S-L, Luostarinen M, et al: Neuromuscular and sensory disturbances in patients with well treated celiac disease. J Neurol Neurosurg Psychiatry 2003; 74:490-494. 41. Chin RL, Sander HW, Brannagan TH, et al: Celiac neuropathy. Neurology 2003; 60:1581-1585. 42. Kleopa KA, Kyriacou K, Zamba-Papanicolaou E, et al: Reversible inflammatory and vacuolar myopathy with vitamin E deficiency in celiac disease. Muscle Nerve 2005; 31:260-265. 43. Bhatia KP, Brown P, Gregory R, et al: Progressive myoclonic ataxia associated with celiac disease. The myoclonus is of cortical origin but the pathology is in the cerebellum. Brain 1995; 118:1087-1093. 44. Kepes JJ, Chou SM, Price LW. Progressive multifocal leukoencephalopathy with 10-year survival in a patient with nontropical sprue. Neurology 1975; 25:1006-1012.

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45. Pereira AC, Edwards MJ, Buttery PC, et al: Choreic syndrome and coeliac disease: a hitherto unrecognised association. Mov Disord 2004; 19:478-482. 46. Gibbons CH, Freeman R: Autonomic neuropathy and coeliac disease. J Neurol Neurosurg Psychiatry 2005; 76:579-581. 47. Jacob S, Zarei M, Kenton A, et al: Gluten sensitivity and neuromyelitis optica: two case reports. J Neurol Neurosurg Psychiatry 2005; 76:1028-1030. 48. Lim WC, Hanauer SB: Emerging biologic therapies in inflammatory bowel disease. Rev Gastroenterol Disord 2004; 4:6685. 49. Ahmad T, Tamboli CP, Jewell D, et al: Clinical relevance of advances in genetics and pharmacogenetics of IBD. Gastroenterology 2004; 126:1533-1549. 50. Loftus EV Jr: Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004; 126:1504-1517. 51. Philpott DJ, Viala J: Towards an understanding of the role of NOD2/CARD15 in the pathogenesis of Crohn’s disease. Best Pract Res Clin Gastroenterol 2004; 18:555-568. 52. Mathew CG, Lewis CM: Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet 2004; 13:161-168. 53. Podolsky DK: Inflammatory bowel disease (1). N Engl J Med 1991; 325:928-937. 54. Veloso FT, Carvalho J, Magro F: Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol 1996; 23:29-34. 55. Christodoulou DK, Katsanos KH, Kitsanou M, et al: Frequency of extraintestinal manifestations in patients with inflammatory bowel disease in northwest Greece and review of the literature. Dig Liver Dis 2002; 34:781-786. 56. Novotny DA, Rubin RJ, Slezak FA, et al: Arterial thromboembolic complications of inflammatory bowel disease. Report of three cases. Dis Colon Rectum 1992; 35:193-196. 57. Rogler G, Scholmerich J: [Extraintestinal manifestations of inflammatory bowel disease]. Med Klin (Munich) 2004; 99:123-130. 58. Greenstein AJ, Janowitz HD, Sachar DB: The extra-intestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients. Medicine 1976; 55:401-412. 59. Lossos A, River Y, Eliakim A, et al: Neurologic aspects of inflammatory bowel disease. Neurology 1995; 45:416-421. 60. Coert JH, Dellon AL: Neuropathy related to Crohn’s disease treated by peripheral nerve decompression. Scand J Plast Reconstr Surg Hand Surg 2003; 37:243-244. 61. Demarquay JF, Caroli-Bose FX, Buckley M, et al: Right-sided sciatalgia complicating Crohn’s disease. Am J Gastroenterol 1998; 93:2296-2298. 62. Greco F, Pavone P, Falsaperla R, et al: Peripheral neuropathy as first sign of ulcerative colitis in a child. J Clin Gastroenterol 2004; 38:115-117. 63. Gondim FA, Brannagan TH 3rd, Sander HW, et al: Peripheral neuropathy in patients with inflammatory bowel disease. Brain 2005; 128:867-879. 64. Lloyd DA, Payton KB, Guenther L, et al: MelkerssonRosenthal syndrome and Crohn’s disease: one disease or two? Report of a case and discussion of the literature. J Clin Gastroenterol 1994; 18:213-217. 65. Summers RW, Harker L: Ulcerative colitis and sensorineural hearing loss: is there a relationship? J Clin Gastroenterol 1982; 4:251-252. 66. Kumar BN, Walsh RM, Wilson PS, et al: Sensorineural hearing loss and ulcerative colitis. J Laryngol Otol 1997; 111:277-278. 67. Weber RS, Jenkins HA, Coker NJ: Sensorineural hearing loss associated with ulcerative colitis. A case report. Arch Otolaryngol 1984; 110:810-812.

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Section

XX

Neurology in General Medicine

68. Hollanders D: Sensorineural deafness—a new complication of ulcerative colitis? Postgrad Med J 1986; 62:753-755. 69. Kumar BN, Smith MS, Walsh RM, et al: Sensorineural hearing loss in ulcerative colitis. Clin Otolaryngol 2000; 25:143-145. 70. Christopoulos C, Savva S, Pylarinou S, et al: Localised gastrocnemius myositis in Crohn’s disease. Clin Rheumatol 2003; 22:143-145. 71. Rang EH, Brooke BN, Hermon-Taylor J: Association of ulcerative colitis with multiple sclerosis. Lancet 1982; 2: 555. 72. Pandian JD, Pawar G, Singh GS, et al: Multiple sclerosis in a patient with chronic ulcerative colitis. Neurol India 2004; 52:282-283. 73. Ray DW, Bridger J, Hawnaur J, et al: Transverse myelitis as the presentation of Jo-1 antibody syndrome (myositis and fibrosing alveolitis) in long-standing ulcerative colitis. Br J Rheumatol 1993; 32:1105-1108. 74. Hershkowitz S, Link R, Ravden M, et al: Spinal empyema in Crohn’s disease. J Clin Gastroenterol 1990; 12:67-69. 75. Rajendra S, Kadir ZA, Karim N, et al: Ulcerative colitis and motor neurone disease: causal or coincidental? Singapore Med J 2003; 44:423-425. 76. Talbot RW, Heppell J, Dozois RR, et al: Vascular complications of inflammatory bowel disease. Mayo Clin Proc 1986; 61:140145. 77. Derdeyn CP, Powers WJ: Isolated cortical venous thrombosis and ulcerative colitis. AJNR Am J Neuroradiol 1998; 19:488490. 78. Musio F, Older SA, Jenkins T, et al: Case report: cerebral venous thrombosis as a manifestation of acute ulcerative colitis. Am J Med Sci 1993; 305:28-35. 79. Aichbichler BW, Petritsch W, Reicht GA, et al: Anti-cardiolipin antibodies in patients with inflammatory bowel disease. Dig Dis Sci 1999; 44:852-856. 80. Papa A, Danese S, Piccirillo N, et al: Thrombopoietin serum levels in patients with inflammatory bowel disease with and without previous thromboembolic events. Hepatogastroenterology 2003; 50:132-135. 81. Oldenburg B, Fijnheer R, van der Griend R, et al: Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications? Am J Gastroenterol 2000; 95:2825-2830. 82. Jackson LM, O’Gorman PJ, O’Connell J, et al: Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden. Q J Med 1997; 90:183-188. 83. Younes-Mhenni S, Derex L, Berruyer M, et al: Large-artery stroke in a young patient with Crohn’s disease. Role of vitamin B6 deficiency–induced hyperhomocysteinemia. J Neurol Sci 2004; 221:113-115. 84. Fukuhara T, Tsuchida S, Kinugasa K, et al: A case of pontine lacunar infarction ulcerative colitis. Clin Neurol Neurosurg 1993; 95:159-162. 85. Druschky A, Heckmann JG, Druschky K, et al: Severe neurological complications of ulcerative colitis. J Clin Neurosci 2002; 9:84-86. 86. Gobbele R, Reith W, Block F: [Cerebral vasculitis as a concomitant neurological illness in Crohn’s disease]. Nervenarzt 2000; 71:299-304. 87. Schluter A, Krasnianski M, Krivokuca M, et al: Magnetic resonance angiography in a patient with Crohn’s disease associated cerebral vasculitis. Clin Neurol Neurosurg, 2004; 106:110-113. 88. Johns DR: Cerebrovascular complications of inflammatory bowel disease. Am J Gastroenterol 1991; 86:367-370. 89. Schulak JA, Moossa R, Block GE, et al: Convulsions complicating colectomy in inflammatory bowel disease. JAMA 1977; 237:1456-1458.

90. Rosencrantz R, Moon A, Raynes H, et al: Cyclosporineinduced neurotoxicity during treatment of Crohn’s disease: lack of correlation with previously reported risk factors. Am J Gastroenterol 2001; 96:2778-2782. 91. Akhan G, Andermann F, Gotman MJ: Ulcerative colitis, status epilepticus and intractable temporal seizures. Epileptic Disord 2002; 4:135-137. 92. Hahn JS, Berquist W, Alcorn DM, et al: Wernicke encephalopathy and beriberi during total parenteral nutrition attributable to multivitamin infusion shortage. Pediatrics 1998; 101:E10. 93. Kawakubo K, Iida M, Matsumoto T, et al: Progressive encephalopathy in a Crohn’s disease patient on long term total parenteral nutrition: possible relationship to selenium deficiency. Postgrad Med J 1994; 70:215-219. 94. Eggspuhler AW, Bauerfeind P, Dorn T, et al: Wernicke encephalopathy—a severe neurological complication in a clinically inactive Crohn’s disease. Eur Neurol 2003; 50:184185. 95. Dutly F, Altwegg M: Whipple’s disease and “Tropheryma whippelii.” Clin Microbiol Rev 2001; 14:561-583. 96. Weiner SR, Utsinger P: Whipple disease. Semin Arthritis Rheum 1986; 15:157-167. 97. Gerard A, Sarrot-Reynauld F, Liozon E, et al: Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine (Baltimore) 2002; 81:443-457. 98. Peters G, du Plessis DG, Humphrey PR: Cerebral Whipple’s disease with a stroke-like presentation and cerebrovascular pathology. J Neurol Neurosurg Psychiatry 2002; 73:336-339. 99. Louis ED, Lynch T, Kaufmann P, et al: Diagnostic guidelines in central nervous system Whipple’s disease. Ann Neurol 1996; 40:561-568. 100. Franca MC Jr, de Castro R, Balthazar ML, et al: Whipple’s disease with neurological manifestations. Arq Neuropsiquiatr 2004; 62:342-346. 101. Perkin GD, Murray-Lyon I: Neurology and the gastrointestinal system. J Neurol Neurosurg Psychiatry 1998; 65:291-300. 102. Topper R, Gartung C, Block F: [Neurologic complications in inflammatory bowel diseases]. Nervenarzt 2002; 73:489-499. 103. Chan RY, Yannuzzi LA, Foster CS: Ocular Whipple’s disease: earlier definitive diagnosis. Ophthalmology 2001; 108:22252231. 104. Schwartz MA, Selhorst JB, Ochs AL, et al: Oculomasticatory myorhythmia: a unique movement disorder occurring in Whipple’s disease. Ann Neurol 1986; 20:677-683. 105. von Herbay A, Ditton HJ, Schuhmacher F, et al: Whipple’s disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology 1997; 113:434-441. 106. Jover R, Compañy L, Gutiérrez A, et al: Minimal hepatic encephalopathy and extrapyramidal signs in patients with cirrhosis. Am J Gastroenterol 2003; 98:1599-1604. 107. Ortiz M, Jacas C, Córdoba J: Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 2005; 42(Suppl 1):S45-S53. 108. Wein C, Koch H, Popp B, et al: Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004; 39:739-745. 109. Quero JC, Schalm SW: Subclinical hepatic encephalopathy. Semin Liver Dis 1996; 16:321-328. 110. Ortiz M, Córdoba J, Alonso J, et al: Oral glutamine challenge and magnetic resonance spectroscopy in three patients with congenital portosystemic shunts. J Hepatol 2004; 40:552-557. 111. Senzolo M, Amodio P, D’Aloiso MC, et al: Neuropsychological and neurophysiological evaluation in cirrhotic patients with minimal hepatic encephalopathy undergoing liver transplantation. Transplant Proc 2005; 37:1104-1107. 112. Mechtcheriakov S, Graziadei IW, Mattedi M, et al: Incomplete improvement of visuo-motor deficits in patients with

chapter 114 neurology of gastroenterology and hepatology

113.

114.

115. 116. 117. 118.

119. 120. 121. 122. 123. 124.

125. 126. 127.

128.

129. 130.

131.

minimal hepatic encephalopathy after liver transplantation. Liver Transpl 2004; 10:77-83. Atterbury CE, Maddrey WC, Conn HO: Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double blind clinical trial. Am J Dig Dis 1978; 23:398-406. Burkhard PR, Delavelle J, Du Pasquier R, et al: Chronic parkinsonism associated with cirrhosis. A distinct subset of acquired hepatocerebral degeneration. Arch Neurol 2003; 60:521-528. Stewart CA, Reivich M, Lucey MR, et al: Neuroimaging in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005; 3:197-207. Hauser RA, Zesiewicz TA, Rosemurgy AS, et al: Manganese intoxication and chronic liver failure. Ann Neurol 1994; 36:871-875. Lodi R, Tonon C, Stracciari A, et al: Diffusion MRI shows increased water apparent diffusion coefficient in the brains of cirrhotics. Neurology 2004; 62:762-766. Kundra A, Jain A, Banga A, et al: Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension. Clin Biochem 2005; 38:696-699. Ong JP, Aggarwal A, Krieger D, et al: Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003; 114:188-193. Wang V, Saab S: Ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003; 114:237-238. Lewis M, Howdle PD: The neurology of liver failure. Q J Med 2003; 96:623-633. Haussinger D, Schliess F: Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy. Neurochem Int 2005; 47:64-70. Jalan R, Shawcross D, Davies N: The molecular pathogenesis of hepatic encephalopathy. Int J Biochem Cell Biol 2003; 35:1175-1181. Balata S, Olde Damink SWM, Ferguson K, et al: Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis. Hepatology 2003; 37:931-939. Izumi Y, Izumi M, Matsukawa M, et al: Ammonia-mediated LTP inhibition: effects of NMDA receptor antagonists and Lcarnitine. Neurobiol Dis 2005; 20:615-624. Jayakumar AR, Rama Rao KV, Kalaiselvi P, et al: Combined effects of ammonia and manganese on astrocytes in culture. Neurochem Res 2004; 29:2051-2056. Li XQ, Dong L, Liu ZH, et al: Expression of gamma-aminobutyric acid A receptor subunits α1, β1, γ2 mRNA in rats with hepatic encephalopathy. World J Gastroenterol 2005; 11:3319-3322. Fitz JG: Hepatic encephalopathy, hepatopulmonary syndromes, hepatorenal syndrome, coagulopathy, and endocrine complications of liver disease. In Feldman M, Friedman LS, Sleisenger MH, eds: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. Philadelphia: WB Saunders, 2002, pp 15431565. Ahboucha S, Layrargues GP, Mamer O, et al: Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol 2005; 58:169-170. Lozeva V, Montgomery JA, Tuomisto L, et al: Increased brain serotonin turnover correlates with the degree of shunting and hyperammonemia in rats following variable portal vein stenosis. J Hepatol 2004; 40:742-748. Yano M, Adachi N, Liu K, et al: Flumazenil-induced improvement of the central dopaminergic system in rats with acute hepatic failure. J Neurosurg Anesthesiol 2005; 17:6974.

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132. Maddrey WC: Role of antibiotics in the management of hepatic encephalopathy. Rev Gastroenterol Disord 2005; 5(Suppl 1):3-9. 133. Shawcross D, Jalan R: Dispelling myths in the treatment of hepatic encephalopathy. Lancet 2005; 365:431-433. 134. Als-Nielsen B, Gluud L, Gluud C: Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev 2004; (2):CD003044. 135. Als-Nielsen B, Gluud LL, Gluud C: Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004; 328:1046-1050. 136. Shawcross DL, Jalan R: Treatment of hepatic encephalopathy. It’s not lactulose. BMJ 2004; 329:112. 137. Blei AT: Treatment of hepatic encephalopathy. Lancet 2005; 365:1383-1384. 138. Morgan MY, Amodio P: Treatment for hepatic encephalopathy: tips from TIPS? Hepatol 2005; 42:626-628. 139. Dursun M, Caliskan M, Canoruc F, et al: The efficacy of flumazenil in subclinical to mild hepatic encephalopathic ambulatory patients. Swiss Med Wkly 2003; 133:118-123. 140. Als-Nielsen B, Gluud L, Gluud C: Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database Syst Rev 2004; (2):CD002798. 141. Córdoba J, Mínguez B, Vergara M: Treatment of hepatic encephalopathy. Lancet 2005; 365:1384-1385. 142. Malaguarnera M, Pistone G, Astuto M, et al: L-Carnitine in the treatment of mild or moderate hepatic encephalopathy. Dig Dis 2003; 21:271-275. 143. Mascarenhas R, Mobarhan S: New support for branched-chain amino acid supplementation in advanced hepatic failure. Nutr Rev 2004; 62:33-38. 144. Ostapowicz G, Fontana RJ, Schiodt FV, et al: Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947954. 145. Vanderperren B, Rizzo M, Angenot L, et al: Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides. Ann Pharmacother 2005; 39:13531357. 146. Syn WK, Naisbitt DJ, Holt AP, et al: Carbamazepine-induced acute liver failure as a part of the DRESS syndrome. Int J Clin Pract 2005; 59:988-991. 147. Dutta U, Mittal S, Ratho RK, et al: Acute liver failure and severe hemophagocytosis secondary to parvovirus B19 infection. Indian J Gastroenterol 2005; 24:118-119. 148. Subramanian V, Shenoy S, Joseph AJ: Dengue hemorrhagic fever and fulminant hepatic failure. Dig Dis Sci 2005; 50:1146-1147. 149. Zwingmann C, Chatauret N, Rose C, et al: Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia. Brain Res 2004; 999:113-118. 150. Jalan R: Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochem Int 2005; 47:78-83. 151. Schiodt FV, Atillasoy E, Shakil AO, et al: Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg 1999; 5:29-34. 152. Blei AT, Olafsson S, Webster S, et al: Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 1993; 341:157-158. 153. Murphy N, Auzinger G, Bernel W, et al: The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004; 39:464-470. 154. Blei AT: The pathophysiology of brain edema in acute liver failure. Neurochem Int 2005; 47:71-77. 155. Liu JP, Gluud LL, Als-Nielsen B, et al: Artificial and bioartificial support systems for liver failure. Cochrane Database Syst Rev 2004; (1):CD003628.

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Section

XX

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156. Mitzner S, Klammt S, Stange J, et al: [Extracorporeal blood purification in severe liver failure with the albumin dialysis MARS—impact on relevant intensive care parameters]. Anasthesiol Intensivmed Notfallmed Schmerzther 2005; 40:199206. 157. Van Woerkom W: La cirrhose hepatique avec alteration dans les centres nerveux evoluant chez des sujets d’age moyen. Nouvelle Iconographie de la Salpetriere. Clin Maladies Systeme Nerveux 1914; 7:41-51. 158. Victor M, Adams RD, Cole M: The acquired (non-wilsonian) type of chronic hepatocerebral degeneration. Medicine (Baltimore) 1965; 44:345-396. 159. Jog MS, Lang AE: Chronic acquired hepatocerebral degeneration: case reports and new insights. Mov Disord 1995; 10:714-722. 160. Wijdicks EF, Wiesner RH: Acquired (non-wilsonian) hepatocerebral degeneration: complex management decisions. Liver Transpl 2003; 9:993-994.

161. Chen W-X, Wang P, Yan S-X, et al: Acquired hepatocerebral degeneration: a case report. World J Gastroenterol 2005; 11:764-766. 162. Saporta MAC, André C, Bahia PRV, et al: Acquired hepatocerebral degeneration without overt liver disease. Neurology 2004; 63:1981-1982. 163. Stracciari A, Guarino M, Pazzaglia P: Acquired hepatocerebral degeneration: full recovery after liver transplantation. J Neurol Neurosurg Psychiatry 2001; 70:136-137. 164. Cakirer S, Karaarslan E, Arslan A: Spontaneously T1-hyperintense lesions of the brain on MRI: a pictorial review. Curr Probl Diagn Radiol 2003; 32:194-217. 165. Park SA, Heo K: Prominent cerebellar symptoms with unusual magnetic resonance imaging findings in acquired hepatocerebral degeneration. Arch Neurol 2004; 61:14581460.

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Martin A. Samuels

THE ANEMIAS Iron deficiency from chronic blood loss is the most common form of anemia. Iron deficiency in the absence of anemia (sideropenia) may decrease the deformability of red blood cells, leading to ischemia in the distribution of small cerebral vessels. This mechanism is particularly important in the context of polycythemia, in which there are increased numbers of red blood cells, each one of which may be iron deficient. Both the polycythemia and the relative sideropenia lead to increased blood viscosity with associated neurological symptoms and signs. Iron deficiency causes a microcytic, hypochromic anemia. Iron deficiency is associated with obsessive-compulsive behaviors that belong to two categories: compulsive eating (pica) and compulsive moving of the limbs, usually the legs (restless legs). Common pica behaviors include the eating of starch (amylophagia), paint chips, earth and clay (geophagia), and ice (pagophagia). The precise relationship between the iron deficiency and pica is unknown, but it is clear that pica does not represent replacement of iron, inasmuch as ice eating, the most common pica behavior, usually does nothing in this regard and many clays contain substances that actually chelate iron, thereby worsening the problem. It seems more likely that pica represents some form of compulsive behavior akin to a tic. The restless legs syndrome is a very common cause of insomnia. It consists of an unpleasant creeping sensation that occurs deep in the legs (and occasionally in the arms) when the person is at rest. The person feels compelled to move the legs to avoid the unpleasant feeling. Most sufferers are women, who pace the floor at night and complain of insomnia. Polysomnographic studies often reveal nocturnal myoclonus. It is likely that restless legs syndrome and nocturnal myoclonus represent various fragments of a single disorder, known as Ekbom’s syndrome.1 Many of the movement disorders associated with iron deficiency are reminiscent of those seen in basal ganglia diseases, but the precise relationship between systemic iron deficiency and these movement disorders is cryptic, although there is some reason to believe that iron is a cofactor for the enzyme tyrosine hydroxylase, which catalyzes the rate-limiting step in the biosynthesis of dopamine from tyrosine. Ekbom’s syndrome may therefore be a dopamine deficiency syndrome distinct from parkinsonism. Patients with Ekbom’s syndrome may respond to iron replacement. The rest are treated with centrally acting dopamine agonists, such as pramipexole or ropinirole. Some patients who fail to respond to a dopamine agonist derive

benefit from a benzodiazepine, clonidine, or clomipramine. Patients diagnosed as having the restless legs syndrome should undergo careful evaluation for anemia, including microscopic study of the blood smear, measurements of serum iron and total iron-binding capacity, and several stool tests for occult blood. Blood and spinal fluid ferritin levels may be assayed in patients without overt evidence of iron deficiency. The term megaloblastic anemia refers to a characteristic pattern of morphological abnormality in the blood and bone marrow that arises from impaired DNA synthesis. This is usually the result of a deficiency of one of two factors, cobalamin (vitamin B12) or folic acid, both of which are essential to the formation of the deoxyribosyl precursors of DNA. This deficiency results in abnormal development of erythroblasts in the marrow so that there is intramedullary hemolysis that results in anemia. The peripheral blood contains macrocytic erythrocytes. The disordered DNA metabolism also affects the maturation of granulocytes, resulting in hypersegmented polymorphonuclear leukocytes in the peripheral blood. Disordered DNA metabolism is clearly not confined to the blood cells, inasmuch as giant epithelial cells are found in many other organs, including the mouth, stomach, and skin. The neurological effects of the megaloblastic anemias probably result from a primary metabolic derangement in neural tissue and are clearly not directly related to the anemia per se.2 Because the blood-forming organs are particularly sensitive to the effects of cobalamin or folate deficiency, it is unusual to find the neurological effects in patients in whom no disorders of the blood are found. Anemia is, however, only one and probably a relatively late sign of cobalamin or folate deficiency, and so it is possible to find patients with the neurological effects of cobalamin or folate deficiency without anemia.3 Cobalamin (vitamin B12) deficiency may have a number of causes, including (1) defective diet (low in animal or bacterial products), (2) defective absorption (deficiency of intrinsic factor as a result of pernicious anemia, gastrectomy, or intestinal disease such as malabsorption or “blind loop” syndrome), and (3) increased metabolism (thyrotoxicoxis, pregnancy, neoplasia). Of these, the most prevalent form of cobalamin deficiency is pernicious anemia. It arises from failure of the gastric fundus to secrete adequate amounts of intrinsic factor to ensure intestinal absorption of vitamin B12. This failure of secretion of the mucoprotein intrinsic factor is caused by atrophy of the fundic glandular mucosa, a process that is usually an immune system–mediated gastritis but may be familial or senile or may

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result from gastric neoplasia. The presence of histamine-fast achlorhydria is a reliable method of diagnosing pernicious anemia but has often been supplanted by measurements of antiintrinsic factor and antiparietal cell antibodies.4 Patients with autoimmune pernicious anemia often have clinical and laboratory evidence of other conditions characterized by autoimmunity, such as vitiligo and thyroiditis. Serum B12 levels have occasionally been found to be erroneously normal in documented cases, and so it is now routine to assess intracellular function by directly measuring serum homocysteine (for folate or cobalamin deficiency) and methylmalonic acid (for cobalamin deficiency). Cobalamin (vitamin B12 or extrinsic factor) exists in two forms, methylcobalamin and adenosylcobalamin, each of which acts as an important cofactor in reactions vital to cellular function. The methylcobalamin system acts to transfer methyl groups from methyltetrahydrofolate to homocysteine, thereby creating tetrahydrofolate, which is required for DNA synthesis, and to methionine. Failure of this system results in impaired DNA synthesis and accumulation of homocysteine. Nitrous oxide, an inhibitor of methyltransferase, causes the syndrome of subacute combined degeneration of the spinal cord, a fact that implies that DNA synthesis failure can cause neurological disease even though neurons are postmitotic and therefore are themselves resistant to such a toxin. It is likely that this toxicity acts on oligodendrocytes, resulting in the demyelinating lesion that is characteristic of subacute combined degeneration. Exposure to nitrous oxide, as in the induction of general anesthesia, may precipitate acute deterioration (anesthesia paresthetica) in patients with otherwise mild or asymptomatic cobalamin deficiency.5 The adenosylcobalamin system acts to metabolize propionic acid by converting methylmalonyl–coenzyme A to succinyl–coenzyme A. Failure of this system results in an accumulation of methylmalonic acid, which is myelinotoxic by promoting the formation of abnormal long-chain fatty acids. Because vitamin B12 is stored in various tissues in large amounts, the appearance of cobalamin deficiency after the cessation of vitamin B12 absorption or intake is delayed by at least 3 years. Despite the fact that pernicious anemia is the most common cause of cobalamin deficiency, it seems clear that vitamin B12 deficiencies of any cause may result in identical clinical pictures. The three neurological manifestations of vitamin B12 deficiency are subacute combined degeneration of the spinal cord, cognitive changes, and optic neuropathy. Subacute combined degeneration of the spinal cord is the term used to designate the spinal cord disease caused by cobalamin deficiency.6 Patients complain of generalized weakness and paresthesias that usually begin distally in the hands. As these symptoms progress, stiffness and weakness in the limbs develop. Loss of vibration sense is the most profound sign, often joined later in the course by joint position sense loss. The Romberg sign is positive, and the gait is unsteady and awkward primarily because of proprioceptive loss (pseudotabetic gait). Weakness and spasticity are usually worse in the legs than in the arms and may progress to a spastic paraplegia if untreated. Babinski’s signs are present, but the deep tendon reflexes are variable. If a sensory level implicating the spinothalamic tracts is found on the trunk, this should always be viewed with the greatest skepticism, and the clinician should exhaustively rule out other causes of spinal cord disease. Many patients with vitamin B12 deficiency have distal symmetrical impairment of

cutaneous sensation, absence of deep tendon reflexes, and even slowed nerve conduction velocities, which suggest a neuropathic component, but this is usually quite mild compared to the myelopathic illness. These manifestations may sometimes be visualized by magnetic resonance imaging and pathologically are seen as regions of spongy myelopathy, quite similar to those seen in human immunodeficiency virus–related myelopathy, raising the question of whether this virus may somehow impair the transmethylation function of cobalamin. Cognitive changes are frequent in patients with vitamin B12 deficiency. In most cases, these changes reflect abnormalities in level of consciousness; inattention, confusion, somnolence, apathy, and delirium are the cardinal features. True dementia, defined as intellectual impairment in the absence of a disorder of level of consciousness, is a relatively rare manifestation of pure vitamin B12 deficiency. Pure cognitive change as the only manifestation of vitamin B12 deficiency is uncommon. Optic neuropathy is the third and last major neurological complication of vitamin B12 deficiency. It is characterized by bilateral involvement of the optic nerves that results in loss of central visual acuity and depressed sensitivity, more so for color than for black and white, in the centrocecal area of the field of vision. This syndrome is clinically similar to a number of other bilateral optic neuropathy syndromes, including tobaccoalcohol amblyopia, diabetic optic neuritis, Leber’s hereditary optic atrophy, and tropical ataxic neuropathy. These syndromes may be linked to an abnormality in cyanide metabolism that results from a shortage of sulfur-donating amino acids. In the 1990s, there was an epidemic of optic neuropathy and myelopathy in Cuba, thought to be caused by multiple B-vitamin deficiency resulting from malnutrition in combination with alcohol and cyanide exposure from cigar smoking and cassava consumption. The epidemic was terminated by vitamin supplementation.7 Folic acid (folate) deficiency accounts for nearly all of the cases of megaloblastic anemia not caused by vitamin B12 deficiency. The causes of folate deficiency are (1) defective diet (low in vegetables and liver), (2) defective absorption from intestinal malabsorption as a result of sprue, steatorrhea, diverticulosis, or short circuits of the gastrointestinal tract or the “blind loop” syndrome; and (3) deranged metabolism caused by an increased requirement from hemolytic anemia, pregnancy, or neoplasia or by impairment of use as a result of liver disease or the administration of folic acid antagonists or anticonvulsants. Unlike those of vitamin B12, the bodily stores of folic acid are quite limited. A folate deficiency syndrome may commence within several months of dietary deprivation, which makes it a much more common problem among the malnourished than is vitamin B12 deficiency. Folate, once absorbed through the entire small intestine, is reduced by specific liver enzymes to tetrahydrofolic acid, a compound that plays a major role in the metabolism of one carbon fragments by its synthesis and transfer of methyl groups. Through this mechanism, folate is vital for the conversion of deoxyuridylate to thymidylate, a precursor needed for DNA synthesis. Thus, tetrahydrofolate derivations are closely linked to vitamin B12–dependent reactions, and the hematological alterations in vitamin B12 and folate deficiency are indistinguishable. Deficiencies of the two vitamins have very similar effects, and a deficiency of one may lead to faulty use of the other. Many patients with vitamin B12 deficiency have concomitant folate deficiency, but most people with the folate deficiency state, which is overwhelmingly more common, have

chapter 115 neurology of hematology no vitamin B12 deficiency. Folic acid deficiency is almost never pure. Because it accompanies malnutrition, it is nearly always associated with multiple vitamin deficiencies. The most common neurological manifestation of this multivitamin deficiency state is a symmetrical sensorimotor polyneuropathy. Some minor degrees of segmental demyelination may also occur, usually as a result of entrapment of metabolically weakened nerves. All the common entrapment neuropathies (e.g., carpal tunnel syndrome, meralgia paresthetica, peroneal palsy, ulnar palsy) are more frequent in patients with an underlying metabolic axonopathy such as that caused by vitamin deficiency. Folate deficiency is associated with neural tube defects, and supplements are therefore routinely prescribed during pregnancy.

THE HEMOGLOBINOPATHIES Most of the manifestations of sickle cell anemia are related to the characteristic property of the sickle cell hemoglobin (HbS) to crystallize under conditions of reduced oxygen tension. This causes sickled erythrocytes to become trapped in terminal arterioles and capillaries, which results in more hypoxia, increased sickling, thrombosis, and infarction. Tissues that normally contain blood at low oxygen tensions, such as renal medulla and pulmonary arterioles, are at greatest risk, but sickling may occur in other organs, including the relatively well-oxygenated brain and spinal cord. The hemolysis results largely from the fact that the sickled erythrocytes are mechanically rigid, less flexible, and more fragile than normal cells. Painful crises are among the most common clinical problems in the management of patients with sickle cell anemia. The abdominal and bone pain, so common in this disease, is probably ischemic pain related to the sickling phenomenon. The treatment for these crises consists of hydration, bed rest, and analgesia. Vascular disease is the more serious neurological aspect of this disorder and probably contributes in a major way to the decrease in life expectancy of patients with sickle cell anemia. The prevalence of overt strokes is about 20% among patients with sickle cell anemia. Most strokes are caused by small-vessel occlusions, which often result in seizures at the onset of a stroke. In some cases, progressive small-vessel occlusions with recurrent development of collateral vessels can lead to an angiographic picture similar to that seen in moyamoya disease. Hemorrhages may result from rupture of these fragile collateral vessels, leading to intracerebral, subarachnoid, spinal, and retinal hemorrhagic strokes in patients with sickle cell disease. The progressive stenosis of the supraclinoid internal carotid artery that leads to the development of the moyamoya pattern may be detected noninvasively with transcranial Doppler ultrasonography. Stroke risk is reduced dramatically through the use of prophylactic transfusions in patients in whom transcranial Doppler examinations reveal that the timeaveraged mean blood velocity in the internal carotid or middle cerebral artery is 200 cm per second or higher.8 Among children younger than 15 years with strokes, sickle cell anemia is present in 7%, and thus it an important cause of stroke in childhood. Spinal cord infarction is also observed in patients with sickle cell anemia much more commonly than in the general population. Massive intracranial hemorrhage is another complication of sickle cell anemia. Large-vessel occlusions also occur in patients with the supraclinoid carotid as the site of

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predilection. Moyamoya disease may be treated with extracranial-intracranial arterial bypass grafting or with temporal-pial synangiosis, with the hope of reducing the likelihood of rupture of the fragile vessels of moyamoya disease. Bacterial infection is the reason for as many as half of all hospitalizations; meningitis is particularly important, accounting for 20% of the deaths. Some deaths among older children and adults with meningitis have been reported, but most occur in patients younger than 3 years. Streptococcus pneumoniae is an unusually common organism in these patients, accounting for about 75% of cases of meningitis. Recurrent meningitis seems also to be unusually common in these patients. The unusual susceptibility of patients with sickle cell anemia to infection is not totally understood, but the factors that are the most important include their functional asplenia and a defect in leukocyte function. Fat embolism in sickle cell anemia occurs with higher-than-expected frequency, and the brain is involved in more than 80% of affected patients in whom it is examined. Bone pain, fever, and altered mental status are the major clinical features. Treatment is controversial, but systemic anticoagulation and exchange transfusions may be used. Only the presence of some amount of HbS leads to the risk of a neurological problem. Sickle cell trait is occasionally associated with neurological complications, especially when patients at risk are exposed to an extremely low oxygen tension (e.g., in high-altitude flying, with anesthesia). The HbSC, HbSD, HbSF, and HbS-thalassemia syndromes are all situations in which there is a risk of neurological complications similar to that in homozygous HbS disease; however, there are fewer neurological problems in these combined hemoglobin disorders than in the pure sickle cell disease. The genetic defect underlying thalassemia involves rates of synthesis of the individual polypeptide chains. Two major varieties of thalassemia exist: one involving defective α-chain synthesis, the other involving β-chain synthesis. The more common β-thalassemia may occur in the heterozygous or homozygous form to produce the syndromes of thalassemia trait or Cooley’s anemia (thalassemia major), respectively. Heterozygosity for α-thalassemia results in a very mild condition and may require an associated hemoglobin abnormality for clinical expression (thalassemia minor). Homozygous αthalassemia is thought to be incompatible with normal fetal development. The susceptibility to infection seen in thalassemia corresponds to that seen in sickle cell anemia but is confined to patients who have undergone splenectomy for control of hemolysis. In about a third of patients with myelopathy resulting from extramedullary hematopoiesis, thalassemia is the underlying disease. The usual location for extramedullary hematopoiesis is various parts of the reticuloendothelial system, particularly the liver, spleen, and lymph nodes. However, the spinal epidural space and the intracranial subdural space (Fig. 115–1) may be involved, with consequent compression of the spinal cord or the brain or both. Most cases involving the spine occur in the thoracic segments posteriorly, usually over multiple levels. Treatment with radiotherapy is usually quite effective.

MYELOPROLIFERATIVE DISORDERS The myeloproliferative disorders include polycythemia rubra vera, myelofibrosis with myeloid metaplasia, chronic

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Figure 115–1. Subdural extramedullary hematopoiesis in a patient with thalassemia.

myelogenous leukemia, and essential thrombocythemia. The proliferation in all of these diseases originates in the bone marrow, liver, or spleen, in which extramedullary blood formation may occur. Strokes are the most common neurological complication seen in polycythemia vera, occurring in 15% to 32% of the patients. As many as 15% of patients with polycythemia vera die of a stroke, five times the number in an agematched control population. Migraine phenomena with or without headache occur when the platelet counts exceed 1,000,000/mm3, as can occur in essential thrombocythemia.

HEMORRHAGIC DIATHESIS Hemophilia may be defined as an inherited hemorrhagic diathesis, characterized by impairment of the first stage of coagulation, the production of thromboplastin from the interaction of platelets, and three or more plasma factors (VIII, IX, and XI). The major peripheral nervous system complication is intramuscular hemorrhages that may compress peripheral nerves.9 Most patients with peripheral nerve compressions may be managed with factor replacement alone, but some may require fasciotomy. Patients with hemophilia must be monitored for intracranial hemorrhage because of the more active lives enabled by vigorous replacement therapy for intra-articular hemorrhages. Bleeding may be intracerebral, subarachnoid, subdural, and epidural. In mild cases (7% to 15% of normal factor levels), intracranial bleeding occurs only after significant trauma. In patients with moderately severe disease (1% to 6% of normal factor levels), only minor trauma may produce hemorrhage, and with severe cases (<1% normal levels), it can occur after no trauma at all. The most practical and accurate method for accurate diagnosis of intracranial hemorrhage is the computed tomographic scan. Subarachnoid hemorrhage may be treated successfully with factor replacement alone, although a ventricular catheter may be necessary to treat hydrocephalus. Subdural and epidural hemorrhages often necessitate surgical therapy, which may be safely accomplished

after factor replacement. Intracerebral hemorrhages are the most difficult to treat. Most patients are managed with medical therapy alone or with medical therapy plus a ventricular cannula for measurement and control of intracranial pressure. Thrombocytopenia is usually an acquired reduction in the number of platelets as a result of either diminished production or increased peripheral destruction. The major neurological complication of thrombocytopenia is intracranial bleeding, the severity and frequency of which is dependent on the severity of the thrombocytopenia. The incidence of intracranial bleeding in thrombocytopenia is substantial when the number of normal platelet falls below 50,000. Intracranial bleeding in thrombocytopenia can occur in the form of multiple small punctate or petechial hemorrhages caused by capillary bleeding (brain purpura), which may become confluent to form major intracerebral hemorrhages. Treatment depends on the etiology of the thrombocytopenia. Platelet transfusions are useful in situations in which there is decreased production. When increased platelet destruction or splenic sequestration is an important factor, therapy may require splenectomy, corticosteroids, intravenous immunoglobulin, and platelet transfusions. When heparininduced thrombocytopenia is recognized, the patient is switched to another anticoagulant, such as a direct thrombin inhibitor. The thrombotic microangiopathies—which include thrombotic thrombocytopenic purpura (TTP); hemolytic uremic syndrome; and the syndrome of hemolytic anemia, elevated liver function test results, and low platelet levels (HELLP)—are disorders caused by aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes.10 TTP (Moschowitz’s disease) causes neurological symptoms because of microvascular brain ischemia.11 The blood smear shows a microangiopathic hemolytic anemia (Fig. 115–2). Neurological manifestations of the disease, which reflect multifocal brain ischemia, are headache; cognitive changes, including altered states of consciousness, agitation, confusion, and delirium; hemiparesis; aphasia; syncope; visual changes; dysarthria; seizures; coma; cranial nerve palsies; paresthesias; and vertigo. TTP is caused by platelet aggregates that contain anti–von Willebrand factor antibody rather than fibrin, as is the case in disseminated intravascular coagulation (DIC). Deficiency of the enzyme that degrades large multimers of von Willebrand factor, a disintegrin and metalloprotease with thrombospondin-1–like domains (ADAMTS-13), causes TTP because the large undegraded multimers of von Willebrand factor are much more likely to produce aggregation of platelets. ADAMTS-13 may be genetically deficient, producing a familial type of TTP, or TTP may be acquired by a probable autoimmune mechanism whereby immunoglobulin G binds and disables ADAMTS-13. The diagnosis is made by identifying a typical blood smear in the appropriate clinical setting. Levels of ADAMTS-13 are less than 5% of normal in active TTP. Plasma exchange (the combination of plasmapheresis, which may remove some of the multimers of von Willebrand factor and autoantibodies against ADAMTS-13, and infusion of fresh-frozen plasma or cryosupernatant, which contains ADAMTS-13) is a treatment that leads to a survival rate of about 90%. Steroids, splenectomy, vincristine, or rituximab may be used in resistant cases. DIC is a relatively common acquired hemorrhagic thrombotic syndrome that occurs as a result of the presence of thrombin in the systemic circulation. The syndrome follows other

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Figure 115–2. Microangiopathic hemolytic anemia blood smear in a patient with thrombotic thrombocytopenic purpura, demonstrating various abnormal shaped red blood cell fragments.

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Figure 115–3. Specimen of nonbacterial endocarditis in a patient with chronic disseminated intravascular coagulation caused by a mucin-secreting adenocarcinoma of the colon.

disease states such as viral and bacterial infections, obstetrical and surgical complications, neoplasms (especially mucinsecreting adenocarcinomas), fat embolism, diabetic ketoacidosis, and head injury. DIC causes thrombosis and bleeding at multiple sites, including the nervous system. The essential neuropathological changes are multiple infarctions, petechial hemorrhages, and occasional small subdural and subarachnoid hemorrhages. Nonbacterial thrombotic (marantic) endocardi-

tis may develop (Fig. 115–3). Fibrin thrombi are found in the cerebral vessels. The clinical syndrome depends on the particular pathology but may include seizures, mental changes, and focal findings. The management of subacute or chronic DIC with heparin may be effective, particularly in patients with thrombotic complications, but removal of the underlying cause (e.g., evacuation of the uterus in cases of abruptio placentae) is the definitive treatment.

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Figure 115–4 Rouleaux formation on the peripheral blood smear of a patient with multiple myeloma.

Hypoprothrombinemia, usually caused by the use of anticoagulant drugs, is a common cause of bleeding. Heparin is a drug that inactivates thrombin, inhibits the conversion of prothrombin to thrombin, and prevents the agglutination of platelets; warfarin acts by antagonizing vitamin K. These two drugs have a similar spectrum of neurological complications. Nervous system hemorrhage in patients taking anticoagulants may involve numerous locations, including intracerebral, subarachnoid, subdural, cranial epidural, spinal epidural, spinal intramedullary, root, plexus, and peripheral nerves. Lumbar puncture is dangerous in the presence of a hemorrhagic diathesis and should be avoided in favor of computed tomography and magnetic resonance imaging as a method for making the diagnosis. In general, the incidence of serious neurological hemorrhage rises above the benefit of anticoagulation when the international normalized ratio exceeds 3.0. For neurological purposes, the target international normalized ratio is 2.0 to 3.0 for all conditions except in patients with mechanical heart valves.

PARAPROTEINEMIAS Paraparoteinemias may be seen in many conditions, including connective tissue diseases and multiple types of malignancy. The plasma cell dyscrasias are a group of disorders characterized by the uncontrolled proliferation of cells normally involved in antibody synthesis. This usually results in the elaboration of a homogeneous immunoglobulin or one of its constituent polypeptide chains. These disorders are often classified according to type of protein that is produced (myeloma, macroglobulinemia, and heavy-chain diseases). Multiple myeloma, characterized by infiltration of the bone marrow with neoplastic plasma cells, is the most common plasma cell dyscrasia. The peripheral blood smear may show abnormal clumping of erythrocytes in stacks of coinlike rows (Rouleaux). This results from the fact that the normal surface charges that

cause red blood cells to repel each other are coated with the paraprotein (Fig. 115–4). Macroglobulinemia is defined by the presence of an excessive amount of immunoglobulin M gamma globulin in the serum. It includes a spectrum of disorders ranging from an apparently benign monoclonal gammopathy to progressive malignant lymphoma. Neurological complications are related primarily to the viscosity of the large abnormal protein or to the development of malignant lymphoma. Heavy-chain diseases are defined by the finding of characteristic immunoglobulin heavy-chain fragments in the serum or urine. The hyperviscosity syndrome is the symptom and sign complex of abnormal levels of consciousness (inattention, drowsiness, stupor, coma, delirium), funduscopic changes characterized by venous engorgement (“sausage veins”), retinal hemorrhages and exudates, blurred vision, and headache The syndrome develops when the relative viscosity of the blood, as measured by a viscosimeter, is greater than 3.0 (normal is <2.0). This increase in viscosity may result from an increase in red blood cell mass (as in polycythemia) but more often results from the presence of large amounts of an abnormal protein, usually a macroglobulin. When abnormal proteins are the cause, treatment consists of plasmapheresis. Cryoglobulinemia is the presence in the serum of proteins that precipitate in the cold and redissolve on warming. These proteins are most often associated with hepatitis C infection, myeloma, and macroglobulinemia, but they may be appear as part of a connective tissue disease or as an isolated finding in the absence of any known underlying cause. About a third of the cryoglobulins are myeloma immunoglobulin G proteins (type I), a third are immunoglobulin M macroglobulins (type II), and a third are a mixture of immunoglobulin M and G molecules (type III). The neurological syndrome associated with cryoglobulinemia is most common in type III, which is the type most often related to an underlying connection tissue disease. The most frequent neurological syndrome is a sensorimotor polyneuropathy with purpura. Many types of polyneuropathies

chapter 115 neurology of hematology are seen in patients with paraproteinemias, including symmetrical polyneuropathy, mononeuropathy multiplex, and various versions of chronic inflammatory demyelinating polyneuropathy, including multifocal motor neuropathy. There may be neuropathies with low levels of paraproteinemia that do not meet criteria for a frank myeloproliferative disorder (monoclonal gammopathy of unclear significance). The Bing-Neel syndrome, the central nervous system syndrome seen in macroglobulinemia, was described before Waldenström named the disease in 1944.12 It is caused in part by the hyperviscosity syndrome, but in addition, some patients exhibit a multifocal disease with a rapid downhill course that is uniformly fatal and unresponsive to plasmapheresis. The spinal fluid in these patients is abnormal, with some pleocytosis and elevated protein levels. The pathology consists of infiltration of lymphocytes and plasma cells, particularly around veins. The syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) is a paraneoplastic syndrome observed in patients with osteosclerotic myeloma. Hepatosplenomegaly, sexual impotence, various skin lesions, and a painful sensorimotor polyneuropathy are usually present. The M component in the serum is produced by an osteosclerotic myeloma, which, when treated, results in improvement in all components of the syndrome.

THE HYPERCOAGULABLE STATES Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are associated with an increased risk of thrombosis (prethrombotic states) or if they have recurrent thrombosis without recognizable predisposing factors (thrombosis-prone).13 The hypercoagulable states are subdivided into those in which a clearly identified, specific abnormality in hemostasis can be found (primary hypercoagulable states) and those in which various diverse clinical conditions have been associated with an increased risk of thrombosis (secondary hypercoagulable states). Cerebral thrombosis (venous and arterial) and embolism are important manifestations. The primary hypercoagulable states result from failure of one of the three physiological anticoagulant mechanisms (antithrombin III, protein C, and the fibrinolytic system) and include antithrombin III deficiency, protein C deficiency, protein C resistance caused by the factor V Leiden mutation, protein S deficiency, fibrinolytic disorders, dysfibrinogenemia, factor XII deficiency, prekallikrein deficiency, the antiphospholipid antibody syndrome, and the prothrombin gene mutation.14 The two major antiphospholipid syndromes are the lupus anticoagulant and the anticardiolipin antibody. The lupus anticoagulant is an antibody to phospholipids that interferes with the formation of the prothrombin activator, a complex of calcium ions, factors Xa and V, and a source of phospholipid, usually the platelet membrane in the coagulation cascade. This immunoglobulin G or M antiphospholipid antibody often causes prolongation of phospholipid-dependent coagulation test times, such as the activated partial thromboplastin time. This antibody is present in about 25% of patients with systemic lupus erythematosus (SLE) and may cross-react with cardiolipin, the antigen commonly used in a blood screening test for syphilis, thus producing a biological false-positive result. Despite the prolonged activated partial thromboplastin time, this antiphospholipid antibody is actually a procoagulant.

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The lupus anticoagulant is diagnosed through a three-step functional test. In addition to patients with SLE, other people at risk for the anticardiolipin antibody include patients taking neuroleptic drugs, those with neoplasms, and those with other autoimmune disorders. Those without underlying disease are said to have the primary antiphospholipid antibody (Hughes’) syndrome, characterized by recurrent episodes of venous and/or arterial thrombosis, recurrent midpregnancy spontaneous abortions, and thrombocytopenia. Migraine, mitral valve prolapse, and livedo reticularis are also overrepresented in these patients (Sneddon’s syndrome). Echocardiography frequently reveals the presence of vegetations on the mitral valve, presumably representing foci of nonbacterial thrombotic endocarditis (NBTE). The nervous system is commonly affected with large- and small-vessel arterial occlusions, venous occlusions, and emboli that probably arise from NBTE, which in turn results from the hypercoagulable state. Many of the neurological syndromes seen in patients with SLE are caused either by thrombosis in situ or by emboli from NBTE (known as LibmanSacks endocarditis in patients with SLE). Treatment of patients who have the antiphospholipid antibody and who suffer recurrent thrombosis is anticoagulation with warfarin (international normalized ratio, 2.0 to 3.0). The secondary hypercoagulable states may be divided into three major groups on the basis of the presumed predominant pathophysiological mechanism: (1) abnormalities of coagulation and fibrinolysis, such as those caused by malignancy, pregnancy, use of oral contraceptives, infusion of prothrombin complex concentrates, and nephrotic syndrome; (2) abnormalities of platelets, such as those caused by myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, hyperlipidemia, diabetes mellitus, and heparin-induced thrombocytopenia15; and (3) abnormalities of blood vessels or rheology, such as those caused by conditions promoting venous stasis (e.g., immobilization, obesity, advanced age, postoperative state), artificial surfaces, vasculitis and chronic occlusive arterial disease, homocystinemia, hyperviscosity (e.g., polycythemia, leukemia, sickle cell disease, leukoagglutination, increased serum viscosity), and TTP. The relationship between increased tendency for thrombosis and malignancy has been known ever since Armand Trousseau described the syndrome that bears his name.16 Migratory phlebothrombosis, pulmonary emboli, and transient or permanent focal neurological deficits are known to be part of a paraneoplastic syndrome usually in patients with mucinsecreting adenocarcinomas. Some of the neurological deficits are caused by thrombosis in situ of cerebral vessels; others are caused by emboli arising from NBTE, which itself is caused by the paraneoplastic hypercoagulable state. Pregnancy increases the risk of thrombosis, probably as a consequence of chronic low-grade DIC, which is a normal development in pregnancy, presumably in preparation for the hemostatic challenge of placental separation. Cerebral venous thrombosis is the major neurological complication of this hypercoagulable state, seen primarily in the postpartum period. It takes two major clinical forms: venous sinus occlusion and cortical vein occlusion. Although these two clinical forms often fuse as the illness progresses, venous sinus thrombosis usually manifests with increased intracranial pressure, whereas cortical vein thrombosis usually begins with partial seizures. Venous hypertension may cause hemorrhage into the brain that can often be visualized by computed tomography or magnetic

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resonance imaging. Magnetic resonance venography is now the “gold standard” neurodiagnostic study when venous occlusive disease is suspected. The treatment for the hypercoagulable state of pregnancy is reserved for patients with demonstrated thrombosis, and it consists of heparin, inasmuch as warfarin crosses the placenta and is possibly teratogenic. Oral contraceptives significantly increase the risk of thrombosis in a way similar to that seen in late pregnancy.

K E Y

P O I N T S

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The restless legs syndrome is part of a larger neurological syndrome (Ekbom’s) that may be caused by iron deficiency.

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Pernicious anemia produces a characteristic myelopathy that begins in the lower cervical region but may spread to affect myelin in the brain and optic nerves.

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The most life-threatening neurological complication of sickle cell anemia is intracerebral hemorrhage from rupture of moyamoya vessels, elaborated because of progressive stenosis of the supraclinoid carotid artery.

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Thalassemia is the most common cause of extramedullary hematopoiesis that affects the nervous system in the subdural intracranial space and the spinal epidural space.

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Spontaneous intracerebral hemorrhage may occur when there are fewer than 50,000 platelets/mm3.

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TTP is treated successfully with plasma exchange.

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POEMS syndrome is the paraneoplastic syndrome caused by osteosclerotic myeloma.

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The primary antiphospholipid antibody syndrome is treated with warfarin; the aim is for an international normalized ratio of 2.0 to 3.0.

Suggested Reading Bain BJ: Diagnosis from the blood smear. N Engl J Med 2005; 353:598-507. Grotta JC, Manner C, Pettigrew LC, et al: Red blood cell disorders and stroke. Stroke 1986; 17:811-817. Markus HS, Hambley H: Neurology and the blood: haematological abnormalities in ischaemic stroke. J Neurol Neurosurg Psychiatry 1998; 64:150-159.

Pollard JD, Young GAR: Neurology and the bone marrow. J Neurol Neurosurg Psychiatry 1997; 63:706-711. Samuels MA: Neurologic aspects of hematologic disease. Curr Neurol 1992; 12:215-240. Samuels MA: Neurologic manifestations of hematologic diseases. In Asbury A, McKhann G, McDonald I, eds: Diseases of the Nervous System, 2nd ed. Philadelphia: WB Saunders, 1992, pp 1510-1521. Samuels MA, Thalinger K: Cerebrovascular manifestations of selected hematologic diseases. Semin Neurol 1991; 11:411-418.

References 1. Ekbom KA: Restless legs. In Vinken PF, Gruyn GW, eds: Handbook of Clinical Neurology, vol 8: Diseases of Nerves. Amsterdam: Elsevier, 1970, pp 311-320. 2. Healton EB, Savage DG, Brust JCM, et al: Neurologic aspects of cobalamin deficiency. Medicine 1991; 70:229-245. 3. Beck WS: Neuropsychiatric consequences of cobalamin deficiency. Adv Intern Med 1991; 36:33-56. 4. Toh B-H, VanDriel IR, Gleeson PA: Mechanisms of disease: pernicious anemia. N Engl J Med 1997; 337:1441-1448. 5. Kinsella LJ, Green R: “Anesthesia paresthetica”: nitrous oxide–induced cobalamin deficiency. Neurology 1995; 45:1608-1610. 6. Adams RD, Kubik CS: Subacute degeneration of the brain in pernicious anemia. N Engl J Med 1944; 231:1-9. 7. Roman GC: On politics and health: an epidemic of neurologic disease in Cuba. Ann Intern Med 1995; 122:530-533. 8. Adams RJ, McKie VC, Hsu L, et al: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5-11. 9. Silverstein MN: Intracranial bleeding in hemophilia. Arch Neurol 1960; 3:1415-1420. 10. Moake JL: Thrombotic microangiopathies. N Engl J Med 2002; 347:589-600. 11. Moschcowitz E: An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. Arch Intern Med 1975; 35:89-95. 12. Bing J, Neel AV: Two cases of hyperglobulinemia with affection of the central nervous system on a toxic-infectious basis. Acta Med Scand 1936; 88:492-506. 13. Schafer AI: The hypercoagulable states. Ann Intern Med 1985; 102:814-828. 14. Nachman RL, Silverstein R: Hypercoagulable states. Ann Intern Med 1993; 119:819-827. 15. Warkentin TE, Chong BH, Greinacher A: Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79:1-9. 16. Trousseau A: Phlegmasia alba dolens. Clin Med Hotel Dieu de Paris 1865; 3:94-100.

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NEUROLOGY OF COMMON ELECTROLYTE DISORDERS ●

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Martin A. Samuels and Julian L. Seifter

HYPEROSMOLALITY AND HYPERTONICITY Normal serum, and therefore body fluid, osmolality is in the range of 275 to 295 mOsm/kg; clinically significant effects are generally seen at levels greater than 325 mOsm/kg. Osmolality may be measured directly by the freezing point depression or calculated as serum osmolarity in milliosmoles per liter with the following formula, which accounts for the millimolar quantities of major serum solutes (where BUN is blood urea nitrogen): 2(Na in mEq/L) + glucose (mg/dL)/18 + BUN (mg/dL)/2.8

Effective hyperosmolality is called hypertonicity and indicates the effect of increased extracellular osmoles to draw water from cells by osmosis. If hyperosmolality is caused by hypernatremia, cells initially shrink until adaptive mechanisms allow cell volume to recover. Similarly, a diabetic patient with hyperglycemia loses cell water and develops a hypertonic syndrome. In contrast, azotemia (i.e., an elevated BUN level) may cause hyperosmolality but not hypertonicity, because the high permeability of urea allows solute movement into cells so that cell water does not leave by osmosis. The difference between hyperglycemia (glucose cannot enter cells) and azotemia is seen by the effect on the serum sodium concentration. Water leaving cells in the hyperglycemic patient lowers serum [Na], whereas serum sodium [Na] is not altered by a rise in BUN. Addition of extrinsic osmoles such as mannitol, like glucose, causes hyperosmolality, hypertonicity, loss of cell water, and hyponatremia. On the other hand, added alcohols that quickly permeate cells, such as ethanol, ethylene glycol, isopropyl glycol, and methanol, act more like azotemia, causing hyperosmolality but not hypertonicity or hyponatremia. Because measured osmolality is increased with addition of these extrinsic solutes but sodium, glucose, and urea are not, there is an osmolal gap, defined as the difference between measured and calculated osmolality. The osmolal gap should be less than 10 mOsm/L. Hypernatremia is defined as a serum sodium concentration higher than 145 mEq/L. In all tissues, hypernatremia leads to loss of intracellular water, which in turn leads to cell shrinkage. The nervous system is unique in that it is capable of generating (or accumulating from the extracellular fluid) solutes referred to as idiogenic osmoles, such as amino acids (glutamine, taurine, glutamate), polyols (myoinositol), and methylamines (glycerophosphorylcholine and choline), to minimize

cell shrinkage, a process that is complete in 1 to 2 days. When hypernatremia is unusually severe (serum sodium level exceeds 160 mEq/L), these mechanisms fail, which leads to encephalopathy. When hypernatremia occurs, antidiuretic hormone (ADH) is released and thirst increases, which lead to renal retention of ingested water and thereby lower the serum sodium level toward normal. Hypernatremia is thus caused by a defect in thirst or inability to access water, inadequate release or effect of ADH, loss of hypotonic fluid, or addition of concentrated sodium. Hyperglycemia is nearly always caused by diabetes mellitus, which results from either inadequate insulin production or insulin resistance. In patients with neurological disease, this is often precipitated by stress, infection, or the therapeutic use of glucocorticoids. Azotemia is caused by renal failure or inadequate renal perfusion (prerenal azotemia). Hyperosmolar agents such as mannitol or glycerol are often used in patients with neurological disease to treat increased intracranial pressure and may result in hyperosmolality. Hyperosmolality usually produces a generalized encephalopathy without localizing or lateralizing features, but an underlying focal lesion (e.g., stroke, multiple sclerosis, neoplasm) could become symptomatic under the metabolic stress of a hyperosmolar state. The prognosis of the hyperosmolality itself is good, but the long-term outlook depends on the cause. For unknown reasons, hyperosmolality alone, particularly when caused by hyperglycemia, may lead to continuous partial seizures, and even careful studies may fail to uncover any underlying lesion. These seizures generally respond promptly to lowering of the serum glucose level. The treatment of hyperosmolality requires calculation of apparent water losses: 1. The normal total body water (NTBW) is calculated as body weight (in kilograms) × 0.6. 2. The total body solute (sodium + potassium) is estimated as NTBW × 140 mEq/L. Note that 140 mEq/L is normal serum [Na] but is approximately equal to intracellular [K] needed to estimate total body solutes. 3. The patient’s body water is calculated as total body solute/patients serum [Na]. 4. The patient’s water deficit is calculated as NTBW – patient’s body water.

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5. Apart from deficit correction, large ongoing losses in the urine (osmotic diuresis or diabetes insipidus) or sweat (fever) are estimated and replaced. The water losses are replaced, with water or 5% dextrose in water, so that the serum sodium level falls no faster than 2 mEq/L/hour. In the hypotensive or volume-depleted patient, normal saline may first be needed to correct blood pressure. In patients with renal failure, dialysis may be required. Insulin is administered, with frequent blood glucose testing, if there is hyperglycemia. Intramuscular and subcutaneous insulin may be unpredictably absorbed, particularly in hypovolemic patients, because of poor tissue perfusion. Rapid-acting insulin, 0.1 U/kg by rapid intravenous infusion followed by 0.05 U/kg/ hour by continuous intravenous infusion, is usually sufficient to reduce the blood glucose level adequately and safely, but the mainstay of hyperglycemia correction in the patient with hyperosmolar type II diabetes is volume expansion, which leads to urinary glucose clearance. Rapid reduction of extreme elevations of glucose should be avoided. Diabetes insipidus is recognized as hypernatremia (>292 Osm) with simultaneous submaximal concentration of the urine. A subcutaneous dose of vasopressin and subsequent measurement of serum ADH level help distinguish central from nephrogenic diabetes insipidus. Treatments include deaminoD-arginine vasopressin, an ADH analog used in the treatment of central diabetes insipidus. Salt restriction and even thiazide diuretics may help in treating nephrogenic diabetes insipidus.

HYPONATREMIA Hyponatremia is defined as a serum sodium level lower than 135 mEq/L, but it may be asymptomatic at levels less than 125 mEq/L in chronic, slowly developing cases. Hypotonicity is always associated with hyponatremia, but hyponatremia may be isotonic (e.g., as an artifact in hyperlipidemia or hyperproteinemia), hypertonic (e.g., hyperglycemia; mannitol), or hypotonic (with impairment of free water excretion in low cardiac output states or the syndrome of inappropriate anti-diuretic hormone [SIADH] or with an enormous free water load, as in psychogenic water drinking). Osmolality is estimated by use of the formula given previously (see discussion of hyperosmolality) and may be measured in the clinical laboratory. The difference between the calculated and measured osmolality (the osmolal gap) should not exceed 10 mOsm/L. The finding of factitious hyponatremia is caused by a laboratory artifact in diluted samples when the solids of plasma are increased (e.g., hyperlipidemia, severe hyperproteinemia as in myeloma). Measurements of the undiluted serum [Na] by the blood gas machine and of the osmolality are not similarly affected. The prognosis of hyponatremia depends on the rate and magnitude and the cause of the fall in serum sodium. In acute hyponatremia (a few hours or less), seizures and severe cerebral edema may be rapidly life-threatening at serum sodium levels as high as 125 mEq/L, whereas patients may tolerate very low serum sodium levels (even below 110 mEq/L) if the process develops over days or more. Rapid correction of acute hyponatremia may be lifesaving, whereas rapid correction of chronic hyponatremia may be dangerous. Nervous system cells initially swell in hypotonic states but then compensate for chronic hyponatremia by losing solute to the extracellular space, followed by water, to restore normal cell volume. If the serum

sodium level rapidly rises after cells regain normal volume, brain cells can rapidly shrink, causing osmotic demyelination (formerly known as central pontine myelinolysis). The clinical picture of osmotic demyelination ranges from mild spasticity to coma, depending on the extent of the demyelinating lesions. The pons is particularly susceptible, possibly simply because the crossing and descending fiber tracts produce a tight grid that does not tolerate fluid shifts as well as does the rest of the brain. The process, however, is not restricted to the pons; it may affect the cerebral white matter as well, leading to the evolution of the name for this disorder from central pontine myelinolysis to pontine and extrapontine myelinolysis to the preferred modern term osmotic demyelination. The cause of hypotonic hyponatremia is best determined by dividing all possibilities into three categories on the basis of the clinical estimate of the state of the extracellular fluid space. Blood pressure and heart rate with orthostatic measurements, the central venous pressure (neck vein distention), and the presence or absence of edema allow all cases of hypotonic hyponatremia to be categorized into three types: hypovolemic (reduced effective blood volume with hypotension, tachycardia and orthostatic intolerance), hypervolemic (edematous states), and isovolemic (retention of free water, no apparent edema). The diagnosis is made with a measurement of the serum sodium, followed by an assessment of extracellular volume. The major diagnoses in each category are hypotonic hypovolemic hyponatremia (gastrointestinal sodium losses; hemorrhage; renal salt wasting, including the cerebral salt wasting syndrome; diuretic excess; and adrenal insufficiency), hypotonic hypervolemic hyponatremia (congestive heart failure, hepatic failure with ascites, nephrotic syndrome), and hypotonic isovolemic hyponatremia (SIADH, psychogenic water drinking, hypothyroidism, and resetting of the osmostat). The treatment depends on the type of hyponatremia. In hypertonic hyponatremia, the underlying disorder (e.g., hyperglycemia, exposure to mannitol) is treated, and only the estimated salt losses are replaced. Factitious hyponatremic disorders (e.g., hyperlipidemia, hyperproteinemia) do not necessitate osmotic treatment, and in fact it may be dangerous to subject such patients to fluid restriction. In hypovolemic hypotonic hyponatremia, volume is replaced with isotonic saline; the underlying renal, adrenal, and gastroenterological conditions are treated, and the cases of cerebral salt wasting (e.g., intracerebral or subarachnoid hemorrhage) are recognized and treated. In hypervolemic hypotonic hyponatremia, free water restriction is used while the underlying edematous disorders (e.g. congestive heart failure, liver failure, nephrotic syndrome) are treated. In isovolemic hypotonic hyponatremia, the chronicity of the syndrome must be considered. In chronic, slowly developing cases of isovolemic hyponatremia, water restriction is used. Antagonism of ADH action in SIADH with demeclocycline may be useful if water restriction alone fails. In acute (less than 48 hours) rapidly developing isovolemic hyponatremia, 3% saline (containing 513 mEq/L of sodium) is used. This solution contains about 0.5 mEq sodium/mL, and because total body water is about 50% body weight, then infusions of 3% saline at 1 to 2 mL/kg raises the serum [Na] by 1 to 2 mEq/L. In an acutely hyponatremic patient, raising the [Na] by 4 to 6 meq/L may be of immediate value, but serum [Na] should not be raised to normal. The correction rate is then slowed to less than 10 mEq/L/24 hours. This is followed by free water restriction.

chapter 116 neurology of common electrolyte disorders Some patients with SIADH may become more hyponatremic with saline infusion as the water is retained and the salt excreted. This response can be predicted if the urinary [Na + K] level exceeds the serum [Na] level. In such a case, furosemide may be a useful adjunct for diluting the urine.

HYPOKALEMIA Hypokalemia is defined as a serum potassium level below 3.5 mEq/L. The serum potassium level may be low because of abnormal distribution between intracellular and extracellular potassium or because of excessive potassium losses (renal or extrarenal). Hypokalemia caused by excessive cellular potassium uptake may be caused by insulin, catecholamines (β2adrenergic agonists), hypokalemic periodic paralysis, alkalosis, and hypothermia. Extrarenal potassium loss (urine potassium level less than 20 mEq/day) may be caused by diarrhea (low serum bicarbonate), cathartic agents, sweating (normal serum bicarbonate), or starvation (anorexia). Renal potassium loss (urine potassium level more than 20 mEq/day) may be caused by hyperreninemia, hyperaldosteronism, renal tubular acidosis, diuretic use, and hypomagnesemia. Vomiting, by causing metabolic alkalosis, actually causes renal potassium losses. Severe hypokalemia (serum potassium less than 3 mEq/L) may be life-threatening because it can cause cardiac arrhythmia and severe muscle weakness or paralysis. The diagnosis of hypokalemia is made with a serum potassium measurement. Urinary potassium measurement may help determine whether the potassium loss is renal or extrarenal, but it should be borne in mind that such measurements are valid only in the presence of normal dietary and urinary sodium levels, inasmuch as sodium restriction may result in some masking of renal potassium wastage. The blood pressure and measured serum sodium, bicarbonate, plasma renin, plasma aldosterone, and urinary chloride levels may also help in the differential diagnosis of the cause of hypokalemia. The treatment of hypokalemia depends on the cause. Potassium balance problems should be corrected, if possible (e.g., by reducing dosages of β2-adrenergic agonists). Dietary sodium restriction (less than 80 mEq/day) reduces renal potassium losses. Oral potassium chloride is used to supplement high-potassium diets in resistant cases of hypokalemia (30 to 50 mEq/day). For severe (less than 3.0 mEq/L) hypokalemia, especially with cardiac arrhythmias and/or severe muscle weakness, intravenous potassium chloride may be administered with continuous cardiac monitoring. Potassium infusions in excess of 20 mEq/hour should also be restricted, to guard against possible hyperkalemic complications.

HYPERKALEMIA Hyperkalemia is defined as a serum potassium concentration of greater than 5.5 mEq/L, but this is rarely problematic unless it exceeds 6 mEq/L. Hyperkalemia may be present in circumstances that do or do not cause an excess of whole body potassium. The causes of hyperkalemia without an excess of potassium are muscle injury (e.g., trauma, persistent seizures, muscle infarction), β2-adrenergic antagonists (e.g., propranolol), insulin resistance, hyperchloremic metabolic acidosis, digitalis poisoning, depolarizing muscle relaxants (e.g., succinylcholine), and hyperkalemic periodic paralysis (muscle

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sodium channel mutation). Common causes of hyperkalemia caused by whole-body potassium excess include Addison’s disease, aldosterone deficiency (e.g., that caused by hyporeninemia, angiotensin-converting enzyme inhibitor therapy, nonsteroidal anti-inflammatory drugs, heparin), and aldosterone resistance (e.g., renal failure, renal tubular disorders, potassium-sparing diuretics). Pseudohyperkalemia may be seen in states of thrombocytosis, leukemic leukocytosis, or hemolysis in the test tube. A plasma [K] measurement may be helpful in ruling out these diagnoses. Also, poor venous access with a tourniquet that causes local tissue ischemia may artifactually raise the serum [K] level in blood drawn from the affected limb. The first sign of hyperkalemia is usually peaking of the T wave of the electrocardiogram, which usually occurs with a potassium level of about 6.0 mEq/L. As the potassium level rises, the QRS complex widens, which is followed by reduction in its amplitude and then disappearance of the T wave. Heart block and loss of P waves are noted. Sudden cardiac arrest may occur. Muscle weakness usually develops. Hyperkalemia may be suspected when the characteristic electrocardiographic pattern is seen, particularly in combination with weakness, sometimes with paresthesias. The diagnosis is confirmed with measurement of the serum potassium. If hyperkalemia is considered life-threatening because it is producing electrocardiographic changes and/or severe muscle weakness, the clinician should treat it by protecting the heart against life-threatening arrhythmias, promoting redistribution of potassium into cells, and enhancing potassium removal. For cardiac protection, calcium gluconate 10% solution should be administered, 20 mL as a rapid intravenous infusion. To promote redistribution of potassium into cells, glucose, 50 g/hour, should be administered intravenously with insulin, 5 U, by rapid intravenous infusion every 15 minutes and with albuterol, 10 to 20 mg, by inhaler. To enhance removal of potassium, sodium polystyrene sulfonate (Kayexalate) may be used: 15-60 g with sorbitol by mouth or 50 to 100 g by retention enema. Loop diuretics, such as furosemide, 40 to 240 mg intravenously over 30 minutes, are useful in the patient undergoing volume expansion. In severe or resistant cases of whole-body potassium excess and in renal failure, hemodialysis may be used.

K E Y

P O I N T S

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As can readily be seen from the determinants of osmolality, in most clinical settings, hyperosmolality is caused by hypernatremia, hyperglycemia, azotemia, or the iatrogenic addition of extrinsic osmoles (e.g., mannitol, glycerol).

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Hyperosmolality usually produces a generalized encephalopathy without localizing features, but an underlying focal lesion (e.g., stroke, multiple sclerosis, or neoplasm) could become symptomatic under the metabolic stress of a hyperosmolar state.

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The prognosis of hyponatremia depends on the rate and magnitude of the fall in serum sodium and its cause.

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Nervous system cells compensate for chronic hyponatremia by excreting solute to avoid water retention. If upon this

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substrate the serum sodium level rapidly rises, brain cells can rapidly shrink, causing osmotic demyelination. ●

Serum potassium may be low because of abnormal distribution between intracellular and extracellular potassium or because of excessive potassium losses (renal or extrarenal).

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For severe (less than 3.0 mEq/L) hypokalemia, especially with cardiac arrhythmias and/or severe muscle weakness, intravenous potassium chloride may be administered with continuous cardiac monitoring.

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If hyperkalemia is considered life-threatening because it is producing electrocardiographic changes and/or severe muscle weakness, the clinician should treat it by protecting the heart against life-threatening arrhythmias, promoting redistribution of potassium into cells, and enhancing potassium removal.

Suggested Reading Ayus JC, Krothapalli RK, Arieff AI: Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med 1987; 317:1190-1195. Burn DJ, Bates D: Neurology and the kidney. J Neurol Neurosurg Psychiatry 1998; 65:810-821.

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NEUROLOGY OF DRUG AND ALCOHOL ADDICTIONS ●

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John C. M. Brust

DEFINITIONS

Psychostimulants

Substance dependence is of two types. Psychic dependence consists of craving and drug-seeking behavior. Physical dependence consists of somatic withdrawal symptoms and signs. Depending on the drug, psychic and physical dependence can occur together or alone. Tolerance is the need for increasing doses of a drug to produce desired effects or to avoid withdrawal symptoms.

Psychostimulant drugs include dextroamphetamine, methamphetamine, methylphenidate, ephedrine, phenylpropanolamine, other anorectics and decongestants, and cocaine. 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) produces effects that appear to straddle those of amphetamine-like drugs and hallucinogens (see later discussion). Intended doses of amphetamine-like psychostimulants and cocaine produce alert euphoria with increased motor activity. Taken parenterally or smoked as alkaloidal cocaine (“crack”) or methamphetamine (“ice”), psychostimulants produce a “rush” psychically indistinguishable from heroin’s. Repeated use causes progressive movement disorders (stereotypy, bruxism, choreoathetosis, dystonia) and psychiatric symptoms (paranoia, hallucinatory psychosis). Overdose causes excitement, delirium, cardiac arrhythmia, hypertensive crisis, malignant hyperthermia, myoclonus, seizures, myoglobinuria, severe metabolic acidosis, shock, coma, and death. Treatment includes benzodiazepine sedation, oxygen, bicarbonate, anticonvulsants, cooling, blood pressure control (with an α-adrenergic blocker or a direct vasodilator), respiratory and blood pressure support, and cardiac monitoring. Psychostimulant withdrawal consists of depression, fatigue, and craving but few objective signs.

ILLICIT DRUG DEPENDENCE Intoxication and Withdrawal Opioids Opioid drugs include agonists (e.g., morphine, heroin, methadone, meperidine, fentanyl, hydromorphone, codeine, oxycodone), antagonists (e.g., naloxone, naltrexone), and partial agonists or mixed agonist/antagonists (e.g., buprenorphine, pentazocine, butorphanol). Intended doses of agonists produce drowsy euphoria, analgesia, miosis, cough suppression, and often nausea, vomiting, pruritus, sweating, postural hypotension, and constipation. Taken parenterally or smoked, heroin produces brief ecstatic “rush,” followed by euphoria and either relaxed “nodding” or hyperactivity. Overdose causes coma, respiratory depression, and pinpoint (but reactive) pupils. Adults with depressed respirations are treated with naloxone, 2 mg intravenously, repeated as needed up to 20 mg. Naloxone is short-acting, and so patients require admission and close observation. Opioid withdrawal symptoms include irritability, lacrimation, rhinorrhea, sweating, mydriasis, myalgia, piloerection, nausea, vomiting, abdominal cramps, and fever. In adults, seizures and delirium are not part of the syndrome, which is hardly ever life-threatening and can usually be prevented or treated with methadone, 20 mg twice/day. In contrast, opioid withdrawal in newborns is protracted, severe, and often fatal. Treatment is with titrated doses of methadone or paregoric.

Marijuana Marijuana, from the hemp plant Cannabis sativa, contains many cannabinoid compounds, of which Δ9-tetrahydrocannabinol (Δ9-THC) is the psychoactive agent. Hashish is made from the plant resin, which contains high concentrations of Δ9-THC. Usually smoked, but sometimes taken orally, marijuana produces relaxed euphoria, often with disinhibition, subjective perception of time slowing, tachycardia, and postural hypotension. High doses cause auditory or visual hallucinations and psychosis, but fatal overdose has not been documented. Withdrawal symptoms other than jitteriness are rare, but craving is common.

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Sedatives Sedative drugs include barbiturates, benzodiazepines, and miscellaneous agents such as glutethimide, ethchlorvynol, and zolpidem. γ-Hydroxybutyrate (GHB) and its precursors γbutyrolactone and 1,4-butaneidiol are “designer drugs” sold as street products. The intended effects of sedatives resemble ethanol intoxication. Overdose causes stupor or coma and respiratory depression. The mainstay of treatment is ventilatory support. With γ-hydroxybutyrate, overdose can also cause hallucinations, myoclonus, and seizures. Sedative withdrawal produces tremor and seizures and can be prevented with titrated doses of a benzodiazepine or a barbiturate. Delirium tremens requires intensive care.

Phencyclidine Phencyclidine (PCP, “angel dust”) is usually smoked. The related agents ketamine and dextromethorphan are more often used orally. Low doses of phencyclidine cause euphoria or dysphoria; increasing intoxication can lead to agitation, hallucinatory psychosis, rhabdomyolysis, tachycardia, hypertension, fever, myoclonus, seizures, coma, respiratory depression, and death. Supportive treatment includes benzodiazepine sedation, forced diuresis, cooling antihypertensives, anticonvulsants, and cardiorespiratory monitoring. Withdrawal signs—nervousness and tremor—are infrequent, but psychic dependence occurs.

pupils, and hallucinatory delirium, progressing to seizures, coma, and death. Treatment includes intravenous physostigmine, 0.5 to 3 mg as needed every 30 minutes to 2 hours, plus supportive care and, if necessary, anticonvulsants. Neuroleptic agents are contraindicated. There are no withdrawal symptoms.

Medical and Neurological Complications of Illicit Drug Use Infection Parenteral users of any drug are subject to an array of infections that often directly or indirectly affect the nervous system, including hepatitis, endocarditis, cellulitis, myositis, osteomyelitis, tetanus, and botulism. In the United States, nonhomosexual drug abusers currently account for 26% of reported cases of acquired immunodeficiency syndrome (AIDS), and male homosexual drug users account for another 6%. Neurological complications of AIDS are the same in parenteral drug users as in other susceptible groups, including patients with tuberculous meningitis and neurosyphilis.

Trauma Trauma may be a consequence of drug intoxication but is more often related to the illegal activities necessary to distribute and procure illegal substances.

Hallucinogens

Seizures

Dozens of hallucinogenic plants are used recreationally around the world. In the United States, the most popular hallucinogenic agents are mescaline (from the peyote cactus), psilocybin and psilocin (from several mushroom species), and the synthetic ergot lysergic acid diethylamide (LSD)/β. Acute effects are perceptual (distortions or hallucinations, usually visual and often elaborate), psychological (altered mood), and somatic (dizziness, tremor). Paranoia or panic can occur, and overdose can produce hypertension and seizures, but fatalities are usually the result of accidents. Treatment consists of a calm environment or a benzodiazepine. There are no withdrawal symptoms.

Seizures are a toxic effect of psychostimulants. With amphetamine-like agents, they usually occur in the setting of obvious overdose. With cocaine, they more often occur in the absence of other symptoms. Cocaine-induced status epilepticus can be very difficult to control. In sedative users, seizures are a withdrawal phenomenon. Opioids acutely lower seizure threshold, but seizures are so rarely a feature of heroin overdose that an alternative cause (e.g., concomitant cocaine use, ethanol withdrawal, meningitis, or head trauma) should be sought. Myoclonus and seizures occur in meperidine users as a result of its toxic metabolite normeperidine.

Inhalants Recreational inhalant use, popular among children and adolescents, involves a wide variety of commercially available products, including aerosols, glues, solvents, paints, and gasoline. Compounds include aliphatic, aromatic, and halogenated hydrocarbons, as well as nitrous oxide (from whipped cream dispensers) and butyl or amyl nitrite (from “room deodorizers”). The intended effect resembles those produced by ethanol; overdose can cause hallucinations, seizures, and death from cardiac arrhythmia or accidents. Treatment is supportive. The only predictable withdrawal symptom is craving.

Anticholinergics The plant Datura stramonium contains anticholinergic compounds, and oral recreational use is popular among American adolescents. Also occasionally abused for its anticholinergic properties is the tricyclic antidepressant amitriptyline. Intoxication produces decreased sweating, fever, dilated unreactive

Stroke Parenteral drug users are at risk for stroke through systemic complications such as hepatitis, endocarditis, and AIDS. Concomitant tobacco or ethanol abuse also increases stroke risk. In psychostimulant users, ischemic stroke can be cardioembolic as a result of myocardial infarction or arrhythmia. Amphetamine and methamphetamine users are prone to intracerebral hemorrhage in the setting of acute hypertension and high fever. They are also at risk for ischemic stroke secondary to cerebral vasculitis affecting either medium-sized arteries (resembling polyarteritis nodosa) or smaller arteries and veins (resembling hypersensitivity angiitis). In cocaine users, hemorrhagic stroke (including, frequently, rupture of an intracranial saccular aneurysm or a vascular malformation) is also usually secondary to acute surges of blood pressure. Ischemic stroke, however, is seldom secondary to vasculitis and is probably most often the result of acute cerebral vasospasm. Intracerebral and subarachnoid hemorrhage are described in

chapter 117 neurology of drug and alcohol addictions “ecstasy” users in the United States, and both over-the-counter products containing phenylpropanolamine and dietary supplements containing ephedra have been banned by the U.S. Food and Drug Administration because of their association with stroke. Heroin has infrequently been associated with ischemic stroke in young people without other risk factors. Phencyclidine and lysergic acid diethylamide are each vasoconstrictive, and both ischemic and hemorrhagic stroke are described in users.

Altered Mentation Dementia in illicit drug users has many potential causes, including concomitant ethanol abuse, malnutrition, infection (especially AIDS), and head trauma. Whether the drugs themselves cause lasting cognitive or behavioral change is more difficult to establish, for pre–drug use psychometric testing is seldom available, and many drug users are probably selfmedicating preexisting medical conditions. Methamphetamine damages both dopaminergic and serotonergic nerve terminals, with lasting brain neurotransmitter disruption; whether such injury is associated with clinically significant cognitive impairment is uncertain. “Ecstasy” destroys serotonin nerve endings, and impaired cognition is described in abstinent users. Cocaine is not directly neurotoxic, but cognitive impairment is described, perhaps the result of widespread cerebral ischemia. Sedatives reversibly impair cognitive function in elderly patients, and they are associated with delayed learning in small children. Persons who sniff products containing toluene develop a toxic leukoencephalopathy with dementia, and those who sniff gasoline have developed lead encephalopathy. Although the existence of a marijuana-induced “antimotivational syndrome” was overstated, more rigorous studies support the existence of lasting subtle cognitive impairment in heavy users. The weight of evidence is against chronic mental abnormalities secondary to the use of opioids or hallucinogenic drugs.

Fetal Effects The effects of illicit drugs on intrauterine development are similarly difficult to determine. Confounders include tobacco, ethanol, or other drug use; lack of prenatal care; malnutrition; and home environment. Studies of the in utero effects of cocaine have yielded conflicting results. Diffuse hypertonia is observed in cocaine-exposed neonates, with disappearance by 2 years of age. In animals, in utero cocaine exposure results in impaired learning; such effects in humans, if they occur at all, appear to be small. Marijuana exposure has been associated with decreased birth weight and impaired executive function. Heroin exposure is also associated with low birth weight and later cognitive impairment. Organic solvents appear to be teratogenic in animals and humans.

Other Neurological Complications Rhabdomyolysis and renal failure have followed use of heroin, amphetamine, cocaine, and phencyclidine. Guillain-Barré–type

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polyneuropathy and brachial or lumbosacral plexopathy (probably immunogenic) have affected heroin users. Severe sensorimotor polyneuropathy occurs in persons who sniff glue containing n-hexane. Myeloneuropathy indistinguishable from combined systems disease in cobalamin deficiency affects persons who sniff nitrous oxide; the cause is inactivation of the cobalamin-dependent enzyme methionine synthase. Acute myelopathy occurs in heroin users; it is unclear whether the mechanism is toxic, immunogenic, or vascular. Spongiform leukoencephalopathy with dementia, ataxia, quadriparesis, and blindness is sometimes fatal and affects heroin users who inhale the vapor of the drug as it is burned on metal foil (“chasing the dragon”); the responsible toxin has not been identified. Severe parkinsonism occurred in parenteral users of a synthetic meperidine analog contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a metabolite of which is toxic to dopaminergic neurons of the substantial nigra. A parenteral heroin user became blind after repeatedly using a preparation containing quinine.

ETHANOL Alcoholism Used in its broadest sense, the term alcoholism refers not only to psychic or physical dependence on ethanol but also the condition of persons who, even if they are abstinent most of the time, get into trouble when they drink. In the United States, 7% of all adults and 19% of adolescents fit this description, and ethanol-related deaths exceed 100,000 per year.

Ethanol Intoxication Ethanol is a cerebral depressant; hyperactivity associated with intoxication results from physiological disinhibition. Euphoria or dysphoria, reduced concentration, and impaired judgment are usually evident at blood ethanol concentrations (BECs) of 50 to 150 mg/dL. BECs of 150 to 250 mg/dL produce ataxia and drowsiness, and BECs above 400 mg/dL can cause coma and respiratory paralysis. Such correlations vary with a person’s tolerance, however. Ethanol’s metabolism produces a fall in BEC of 10 to 25 mg/dL per hour, and no practical pharmacological agent hastens the process. Acute ethanol poisoning causes more than 1000 deaths annually in the United States, and although it is important to consider such disorders as hypoglycemia, subdural hematoma, and meningitis in stuporous alcoholic patients, it is also important to remember that ethanol intoxication alone can be fatal. As with other sedative agents, management of severe ethanol overdose requires ventilatory support in an intensive care unit (Table 117–1). Hypovolemia, acid-base or electrolyte imbalance, and abnormal temperature also require attention. Obstreperous or violent patients should not receive sedatives (including neuroleptic agents), which can push them into stupor and respiratory depression. Analeptics are also contraindicated. Hemodialysis or peritoneal dialysis can be considered for BECs above 600 mg/dL; for severe acidosis; for severely intoxicated children; and for concurrent ingestion of methanol, ethylene glycol, or other dialyzable drugs. Ethanol is often taken with other drugs, legal and illicit.

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T A B L E 117–1.

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Treatment of Acute Ethanol Intoxication

For Obstreperous or Violent Patients Isolation, calming environment, reassurance; avoidance of sedatives Close observation For Stuporous or Comatose Patients If hypoventilation is present, artificial respiration in an intensive care unit If serum glucose is in doubt, intravenous 50% glucose with parenteral thiamine Careful monitoring of blood pressure; correction of hypovolemia or acid-base imbalance Consideration of hemodialysis if patient is severely acidotic, deeply comatose, or apneic Avoidance of emetics or gastric lavage Avoidance of analeptics Consideration of other possible causes of coma in an alcoholic patient

Ethanol Dependence and Withdrawal “Hangover,” characterized by headache, nausea, sweating, and nervousness, can occur in anyone after a brief period of heavy drinking. “Ethanol withdrawal,” in contrast, signifies physical dependence. Early symptoms—usually within a day or two of abstinence—include combinations of tremor, hallucinations, and seizures. Appearing later is the syndrome of delirium tremens. The most common ethanol withdrawal symptom is tremulousness, which often appears in the morning after at least several days of drinking and is usually promptly relieved by ethanol. If drinking cannot continue, tremor becomes more intense, with insomnia, agitation, facial and conjunctival flushing, sweating, nausea, and tachycardia. Mentation is usually intact. In some patients, tremor can persist for weeks or longer. Approximately 25% of ethanol-dependent patients develop perceptual disturbances, including nightmares, illusions, and hallucinations, which are most often visual and in which imagery consists of insects, animals, or people. Insight varies. Hallucinations tend to be fragmentary, lasting minutes at a time for several days. Auditory hallucinations with a threatening context sometimes last much longer but rarely evolve into a persistent hallucinatory state with paranoid delusions. Ethanol can precipitate seizures in any epileptic person. “Ethanol-related seizures” occur in alcoholic persons not otherwise epileptic. Traditionally considered a withdrawal phenomenon, these seizures sometimes occur during active drinking or after more than a week of abstinence, which is suggestive of more than one mechanism. The minimum duration of drinking necessary to cause seizures is unknown, but as little as 50 g of absolute ethanol daily increases risk. Seizures are usually generalized tonic-clonic and occur singly or in a brief cluster. Status epilepticus and focal features are infrequent. Ethanol-related seizures can accompany tremor or hallucinosis, or they can occur in otherwise asymptomatic subjects. Diagnosis depends on an accurate history and exclusion of other cerebral lesions. A patient with prior ethanol-related seizures might on a later emergency department visit have seizures caused by hypoglycemia, central nervous system infection, or cerebral trauma. Delirium tremens usually begins between 48 and 72 hours after the last drink, often in a patient who is hospitalized for

T A B L E 117–2. Treatment of Ethanol Withdrawal Prevention or Reduction of Early Symptoms Diazepam, 5-20 mg; chlordiazepoxide, 25-100 mg; or lorazepam, 1-4 mg, PO or IV, repeated hourly until sedation or mild intoxication; successive daily doses tapered, with resumption of higher dose if withdrawal symptoms recur Thiamine, 100 mg, and multivitamins, IM or IV Magnesium, potassium, and calcium replacement as needed Delirium Tremens Diazepam, 10 mg IV, or lorazepam, 2 mg IV or IM, repeated every 5 to 15 min until patient is calmed; maintenance dose every 1-4 h, PRN If refractory to benzodiazepines, phenobarbital 260 mg IV, repeated in 30 min, PRN If refractory to phenobarbital, pentobarbital, 3-5 mg/kg IV, with endotracheal intubation and repeated doses to produce general anesthesia Careful attention to fluid and electrolyte balance; several liters of saline per day, or even pressors, may be needed Cooling blanket or alcohol sponges for high fever Prevention or correction of hypoglycemia Thiamine and multivitamin replacement Consideration of coexisting illness (e.g., liver failure, pancreatitis, meningitis, subdural hematoma) IM, intramuscularly; IV, intravenously; PO, orally; PRN, as needed.

another reason. Symptoms may either follow withdrawal seizures or be the first manifestation of withdrawal. Seizures are not a feature of delirium tremens, which consists of tremor, delirium, hallucinations, and autonomic instability. Symptoms usually begin and end abruptly and last from hours to a few days. Patients are agitated and severely inattentive, with coarse tremor, fever, tachycardia, and profuse sweating. The mortality rate is as high as 15%; death is usually from other diseases such as pneumonia or cirrhosis but sometimes from unexplained shock or no apparent cause. Treatment of ethanol withdrawal begins with prevention or reduction of early symptoms (Table 117–2). Benzodiazepines, which have cross-tolerance with ethanol, should be given to recently abstinent alcoholic persons or those with mild early withdrawal symptoms. Neuroleptic agents, which are not crosstolerant with ethanol and which lower seizure threshold, should be avoided except in patients whose only symptoms are hallucinations or in whom hallucinations have outlasted other withdrawal symptoms. Ethanol should be avoided because it has a low margin of safety and is directly toxic to organs, including the brain. Phenytoin is of no value in preventing seizures during withdrawal. Parenteral lorazepam given to patients after an ethanol withdrawal seizure reduces the likelihood of seizure recurrence. Status epilepticus during ethanol withdrawal is treated as in other situations. Long-term anticonvulsants are usually not indicated in patients with ethanol withdrawal seizures; drinkers do not take them, and abstainers do not need them. Epileptic alcoholic patients whose seizures are triggered by ethanol do need anticonvulsant therapy, even though compliance is unlikely. Hypomagnesemia, common during early withdrawal, is treated with magnesium sulfate. Hypokalemia and hypocalcemia may also be present. Thiamine and multivitamins should be given parenterally.

chapter 117 neurology of drug and alcohol addictions Delirium tremens is a medical emergency necessitating intensive care (see Table 117–2). In contrast to other withdrawal syndromes, once delirium tremens is present, symptoms are not immediately reversible with any agent. Parenteral benzodiazepines are given in titrated (and sometimes huge) doses. Patients with liver disease are very sensitive to sedative drugs, and in some patients, as delirium tremens clears, hepatic encephalopathy takes its place. General management of delirium tremens includes attention to fluid and electrolyte balance, cardiorespiratory monitoring, and consideration of coexisting illnesses.

Nutritional Disorders Associated with Alcoholism Many alcoholic patients have deficiencies of thiamine and other vitamins, and a number of neurological disorders have been attributed to these deficiencies. It is increasingly evident, however, that direct ethanol toxicity also plays a role in these disorders. Vitamin deficiency is discussed further in Chapter 109.

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Untreated Wernicke-Korsakoff syndrome is fatal, and the mortality rate is 10% among treated patients, often the result of concomitant liver failure, sepsis, or delirium tremens. Treatment consists of parenteral thiamine and multivitamins, 50 to 100 mg/day. Fluid and electrolyte imbalance (including hypomagnesemia) require attention, and tachycardia and postural hypotension mandate strict bed rest. With thiamine treatment, ocular abnormalities begin to improve within a few hours and, with the exception of residual nystagmus, usually clear within a few days. Mental symptoms improve either completely or with residual chronic Korsakoff’s amnesia. Gait ataxia also improves, although often incompletely.

Alcoholic Cerebellar Degeneration Degeneration of the anterior cerebellar vermis is common in patients with acute Wernicke’s syndrome, but it more often occurs alone. Gait ataxia without limb ataxia or dysarthria is the typical presentation, evolving over weeks to months. Ataxia of this type is less likely to improve with nutritional supplementation than is the ataxia associated with Wernicke’s syndrome.

Wernicke-Korsakoff Syndrome Wernicke’s and Korsakoff’s syndromes share the same pathology, but they are clinically distinct. They are the result of thiamine deficiency, but direct ethanol neurotoxicity could be contributory. Full-blown Wernicke’s syndrome consists of the triad of abnormal mentation, eye movements, and gait. Korsakoff’s syndrome is a purely mental disorder differing qualitatively from Wernicke’s syndrome. The mental abnormalities of Wernicke’s syndrome usually evolve over days or weeks, with inattentiveness, indifference, lethargy, and impaired memory. Selective amnesia is unusual. Abnormal eye movements begin with nystagmus and abducens or horizontal gaze paresis and progress to complete external ophthalmoplegia. Ptosis is rare, and pupillary light reactivity is normal. Truncal ataxia may prevent standing, but dysarthria and limb ataxia are unusual. Of importance, however, is that mental symptoms, including progression to coma, can occur in the absence of abnormal eye movements or ataxia. Many affected patients also have peripheral neuropathy, and some have autonomic signs, including tachycardia, postural hypotension, and sudden circulatory collapse after exertion. Beriberi heart disease is rare, however. The diagnosis of Wernicke’s syndrome is usually based on history and examination. Decreased blood transketolase (a thiamine-requiring enzyme) is the most specific available laboratory test. In most patients, the more purely amnestic syndrome of Korsakoff emerges as the other mental symptoms of Wernicke’s syndrome respond to treatment. Amnesia is both anterograde and retrograde, and alertness, attentiveness, and behavior are relatively preserved. Confabulation is frequent, especially early in the course, and patients sometimes are lacking in insight to the point of anosognosia. Histopathological lesions of Wernicke-Korsakoff syndrome affect principally the medial thalamus and hypothalamus, the periaqueductal midbrain, and the pons and medulla beneath the fourth ventricle. There are neuronal and axonal loss, gliosis, prominent blood vessels, and sometimes petechial hemorrhages. The anterior cerebellar vermis can exhibit loss of Purkinje cells.

Alcoholic Polyneuropathy Alcoholic sensorimotor polyneuropathy begins with paresthesias in the feet and sometimes with burning or lancinating pain. Impaired vibratory sense is usually the earliest sign; proprioception is preserved until other sensory loss is substantial. Weakness also begins distally in the legs but may progress proximally and involve the arms. Peripheral autonomic abnormalities can include urinary and fecal incontinence, hypothermia, hypotension, cardiac arrhythmia, and altered sweat patterns. The cerebrospinal fluid is usually normal except for occasional mild protein elevation. Pathologically, both axons and myelin are degenerated. Both nutritional deficiency and ethanol toxicity appear to be causal in most patients. Clinical studies reveal that pure thiamine deficiency results in a rapidly progressive, largely motor neuropathy, whereas the neuropathy of non–thiamine-deficient alcoholic patients is largely sensory and slowly progressive. Peripheral nerve pressure palsies, especially involving the radial and peroneal nerves, are common in alcoholic patients.

Alcoholic Amblyopia Progressing over days or weeks, alcoholic amblyopia consists of central or centrocecal scotomas and temporal disc pallor. Pathologically, there is demyelination of the optic nerves, chiasm, and tracts, especially affecting the maculopapular bundle. Amblyopia does not progress to total blindness. Improvement follows nutritional supplementation even in subjects who continue to drink, but direct toxicity from ethanol (as well as from compounds in tobacco smoke) may play a contributory role.

Pellagra Alcoholics with nicotinic acid deficiency develop pellagra, with dermatological, gastrointestinal, and neurological symptoms that include amnesia, delusions, hallucinations, and delirium.

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Improvement follows treatment with nicotinic acid plus other vitamins, deficiency of which can contribute to symptoms.

secondary to subdural or intraparenchymal hematoma can be too readily attributed to drunkenness.

Nonnutritional Neurological Complications of Alcoholism

Stroke

Alcoholic Liver Disease Altered mention in an alcoholic patient should always raise the possibility of hepatic encephalopathy, which can accompany intoxication, withdrawal, Wernicke’s syndrome, meningitis, cerebral trauma, or other alcoholic states and which can be precipitated by sedative medications. Also encountered in alcoholic cirrhotic patients is a syndrome of altered mentation, myoclonus, and progressive myelopathy after portocaval shunting. In acquired chronic hepatocerebral degeneration, repeated bouts of hepatic coma result in a syndrome of dementia, ataxia, tremor, choreoathetosis, muscular rigidity, and asterixis.

Hypoglycemia Alcoholic persons often do not eat properly and have reduced glycogen stores, and the metabolism of ethanol to acetaldehyde and acetyl–coenzyme A depletes nicotinamide adenine dinucleotide levels. The resulting impairment of gluconeogenesis causes hypoglycemia with altered behavior, seizures, coma, or focal neurological deficit. Of note is that symptoms can occur during active drinking and so are mistaken for intoxication or ethanol-related seizures. Without prompt treatment with intravenous 50% dextrose, residual symptoms, including dementia, are common. Ethanol stimulates intestinal release of secretion, which aggravates reactive hypoglycemia by enhancing insulin release. Children are especially susceptible to this form of hypoglycemia.

As with coronary artery disease, numerous epidemiological studies have shown that low-to-moderate ethanol intake reduces the risk of ischemic stroke, whereas heavy intake increases it. For hemorrhagic stroke, any ethanol intake increases risk in a dose-dependent manner. In the United States, the protective effect holds for men and women and for blacks, whites, and Hispanics, and it is conferred by wine, beer, and spirits. Some studies describe a special benefit of red wine, perhaps related to antioxidant properties of its flavanoid content. In asymptomatic subjects, moderate ethanol consumption reduces the risk of both carotid atherosclerosis and leukoaraiosis. Ethanol has numerous effects that could influence stroke risk. Acutely and chronically, ethanol raises blood pressure. It lowers blood levels of low-density lipoproteins, raises levels of high-density lipoproteins, decreases fibrinolysis, and has both positive and negative effects on C-reactive protein, platelet reactivity, and cerebral vasoconstriction. Alcoholic cardiomyopathy predisposes to cardioembolic stroke.

Alcoholic Myopathy Alcoholic myopathy consists of a spectrum. At its mildest, the serum creatine kinase is elevated, but there are no symptoms. At its most severe, there are acute rhabdomyolysis and myoglobinuria. In the middle of the spectrum is rapidly progressive proximal weakness resembling polymyositis. The cause is ethanol toxicity, not nutritional deficiency, and symptoms sometimes emerge during a binge. Alcoholic cardiomyopathy often coexists. Symptoms improve with abstinence.

Alcoholic Ketoacidosis

Marchiafava-Bignami Disease

Starvation, increased lipolysis, and impaired fatty acid oxidation during heavy drinking result in the accumulation of β-hydroxybutyric acid and lactic acid and in alcoholic ketoacidosis. The patient has often interrupted a binge when overcome by anorexia and then develops vomiting, dehydration, confusion, obtundation, and hyperventilation. The blood glucose level can be low, normal, or moderately elevated. Serum insulin levels are low. When β-hydroxybutyrate is the major ketone present, the nitroprusside test result can be negative. Treatment includes infusion of glucose (and thiamine), correction of dehydration, and attention to electrolyte abnormalities. Small amounts of bicarbonate can be given, but insulin is seldom needed.

Nearly always occurring in alcoholic patients, MarchiafavaBignami disease produces symptoms greatly exceeding what would be predicted by the pathology: namely, demyelination within the middle zone of the corpus callosum. The earliest symptoms are usually mental, including psychosis and dementia, followed by seizures, fluctuating hemiparesis, aphasia, dyskinesias, and ataxia, with progression to coma and death over months. The lesions can be seen with magnetic resonance imaging, which sometimes reveals spontaneous remission. The cause is unknown.

Infection Alcoholic persons are immunosuppressed, and central nervous system infection should always be suspected in drinkers with altered mentation.

Trauma Alcoholic persons are trauma prone, and coexisting coagulopathy increases the risk of intracranial or spinal hemorrhage. As with other alcoholic complications, abnormal mental status

Alcoholic Dementia A long-standing controversy is whether ethanol as a direct neurotoxin can cause progressive cognitive decline in the absence nutritional deficiency, cerebral trauma, or other indirect mechanisms. Properly controlled studies reveal dose-related neuropathological changes and impaired learning in animals receiving ethanol, and a variety of neuropathological abnormalities are described in the brains of cognitively impaired heavy drinkers without evident nutritional deficiency. It is possible that ethanol neurotoxicity and thiamine deficiency are synergistic in their effects on cognitive function. On the other hand, several attempts to identify a safe dose threshold for alcoholic dementia, similar to ethanol’s effects on

chapter 117 neurology of drug and alcohol addictions T A B L E 117–3. Major Clinical Features of Fetal Alcohol Syndrome Central nervous system

Impaired growth Abnormal facies Eyes Nose Mouth Maxilla

Mental retardation Microcephaly Hypotonia Poor coordination Hyperactivity Prenatal for length and weight Postnatal for length and weight Diminished adipose tissue Short palpebral fissures Short, upturned Hypoplastic philtrum Thin vermilion lip borders Retrognathia in infancy Micrognathia or prognathia in adolescence Hypoplastic

ischemic stroke, found that low-to-moderate amounts reduce the risk of both vascular dementia and Alzheimer’s dementia, whereas higher levels of intake increase the risk. Protection is conferred by spirits, beer, and wine. The protective mechanism is unknown but might be related to the antioxidant properties of alcoholic beverages, especially red wine.

treatment modality, pharmacological or otherwise, is appropriate for all. Only three drugs are approved by the U.S. Food and Drug Administration for treating chronic alcoholism. Disulfiram, which inhibits the metabolism of acetaldehyde, leading to its accumulation, causes severe and potentially dangerous symptoms when ethanol is consumed, including flushing, throbbing headache, dyspnea, nausea, vomiting, chest pain, hypotension, and cardiac arrhythmia. Disulfiram, taken in the morning when the urge to drink is least, helps only patients who strongly wish to abstain. Side effects unrelated to ethanol ingestion include drowsiness, psychiatric symptoms, and peripheral neuropathy. The μ-opioid receptor antagonist naltrexone reduces ethanol consumption in animals and humans. Efficacy may depend on a single nucleotide polymorphism within the μopioid receptor gene. Acamprosate, approved by the U.S. Food and Drug Administration in 2004, blocks glutamate N-methyl-D-aspartate receptors, an action shared by ethanol itself.

K E Y

Treatment of Chronic Alcoholism The treatment of alcoholism is by and large unsatisfactory, and the heterogeneity of the alcoholic population predicts that no

P O I N T S

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Different classes of recreational drugs produce very different symptoms and signs during overdose and withdrawal.

●

Depending on the agent, seizures in a drug abuser may be the result of intoxication, of withdrawal, or of a medical complication such as central nervous system infection or stroke.

●

Lasting cognitive impairment is a well-documented consequence of alcoholism, and both nutritional deficiency and direct neurotoxicity probably contribute.

●

The degree to which other agents of abuse cause lasting cognitive impairment is controversial and plagued by confounding factors.

●

Similarly, in utero exposure to ethanol clearly has detrimental lasting cognitive effects, but the teratogenicity of other illicit drugs is difficult to quantitate.

●

In addition to impaired cognition, neurological complications of alcoholism include optic atrophy, cerebellar degeneration, polyneuropathy, and Marchiafava-Bignami disease.

●

Mild to moderate doses of ethanol appear to decrease the risk of ischemic stroke, whereas high doses increase the risk.

Fetal Alcohol Syndrome In utero exposure to ethanol causes congenital malformations and delayed psychomotor development. The fetal alcohol syndrome consists of cerebral dysfunction, growth deficiency, and distinctive faces; less often there are abnormalities of the skeleton, heart, urogenital organs, skin, and muscles (Table 117–3). Some children of alcoholic mothers have borderline or retarded intellect without other features of fetal alcohol syndrome (“fetal alcohol effects”), and each anomaly of fetal alcohol syndrome can occur alone or in combination with others. Neuropathological changes include abnormalities of the corpus callosum, hydrocephalus, cerebellar dysplasia, abnormal neuronal migration, heterotopic cell clusters, and microcephaly. They occur independently of maternal malnutrition, tobacco or other drug use, and age, and they are reproducible in animals. Binge drinking, which abruptly exposes tissues to large amounts of ethanol, may be more dangerous than chronic exposure. Early gestation, at a time when a woman may be unaware she is pregnant, appears to be the period in which the fetus is most vulnerable. In humans, the risk of ethanol-induced birth defects has been established with more than 3 oz of absolute ethanol daily, but below that a threshold of safety has not been established. It is estimated that in the United States, the combined incidence of fetal alcohol syndrome and fetal alcohol effects is nearly 1% of all live births and that fetal alcohol effects may affect 1% of infants born to women who drink 1 oz of ethanol daily early in pregnancy.

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Suggested Reading Brust JCM: Ethanol. In Spencer PS, Schaumburg HH, eds: Experimental and Clinical Neurotoxicology, 2nd ed. Baltimore: Williams & Wilkins, 1999, pp 541-557. Brust JCM: Neurological Aspects of Substance Abuse, 2nd ed. Boston: Butterworth-Heinemann, 2004. Cami J, Farré M: Drug addiction. N Engl J Med 2003; 349: 975-986. Graham AW, Schultz TK, Mayo-Smith MF, et al, eds: Principles of Addiction Medicine, 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine, 2003. Kosten TR, O’Connor PG: Management of drug and alcohol withdrawal. N Engl J Med 2003; 348: 1786-1795.

CHAPTER

NEUROLOGY

OF ●

●

118

ENDOCRINOLOGY ●

●

Rexford S. Ahima and Malaka B. Jackson

CLASSIFICATION OF HORMONES Multicellular organisms have developed complex mechanisms to ensure regulation of metabolism. Although the nervous system and endocrine system were classically considered to play crucial and largely independent roles in this process, studies over several decades demonstrated that these systems converge to maintain homeostasis and various physiological functions. In its simplest form, the endocrine system may be viewed as consisting of an endocrine gland: that is, a collection of specialized cells that synthesize and secrete a hormone and a target tissue that responds to this hormone. Hormones are chemical substances, produced by endocrine organs or cells dispersed in major organ systems, that act at distant tissues through the blood to exert their biological actions. Hormones are often classified according to structure or function. Peptide or protein hormones, such as gut and anterior pituitary hormones, are typically synthesized as larger precursor proteins (preprohormones) on ribosomes attached to the rough endoplasmic reticulum. The signal (“pre-”) peptide is cleaved by a peptidase on the inner membrane of the rough endoplasmic reticulum, resulting in a prohormone that is released into the rough endoplasmic reticulum lumen and transported to the Golgi apparatus. Here, the prohormone undergoes further cleavage and, in some instances, formation of disulfide bonds and other modifications such as glycosylation. The resulting hormone product is typically stored in secretory vesicles and released through exocytosis. The latter may occur constitutively in addition to being regulated by an endogenous chemical signal: for example, elevated glucose level in the case of insulin; a tropic hormone, such as adrenocorticotropic hormone (ACTH), in regulation of cortisol; or a neural stimulus, as is the case of vagal regulation of gastrointestinal hormones. Exocytosis is energetically dependent, requiring an influx of calcium and an intact cytoskeleton. Steroid hormones are derived from enzymatic processing of a cholesterol precursor (Fig. 118–1). Conversion of cholesterol to pregnenolone through side-chain cleavage is the first step in the steroidogenic pathway and occurs in all steroidogenic tissues (i.e., adrenal cortex, testes, ovaries, and placenta). Further metabolism is determined by specific enzymes that mediate hydroxylation, methylation, and demethylation. Corticosteroids and progestins contain 21 carbons; androgens, 19 carbons; and estrogens, 18 carbons and aromatic A-ring. Because 11- and 21-hydroxylases are expressed only in the

adrenal cortex, the production of glucocorticoids and mineralocortiocoids occurs only in this gland. Cortisol, the principal glucocorticoid, is synthesized mostly by zona fasciculata cells and hydroxylated at the 17-carbon position and exerts major effects on glucose and various metabolic processes. Aldosterone, the principal mineralocorticoid, is a 17-deoxycorticosteroid produced in the zona glomerulosa of the adrenal cortex. Progesterone is the main steroid secreted by the placenta and ovaries and also serves as a precursor for corticosteroids and other sex steroid hormones. Catecholamines, named for the catechol ring derived from tyrosine, are the best-known hormones derived from amino acids and secreted from chromaffin cells in the adrenal medulla. Epinephrine is the principal hormone secreted by the adrenal medulla, which occupies the innermost part of the adrenal gland. Although the predominant source of norepinephrine in the blood is the sympathetic nerve terminal, the adrenal medulla derived from the neuroectoderm receives preganglionic sympathetic innervation and has the ability to produce and secrete norepinephrine. Catecholamines can be synthesized from phenylalanine; however, the majority are generated from tyrosine. Oxidation of tyrosine to dihydroxyphenylalanine is catalyzed by tyrosine hydroxylase and represents the rate-limiting step in catecholamine synthesis. Dihydroxyphenylalanine is converted to dopamine by L-aromatic amino acid decarboxylase, followed by conversion to norepinephrine by dopamine-β-hydroxylase. Unlike tyrosine hydroxylase and L-aromatic amino acid decarboxylase, dopamine-βhydroxylase is located in the cytosol of the chromaffin cell. Phenylethanolamine-N-methyltransferase catalyzes the conversion of norepinephrine to epinephrine. These catecholamines are stored in different granules and carried by specific transporter proteins. The secretion of catecholamines occurs through exocytosis in response to stimulation by preganglionic cholinergic fibers innervating the adrenal medulla, as well as by nutrient or peptide signals. Interestingly, the chromaffin granules contain various peptides, such as neuropeptide Y and enkephalins, which modulate catecholamine secretion.

MECHANISMS OF HORMONE ACTION Hormones by definition are transported in the blood, although the methods for transporting peptides, steroids, and catecholamines vary, depending on solubility. Peptide and protein

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Cholesterol CH3 H3C

C

O

17-Hydroxypregnenolone

Dehydroepiandrosterone

17-Hydroxyprogesterone

Androstenedione

Estrone

Testosterone

17β-Estradiol

H3 C Pregnenolone

HO

Progesterone CH3 H3C

C

O

H3 C

O 11-Deoxycorticosterone

OH CH3

11-Deoxycortisol

OH CH3

CH3 Corticosterone

Cortisol H2COH

Aldosterone

HO H3 C

H2COH

O HO H3 C

C CH

H3C

C

O

HO

O

.... OH Estriol

O

O

O ■

Figure 118–1. Biosynthesis of steroid hormones.

hormones are hydrophilic and dissolve directly or associate with albumin in the plasma. Insulin circulates as monomeric and polymeric forms, whereas some anterior pituitary hormones circulate as dissociated subunits. Steroid and thyroid hormones, in contrast, are insoluble and bind to transport proteins (corticosteroid-binding globulin in the case of cortisol and thyroid-binding globulin and transthyretin in the case of thyroxine). The hormone bound to the carrier protein cannot interact with the receptor, but it serves as a reserve to replenish the free (bioactive) form. Nonetheless, the bound hormone exists in equilibrium with free hormone and receptor-bound fractions. The free hormone level increases as the rate of hormone degradation and clearance rises. On the other hand, conditions that increase the amount of carrier proteins, such as pregnancy and liver disease, elevate total hormone levels, although the balance between free and bound hormone is preserved. In view of the fact that hormone concentrations are very low, in the range of 10−15 to 10−9 M, and more than 100-fold lower than levels of similar sterols, amino acids, and polypeptides,

how do target cells identify hormones to initiate specific biological effects? In general, receptors for peptide, amine, and steroid hormones have a domain that recognizes and binds the hormone, with subsequent activation of a signaling mechanism that transduces the information into an intracellular action. Steroid and thyroid hormones and retinoic acid are lipophilic; associate with transport proteins in the blood, which prolongs their plasma half-life; and readily cross the plasma membrane in target tissues and bind to receptors in the nucleus or cytoplasm (Table 118–1; Fig. 118–2).1,2 The hormone-receptor complex undergoes activation, which leads to changes in chromatin, binding to specific regions of DNA, and transcription or inactivation of target genes. Studies since the 1980s have led to greater understanding of steroid-regulated genes, hormone response elements (i.e., short DNA segments that bind to specific steroid receptor-hormone complexes), and how these cis-acting DNA elements interact with transacting factors.3-5 Transacting factors include coactivator and corepressor molecules that modulate transcription.5 For example, in the absence of hormone, thyroid and retinoic acid receptors associate with

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T A B L E 118–1. Classification of Hormone Receptors Steroid Family

Seven-Transmembrane Domain

Single Transmembrane

Hormone Estrogen Thyroid hormone Mineralocorticoid Glucocorticoid Progesterone Vitamin Vitamin D Retinoic acid Others Oxysterol (liver X receptor) Bile acid Fatty acid (PPAR) Xenobiotic (Pregnane X receptor)

α2-adrenergic (inhibitory) β-adrenergic ACTH Calcium sensing FSH LH Melanocortin Parathyroid Somatostatin (inhibitory) TRH TSH Vasopressin

Guanylyl Cyclase Atrial natriuretic peptide Growth Factor Receptor Insulin Insulin-like growth factor Epidermal growth factor Cytokine Receptor Prolactin Growth hormone Leptin Interleukin-6 Erythropoietin Colony-stimulating factor

ACTH, adrenocorticotrophic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PPAR, peroxisome proliferator-activated receptor; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

■

H

signaling. Most steroid receptors under basal conditions exist in the cytoplasm as complexes with heat-shock proteins (HSPs). The steroid (H) crosses the plasma membrane into the cytoplasm and associates with the receptor (R)–HSP complex, resulting in dissociation of HSPs. This exposes a nuclear translocation signal, leading to transport of the hormone-receptor complex into the nucleus, where it binds to a hormone response element (HRE) in the DNA and associates with various transcription proteins to regulate gene expression. AAAA, mRNA, messenger RNA; TATA.

Plasma membrane

HSP

Protein

HSP R

HSP R

Cytoplasm H R

H R

H R

H

mRNA

Figure 118–2. Steroid receptor

AAAA

Transcription complex Pre-mRNA

R

Nucleus HRE

TATA

NcoR, SMRT and other proteins, which results in repression of target genes. Binding by thyroxine dissociates the complex culminating in gene activation. Members of the p160 family of coactivators (e.g., SRC-1, NCoA-1, GRIP 1, TIF2, and p/CIP) have been implicated in the function of corticosteroids and other steroids. Polypeptides, glycoprotein hormones, and catecholamines are water soluble, have no transport proteins, and possess a relatively short half-life. These hormones bind to surface receptors on the plasma membrane and generate second-messenger

molecules (Fig. 118–3). Epinephrine, as well as several neuropeptides and gut and pituitary hormones, including neuropeptide Y, cholecystokinin, vasopressin, glucagon, ACTH, thyroid-stimulating hormone (TSH), and luteinizing hormone, bind to their respective membrane receptors, stimulate adenylate cyclase located on the inner plasma membrane, and catalyze the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate.6 Activation or inactivation of adenylate cyclase occurs through the guanosine triphosphate–dependent regulator proteins (e.g. Gs [stimulatory] and

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Hormone binding domain Plasma membrane

Figure 118–3. Examples of membrane-associated hormone receptors. AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; IL-6, interleukin-6; NPY, neuropeptide Y; TRH, thyrotropin-releasing hormone.

NH2

Kinase COOH

Guanylyl cyclase

Seven-transmembrane domain receptor (e.g. adrenergic, TRH, CRH, AVP, NPY)

Guanylyl cyclase receptor (e.g. atrial natriuretic peptide)

B

A

Tyrosine kinase

Associated protein with tyrosine kinase activity Cytokine receptor (e.g. IL-6, growth hormone, leptin)

C

Growth factor receptor (e.g. insulin, epidermal growth factor)

D

Gi [inhibitory]).7 Changes in cAMP exert diverse effects on metabolism through various substrates, such as the transcription factor cAMP response element binding protein (CREB). CREB phosphorylation by cAMP leads to interaction with the coactivator CREB-binding protein, which results in stimulation of gene transcription.8 These effects can be terminated by hydrolysis of cAMP by phosphodiesterases or dephosphorylation by phosphoprotein phosphatases.9 Some polypeptide hormones produced by vascular tissues, such as atrial natriuretic factor, stimulate guanosine triphosphate by guanylate cyclase and increase cyclic guanosine monophosphate (cGMP), which leads to activation of cGMPdependent protein kinase, phosphorylation, and alteration in the of smooth muscle proteins.10 This effect is terminated by specific cGMP phosphodiesterase. Other hormones signal through phosphatidylinositides and calcium. The actions of ACTH in the adrenal cortex, luteinizing hormone in the ovaries and Leydig cells of the testes, and angiotensin II in vascular tissues have been associated with activation of phospholipase C, which mediates the hydrolysis of phosphatidylinositol-4,5biphosphate (PIP2) to 1,4,5-triphosphate (PIP3) and diacylglycerol. Binding of PIP3 to organelles increases intracellular Ca2+.9 Diacylglycerol activates protein kinase C, which phosphorylates various substrates involved in metabolism.

Cytokine receptors lack intrinsic tyrosine kinase activity but associate with proteins that are tyrosine kinases.11,12 For example, growth hormone, prolactin, inflammatory cytokines, and leptin bind to their receptors, which activate cytoplasmic protein tyrosine kinases, such as Jak1 and Jak2.11-13 These then phosphorylate other proteins, such as signal transducers and activators of transcription (STAT) proteins and docking proteins containing Src homology 2 (SH2) domains, culminating in transcriptional activation of neuropeptides and various target genes. In contrast, the insulin receptor possesses intrinsic tyrosine kinase activity in the cytoplasmic domain that is activated upon binding of insulin to the extracellular domain of the receptor. This autophosphorylation of insulin receptor leads to phosphorylation of insulin receptor substrates, activation of PI-3 kinase, and a cascade of biochemical events underlying insulin’s effects on glucose uptake, lipid and protein metabolism, and growth.14

REGULATION OF HORMONE LEVELS AND RHYTHMS Hormones generally regulate existing reactions instead of initiating de novo reactions. In contrast to the rapid time course

chapter 118 neurology of endocrinology of nervous activity, which lasts from milliseconds to seconds, the action of hormones is often prolonged and may persist for some time after the hormone is withdrawn. However, as discussed in detail later, the neurosecretory system allows the neural pathways in the hypothalamus, brainstem, and other regions of the central nervous system to interact with peripheral endocrine tissues, such as the thyroid, adrenal gland, and gonads. Hormone concentrations in the blood vary, depending on the rate of synthesis, secretion, and clearance. In the case of clearance, steroids undergo a series of reductions and conversion into water-soluble metabolites excreted by the liver or kidneys. Peptide hormones are often degraded by specific peptidases, whereas catecholamines undergo enzymatic conversion into inactive metabolites by deamination and 3-Omethylation or uptake by neurons and extraneuronal tissues. Epinephrine, norepinephrine, dopamine, and their metabolites are excreted by the kidneys. Hormone systems are subject to principles of homeostasis. A controlled variable, often the circulating hormone or related chemical signal, determines the rate of release of the hormone. The negative feedback loop, in which the hormone acts to inhibit its output, is fundamental to most endocrine systems and best exemplified by the interactions among the hypothalamus, trophic hormones from the pituitary gland, and hormones produced by peripheral endocrine glands. The positive feedback loop is less common and involves a stimulation of hormone by the controlled variable. For example, a rise in estrogen level boosts luteinizing hormone secretion, which leads to a further rise in estrogen level. Oscillation of hormone concentration is minimized to a “set point,” probably as a result of proportional coupling between hormone production and the function of the effector systems. In some cases, hormones produced by the same endocrine organ are regulated in opposite directions. For example, blood glucose rises after a meal, stimulates insulin secretion by pancreatic β cells, which then activates glucose uptake by muscle and fat and by lowering glucose and insulin levels. In contrast, glucagon is increased in response to falling glucose levels during fasting and stimulates glucose production via gluconeogenesis. Although these feedback mechanisms are often restricted to the interacting organs—that is, they are in closed loops—they are also subject to influences from the nervous and other systems, as open loops. As with virtually all functions of animals, the endocrine system is subject to cyclic changes. The most common endocrine rhythm has a period of approximately 24 hours (i.e., circadian), which follows an intrinsic program driven by a “biological clock,” the suprachiasmatic nucleus. In contrast, diurnal rhythms can be circadian or influenced by shifts in light and dark. Diurnal rhythm is an example of entrainment of a free running rhythm by an external cue, the zeitgeber. Meal patterns also entrain the rhythms of gut hormones. Cortisol levels peak in the morning between 2:00 and 4:00 A.M. and reach a nadir at night. In contrast, growth hormone and prolactin levels peak at night. TSH secretion is lowest between 9:00 A.M. and 12:00 noon and maximal at night. It is well known that the cortisol rhythm can be altered by light and dark, feeding, and stress. In addition to diurnal rhythms, hormones are secreted in bursts, known as an ultradian rhythm. For example, luteinizing hormone is secreted in rapid, high-amplitude pulses at night in adolescents; in adults, in contrast, luteinizing

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hormone pulses are lower and occur throughout the 24-hour period. Episodic hormone pulses have also been described for growth hormone, corticotropin, and prolactin, and loss of these rhythms has been linked to hypothalamic dysfunction. Infradian rhythms last longer than a day and best exemplified by the menstrual cycle.

NEUROENDOCRINOLOGY As mentioned earlier, the nervous and endocrine systems work in concert to regulate metabolism. The study of the interrelationship between these systems, which was first described in lower animals, was subsequently confirmed in mammals. This area of study, known as neuroendocrinology, focuses on how hormones affect neurotransmission and how the nervous system in turn regulates the endocrine system. The neurosecretory neuron plays a pivotal role in linking the hypothalamus and other regions of the brain to endocrine glands. Neurosecretory cells share similarities with neurons, such as a cell body, axons, dendrites, and a plasma membrane that exhibits tonic activity, conducts action potentials, and releases neurotransmitters at terminals. Despite being innervated, neurosecretory cells are distinguished from ordinary neurons in that they terminate on blood vessels rather than on other neurons. As a result, their secretions are released into blood, acting as hormones at distant target organs. The following sections focus on the organization and functions of neurosecretory cells in the hypothalamus.

Development and Structure of Hypothalamic-Pituitary Unit The hypothalamic-pituitary unit is derived from the ventral diencephalons.15 Between the third and fourth weeks of embryonic development, the sulcus limitans divides the alar (dorsal) and basal (ventral) plates of the neural tube. At about the fifth week, the hypothalamic sulcus divides the alar plate into a dorsal portion, which gives rise to the thalamus, and a ventral portion, which forms the hypothalamus, infundibulum, and posterior pituitary gland.16 The anterior pituitary gland begins as a diverticulum of the ectodermal lining in the roof of the buccal cavity (Rathke’s pouch) and expands dorsally to invest the infundibular stalk by the eighth week. In the adult, the hypothalamus lies in the ventral aspect of the brain directly above the pituitary gland, which lies within the sella turcica in the sphenoid bone. Although the hypothalamus occupies barely 2% of brain volume, it performs critical functions, ranging from regulation of hormones and autonomic function to regulation of complex behaviors such as feeding and control of metabolism. The hypothalamus extends from the lamina terminalis, anterior commissure, and optic chiasm rostrally to the mammillary body and cerebral peduncle caudally. It is bounded laterally by the thalamus, subthalamus, and internal capsule and dorsally by the hypothalamic sulcus separating it from the main mass of the thalamus. The third ventricle lies in the middle of the hypothalamus, lined by epithelial cells with tight junctions and interconnected with other ventricles and the subarachnoid space. The floor of the hypothalamus forms the tuber cinereum, connected by the median eminence and infundibulum with the posterior pituitary gland.

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T A B L E 118–2. Anterior and Posterior Pituitary Hormones Hormone

Source and Chemistry

Function

Disease State

ACTH

Corticotroph; 39–amino acid peptide derived from POMC

Excess: Cushing’s disease Deficiency: secondary adrenal insufficiency

FSH

Gonadotroph; 29-kDa glycoprotein consisting of α subunit shared with other glycoproteins and FSH-specific β subunit (115 amino acids) Gonadotroph; 29-kDa glycoprotein consisting of α subunit shared with other glycoproteins and LH-specific β subunit (115 amino acids) Somatotroph; 191–amino acid nonglycosylated protein

Stimulates cortisol in adrenal zona fasciculata and sex steroids in zona reticularis Stimulates aromatase, inhibits inhibin, and promotes ovarian folliculogenesis in women; stimulates spermatogenesis in men Stimulates steroid synthesis in the theca interna, lutein, and hilar cells; increases luteinization and formation of the corpus luteum Stimulates IGF-1 production, linear growth, and muscle and reduces fat

LH

GH

PRL TSH

AVP

Oxytocin

Lactotroph; 198–amino acid protein; pituitary PRL is mostly nonglycosylated Thyrotroph; 28-kDa glycoprotein comprising shared α subunit and TSH-specific β subunit (112 amino acids) Magnocellular neurons in PVN and SON; cyclic nonapeptide Magnocellular neurons in PVN and SON; cyclic nonapeptide

Stimulates milk production and inhibits gonadotropin secretion Stimulates synthesis and secretion of thyroid hormone Stimulates absorption of water in the renal distal tubule and collecting duct Stimulates contraction of uterine muscle Stimulates myoepithelial contraction in lactating breast, resulting in milk ejection

Deficiency may result from infarction (e.g., secondary to postpartum hemorrhage, inflammatory or infiltrative lesions of pituitary) Deficiency may result from infarction (e.g., secondary to postpartum hemorrhage, inflammatory or infiltrative lesions of pituitary) Excess causes gigantism in children and acromegaly in adults Deficiency causes dwarfism in children; in adults, deficiency is associated with fatigue, decreased muscle mass, and increased fat Excess disrupts gonadal function, reduces libido, and induces galactorrhea TSH-producing adenoma is rare and causes hyperthyroidism Deficiency is often associated with hypopituitarism and causes hypothyroidism Deficiency or receptor defect causes diabetes insipidus Excess, as in SIADH, causes water retention, hyponatremia, and hypo-osmolar plasma —

ACTH, adrenocorticotrophic hormone; AVP, arginine vasopressin; FSH, follicle-stimulating hormone; GH, growth hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; POMC, proopiomelanocortin; PRL, prolactin; PVN, paraventricular nucleus; SIADH, syndrome of inappropriate diuretic hormone; SON, supraoptic nucleus; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

The median eminence is located at the base of the hypothalamus.17 The arcuate (infundibular) nucleus overlies the median eminence. This structure, along with other circumventricular organs (i.e., organum vasculosum of the lamina terminalis, subfornical, choroid plexus, pineal gland, subfornical and area postrema) located in the walls of the lateral third, and fourth ventricles, have a rich capillary plexus with fenestrated capillaries, rendering adjacent regions outside the blood-brain barrier.18 These structures provide a window through which polypeptide and protein hormones in the blood can communicate with neurons in the hypothalamus and other brain areas. The hypothalamus is divided into nine zones containing various neuronal groups.16,19 In the longitudinal plane, the hypothalamus is divided into a midline zone adjacent to the third ventricle; a medial zone containing preoptic, anterior, ventromedial, dorsomedial, paraventricular, posterior, and mammillary neuronal groups; and a lateral zone separated from the medial zone by the fornix. Three hypothalamic zones are defined in the horizontal plane: supraoptic, tuberal, and mammillary, in a rostral-to-caudal direction. Histologically, the hypothalamus contains large (magnocellular) neurons that produce vasopressin and oxytocin in the lateral subdivision of the paraventricular nucleus (Fig. 118–4) and supraoptic nucleus. The axons of these neurons collect to form the posterior pituitary gland. Magnocellular neurons co-localize angiotensin II, corticotropin-releasing hormone (CRH),

enkephalins, and cholecystokinin. Parvicellular neurons are located in the periventricular and paraventricular hypothalamic areas, and synthesize peptides (e.g., thyrotropin-releasing hormone [TRH], CRH, and somatostatin) that are released into the portal system surrounding the infundibular stalk and regulate the secretion of hormones by anterior pituitary cells. These components are discussed in the next sections in regard to the synthesis and secretion of hormones, their physiological functions, and their roles in disease states. The anterior pituitary gland receives arterial blood from the internal carotid arteries via the hypophysial arteries.20 The superior hypophysial artery forms a capillary plexus in the median eminence that drains into long portal veins along the infundibular stalk. These portal veins divide into another capillary plexus and then re-form into venous channels that drain into the cavernous sinus. The infundibular stalk and posterior pituitary are supplied by branches of the middle and inferior hypophysial arteries, and the latter form a capillary plexus in the posterior pituitary gland, where axons from magnocellular neurons in the paraventricular nucleus and supraoptic nucleus terminate.20 Veins from the posterior lobe drain to the cavernous sinus and into the systemic circulation. The hypophysial portal system allows the hypothalamus to control anterior pituitary function and enable blood flow between the posterior and anterior lobes, as well as retrograde flow from the pituitary gland to hypothalamus.

chapter 118 neurology of endocrinology Paraventricular Hypothalamic Nucleus

Autonomic

Parvicellular (CRH, TRH, SS)

Magnocellular (AVP, OXY)

Median eminence Internal zone External zone

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traversing the infundibular stalk or terminals in the neurohypophysis. In contrast, nephrogenic diabetes insipidus results from genetic or acquired defects of AVP receptors. Compulsive water drinking and use of ethanol and drugs that interfere with V2 receptors in the collecting duct epithelium all produce polyuria. The distinction between central and nephrogenic diabetes insipidus is facilitated by administering AVP or a longer acting analog, desmopressin, which reverses central but not nephrogenic diabetes insipidus.21 Hypersecretion of AVP may occur in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), which is characterized by hypervolemia or euvolemia, hyponatremia, and reduced plasma osmolality. SIADH may be caused by central nervous system pathology such as brain tumors, abscesses and inflammation, drugs (including nicotine, phenothiazines, tricyclic antidepressants, and vincristine), pulmonary diseases (such as tuberculosis and bacterial or viral pneumonia), and acquired immunodeficiency syndrome. The primary treatment of SIADH is water restriction.21,22

Portal vein

Oxytocin ■

Figure 118–4. Subdivisions of the hypothalamic paraventricular nucleus. Hypophysiotropic parvicellular neurons regulate cells in the anterior pituitary via the portal venous plexus in the external zone of the median eminence. The axons from magnocellular neurons reach the posterior pituitary after traversing the internal zone of the median eminence. AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; OXY, oxytocin; SS, somatostatin; TRH, thyrotropin-releasing hormone.

Neurohypophysial Hormones

(Table 118–2)

Arginine Vasopressin Arginine vasopressin (AVP) also called antidiuretic hormone, and oxytocin are cyclic nonapeptides produced by distinct magnocellular neurons in the paraventricular nucleus and supraoptic nucleus and released in the capillary plexus surrounding the posterior pituitary gland.21 The preprohormones are converted to prohormones by cleavage of the signal peptide. Subsequent cleavage of the prohormones yields one molecule each of AVP (molecular weight, 1084) and oxytocin (molecular weight, 1007), and a large protein called neurophysin (molecular weight, 10,000). AVP causes contraction of vascular smooth muscle and stimulates water absorption by the kidneys. Although the pressor effect of AVP does not appear to be crucial under normal physiological conditions, the antidiuretic effect of AVP is crucial for maintaining water balance. AVP binds to V1 and V2 receptors, stimulates adenylate cyclase, and increases cAMP levels in target tissues, which culminate in its pressor and antidiuretic effects.21,22 AVP secretion is increased when plasma osmolality increases. The latter is monitored by osmoreceptors located in the anterior hypothalamus, which activate magnocellular neurons, increase plasma AVP, and reduce free water clearance by the kidneys. AVP deficiency causes the production of large volumes of very dilute urine (polyuria), resulting in polydipsia. This condition, known as diabetes insipidus, may result from central (hypothalamic) or peripheral (renal) causes.21,22 Central diabetes insipidus may be secondary to traumatic injury, granulomatous disease, or other infiltrative diseases that affect axons

Oxytocin facilitates milk ejection during lactation by stimulating contraction of myoepithelial cells in the breast. Moreover, oxytocin stimulates contraction of uterine smooth muscle during parturition. The latter effect is mimicked by infusing oxytocin (Pitocin) to induce labor. In nonmammalian species, oxytocin has also been implicated in feeding behavior, regulation of autonomic function, and stress responses.

Adenohypophysial Hormones

(Table 118–2)

Anterior pituitary cells were first described as acidophils, basophils, and chromophobes, on the basis of hematoxylineosin staining (Fig. 118–5). The development of electron microscopy and immunohistochemistry enabled anterior pituitary cells to be classified according to secretory products: somatotrophs (growth hormone), lactotrophs (prolactin), thyrotrophs (TSH), corticotrophs (ACTH), and gonadotrophs (luteinizing hormone and follicle-stimulating hormone).23 These cells derive from a common primordium, and their development is regulated by transcription factors. Thyrotrophs, lactotrophs, and somatotrophs derive from a common lineage, determined by Prop-1 and Pit-1, whereas corticotrophs and gonadotrophs develop from independent lineages.24

Growth Hormone Growth hormone–producing cells constitute about 50% of anterior pituitary cells and are typically located in the lateral portion of the gland.25 Growth hormone–releasing hormone is produced by neurons in the arcuate nucleus and stimulates the secretion of growth hormone. In contrast, somatostatin produced by neurons in the periventricular region inhibits growth hormone secretion. The primary function of growth hormone is to promote linear growth, mostly through stimulating the level of insulin-like growth factor 1, which increases amino acid uptake, transcription, and protein synthesis. Growth hormone prevents protein catabolism while enhancing lipolysis. Moreover, growth hormone decreases carbohydrate use and glucose uptake, which may result in glucose intolerance and diabetes.

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Figure 118–5. Illustration of sagittal section of the pituitary gland, displaying the anterior and posterior components. The pars intermedia is prominent in rodents but rudimentary in humans. Acidophils, basophils, and chromophobe cells in the anterior pituitary gland are shown in red, blue, and sky-blue, respectively.

Lamina terminalis

Mamillary body

Third ventricle

Optic chiasm Median eminence Upper infundibular stalk Pars tuberalis

Adenohypophysis (anterior lobe)

Lower infundibular stalk

Pars nervosa Pars distalis

Neurohypophysis

Pars Intermedia

Growth hormone is secreted episodically and has a short halflife (20 to 50 minutes); thus, insulin-like growth factor 1 measurement is a better assessment of growth hormone function. Early morning growth hormone level is typically less than 2 ng/ mL, and the hormone circulates mostly bound to protein. Congenital growth hormone deficiency may be familial or sporadic and leads to dwarfism.26 Functional growth hormone deficiency may occur in malnutrition and emotional deprivation, leading to growth retardation. In adults, the loss of growth hormone from mass lesions and infiltrative diseases of the sella or pituitary infarction (e.g., Sheehan’s syndrome) has been associated with fatigue, hypoglycemia, reduction in muscle, and increased adiposity.26 Hormone replacement with recombinant human growth hormone ameliorates these symptoms. Growth hormone–secreting adenomas are the second most common functional pituitary tumors (after prolactinomas).27 Excess growth hormone leads to gigantism in children and acromegaly in adults. Typical manifestations of acromegaly include enlargement of the hands and feet, gnathopathy in association with malocclusion of the teeth, soft tissue overgrowth involving the skin (papillomas and tags) and colonic mucosa, cardiomegaly, hypertension, hyperphydrosis, glucose intolerance, irregular menses, decreased libido, goiter with or without hypothyroidism, headache, and visual defect. The diagnosis is based on the history and physical examination findings, elevation of insulin-like growth factor 1 level, failure of growth hormone to be suppressed by an oral glucose load, and imaging of the sella with magnetic resonance imaging or computed tomographic scan. The standard treatment for acromegaly is transsphenoidal resection.27 In rare cases, a craniotomy and transtemporal approach may be needed for major suprasellar extension of the tumor. Residual tumor is treated medically

Posterior lobe

with octreotide and occasionally with bromocriptine, which is less effective. Gamma knife radiotherapy has been used to control tumor localized to the sella, and conventional irradiation has been used for recurrent extensive disease, although there is higher risk for hypopituitarism and cognitive deficits.

Prolactin Prolactin is synthesized and secreted by lactotrophs of the anterior pituitary and stimulates lactation in the postpartum period.28 Prolactin secretion is pulsatile and peaks between 4:00 and 7:00 A.M. Although TRH and serotonin increase prolactin level, it is unlikely that this serves a physiological role. Rather, prolactin is subject mostly to inhibition by dopamine produced by arcuate hypothalamic neurons. The most common hypersecreting pituitary tumor is a prolactin adenoma. The typical features include galactorrhea, gonadal dysfunction (oligorrhea or amenorrhea, infertility), decreased libido and impotence in men, and manifestations of estrogen deficiency, such as vaginal dryness and osteopenia, in women. The diagnosis of prolactinoma is based on history and physical examination findings, and a basal prolactin level greater than 200 ng/mL virtually establishes the diagnosis of a prolactin tumor. Magnetic resonance imaging frequently reveals a microadenoma (<1 cm in diameter). Bromocriptine, a dopamine agonist, is effective therapy for prolactin tumors but is frequently associated with dizziness, postural hypotension, nausea, and vomiting. Cabergoline is a nonergot dopamine agonist that can be administered once or twice weekly and has fewer side effects than does bromocriptine.27 Transsphenoidal surgery is rarely indicated for prolactinomas, because drug therapy is highly effective (80% to 90%). However, surgery by

chapter 118 neurology of endocrinology a skilled practitioner is a treatment option in the presence of microadenoma and drug intolerance.

Adrenocorticotropic Hormone ACTH is processed from a precursor molecule, proopiomelanocortin in the corticotroph, and stimulates the secretion of glucocorticoids and, to a lesser degree, mineralocorticoids and androgenic steroids from the adrenal cortex.25 The physiological secretion of ACTH is regulated by CRH in a pulsatile manner. ACTH levels peak before sleep ends and decreases as the day progresses. This diurnal rhythm precedes and is coupled to cortisol levels. In addition, both ACTH and cortisol levels are subject to stimulation by stress, depression, interleukin-1, and AVP. Negative feedback regulation of ACTH occurs through a long loop from cortisol, a short loop from ACTH itself at the pituitary gland, and an ultrashort loop from ACTH at CRH-producing neurons in the hypothalamus. ACTH deficiency manifests as adrenal insufficiency, often in the setting of hypopituitarism, although isolated ACTH deficiency may result from lymphocytic hypophysitis. Pituitary ACTH hypersecretion (Cushing’s disease) is the commonest cause of hypercortisolism (Cushing’s syndrome).29 Excess ACTH may be produced by hyperplastic or adenomatous corticotrophs. The onset of Cushing’s disease is often insidious, and the disease may progress over months to years. As with most endocrinopathies, this condition is more prevalent in women. Typically, patients develop central obesity, moon facies, malar plethora, proximal myopathy, hypertension, glucose intolerance, amenorrhea or impotence, violaceous striae, easy bruising, and neuropsychiatric symptoms. Poor wound healing and osteoporosis may also develop. Virilization in women points more to adrenal carcinoma. The diagnosis of Cushing’s syndrome involves a documentation of endogenous hypercortisolemia through 24-hour urine collection or through failure of suppression of cortisol by overnight dexamethasone treatment. Cushing’s disease must be distinguished from exogenous glucocorticoid treatment; pseudo-Cushing’s disease as seen in obesity, depression, and alcoholism; ectopic ACTH production (e.g., from lung tumors), and rare CRH-producing tumors in the hypothalamus, lungs, and gastrointestinal tract. In all cases, biochemical evaluation is crucial. Imaging of the pituitary gland and other organs and petrosal venous sampling are used to confirm and localize the lesion.29 Transsphenoidal resection is the treatment of choice for ACTH-secreting pituitary adenomas.27 In rare cases, adrenalectomy is performed to correct excess cortisol when the ACTH lesion cannot be located. Medical treatment with ketoconazole, metyrapone, and aminoglutethimide has been used as adjunctive therapy, and mitotane is used to reduce tumor bulk in adrenal carcinoma.

Thyrotropin TSH is a glycoprotein composed of α and β subunits. The structure of the α subunit is shared with follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin, but the β subunit is unique to TSH and responsible for its bioactivity. TRH stimulates TSH secretion, whereas somatostatin inhibits TSH secretion. TSH stimulates the synthesis and release of thyroid hormone. As with other trophic hormones, the production and secretion of TSH in the thy-

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rotrophs is influenced by negative feedback regulation by thyroid hormone and a short feedback loop by TSH in the pituitary gland. TSH deficiency often occurs in the setting of hypopituitarism and manifests with features of hypothyroidism, such as cold intolerance, fatigue, weight gain, menstrual irregularities, slow mentation, and delayed reflexes on physical examination. Isolated TSH tumors are rare and manifest as hyperthyroidism.

Adipose-Brain Axis The notion that adipose tissue is merely a specialized depot for storing energy in the form of fat is no longer valid.30 Indeed, it has been known since the 1970s that adipose tissue is a major site for metabolism of sex steroids. The discovery of leptin in 1994 confirmed the active role of adipose tissue as a source of hormones.31 In addition to leptin, adipose tissue secretes bioactive peptides, including adiponectin, angiotensin, proinflammatory cytokines, and proteins involved in coagulation, which act locally through autocrine/paracrine mechanisms and systemically to regulate energy balance, in addition to regulating neuroendocrine, cardiovascular, and immune functions.30 Leptin is secreted in proportion to fat mass. Thus, leptin concentration is higher in obese than lean individuals. Moreover, leptin responds to nutritional status: The level falls during fasting and increases over several hours after feeding. These changes are mediated, at least in part, by insulin and glucose. Congenital deficiency of either leptin or leptin receptors causes hyperphagia, morbid obesity, insulin resistance, immunodeficiency, and a variety of endocrine deficits, most notably hypothalamic hypogonadism, mild tertiary hypothyroidism, and growth hormone deficiency.32 These abnormalities are reversed by leptin treatment, which confirms a causal role. Interestingly, the loss of adipose tissue in lipodystrophic humans and rodents produces metabolic changes identical to those of leptin deficiency. Furthermore, the fall in leptin level during fasting triggers changes in the neuroendocrine axis and immune function similar to those of congenital leptin deficiency and lipodystrophy. In all cases, leptin replacement ameliorates the metabolic and hormonal abnormalities.30 Studies so far suggest that the primary site of leptin action is the hypothalamus.33 Leptin enters the brain via a saturable process and binds to receptors in the hypothalamus, brainstem, and other regions of the brain. Leptin target neurons in the arcuate nucleus express orexigenic peptides, such as neuropeptide Y and agouti-related peptide, and anorexigenic peptides, such as proopiomelanocortin (the precursor of αmelanocyte–stimulating hormone) and cocaine- and amphetamine-regulated transcript (CART) (Fig. 118–6). Leptin inhibits feeding by suppressing the levels of neuropeptide Y and agoutirelated peptide and by increasing proopiomelanocortin and CART. This net reduction in orexigenic peptides results in weight loss, caused by appetite suppression and increase in metabolic rate. Leptin also controls the synthesis and release of hypophysiotropic hormones, such as TRH and CRH, and may regulate gonadal function at the levels of the hypothalamus and gonadotrophs within the pituitary gland.33 The leptin receptor belongs to the family of class 1 cytokine receptors that includes interleukin-6, prolactin, and growth hormone (see Fig. 118–3).13 Binding of leptin to its receptor stimulates phosphorylation of tyrosine residues in the

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Neurology in General Medicine intracellular domain, leading to activation of Jak2, and phosphorylation and activation of STAT3 (Fig. 118–7). The latter is translocated to the nucleus, where it acts in concert with various transcription factors to regulate the expression of neuropeptides and other genes. The leptin signal is terminated through induction of suppressor of cytokine signaling 3 (SOCS3).34,35 As predicted, the loss of the leptin receptor in humans and rodents, or the targeted ablation of STAT3, recapitulates the obese phenotype of leptin deficiency. In contrast, haploinsufficiency of SOCS3 and, more specifically, ablation of SOCS3 in neurons, enhances leptin sensitivity, leading to inhibition of feeding, weight loss, and improvement in glucose and lipid levels.34,35 Studies have also demonstrated an interaction between the signal transduction of leptin and insulin.36 Both these hormones act through PI-3 kinase to regulate metabolism (see Fig. 118–7). Despite these advances, the role of leptin in polygenic and diet-induced obesity remains unclear, as the rise in endogenous leptin is unable to prevent weight gain in most cases of obesity. Potential mechanisms include an impairment of hypothalamic leptin transport or subtle disruptions in signaling mechanisms distal to the leptin receptor, leading to leptin resistance.37 The disruption in signaling mechanisms may involve changes in the levels and function of SOCS3 and various neurotransmitters.

Paraventricular nucleus +CRH +TRH MC4R +

− Arcuate nucleus

α-MSH/ CART

NPY/AGRP OB-Rb Leptin

−

Decreased feeding Increased thermogenesis Increased fatty acid oxidation Increased insulin sensitivity

+

Adipose tissue ■

Figure 118–6. Leptin targets in the hypothalamus. Leptin directly inhibits neuropeptide Y (NPY) and agouti-related peptide (AGRP) neurons in the arcuate nucleus and stimulates αmelanocyte–stimulating hormone (α-MSH) and cocaine- and amphetamine-regulated transcript (CART) neurons, leading to activation of second-order corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus. These neurons express melanocortin 4 receptor (MC4R) and mediate the effect of leptin to inhibit feeding, increase energy expenditure, and reduce glucose levels. OB-Rb, leptin receptor.

■

Insulin

Leptin

Plasma membrane

Y Y

Y Y

IRS Y

PIP2

PIP3

PDK1

Jak2

p110

IRS Y P13K

p110 p85

Y STAT3 Nucleus

Y STAT3

IRS Y

Jak2

AKT

PKC

Transcription complex

Y Y

Jak2 Y STAT3

Figure 118–7. Convergence of insulin and leptin signal transduction. Insulin binds to its receptor and phosphorylates key tyrosine (Y) residues in the cytoplasmic domain. Insulin receptor substrates (IRS) bind to these phosphorylated residues and become phosphorylated and activated, leading to activation of PI-3 kinase. PI-3 kinase triggers the conversion of phosphatidylinositol-4,5biphosphate (PIP2) to 1,4,5triphosphate (PIP3), and phosphorylation and activation of 3-phosphoinositide–dependent kinase 1 (PDK1) and (AKT). Leptin binds to the long receptor that belongs the class 1 cytokine receptor family. The receptor dimerizes and recruits an extrinsic kinase, Jak2, that phosphorylates the leptin receptor and enables STAT3 binding, STAT3 is phosphorylated, dimerizes and enters the nucleus, where it regulates gene expression. Studies have shown that leptin is capable of regulating PI-3 kinase, possibly through Jak2, raising the possibility of interaction between these signaling pathways. P110, P13K, PKC.

chapter 118 neurology of endocrinology CONCLUSION Clinicians’ understanding of the convergence of the endocrine and nervous systems has increased since the 1950s. The hypothalamus plays a central role in this process by serving as a sensor of neural and hormonal signals, integrating the information and acting as an effector system to regulate hormone levels, feeding, autonomic function, and the immune and cardiovascular systems. Knowledge in these areas has benefited immensely from genetic models in rodents and humans and from molecular biological, physiological, and pharmacological approaches. Further understanding of the homeostatic mechanisms that control feeding, body weight, and the neuroendocrine axis will provide new insights into the pathogenesis of various diseases and lead to development of rational and effective therapies.

K E Y

P O I N T S

●

The nervous and endocrine systems act in concert to regulate metabolism.

●

Neurosecretory cells in the hypothalamus release trophic hormones that control the anterior pituitary gland or act systemically.

●

Dysregulation of the neuroendocrine system causes multisystemic diseases.

Suggested Reading Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116:337-350. Niswender KD, Baskin DG, Schwartz MW: Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 2004; 15:362-369. Pierce KL, Premont RT, Lefkowitz RJ: Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002; 3:639-650. Smith CL, O’Malley BW: Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004; 25:45-71. Shimon I, Melmed S: Management of pituitary tumors. Ann Intern Med 1998; 129:472-483.

References 1. Bhargava A, Pearce D: Mechanisms of mineralocorticoid action: determinants of receptor specificity and actions of regulated gene products. Trends Endocrinol Metab 2004; 15:147153. 2. Zhang J, Lazar MA: The mechanism of action of thyroid hormones. Annu Rev Physiol 2000; 62:439-466. 3. Gruber CJ, Gruber DM, Gruber IM, et al: Anatomy of the estrogen response element. Trends Endocrinol Metab 2004; 15:7378. 4. Smith CL, O’Malley BW: Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004; 25:45-71. 5. Torchia J, Glass C, Rosenfeld MG: Co-activators and corepressors in the integration of transcriptional responses. Curr Opin Cell Biol 1998; 10:373-383.

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6. Pierce KL, Premont RT, Lefkowitz RJ: Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002; 3:639-650. 7. Gainetdinov RR, Premont RT, Bohn LM, et al: Desensitization of G protein–coupled receptors and neuronal functions. Annu Rev Neurosci 2004; 27:107-144. 8. Farfel Z, Bourne HR, Iiri T: The expanding spectrum of G protein diseases. N Engl J Med 1999; 340:1012-1020. 9. Meyer TE, Habener JF: Cyclic adenosine 3′,5′-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid–binding proteins. Endocr Rev 1993; 14:269-290. 10. Drewett JG, Garbers DL: The family of guanylyl cyclase receptors and their ligands. Endocr Rev 1994; 15:135-162. 11. Carter-Su C, Smit LS: Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. Recent Prog Horm Res 1998; 53:61-82. 12. Pazin MJ, Williams LT: Triggering signaling cascades by receptor tyrosine kinases. Trends Biochem Sci 1992; 17:374378. 13. Tartaglia LA: The leptin receptor. J Biol Chem 1997; 272:60936096. 14. Cheatham B, Kahn CR: Insulin action and the insulin signaling network. Endocr Rev 1995; 16:117-142. 15. Sheng HZ, Westphal H: Early steps in pituitary organogenesis. Trends Genet 1999; 15:236-240. 16. Markakis EA: Development of the neuroendocrine hypothalamus. Front Neuroendocrinol 2002; 23:257-291. 17. Knigge KM, Scott DE: Structure and function of the median eminence. Am J Anat 1970; 129:223-244. 18. Johnson AK, Gross PM: Sensory circumventricular organs and brain homeostatic pathways. FASEB J 1993; 7:678-686. 19. Swanson LW, Mogenson GJ: Neural mechanisms for functional coupling of autonomic, endocrine and somatomotor responses in adaptative behavior. Brain Res 1981; 228:1-34. 20. Leclercq T, Grisoli F: Arterial blood supply of the normal human pituitary gland. J Neurosurg 1983; 58:678-681. 21. Roberston GL: Diabetes insipidus. Endocrinol Metab Clin North Am 1995; 24:549-572. 22. Bourque CW, Oliet SHR, Richard D: Osmoreceptors, osmoreception and osmoregulation. Front Neuroendocrinol 1994; 15:231-274. 23. Nakane PK: Classifications of anterior pituitary cell types with immunoenzyme histochemistry. J Histochem Cytochem 1970; 18:9-20. 24. Cohen LE, Radovick S: Molecular basis of combined pituitary hormone deficiencies. Endocr Rev 2002; 23:431-442. 25. Fitzgerald KT: The structure and function of the pars tuberalis of the vertebrate adenohypophysis. Gen Comp Endocrinol 1979; 37:383-399. 26. Vance ML, Mauras N: Growth hormone therapy in adults and children. N Engl J Med 1999; 341:1206-1216. 27. Shimon I, Melmed S: Management of pituitary tumors. Ann Intern Med 1998; 129:472-483. 28. Ben-Jonathan N, Hnasko R: Dopamine as a prolactin (PRL) inhibitor [Review]. Endocr Rev 2001; 22:724-763. 29. Findling JW, Raff H: Screening and diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am 2005; 34:385402. 30. Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116:337-350. 31. Zhang Y, Proenca R, Maffei M, et al: Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425-432. 32. Ahima RS, Flier JS: Leptin. Annu Rev Physiol 2000; 62:413437. 33. Ahima RS, Saper CB, Flier JS, et al: Lepin regulation of neuroendocrine systems. Front Neuroendocrinol 2000; 21:263307.

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34. Howard JK, Cave BJ, Oksanen LJ, et al: Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 2004; 10:734738. 35. Mori H, Hanada R, Hanada T, et al: Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to dietinduced obesity. Nat Med 2004; 10:739-743.

36. Niswender KD, Baskin DG, Schwartz MW: Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 2004; 15:362369. 37. Munzberg H, Myers MG Jr: Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 2005; 8:566570.

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NEUROLOGY OF RHEUMATOLOGY, IMMUNOLOGY, AND TRANSPLANTATION ●

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Richard Rosenbaum

Evaluation of patients with rheumatic, inflammatory, or posttransplantation neurological syndromes is challenging because these patients can have a wide variety of disease-specific neurological pathological processes, adverse effects of medications, or, if they have been immunosuppressed, opportunistic infections. They often need a thorough evaluation that might include characterizing the activity of their systemic illness, imaging of brain or spinal cord, electrodiagnostic studies, and spinal fluid examination.

PRIMARY SJÖGREN’S SYNDROME Sjögren’s syndrome is an autoimmune disease that affects exocrine glands and has protean neurological effects.1 The sicca syndrome of dry eyes and dry mouth is its signature characteristic, but other systemic manifestations include arthralgias and myalgias, fatigue, and weight loss. Sjögren’s syndrome can affect the lungs, kidneys, and thyroid; can cause small- or medium-vessel vasculitis; and can have hematological manifestations, such as anemia, lymphoma, neutropenia, and monoclonal gammopathy. The diagnosis is supported by objective evidence of sicca syndrome, such as positive results of Schirmer’s test for tear production, findings from lip biopsy, and the presence of specific autoantibodies (anti-Ro [SSA] and anti-La [SSB]). Sjögren’s syndrome can be associated with other inflammatory diseases, such as rheumatoid arthritis, in which case it is termed secondary Sjögren’s syndrome. The neurological aspects discussed as follows are associated with primary Sjögren’s syndrome.

Central Nervous System Manifestations Mild deficits on psychometric testing are the most common cerebral abnormalities in patients with Sjögren’s syndrome. In rare cases, the neuropsychological impairment is severe enough to cause dementia. Deficits are sometimes correlated with specific areas of brain hypoperfusion, demonstrable with techniques such as single photon emission computed tomography (SPECT), even in patients who have normal magnetic resonance imaging (MRI) brain scans and no other manifestations of central nervous system (CNS) disease.2 A wide variety of focal brain lesions can occur in patients with Sjögren’s syndrome. The findings can appear gradually or

as suddenly as a stroke. Sjögren’s syndrome affects either gray or white matter, above or below the tentorium; thus, clinical manifestations are diverse and include hemiparesis or hemisensory loss, ataxia, eye movement abnormalities, and dysarthria. At times, CNS disease in Sjögren’s syndrome follows a relapsing-remitting multifocal pattern, mimicking the course of multiple sclerosis. Nonetheless, surveys in multiple sclerosis clinics suggest that the incidence of sicca syndrome among patients with multiple sclerosis approximates that in the general population. Clues that a relapsing-remitting CNS illness might be associated with Sjögren’s syndrome include older age at onset; associated peripheral neuropathy; lesions on spinal MRI that span multiple spinal segments; atypical brain MRI appearance for multiple sclerosis, such as gray matter lesions or absence of lesions in the corpus callosum; and lack of cerebrospinal fluid (CSF) oligoclonal bands. Sjögren’s syndrome is rarely associated with aseptic meningitis, which is sometimes recurrent. Pleocytosis, usually mild, can also be found in some patients with focal or multifocal CNS syndromes. CSF protein level is sometimes increased, and glucose level is usually normal. Oligoclonal bands are present in CSF in a minority of patients. Myelopathy caused by intramedullary spinal cord lesions is among the most common of CNS abnormalities in Sjögren’s syndrome. The clinical varieties include acute, subacute, or chronic transverse myelopathies; lateralized spinal cord inflammation leads to hemicord syndromes, such as hemiplegia; motor syndromes resembling motor neuron disease or primary lateral sclerosis; and predominantly posterior cord abnormalities. Spinal cord MRI is abnormal in approximately 75% of patients with clinical myelopathies, usually showing areas of hyperintensity on T2-weighted scans. On occasion, the cord appears swollen. In some cases, the lesions are enhanced with gadolinium. The MRI lesions usually extend over multiple spinal levels, in contrast to the localized appearance that is typical of the plaques of multiple sclerosis.

Peripheral Nervous System Manifestations Symmetrical length-dependent neuropathy is the most common peripheral nervous system finding in patients with Sjögren’s syndrome and can be the presenting clinical finding.

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Manifestations include small- or mixed-fiber sensory axonal neuropathy or sensorimotor neuropathies. Motor neuropathies resembling Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy are infrequent. Clinical peripheral nervous system disease probably occurs in 10% to 20% of patients with primary Sjögren’s syndrome; a higher incidence of peripheral nerve abnormalities is noted among patients with Sjögren’s syndrome who are carefully screened with quantitative sensory and electrodiagnostic testing. Conversely, if patients with idiopathic axonal neuropathies are screened for Sjögren’s syndrome, a few meet definite diagnostic criteria for Sjögren’s syndrome, and more have isolated features of Sjögren’s syndrome, such as symptoms of sicca syndrome or a positive findings on lip biopsy.3 Most patients with peripheral neuropathy and sicca syndrome do not eventually develop other extraglandular manifestations of Sjögren’s syndrome.4 Nerve biopsy findings in patients with peripheral neuropathy and Sjögren’s syndrome are generally no more specific than those in other axonal neuropathies. Nonspecific epineurial inflammatory cells are often present, but there is rarely definite evidence of vasculitis.4 Sensory neuronopathy, apparently caused by inflammation in the dorsal root ganglia, is an uncommon but distinctive manifestation of Sjögren’s syndrome. The sensory findings can manifest acutely or indolently, often in a proximal, asymmetrical pattern. Dysfunction of large-fiber functions can cause loss of joint position sense and of tendon reflexes, pseudoathetosis and ataxia, and low-amplitude or unobtainable sensory nerve action potentials. Pain and temperature fiber dysfunction can cause sensory loss and neuropathic pain. The sensory neuronopathy often is the presenting manifestation of Sjögren’s syndrome in these patients; however, investigation shows typical diagnostic findings such as sicca syndrome symptoms, abnormal results of tests of tear and saliva production, and positive lip biopsy findings. Nonetheless, patients with Sjögren’s sensory neuronopathy usually do not have systemic extraglandular disease. MRI of the spinal cord often reveals bright signal intensity on the posterior columns on T2-weighted images. Sjögren’s syndrome can cause branch trigeminal sensory neuropathies, unilaterally or bilaterally, with a predilection for the mandibular or maxillary divisions of the nerve. Pathology is probably inflammation of the gasserian ganglion, analogous to disease of the dorsal root ganglion in sensory neuronopathy, which sometimes accompanies the trigeminal neuropathy. Sjögren’s syndrome can also affect the olfactory, facial, and audiovestibular nerves. Severe autonomic neuropathy with manifestations such as orthostatic syncope and nocturnal diarrhea is an unusual accompaniment of Sjögren’s syndrome. The autonomic neuropathy can be the sole neurological abnormality or can cooccur with sensory neuronopathy or peripheral neuropathy. When patients with Sjögren’s syndrome are questioned closely, they often reveal milder symptoms of autonomic dysfunction, such as orthostatic lightheadedness. Furthermore, detailed autonomic testing, such as tilt-table testing or comparison of heart rates during inspiration and expiration, often reveals asymptomatic autonomic dysfunction. Mononeuritis multiplex is unusual in patients with Sjögren’s syndrome. When it does occur, systemic manifestations of Sjögren’s syndrome, such as cutaneous vasculitis or Raynaud’s phenomenon, are usually present. Many such patients have cryoglobulinemia. Nerve biopsy sometimes

demonstrates evidence of vasculitis or nonspecific lymphocytic proliferation. In rare cases, patients with Sjögren’s syndrome have prominent disease of α motor neurons, which differs from classic amyotrophic lateral sclerosis by the presence of other neurological changes such as CNS disease beyond the pyramidal tract. Many patients with Sjögren’s syndrome complain of mild weakness or myalgias but have no serious muscle pathology. They usually have normal creatine kinase levels and electromyograms. Infrequently, Sjögren’s syndrome coexists with polymyositis or dermatomyositis. A rare complication of Sjögren’s syndrome is reversible hypokalemic paralysis caused by distal renal tubular acidosis. Information on neurological responses to treatment is limited to uncontrolled observations in small series of patients. Steroids are rarely helpful in patients with axonal polyneuropathies.1 The neuronopathy is poorly responsive to steroids or immunosuppression.5,6 Myelopathy and other CNS syndromes are more likely to improve with steroid treatment. In patients with severe myelopathy or mononeuritis multiplex, cyclophosphamide in combination with steroid therapy sometimes yields apparent benefit.1 Case reports suggest improvement in myelopathy treated with steroids and azathioprine or chlorambucil or in sensory neuronopathy treated with intravenous immunoglobulin. Responses to plasmapheresis have been mixed.7 A least one patient experienced improvement after treatment with the anti–tumor necrosis factor antibody infliximab.8

PROGRESSIVE SYSTEMIC SCLEROSIS Progressive systemic sclerosis is an uncommon illness that causes excessive tissue fibrosis and vascular changes. It is often referred to as scleroderma, which more precisely is the skin thickening and fibrosis caused by the disease. Localized forms of scleroderma can occur without progressive systemic sclerosis and do not have the same prognostic or neurological implications. In progressive systemic sclerosis, the skin is affected in a number of other ways, including calcifications, telangiectasias, finger swelling, and sclerodactyly (tightening of the skin of the digits). Raynaud’s phenomenon occurs in as many as 90% of patients with progressive systemic sclerosis. Other systemic manifestations are gastrointestinal disease, especially impaired esophageal motility; pulmonary disease, such as fibrosis or pulmonary hypertension; renal or cardiac involvement, especially with hypertension; hypothyroidism; sicca syndrome; and arthralgias and tenosynovitis. Dysphagia is often present because of esophageal disease and is usually not an indication of bulbar neurological dysfunction. The syndrome of subcutaneous calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (CREST) may be present with less systemic involvement. More than half the patients with progressive systemic sclerosis have evidence of autoimmunity such as antinuclear antibodies or, less common but more specific, antibodies against centromeres, topoisomerase I, RNA polymerase III, or Scl-70. These provide some prognostic clues: anti–SCL-70 antibody is more often associated with fully developed progressive systemic sclerosis, whereas anticentromere antibodies are associated with CREST.

chapter 119 neurology of rheumatology, immunology, and transplantation Neurological complications are relatively limited in patients with progressive systemic sclerosis. These include headache, myopathy, trigeminal neuropathy, peripheral neuropathy, autonomic neuropathy, ectopic calcifications, and stroke. Patients with progressive systemic sclerosis may have nonspecific cerebral calcifications in the basal ganglia and dentate nuclei. These are best visualized by computed tomography and are present in about one third of patients with progressive systemic sclerosis in a consecutive series. In rare cases, focal cerebral gyral or spinal ligamentous calcifications occur. Cervical or even thoracic paraspinal calcifications are also unusual. These can adjoin the facet joints and extend into neuroforamina, at times compressing nerve roots. Patients with progressive systemic sclerosis are at increased risk of peripheral vascular disease, including extracranial carotid artery stenosis, in comparison with controls. This risk is independent of additional stroke risk if they are hypertensive. In a few instances, patients with progressive systemic sclerosis have developed a diffuse or multifocal encephalopathy associated with a diffuse cerebral vasculopathy, in which angiography demonstrates multifocal narrowing of medium-sized intracerebral arteries. Reports of cerebral aneurysms in patients with progressive systemic sclerosis are so few that it is unclear whether the concurrent conditions are coincidental or pathogenically linked. Trigeminal sensory neuropathy, clinically similar to trigeminal neuropathy that is found in Sjögren’s syndrome, occurs in approximately 4% of patients with progressive systemic sclerosis. There are isolated reports of acute myelitis in patients with progressive systemic sclerosis. Peripheral nerve abnormalities in patients with progressive systemic sclerosis are varied and uncommon and include carpal tunnel syndrome, distal axonal sensory neuropathy, transverse myelitis, and mononeuritis multiplex. For example, in a series of 125 patients, four had carpal tunnel syndrome. Symmetrical distal sensory neuropathy, lumbar or brachial plexopathies, and mononeuritis multiplex were even less frequent. An occasional patient has asymptomatic mildly abnormal nerve conduction. Some patients have focal abnormalities of cutaneous sensation. Some patients with progressive systemic sclerosis have autonomic nervous system deficits, such as decreased sudomotor sweating, evident on autonomic testing. Clinical autonomic neuropathy, with manifestations such as orthostatic hypotension or impotence, can also occur. Patients with progressive systemic sclerosis often have mild symmetrical weakness, especially proximally. Some have mild elevation of creatine kinase levels and mild electromyographic abnormalities, such as decreased motor unit duration. Less frequently, progressive systemic sclerosis and inflammatory myopathy can occur in the same patient.

RHEUMATOID ARTHRITIS Rheumatoid arthritis is a chronic (duration, >6 weeks), symmetrical, inflammatory polyarthritis with a predilection for metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. The prevalence is 1% to 2% in many population groups; women are more commonly affected. Joints develop synovial proliferation and erosion of cartilage and bone, which lead to chronic deformities. Modern diseasemodifying antirheumatic drugs can prevent or decrease the

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proliferative, erosive process. Rheumatoid arthritis can have nonarticular manifestations, including subcutaneous rheumatoid nodules; sicca syndrome; Felty’s syndrome of hypersplenism; amyloidosis; scleritis or episcleritis; lung or heart involvement; anemia of chronic disease; eosinophilia; thrombocytosis; and vasculitis. Rheumatoid arthritis can be accompanied by autoantibodies. For example, rheumatoid factor is present in about 80% of patients, but this finding is nonspecific. Important neurological issues in patients with rheumatoid arthritis are headache, spinal disease especially at the atlantoaxial joint, peripheral nerve disease, muscle weakness, and, in rare cases, rheumatoid vasculitis or pachymeningitis. The neurological complications of rheumatoid arthritis are indications of advanced or severe disease. Serological testing for rheumatoid factor is not useful for investigating neurological disease in patients who do not have clinical arthritis.

Headache Neck or head pain, particularly occipital headache, is common among patients with rheumatoid arthritis. For some, this is independent of specific cervical spine pathology, but for others, pain is correlated with lateral subluxation of the atlantoaxial joint. In patients with severe intractable neck or occipital pain and demonstrable atlantoaxial joint lateral subluxation, surgical stabilization of the joint can decrease the pain.

Brown’s Syndrome Tendonitis of the superior oblique tendon (Brown’s syndrome) can cause eye pain, intraorbital clicking with eye movement, and decreased eye elevation, especially when the eye is abducted. It is important to distinguish this rare complication of rheumatoid arthritis from neurological causes of impaired eye movement.

Atlantoaxial Disease Rheumatoid arthritis can affect the cervical spine, where ligamentous inflammatory changes lead, in particular, to atlantoaxial joint subluxation (Fig. 119–1). Subluxation is usually anterior but can also occur vertically, laterally, or posteriorly. Anterior atlantoaxial subluxation was found in fewer than 3% of patients who had had rheumatoid arthritis for less than 5 years, 15% of those who had had the disease for 10 to 15 years, and 26% of those who had had the disease for more than 15 years.9 Once present, the subluxation may not increase; however, in a decade, at least 25% of those with subluxation have progression in subluxation, varying from 1 to 7 mm. Atlantoaxial subluxation is usually asymptomatic but can cause spinal cord compression. As compression worsens, signs of myelopathy, including sphincter disturbance, sensory deficits, extensor plantar responses, or weakness in legs or all extremities, can evolve. The risk of myelopathy increases as the atlantoaxial separation in flexion increases and as the diameter of the spinal canal at the C1 level decreases (Fig. 119–2). Soft tissue pannus, vascular compromise, and intermittent spinal cord compression during neck movement also influence the degree of myelopathy. The myelopathy usually evolves insidiously but can worsen suddenly. Arm and leg weakness is more

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Neurology in General Medicine common than weakness limited to the legs. Patients typically also have sensory findings, spasticity, sphincter dysfunction, and extensor plantar responses. Vertical atlantoaxial subluxation can damage the brainstem. In addition to the spastic quadriparesis, sensory changes, and sphincter disturbances noted with horizontal subluxation, brainstem compression can cause bulbar palsy, trigeminal or high cervical patterns of sensory loss, ophthalmopareses and nystagmus, drop attacks, hydrocephalus, and sleep apnea. A less common mechanism of brainstem injury is vertebrobasilar stroke caused by distortion of the vertebral arteries in the subluxed neck. Patients with atlantoaxial instability risk spinal cord compression during intubation or anesthesia. Patients with advanced rheumatoid arthritis should be assessed for atlantoaxial subluxation before surgery and have extra attention to neck protection during intubation and anesthesia. Soft or hard cervical collars can alleviate head or neck pain associated with atlantoaxial subluxation but do not stabilize the spine or prevent neurological complications. A halo with cervical traction can stabilize the neck and can be used for preoperative stabilization or, less frequently, for chronic treatment. The indications for surgery for atlantoaxial subluxation rely more on clinical signs of myelopathy or brainstem compression than on the measured extent of the subluxation. Spontaneous

Figure 119–1. Lateral radiograph of the cervical spine, revealing anterior atlantoaxial dislocation, defined as movement of the atlas more than 3 mm forward from the axis. The odontoid and pedicle of C2 and elements of the ring of C1 are outlined. (From Rosenbaum RB, Campbell SM, Rosenbaum JT: Clinical Neurology of Rheumatic Diseases. Boston: Butterworth-Heinemann, 1996, Figure 8.3B.)

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hyperreflexia in patients with rheumatoid atlantoaxial (A-A) joint separation is related to the distance of atlantoaxial separation (A) and to the sagittal diameter of the spinal canal at C1 (B). (From Rosenbaum RB, Campbell SM, Rosenbaum JT: Clinical Neurology of Rheumatic Diseases. Boston: ButterworthHeinemann, 1996, Figure 8.5.)

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chapter 119 neurology of rheumatology, immunology, and transplantation odontoid fracture is another indication for surgery. Among patients undergoing surgery, most do not regain lost neurological functions, but the subluxed segment is stabilized and progressive neurological deterioration is avoided. Patients with rheumatoid arthritis, like all adults, are likely to develop degenerative cervical spondylosis below C1-C2 as they age. In addition, rheumatoid pannus can develop in the cervical epidural space and contribute to spinal stenosis. The pannus is usually enhanced on MRI scans.

Peripheral Neuropathy Patients with chronic rheumatoid arthritis can develop a length-dependent symmetrical sensory neuropathy. Other peripheral nerve problems are autonomic neuropathy; nerve entrapments, exemplified by carpal tunnel syndrome; and mononeuritis multiplex. The sensory neuropathy is usually mild, starting in the feet. In a population-based survey, it was noted in only about 2% of patients with rheumatoid arthritis. However, the incidence is higher in patients with more severe disease. No specific treatment is necessary. Nerve biopsy, if performed, sometimes reveals changes in epineurial blood vessels; nonetheless, this distal symmetrical neuropathy is not a harbinger of rheumatoid vasculitis or mononeuritis multiplex. The peripheral neuropathy can include autonomic fibers, so that patients have impaired sweating in the regions of sensory loss. Some patients have other autonomic changes such as abnormal postural and cardiovascular reflexes, even in the absence of sensory neuropathy. Carpal tunnel syndrome is the most common neurological manifestation of rheumatoid arthritis, occurring in 25% or more of patients, especially in those with hand flexor tenosynovitis. Successful anti-inflammatory treatment of the tenosynovitis can decrease the symptoms of carpal tunnel syndrome. When anti-inflammatory treatment does not succeed, patients usually respond well to carpal tunnel surgery, sometimes accompanied by tenosynovectomy. Other, less common nerve entrapments in patients with rheumatoid arthritis include ulnar nerve compression at the ulnar groove, radial or posterior interosseus nerve compression, compression of the peroneal or posterior tibial nerves by a Baker’s cyst in the popliteal region, tarsal tunnel syndrome, or digital neuropathies. Multiple compression neuropathies should be distinguished from mononeuritis multiplex caused by vasculitic nerve infarcts. Nerve infarcts typically cause sudden, sometimes painful, mononeuropathies, often affecting the nerve proximally rather than at classic sites of compression. However, mononeuritis multiplex can also manifest more insidiously or more symmetrically. Development of rheumatoid vasculitis often heralds more aggressive inflammatory disease and is an indication for more aggressive therapy; therefore, patients with rheumatoid arthritis whose neuropathies exceed typical distal sensory neuropathy or carpal tunnel syndrome should undergo thorough evaluation.

Pachymeningitis Pachymeningitis is a rare, late complication of rheumatoid arthritis. Patients can have a variety of symptoms caused by focal meningeal thickening or meningeal rheumatoid nodules.

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Symptoms include headache, seizures, and cranial neuropathies, such as optic or auditory neuropathies. MRI can demonstrate focal or multifocal meningeal thickening, which is often enhanced with gadolinium. CSF study can demonstrate high protein levels, low glucose levels, and mild pleocytosis; less frequently, CSF study reveals hundreds of white blood cells per centimeter, which is suggestive of leptomeningeal inflammation. Case reports describe mixed responses to high-dose corticosteroids or more aggressive immunosuppressive measures. Similar pachymeningitis can occur in Wegener’s granulomatosis, Sjögren’s syndrome, sarcoidosis, vasculitis, granulomatous infections, and malignancies.

INFLAMMATORY SPONDYLOARTHROPATHIES Ankylosing spondylitis is the prototypical inflammatory spondyloarthropathy. In addition, reactive arthritis, psoriatic arthritis, and arthritis associated with inflammatory bowel disease can cause inflammatory spinal arthritis. Men are more frequently affected. Together, these spondyloarthropathies are as prevalent as rheumatoid arthritis. They cause inflammation of the sacroiliac joints, facet joints, and spinal ligaments, which results in the clinical syndrome of “inflammatory low back pain,” a pain that develops insidiously, persists for months, waxes and wanes, worsens at night or at rest, causes morning stiffness, and tends to improve with activity. As the disease progresses, patients may lose spinal range-of-motion and eventually develop spinal deformities or fusions. Systemic manifestations can include peripheral inflammatory arthritis; Achilles tendinitis; mucocutaneous lesions, such as psoriasis or urethritis; uveitis; gastrointestinal inflammation; and cardiac disease, especially aortitis or aortic insufficiency. Pelvic radiographs often reveal evidence of sacroiliitis. Approximately 90% of patients with ankylosing spondylitis possess the allele for human leukocyte antigen (HLA) B-27, but because this allele is less prevalent in the other varieties of inflammatory spondyloarthropathy and because only 5% of those possessing this allele develop ankylosing spondylitis, HLA B-27 testing must be interpreted in clinical context. Patients with advanced spinal deformities caused by inflammatory spondyloarthropathy, like those with rheumatoid arthritis, can develop atlantoaxial subluxation. In addition, advanced spinal ankylosis predisposes to spinal fractures after minor trauma. The disease process can destroy intervertebral discs, leading to local pain and, in rare cases, to an epidural inflammatory mass. A distinctive complication of advanced inflammatory spondyloarthropathy is lumbar arachnoid diverticula that can cause cauda equina dysfunction and can be diagnosed by spinal imaging such as myelography, computed tomography, or MRI.

SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease that affects many organ systems. The American College of Rheumatology classification criteria for SLE10 require for diagnosis that a patient have any 4 of 11 criteria: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disease, neurological disorder, hematological disease, immunological changes, and antinuclear antibodies. SLE most commonly affects young women.

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T A B L E 119–1. American College of Rheumatology Classification of Neuropsychiatric Syndromes Observed in Systemic Lupus Erythematosus Central Nervous System

Peripheral Nervous System

Aseptic meningitis

Acute inflammatory demyelinating polyneuropathy Autonomic disorder Mononeuropathy, single or multiplex Myasthenia gravis Cranial neuropathy Plexopathy Polyneuropathy

Cerebrovascular disease Demyelinating disease Headache Movement disorder (chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis

From The American College of Rheumatology nomenclature and case definitions of neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42:599-608.

Neurological manifestations of SLE take many forms (Table 119–1). A patient with SLE can have more than one of the syndromes. Each syndrome might have causes other than lupus, and so the diagnosis of neuropsychiatric lupus requires the presence of one of these neurological syndromes; the systemic diagnosis of SLE is based on other data, such as the American College of Rheumatology diagnostic criteria for SLE, and exclusion of alternative diagnoses. For example, the identification of a case of meningitis as lupus-related aseptic meningitis rests on establishing the diagnosis of SLE; ruling out infectious causes of meningitis, especially opportunistic infections; and ruling out drug-induced meningitis, such as that caused by nonsteroidal anti-inflammatory drugs. For some patients, a neuropsychiatric syndrome is the first clinical manifestation of SLE. In these cases, the diagnosis of possible neuropsychiatric lupus can be entertained on the basis of characteristic presentation and serological findings, but proof of the diagnosis may await appearance of other conditions that fulfill the diagnostic criteria for SLE.

Central Nervous System Manifestations Aseptic Meningitis Aseptic meningitis affects fewer than 1% of patients with SLE. Recurrent or chronic meningitis is much less common. CSF study typically reveals mild pleocytosis, normal glucose level, and normal or elevated protein level.

patients with lupus, intracranial vasculitis is actually extremely rare in these patients.

Demyelinating Disease Neuropsychiatric SLE infrequently mimics relapsing-remitting multiple sclerosis, including classic manifestations of multiple sclerosis such as optic neuritis, myelitis, or internuclear ophthalmoplegia. Distinguishing multiple sclerosis from this variety of neuropsychiatric lupus is complicated because lupus can be associated with white matter abnormalities visible on MRI and occasionally with CSF oligoclonal bands. Furthermore, patients with multiple sclerosis can have mild elevations in antinuclear antibodies. As is common with autoimmune diseases, more patients develop both lupus and multiple sclerosis than would be predicted by chance alone. Optic neuritis affects about 1% of patients with lupus, many of whom have additional neuropsychiatric abnormalities, such as the combination of optic neuritis and myelitis (neuromyelitis optica). MRI of the optic nerve is essential for ruling out an alternative compressive cause of optic neuropathy, and often in lupus, optic neuropathy manifests as optic nerve swelling and enhancement. Treatment of lupus optic neuritis usually starts with oral or intravenous steroids. Patients who do not experience improvement with steroids often do so after treatment with intravenous cyclophosphamide.

Headache Headaches, including tension headache, migraine with aura, and migraine without aura, are more common in patients with SLE than in matched controls.11 These headaches are not necessarily evidence of active inflammatory disease. However, other causes of headache, such as pseudotumor cerebri or meningitis, merit consideration before the headache is attributed to common benign categories.

Movement Disorder Unilateral or bilateral chorea is a distinctive form of neuropsychiatric lupus that affects fewer than 1% of patients with lupus. It may be the first manifestation of lupus or may develop later in the disease, often progressing insidiously and then resolving over weeks or months. It can be exacerbated by pregnancy or oral contraceptives. Most patients with lupus-related chorea have antiphospholipid antibodies, but only a minority have demonstrable strokes or specific focal brain lesions. Neuroleptic agents sometimes palliate the chorea. Steroid therapy or attempts to suppress antiphospholipid antibodies seem to help in some patients, but proof of efficacy is lacking, inasmuch as the chorea can also remit spontaneously.

Cerebrovascular Disease Patients with SLE are at increased risk for strokes and myocardial infarction through a variety of mechanisms. Part of the risk is attributable to traditional risk factors such as hypertension, hyperlipidemia, diabetes, smoking, or hyperhomocysteinemia. In addition, patients with SLE are at increased risk of stroke if they have antiphospholipid antibodies or cardiac valve vegetations. Patients with lupus and stroke should be checked for cardiac, large-vessel, and small-vessel disease. Although vasculitis is routinely mentioned as a possible cause of stroke in

Myelopathy Acute myelitis occurs in perhaps 1% of patients with SLE; this rate is higher than the prevalence of myelitis in the general population.12 Patients may have paraparesis or quadriparesis; bilateral sensory dysfunction, often to a thoracic level; and sphincter dysfunction. At times, posterior column function is relatively preserved. T2-weighted MRI of the spinal cord often reveals an area of hyperintensity within the cord. MRI evidence of continuous abnormality over multiple spinal segments is

chapter 119 neurology of rheumatology, immunology, and transplantation more indicative of a systemic inflammatory cause of myelitis, such as SLE or Sjögren’s syndrome, than of viral infection or multiple sclerosis. Even when the MRI is normal, it allows exclusion of alternative diagnoses such as cord compression by fracture, subluxation, epidural abscess or hemorrhage, or epidural lipomatosis. Spinal fluid studies in patients with acute myelitis often reveal mild pleocytosis and protein level elevation. An occasional patient appears to have an anterior spinal artery infarction or vasculitis within the spinal cord, but pathological findings are inconsistent. Patients with lupus and myelitis have an increased incidence of antiphospholipid antibodies. Lacking controlled treatment trials, many clinicians routinely treat the myelitis with high-dose steroids, such as 1 g of methylprednisolone daily for 3 days or more. Other options include cyclophosphamide and plasmapheresis. A retrospective literature review demonstrated complete recovery in 50% of cases, partial recovery in 29%, and no recovery in 21%.

Seizure Disorder Seizures occur in more than 10% of patients with SLE, a rate well above the prevalence in the general population.13 In some patients, particularly those who have had strokes or focal cerebritis, the seizures are secondary to focal brain lesions. Patients with antiphospholipid antibodies are more likely to have seizures. In other patients, the seizures are associated with systemic or metabolic abnormalities, such as hypertensive encephalopathy, uremia, infections, or electrolyte abnormalities.

Cognitive Dysfunction Subtle cognitive dysfunction is the most common neuropsychiatric abnormality in patients with SLE, affecting as many as 80% of patients. If less sensitive psychometric measures are used, the prevalence of cognitive impairment can still exceed 20%. Cognitive dysfunction often occurs without overt evidence of strokes or focal brain lesions. Cognitive abnormalities often fluctuate over months, and the prevalence can decrease over time.14 However, cognition can deteriorate progressively, especially in patients with antiphospholipid antibodies, chronic prednisone use, diabetes, depression, and less education.15 Chronic aspirin use is correlated with better long-term cognitive status.

Mood or Anxiety Disorders Patients with SLE are prone to mood disorders, including anxiety, depression, and, less frequently, mania. Patients’ moods, just like their cognition, often fluctuate. Major depressive-like episodes occur in 20% or more of patients.

Psychosis and Acute Confusional State Patients with SLE can develop acute confusion or delirium. These patients may have an acute organic psychosis or acute cognitive deficit, with or without clouding of consciousness. The differential diagnosis includes metabolic derangements, hypertensive encephalopathy, medication toxicity, focal brain lesions, meningoencephalitis, seizures, and opportunistic infections. More than one mechanism often contributes for a single individual; therefore, these patients usually need a thor-

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ough clinical and laboratory evaluation as well as brain MRI, electroencephalography, and CSF examination. In a small percentage of patients with SLE, episodes of acute psychosis develop. The psychosis can arise de novo or be provoked by initiation of or increase in corticosteroid therapy. Patients with hypoalbuminemia seem to be at increased risk for steroid-induced psychosis.16 When the psychosis is not attributable to steroids, high-dose steroids are often therapeutic. Reports of an association between autoantibodies to ribosomal P and psychosis have not been consistently confirmed.

Neuroimaging Brain imaging abnormalities by computed tomography, MRI, or SPECT are common in patients with SLE. Findings of focal cerebral ischemia are usually correlated with clinical episodes of stroke but are occasionally seen in patients with lupus who do not have clinical evidence of neuropsychiatric syndromes. Bright lesions on MRI sequences such as fluid-attenuated inversion recovery imaging, proton density sequences, or T2-weighted sequences, particularly in periventricular or subcortical white matter, are also seen in patients with lupus who have no known neuropsychiatric disease and are even more common in those with CNS symptoms. SPECT frequently reveals areas of focal hypoperfusion in patients with lupus, regardless of whether they have clinical CNS disease.17

Peripheral Nervous System Manifestations Cranial Nerves III to XII When patients with SLE develop cranial nerve dysfunction, they must be evaluated for brainstem causes and for ancillary causes such as infectious basilar meningitis. For example, abnormal eye movements can develop by many different mechanisms (Table 119–2). In addition, patients with lupus can develop idiopathic neuropathy of almost any cranial nerve, most frequently the facial nerve, affected in 0.5% of these patients in one clinical series.

Polyneuropathy Symmetrical, length-dependent sensory or sensorimotor neuropathy is the most common peripheral nervous system manifestation of SLE, occurring in approximately 20% of patients.

T A B L E 119–2. Examples of Neuro-ophthalmoplegic Findings in Patients with Systemic Lupus Erythematosus Pupil-sparing cranial nerve III palsy Unilateral internuclear ophthalmoplegia Bilateral internuclear ophthalmoplegia Ophthalmoplegia with Miller-Fisher syndrome Brown’s syndrome Painful ophthalmoplegia Orbital pseudotumor Ptosis Anisocoria Isolated cranial nerve VI palsy Adapted from Rosenbaum RB, Campbell SM, Rosenbaum JT: Clinical Neurology of Rheumatic Diseases. Boston: Butterworth-Heinemann, 1996.

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The neuropathy is usually mild, chronic, and slowly progressive and rarely warrants nerve biopsy. Biopsy findings are usually those of axonal destruction, often accompanied by epineurial vasculitis. In the setting of known lupus, this histological vasculitis is not an indication for more aggressive immunosuppression unless the neuropathy itself is aggressive or the patient has other evidence of lupus activity.

Acute Inflammatory Demyelinating Polyneuropathy Acute ascending neuropathic paralysis with clinical features of Guillain Barré syndrome affects fewer than 1% of patients with SLE. This syndrome is treated like other instances of GuillainBarré syndrome, including use of plasmapheresis or intravenous immunoglobulin. Rare patients with SLE develop an acute axonal motor neuropathy in which nerve biopsy may be needed to distinguish acute vasculitic neuropathy from one of the axonal variants of Guillain-Barré syndrome. Case reports also document the occasional co-occurrence of SLE and chronic inflammatory demyelinating neuropathy.

Mononeuropathy, Single or Multiplex Carpal tunnel syndrome is common in young women, especially those between 35 and 55 years old, and is probably even more common in those with SLE. Patients with lupus can also develop other compression mononeuropathies such compression at the ulnar groove. Vasculitic mononeuritis multiplex is a known but extraordinary complication of SLE.

Autonomic Neuropathy, Myasthenia Gravis, Plexopathy Patients with SLE can have sympathetic or parasympathetic dysfunction, including pupillary abnormalities, impaired sweating, abnormal cardiac reflexes, and gastrointestinal dysfunction. The occasional occurrence of myasthenia gravis is another example of increased frequency of other autoimmune diseases in patients with SLE. The co-occurrence of lupus and EatonLambert myasthenic syndrome is even less common. Neural-

gic amyotrophy or acute brachial plexitis is another inflammatory condition that can coincide with SLE.

ORGAN TRANSPLANTATION In patients who have undergone organ transplantation, neurological evaluation and treatment is additionally complex.18 Ten percent or more have neurological complications. Before transplantation, the patients often have encephalopathy or neuromuscular disease related to underlying disease organ failure. Neurological complications of renal failure, hepatic failure, cardiopulmonary failure, and malignancy are covered in elsewhere in this book. In addition, liver, kidney, or other organ failure can induce metabolic derangements or lead to drug toxicities related to defective drug metabolism.

Acute Postoperative Encephalopathy (Coma, Failure to Awaken) When patients do not fully awaken after transplantation, the differential diagnosis is extensive. They may have residual effects of the organ failure that necessitated the transplantation. Some, especially after heart or heart-lung transplantation, have acute postoperative brain injuries such as stroke or hypoxia-anoxia encephalopathy. Many of the drugs used for anesthetic management, such as benzodiazepines, opiates, thiopental, propofol, inhalation anesthetics, or neuromuscular blocking agents, can impair neurological function. Failure of the transplanted organ can cause metabolic disturbances that contribute to the encephalopathy. Immunosuppressive drugs can have direct neurological toxicity (Table 119–3) or predispose to opportunistic CNS infections. Central pontine myelinolysis is another potential cause of coma or disturbed consciousness in patients in the acute postoperative period. Corticospinal and cranial nerve dysfunction can lead to quadriparesis, pseudobulbar palsy, and impaired eye movements, so that full assessment of consciousness can be difficult. Central pontine myelinolysis is most common after liver transplantation and is often but not invariably tied to rapid cor-

T A B L E 119–3. Some Neurological Adverse Effects of Anti-inflammatory and Immunosuppressant Drugs Drug

Adverse Effects

Antimalarials (chloroquine, hydroxychloroquine)

Headache, mental status changes, seizures, impaired accommodation, scotomata, retinopathy, hearing loss, vestibulopathy, movement disorder, peripheral neuropathy, vacuolar myopathy, myasthenic syndrome Aseptic meningitis, seizures Peripheral neuropathy, myopathy Myopathy, psychosis, seizures, depression or mania, epidural lipomatosis Tremor, leukoencephalopathy, seizures, encephalopathy, hallucinations, akinetic mutism, paresthesias, dysesthesia, hemolytic-uremic syndrome, TTP Peripheral neuropathy Aseptic meningitis, headache, stroke Encephalopathy (at high doses) Aseptic meningitis, seizures, encephalopathy, hearing loss, vestibulopathy Headache, aseptic meningitis, encephalopathy (myoclonus, seizures, psychosis) Inflammatory myopathy, myasthenia Aseptic meningitis, seizures, encephalopathy

Azathioprine Colchicine Corticosteroids Cyclosporine, tacrolimus Gold IVIg Methotrexate Nonsteroidal anti-inflammatory drugs OKT3 monoclonal antibodies Penicillamine Sulfasalazine

IVIg, intravenous immunoglobulin; TTP, thrombotic thrombocytopenic purpura.

chapter 119 neurology of rheumatology, immunology, and transplantation T A B L E 119–4. Examples of Drugs That May Cause Seizures in Transplant Recipients Aminoglycosides Penicillins Imipenem Vancomycin Lidocaine Isoniazid Narcotics Theophylline Tricyclic antidepressants Antipsychotics (rarely) Aqueous iodinated contrast agents Adapted from Wijdicks EFM, ed: Neurologic Complications in Organ Transplant Recipients. Boston: Butterworth-Heinemann, 1999, p 120.

rection of hyponatremia. Acute demyelination may not be limited to the pons and can include other white matter sites such as the external and extreme capsules. An acute encephalopathy, with manifestations such as headache, altered mental status, seizures, or coma, accompanying renal graft rejection, was described in the early 1980s.19 It is not easily explained by changes in blood pressure, medication toxicity, or electrolyte changes. It is more common when rejection is more severe and improves concomitantly with steroid therapy of the rejection episode.19 This syndrome has been neither reported in relation to nonrenal transplants nor examined in more detail in more recent series.

Seizures Seizures affect between 2% and 40% of transplant recipients, particularly recipients of hearts or livers. The risk of seizures is highest in the first few days after transplantation. A common cause of seizures is toxicity of immunosuppressive drugs, especially cyclosporine, tacrolimus, or OKT3. Cyclosporineassociated seizures are more common in patients who also have hypomagnesemia, hypocholesterolemia, hypertension, hemolytic-uremic syndrome, total body irradiation, or treatment with busulfan and cyclophosphamide (see Wijdiks, 1999, p. 117).18 Seizures can also be caused by myriad metabolic possibilities, including low or high levels of sodium, calcium, or glucose and hepatic or renal failure. A number of drugs can cause seizures (Table 119–4), especially if drug levels are increased as a result of renal failure. Transplant recipients who suffer seizures must be evaluated for structural brain lesions such as ischemic or hemorrhagic strokes, cerebral vein thrombosis, opportunistic CNS infections, or posthypoxic encephalopathy. When seizures occur late after transplantation, metabolic causes are less common, but de novo malignancies and intracranial spread of malignancies (especially in patients who have undergone bone marrow transplantation for leukemia or lymphoma) must be considered.

Opportunistic Infections Transplant recipients are at risk for opportunistic infections, particularly when they take medications to suppress T cell function. Diagnosis of these infections is aided by understanding the

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timing of susceptibility, the specific neurological infectious syndromes, and the most likely causative organisms. During the first month after transplantation, opportunistic infectious risks are relatively low, and infections that do occur are often typical problems of ill, hospitalized patients, such as pneumonia, catheter infections, wound infections, and viral hepatitis. The risk, for most patients, of opportunistic infection is highest between the first and sixth months after transplantation. After 6 months, most patients with successful transplants can take reduced dosages of immunosuppressants and are at lower infectious risks. Some patients at this stage have acquired chronic viral infections, such as hepatitis B or C or cytomegalovirus. The few who require continued aggressive immunosuppression to prevent rejection remain at risk for opportunistic infections. The most clinically important entities causing opportunistic infections in transplant recipients are Listeria monocytogenes, Cryptococcus neoformans, and Aspergillus species, especially fumigatus. Listeria infection is usually acquired from contaminated foods, such as milk products, and produces an acute febrile gastrointestinal illness, which in some cases is then followed by CNS infection. The CNS disease may be an acute meningitis, chronic meningitis, or brainstem encephalitis (rhombencephalitis). Prophylactic treatment of immunosuppressed transplant recipients with trimethoprimsulfamethoxazole decreases their risk of Listeria infection. Chronic cryptococcal meningitis affects perhaps 1% to 2% of transplant recipients and is diagnosed an average of 2 years after transplantation, especially in patients who still require two or more immunosuppressant drugs. The risk is higher after heart or small bowel transplantation. Focal brain lesions are a much less common manifestation. The rate of mortality from cryptococcal meningitis in transplant recipients approaches 50%.20 The differential diagnosis of chronic meningitis in transplant recipients includes other entities such mycobacterial infections, histoplasmosis, and coccidioidomycosis. Aspergillus infection typically begins in the respiratory tract, causing bronchopneumonia or sinusitis, but the organisms can also enter the body where skin has been interrupted or as microscopic infection from the donor organ. They invade blood vessels, so that when they spread to the CNS, Aspergillus organisms can cause ischemic or hemorrhagic strokes or abscesses. Patients more often present with seizures or focal neurological findings than with nonspecific complaints such as fever and headache. The diagnosis is often supported by focal or multifocal abnormalities on brain MRI. The CSF does not invariably show inflammatory changes. Brain abscess occurs in fewer than 1% of transplant recipients. Although Aspergillus is by far the most common organism, many other organisms bear consideration, including Candida, Mucorales, Toxoplasma, and Nocardia. The risk of pyogenic abscess is not increased in these patients. The abscess risk is higher in recipients of heart or heart-lung transplants. The rate of mortality among transplant recipients with brain abscess is more than 80%.21 The most common cause of acute meningitis in transplant recipients is Listeria infection. Another important cause of acute meningitis is Strongyloides stercoralis. In persons from endemic areas of the southern United States, Latin America, or Southeast Asia, the nematode S. stercoralis is a common asymptomatic colonizer of the gut. In immunosuppressed patients, the larvae can infect and penetrate the gut wall, not

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only spreading themselves but also promoting gram-negative infections. The result can be acute gram-negative bacterial meningitis or eosinophilic meningitis caused directly by the nematode. Immunosuppressed transplant recipients are at increased risk for reactivation of herpes varicella-zoster infections and for primary varicella-zoster infection. The risk of the latter can be decreased by varicella vaccination of seronegative individuals before transplantation. Many transplantation physicians accompany immunosuppression with prophylactic antibiotic therapies. Depending on the setting, this can include prophylaxis against Pneumocystic carinii, Listeria, Nocardia, Toxoplasma, and Strongyloides. Immunosuppressed patients can also develop progressive multifocal leukoencephalopathy.

Central Nervous System Neoplasms Immunosuppressed transplant recipients are at increased risk for developing malignancies, including brain tumors. The brain tumor risk is nearly equally divided between systemic and primary CNS lymphomas. There is no apparent increased risk of developing gliomas. Approximately half of the lymphomas are discovered within 1 year of transplantation, during the time of most aggressive immunosuppression. Bone marrow transplant recipients are at greatest risk. The lymphomas are part of a spectrum of post-transplantation lymphoproliferative disorders, many of which are related to Epstein-Barr virus infection. Other viruses such as cytomegalovirus and hepatitis C may play a role in some instances. The manifestation is typically with focal or multifocal brain abnormalities. Although some CNS lymphomas have characteristic MRI appearances, the differential diagnosis often includes infections such as toxoplasmosis. Treatment with high-dose corticosteroids can lead to rapid but temporary tumor suppression and can obscure MRI and pathological findings. Unless the size of a brain mass necessitates urgent treatment, steroid therapy is best postponed until the diagnosis is established by biopsy. In addition to classic treatments with chemotherapy or radiation, options include reduction in immunosuppression. Antiviral drugs are sometimes used in cases associated with Epstein-Barr virus infection, but their value is debatable. Drugs such as anti–B cell monoclonal antibodies (rituximab), aimed at the altered immune response in these patients, must cross the blood-brain barrier if they are to be effective against CNS lymphoma.

Strokes Transplant recipients can experience strokes in the perioperative and early postoperative periods. There are many potential sources, starting with any preexisting risk from the conditions that lead to transplantation. Patients undergoing heart or lung transplantation can suffer cardiogenic or air emboli. Anoxic or hypoxic encephalopathy can follow hypotension or hypoxia. The risk of hypertensive encephalopathy increases in patients taking cyclosporine or during renal graft rejection. Intravascular opportunistic infection, especially with Aspergillus, can cause multifocal strokes. Noninfectious thrombotic endocarditis is a potential risk factor for stroke after bone marrow transplantation.

Intracranial hemorrhages form a larger proportion of all strokes in transplant recipients than in the general population. These hemorrhages include strokes caused by coagulopathies, such as disseminated intravascular coagulation, endovascular infection, cerebral emboli, hypertension, and aneurysms. Ischemic infarction of the distal spinal cord can occur if cord blood flow is disturbed during renal transplantation.22

Neuropathy Transplantation can be long and complex surgery. Patients are at risk of anesthesia-associated compression mononeuropathies at well-known sites of vulnerability such as the ulnar groove. In addition, technical surgical demands increase the risks for some patients. For example, like other patients undergoing open heart surgery, heart transplant and perhaps liver recipients have an increased incidence of postoperative brachial plexopathy. Phrenic neuropathy can occur as a complication of thoracotomy. Femoral neuropathy can follow renal and, less commonly, liver transplantation. Retroperitoneal hemorrhage can compress the lumbar plexus. Peroneal, sciatic, and saphenous neuropathies have been described. Access catheters are another potential cause of nerve injury. Neuropathies in the arm can occur as a result of dialysis shunts or after placement of venous or arterial lines. Horner’s syndrome can be caused by internal jugular vein cannulation. Transplant recipients are vulnerable to generalized weakness through a variety of mechanisms; the timing of the weakness in relation to the transplantation is helpful in establishing the differential diagnosis. Acute generalized weakness that persists after surgery can result from prolonged effects of neuromuscular blocking agents. Patients with liver failure may be slow to metabolize succinylcholine. Peripheral nerve stimulators are useful for assessing neuromuscular junction function in the unresponsive postoperative patient. Acute illness myopathy causing proximal, more than distal, weakness can be evident in the early weeks after transplantation. It follows use of high-dose corticosteroids and neuromuscular blocking agents and affects a small percentage of patients after liver, heart, or lung transplantation. Toxic myopathies should be considered in the differential diagnosis of patients with myalgias or proximal weakness. Considerations include the painless symmetrical proximal weakness of steroid myopathy; myopathy caused by cyclosporine; myalgias in patients taking cyclosporine or tacrolimus; and myalgias, weakness, or rhabdomyolysis caused by statins. Like all critically ill patients, patients in the early weeks after transplantation are at risk for length-dependent axonal sensorimotor polyneuropathy. Cyclosporine or tacrolimus is another potential cause of length-dependent neuropathy. Some patients complain of distal paresthesias or dysesthesias, but neuropathy severe enough to cause weakness or slow nerve conduction is unusual. A few patients develop Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy days or months after bone marrow or solid organ transplantation. Almost all these patients are immunosuppressed, and they usually have serological evidence of cytomegalovirus infection. Treatment is with intravenous immunoglobulin or plasmapheresis, just as for inflammatory demyelinating neuropathies in patients not undergoing transplantation.23 In cases associated with graft-

chapter 119 neurology of rheumatology, immunology, and transplantation versus-host disease or episodes of transplant rejection, more aggressive immunosuppression can help with both the neuropathy and transplant-associated immunological crisis.

GRAFT-VERSUS-HOST DISEASE Chronic graft-versus-host disease is a multiorgan inflammatory complication of bone marrow transplantation that develops 3 months or more after transplantation and affects between one third and two thirds of transplant recipients. The skin and liver are the organs most frequently affected. Findings can be similar to those of other autoimmune disorders, including scleroderma or eosinophilic fasciitis, esophageal disease, sicca syndrome, and biliary cirrhosis. Laboratory changes can include lymphopenia, thrombocytopenia, and antinuclear antibodies. Neurological complications include inflammatory muscle disease similar to polymyositis with findings such as proximal weakness; elevated creatine kinase level; electromyographically evident small, short, easily recruited motor unit potentials sometimes accompanied by fibrillations; and myositic changes evident on muscle biopsy. The myositis is clinically evident in fewer than 1% of patients with graft-versus-host disease.24 The myositis has been successfully treated with immunosuppressive drugs, including prednisone, azathioprine, and cyclosporine. Myasthenia gravis with classical clinical findings and presence of antiacetylcholine receptor antibodies is an even less common accompaniment of graft-versus-host disease.

SUMMARY Treating neurological patients with systemic inflammatory disease or after transplantation is challenging. Each systemic disease has an idiosyncratic natural history and set of possible complications. Care is complicated by systemic inflammatory and metabolic derangements and by complex drug regimens. Choice of therapy is often based on clinical experience rather than on controlled data.

K E Y

P O I N T S

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Focal neurological effects of disease are (1) neurological inflammatory syndromes such as meningitis and myelitis, including syndromes peculiar to the systemic disease (e.g., chorea in SLE, sensory neuronopathy in Sjögren’s syndrome), and (2) stroke.

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Diffuse or poorly localized neurological effects include cognitive impairment in SLE.

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Systemic disease can produce metabolic effects.

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Treatment can produce neurological effects.

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Opportunistic infections occur with these diseases.

Suggested Reading Brey RL, Holliday SL, Saklad AR, et al: Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology 2002; 58:1214-1220.

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Delalande S, de Seze J, Fauchais A-L, et al: Neurologic manifestations in primary Sjögren’s syndrome. A study of 82 patients. Medicine 2004; 83:280-291. McLaurin EY, Holliday SL, Williams P, et al: Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology 2005; 64:297-303. Rosenbaum RB, Campbell SM, Rosenbaum JT: Clinical Neurology of Rheumatic Diseases. Boston: Butterworth-Heinemann, 1996. Wijdicks EFM, ed: Neurologic Complications in Organ Transplant Recipients. Boston: Butterworth-Heinemann, 1999.

References 1. Delalande S, de Seze J, Fauchais A-L, et al: Neurologic manifestations in primary Sjögren’s syndrome. A study of 82 patients. Medicine 2004; 83:280-291. 2. Belin C, Moroni C, Caillat-Vigneron N, et al: Central nervous system involvement in Sjögren’s syndrome: evidence from neuropsychological testing and HMPAO-SPECT. Ann Med Interne (Paris) 1999; 150:598-604. 3. Gorson KC, Ropper AH: Positive salivary gland biopsy, Sjögren syndrome, and neuropathy: clinical implications. Muscle Nerve 2003; 28:553-560. 4. Grant IA, Hunder GG, Homburger HA, et al: Peripheral neuropathy associated with sicca complex. Neurology 1997; 48:855-962. 5. Griffin JW, Cornblath DR, Alexander E, et al: Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren’s syndrome. Ann Neurol 1990; 27:304-315. 6. Font J, Ramos-Casals M, de la Red G, et al: Pure sensory neuropathy in primary Sjögren’s syndrome. Longterm prospective follow-up and review of the literature. J Rheumatol 2003; 30:1552-1557. 7. Chen W-H, Yeh J-H, Chiu H-C: Plasmapheresis in the treatment of ataxic sensory neuropathy associated with Sjögren’s syndrome. Eur Neurol 2001; 45:270-274. 8. Caroyer J-M, Manto MU, Steinfeld SD: Severe sensory neuronopathy responsive to infliximab in primary Sjögren’s syndrome. Neurology 2002; 59:1113-1114. 9. Naranjo A, Carmona L, Gavrila D, et al: Prevalence and associated factors of anterior atlantoaxial luxation in a nation-wide sample of rheumatoid arthritis patients. Clin Exp Rheumatol 2004; 22:427-432. 10. The American College of Rheumatology nomenclature and case definitions of neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42:599-608. 11. Ainiala H, Hietaharju A, Loukkola J, et al: Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum 2001; 45:419-423. 12. Kovacs B, Lafferty TL, Brent LH, et al: Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis 2000; 59:120-124. 13. Appenzeller S, Cendes F, Costallat LTL: Epileptic seizures in systemic lupus erythematosus. Neurology 2004; 63:18081812. 14. Hanly JG, Hong C, Smith S, et al: A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus. Arthritis Rheum 1999; 42:728-734. 15. McLaurin EY, Holliday SL, Williams P, et al: Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology 2005; 64:297-303. 16. Brey RL, Holliday SL, Saklad AR, et al: Neuropsychiatric syndromes in lupus. Prevalence using standardized definitions. Neurology 2002; 58:1214-1220. 17. Sabbadini MG, Manfredi AA, Bozzolo E, et al: Central nervous system involvement in systemic lupus erythematosus patients

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without overt neuropsychiatric manifestations. Lupus 1999; 8:11-19. 18. Wijdicks EFM, ed: Neurologic Complications in Organ Transplant Recipients. Boston: Butterworth-Heinemann, 1999. 19. Gross MLP, Sweny P, Pearson RM, et al: Rejection encephalopathy. An acute neurological syndrome complicating renal transplantation. J Neurol Sci 1982; 56:23-34. 20. Wu G, Vilchez RA, Eidelman B, et al: Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis 2002; 4:183-188.

21. Selby R, Ramirez CB, Singh R, et al: Brain abscess in solid organ transplant recipients. Arch Surg 1997; 132:304-310. 22. Jablecki CK, Aguilo JJ, Piepgras DG, et al: Paraparesis after renal transplantation. Ann Neurol 1977; 2:154-155. 23. El-Sabrout RA, Radovancevic B, Ankoma-Sey V, et al: GuillainBarré syndrome after solid organ transplantation. Transplantation 2001; 71:1311-1316. 24. Stevens AM, Sullivan KM, Nelson JL: Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatoloy (Oxford) 2003; 42:34-39.

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NEUROLOGY OF PULMONOLOGY ACID-BASE DISTURBANCE ●

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Boby Varkey Maramattom and Eelco F. M. Wijdicks

Respiration is essential for cellular metabolism, and no other organ is more dependent on oxygen supply than is the brain. The consequences of disturbances in gas exchange are readily reflected in disturbance of neuronal function, in neuronal injury, or in death. The respiratory system is crucial for the gas exchange and plays a large part in acid-base homeostasis. Neuronal integrity and respiratory regulation are highly interdependent. A brief conceptualization of the neurological control of breathing is necessary for understanding various disordered respiratory patterns. Clinical respiratory abnormalities can be viewed in three contexts: disturbances in the neural control of respiration, in the respiratory apparatus, or in the carriage or composition of blood gases. This chapter describes abnormalities associated with neurological control of respiration and neurological consequences of respiratory dysfunction.

NEURAL CONTROL OF RESPIRATION The nervous system is intricately connected to the mechanics of respiration at various levels. From the cerebral cortex via the brainstem to the level of the lower motor neurons, the nervous system regulates respiratory effort. It is aided by feedback from peripheral chemoreceptors and mechanoreceptors (Fig. 120–1).1 The anterior horn cells controlling respiratory muscles represent the lower motor neurons, which control the actual mechanics of breathing. Inspiratory muscles generate subatmospheric pressures within the thorax and induce airflow and gas exchange at the alveolar level. Respiratory activity takes place predominantly at an autonomic level. Modulation of this automatic control is also evident in various functions such as sneezing, vomiting, coughing, and swallowing. However, voluntary control of the respiratory and upper airway musculature is necessary for communication and speech. Although respiration is a complex process involving pulmonary ventilation, gas exchange at the alveolar level, and gas transport to tissues, neurological conditions influencing respiration involve primarily abnormalities in pulmonary ventilation and air movement into and out of the respiratory tract. To better understand the neural control of breathing, it is essential to have an overview of the components and regulatory structures involved in this complex action.

Lower Motor Components of Respiration The lower motor components are composed of neurons innervating the diaphragm, intercostal muscles, abdominal muscles, and other accessory muscles.1 During quiet breathing, only the diaphragm is vigorously active, with some contribution from the abdominal and external intercostal muscles. These muscles work in conjunction with muscles of the upper airway to maintain a patent airway and ensure an uninterrupted passage to air. The diaphragm is the most important inspiratory muscle, and it derives its nerve supply via the phrenic nerve from spinal cord segments C3-C5. Other inspiratory muscles include the external intercostal muscles, the parasternal intercostal muscles, and the scalene muscles. Inspiration is an active process by which air flow and lung expansion are achieved. During quiet inspiration, the diaphragm descends into the abdominal cavity and increases the vertical dimension of the thoracic cage. Simultaneously, the external intercostal muscles, parasternal intercostal muscles, and scalene muscles elevate the upper ribs and sternum, increasing the anteroposterior diameter of the thorax (pumphandle movement). As the thoracic cage expands, it reduces the intrapleural pressure. This generates subatmospheric pressures, inducing air flow and expansion of the lung parenchyma. However, during deep breathing (minute volume, >40L/minute) or when the resistive load of the respiratory system increases, as in asthma or chronic obstructive pulmonary disease, additional muscles are recruited for inspiration. These accessory muscles of inspiration include the sternocleidomastoid, pectoralis minor and major, serratus anterior, latissimus dorsi, and serratus posterior superior muscles. Expiration, in contrast, is a passive process produced by elastic recoil of the thoracic cage. Active expiratory muscles such as the abdominal muscles and the internal intercostal muscles are called into action only during exercise and during vigorous and deep breathing. Upper airway structures are crucial in maintaining the patency of airways. Dysfunction of these structures is readily evident in abnormalities of speech and swallowing, as well as in obstructive sleep apneas and other breathing disorders. The muscles of the nose, mouth, soft palate, pharynx, epiglottis, and larynx work in conjunction to ensure a free flow of air into the trachea and bronchi. Somatic innervation of these muscles

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Motor cortex

Supplementary motor area

Sensory cortex (sensation of breathlessness)

Limbic system

Voluntary breathing

P VR G

Peripheral chemoreceptors (arterial blood gases)

VII

XII

Lateral corticospinal tract

N A V R G

IX nerve CC X nerve

Involuntary breathing

D R G

Reticulospinal pathway

Spinal respiratory neurons

Mechanical receptors

Respiratory muscles

Ventilation

■

Figure 120–1. A representation of the neural control of breathing: the main systems involved in voluntary and involuntary breathing and their final activation of the respiratory muscles via the lateral corticospinal and reticulospinal pathways. CC, central chemoreceptors; DRG, dorsal respiratory group; NA, nucleus ambiguus; PRG, pontine respiratory group; V, sensory nucleus of V; VRG, ventral respiratory group. (From Bolton C, Chen R, Wijdicks EFM, et al: Anatomy and physiology of the nervous system control of respiration. In Bolton C, Chen R, Wijdicks EFM, et al, eds: Neurology of Breathing. Philadelphia: Butterworth-Heinemann, 2004, pp 19-35.)

chapter 120 neurology of pulmonology and acid-base disturbance is provided by the lower cranial nerves: V, VII, IX, X, and XII.

Chemical Regulation of Respiration Breathing is influenced by input from peripheral and central chemoreceptors. Peripheral chemoreceptors located in the carotid bodies (at the common carotid bifurcations) and the aortic bodies are influenced primarily by hypoxia. Other, less important stimuli include hypercarbia, acidosis, and hypoperfusion. Central chemoreceptors in the pons (locus ceruleus) and medulla (raphe nuclei, ventrolateral nuclei, and nucleus of tractus solitarius) are influenced primarily by changes in carbon dioxide tension (PCO2) concentrations. These neurons project their dendrites to the surface of the brainstem, where they abut the circulating cerebrospinal fluid. Arterial PCO2 (PaCO2) changes are reflected by changes in cerebrospinal fluid pH. The precise mechanisms by which these structures influence automatic breathing are still a subject of study. Although breathing in the awake human is not closely influenced by these structures, their feedback becomes vital during sleep. Although peripheral chemoreceptors can be removed or destroyed during carotid endarterectomy, they do not clinically affect respiration. Lesions of the central chemoreceptors, in contrast, lead to respiratory abnormalities and apnea during deep sleep. This is probably because peripheral inputs are overridden in favor of central chemoreceptor inputs during sleep.

Upper Motor Components of Respiration Normal respiration is an automatic rhythmic subconscious function that is modulated during complex activities such as speech, singing, laughter, hiccups, and vomiting. Three parallel pathways influence these separate components of respiration. Automatic breathing is regulated primarily by lower brainstem nuclei. These consist of pontine and medullary groups of nuclei. The most vital structures are neurons in the ventral respiratory group of the medulla. A subcomponent of this group, the pre-Bötzinger region, probably performs a pacemaker or driving function that initiates inspiration. It is supported by the pontine respiratory group and components of the dorsal and ventral respiratory group neurons of the medulla. Collectively, these are termed the pontomedullary respiratory generator. This generator produces a resting respiratory rate of 12 to 15 breaths per minute. In humans, this generator is modified by pulmonary and cardiovascular reflexes. The pulmonary reflexes termed the Hering-Breuer reflex are of minimal importance in humans. However cardiovascular reflexes are closely interlinked with respiratory patterns. This is readily evident in the phenomenon of respiratory sinus arrhythmia, in which the heart rate speeds up during inspiration and slows down during expiration. The parasympathetic innervation of the cardiac pacemaker predominates over the sympathetic innervation, and sinus arrhythmia is generated by phasic inhibition of vagal output to the sinus node. Moreover, polysynaptic connections in the medulla mediate respiratory modulation during complex reflex responses such as vomiting. The proximity of neurons involved in respiration and those of the lower motor neuron nuclei result in close intermingling and intermodulation of activity.

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Nevertheless, pathways that subserve higher order functions such as speech, singing, and voluntary control of breathing exist in parallel to the automatic pathways. As in motor control of limb muscles, activation of cortical networks between the motor area, premotor area, supplementary motor area, basal ganglia, and cerebellum influence and modify respiratory rhythms. These networks are normally silent and are called into action during speech and singing, during which they inhibit automatic breathing and modulate the upper airway and respiratory rhythms. The third pathway is postulated to arise from the limbic system and modulates respiratory rhythms in response to emotional stimuli. This pathway, however, is not as well understood as the automatic and voluntary pathways. Automatic respiration is mediated via the reticulospinal tract, which lies in the anterolateral funiculus of the spinal cord, and voluntary respiration is mediated via the corticospinal tracts.

ABNORMAL RESPIRATORY PATTERNS IN NEUROLOGICAL DISEASES Neurological illnesses can manifest with respiratory abnormalities involving the depth, rate, rhythm, or modulation of breathing. It is helpful to view these abnormalities in the context of dysfunction occurring at different levels of the neuraxis. Respiratory abnormalities can arise from dysfunction at the level of the lower motor neuron, mechanoreceptors and chemoreceptors, or higher centers of respiration. Patients can present with dyspnea, abnormal respiratory patterns, respiratory failure, or difficulty in weaning from a ventilator.

Respiratory Failure Neurological disorders can produce dyspnea or frank respiratory failure. Respiratory failure exists when arterial oxygen tension (PaO2) is less than 60 mm Hg or when PaCO2 exceeds 50 mm Hg when the patient is breathing air, and it is the end result of respiratory dysfunction. It can exist in acute and chronic forms. Acute respiratory failure manifests dramatically, and most patients are immediately intubated and ventilated. Nearly 300,000 cases of acute respiratory failure are encountered each year in the United States; the approximate incidence is 137 cases per 100,000 population.2 The number of cases related to neurological disorders is not known. Nevertheless, even if it is assumed that only 0.5% to 1% of cases of acute respiratory failure are related to neurological causes, they add up to 1500 to 3000 cases per year in the United States alone. In clinical practice, the neurologist is most often consulted about patients with respiratory failure in which a clear pulmonary or medical cause is not evident. Sometimes the neurologist is consulted when there is difficulty in weaning a patient from a ventilator. This is common in the intensive care unit with critically ill patients who may display a necrotizing myopathy.3 Alternatively, respiratory failure may supervene in patients with known neurological illness such as myasthenia gravis or Guillain-Barré syndrome. Examination reveals tachypnea, brow sweating, tachycardia, weak cough, paradoxical respiration, and diminished respiratory muscle strength on pulmonary function tests. Patients with chronic respiratory

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T A B L E 120–1. Neuromuscular Conditions Resulting in Respiratory Failure Muscle Diseases Muscular dystrophies Acid maltase deficiency Myotonic dystrophy Inflammatory myopathies Mitochondrial myopathies Hypokalemic myopathy Hypophosphatemic myopathy Critical illness–related myopathy Neuromuscular Junction Disorders Myasthenia gravis Disorders induced by neuromuscular blocking agent Organophosphorus poisoning Snake/spider bite Botulism Lambert-Eaton myasthenic syndrome Antibiotic-induced myasthenia Tick paralysis Congenital myasthenic syndromes Peripheral Neuropathies Acute inflammatory demyelinating polyneuropathy (AIDP) Critical illness–related polyneuropathy Phrenic neuropathies Toxic neuropathies Chronic idiopathic demyelinating polyneuropathy (CIDP) Porphyric neuropathy Diphtheria Vasculitis: systemic lupus erythematosus (SLE) Lymphoma Anterior Horn Cell Disorders Acute poliomyelitis Amyotrophic lateral sclerosis (ALS) Spinal muscular atrophies Disorders of Spinal Cord Transverse myelitis Spinal cord infarction High cervical cord trauma Spinal cord tumors Spinal arteriovenous malformations Spinal cord hemorrhage Syringomyelia

insignificant. Respiratory failure is not a major problem unless other medical complications occur. Rare exceptions to this caveat include central hypoventilation syndromes resulting from congenital or acquired disorders of medullary respiratory center or apneic seizures. By and large, central disorders produce certain characteristic respiratory patterns in the context of acute devastating neurological illnesses. Most of these patterns, such as Cheyne-Stokes respiration, central neurogenic hyperventilation, apneustic breathing, and ataxic breathing, affect primarily the rate and rhythm of breathing. A number of nonneurological conditions can also produce these respiratory patterns.

Cheyne-Stokes Respiration This respiratory pattern is characterized by repeated cycles of incremental hyperventilation, decremental hypoventilation (in a waxing-and-waning pattern), followed by a short period of apnea. It may occur in a variety of conditions but is classically associated with diffuse bilateral hemispherical dysfunction (especially cerebrovascular disease) and is thought to be caused by a reduced central response to carbon dioxide. It is also associated with other medical conditions, notably congestive cardiac failure.

Central Neurogenic Hyperventilation Central neurogenic hyperventilation is a specific disorder characterized by sustained hyperventilation, often resulting in PaCO2 of less than 35 mm Hg. It persists during sleep and is often associated with respiratory alkalosis. It should be differentiated from nonneurological causes of hyperventilation, including metabolic acidosis, organ failure, and other medical causes. Hence, it is often a diagnosis of exclusion or associated with characteristic neurological disorders. Central neurogenic hyperventilation is classically described with upper pontine lesions or with primary central nervous system lymphomas. It may also be present with pontine tumors. Nevertheless, lesions anywhere in the brainstem can be associated with central neurogenic hyperventilation.

Apneustic Breathing

failure may present with an insidious onset of sensorial alteration and coma. The commonest neurological causes of respiratory failure are neuromuscular and spinal cord disorders.4 Peripheral disorders result in respiratory muscle weakness, alveolar hypoventilation, and type II respiratory failure. Table 120–1 lists some of the common neuromuscular and spinal disorders producing respiratory weakness. Most of these disorders can manifest with acute or chronic respiratory failure. Associated findings, pulmonary function test results, neurophysiological evaluation findings, and muscle/nerve biopsy findings help identify most of these peripheral or spinal causes of respiratory failure.

Abnormal Respiratory Patterns Central causes uncommonly result in respiratory failure. Many supraspinal neurological disorders produce a “restrictive” pattern on pulmonary function tests, which is often clinically

This pattern is characterized by brief pauses at the end of inspiration or alternating pauses at the inspiration and expiration. It is often encountered with bilateral lesions of the pontine tegmentum affecting the pontine pneumotaxic center.5 This center is involved in sending inhibitory impulses to the apneustic center and medulla that terminate inspiration and initiate passive expiration. Although readily reproducible in laboratory animals through introduction of pontine lesions, it is rarely observed in clinical practice. Isolated case reports describe reversal of apneustic breathing after stroke with buspirone.6

Ataxic Breathing This is an agonal pattern of breathing that often occurs before impending cardiac arrest. It is completely irregular and is observed with medullary lesions.

Hiccups Although hiccups are by and large encountered in normal individuals in certain circumstances, they occasionally result from

chapter 120 neurology of pulmonology and acid-base disturbance central nervous system lesions. The paradigm of such a lesion is a lateral medullary infarct. Hiccups are characterized by inspiratory movements in the diaphragm and external intercostal muscles, followed immediately by glottic closure. This results in ineffectual inspiration. It is more likely to supervene during inspiration than during expiration.

Disorders of Automatic Breathing Automatic breathing may be selectively impaired in some disorders that affect the neurons of the medullary ventral respiratory group. During wakefulness, voluntary breathing may be able to sustain respiration. During slow-wave sleep, however, automatic breathing is essential for maintaining respiration. In these disorders, central apnea and hypoxemia supervene during sleep. This condition is termed Ondine’s curse, after the story of a mythical figure, Hans, who was cursed by his jilted lover, Ondine. He was doomed to lose all automatic functions and thus had to stay awake in order to ensure continued breathing. In the modern era, it was most commonly observed in bulbar poliomyelitis, in which the ventral respiratory group neurons were involved. Nowadays it is also observed after high anterior cervical lesions, which affect the reticulospinal tracts subserving automatic respiration. This is particularly common after fibrocartilaginous embolism to the C3-C4 segments of the spinal cord.7 During sleep, automatic centers rely on feedback from central chemoreceptors to regulate breathing. This can be impaired in patients with the rare syndrome of central congenital hypoventilation syndrome. Such patients have a defect in central and peripheral chemoreception that impairs automatic control of breathing. Marked cyanosis and apnea occur during sleep in infants with this syndrome.

Obstructive Sleep Apnea At this juncture, it is appropriate to consider vascular lesions in areas of the brainstem adjoining the respiratory center. Involvement of the motor nuclei of the lower cranial nerves (especially nucleus ambiguous) in the medulla leads to weakness of the upper airway structures and obstructive sleep apnea. In addition, dysphagia predisposes to aspiration of oropharyngeal secretions and to pulmonary infections.

Disorders of Voluntary Breathing Voluntary control of breathing is mediated primarily via the corticospinal and corticobulbar tracts and is important in activities such as speech, singing, and voluntary breath holding. Disorders involving this mechanism occur mainly in bilateral pontine infarctions and lesions involving the pontine tegmentum that interrupt the descending motor pathways. The classical situation is that of patients with a “locked-in” syndrome. Such patients have a constant unvarying respiratory rhythm that cannot be modulated voluntarily. Thus, they are unable to hold their breath, breathe in deeply, or cough voluntarily. Reflex responses and responses to chemoreceptors remain intact. Partial lesions of the high cervical cord that selectively involve the corticospinal tracts at the C3-C4 segments can also produce a similar condition.7

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An analogous disorder occurs in patients with bilateral hemispherical disorders (especially elderly patients with diffuse cerebrovascular disease). Such patients can have a respiratory “apraxia” in which they are unable to voluntarily hold their breath or take a deep breath on command. Swallowing on command is also impaired, although automatic swallowing is preserved. These patients commonly also display other “release reflexes” such as frontal release reflexes and gegenhalten.

Assorted Disorders of Breathing A number of uncommon disorders of breathing also merit mention. Some of these are subclinical entities detected on examination or investigations. Others manifest with a variety of clinical problems and may be mistaken for anxiety-induced hyperventilation or panic attacks. Hemiplegic patients can display reduced diaphragmatic and chest wall excursions on the weak side. More often than not, they are clinically insignificant. The basal ganglia also play an important role in motor control and are involved in a wide variety of neurological disorders. Dystonia can involve muscles of the diaphragm, as well as those of the upper airway, producing subjective dyspnea.8 Chorea and dyskinesias (notably levodopa-induced dyskinesias) can interfere with breathing and produce subjective dyspnea. Diaphragmatic flutter is a rare condition characterized by dyspnea, epigastric pulsations, abdominal pain, hyperventilation, and repetitive diaphragmatic contraction at a rate of approximately 3 Hz.9 It is considered to be a form of myoclonus and, as such, responds to a number of antiepileptic drugs (phenytoin, carbamazepine, and benzodiazepines), as well as to phrenic nerve crush. It can be unilateral or bilateral and may occur after encephalitis or lesions impinging on the phrenic nerve roots. Other pulmonary disorders such as neurogenic pulmonary edema are sometimes associated with devastating neurological illnesses such as subarachnoid hemorrhage or intracerebral hemorrhage.10 These disorders, however, are outside the scope of this chapter.

NEUROLOGICAL CONSEQUENCES OF RESPIRATORY INSUFFICIENCY Although in the following discussion each condition is described as a separate entity, it should be realized that “isolated” clinical gas abnormalities are uncommon.

Hypoxia The paradigm of acute severe hypoxia is exemplified by altitude sickness. At high altitudes, mountain climbers experience a variety of symptoms such as headaches, delirium, hallucinations, ataxia, amnesia, gait disturbances, and seizures, which are readily reversible with oxygen therapy or descent to lower altitudes. Cerebral edema with resultant papilledema also occurs. Another commonly encountered clinical scenario is cardiac arrest. The brain is exceptionally dependent on oxygen, and patients become unconscious within 20 seconds of cardiac arrest. Neuronal adenosine triphosphate stores are depleted within seconds, and neuronal damage ensues. Neurons in

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selected areas such as the hippocampus, basal ganglia, cortical lamina, cerebellum, and spinal cord are particularly involved because of their lower capacity to withstand hypoxia. Nevertheless, it is believed that pure hypoxia alone is not responsible for neuronal injury unless it is accompanied by neuronal ischemia. In isolated hypoxia (PaO2 < 20 mm Hg), irreversible neuronal injury is prevented by a manifold increase in cerebral blood flow. Hypoxia also induces cerebral vasodilatation directly and indirectly through the production of vasoactive factors.11 When ischemia coexists, there is a massive outpouring of excitatory neurotransmitters, such as glutamate. This activates α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors and N-methyl-D-aspartate receptors, opens ion channels, and initiates enzymatic cascades that induce neuronal cell death. Neurological sequelae occurring after successful resuscitation from cardiac arrest vary from amnesia, motor and gait disturbances, and myoclonus to severe dementia. Chronic hypoxia produces more insidious neurological damage. Patients with chronic obstructive pulmonary disease have an increased incidence of small-fiber peripheral neuropathy, which is linked to chronic hypoxia.12,13 Likewise, an asymptomatic autonomic neuropathy is encountered in these patients, although the etiological link is weaker with this entity.

Hyperoxia Hyperoxia is encountered in humans exposed to hyperbaric environments. Such situations occur in patients undergoing hyperbaric therapies and in deep sea divers. These people experience short-term myopia as a result of direct hyperoxiainduced ocular lens changes. Neurological manifestations are transient and limited to headache and, in rare cases, seizures.14 Hyperoxia is also frequently encountered in patients on ventilators, in whom inadvertent hyperventilation or high fractional inspired oxygen concentrations result in elevated PaO2. The effect of hyperoxia in these clinical situations is unclear.

diorespiratory depression. Neurological involvement is dependent on the rate of rise of carbon dioxide. Acute hypercarbia can produce drowsiness, coma, tremors, asterixis, myoclonus, seizures, papilledema, and fatal cardiac arrhythmias. Carbon dioxide rapidly diffuses across the blood-brain barrier and reduces cerebrospinal fluid pH. This results in postsynaptic glutamate receptor inhibition and resultant depression of the central nervous system. Although hypercarbia is commonly encountered along with hypoxia, isolated carbon dioxide– induced narcosis can be encountered. This situation is typically encountered in elderly patients with chronic obstructive pulmonary disease to whom only supplemental oxygen is administered. Arterial blood gas analysis in these patients reveals normal PaO2 levels with extremely high PaCO2 levels. This concept can be understood by studying the alveolar gas equations: Alveolar PO2 = barometric pressure × (inspired O2 − O2 uptake/alveolar ventilation) Alveolar PCO2 = barometric pressure × (mean inspired CO2 + CO2 output/alveolar ventilation)

During hypoventilation, the fall in alveolar oxygen tension (PO2) can be overcome by an increase in inspired oxygen while the alveolar carbon dioxide tension continues to rise. This phenomenon is used to diagnostic advantage in the apnea test for brain death, in which supplemental high-flow oxygen is administered through a cannula placed at the level of the carina and the ventilator is disconnected. In the appropriate clinical context, the apnea test result is suggestive of brain death if a rise in PaCO2 of more than 20 mm Hg does not result in respiratory efforts. Chronic hypercarbia produces milder neurological dysfunction as a result of compensatory nervous system adaptation. Nevertheless, morning headaches, asterixis or tremulousness, inattention, and cognitive dysfunction are often encountered in such patients. Cerebral edema and papilledema are often encountered in these patients. An important caveat in the treatment of these patients is that correction of hypercarbia should be attempted gradually. Rapid correction induces cerebral vasoconstriction and worsens the encephalopathy.

Nitrogen-Induced Narcosis A discussion of the neurological aspects of respiration would be incomplete without mention of nitrogen-induced narcosis (inert gas narcosis), once known as the “raptures of the deep.” This condition was frequently encountered in the past by deep sea divers, who breathed air at high ambient pressure (>4 atm). Increasing partial pressures of nitrogen in the blood led to impaired cognition, incoordination, and disruption of the normal thought process. Prolonged or higher concentrations led to coma and death. The narcotic potential of inert gases such as nitrogen is related to their lipid solubility (the content of which is high in the central nervous system). Substitution of nitrogen with less lipid-soluble gases such as helium has resulted in a decreased incidence of nitrogeninduced narcosis.

Hypercarbia Although hypoxia is considered more dangerous and harmful to the brain, hypercarbia also produces neurological and car-

Hypocarbia/Hyperventilation Hypocarbia exists when the PaCO2 concentration falls below the normal range of 35 to 45 mm Hg. It is encountered in syndromes of hyperventilation. Such situations are encountered in voluntary or iatrogenic hyperventilation or are induced by systemic or central nervous system disorders. Patients present with a variety of neurological symptoms, including lightheadedness, tinnitus, cheiro-oral paresthesias, blurring of vision, tetany, and seizures. These symptoms are mediated by various mechanisms. Hyperventilation-induced respiratory alkalosis induces calcium shift and hypocalcemia, which is responsible for the peripheral paresthesia and tetany. Hypocarbia shifts the hemoglobin-oxygen dissociation curve to the left, reducing tissue delivery of oxygen and causing tissue hypoxia. Hypocarbia also induces cerebral vasoconstriction, reducing cerebral blood flow. This phenomenon is used to therapeutic advantage during hyperventilation for reduction of increased intracranial pressure.

chapter 120 neurology of pulmonology and acid-base disturbance Air Embolism and Decompression Sickness All of the disorders just described involve abnormalities in the partial pressures of gases dissolved in the blood. In normal circumstances, gases dissolve in blood in proportion to their partial pressure (Henry’s law). However, there are other conditions in which this gas-blood equilibrium is disturbed and bubbles of gas form. The following discussion pertains to such phenomena. A discussion on respiration would be incomplete without a reference to these disorders. Arterial air embolism occurs with trauma, arterial cannulations, and surgical procedures. Exposure to extremely high atmospheric pressures during dives can cause rupture of pulmonary alveoli and entry of air into pulmonary veins. The resultant air bubbles act as embolic fragments and produce changes in mental status and focal neurological deficits. Similarly, when deep sea divers ascend too rapidly, there is no time for arterial gases to equilibrate, and nitrogen dissolved in adipose tissue bubbles out into the blood stream, causing decompression sickness (the “bends”). Again, gas bubbles cause neurological dysfunction in myriad ways. They can act as mechanical emboli, induce coagulation cascades at the bubble-blood interface, and cause mechanical compression and distention of vascular structures and tissues. Although cutaneous, musculoskeletal, and cardiopulmonary manifestations predominate, the nervous system is another favored site of injury. Visual symptoms, spinal cord injury, labyrinthine symptoms, focal neurological deficits, and altered mental status can occur. Although air embolism and decompression sickness produce similar neurological abnormalities, the underlying pathophysiological processes are different. Nevertheless, similar treatment protocols, involving recompression with 100% oxygen in hyperbaric chambers, are used for both conditions.14

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plasma HCO3 concentration up to a maximum of 55 to 60 mm Hg. If PaCO2 fails to increase appropriately, a mixed acid-base disturbance such as additional respiratory alkalosis should be considered.20 Such disorders manifest less frequently in neurological practice and are hence not considered in greater detail.

CONCLUSIONS The nervous and respiratory systems are intricately interconnected and interdependent. Because of the complexity of the relationship, a wide variety of abnormalities are encountered in clinical practice. Knowledge of the various neural pathways and structures that regulate respiration is vital to interpretation and analysis of respiratory dysfunction by neurologists.

K E Y

P O I N T S

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Breathing is controlled and regulated by different parts of the nervous system.

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Different pathways subserve automatic, voluntary, and emotional control of respiration.

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Neurological abnormalities of respiration can arise from involvement of any or all of these pathways.

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Abnormalities in blood gases lead to immediate changes in neuronal functioning.

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The respiratory system closely regulates acid-base balance and is in turn influenced by these parameters.

ACID-BASE BALANCE AND RESPIRATION

Suggested Reading

The respiratory system works closely with the kidneys, the liver, and an effective circulation in maintaining homeostasis and acid-base balance. Nearly 15,000 mmol of carbon dioxide is produced every day and eliminated by the respiratory system. The pH of blood is immediately altered by respiratory changes, and vice versa.15 For clinical purposes, a linear relationship can be assumed to exist between pH and acute changes in PaCO2. Hence, for every increase in PaCO2 of 20 mm Hg above normal, the pH falls by 0.1, and for every decrease of PaCO2 of 10 mm Hg below normal, the pH rises by 0.1. Respiratory alkalosis can be produced by voluntary and involuntary hyperventilation. Respiratory acidosis occurs during respiratory failure. Although metabolic acid-base disturbances are better understood with the newer concept of Stewart’s model,16 most clinicians rely on the simplified concept of anion gap and base excess. Stewart’s model postulates that acid-base balance depends on a number of factors, including PaCO2 levels, strong ion difference, and concentrations of weak acids.17,18 Metabolic acidosis from a variety of disorders results in compensatory respiratory changes. PaCO2 is “blown off’” in an attempt to normalize pH, and patients display hyperventilation. Metabolic alkalosis may result in compensatory hypoventilation and respiratory acidosis but is less commonly observed.19 The PaCO2 increases by 0.5 to 0.7 mm Hg for every 1.0-mm increase in

Bolton C, Chen R, Wijdicks EFM, et al: Anatomy and physiology of the nervous system: control of respiration. In Bolton C, Chen R, Wijdicks EFM, et al, eds: Neurology of Breathing. Philadelphia: Butterworth-Heinemann, 2004, pp 19-35. Corey HE: Bench-to-bedside review: fundamental principles of acid-base physiology. Crit Care 2005; 9:184-192. Howard RS, Rudd AG, Wolfe CD, et al: Pathophysiological and clinical aspects of breathing after stroke. Postgrad Med J 2001; 77:700-702. Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003; 168:10-48. Leach RM, Rees PJ, Wilmshurst P: Hyperbaric oxygen therapy. BMJ 1998; 317:1140-1143.

References 1. Bolton C, Chen R, Wijdicks EFM, et al: Anatomy and physiology of the nervous system control of respiration. In: Bolton C, Chen R, Wijdicks EFM, et al, eds: Neurology of Breathing. Philadelphia: Butterworth-Heinemann, 2004, pp 19-35. 2. Behrendt CE: Acute respiratory failure in the United States: incidence and 31-day survival. Chest 2000; 118:1100-1105. 3. Maramattom B, Wijdicks EF, Sundt TM, et al: Flaccid quadriplegia due to necrotizing myopathy following lung transplantation. Transplant Proc 2004; 36:2830-2833.

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4. Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003; 168:10-48. 5. Howard RS, Rudd AG, Wolfe CD, et al: Pathophysiological and clinical aspects of breathing after stroke. Postgrad Med J 2001; 77:700-702. 6. El-Khatib MF, Kiwan RA, Jamaleddine GW: Buspirone treatment for apneustic breathing in brain stem infarct. Respir Care 2003; 48:956-958. 7. Howard RS, Thorpe J, Barker R, et al: Respiratory insufficiency due to high anterior cervical cord infarction. J Neurol Neurosurg Psychiatry 1998; 64:358-361. 8. Braun N, Abd A, Baer J, et al: Dyspnea in dystonia. A functional evaluation. Chest 1995; 107:1309-1316. 9. Cvietusa PJ, Nimmagadda SR, Wood R, et al: Diaphragmatic flutter presenting as inspiratory stridor. Chest 1995; 107:872875. 10. Friedman JA, Pichelmann MA, Piepgras DG, et al: Pulmonary complications of aneurysmal subarachnoid hemorrhage. Neurosurgery 2003; 52:1025-1031; discussion, Neurosurgery 2003; 52:1031-1032. 11. Markus HS: Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353-361. 12. Appenzeller O, Parks RD, MacGee J: Peripheral neuropathy in chronic disease of the respiratory tract. Am J Med 1968; 44:873-880.

13. Thomas PK, King RH, Feng SF, et al: Neurological manifestations in chronic mountain sickness: the burning feet-burning hands syndrome. J Neurol Neurosurg Psychiatry 2000; 69:447452. 14. Leach RM, Rees PJ, Wilmshurst P: Hyperbaric oxygen therapy. BMJ 1998; 317:1140-1143. 15. Williams AJ: ABC of oxygen: assessing and interpreting arterial blood gases and acid-base balance. BMJ 1998; 317:12131216. 16. Stewart PA: Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983; 61:1444-1461. 17. Corey HE: Bench-to-bedside review: fundamental principles of acid-base physiology. Crit Care 2005; 9:184-192. 18. Fencl V, Jabor A, Kazda A, et al: Diagnosis of metabolic acidbase disturbances in critically ill patients. Am J Respir Crit Care Med 2000; 162:2246-2251. 19. Perrone J, Hoffman RS: Compensatory hypoventilation in severe metabolic alkalosis. Acad Emerg Med 1996; 3:981-982. 20. Galla JH: Metabolic alkalosis. J Am Soc Nephrol 2000; 11:369375.

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Geoffrey Miller

CLASSIFICATION AND CLINICAL FEATURES The term cerebral palsy is not a diagnosis, nor does its use denote a specific etiology or degree of severity. The term defines a condition whose cause is no longer active and that occurred during brain development. The cerebral palsies are a heterogeneous group of clinical syndromes that are characterized by motor and postural dysfunction caused by a nonprogressive lesion in the developing brain. Although the disorder itself is nonprogressive, the appearance of neuropathological lesions and their clinical expression change over time as the brain matures.1 Classification of the cerebral palsy syndromes is based on the type and distribution of the motor abnormality (Table 121–1). An overlap of findings can occur, but the principal features are usually evident by age 5 years. Patients with a spastic syndrome have the features of an upper motor neuron syndrome. These include the positive signs of spastic hypertonia, hyperreflexia, extensor plantar responses, clonus, and contractures. Negative signs include slow, effortful, uncoordinated voluntary movements; poor fine motor function; difficulty isolating individual movements; and fatigability. The spastic syndromes are subdivided according to the distribution of abnormal signs. In spastic diplegia, the legs are more affected than the arms. In spastic quadriplegia, the arms are involved equally or more than the legs, and in hemiplegia, one side of the body is involved. Dyskinetic signs may be found in all the spastic syndromes. Spastic diplegia can occur in both full-term and preterm infants, but it is associated particularly with prematurity, the risk increasing with the degree of prematurity, and is often associated with periventricular leukomalacia and ventriculomegaly. Patients with mild leukomalacia have relatively good hand function and fewer associated disabilities. Those with more severe involvement have compromised hand function, contractures, cortical sensory impairment, and involuntary movements and are more likely to have strabismus and visual impairment. Poor growth, particularly below the waist, is usually present. Asymmetrical diplegia, which can be found in preterm infants after unilateral hemorrhagic infarction, is associated with more severe disabilities than is symmetrical spastic diplegia. Spastic hemiplegia typically affects full-term infants of normal birth weight and may be caused by prenatal cere-

brovascular events, neonatal stroke, or cerebral dysgenesis. Postnatal causes include arterial and venous stroke, trauma, infection, and vasculopathies.2 The condition may be missed during early infancy without careful examination and may manifest later as early hand dominance and reduced movement or abnormal posturing on one side. A focal seizure, or a secondarily generalized one, may be the first indication of its presence. The typical hemiplegic gait is noted when the child begins to walk or run; walking and running usually begin within the normal age range, or are only mildly delayed, unless marked mental retardation is present. In general, frank disorders of language are related more closely to cognitive abilities than to the side of the lesion. Cortical sensory deficits on the affected side are correlated with poor growth, although not with the severity of the motor deficit.3 Spastic quadriplegia1 is the most severe form of spastic cerebral palsy. Causes include prenatal infection or cerebral dysgenesis occurring in full-term infants who are small for gestational age, severe perinatal or postnatal diffuse brain insults, and extreme prematurity. Common associated features include marked mental retardation, profound motor disability, dysarthria or anarthria, seizures, hip deformity, scoliosis, and limb contractures. Sensory impairment, in particular visual, may be present, in addition to microcephaly. The dyskinetic cerebral palsy syndromes1 typically affect full-term infants and can follow severe acute full-term perinatal asphyxia because of selective basal ganglia damage and status marmoratus.4 These syndromes are divided into two types: mainly athetoid, in which the abnormal movements are a combination of athetosis and chorea, and mainly dystonic. Dysarthria and oropharyngeal difficulties are present in conjunction with facial grimacing. Retained primitive reflexes are a feature. Emotion, change in posture, or intended movement may worsen or induce the abnormal movements. Those with the mainly dystonic form tend to be more severely disabled, with anarthria and poor feeding, and are unable to ambulate. Manifestation in early infancy is with delayed psychomotor development, decreased tone, drooling, grimacing, and abnormal retention of primitive reflexes. The involuntary movements develop with time and may not be clearly apparent until ages 2 to 3 years. Contractures usually do not develop unless they are positional. Patients with ataxic cerebral palsy usually are born at term, and most cases are

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T A B L E 121–1. Cerebral Palsy Syndromes Spastic Diplegia Good hand function Poor hand function Asymmetrical Hemiplegia Arm involved more than leg Leg involved as much as or more than arm Quadriplegia Dyskinetic Mainly athetoid Mainly dystonic Ataxic Simple ataxia Ataxic diplegic Atonic From Miller G: Cerebral palsies: an overview. In Miller G, Clark GD, eds: The Cerebral Palsies. Causes, Consequences, and Management. Boston: ButterworthHeinemann, 1998, pp 1-36.

caused by early prenatal events,1 including genetic causes.5 They manifest with congenital hypotonia and delayed language and gross motor skills. The development of speech, which is typically slow, jerky, and explosive, is related to intellectual ability. The ataxia usually improves with age. The diagnosis is made by exclusion, with the recognition that all patients with cerebral palsy have some degree of incoordination and disturbed posture. The condition should also be distinguished from metabolic and degenerative disorders, which may manifest with some of the same features. The atonic syndromes are a form of cerebral palsy that is not often described. Affected infants are born at term with severe hypotonia. Many have cerebral dysgenesis, microcephaly, and profound mental retardation. Development is extremely delayed, and the children never stand or walk. Those findings that characterize other cerebral palsy syndromes are absent. Tone remains decreased for one to two years and then becomes variable and paratonic.

ASSOCIATED DISORDERS Other disorders of brain function frequently accompany the motor abnormalities that characterize cerebral palsy.6 These include mental retardation, epilepsy, and abnormalities of vision, hearing, language, cortical sensation, attention, learning, and behavior. Dyspraxias and agnosias may interfere with skilled tasks, independently from the severity of gross motor dysfunction. Mental retardation often, but not always, is correlated with the severity of motor handicap, and patients with atonic cerebral palsy or spastic quadriplegia are the most severely affected. Seizures are also most common in atonic cerebral palsy and spastic quadriplegia, in addition to acquired hemiplegia, and least common in mild symmetrical spastic diplegia and mainly athetoid cerebral palsy.1 Ocular and visual abnormalities are common and include refractive error, strabismus, amblyopia, field defects, cortical visual impairment, and eye movement abnormalities. Disorders of speech and

language are frequent and often complex, and it is important to assess for hearing loss. Although failure to thrive and poor nutrition may be related to nonnutritional factors, poor nutrition often plays a significant role in the severity of cerebral palsy and can be combated by the early use of a gastrostomy.7 Palatopharyngeal incoordination and gastroesophageal reflux contribute to chronic respiratory disease in patients with severe cerebral palsy, and this is further worsened by respiratory muscle incoordination, chest deformity, and sleep apnea. Immobile patients are at risk for osteopenia and fractures, and orthopedic disorders, including hip dislocation and scoliosis, are common. Although the primary neuropathological lesion is static, neurological signs may change or worsen with increasing age.8 However, sometimes the changes are caused by a spondylotic myelopathy. Drug reactions may also be cause of new or worsening neurological signs: for example, they may follow intake of carbamazepine or phenytoin.

DIAGNOSIS Early diagnosis can be made on the basis of a combination of history and clinical findings. These include motor delay, abnormal or delayed postural responses, persistence of primitive reflexes, and abnormal neurological signs. The finding of an isolated abnormality such as mild hypertonia or hyperreflexia in the setting of normal development and behavior is an indication to observe closely. In most cases, if these findings remain isolated, they resolve during the first year of life. A diagnosis may be suspected if there is abnormal behavior such as undue irritability or excessive docility, abnormal oromotor or oculomotor findings, and developmental delay. Primitive reflexes may be asymmetrical or persistent, and postural reactions delayed. Accompanying abnormal neurological signs may include hypotonia and hyperreflexia. Spasticity may not be evident until 6 months of age, whereas dyskinesias may not be obvious until the second year and ataxia even later. By definition, definite diagnosis requires serial examinations. Thus, an early history might be poor feeding and sleeping in a young infant, who is often irritable, is visually inattentive, arches when handled, and has poor head control when pulled to a sitting position. Examination includes an evaluation of posture and tone in prone and supine positions, when pulled to sit, in supported sitting, and in ventral and vertical suspension. Although abnormal findings are suggestive of an abnormal nervous system, and not necessarily cerebral palsy, in the correct setting the diagnosis can be made after serial evaluation. Similarly, the presence of primitive reflexes such as the tonic neck, tonic labyrinthine, and positive support reflexes might suggest the diagnosis.9 These usually are suppressed between the ages of 3 and 6 months, but if they are maintained or obligatory, this is abnormal. For example, a tonic labyrinthine response can be elicited in the supine position by extending or flexing the neck; extending causes flexion of the limbs, and flexing causes limb extension. An abnormal positive support response, occurring when the baby is held in vertical suspension, is extension of the legs, and weight bearing elicits sustained plantar flexion of the feet. Coordination of the upper limbs is also affected, and a failure to develop a pincer grasp, in conjunction with splaying of the hand when attempting to reach and grasp, may also be observed.

chapter 121 neurology of cerebral palsy NEUROIMAGING Magnetic resonance imaging has become a useful diagnostic instrument during the neonatal period. Abnormal signal in the posterior limb of the internal capsule after hypoxic-ischemic injury is correlated with adverse neurodevelopmental outcome,10 as is abnormal appearance on diffusion-weighted imaging.11 In the newborn brain, the imaging sequence most sensitive to injury depends on the timing of the injury. During the first few days, diffusion-weighted imaging is most sensitive, particularly from days 2 through 4. At 1 week, T1- and T2weighted images are most sensitive.12 Later in life, magnetic resonance imaging can identify a lesion in the majority of cases and can often provide information regarding the timing of the insult.13,14

INVESTIGATIONS Cerebral palsy is a diagnosis of exclusion. A practice parameter from the American Academy of Neurology and the Child Neurology Society (Ashwal et al, 2004)14 stressed that it is important to determine that the condition is not progressive or degenerative. Thus, a detailed history and examination are important, in addition to screening for mental retardation, vision and hearing abnormalities, speech and language disorders, and nutrition and feeding. Magnetic resonance imaging of the brain is recommended as an aid to determining etiology and prognosis. Metabolic and genetic testing should be performed if the history or findings on neuroimaging do not identify a specific structural abnormality or clear evidence of a diagnosis, or if there are atypical features in the history or examination that might be suggestive of a neurometabolic or neurogenetic disorder.

ETIOLOGY Cerebral palsy occurs in about 2 per 1000 live births; the rate increases with decreasing gestational age.15 About half the cases occur in infants born at term, and most of these are caused by prenatal factors. Perinatal asphyxia in term infants contributes only a small proportion to the overall numbers.16 Cerebral palsy has been reported in 12% of infants born with a gestational age of less than 27 weeks and in 8% of infants with a birth weight of less than 800 g.17 The American College of Obstetricians and Gynecologists, in collaboration with the American Academy of Pediatrics (2003), have published criteria for establishing a link between intrapartum events and later cerebral palsy.18 These criteria include (1) evidence of metabolic acidosis in fetal umbilical cord arterial blood at delivery with a pH of less than 7 and a base excess of more than 12 mmol/L, although this by itself is not a useful finding, inasmuch as most newborns with this finding are neurologically normal later; (2) early-onset moderate or severe neonatal encephalopathy in infants of 34 or more weeks’ gestation; (3) a spastic or dyskinetic cerebral palsy; and (4) exclusion of other identifiable etiologies such as trauma, coagulation disorders, infection, or genetic disorders. An intrapartum association may be suggested if there is a sentinel event immediately before or during labor such as a ruptured uterus, placental abruption, umbilical cord prolapse, amniotic fluid embolism, maternal cardiac arrest, or severe hemorrhage. Although abnormal fetal heart rate patterns such

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as late decelerations and loss of beat-to-beat variability may be present in infants who later develop cerebral palsy, the falsepositive rate is 99%. Other findings include evidence of multiple organ damage. In many children, cerebral palsy is the result of a brain malformation.19 Brain malformations result from abnormal brain development that might affect cell proliferation, migration, differentiation, survival, or synaptogenesis. This could occur as a result of exposure to radiation, teratogens, or infectious agents during a critical period of gestation. Chromosomal abnormalities can be associated with malformations, as can some neurocutaneous syndromes such as hypomelanosis of Ito or the linear sebaceous nevus syndrome with hemimegalencephaly. Many malformations have a known genetic basis. X-linked lissencephaly/subcortical band heterotopia is caused by mutations of the X-linked gene that codes for doublecortin, a microtubule-associated protein. Because of random X-inactivation, affected boys and men have type 1 lissencephaly, and affected girls and women may have the less severe form, characterized by subcortical band heterotopia. The Miller-Dieker syndrome is also associated with type 1 lissencephaly and caused by a microdeletion at locus 17q13.3 that involves the LIS 1 gene product platelet activating factor acetylhydrolase, which is involved in the regulation of microtubules and neuronal migration. Bilateral periventricular nodular heterotopia is an Xlinked dominant disorder, lethal in male fetuses, and is caused by a mutation in the filamin 1 gene. Filamin 1 is a cytoskeletal actin-binding protein that plays an important role in cellular movement. Polymicrogyria is a cortical malformation in which there is an excessive number of small gyri separated by abnormally shallow sulci. The underlying cytoarchitecture is abnormal. Causes are both nongenetic and genetic. Nongenetic causes include infections, such as cytomegalovirus, and inadequate perfusion. Genetic forms20 include the autosomal recessive bilateral frontoparietal polymicrogyria, which is related to mutations in the GPR56 gene on chromosome 16; bilateral perisylvian polymicrogyria, some cases of which are linked to a mutation at locus Xq28; autosomal recessive bilateral generalized polymicrogyria; and possibly sporadic bilateral frontal polymicrogyria and bilateral parasagittal parieto-occipital polymicrogyria. Schizencephaly is a neuronal migration disorder characterized by a unilateral or bilateral cleft, lined with polymicrogyria, extending from the pial surface to the lateral ventricle.21 All these conditions may manifest with seizures and various types of spastic cerebral palsy. Some cases are caused by mutations in the homeobox gene EMX2. Another homeobox gene associated with brain malformations is the ARX gene, located at Xp22.13.22 Abnormal phenotypes include X-linked lissencephaly with ambiguous genitalia, hydranencephaly with ambiguous genitalia, and Partington’s syndrome (mental retardation, dystonic hand movements, dysarthria, and awkward gait). The risk of cerebral palsy is increased among multiple births, and in utero death of a twin increases the risk.23 Some cases may be caused by an unrecognized fetal death of a twin.24 Perinatal stroke contributes to the etiology of cerebral palsy, particularly spastic hemiplegia. The condition may manifest with a neonatal seizure, or it may not be recognized until later in infancy or early childhood. The stroke is often arterial but can be caused by sinovenous thrombosis. Risk factors include preeclampsia, intrauterine growth retardation, and coagulation

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abnormalities. The last include decreased levels of protein C, protein S, and antithrombin III; increased lipoprotein and homocysteine levels; and genetic factors such as factor V Leiden and factor II mutations.2 Intracranial hemorrhage in a full-term infant may manifest with seizures, abnormal movements, apnea, lethargy, irritability, and a bulging fontanelle.25 Residual germinal matrix may be the source of a thalamic hemorrhage. Predisposing factors for cerebral vein thrombosis, such as sepsis, congenital heart disease, coagulopathy, and electrolyte disturbance, may also be present26. Infectious causes include congenital infections such as cytomegalovirus, syphilis, varicella, and toxoplasmosis. Chorioamnionitis is associated with cerebral palsy in both fullterm and preterm infants27,28 and is thought to be related to increased concentrations of inflammatory mediators, such as interleukins and tumor necrosis factor,29 which are part of an inflammatory response that damages white matter. Cerebral palsy develops in about 5% to 15% of surviving preterm infants1 and is associated with periventricular leukomalacia, ventriculomegaly, posthemorrhagic hydrocephalus, and periventricular hemorrhagic infarction.1 Periventricular leukomalacia is necrosis of cerebral white matter with a characteristic distribution dorsolateral to the external angles of the lateral ventricles and adjacent to the trigones and to the frontal horn and body of the lateral ventricles.30 In the preterm infant, this region is more vulnerable to insults such as ischemia or infection30; parts of the immature brain are more vulnerable to various insults and become less vulnerable as the brain matures. Several reasons have been proposed to explain this. These include the vascular anatomy in the preterm infant, in whom two systems supply blood to the cerebral hemispheres; both course from the brain surface. The ventriculofugal system travels down to the ventricles and then back into the brain toward the cortex. The ventriculopetal system penetrates into the brain toward the ventricles. The systems form a boundary zone around the ventricles, which can become a watershed region.31 Glial cells in the periventricular region, particularly oligodendrocytes, are vulnerable to damage, inasmuch as they are actively differentiating and their metabolic activity is increased. They are also more prone to excitotoxic damage brought about by glutamate, which increases after ischemic injury and is mediated by free radical attack.1 The region is also susceptible to cytokines, which are produced in maternal and fetal infections.32

ACQUIRED POSTNATAL CAUSES Most acquired postnatal cases of cerebral palsy are the spastic form.33 Causes include severe hypoxic-ischemic insults such as near-drowning, stroke, trauma, and infection.

PROGNOSIS Most children with cerebral palsy survive to adulthood, survival depending on the degree of disability.34 Although the rate of mortality is affected by the aggressiveness and quality of care, patients who are immobile and require tube feeding are more likely to die early from respiratory disease.35 Early prediction of motor outcome can be difficult and depends on several factors.1,36,37 The prognosis for walking is poor in children who do not achieve head control by age 20

T A B L E 121–2. Priorities of Management of Cerebral Palsy in Order of Importance Social and emotional development Communication Education Nutrition Mobility Maximal independence in activities of daily living

months, retain primitive reflexes and have no postural responses by age 24 months, and do not crawl by about 5 years of age. Conversely, the prognosis for walking is good for those who sit independently by age 2 years and crawl before 30 months. Restricted or aided ambulation may be achieved by those who sit between ages 3 and 4 years. Intelligence, social factors, and the availability of services may affect these outcomes.

MANAGEMENT The priorities of management are listed in Table 121–2. Details of these are beyond the scope of this chapter. However, of importance is that management is best delivered in specialized multidisciplinary clinics or centers that have access to psychologists, social workers, and therapists.

K E Y

P O I N T S

●

The cerebral palsies are nonprogressive disorders classified according to motor dysfunction.

●

They are heterogeneous and caused by nondegenerative abnormalities of the developing brain.

●

About half of cases occur in full-term infants.

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Perinatal asphyxia is responsible for only a small proportion of cases, and these patients have a readily identifiable clinical history.

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Incidence increases with decreasing gestational age.

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Associated disorders can cover the full range of abnormal brain function.

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Diagnosis requires serial examinations and is based on a combination of history and clinical findings.

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Cerebral palsy is a diagnosis of exclusion.

Suggested Reading American College of Obstetricians and Gynecologists Task Force on Neonatal Encephalopathy and Cerebral Palsy, American College of Obstetricians and Gynecologists, American Academy of Pediatrics: Neonatal Encephalopathy and Cerebral Palsy: Defining the Pathogenesis and Pathophysiology. Washington, DC: American College of Obstetricians and Gynecologists, 2003. Ashwal S, Russman BS, Blasco PA, et al: Diagnostic assessment of the child with cerebral palsy. Neurology 2004; 62:851-863.

chapter 121 neurology of cerebral palsy Ferriero DM: Neonatal brain injury. N Engl J Med 2004; 351:19851995. Miller G, Clark GD, eds: The Cerebral Palsies. Causes, Consequences, and Management. Boston: Butterworth-Heinemann, 1998, pp 1-36. O’Shea TM: Cerebral palsy in very preterm infants: new epidemiological insights. Ment Retard Dev Disabil Res Rev 2002; 8:135146.

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19.

References 1. Miller G: Cerebral palsies: an overview. In Miller G, Clark GD, eds: The Cerebral Palsies. Causes, Consequences, and Management. Boston: Butterworth- Heinemann, 1998, pp 1-36. 2. Ferriero DM: Neonatal brain injury. N Engl J Med 2004; 351:1985-1995. 3. Cooper J, Majnemer A, Rosenblatt B, et al: The determination of sensory deficits in children with hemiplegic cerebral palsy. J Child Neurol 1995; 10:300-3007. 4. Menkes JH, Curran J: Clinical and MR correlates in children with extrapyramidal cerebral palsy. AJNR Am J Neuroradiol 1994; 15:451-457. 5. Miller G, Cala LA: Ataxic cerebral palsy—clinicoradiologic correlation. Neuropediatrics 1989; 20:84-89. 6. Murphy CC, Yeargin-Allsopp M, Decoufle P, et al: Prevalence of cerebral palsy among 10-year-old children in metropolitan Atlanta 1985 through 1987. J Pediatr 1993; 123:513-520. 7. Rogers B: Feeding method and health outcomes of children with cerebral palsy. J Pediatr 2004; 145(2 Suppl):528532. 8. Scott BL, Jankovic J: Delayed-onset progressive movement disorders after static brain lesions. Neurology 1996; 46:6874. 9. Zafeirou DI, Tslkoulas IG, Kremenopoulos GM: Prospective follow-up of primitive reflex profiles in high-risk infants: clues to an early diagnosis of cerebral palsy. Pediatr Neurol 1995; 13:148-152. 10. Rutherford MA, Pennock JM, Counsell SJ, et al: Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic ischemic encephalopathy. Pediatrics 1998; 102:323-328. 11. Hunt RW, Neill JJ, Coleman LT, et al: Apparent diffusion coefficient in the posterior limb of the internal capsule predicts outcome following perinatal asphyxia. Pediatrics 2004; 114:999-1003. 12. Neil JJ, Inder TE: Imaging perinatal brain injury in premature infants. Semin Perinatol 2003; 28:433-443. 13. Yin R, Reddihough D, Ditchfield M, et al: Magnetic resonance imaging findings in cerebral palsy. J Pediatr Child Health 2000; 36:139-144. 14. Ashwal S, Russian BS, Blasco PA, et al: Diagnostic assessment of the child with cerebral palsy. Neurology 2004; 62:851-863. 15. Nelson KB: The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil Res Rev 2002; 8:146-150. 16. Perlman JM: Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy: medico-legal issues. Pediatrics 1997; 99:851-859. 17. Lorenz JM, Wooliever DE, Jetton JR, et al: A quantitative review of mortality and developmental disability in extremely

20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

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premature newborns. Arch Pediatr Adolesc Med 1998; 152:425435. American College of Obstetricians and Gynecologists Task Force on Neonatal Encephalopathy and Cerebral Palsy, American College of Obstetricians and Gynecologists, American Academy of Pediatrics: Neonatal Encephalopathy and Cerebral Palsy: Defining the Pathogenesis and Pathophysiology. Washington, DC: American College of Obstetricians and Gynecologists, 2003. Ross ME, Walsh CA: Human brain malformations and their lessons for neuronal migration. Annu Rev Neurosci 2001; 24:1041-1070. Chang BS, Piao X, Gianni C, et al: Bilateral generalized polymicrogyria (BGP): a distinct syndrome of cortical malformation. Neurology 2004; 62:1722-1728. Foldrary-Schaefer N, Bautista J, Andermann F, et al: Focal malformations of cortical development. Neurology 2004; 62(Suppl 3):S14-S19. Suri M: The phenotypic spectrum of ARX mutations. Dev Med Clin Neurol 2005; 47:133-137. Petterson B, Nelson KB, Watson L, et al: Twins, triplets, and cerebral palsy in births in Western Australia in the 1980’s. BMJ 1993; 307:1239-1243. Pharoah PO: Twins and cerebral palsy. Acta Pediatr 2001; 90(Suppl 436):6-10. Hanigan WC, Powell FC, Miller TC, et al: Symptomatic intracranial hemorrhage in full term infants. Child Nerv Syst 1995; 11:698-703. Roland EH, Flodmark O, Hill A: Thalamic hemorrhage with intraventricular hemorrhage in the full term newborn. Pediatrics 1990; 85:737-742. Wu YW, Escobar GJ, Grether JK, et al: Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003; 290:2677-2684. O’Shea TM: Cerebral palsy in very preterm infants: new epidemiological insights. Ment Retard Dev Disabil Res Rev 2002; 8:135-146. Nelson KB, Dambrosia JM, Grether JK, et al: Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 1998; 44:665-675. Inder TE, Volpe JJ: Mechanisms of perinatal brain injury. Semin Neonatal 2000; 5:3-16. Takashima S, Tanaka K: Development of cerebrovascular architecture and its relationship to periventricular leukomalacia. Arch Neurol 1978; 35:11-19. Dammann O, Leviton A: Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997; 42:1-8. Pharaoh PO, Cooke T, Rosenbloom L: Acquired cerebral palsy. Arch Dis Child 1989; 64:1013-1016. Strauss D, Shavelle R: Life expectancy of adults with cerebral palsy. Dev Med Child Neurol 1998; 40:369-374. Eyman RK, Grossman HJ, Chaney RH, et al: Survival of profoundly disabled people with several mental retardation. Am J Dis Child 1993; 147:329-336. Molnar GE, Gordon SU: Cerebral palsy: predictive value of selected clinical signs for early prognostication of motor function. Arch Phys Med Rehabil 1979; 57:153-158. Rosenbaum PL, Walter SD, Hanna SE, et al: Prognosis for gross motor function in cerebral palsy: creation of motor development curves. JAMA 2002; 288:1357-1363.

INDEX

Note: Page numbers followed by the letter f refer to figures; those followed by t refer to tables.

A A band, of sarcomere, 1095, 1096f ABCD1 gene, in X-linked adrenoleukodystrophy, 281 ABCR4 gene, in Stargardt disease, 277 Abortion, elective, for neural tube defects, 498 Abscess brain after organ transplantation, 1565 epilepsy due to, 698 epidural, 519-520, 520t, 521f spinal cord, intramedullary, 520 Absence seizures, 675. See also Seizure(s). impaired consciousness in, 695 in childhood, 703 treatment of, 714 treatment of, 710-712 Absence status epilepticus, 719, 721f. See also Status epilepticus. Abstract thinking, 14 Abuse of alcohol. See Alcoholism; Ethanol entries. of illicit drugs, 1537-1539. See also named substance. intoxication and withdrawal in, 1537-1538 medical and neurological complications of, 1538-1539 Acalculia, 13 Accidents, vehicular Alzheimer’s disease and, 855 sleep-related, 204-205 Acebutolol, for tremor, 419 Aceruloplasminemia, 305 Acetazolamide for epilepsy, in women, 716 for idiopathic intracranial hypertension, 812 for seizures, 712 Acetylcholine receptor antibodies myasthenia gravis with, 1226-1227 myasthenia gravis without, 1228 Acetylcholine receptor deficiency syndromes, 1231, 1232t Acetylcholine receptor/muscle-specific receptor tyrosine kinase antibody–negative myasthenia gravis, 1228 Acetylcholinesterase deficiency syndrome, 1232t N-Acetylcysteine, for amyotrophic lateral sclerosis, supplemental, 870t N-Acetylglutamate synthase deficiency, 1470t, 1473

Achromatopsia, congenital, 275-276 Acid maltase deficiency, 1195 Acid-base balance, respiration and, 1575 Aciduria, organic, 1441 Acoustic neuroma (vestibular schwannoma), 1338 Acoustic reflex, in evaluation of hearing, 320321 Acousticomnestic aphasia, 36 Acquired immunodeficiency syndrome (AIDS). See Human immunodeficiency virus (HIV) infection entries. ACTA1 gene in congenital myopathies, 1170 in nemaline myopathy, 1176 ACTH. See Adrenocorticotropic hormone (ACTH). Action tremor, 417 Action-intentional disorders, 75 Activation, of tremors, 417, 418t Activities of daily living in Alzheimer’s disease, 852 in rehabilitation programs, 1427-1428 Acute disseminated encephalomyelitis, 519 Acute inflammatory demyelinating polyradiculoneuropathy, 1137 Acute motor-sensory axonal neuropathy, 1137 Acute necrotizing myopathy, 1371 Acyclovir for herpes simplex encephalitis, 1256 for herpes zoster virus infection, 1136 Adaptive equipment, in rehabilitation, 1428, 1428f-1430f, 1428t, 1430t Addenbrooke’s Cognitive Examination (ACE), 15 Addison-only phenotype, in X-linked adrenoleukodystrophy, 1066 Adenohypophysial hormones, 1551, 1552f Adenosine, in cerebral circulation regulation, 546 ADH (antidiuretic hormone), 1551 source and function of, 1550t Adhesions, in tethered cord syndrome, 499 Adipose-brain axis, 1553-1554, 1554f Adolescents attention-deficit hyperactivity disorder in, 132 epileptic syndromes in, 703 metachromatic leukodystrophy in, 1069 vanishing white matter disease in, 1080 Adrenal cortex, in X-linked adrenoleukodystrophy, 1066

Adrenocorticotropic hormone (ACTH), 1553 for West’s syndrome, 713 source and function of, 1550t Adrenoleukodystrophy neonatal, 281 X-linked, 281-282, 1065-1069. See also Xlinked adrenoleukodystrophy. Adrenomyeloneuropathy, 510 cerebral form of, 1065 neuroimaging of, 1067 “pure,” 1065 pathogenesis of, 1068 pathology of, 1066 Advanced sleep phase syndrome, 196 ADVISE mnemonic, 609 Affect, 6, 235 blunting of, 6 Affective disorders, 235-243. See also specific disorder, e.g., Depression. African trypanosomiasis, 1273, 1275 treatment of, 1275, 1276t Age of onset of blindness, 275 of brain tumors, 1324 of cognitive impairment, 3 of dystonia, 443, 444t of epilepsy, 698, 698t of hereditary spastic paraplegia, 903 of myasthenia gravis early, 1226, 1227t late, 1227, 1227f, 1227t Aggression, in Alzheimer’s disease, 852 Agitation in Alzheimer’s disease, 852 in dementia, management of, 853t, 856 in Lewy body dementia, 912 management of, 856 Agnosia lexical, 36 visual, 60-61, 61t apperceptive, 62 associative, 62-63, 63f compensatory techniques for, 68 screening for, 67t Agrammatism, in Broca’s aphasia, 34 Agraphia, 4 acquired neurogenic, 40, 40t alexia with, 40 alexia without, 39-40, 60, 61t, 62 screening for, 67t classification of, 40t, 41t testing of, 12

1583

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Index

AIDS (acquired immunodeficiency syndrome). See Human immunodeficiency virus (HIV) infection entries. Air conduction thresholds, 319-320 Air embolism, 1575 Airway, restriction of, during apneic event, 203, 204f Akinetic mutism, 118 Akinetopsia, 64, 64t, 65f screening for, 67t Albendazole, for Taenia solium cysticercosis, 1279 Albinism, 276, 276f Albumin, production of, in pregnancy, 1491 Alcohol withdrawal–related seizures, treatment of, 714 Alcoholism, 1539 amnesic periods associated with, 49 chronic, treatment of, 1543 nonnutritional neurological complications of, 1542-1543 nutritional disorders associated with, 1541 Aldolase deficiency, 1198 Alexander’s disease clinical features of, 1076 diagnosis of, 1077 genetics of, 1076 neuroimaging of, 1076, 1077f pathogenesis of, 1077 synonyms for, 1076 treatment of, 1078 Alexia, 4, 39-40 aphasic, 40 deep, 39, 39t neurological classification of, 39 pure, 13, 39-40 surface, 39, 39t with agraphia, 40 without agraphia, 39-40, 60, 61t, 62 screening for, 67t Aliquorrhea, 817 Alkaloids, vinca, neurological complications caused by, 1354-1355 Allergic encephalomyelitis, 1057, 1059t Allesthesia, 74 Allodynia, in migraine, 736 Almotriptan, for migraine, 745t, 746 Alpha-agonists, prophylactic, for chronic daily headache, 768t Alpha-fetoprotein, 1490 maternal serum, in diagnosis of neural tube defects, 498 Alpha-synuclein (PARK1) gene, in Parkinson’s disease, 928t, 929-930, 932 Alprazolam, for tremor, 421, 422t Alteplase Thrombolysis for Acute Noninterventional Therapy Ischemic Stroke (ATLANTIS) study, 572 Alternate cover test, for diplopia, 272 Alternative pathway therapy, for urea cycle disorders, 1475, 1475f Alternative therapy, for epilepsy, 718 Aluminum walkers, 1428t, 1429f Alzheimer’s cells, in Wilson’s disease, 1449 Alzheimer’s disease, 846-856 amyloid hypothesis for, 847-848, 848f arguments against, 848-849 apathy in, 242 causes of, 851t definition of, 846 dementia in, 846 agitation and, management of, 853t, 856 medical and neurological conditions contributing to, 852 depression in, 236-237, 852 diagnosis of, 850-853

Alzheimer’s disease (Continued) cognitive and visuospatial domains in, 851 history in, 851, 851t mental status examination in, 852, 854t psychiatric factors in, 852 special tests in, 853 DSM-IV criteria for, 847t epidemiology of, 846 genetics in, 846-847, 848t management of durable power of attorney in, 856 establishing cause in, 853t, 856 finances in, 856 grading severity in, 856 intervention in, 856 pharmacological, 854, 854t safety issues in, 855-856 therapies in development in, 854-855 markers for, 853 memory impairment associated with, 53, 54f neurofibrillary tangles in, 849-850, 849f neuroimaging of, 853, 854f, 855f NINCDS-ADRDA criteria for, 847t pathological diagnostic criteria for, 850 pathology of, 849-850, 849f plaques in amyloid protein, 847-848, 848f nonamyloid component of, 850 senile, 849-850, 849f putative protective factors for, 848t risk factors for, 847t vs. vascular dementia, 642t Amantadine for dyskinesia, 946 for parkinsonism, in multiple system atrophy, 967 for Parkinson’s disease, 945 for tremor, 422t Amblyopia alcoholic, 1541 toxic, centrocaecal scotoma due to, 266f Ambulation, community, definition of, 497 Ambulatory monitoring systems, in assessment of gait, 460-461, 461f, 462f Amebiasis, 1273, 1275t Amebic encephalitis, 1273, 1275t American Spinal Injury Association (ASIA) classification, of spinal cord injury, 1423, 1424f American Spinal Injury Association (ASIA) impairment scale, of spinal cord injury, 1423, 1425f Amino acid disorders, retinopathy and optic neuropathy associated with, 280-281 Aminoaciduria, persistent, in Wilson’s disease, 1450 Aminoglycosides, for muscular dystrophy, 1159 Amiodarone, toxic neuropathy due to, 1120 Amitriptyline for progressive supranuclear palsy, 973 prophylactic for migraine, 747t, 748 for tension-type headache, 759, 759t Amnesia, 44-45, 44f alcohol-induced, 49 electroconvulsive therapy–induced, 49 emergency management of, 51t for non-REM parasomnias, 197 hysterical, 55 Korsakoff’s psychosis causing, 50-51 lesion sites associated with, 49-50, 50f post-traumatic, 49 transient epileptic, 49 transient global, 48 Amnesic syndrome, 44 Amnestic mild cognitive impairment, 53

Amniocentesis, in diagnosis of neural tube defects, 498 Amoxicillin, for Lyme disease, 1135 Amphiphysin antibodies, in stiff-person syndrome, 1368, 1368f Amphotericin B for blastomycosis, 1290 for cryptococcosis, 1289 for histoplasmosis, 1290 for mucormycosis, 1291 Amputation, for malignant peripheral nerve sheath tumor, 1382 Amsler grid, defect in, due to age-related macular dystrophy, 269, 269f Amyloid hypothesis, of Alzheimer’s disease, 847848, 848f arguments against, 848-849 Amyloid precursor protein, in Alzheimer’s disease, 847, 848f β Amyloid protein, in Alzheimer’s disease, 847848 Amyotrophic lateral sclerosis, 859-873 anxiety in, management of, 873 clinical features of, 860-862 definition of, 859 dementia in, 865 management of, 873 depression in, management of, 872-873 diagnostic criteria for, 859, 861t diagnostic studies of electrophysiological testing in, 867, 868t laboratory testing in, 867, 870t muscle and nerve biopsy in, 867 neurophysiological evaluation in, 866-867, 867f, 869f differential diagnosis of, 862-865 symptom-based, 863t with lower motor neuron features, 864t dysarthria in, management of, 872 dysphagia in, 860-862, 862t management of, 872 dyspnea in, management of, 871-872, 871t environmental factors in, 866 epidemiology of, 860t fasciculations in, 860 management of, 871 fatigue in, management of, 871 genetic factors in, 866, 866t Internet Resources on, 859-860, 861t laryngospasm in, management of, 872 management of, 868-873 antioxidant supplementation in, 869, 870t excitotoxiciy in, 868 neuroinflammation and microglial activation in, 868-869 neurotrophic growth factors in, 869-870 pharmacological, 868, 870, 870t stem cell therapy in, 870 symptomatic and supportive care in, 870871 terminal care, 873 muscle cramps in, 860 management of, 871 nomenclature in, 859, 860t pain management in, 873 pathogenesis of, 865-866, 866t prognosis of, 873 relationship between other motor neuron diseases and, 860f respiratory muscle weakness in, 862t management of, 872t sialorrhea or drooling in, management of, 872 sleep disturbance in, 862 management of, 871-872

index Amyotrophic lateral sclerosis (Continued) spasticity in, management of, 871 with atypical features, 865 Amyotrophy, diabetic, 1114 Analgesics for cluster headache, 778 for migraine, 744, 744t Anastomoses external carotid–internal carotid, 541 leptomeningeal, 541, 542f venous, 623 Andersen syndrome, 1191 Anemia, sickle cell, 1527 Anencephaly, 495 Anesthetics, topical, for cluster headache, 778 Aneurysm atrial septal, stroke associated with, 554 conditions associated with, 589 intracranial coiling and clipping of, headache after, 799 diagnosis of, 589 epidemiology of, 587 etiology of, 587-588, 588f headache secondary to, 796, 796t manifestations of, 588-589 rupture of, 587-590 during pregnancy, 1496 treatment of, 589-590 Angiitis Aβ-related, 1317 primary headache secondary to, 798-799 of central nervous system, 1314-1315 Angioendothelioma, malignant, 1317 Angiography CT, of ischemic stroke, 566 MR of cerebral vasculitis, 1318 of ischemic stroke, 566-567 of spinal cord tumors, 1345 Angioma, cavernous, radiation-induced, 1358, 1358f Angiopathy, proliferative and hemorrhagic, vs. brain arteriovenous malformations, 599 Angioplasty, prophylactic, for ischemic stroke, 581-582 Angiostrongylus cantonensis infection, 1276, 1276t Angiotensin II receptor antagonists, for migraine, 749-750 Angiotensin-converting enzyme inhibitors, for migraine, 749 Anhedonia, 235 in Parkinson’s disease, management of, 946 Animal toxins, 1485 Aniridia, congenital, 276 Anisocoria, pupillary responses in, 270, 271f Anomia, testing of, 12 Anomic aphasia, 37 Anonnacin, associated with Parkinson’s disease, 933 Anophthalmia, 274 Anosmia in Alzheimer’s disease, 918 in multiple sclerosis, 1019 Anosodiaphoria, 75 Anosognosia, 8, 75 examination of, 77 Anterior cingulate circuit, in executive function, 85 Anterior cord syndrome, 1403 Anterior horn cell syndrome, 513t, 515t, 519 vs. amyotrophic lateral sclerosis, 862 Anterior spinal cord syndrome, 513t Anterograde amnesia, 44, 44f Anterograde episodic memory, 5

Antibiotics for bacterial meningitis, 1240-1241, 1241t, 1242t for leprosy, 1131-1132 for Whipple’s disease, 1516 toxic neuropathy due to, 1120, 1120t Antibody(ies). See Immunoglobulin(s); specific antibody. Anticholinergics for dystonia, 450-451, 451t in corticobasal ganglionic degeneration, 975 for neurogenic detrusor overactivity, 365-366, 365t for Parkinson’s disease, 945 for tremor, 422t intoxication and withdrawal of, 1538 Anticoagulants for cerebral vein and sinus thrombosis, 628629 for cerebral venous sinus thrombosis, 797 prophylactic, for ischemic stroke, 576-578 oral, 577-579 Anticonvulsants for traumatic brain injury, 1394 prophylactic for cerebral vein and sinus thrombosis, 629 for chronic daily headache, 768t, 769t for migraine, 747t, 748-749 Anti-CV2/CRMP5 antibodies, in paraneoplastic sensory neuropathy, 1369, 1369f Antidepressants for apathy, 243 for depression, 239 prophylactic for chronic daily headache, 768t, 769t for migraine, 747-748, 747t tricyclic, for autism, 135 Antidiuretic hormone (ADH), 1551 source and function of, 1550t Antidyskinetic agents, for gait disturbances, 468 Antiemetic agents, for migraine, 744 Antiepileptic agents, 707-713 for alcohol and drug withdrawal–related seizures, 714 for benign epilepsy with centrotemproal spikes, 714 for childhood absence epilepsy, 714 for elderly, 717 for epileptic seizures, in pregnancy, 1500 for febrile convulsions, 714 for generalized seizures, 710-712 for juvenile myoclonic epilepsy, 714 for Lennox-Gastaut syndrome, 714 for lesional epilepsy, 714-715 for neonatal seizures, 713 for partial and tonic-clonic seizures, 708-710 for trigeminal neuralgia, 838 for West’s syndrome, 713-714 for women, 715-716 principles of use of, 707-708 specific, 708 toxemia of pregnancy and, 716-717 with narrow spectrum of action, 712-713 withdrawal of, 717 Antiexcitotoxic agents, for amyotrophic lateral sclerosis, 870t Antiganglioside antibodies, in multiple sclerosis, 1007 Antigliadin antibodies, IgG, in gluten ataxia, 1512 Anti-Hu antibodies, in autoimmune autonomic neuropathy, 358 Anti-inflammatory agents for amyotrophic lateral sclerosis, 870t nonsteroidal, for migraine, 744, 744t

1585

Antineutrophil cytoplasmic antibodies, 13131314 Antioxidants, for amyotrophic lateral sclerosis, supplemental, 869, 870t Antiparkinsonism drugs, for corticobasal ganglionic degeneration, 975 Antiphospholipid antibodies, strokes associated with, 579 Antiphospholipid syndrome, 618 Antiplatelet therapy, prophylactic, for ischemic stroke, 574-575 combination agents in, 575-576 Antipsychotic agents for delirium, 150 for Gilles de la Tourette syndrome, 216-217 Antirecoverin antibodies, in paraneoplastic visual syndromes, 1371, 1371f Antispastic agents, for gait disturbances, 467468 Antisynthetase syndrome, 1212 Antitoxin, diphtheria, administration of, 1487 Anti–tumor necrosis factor-α therapy, for relapsing-remitting neurosarcoidosis, 1309 Anton’s syndrome, 564-565 after infarction, 564-565 Anxiety assessment of, 6-7 in Alzheimer’s disease, 852 in amyotrophic lateral sclerosis, management of, 873 in Lewy body dementia, 912 in multiple sclerosis, management of, 1051 in systemic lupus erythematosus, 1563 memory impairment associated with, 55 Apathy, 241-243 cerebral regions associated with, 241-242, 242f definition of, 8 in Alzheimer’s disease, 242 in cerebrovascular disease, 243 in frontotemporal dementia, 243 in parkinsonian syndromes, 243 in Parkinson’s disease, 243 in vascular dementia, 243 neurological conditions associated with, 243t treatment of, 243, 243f Aphasia, 4, 33-38. See also specific type. classification of, by fluency and comprehension, 34t, 984t fluent with impaired repetition and comprehension, 36 with normal comprehension and impaired repetition, 36-37 with normal repetition and impaired comprehension, 37 with normal repetition and preserved comprehension, 37 nonfluent progressive, 984t case study of, 987, 989f with impaired repetition, 34-35, 34t, 35f with normal repetition, 35-36 with normal repetition and impaired comprehension, 38 primary progressive, 38, 983 Aphasic status epilepticus, 721. See also Status epilepticus. Aphemia (speech dyspraxia), 34, 34t neuroanatomy of, 34 Aphonia (hoarseness), 159 psychogenic, 159 Apnea definition of, 203 sleep. See Sleep apnea entries. Apnea testing, in brain death, 108, 108t, 109t

1586

Index

Apneustic breathing, 100, 1572 Apolipoprotein E genotype, in frontotemporal dementia, 986 Apolipoprotein genotype, as risk factor for Alzheimer’s disease, 846, 848t Aponeurotic ptosis, 271 APP gene, in early-onset Alzheimer’s disease, 848t Appearance, assessment of, 6 Apperception, in sensory impressions, 60-61 Appetite, assessment of, 8 Apraxia, 13, 402-413 face, 412 gait, 413 limb, 402-412 callosal, 408 dissociation, 408 evaluation of, 402-403, 403t, 405f-407f ideational or conceptual, 404-405, 407 pathophysiology of, 409 ideomotor, 407-408 pathophysiology of, 410 imitation of actions in, 411-412 modality-specific, 408 neural processes underlying, 408-409 pathophysiology of, 409-411 praxic errors in, 403, 405f-407f limb-kinetic type of, 410-411 types of, 404t praxic functions in, lateralization of, 403404 treatment of, 412 types of, 404-405, 407-408 limb-kinetic, 408 pathophysiology of, 410-411 oculomotor, 64, 64t speech, 156-157 trunk, 412-413 Arboviral encephalitis, 1253-1254 Arginase deficiency (hyperargininemia), 1470t, 1474 Arginine, for urea cycle disorders, 1475 Arginine vasopressin, 1551 source and function of, 1550t Argininosuccinic acid synthase deficiency, 1470t, 1474 Argininosuccinic aciduria deficiency, 1474 Arnold-Chiari malformation, 348 Arotinolol, for tremor, 421, 421t Arousal, confusional, 197 Arousal deficits, treatment of, 80 Arsenic intoxication, 1122, 1477-1478 complications and management of, 1478, 1478t neuropathy due to, 1122 Artemether, for falciparum malaria, 1285 Arterial dissection, 615 stroke due to, 555-556, 555f, 556f Arteriosclerosis, 613, 615 Arteriovenous fistula, of brain, 595, 596, 597f Arteriovenous malformations of brain, 595-602 angioarchitecture of, 595, 596f, 597f, 598 calcifications in, 598 classification of, 595 clinical manifestations of, 599-600 diagnosis of, 601 false, 599 headache in, 600-601 hemorrhage in, 600 in neonates, infants, and children, 600 in pregnancy, management of, 1496-1497 incidence of, 595 multiple, 598-599 neurological deficits in, 600 seizure in, 600

Arteriovenous malformations (Continued) therapy for indications for, 601 modes of, 602 specific factors affecting, 601-602 topography of, 595-596, 598, 598t of spinal cord, 602-607 angioarchitecture of, 602, 603f, 604f classification of, 602, 603t clinical presentation of, 604-606 diagnosis of, 606 genetic hereditary lesions in, 603 genetic nonhereditary lesions in, 603-604 hemorrhage in, 604-605 imaging of, 606 incidence of, 602 nonhemorrhagic symptoms in, 605-606 treatment of, 606-607 Arteritis, giant cell, 298, 298f, 1320 headache secondary to, 797-798, 797f, 798t Artesunate, for falciparum malaria, 1285 Arthritis, rheumatoid, 1559-1561 Arthrogryposis multiplex congenita, 1228 ARX gene, in cerebral palsy, 1579 Ascending reticular activating system, 98 Aseptic meningitis. See also Meningitis. in systemic lupus erythematosus, 1562 Asperger’s disorder, 131 vs. autistic disorder, 129 Aspergillosis, 1291 after organ transplantation, 1565 Aspergillus, in spinal epidural abscess, 520 Aspergillus flavus, 1291 Aspergillus fumogatus, 1291 Aspergillus niger, 1291 Aspergillus terreus, 1291 Aspiration, oropharyngeal weakness causing, 861 Aspirin for tension-type headache, 759t prophylactic, for ischemic stroke, 574-575, 575f Aspirin with clopidogrel, prophylactic, for ischemic stroke, 575-576 Aspirin with dipyridamole, prophylactic, for ischemic stroke, 576 Association, in sensory impressions, 61 Associative agnosia, 61t, 62 environmental, 63 for familiar faces, 62-63, 63f Asterixis, 428 Astrocytes, in spinal cord injury, 1402 Astrocytoma of brain genetics in, 1330 imaging, pathology, and histology of, 1332f pathology of, 1328, 1329f of spinal cord, 528, 528t, 530 magnetic resonance imaging of, 1344, 1344f outcome for, 1349 radiation therapy for, 1349 Astroglial scar, in spinal cord injury, 1402 Ataxia. See also specific type, e.g., Friedreich’s ataxia. definition of, 337 gluten, 1512 inherited, 887-896. See also Inherited ataxia. macular changes in, 305, 305f optic, 64, 64t Ataxia hemiparesis, 556t, 557 Ataxia-telangiectasia, 887, 1443 Ataxic (Biot’s) breathing, 100 Ataxic dysarthria, 158-159, 158t, 160 Ataxic gait, 465t Ataxic respiration, 1572

Atelectasis, tympanic membrane, conductive hearing loss due to, 331 Atenol, for tremor, 419 Atherosclerosis, 611-613 circulating triglyceride load in, 611-612 diet and, 612 effect of inflammation in, 612-613 genetic causes of, 612, 615t large-artery, ischemic stroke due to, 552-553 pathogenesis of, 611-612, 616f small-artery, ischemic stroke due to, 553-554 tobacco smoke associated with, 619 Atlantoaxial disease, 1559-1561, 1560f Atlantoaxial dislocation, 489t, 491-492 Atlanto-occipital dislocation, 1398, 1398f Atlas (C1) fracture of, 1398, 1399f occipitalization of, 489t, 491 Atomoxetine, for autism, 135 Atonic seizures, 675-676, 694. See also Seizure(s). ATP7A gene, in Menkes disease, 1439 Atrial fibrillation, and cardioembolic stroke, 577 Atrial natriuretic factor, in regulation of blood pressure, 354 Atrial septal aneurysm, stroke associated with, 554 Atrophy, in multiple sclerosis, 1039 Atropine sulfate, for organophosphate insecticide toxicity, 1485 Attention focusing, in executive function, 87, 87f in Alzheimer’s disease, 851 neurocognitive assessment of, 4 neurocognitive examination of, 12, 12t Attention-deficit hyperactivity disorder, 129-138 autism with, 131 clinical features of, 131-132 DSM-IV-TR diagnostic criteria for, 129-130 epidemiology of, 130 genetic theories of, 134 Gilles de la Tourette syndrome associated with, 216 management of, 135 neuroanatomical and neuroimaging studies of, 134 neurocognitive theories of, 133-134 Audiological tests, for hearing, 319 Audiometry pure-tone, 319-320 speech, 320 Auditory brainstem response, in evaluation of hearing, 321 Auditory canal external stenosis or absence of, conductive hearing loss due to, 330-331 tumors of, conductive hearing loss due to, 330 internal, magnetic resonance imaging of, 322 Auditory neuronal loss, contributing to presbycusis, 332 Auditory seizures, 676. See also Seizure(s). Auditory system, disorders of, 329-333. See also Hearing loss. Auditory threshold, definition of, 319 Aura, migraine with, 343, 739-741, 742. See also Migraine. cortical spreading depression in, 739-740, 740f diagnostic criteria of, 742t Australian Streptokinase (ASK) Study, 570 Autism, 129-136 attention-deficit hyperactivity disorder with, 131 clinical features of, 130-131

index Autism (Continued) epidemiology of, 130 genetic theories of, 133 management of behavioral therapy in, 134 drug therapy in, 135 educational program in, 134-135 improved communication skills in, 135 parent training in, 135 neuroanatomical and neuroimaging studies of, 133 neurocognitive theories of, 132-133 vs. Asperger’s disorder, 129 Autoantibodies, in inflammatory myopathies, 1217 Autoimmune autonomic neuropathy, anti-Hu antibodies in, 358 Autoimmune disorders, 1316 thrombosis associated with, 618 Autoimmune limbic encephalitis, rare forms of, 705 Automatic breathing disorders, 1573 Autonomic dysfunction in Lewy body dementia, 913t, 914 treatment of, 922t, 923 in multiple sclerosis, 1022 in multiple system atrophy, 357-358, 373-374 management of, 967-968 Autonomic failure disorders. See also specific disorder. primary, 372-386 acute/subacute, 374-375 treatment of, 382-383 bladder function testing in, 379-380 brain imaging of, 381 cardiovascular function testing in, 378-379 causes of, 357-358 chronic, 375-378 treatment of, 383, 384t, 385-386 classification of, 372, 373t clinical presentation of, 374-378 functional imaging of, 382 laboratory assessment of, 378-382, 379t neuroendocrine testing in, 380-381 neuropathology of, 372-374 sphincter electromyography of, 380 structural imaging of, 381-382 treatment of, 382-386, 384t palliative, 386 Autonomic function tests, for multiple system atrophy, 963 Autonomic hyperreflexia, rehabilitation strategies for, 1431 Autonomic nervous system activity of, during sleep states, 181 primary failure of. See Autonomic failure disorders, primary. Autonomic neuropathy, diabetic, 1114 Autonomic tests, for Lewy body dementia, 917, 920f Autoregulation, of cerebral circulation, 544-545, 544f, 545f Autosomal dominant centronuclear myopathy, 1177 Autosomal dominant cerebellar ataxia, 887, 888t, 890-891 clinical signs in, 891t genetic characteristics of, 894t Harding’s classification of, 892t Autosomal dominant hereditary spastic paraplegia, 900t. See also Hereditary spastic paraplegia. Autosomal dominant limb girdle muscular dystrophy, 1149, 1150t

Autosomal dominant nocturnal frontal epilepsy, 678 genetics of, 683t, 684 Autosomal dominant optic atrophy, 279-280, 279f Autosomal recessive centronuclear myopathy, 1177 Autosomal recessive cerebellar ataxia, 887, 888890, 888t nonneurological manifestations of, 890t pathophysiology of, 889t test availability of, 892t Autosomal recessive hereditary spastic paraplegia, 900t-901t. See also Hereditary spastic paraplegia. Autosomal recessive limb girdle muscular dystrophy, 1149, 1150f Axenfeld-Riger spectrum, of ocular malformations, 274 Axis (C2) fracture, 1398-1399, 1399f posterior elements of, 1399 Axon, of nerves, 1409, 1410f Axonal degeneration, in multiple sclerosis, disability and, 1007-1008, 1008f, 1009f Axonal hyperexcitability, in multiple sclerosis, 1005-1006 Axonal injury, diffuse, 1388 Axonal transmission, ephaptic, 1006 Axonal transport abnormality of, hereditary spastic paraplegia due to, 902 genes associated with, 1103 Axonotmesis, classification of, 1410f, 1411 Azathioprine for cerebral vasculitis, 1319 for inflammatory myopathies, 1218, 1218t for myasthenia gravis, 1230t for relapsing-remitting neurosarcoidosis, 1309 Azithromycin, prophylactic, for bacterial meningitis, 1243t Azotemia, 1533

B Babinski sign, 109 in amyotrophic lateral sclerosis, 860 in subacute spinal cord degeneration, 1526 Back pain, in spinal cord disease, 511 Baclofen, for dystonia, 451, 451t Bacterial meningitis, 1236-1243, 1237t. See also Meningitis, bacterial. Bacterial toxins, 1486-1487 Balance. See also Gait entries. examination of, 322-326 caloric testing in, 325 computerized dynamic posturography in, 326 electronystagmography in, 324 electro-oculography in, 324 functional reach testing in, 459 head and neck in, 323 oculomotor testing in, 323, 324-325 patient history in, 322-323 physical assessment in, 323 positional testing in, 323-324, 325 positioning testing in, 325 postural control testing in, 324 retropulsion testing in, 459 rotational chair testing in, 325-326 impaired. See also Falls. after stroke, management of, 649 rehabilitation strategies for, 1427

1587

Balance. See also Gait entries. (Continued) in locomotion, 455 mechanisms of, 337, 338f Balint’s syndrome, 64, 64t after infarction, 564 screening for, 67t Balloon compression, percutaneous, for trigeminal neuralgia, 839 Band heterotopia, subcortical genes associated with, 686t neuroimaging of, 664-665, 666f, 686f Barbiturate hypnotics, for migraine, 744 Bardet-Biedel syndrome, 283 Barotrauma, otitic, 345-346 Bartonella henslae, 300 Basal ganglia lacunes, 639 Basal ganglia lesions, vascular dementia due to, 638-639 Basal ganglia motor pathways, in Huntington’s disease, 638, 882f Basal ganglionic features, in multiple sclerosis, 1022 Basal veins of Rosenthal, anatomy of, 621 Basilar artery branches of, embolic material in, 558t, 562564, 563f occlusion of, 563 penetrators of, 558t, 562, 563f top of, embolization of, 558t, 564, 564f Basilar impression, 489t, 490-491 Basilar membrane, stiffening of, contributing to presbycusis, 332 Battery tests, of executive function, 86-88, 87f, 91 Beaver Dam Eye Study, 307, 308 Becker muscular dystrophy, 1142, 1143t clinical features of, 1146, 1147f definition of, 1145 etiology and pathophysiology of, 1146-1147, 1148f phenotypic differentiation of, 1151t Becker myotonia congenita, 1187, 1188 Bedside, cognitive assessment beyond, 16 Bedside tests, of executive function, 90-91 Behavior(s) abnormal clinical assessment of, 8-9 in HIV-associated dementia, 1265 assessment of, 6 disruptive in attention-deficit hyperactivity disorder, 131-132 in autism, 131 in Wilson’s disease, 1448 everyday and emotional, reports of, in executive function assessment, 89-90 pica, 1525 Behavioral therapy for autism, 134 for speech disorders, 161 Behçet’s disease, retinal involvement in, 296297, 297f Behr disease, 280 Bendroflurozide, for Meniere disease, 349 Benign childhood epilepsy. See also Epilepsy. with centrotemporal spikes, 703, 704f Benign familial infantile convulsions, genetics of, 683, 683t, 684f Benign familial neonatal convulsions, genetics of, 683-684, 683t Benign paroxysmal positional vertigo, 322, 344, 344t, 345f diagnostic characteristics of, 346t treatment of, 349 Benign recurrent vertigo, 344

1588

Index

Benzodiazepine(s) for dystonia, 451, 451t for restless leg syndrome, 481 for seizures, 712 for status epilepticus, 724-725 Benzodiazepine receptor agonists for insomnia, 189, 189t for REM sleep behavior disorder, 198 Beriberi, 1123 Berry aneurysm, 587 Best’s vitelliform macular dystrophy, 277-278 Beta-blockers, prophylactic for chronic daily headache, 768t, 769t for migraine, 747, 747t Bielschowski head-tilt test, for diplopia, 272273, 273f Binswanger’s disease, 639 Biochemical markers, of vegetative state, 123 Biological markers, of epileptic seizures, 697 Biopsy for cerebral vasculitis, 1319 liver, for Wilson’s disease, 1449 muscle for amyotrophic lateral sclerosis, 867 for hereditary spastic paraplegia, 904 for inclusion body myositis, 1215, 1215f for polymyositis, 1214, 1215f nerve, for amyotrophic lateral sclerosis, 867 of malignant peripheral nerve sheath tumor, 1375-1376 tissue, for neurosarcoidosis, 1307 Biot’s (ataxic) breathing, 100, 1572 Bipolar disorder, multiple sclerosis associated with, 1017 Birth, live, maternal brain death and, 112-113 Blackouts, alcoholic, 49 Bladder function of, neuroanatomy and neurophysiology in, 362-363 hyporeflexic, 363 Bladder dysfunction, 363-366 diagnostic testing of, 363, 363t electromyography of, 363-364 in multiple sclerosis, 365 treatment of, 1051 in multiple system atrophy, 364-365, 964 in Parkinson’s disease, 937 management of, 947 neurological diseases and, 364-365 patterns of, 363t treatment of, 365-366, 365t, 384t, 385 ultrasonography of, 364 urodynamic testing of, 363 Bladder function testing, of primary autonomic failure, 379-380 Blastomyces, in spinal epidural abscess, 520 Blastomyces dermatitidis, 1290 Blastomycosis, 1290 Bleeding. See Hemorrhage. Blepharospasm, 445 Blind spots, due to bilateral papilledema, 268f Blindness. See also Visual loss. color, prevalence of, 260 genetic causes of, 274-283 age of onset and course of, 275 classification of, 274 dermatological, skeletal, ocular, or renal disease and, retinopathy/optic neuropathy associated with, 282-283 evaluation of, 275 localization of, 275 optic nerve disease in childhood and adulthood onset of, 279280, 279f, 280f congenital, 278-279, 279f, 279t presentation in, 274

Blindness. See also Visual loss. (Continued) retinal disease in childhood and adulthood onset of, 277278, 278f congenital, 275-277, 276f, 277f systemic and neurodegenerative disease and, retinopathy/optic neuropathy associated with, 280-282, 281f night, congenital stationary, 278 Blood pressure. See also Hypertension; Hypotension. during pregnancy, 1491-1492 in ischemic stroke management of, 569 prophylactic control of, 579-580 peptides in regulation of, 354 Blood tests for Lewy body dementia, 914 for multiple sclerosis, 1031, 1032t for restless leg syndrome, 475 Blue Mountain Eye Study, 307 Body image, in neglect syndrome. See Personal neglect (hemiasomatognosia). Boilermakers notch, in sensorineural hearing threshold, 332 Bone marrow transplantation for globoid leukodystrophy, 1073 for metachromatic leukodystrophy, 1071 neuropathies after, 1566-1567 Bonnet-Dechaume-Blanc syndrome, 599 Borrelia burgdorferi, 300, 1134, 1245. See also Lyme entries. Bortezomib, toxic neuropathy due to, 1121 Botulinum toxin, 1486 for chronic daily headache, 768t for dystonia, 451, 451t in corticobasal ganglionic degeneration, 975-976 for migraine, 750 for tremor, 421, 421t for trigeminal neuralgia, 838 Bovine spongiform encephalopathy, 1297, 1298, 1298t Braak staging, of Parkinson’s disease, 928, 929f Brachial neuropathy, radiation-induced, 13591360 Bradykinesia in Parkinson’s disease, 936 sphincter, in Parkinson’s disease, 364 Bradykinetic/hypokinetic gait, 464t Brain. See also Cerebral; Cerebro- entries; specific part. arterial supply to, 540-541, 541f, 542f arteriovenous malformations of, 595-602. See also Arteriovenous malformations, of brain. collateral blood supply to, 541 gross appearance of, in Alzheimer’s disease, 849, 849f malformations of, genes associated with, 686t microcirculation to, 543 venous drainage of, 542, 543f Brain abscess after organ transplantation, 1565 epilepsy due to, 698 Brain death, 106-114 confirmatory laboratory tests of, 108, 108t, 110-112, 110f, 111f definition of, 97 legal or statutory, 107 diabetes insipidus preceding, 113 diagnosis of, 107-108 clinical observations compatible with, 109110 differential diagnosis of, 112 family attitudes toward, 113

Brain death (Continued) formulations associated with, 106-107 in neonates and children, 112 management of, 113 maternal, and live birth, 112-113 organ procurement after, 114 religious attitudes toward, 113 research and teaching and, 113 U.K. guidelines for, 107-108, 108t U.S. guidelines for, 108, 109t Brain imaging of parenchyma, in ischemic stroke, 565 of primary autonomic failure, 381 Brain injury traumatic anticoagulant medications and, adverse effects of, 1391-1392 anticonvulsant therapy for, 1394 classification of, 1386-1387, 1387t clinical assessment of, 1391-1392 coexisting spinal injury and, 1392 diffuse and focal, 1388 hospital admission for, 1392-1393 imaging of, 1387, 1388f-1391f, 1393f, 1394f intracranial pressure monitoring in, 1393, 1394f leading causes of, 1386 mania in, 241 outcome of, 1394-1395 physical examination of, 1392 primary and secondary, 1387 psychosis in, 229 raised intracranial pressure in, management of, 1393-1394 recommendations in, 1395 specific injuries in, 1388-1391 steroids for, 1394 surgical issues in, 1393 “talk and die” injuries in, 1392, 1393f trauma care systems for, 1386 treatment of, 1392-1394 types of, 1387-1388 vascular. See Stroke. Brain lesions, in Sjögren’s syndrome, 1557 Brain parenchyma, imaging of, in ischemic stroke, 565 Brain tumor(s). See also specific tumor, e.g., Astrocytoma. clinical features of, 1325-1326 diagnosis of, 1326-1327 epidemiology of, 1324 etiology of, 1324-1325 extra-axial, 1337-1338 genetic factors in, 1328, 1330 headache secondary to, 800-801 inta-axial, 1334-1336 metastatic, 1337 of posterior fossa, 347 pathogenesis of, 1325 pathology of, 1327-1328, 1327t, 1329f prognosis for, 1336-1338 radiotherapy-induced, 1324 treatment of, 1330-1334 chemotherapy in, 1332-1333 radiotherapy in, 1331-1332, 1332f supportive, 1333-1334, 1334f surgical, 1330-1331 WHO classification of, 1328t WHO grading of, 1327 Brainstem, role of, in bladder control, 362 Brainstem auditory evoked potentials in brain death, 111-112 in comatose patient, 106 in multiple sclerosis, 1033-1034, 1034f Brainstem death, 107. See also Brain death. Brainstem disease, trigeminal neuralgia in, 836

index Brainstem lesions, arteriovenous, 598 Brainstem myoclonus, 437t Brainstem reflexes, absent, in brain death, 108, 109t Branching enzyme deficiency, 1196 BRD2 gene, in inheritance of epilepsy, 687 Breast-feeding, antiepileptic agents and, 15001501 Breathing. See Respiration. Broca’s aphasia, 34-35 agraphia in, 40t alexia with, 40 apraxia with, 157 neuroanatomy of, 35, 35f Bromocriptine for parkinsonism, in multiple system atrophy, 967 for prolactinoma, 1551 for restless leg syndrome, 482t Brown’s syndrome, 1559 Brown-Séquard syndrome, 513t, 1403 Bruch’s membrane, 295 Brudzinski’s sign, 1238 Bulbar palsy, corticobulbar tract lesions and, 155-156, 158, 158t Bull’s angle, in basilar impression, 491 Burst fracture, of thoracolumbar junction, 1400, 1400f Butalbital, for medication overdose–headache, 768 Butterbur (Petasites hybridus), prophylactic for chronic daily headache, 768t for migraine, 749

C C27-steroid hydroxylase deficiency, in cerebrotendinous xanthomatosis, 1078 Cabergoline, for prolactinoma, 1551 CACNA1A gene, in migraine, 739 Cacosmia, 173 CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), 309, 639-640, 743 Cadence, in locomotion, 456-457 Calcifications, in brain arteriovenous malformations, 598 Calcium channel blockers for amyotrophic lateral sclerosis, 870t prophylactic for chronic daily headache, 768t, 769t for migraine, 747t, 748 Calcium channel disorders, 1190-1191 Callosal apraxia, 408 CALM-PD study, of Parkinson’s disease, 948, 949-950 Caloric testing, of balance, 325 Cambridge Contextual Reading Test, 4 Campylobacter jejuni, 1138 Campylobacter jejuni infection, inflammatory bowel disease and, 1514 Canavan’s disease clinical features of, 1075 genetics of, 1075 pathogenesis of, 1075-1076 synonyms for, 1074 treatment of, 1076 Cancellation tests, for spatial neglect, 76, 76f Cancer therapy. See also specific modality, e.g., Chemotherapy. neurological complications of, 1353-1360 chemotherapy-induced, 1353-1356, 1354t cranial irradiation–induced, 1356-1358, 1356f-1358f

Cancer therapy (Continued) spinal cord/plexus irradiation–induced, 1359-1360, 1359f timing of, 1353 Candesartan, for migraine, 749-750 Candida albicans, endophthalmitis caused by, 302 Canes, 1428f, 1428t Capgras’s syndrome, Lewy body dementia and, 912 Capsaicin, prophylactic, for cluster headache, 781-782 Carbamazepine for partial and tonic-clonic seizures, 708 for trigeminal neuralgia, 838 Carbamoyl phosphate synthase deficiency, 1470t, 1473 Carbergoline, for restless leg syndrome, 482t Carbon dioxide, in cerebral circulation regulation, 546 Carbon monoxide intoxication, 1483-1484, 1483t Parkinson’s disease and, 933 Carbonic anhydrase inhibitors, for idiopathic intracranial hypertension, 812 Carcinoma-associated retinopathy, 304 Carcinomatous meningitis. See also Meningitis. headache associated with, 801 Cardiac hypertrophy, adrenaline infusions causing, 1507 Cardiac output, during pregnancy, 1491 Cardioembolic stroke, 554. See also Stroke. oral anticoagulation for, 577-578 source of, workup for, 568 Cardiopathy, electrolyte-steroid, 1505 Cardiovascular agents, toxic neuropathy due to, 1120-1121, 1120t Cardiovascular dysfunction, in multiple system atrophy, 964 Cardiovascular function testing, of primary autonomic failure, 378-379 Cardiovascular sequelae, in obstructive sleep apnea-hypopnea, 205 Caretakers, informal, of stroke patient, 648-649 Carmustine, neurological complications caused by, 1355 Carnitine palmitoyltransferase I defect, 1200 Carnitine palmitoyltransferase II defect, 1200 Carnitine uptake defect, 1200 Carnitine:acylcarnitine translocase defect, 1200 β-Carotene, for amyotrophic lateral sclerosis, supplemental, 870t Carotid artery dissection of, stroke due to, 555, 555f, 556f internal, embolic material in, 561 Carotid endarterectomy headache after, 799 prophylactic, for ischemic stroke, 581 Carotid stenosis, associated with venous stasis retinopathy, 308 Carpal tunnel syndrome, 1561 in systemic lupus erythematosus, 1564 Cat scratch fever, 300 Catamenial seizures. See also Seizure(s). treatment of, 715-716 Cataracts in myotonic dystrophy, 305 in neurofibromatosis type 2, 306 Catatonia, assessment of, 9 Catecholamines, 1545 Catechol-O-methyl transferase inhibitors, for Parkinson’s disease, 941-942, 942f Cauda equinus syndrome, 513t Caudal dysplasia, 504 Caudal eminence, in nervous system development, 488

1589

Caudal regression syndrome, 504 Caudate atrophy, in Huntington’s disease, 882, 882f Cavernous hemangioma, radiation-induced, 1358, 1358f Cavernous sinuses anatomy of, 622, 623f thrombosis of, 624-625 Cayman’s ataxia, 889 CD4 T cells, in HIV infection, 1132, 1133, 1261 CD8 T cells, in diffuse infiltrative lymphocytosis syndrome, 1133 Ceftriaxone for amyotrophic lateral sclerosis, 870 for Lyme disease, 1135 prophylactic, for bacterial meningitis, 1243t Celiac disease, 705, 1511-1513 ataxia in, 1512 enteropathy-associated T cell lymphoma associated with, 1511 epilepsy in, 1512-1513 inflammatory myopathy in, 1513 learning disabilities in, 1513 migraine in, 1513 neurological dysfunction in, 1511-1512, 1512t peripheral nerve involvement in, 1513 Celiac neuropathy, 1123 Cell body, of nerves, 1409, 1410f Cell death, myocardial, 1506 Cellular mechanisms, in neurobiology of learning and memory, 45-46 Central chronic inflammatory demyelinating neuropathy, 1117 Central cord syndrome, 513t, 1403, 1403f Central core disease and malignant hyperthermia susceptibility, 1171 genetics of, 1171-1173 clinical features of, 1170-1171, 1172f gene defects in, 1169t histopathology of, 1170, 1171f Central hearing loss, 330. See also Hearing loss. Central (transtentorial) herniation, in comatose patient, 102-103, 103t Central motor conduction, in multiple sclerosis, 1034 Central nervous system fungal infections of, 1289-1291. See also specific infection. immunological and inflammatory disorders of, 1314t involvement of in inflammatory bowel disease, 1514-1515, 1515t in Sjögren’s syndrome, 1557 in systemic lupus erythematosus, 15621563 lymphoma of, 530, 1336 after organ transplantation, 1566 paraneoplastic neurological disorders of, 1361, 1362f. See also Paraneoplastic neurological disorder(s). parasitic infections of, 1273-1289, 1274t. See also specific infection. physiological changes in, generalized convulsive status epilepticus and, 722 primary angiitis of, 1314-1315 headache secondary to, 798-799 syphilitic invasion of, 1245 vasculitis of, 1317-1320 blood tests in, 1318 cerebrospinal fluid analysis in, 1318 clinical definition of, 1314 clinical features of, 1317 diagnosis of, 1317-1319, 1318t drug- and toxin-induced, 1317

1590

Index

Central nervous system (Continued) histopathology of, 1319 primary, 1314 radiography of, 1318-1319 treatment of, 1319-1320 viral-induced demyelination of, mechanisms of, 1058t Centronuclear (myotubular) myopathy, 11761178 clinical features of, 1177 gene defects in, 1169t genetics of, 1177-1178 histopathology of, 1171f, 1177 Cephalgias, trigeminal automatic, 773-785. See also Trigeminal automatic cephalgias. Cerebellar artery anterior inferior, embolic material in, 558t, 562 superior, embolic material in, 558t, 562 Cerebellar ataxia autosomal dominant, 887, 888t, 890-891, 891t, 894t autosomal recessive, 887, 888-890, 888t, 889t, 890t, 892t mitochondrial, 887, 888t, 891-892 X-linked, 887, 888t, 891 Cerebellar atrophy, excess daytime sleepiness due to, 192 Cerebellar degeneration alcoholic, 1541 paraneoplastic, 1365t, 1367-1368 Cerebellar disorders affecting speech, 158-159 in multiple system atrophy, 962, 963t Cerebellar hemorrhage, 347 Cerebellar herniation, 492. See also Chiari malformation. in comatose patient, 104 Cerebellar infarction, 347 Cerebellar intention tremor. See Intention tremor. Cerebellar lesions, arteriovenous, 598 Cerebellar tremor, 424-425 treatment of, 425 Cerebellopontine angle, tumors of, 346-347 Cerebral aneurysm, 587 rupture of, 589 Cerebral angiography headache after, 799 of brain death, 110-111, 110f Cerebral angiopathy, reversible, headache secondary to, 799, 799t Cerebral artery, 541f anterior embolic material in, 558t, 560-561, 560f lesions of, vascular dementia due to, 638 areas irrigated by, 542f boundary zones in, 542f embolic material in, 557, 558t, 559-561, 559f, 560f middle embolic material in, 557, 558t lower division occlusion of, 558t, 560 stem embolic material in, 557, 558t, 559560 stem occlusion of, 557, 558t, 559, 559f upper division occlusion of, 558t, 559-560, 559f posterior embolic material in, 559t, 564 infarction of, vascular dementia due to, 637 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), 309, 639640, 743

Cerebral circulation arterial, 540-541, 541f, 542f autoregulation of, 544-545, 544f, 545f collateral blood supply in, 541, 542f endothelial regulation of, 546-547, 547f imaging of, in ischemic stroke, 565 metabolic regulation of, 546 neurogenic regulation of, 545-546, 545t physiology of, 543-544 venous, 542, 543f Cerebral cortex arteriovenous lesions of, 596, 598 involvement of, in restless leg syndrome, 473 vision-related disorders of. See Vision-related cortex disorders. visual input in, 59, 59f-61f Cerebral edema, treatment of, 1241 Cerebral hemorrhage, reduced CSF absorption due to, 826 Cerebral herniation, in comatose patient, 102, 102f Cerebral metabolism, measurement of, in vegetative state, 123, 125f Cerebral palsy, 1577-1580 acquired postnatal causes of, 1580 classification of, 1577, 1578t clinical features of, 1577-1578 diagnosis of, 1578 disorders associated with, 1578 etiology of, 1579-1580 management of, 1580, 1580t neuroimaging of, 1579 prognosis of, 1580 Cerebral palsy syndromes, 1578t Cerebral perfusion pressure, calculation of, 1393 Cerebral phenotype, in X-linked adrenoleukodystrophy, 1065 neuroimaging of, 1066-1067 pathogenesis of, 1068 pathology of, 1066 Cerebral small-vessel disease, 308 Cerebral tissue perfusion, in ischemic stroke assessment of, 567-568 failure of, 552 Cerebral vasculitis. See Central nervous system, vasculitis of. Cerebral vasospasm, 589-590 Cerebral vein, 543f deep, anatomy of, 621 thrombosis of, 621-630. See also Venous thrombosis, cerebral. Cerebral venous sinus thrombosis, 621-630. See also Venous thrombosis, cerebral. headache secondary to, 797 Cerebral ventricles, cerebrospinal fluid flow patterns in, 825, 826f Cerebrofacial arteriovenous metameric syndromes, 599 Cerebroretinal neurodegenerative diseases, 282 Cerebrospinal fluid absorption of, reduction in, 826-827 analysis of, 817-818 in bacterial meningitis, 1240, 1240t in cerebral vasculitis, 1318 in Lewy body dementia, 915 in neurosarcoidosis, 1304, 1307 in progressive supranuclear palsy, 970 in spinal cord tumors, 1345 in syphilitic meningitis, 1245 in tuberculous meningitis, 1244 in viral meningitis and encephalitis, 1252 circulation of, 825, 826f obstruction in, 825-826, 826f creatine kinase BB activity of, as marker in vegetative state, 123

Cerebrospinal fluid (Continued) immunoglobulin abnormalities of, in multiple sclerosis, 1031-1032, 1032f overproduction of, 827 Cerebrospinal fluid leaks, 817-822 background and terminology of, 817 spontaneous clinical manifestations of, 817, 818t complications of, 822 CT myelography of, 818-819, 820f diagnosis of, 817-820 etiology of, 817 fast-flow, 819-820 head CT scan of, 818 MR imaging of, 818, 820f, 820t abnormalities of, 820-821, 821f prognosis of, 822 radioisotope cisternography of, 818, 819f slow-flow, 820 treatment of, 821-822, 822t variability of, 818t, 821, 821f Cerebrotendinous xanthomatosis, 1078-1079 Cerebrovascular disease. See also Stroke; Transient ischemic attack. apathy in, 243 depression in, 238 headache secondary to, 793-799, 794f. See also under Headache. in systemic lupus erythematosus, 1562 inflammatory bowel disease and, 1515 mania in, 239 retinal involvement in, 307-310, 308f, 309f Cerebrum, role of, in sexual function, 366 Cerumen impaction, causing conductive hearing loss, 330 Cervical artery dissection, headache secondary to, 794-796, 795f Cervical dystonia (spasmodic torticollis), 445 Cervical myelopathy excess daytime sleepiness due to, 192 spondylitic, 523-524, 523t, 524f Cervical spine injury to, 1398-1399, 1398f, 1399f rheumatoid arthritis affecting, 1559-1561, 1560f Cervicogenic headache, 801 Chamberlain’s line, in basilar impression, 490 Chance fracture, 1401, 1401f Charcot-Marie-Tooth disease, 1099-1100 genetic classification of, 1101t genetic counseling in, 1108 genetic testing for, 1106-1108, 1106f, 1107f inheritance pattern in, 1101 mutation frequencies for, 1106t replication of chromosomal segment harboring PMP22 resulting in, 1102, 1102f Chelation therapy, for lead intoxication, 1479 Chemotherapy for brain tumors, 1332-1333 for gliomas, 1335 for malignant glioma, 1335-1336 for spinal cord tumors, 1349 neurological complication(s) of, 1353-1356 encephalopathy as, 1353, 1354t neuropathy as, 1353, 1354t seizures as, 1354 specific chemotherapeutic agents causing, 1354-1356 stroke, 1354 Chemotherapy agents. See also specific agent. neurological complications caused by, 13541356 toxic neuropathy due to, 1120t, 1121 Chenodeoxycholic acid, for cerebrotendinous xanthomatosis, 1078

index Cherry-red spot, in Tay-Sachs disease, 310 Cheyne-Stokes breathing, 100, 1572 Chiari malformation, 489t, 492-493 definition of, 492 headache secondary to, 799-800, 800f, 800t MR imaging of, 493, 494f, 498f syringomyelia with, 493, 522 types of, 493 Chickenpox, 1136 Chickpea toxins, 1485-1486 Children. See also Infants; Neonates. brain arteriovenous malformations in, 600 brain death in, 112 epileptic syndromes in, 703, 704f treatment of, 714 metabolic diseases in, ophthalmological features of, 310 multiple sclerosis in, 1016-1017 Wilson’s disease, 1448 Chinese Acute Stroke Trial (CAST), 574 Chlordiazepoxide, for ethanol withdrawal symptoms, 1540t Chloride channel disorders, 1187-1189, 1189f Cholesteatoma, conductive hearing loss due to, 330, 331 Cholesterol, strategies for reducing, 580 Choline acetyltransferase deficiency syndrome, 1232t Cholinergic dysautonomia, clinical presentation of, 375 Cholinesterase inhibitors, for Alzheimer’s disease, 854t Chorea Huntington’s. See Huntington’s disease. in systemic lupus erythematosus, 1562 Choriomeningitis, lymphocytic, 1249 Choroid, 295 Choroid plexus, arteriovenous lesions of, 598 Choroid plexus papilloma, overproduction of CSF due to, 827 Choroidal artery, anterior, embolic material in, 558t, 561 Choroidal vein, posterior, anatomy of, 621 Choroideremia, 278 Choroiditis, Pneumocystis carinii–related, 302 Chronic daily headache, 763-769. See also Headache, chronic daily. Chronic inflammatory demyelinating neuropathy, variants of, 1117 Chronotherapy, for delayed sleep phase syndrome, 196 Churg-Strauss syndrome, 1316 ocular involvement in, 298 Cingulate circuit, anterior, in executive function, 85 Cingulate herniation, in comatose patient, 104 Ciprofloxacin, prophylactic, for bacterial meningitis, 1243t Circadian rhythm disorders of, 195-196 effects of, on normal and abnormal neurophysiological functions, 195 regulation of hormones and, 1549 in sleep and wakefulness states, 182 interaction of homeostatic regulation with, 182 seizures and, 193 sleep disorders associated with, international classification of, 186t Circle of Willis, 540, 541, 541f Circulation cerebral. See Cerebral circulation. spinal cord, 542-543 Circumloculations, 33

Cisplatin neurological complications caused by, 1354 toxic neuropathy due to, 1121 Cisternography, radioisotope, of cerebrospinal fluid leaks, 818, 819f Citrin deficiency, 1470t, 1474 Citrulline, for urea cycle disorders, 1475 Citrullinemia Type I deficiency, 1474 CLCN1 gene, in chloride channel disorders, 1187, 1188 Clobazam, for seizures, 713 Clofazimine, for leprosy, 1131 Clonazepam for myoclonus, 442t in corticobasal ganglionic degeneration, 976 for non-REM parasomnias, 198 for REM sleep behavior disorder, 198, 923 for seizures, 712-713 for tremor, 421t, 422t for West’s syndrome, 714 Clonic seizures, 675, 694. See also Seizure(s). Clonidine, for medication overdose–headache, 768 Clonus, 428 Clopidogrel, prophylactic, for ischemic stroke, 575 Clopidogrel and aspirin, prophylactic, for ischemic stroke, 575-576 Clorazepate, for seizures, 713 Clostridium tetani, 1487 Clozapine for schizophrenia, 227 for tremor, 422t, 424 Cluster attacks, 776-777 Cluster bout, 777 Cluster breathing, 100 Cluster headache, 775-782. See also Headache, cluster. Cluster-tic, vs. trigeminal neuralgia, 836 CMV. See Cytomegalovirus (CMV) entries. Coactivation sign, in psychogenic tremor, 427 Coagulation changes, in pregnancy, 1492, 1492t Cobalamin, for vitamin B12 deficiency, 1461 Cobalamin deficiency. See Vitamin B12 deficiency. Cobb’s syndrome, 604 Cocaine, alkaloidal, 1537 Coccidioides, in spinal epidural abscess, 520 Coccidioidomycosis, 1290 Cochlear hair cells, loss of, contributing to presbycusis, 332 Cockayne’s syndrome, 282-283, 889-890 Codon 129 polymorphism, 1298-1299, 1299t Coenzyme Q10 for amyotrophic lateral sclerosis, supplemental, 870t for Parkinson’s disease, 949f, 950 Cognition, in multiple sclerosis, 1017 Cognitive assessment instruments, standardized, 15-16 Cognitive disinhibition, 8-9 Cognitive domains, 22, 23t in Alzheimer’s disease, 851 individual, neuropsychological assessment of, 22 testing of, prerequisites for, 22, 23f Cognitive flexibility, in executive function, 87-88 Cognitive function, in gait control, 463, 465466, 466f Cognitive impairment in Lewy body dementia, 911-912, 913t treatment of, 386, 919-920, 921t in multiple sclerosis, treatment of, 1051 in schizophrenia, 223-224 in systemic lupus erythematosus, 1563

1591

Cognitive impairment (Continued) in urea cycle disorders, 1472 mild, in Alzheimer’s disease, 850, 851t Cognitive-behavioral therapy for conversion syndrome, 255, 255f for insomnia, 188 Coiling and clipping, of intracranial aneurysm, headache after, 799 Colchicine, toxic neuropathy due to, 1120t, 1121 Cold pressor test, 355t Cold-induced nerve injury, 1417-1418 Colitis, ulcerative. See Ulcerative colitis. Color agnosia, 61, 61t, 62 screening for, 67t Color blindness, prevalence of, 260 Color vision, assessment of, 260 Coma, 98-106 after organ transplantation, 1564-1565 anatomy of, 99, 99f clinical assessment of, 100-104 conscious state in, 100, 100t eye motion in, 101-102, 101f herniation syndromes in, 102-104, 102f, 103t, 104t motor examination in, 102 pupil examination in, 101 respiratory pattern in, 100 vital signs in, 101 definition of, 97 differential diagnosis of, 104 electroencephalogram of, 105 emergence from, into vegetative state, 117, 126, 126f. See also Vegetative state. etiology of, 98-99, 99t evoked potentials in, 106 investigation of, 105, 105f lumbar puncture for, 105 neuroparasites causing, 1274t pathophysiology of, 99-100 power spectral analysis of, 105-106 Communication, impaired, rehabilitation strategies for, 1431 Communication devices, alternative, for speech disorders, 161 Communication skills, improvement of, in management of autism, 135 Community ambulation, definition of, 497 Compartmentalization phenomena, 249 Complete infarctions, in vascular dementia, 640 Complete transverse spinal cord syndrome, 513t Complex partial seizures, 676-677. See also Seizure(s). impaired consciousness in, 695 Complex partial status epilepticus, 719, 720f. See also Status epilepticus. Complimentary therapy, for epilepsy, 718 Comprehension, of language, 12 Compression of nerve roots, clinical features associated with, 525t of peripheral nerves, chronic, 1415 Compressive optic neuropathy, visual loss in, 290-291, 291f Compulsions, 7. See also Obsessive-compulsive disorder. definition of, 217 Computed tomography (CT) of brain death, 112 of cerebral vein and sinus thrombosis, 625 of cerebrospinal fluid leaks, 818 of hydrocephalus, 827, 828f of ischemic stroke, 565 of multiple sclerosis, 1034, 1034f of Parkinson’s disease, 938 of spinal cord tumors, 1343-1344

1592

Index

Computed tomography (CT) (Continued) of subarachnoid hemorrhage, 796, 797f of traumatic brain injury, 1386, 1388f-1391f, 1393f, 1394f Computed tomography (CT) angiography, of ischemic stroke, 566 Computed tomography (CT) myelography of cerebrospinal fluid leaks, 818-819, 820f of peripheral nerve injury, 1414, 1414f of spinal cord tumors, 1343-1344 Computerized dynamic posturography, of balance, 326 Conceptual apraxia, 405, 407 pathophysiology of, 409 Conceptualization, of language, 31 Concurrent validity, of tests, 24 Concussion, 1388 labyrinthine, 346 Conduction aphasia, 36-37 clinical features of, 37 neuroanatomy of, 37 Conductive hearing loss, 318. See also Hearing loss. acoustic reflex in, 321 causes of, 319-321 Cone dystrophies, 277 Cones, retinal, 295 Confirmatory tests, for brain death, 108, 108t, 110-112, 110f, 111f Confusion, in systemic lupus erythematosus, 1563 Confusional arousals, 197 Congenital hypomyelinating neuropathy, 1101 Congenital muscular dystrophy, 1149, 1155 clinical features, etiology, and pathophysiology of, 1155, 1155f, 1156f forms of, 1144t phenotypic differentiation of, 1153t Congenital myasthenic syndromes, 1225t, 1231, 1232t Congenital myopathies, 1168-1178. See also specific disease, e.g., Central core disease. clinical features of, 1168-1169 epidemiology of, 1168 investigations of, 1169 major gene defects in, 1169t management of, 1170 Congenital stationary night blindness, 278 Coning (herniation syndromes), in comatose patient, 102-104, 102f, 103t, 104t Connexin 26 defects, in hereditary hearing loss, 329 Connexin 30 defects, in hereditary hearing loss, 329 Connexin 32, 1103 Conscious state assessment of, in comatose patient, 100, 100t deterioration of, in adult hydrocephalus, 827 Consciousness, 97-98 complete loss of. See also Coma. seizures associated with, 694-695 higher order, 97 impairment of, seizures characterized by, 695-696 in multiple sclerosis, 1017 preserved, abnormal sensations with, in seizures, 696-697 primary, 97 Consortium to Establish a Registry for Alzheimer’s disease (CERAD) criteria, for Alzheimer’s disease, 850 Constipation in multiple sclerosis, 1022 in Parkinson’s disease, 936 treatment of, 384t, 385 Construct validity, of tests, 24

Content validity, of tests, 24 Continuous positive airway pressure, nasal for central sleep apnea, 210 for obstructive sleep apnea-hypopnea, 207, 208f Contraction band necrosis, 1506, 1506f causes of, 1507-1508 Contusion, 1388, 1388f Conus medullaris lesions, 513t Conversion, 249 Conversion hysteria, vs. factitious disorder and malingering, 250t Conversion syndrome, 249-255 abnormal movements in, 251-252, 252t clinical features of, 250-253 definition of, problems with, 249-250, 250f, 250t individual symptoms in, 251-252 management of behavioral approaches to, 254 framework for rehabilitation in, 255 pharmacological, 255 psychological, 255, 255f referral to psychiatrist/psychologist in, 254 resources available for, 253-254 strategies in, 254 motor symptoms in, 250-251 paralysis in, 251 prognosis of, 253, 253t seizures in, 252, 252t sensory disturbances in, 252-253 visual disturbances in, 253 Convulsions benign familial infantile, genetics of, 683-684, 683t benign familial neonatal, genetics of, 683-684, 683t febrile, treatment of, 714 seizures associated with, 694-695 Coordination, impaired, rehabilitation strategies for, 1427 Copper, hepatic, in Wilson’s disease, 1449 Copper deficiency myeloneuropathy, 1464 Copper deficiency myelopathy, 509 Coprolalia, in Gilles de la Tourette syndrome, 214 Cord sign, in cerebral vein and sinus thrombosis, 625 Cortical dysfunction, in corticobasal ganglionic degeneration, management of, 976 Cortical lesions, in multiple sclerosis, 1008 Cortical myoclonus, 435, 437t clinical features of, 435-436, 436f diseases causing, 438t physiological mechanisms of, 438-439, 440f Cortical release signs, neurocognitive examination of, 15 Cortical spreading depression, in migraine aura, 739, 740f Cortical syndromes, of ischemic stroke, 557565, 558t-559t anterior circulation in, 557, 558t, 559-560 posterior circulation in, 559t, 561-565 Cortical tremor, 428, 435 Corticobasal degeneration ganglionic, 973-976 ancillary investigations of, 974 clinical course of, 974 clinical presentation and prognosis of, 973974, 974t cortical dysfunction in, management of, 976 diagnostic criteria in, 974, 974t dystonia in, management of, 975-976 epidemiology of, 973 genetic factors in, 974

Corticobasal degeneration (Continued) management of, 975-976 practical, 976 principles of, 974, 975t myoclonus in, management of, 976 parkinsonism in, management of, 975 in frontotemporal dementia, 984 vs. Parkinson’s disease, 938 Corticobulbar tract in speech and swallowing, 155, 156f upper motor neuron lesions of, 155-156 Corticospinal tract, embryonic development of, hereditary spastic paraplegia due to, 902 Corticosteroids for bacterial meningitis, 1240-1241, 1241t, 1242t for migraine, 746 for multiple sclerosis, 1048 for muscular dystrophy, 1159 for tuberculous meningitis, 1244 neurological complications caused by, 1356 systemic, for metastatic epidural spinal cord compression, 532 Corynebacterium diphtheriae, 1137, 1486 Cotton wool spots, in systemic lupus erythematosus, 297, 297f Course-modifying therapy, for multiple sclerosis, 1046-1049 benefits of, 1046t FDA-approved, 1046t Coxsackie virus, in myelitis and meningomyelitis, 516 “Crack” cocaine, 1537 Cramp(s) muscle, in amyotrophic lateral sclerosis, 860 management of, 871 writer’s, 445-446 Cranial dystonia, 445 Cranial meningocele, 495 Cranial nerve(s). See also specific cranial nerve. examination of, in balance disorders, 323 function of, in motor speech and swallowing, 155, 157f involvement of in multiple sclerosis, 1018-1019 in systemic lupus erythematosus, 1563, 1563t progressive deficits of, brain tumors and, 1326 Cranial neuropathy, radiation-induced, 13561357 Craniopharyngioma, bitemporal hemianopia due to, 265f Craniorachischisis, 495 Cranium penetrating trauma to, 1391 structural disorders of, headache secondary to, 801-802 CRB1 gene, in Leber’s congenital amaurosis, 275, 276f C-reactive protein, in giant cell arteritis, 797798 Creatine for amyotrophic lateral sclerosis, 870 supplemental, for muscular dystrophy, 1159 Creatine kinase, as marker of epileptic seizures, 697 Creatine kinase BB activity, as marker in vegetative state, 123 Cree leukodystrophy, 1080 CREST syndrome, 1558 Creutzfeldt-Jakob disease genetic clinical features of, 1299 epidemiology of, 1297

index Creutzfeldt-Jakob disease (Continued) iatrogenic clinical features of, 1299-1300 epidemiology of, 1298 sporadic clinical features of, 1299, 1299t, 1300f epidemiology of, 1297 variant clinical features of, 1300, 1300f epidemiology of, 1298, 1298f secondary transmission of, 1301 Criterion validity, of tests, 24 Crohn’s disease cerebrovascular events in, 1515 clinical characteristics of, 1513-1514 extraintestinal manifestations of, 1514 gastrointestinal features of, 1512t increased incidence of, 1513 NOD2/CARD15 gene in, 1513 Crossed neglect, 77 Crptococcal meningitis. See also Meningitis. after organ transplantation, 1565 Crutches, 1428f, 1428t Cryoglobulinemia, 1316, 1530-1531 plasmapheresis for, 1319 Cryptococcosis, 1289 ocular involvement in, 302, 303f Cryptococcus, in spinal epidural abscess, 520 Cryptococcus neoformans, 1289 Cryptococcus neoformans infection, after organ transplantation, 1565 Cryptogenic stroke, 554-555. See also Stroke. CT. See Computed tomography (CT). Cueing techniques, for gait disturbances, 466467 Cushing’s disease, 1553 Cushing’s reflex, 99 Cushing’s syndrome, 1553 Cutaneous reflexes, 514t Cutaneous stigmata, in tethered cord syndrome, 499-500, 501f Cx32 gene, in inherited neuropathies, 1103 Cyclooxygenase (COX) inhibitors, increased ischemic events associated with, 619 Cyclophosphamide for cerebral vasculitis, 1319 for inflammatory myopathies, 1218, 1218t for relapsing-remitting neurosarcoidosis, 1309 for vasculitis, 1119 Cyclosporine for inflammatory myopathies, 1218, 1218t for myasthenia gravis, 1230t Cyproheptadine, prophylactic, for migraine, 749 Cyst(s) Dandy-Walker, hydrocephalus due to, 827 developmental, in tethered cord syndrome, 499 in spinal cord injury, 1402 subcortical, megalencaphalic leukodystrophy with, 1081-1082, 1081f Cysticercosis, 1274t Taenia solium clinical presentation of, 1277 diagnosis of, 1277, 1278f-1284f epidemiology of, 1276-1277 treatment of, 1277, 1279, 1285f Cystosine arabinoside, neurological complications caused by, 1355 Cytokine(s) in inflammation, 1006-1007 in pregnancy, 1493 Cytokine receptors, 1548 Cytomegalovirus (CMV), 1133-1134 Cytomegalovirus (CMV) encephalitis, treatment of, 1256

Cytomegalovirus (CMV) lumbosacral polyradiculopathy, 1133-1134 Cytomegalovirus (CMV) myelitis, 518 Cytomegalovirus (CMV) retinitis, 298, 298f, 301

D Dancing mania. See Huntington’s disease. Dandy-Walker cyst, hydrocephalus due to, 827 Dapsone for leprosy, 1131 toxic neuropathy due to, 1120 Darwinism, neural, 98 Data, quantitative vs. qualitative, in neurocognitive examination, 11, 11f DATATOP study, of Parkinson’s disease, 944, 944f, 948 Daytime sleepiness, excessive, 190-193 due to cerebellar atrophy, 192 due to cervical myelopathy, 192 due to dementia, 193 due to dystonia, 192 due to epilepsy, 193, 193t due to Lewy body dementia, treatment of, 922t, 923 due to medical and neurological disease, 190191 due to multiple sclerosis, 191-192 due to multisystem atrophy, 192 due to Parkinson’s disease, 192 due to poliomyelitis, 192 due to stroke, 191 Deafness. See also Hearing loss. in multiple sclerosis, 1020 pure word, 36 Death brain. See Brain death. brainstem formulation in, 107 circulatory formulation in, 107 definition of, 106 higher brain formulation in, 107 whole brain formulation in, 106-107 Debranching enzyme deficiency, 1196 Decarboxylase inhibitor, for parkinsonism, in multiple system atrophy, 967 Decerebrate posturing, in comatose patient, 102 Decision theory, in psychometrics, 26, 27t Decision-making capacity, in management of delirium, 150 Declarative (explicit) memory, 43, 44t subdivision of, 43-44 Decompression sickness, 1575 Decorticate posturing, in comatose patient, 102 Deep-brain stimulation for Parkinson’s disease, 947-948, 947t adverse events with, 947 high-frequency, for gait disturbances, 468 Dejerine-Sottas neuropathy, 1100-1101 Delayed sleep phase syndrome diagnosis of, 195 treatment of, 196 Delirium, 141-150 baseline vulnerability factors in, 143, 143t causes of, 148, 148t clinical features of, 146 clinical syndromes of, 141, 143 course of, 143 definition of, 141 diagnosis of, 146, 147f differential diagnosis of, 146, 147t drug-induced, 148, 148t

1593

Delirium (Continued) DSM-IV diagnostic criteria for, 142f epidemiology of, 141, 143 ethical issues in, 150 in systemic lupus erythematosus, 1563 management of, 147-150 aims in, 147 algorithm in, 149f decision-making capacity in, 150 nonpharmacological, 148-150 pharmacological, 150 prevention in, 147-148 pathophysiology of, 145-146 precipitating factors in, 143-144, 144f-145f prevalence and incidence of, 141, 142t risk factors for, 143-144 sequelae of, 143 Delirium tremens ethanol withdrawal causing, 1540 management of, 1541 management of, 150 Delis-Kaplan Executive Function Scale (DKEFS), 86-87 Delusions, 7 in Lewy body dementia, 912 Dementia alcoholic, 1542-1543 due to radiation-induced leukoencephalopathy, 1357, 1358f excess daytime sleepiness due to, 193 frontotemporal. See also Frontotemporal dementia. HIV-associated, 1261, 1264f clinical features of, 1264t HAART for, 1264-1266 limited efficacy of, 1266 progression of, 1265 radiological and neuropathological features of, 1265, 1265t, 1266f risk factors for, 1265, 1265t in Alzheimer’s disease, 846 agitation and, management of, 853t, 856 medical and neurological conditions contributing to, 852 in amyotrophic lateral sclerosis, 865 management of, 873 in Huntington’s disease, 881 in illicit drug abusers, 1539 in normal-pressure hydrocephalus, 830 in severe disabling multiple sclerosis, 1017 in X-linked adrenoleukodystrophy, 1066 late-onset, in hereditary spastic paraplegia, 903-904 memory disturbance in, 5 multi-infarct, 637, 639t postapoplectic, 635 semantic, 38 “sundowning” in, 3 vascular, 635-643. See also Vascular dementia. visuospatial disturbance in, 5 with Lewy bodies. See Lewy body dementia. Dementia praecox, 223 Dementia pugilistica, 1388, 1395 Demyelinating axons, mechanosensitivity of, 1006 Demyelinating disease. See also specific disease, e.g., Multiple sclerosis. in systemic lupus erythematosus, 1562 schizophrenia-like psychosis in, 229 Demyelinating neuropathy chronic inflammatory, 1117 multifocal sensorimotor, 1118-1119 paraprotrein-associated, 1117-1118 Demyelinating polyneuropathy, HIV-associated, 1268

1594

Index

Demyelination in multiple sclerosis, 1002-1003, 1003f activity-dependent conduction block and, 1003, 1005f effects of temperature on, 1002-1003, 1004f ion channels in, adaptive changes of expression of, 1004-1005 of central nervous system, viral-induced, mechanisms of, 1058t Dennis classification, of lumbar spine injuries, 1400 Dentatorubral-pallidoluysian atrophy (Smith’s disease), 887, 891 Deoxyribonucleic acid. See DNA entries. Depersonalization, 249 in anxiety states, 7 Depression, 235-239 cerebral regions associated with, 235, 236f in Alzheimer’s disease, 236-237, 852 in amyotrophic lateral sclerosis, management of, 872-873 in cerebrovascular disease, 238 in epilepsy, 238 in Huntington’s disease, 882 in multiple sclerosis, 238 management of, 1051 in parkinsonian syndromes, 238 in Parkinson’s disease, 238 management of, 946 in systemic lupus erythematosus, 1563 in vascular dementia, 238 memory impairment associated with, 55 mood changes in, 235 neurologic and psychotropic agents associated with, 237t neurologic conditions associated with, 236, 237t treatment of, 238-239, 239f Derealization, 249 in anxiety states, 7 Dermal sinus tracts, in tethered cord syndrome, 499 Dermatological disease, retinopathy/optic neuropathy associated with, 282 Dermatomes, 488 distribution of, 514f Dermatomyositis associated clinical manifestations in, 12121213 management of, 1218 autoantibodies in, 1217 clinical presentation of, 1211, 1212t, 1213f diagnosis of, 1213-1217, 1214t differential diagnosis of, 1218-1219 histopathology of, 1213f, 1214 immunopathogenesis in, 1216, 1216f malignancy associated with, 1213 paraneoplastic, 1370-1371 prognosis of, 1219 treatment of, 1218, 1218t Dermatomyositis sine myositis, 1211 Detachment phenomena, 249 Detrusor areflexia, in spinal cord injury, 365 Detrusor hyperreflexia, 363 in spinal cord injury, 365 Detrusor muscle, acontractile or hypoactive, treatment of, 366 Detrusor overactivity, neurogenic, 363 treatment of, 365-366, 365t Detrusor-sphincter dyssynergia, neurogenic, 363 treatment of, 366 Developmental venous anomalies, with ectasias, 599 Devic’s disease, 1016. See also Multiple sclerosis.

Dexamethasone for bacterial meningitis, 1241 for medication overdose–headache, 767 for Taenia solium cysticercosis, 1279 systemic, for metastatic epidural spinal cord compression, 532 DHCR7 gene, in Smith-Lemli-Opitz syndrome, 1442-1443 Diabetes insipidus, 1534 preceding brain death, 113 Diabetes mellitus, neuropathies associated with, 1113-1116, 1114f, 1114t, 1116f, 1116t Diabetic amyotrophy, 1114 Diabetic autonomic neuropathy, 1114 Diabetic polyneuropathy, 1113-1115, 1114f etiology of, 1114-1115 treatment of, 1115 Dialysis, for urea cycle disorders, 1475 Diaphragmatic flutter, 1573 Diastematomyelia, 502 Diazepam for delirium tremens, 1540t for ethanol withdrawal symptoms, 1540t for febrile convulsions, 714 for seizures, 713 for status epilepticus, 723f, 724-725 Diencephalon lesions arteriovenous, 598 memory impairment associated with, 50 Diet, atherosclerosis and, 612 Dietary states, polyneuropathy associated with, 1123 Dietary therapy for urea cycle disorders, 1476 ketogenic, for epilepsy, 717 with Lorenzo’s oil, for X-linked adrenoleukodystrophy, 1069 Diffuse infiltrative lymphocytosis syndrome, CD8 T cells in, 1133 Diffusion tensor imaging, of malformations caused by abnormal cortical development, 667 Digital subtraction angiography, of arteriovenous malformations, 601 α-Dihydroergocryptine, for restless leg syndrome, 482t Dihydroergotamine for cluster headache, 778 prophylactic, 780 for migraine, 744t, 746 Diphtheria, 1137, 1486-1487 Diplegia, spastic, in cerebral palsy, 1577 Diplomyelia, 502 Diplopia, examination of, 272-273, 273f Dipyridamole with aspirin, prophylactic, for ischemic stroke, 576 Disability, in multiple sclerosis, 1024-1025 DISC1 gene, in schizophrenia, 224 Disinhibition assessment of, 8-9 in Alzheimer’s disease, 852 Dislocation atlantoaxial, 489t, 491-492 atlanto-occipital, 1398, 1398f cervical (C3 to C7), 1399, 1400f Disseminated intravascular coagulation, 15281529, 1529f Dissociation, 249 classification of, 250t Dissociation apraxia, 408 Distraction, inhibiting, in executive function, 87, 87f Diurnal rhythms, regulation of, hormones and, 1549 Divalproex, prophylactic, for migraine, 747t, 748

Dizziness, 318, 322. See also Vertigo. definition of, 337 in temporal bone fractures, 346 migraine-related, 344 treatment of, 349 DJ-1 (PARK7) gene, in Parkinson’s disease, 928t, 931 DMPK gene, in myotonic dystrophies, 1192, 1193 DMWD gene, in myotonic dystrophies, 1193 DNA, mitochondrial genetics of, 1201-1202, 1203f in common disease phenotypes, 1203-1204 mutations in, clinical disorders caused by, 1202-1203, 1205t DNA repair defective, in inherited ataxias, 889 single-strand, genes associated with, 1105 DNM2 gene, in inherited neuropathies, 11051106 Docetaxel (Taxotere) neurological complications caused by, 1355 toxic neuropathy due to, 1121 Doll’s eye reflex absent, in brain death, 108t in comatose patient, 101-102 Donepezil, for Alzheimer’s disease, 854t L-Dopa. See Levodopa. Dopamine agonists for parkinsonism in corticobasal ganglionic degeneration, 975 in multiple system atrophy, 967 for Parkinson’s disease, 942-943, 943f, 948950, 949f initiation of, 945 for restless leg syndrome, 481, 482t for tremor, 422t Dopamine antagonists, for Huntington’s disease, 883 Dopamine hypothesis, in schizophrenia, 225 Dopamine-depleting agents, for Huntington’s disease, 884 Dopaminergic agents, for dystonia, 450, 451t Dopaminergic function, in restless leg syndrome, 472 Dopaminomimetic agents, for gait disturbances, 468 Dopa-responsive dystonia (Segawa disease), 446, 1439-1440 Doppler ultrasonography. See also Ultrasonography. of ischemic stroke, 565-566, 566f, 567f Dorsolateral prefrontal circuit, in executive function, 85 Double vision, in papilledema, 285 Doxepin, prophylactic, for migraine, 748 Doxycycline for falciparum malaria, 1285 for Lyme disease, 1135 Drainage, for hydrocephalus, 828 Dravet’s syndrome. See Severe myoclonus epilepsy in infancy. Dreams, vivid, sleep disruption due to, 192 Driving, assessment of, in people with higher visuoperceptual disorders, 67 Drooling, in amyotrophic lateral sclerosis, management of, 872 Drop attack, 436 Drug(s). See Pharmacotherapy; specific drug or drug group. Drug abuse definitions of, 1537 illicit, 1537-1539. See also named substance. intoxication and withdrawal in, 1537-1538

index Drug abuse (Continued) medical and neurological complications of, 1538-1539 Drug withdrawal–related seizures. See also Seizure(s). treatment of, 714 Drug-induced myoclonus, 438, 439f Drug-induced tremor, 427-428 Drug-induced vasculitis, 1317 Dry beriberi, 1123 DTNBP1 gene, in schizophrenia, 224 Dual tasking, in executive function, 88-89 Duchenne muscular dystrophy, 1142, 1143t clinical features of, 1145-1146, 1147f definition of, 1145 etiology and pathophysiology of, 1146-1147, 1148f phenotypic differentiation of, 1151t Duplex Doppler ultrasonography. See also Ultrasonography. of ischemic stroke, 565-566, 566f Durable power of attorney, for Alzheimer’s patient, 856 Dural sinuses, anatomy of, 622-623, 622f, 624f Duret hemorrhage, 103 Dynamin2 (DNM2), 1105-1106 Dysarthia–clumsy hand syndrome, 556t, 557 Dysarthria(s), 157-158 ataxic, 158-159, 158t, 160 definition of, 158 flaccid, 158-159, 158t, 160 hyperkinetic, 158t, 159, 160 hypokinetic, 158t, 159, 160 in amyotrophic lateral sclerosis, management of, 872 in multiple sclerosis, 1020 mixed, 159 spastic, 158, 158t Dysautonomia cholinergic, clinical presentation of, 375 in multiple system atrophy, 962 Dyschromatopsia, 60, 61t, 62 screening for, 67t Dysembryonic neuroepithelial tumors, neuroimaging of, 664, 665f Dyskinesia in cerebral palsy, 1577, 1578t in Parkinson’s disease, 946 paroxysmal, 452-453 secondary, 453 tardive, neuroleptics causing, 227 Dyskinetic gait, 465t Dysosmia, 171, 173 Dysphagia after stroke, management of, 649 in amyotrophic lateral sclerosis, 860-862, 862t management of, 872 in multiple sclerosis, 1020 in progressive supranuclear palsy, management of, 973 neurogenic, 161, 162f, 163f, 164-168 assessment of, 164 instrumental, 166, 166f, 167f management of, 166-168 medical history in, 164 normal feeding in, 168 oral feedings in, 166-167 oral peripheral examination of, 164-165 oral trials in, 165-166, 165f swallowing therapy for, 168 rehabilitation strategies for, 1431 Dysphasic status epilepticus, 721. See also Status epilepticus.

Dysphonia, 159 spasmodic, 159 psychogenic, 159, 160f Dysphoria (sadness), 235 Dyspnea, in amyotrophic lateral sclerosis, management of, 871-872, 871t Dystonia, 443-452 cervical, 445 classification of, 443, 444t clinical features of, 444-448, 444t cranial, 445 definition of, 443 distribution of, 443, 444t dopa-responsive, 446 epidemiology of, 443-444 etiology of, 443, 444t excess daytime sleepiness due to, 192 heredodegenerative disorders causing, 447, 448t in corticobasal ganglionic degeneration, management of, 975-976 investigation of, 448, 449f, 449t laryngeal, 446 limb, task-specific, 445-446 molecular genetic studies of, 450 neurophysiological studies of, 448-450 orofacial, in multiple system atrophy, 962f pathophysiology of, 448-450 primary, 444-446, 445t psychogenic, 447-448 secondary, 446-447 causes of, 447t treatment of, 450-452 pharmacological, 450-451, 451t surgical, 451t, 452 tremor associated with, 424 Dystonia parkinsonism, rapid-onset, 447 Dystonia-plus syndromes, 446-447 Dystonic crisis, 452 Dystonic myoclonus, periodic, 437, 437t Dystrophin gene, in muscular dystrophy, 1146 DYT genes, in dystonia, 444, 445t, 446

E Eale’s disease, 1314 Ear. See specific part. Early growth response 2 (EGR2), 1103-1104 Eastern equine encephalitis, 1254 EBV. See Epstein-Barr virus (EBV) entries. Echo phenomena, 9 Echolalia assessment of, 9 in Gilles de la Tourette syndrome, 214 Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET), 572 Echopraxia assessment of, 9 in Gilles de la Tourette syndrome, 214 Echovirus, in meningomyelitis, 516 Eclampsia, 716-717. See also Preeclampsiaeclampsia. definition of, 1497 Economic sequelae, of delirium, 143 Edema, cerebral, treatment of, 1241 Educational program, structured and consistent, in management of autism, 134-135 Eflornithine, for African trypanosomiais, 1276t EGFR gene, in brain tumors, 1325 EGR2 (early growth response 2), 1103-1104 EGR2 gene, in inherited neuropathies, 11031104 Eicosanoids, in cerebral circulation regulation, 547

1595

Ekbom’s syndrome, 1525 El Escorial diagnostic criteria, for amyotrophic lateral sclerosis, 859, 861t, 868t Elderly, epilepsy in, treatment of, 717 Electrical injury, to peripheral nerves, 1418 Electrocardiography, of neurogenic heart disease, 1507, 1507f Electrocochleography, 321 Electroconvulsive therapy amnesia associated with, 49 for depression, 239 Electroencephalography jerk-locked back averaging, of myoclonus, 440, 440t, 441f of brain death, 111 of comatose patient, 105 of epileptic syndromes, 697, 698f, 699, 699f702f, 702 of Lewy body dementia, 915 of vegetative state, 119-120, 120f-122f Electrolyte disorders, 1533-1536. See also specific disorder. Electromyography of amyotrophic lateral sclerosis, 867, 868t, 869f of bladder dysfunction, 363-364 of myoclonus, 440, 440t of peripheral nerve injury, 1413-1414 sphincter of multiple system atrophy, 964 of primary autonomic failure, 380 Electronystagmography, 324 Electro-oculography, 324 Eletriptan, for migraine, 745t, 746 ELLDOPA study, of Parkinson’s disease, 945, 945f, 949 Embolization endovascular, for spinal cord arteriovenous malformations, 606-607 glue, for brain arteriovenous malformations, 602 Embolus (embolism) air, 1575 retinal, 307-308, 308f Emergency department management, of spinal trauma, 1404 Emergency room evaluation, of ischemic stroke, 569 Emery Dreifuss muscular dystrophy, 1142, 1143t, 1146f definition of, 1155-1156 etiology and pathophysiology of, 1156 phenotypic differentiation of, 1151t Empty delta sign, in cerebral vein and sinus thrombosis, 625 Empty speech, 33 EMX2 gene, in cerebral palsy, 1579 Encephalitis amebic, 1273, 1275t limbic autoimmune, rare forms of, 705 immune system–mediated, 51, 52f nonparaneoplastic, 51, 52f paraneoplastic, 51, 52f, 1367, 1367f viral, 51-53 viral causes of, 1250t clinical syndromes associated with, 12521255, 1253f, 1254f diagnosis of, 1250, 1252 etiology and pathogenesis of, 1255, 1255f HIV–associated, pathological features of, 1263f limbic, 51-53 specific etiologies in, 1250, 1251f treatment of, 1255-1256

1596

Index

Encephalocele, 495 Encephalomyelitis acute disseminated, 519, 1057-1059 clinical features of, 1058, 1058f definition of, 1057 epidemiology of, 1057, 1058t hyperacute form of, 1059-1060 pathophysiology of, 1058-1059, 1059f, 1059t prevention and treatment of, 1060 terminology in, 1057 experimental allergic, 1057, 1059t paraneoplastic, 1365t, 1366-1367, 1366f postinfectious, 1057, 1059t post-rabies vaccine, 1057, 1059t Encephalopathic syndrome, 624-625 Encephalopathy(ies), 1434-1444 chemotherapy-induced, 1353, 1354t complex genetics in, 1435 concept and context of disease in, 1434 diagnosis of, 1437 diffuse, in inflammatory bowel disease, 1515 epileptic, 678 prognosis of, 679 future therapies for, groundwork for, 14371438, 1437t hepatic chronic, 1517-1518, 1517t minimal, 1517 hypertensive, headache associated with, 803 manifestations unfolding with time in, 14341435 metabolic. See also specific type. classification of, 1438-1444, 1438t extraneurological manifestations of, 1436t fulminant, 1443-1444, 1444t pleomorphic phenomenology in, 1435-1436, 1436t, 1437t postoperative, after organ transplantation, 1564-1565 static, episodic, or progressive disease in, 1435 Wernicke’s. See Wernicke-Korsakoff syndrome. Endarterectomy, carotid, prophylactic, for ischemic stroke, 581 Endocarditis, nonbacterial thrombotic, 1531 Endomysium, of muscle, 1095, 1096f Endoneurium, 1409, 1410f Endophthalmitis, Candida albicans–related, 302 Endosomes, genes associated with, 1104 Endothelial regulation, of cerebral circulation, 546-547, 547f Endothelin, in regulation of blood pressure, 354 Endovascular embolization, for spinal cord arteriovenous malformations, 606-607 Enolase, serum neuron-specific, as marker in vegetative state, 123 β-Enolase deficiency, 1198 Entacapone, for Parkinson’s disease, 942 Entamoeba histolytica, 1273 Enteropathy, gluten-sensitive, 1511-1512, 1512t Enteroviruses, in meningitis, 1249 Entrapment neuropathy, HIV-associated, 1268 Environmental agnosia, 61t, 63 screening for, 67t Environmental factors in amyotrophic lateral sclerosis, 866 in autism, 133 in Parkinson’s disease, 933-934 Environmental spatial relations, impaired, 64, 64t Environmental toxin(s), 1477-1487. See also specific toxin. animal, 1485 bacterial, 1486-1487

Environmental toxin(s) (Continued) gaseous, 1483-1484, 1483t metal, 1477-1481 organic solvents as, 1481-1483, 1481t pesticides as, 1484-1485 plant, 1485-1486 Enzyme(s), muscle, in inflammatory myopathies, 1214 Enzyme-linked immunoelectrotransfer blot assay, for Taenia solium cysticercosis, 1277 Enzyme-linked immunosorbent assay, for Taenia solium cysticercosis, 1277 Ependymoma magnetic resonance imaging of, 1344, 1345f of spinal cord, 527-528, 528t, 529f outcome for, 1349 Epidermolysis bullosa with muscular dystrophy forms of, 1143t phenotypic differentiation of, 1153t Epidural abscess, spinal, 519-520, 520t, 521f Epidural blood patches, for cerebrospinal fluid leaks, 822 Epidural hematoma, 1389-1390, 1390f Epilepsia partialis continua, 428, 435, 437t, 721 clinical features of, 436 diagnosis of, 692 Epilepsy, 677-679, 677t. See also Seizure(s). age of onset of, 698, 698t autosomal dominant nocturnal frontal, 678 genetics of, 683t, 684 benign, with centrotemporal spikes, treatment of, 714 clinical approach to, 674-675, 674t clinical spectrum of, 673-679 definitions and epidemiology in, 673-674, 674f complex inheritance of, 687 definitions of, 673 depression in, 238 diagnosis of, 691 step 1: defining seizure type in, 692-697 step 2: identifying epileptic syndrome in, 697-706 electroencephalography of, 697, 698f, 699, 699f-702f, 702 excess daytime sleepiness due to, 193, 193t family history of, 697 generalized genetics of, 681-683, 683t treatment of, 710-712 with febrile seizures, 679 genetics of, 682, 683t genetically-linked, 681-687, 683t glossary of terms in, 684t pharmacogenetic principles of, 681, 682f population, 681 voltage-gated or ligand-gated channels in, 683, 684f in celiac disease, 1512-1513 in pregnancy, 1499-1501 consequences of, 1499-1500 management of, 1500-1501 in women, issues related to, 715-716 treatment of, 716 incidence of, 673, 674f international classification of, 677, 677t juvenile myoclonic. See Juvenile myoclonic epilepsy. lesional, 714-715 treatment of, 715 malformations caused by abnormal cortical development causing, 662-670. See also Malformations caused by abnormal cortical development (MCD). myoclonic. See Myoclonus epilepsy. neuroimaging of, 701-702, 702f, 703f

Epilepsy (Continued) neurological and general examinations in, 699 partial nonidiopathic, 703-704, 704f, 705 treatment of, 708-710 past history in, 697-698 prevalence of, 674 prognosis of, 679 psychotic symptoms in, 228 sexual dysfunction in, 367 temporal lobe genetics of, 683t, 684-685 memory impairment associated with, 49 mesial, 679 treatment of, 707-718 antiepileptic agents in, 707-713 for elderly, 717 for generalized seizures, 710-712 for partial and tonic-clonic seizures, 708710 for specific syndromes, 713-714 for structural lesions, 714-715 for women, 715-716 principles of use of, 707-708 specific, 708 toxemia of pregnancy and, 716-717 with narrow spectrum of action, 712-713 withdrawal of, 717 complimentary and alternative therapies in, 718 ketogenic diet in, 717 palliative procedures in, 718 resective surgery in, 717-718 Epilepsy surgery, for malformations caused by abnormal cortical development, 669 prospects for improving outcome of, 669-670, 670f Epileptic encephalopathy, 678 prognosis of, 679 Epileptic myoclonus. See Myoclonus epilepsy. Epileptic seizures. See Seizure(s), epileptic. Epileptic syndromes, 677-679, 677t. See also Epilepsy. classification of in neurological practice, 705-706 systemic approach to, 702 familial vs. conventional, 679 in late childhood and adolescence, 703, 704f in neonates, infants, and children, 703 Epimysium, of muscle, 1095, 1096f Epineurium, 1409, 1410f Episodic ataxia, 891 Episodic memory, 43-44 anterograde, 5 Epstein-Barr virus (EBV) infection, acute disseminated encephalomyelitis with, 1058, 1058f Epstein-Barr virus (EBV) meningitis, 1252 Epstein-Barr virus (EBV) myelitis, 518 Epworth Sleepiness Scale, 210t Equipment, adaptive, in rehabilitation, 1428, 1428f-1430f, 1428t, 1430t Erectile dysfunction, treatment of, 367-368, 368t, 384t, 385 Ergotamine for cluster headache, 778 prophylactic, 780 for migraine, 744t, 746 Erythema migrans, disseminated, in Lyme disease, 1134, 1134f Erythrocyte sedimentation rate, in giant cell arteritis, 797-798 Erythropoietin, to improve blood pressure, 359 Essential tremor. See Tremor, essential. Estradiol, in pregnancy, 1490, 1491f

index Estriol, in pregnancy, 1490 Estrogens in pregnancy, 1490 prothrombic influence of, 618 Estrone, in pregnancy, 1490, 1491f Ethambutol, for tuberculous meningitis, 1244t Ethanol, 1539-1543 dependence on, 1540 intoxication with, 1539, 1540t disorders associated with, 1541-1542 nonnutritional neurological complications of, 1542-1543 prothrombic consequence of, 619 withdrawal from, 1540-1541, 1540t Ethical considerations, of vegetative state, 127 Ethical issues, in management of delirium, 150 Ethosuximide, for seizures, 712 Ethylene glycol, exposure to, 1481, 1481t European Cooperative Acute Stroke Study (ECASS), 570 European Stroke prevention Study II (ESPS-II), 576 Evoked potentials. See also Brainstem auditory evoked potentials; Somatosensory evoked potentials. in brain death, 111-112 in comatose patient, 106 in multiple sclerosis, 1032-1034, 1032f-1034f Excitotoxicity glutamate, in multiple sclerosis, 1007-1008 in amyotrophic lateral sclerosis, management of, 868 in spinal cord injury, 1402 Executive function, 83-91 assessment of affective, social, and judgmental changes in, 86 collateral information in, 89-90 dual tasking in, 88-89 formal, 86-90 in Alzheimer’s disease, 851 level of premorbid ability in, 86 planning and hypothesis generation in, 89, 90f qualitative observations in, 90 release signs (primitive reflexes) in, 91 tests in. See also specific test. bedside, 90-91 common problems affecting, 86 multifactorial, 86 neuropsychological, 86-88, 87f, 88f office-based, 86 practice effects in, 86 verbal fluency performance in, 89 characterization of, 83 neuroanatomical substrates of, 85-86, 85f neurocognitive assessment of, 5-6 neurocognitive examination of, 14, 15t neuropsychological model(s) of, 83-85 supervisory attentional system, 84-85, 84f working memory, 83-84, 84f Exercise-induced dyskinesia, paroxysmal, 453 Exercises for gait disturbances, 466, 467t in rehabilitation schemes flexibility, 1425, 1427 strengthening, 1427 Expanded disability status scale (EDSS) score, in multiple sclerosis, 1024-1025 Expiration, 1569. See also Respiration. External carotid–internal carotid anastomoses, 541 Extinction motor, 75 sensory, 73-74

Extraocular muscles, function of, in comatose patient, 101-102, 101f Extrapyramidal disorders. See also specific disorder, e.g., Parkinson’s disease. affecting speech, 159 mania in, 239 Eye(s). See also Ocular; Oculo- entries; specific part. inflammatory disorders of, 295 movement of, in comatose patient, 101-102, 101f “Eye of tiger” sign, in cerebral iron accumulation, 448, 449f Eyeball, anatomy of, 295 Eyelids, examination of, 271

F Face apraxia, 412 Face validity, of test, 24 Faces, associative visual agnosia for, 61, 61t, 62-63, 63f Facial nerve (VII), function of, in speech and swallowing, 155, 157f Facial pain. See also Trigeminal neuralgia. atypical, 837, 837f Facial palsy, in multiple sclerosis, 1019 Factitious disorder, vs. conversion hysteria and malingering, 250t Factor(s), procoagulant, in pregnancy, 1492, 1492t Factor VIIa, recombinant, reversal of anticoagulant effects with, 1391-1392 Failure to awaken, after organ transplantation, 1564-1565 Falls. See also Balance; Gait entries. clinical work-up of, 458, 459f gait disturbances and, 455 history taking for, 457-458, 458t psychological consequences of, 458 risk of, impaired cognitive function and, 463, 465 seizures associated with, 694-695 False aneurysm, 590 Famciclovir, for herpes zoster virus infection, 1136 Familial forms, of amyotrophic lateral sclerosis, 866t Familial hemiplegic migraine, 344, 737 Familial infantile convulsions, benign, genetics of, 683, 683t, 684f Familial lateral temporal lobe epilepsy, genetics of, 683t, 684-685 Familial neonatal convulsions, benign, genetics of, 683-684, 683t Familial spastic paraplegia. See Hereditary spastic paraplegia. Family attitudes, toward brain death, 113 Family history in mental status assessment, 10 of Alzheimer’s disease, 852 positive, in restless leg syndrome, 474 Fasciculations in amyotrophic lateral sclerosis, 860 management of, 871 postexercise, in Lambert-Eaton myasthenic syndrome, 867 Fascioscapulohumeral muscular dystrophy, 1142, 1143t clinical features of, 1156, 1157f definition of, 1156 etiology and pathophysiology of, 1157 phenotypic differentiation of, 1151t

1597

Fatigue in amyotrophic lateral sclerosis, management of, 871 in multiple sclerosis, 1017 treatment of, 1050 poststroke, 653 Fatty acid oxidation, 1198-1199, 1199f disorders of biochemical evaluation of, 1200-1201 clinical features of, 1200 treatment of, 1201 Fatty aldehyde dehydrogenase deficiency, 10791080 Febrile convulsions, treatment of, 714 Febrile seizures, 678. See also Seizure(s). complicated, 697 generalized epilepsy with, 679 genetics of, 682, 683t genetics of, 685, 687 Felbamate, for generalized seizures, 712 Ferrous sulfate with vitamin C, for iron deficiency, in restless leg syndrome, 476 Festinating gait, 463, 463t Fetal alcohol syndrome, 1543, 1543t Fetal nigral transplantation, for Parkinson’s disease, 947t, 948 α-Fetoprotein, 1490 maternal serum, in diagnosis of neural tube defects, 498 Fetus, effects of illicit drugs on, 1539 Feverfew (Tanacetum parthenium), prophylactic for chronic daily headache, 768t for migraine, 749 Fiberoptic endoscopic study, of swallowing, 166, 167f Filum terminale, thickened, tight, in tethered cord syndrome, 499 Finances, of Alzheimer’s patient, 856 Fisher syndrome, 1137 Fistula, arteriovenous, of brain, 595, 596, 597f Flaccid dysarthria, 158-159, 158t, 160 Flexibility, cognitive, in executive function, 8788 Flexibility exercises, in rehabilitation schemes, 1425, 1427 Floppy infant syndrome, in congenital myopathy, 1169 Fluconazole for blastomycosis, 1290 for coccidioidomycosis, 1290 for cryptococcosis, 1289 for histoplasmosis, 1290 Flucytosine, for cryptococcosis, 1289 Fludrocortisone, for orthostatic hypotension, 359, 359t Fluency of language, 32-33, 32t verbal, in executive function, 89 Fluent aphasia. See Aphasia, fluent. Fluent progressive aphasia, 38 Fluff test, for personal neglect, 77 Fluid-attenuated inversion recovery (FLAIR) imaging of focal cortical dysplasia, 664, 664f of multiple sclerosis, 1036, 1037f Flunarizine, prophylactic, for migraine, 747t, 748 5-Fluorouracil, neurological complications caused by, 1355 Fluphenazine, for Huntington’s disease, 883 Flutter, diaphragmatic, 1573 Focal cortical dysplasia, 662. See also Malformations caused by abnormal cortical development (MCD). classification of, 663, 663t

1598

Index

Focal cortical dysplasia (Continued) molecular defects associated with, 664 neuroimaging of, 664, 664f Folic acid (folate) deficiency of, 1461-1462 anemia due to, 1526-1527 dosages of, 498 supplementation with in prevention of neural tube defects, 498 to minimize antiepileptic drug teratogenicity, 716 Follicle-stimulating hormone (FSH), source and function of, 1550t Footdrop, in Wernicke-Korsakoff syndrome, 1457, 1458f Forebrain, lesions of, memory impairment associated with, 50 Forme cérébrale de la cholestérinose généralisée, 1078-1079 Formulation, of language, 31-32, 32t Fornix, lesions of, memory impairment associated with, 50 Fosphenytoin for seizures, 713 for status epilepticus, 723f, 725 Fracture(s) atlas (C1), 1398, 1399f axis (C2), 1398-1399, 1399f posterior elements of, 1399 cervical (C3 to C7), 1399, 1400f Chance, 1401, 1401f Pincer, 1405f skull, 1390, 1391f temporal bone, 346 thoracic, 1400, 1400f thoracolumbar junction, 1400, 1400f Fragile X mental retardation 1 (FMR1) “gray zone” allele, in multiple system atrophy, 963 FRDA gene, in Friedreich’s ataxia, 1443 Free radicals, in spinal cord injury, 1402 Freezing of gait, 458 Frequency, of tremors, 417, 418t Fresnel prisms, for spatial neglect, 80, 81f Friedreich’s ataxia, 887, 1443 clinical features of, 889 late-onset, 888 treatment of, 895 vs. vitamin E deficiency, 1463, 1463f Frisén Scale, for idiopathic intracranial hypertension, 808, 808t Frivatriptan, for migraine, 745t, 746 Frontal Assessment Battery, 16 Frontal Behavioral Inventory, 90 Frontal cortex, information flow to, in executive function, 85-86 Frontal lobe dementia, 984t case study of, 987, 988f Frontal lobe tumors, seizures associated with, 1326 Frontal Systems Behavioral Scale, 90 Frontoparietal circuits, dysfunction of, in limb apraxia, 409 Frontotemporal dementia, 54-55, 54f, 55f, 983992 apathy in, 243 apolipoprotein E genotype in, 986 clinical features of, 983-984, 984t clinical vignette(s) of, 987-991 case 1: frontal lobe dementia, 987, 988f case 2: progressive nonfluent aphasia, 987, 989f case 3: semantic dementia, 987-989, 990f case 4: progressive prosopagnosia, 989-991, 992f corticobasal degeneration in, 984

Frontotemporal dementia (Continued) familial forms of, 986 future directions in, 991 genetic factors in, 985-986 genetic testing for, 986-987, 987t imaging of, 991 Internet Resources for, 991t Neary classification of, 983, 984t pathology of, 984-985, 985t, 986f primary progressive aphasia in, 983 tau haploid in, 986 tau mutations in, 985-986, 986f terminology in, 984t treatment of, 991 with motor neuron disease, 984 with parkinsonism, 983-984 FSH (follicle-stimulating hormone), source and function of, 1550t Fukuda stepping test, of balance Fulminant metabolic encephalopathies, 14431444, 1444t Functional impairment, evaluation of, 4, 4t Functional Independence Measure (FIM) instrument, 1426f Functional reach test, of balance, 459 Fungal infections. See also specific infection; specific organism. of central nervous system, 1289-1291 of retina, 302, 303f Fusiform aneurysm, 587 FZD4 gene, in hereditary vitreoretinopathies, 276

G Gabapentin for partial and tonic-clonic seizures, 709 for restless leg syndrome, 481 for tremor, 421, 421t prophylactic, for migraine, 747t, 748 GABBR1 gene, in inheritance of epilepsy, 687 Gag reflex, 155 Gait, 455 antalgic, 458 assessment of, 457-463 history taking in, 457-458, 458t, 459f physical examination in, 458-460, 460t quantitative, 460-461, 461f, 462f rating scales in, 460 timed tests in, 459-460 control of, cognitive function in, 463, 465466, 466f spastic, in hereditary spastic paraplegia, 902, 903 Gait apraxia, 413 Gait ataxia, in multiple system atrophy, 961, 962, 963t Gait cycle, 456-457, 457f Gait disturbance(s), 455-468 classification of, 462, 464t-465t system-oriented, 462t cueing techniques for, 466-467 dystonic, 458 episodic, 463, 463t, 465t etiology and pathophysiology of, 461-463 falls as complication of, 455. See also Falls. festination as, 463, 463t freezing as, 458, 463, 463t in hereditary spastic paraplegia, 902, 903 in normal-pressure hydrocephalus, 830 medical treatment for, 467-468 rehabilitation strategies for, 466, 467t, 1427 surgical interventions for, 468 therapeutic interventions for, 466

Gait disturbance(s) (Continued) vitamin E deficiency and, 1463f walking aids for, 467 Gait mats, 460 Galactosemia, 1441-1442 Galantamine, for Alzheimer’s disease, 854t GALT gene, in galactosemia, 1441 Gamma knife radiosurgery, for trigeminal neuralgia, 838 Gamma-aminobutyric acid system, in schizophrenia, 224, 226 Ganglioglioma, neuroimaging of, 664, 666f Ganglion, intraneural, 1380 GARS gene, in inherited neuropathies, 1105 Gas(es), toxicity of, 1483-1484, 1483t Gastrocnemius myalgia syndrome, 1514 Gastrointestinal disease, 1511-1516. See also specific disorder, e.g., Celiac disease. misdiagnosis of, 696 Gastrulation, process of, 488 Gaze apraxia, oculomotor, 64 Gaze impairment, vertical, in Whipple’s disease, 1516 Gaze nystagmus, 323, 325 GCH-1 gene, in Segawa disease, 1439 GDAP1 gene, in inherited neuropathies, 1104 Gelastic (laughter) seizures, 676 Gene(s). See also specific gene. associated with axonal transport, 1103 associated with brain malformations, 686t associated with DNA single-strand break repair, 1105 associated with endosomes, 1104 associated with peripheral nerve structure, 1102-1103, 1105-1106 associated with progressive myoclonic epilepsy, 685t associated with signaling, 1104 associated with transport through myelin, 1103 in early-onset Alzheimer’s disease, 848t in inherited neuropathies, 1100t in Parkinson’s disease, 928-932, 928t mitochondrial, 1104-1105 pseudodeficiency, in metachromatic leukodystrophy, 1070 susceptibility, in multiple sclerosis, 998-999 undefined defective, in leukodystrophies, 1083, 1083t Gene testing, role of, in diagnosis of hereditary spastic paraplegia, 904-905 Gene therapy, for muscular dystrophy, 1160 Generalized convulsive status epilepticus. See also Status epilepticus. definition of, 719 physiological changes in, 722, 722t Generalized epilepsy. See also Epilepsy. genetics of, 681-683, 683t with febrile seizures, 679 genetics of, 682, 683t Generalized seizures, 675. See also Seizure(s). myoclonic, preserved consciousness in, 696697 partial, 694 treatment of, 710-712 Genetic counseling in hereditary spastic paraplegia, 905-906 in inherited neuropathies, 1108 Genetic disease, blindness due to, 274. See also Blindness, genetic causes of. Genetic factors in Alexander’s disease, 1076 in Alzheimer’s disease, 846-847, 848t in amyotrophic lateral sclerosis, 866, 866t in brain tumors, 1328, 1330 in Canavan’s disease, 1075

index Genetic factors (Continued) in corticobasal ganglionic degeneration, 974 in globoid leukodystrophy, 1072 in Huntington’s disease, 879-880, 880f, 881f in inherited neuropathies, 1102-1106, 1102f in metachromatic leukodystrophy, 1070 in multiple sclerosis, 997-998 in multiple system atrophy, 962-963 in neural tube defects, 497 in Parkinson’s disease, 928-932, 928t in Pelizaeus-Merzbacher disease, 1074 in progressive supranuclear palsy, 969 in Wilson’s disease, 1449-1450 in X-linked adrenoleukodystrophy, 1067 Genetic lesions, in spinal cord arteriovenous malformations hereditary, 603 nonhereditary, 603-604 Genetic studies of dystonia, 450 of schizophrenia, 224, 225f Genetic testing for frontotemporal dementia, 986-987, 987t for Huntington’s disease, 882 for inherited neuropathies, 1106-1108, 1106f, 1106t, 1107f Genetic theories of attention-deficit hyperactivity disorder, 134 of autism, 133 Geniculate neuralgia, vs. trigeminal neuralgia, 837 Gerstmann’s syndrome, 13 GH. See Growth hormone (GH). Giant cell arteritis, 1320 choroidal insufficiency in, 298, 298f headache secondary to, 797-798, 797f, 798t Gilles de la Tourette syndrome diagnosis of, 215 DSM-IV-TR definition of, 214 epidemiology of, 215 etiology of, 215 management of nonpharmacologic, 216 pharmacologic, 216-217 prognosis of, 216 psychopathology associated with, 215-216 recommendations for, 217-218 tics in, 214 Glasgow Coma Scale, 100, 100t, 1386-1387, 1387t, 1423 Glasgow Outcome Scale, 1387, 1387t Glatiramer acetate, for multiple sclerosis, 1046t, 1047 Glaucoma, arcuate scotoma due to, 267f Glial tumors, of spinal cord, 527-530, 528t, 529f Glioblastoma multiforme, 1328, 1329f effect of corticosteroids on, 1333-1334, 1334f genetics in, 1330 imaging, pathology, and histology of, 1332f Glioma malignant, treatment of, 1335-1336 pathology of, 1327-1328 treatment of, 1334-1335 Globe, colobomatous malformations of, 274 Globoid cells, in globoid leukodystrophy, 1071 Globoid leukodystrophy clinical features of, 1071 diagnosis of, 1072-1073 genetics of, 1072 neuroimaging of, 1071-1072, 1072f pathogenesis of, 1073 pathology of, 1071 synonyms for, 1071 treatment of, 1073

Glossopharyngeal nerve (IX), function of, in speech and swallowing, 155, 157f Glossopharyngeal neuralgia, vs. trigeminal neuralgia, 836 Glucose intolerance, 1115 Glucose transporter type 1 deficiency, 1439 α-Glucosidase deficiency, 1195 Glue embolization, for brain arteriovenous malformations, 602 GLUT1 gene, in glucose transporter type 1 deficiency, 1439 Glutamate excitotoxicity, in multiple sclerosis, 1007-1008 Glutamate hypothesis, in schizophrenia, 225 Glutamate receptor antagonists, for spinal trauma, 1406 Glutaric aciduria type 2, 1200 Glutathione, levels of, in Parkinson’s disease, 935, 935t Gluten ataxia, 1512 Gluten-sensitive enteropathy, 1511-1512, 1512t Glycogen storage disorders clinical features, diagnosis, and management of, 1195-1198 glycolytic pathway in, 1195, 1196f neurological features of, 1197t Glycogenosis type II, 1195, 1197t type III, 1196, 1197t type IV, 1196, 1197t type V, 1197, 1197t type VII, 1197-1198, 1197t type VIII, 1197 type IX, 1197t, 1198 type X, 1197t, 1198 type XI, 1197t, 1198 type XII, 1197t, 1198 type XIII, 1197t, 1198 Glycolytic pathway, 1195, 1196f distal, disorders of, 1198 Glycosylation disorders, 1440 Glycyl tRNA synthetase, 1105 Gnathostoma spinigerum, 1286 Gnathostomiasis, 1286 Goldman field, in vision assessment, 260, 261f Goldmann-Favre syndrome, 276 Golgi abnormality(ies), hereditary spastic paraplegia due to, 902 GPR56 gene, in cerebral palsy, 1579 Graft-versus-host disease, after organ transplantation, 1567 Granulomatosis lymphomatoid, 1317 Wegener’s, 1315 orbital involvement in, 298 Gray matter, neuronal loss in, multiple sclerosis and, 1008 GRM3 gene, in schizophrenia, 224 Growth hormone (GH), 1551-1552 congenital deficiency of, 1552 source and function of, 1550t Guillain-Barré syndrome, 1137-1138 HIV-associated, 1132, 1132t pathogenesis of, 1138 Gunshot wounds, to head, 1391 Gustatory disorders clinical approach to, 175 drug-induced, 173t history of, 175-176, 176t investigation of, 176 management of, 176 office assessment of, 176 Gustatory seizures, 676. See also Seizure(s).

1599

H H zone, of sarcomere, 1095, 1096f HAART. See Highly active antiretroviral therapy (HAART). Half-sibling studies, of multiple sclerosis, 998 Hallucinations, 7-8 definition of, 7 in Lewy body dementia, 912 in Parkinson’s disease, management of, 946 olfactory, 676 Hallucinogens, intoxication and withdrawal of, 1538 Haloperidol for autism, 135 for delirium, 150 for Huntington’s disease, 883 Hamartoma lipofibromatous, 1380 of tuberous sclerosis complex, neuroimaging of, 664, 665f retinal, 306, 306f Hand tremor, treatment of, 421, 421t, 422t Hansen’s disease. See Leprosy. Harding’s classification, of autosomal dominant cerebellar ataxia, 891t Hashimoto’s disease, 705 Hashish, 1537 hCG (human chorionic gonadotropin), in pregnancy, 1490 HCV (hepatitis C virus), infection with, 1136 Head and neck, examination of in balance disorders, 323 in hearing loss, 318-319 Head thrust testing, of balance, 323 Head trauma, 1386-1395. See also Brain injury, traumatic. development of care systems for, 1386 gunshot, 1391 prevention of, 1386 severe, epilepsy following, 697-698 Head tremor in Parkinson’s disease, 936 treatment of, 421-422, 421t, 422t Headache, 734-737 after carotid endarterectomy, 799 after cerebral angiography, 799 after coiling and clipping of intracranial aneurysm, 799 anatomy of, 734, 735f associated with brain tumors, 1325 cerebrospinal fluid leakage and, 817-822. See also Cerebrospinal fluid leaks. variations in, 818t cervicogenic, 801 chronic daily, 763-769 as progression of disease, 766, 766f clinical characterization of, 763-766 definition of, 763 epidemiology of, 763 medication overdose and, 767 treatment of, 767-768 pathophysiology of, 766-767, 766f prevalence of, 764t risk factors for, 766, 769t treatment of, 767-768, 768t, 769t cluster, 775-782 brain imaging of, 774, 774f clinical features of, 775t, 776-777 diagnostic criteria for, 776t epidemiology of, 776 natural history of, 777 treatment of, 777-782, 777t abortive agents in, 777-779 patient education in, 777

1600

Index

Headache (Continued) preventive, 779-782 surgical, 782 idiopathic stabbing, vs. trigeminal neuralgia, 837 in brain arteriovenous malformations, 600601 in HIV infection, 1269 in intracranial hypertension syndrome, 624 in multiple sclerosis, 1017-1018 in rheumatoid arthritis, 1559 in systemic lupus erythematosus, 1562 migraine. See Migraine. neuroparasites causing, 1274t pain of, 734-735 modulation of, 736-737 neurogenic inflammation during, 735, 735f peripheral mechanisms and nociceptor activation in, 735-736, 735f persistent daily, 764, 765t, 766 red flags associated with, 794t Schaltenbrand’s, 817 secondary to cerebral venous sinus thrombosis, 797 secondary to cervical artery dissection, 794796, 795f secondary to Chiari malformation, 799-800, 800f, 800t secondary to giant cell arteritis, 797-798, 797f, 798t secondary to homeostasis disorders, 802-803, 802t secondary to hypertension, 802-803 secondary to intracranial aneurysms, 796, 796t secondary to intracranial infection, 802 secondary to intracranial neoplasm, 800-801 secondary to ischemic stroke, 793-794 secondary to neck of cranial structure disorders, 801-802 secondary to obstructive sleep apnea, 802, 802t secondary to primary angiitis of central nervous system, 798-799 secondary to reversible cerebral angiopathy, 799, 799t secondary to subarachnoid hemorrhage, 796797, 796t, 797f sentinel (warning), 796 sinus, 801-802 tension-type, 757-760 chronic, 764, 765t clinical features of, 757 definition of, 757 diagnostic criteria for, 758t epidemiology of, 757 etiology and pathophysiology of, 757-758 treatment of, 758-760 acute therapy in, 759, 759t nonpharmacological, 759-760 preventive, 759, 759t thunderclap, 796 differential diagnosis of, 796t Headache phase, of migraine, 742 Head-shaking nystagmus, 323 Hearing, examination of, 318-322 acoustic reflex in, 320-321 audiological tests in, 319 auditory brainstem response in, 321 electrocochleography in, 321 otoacoustic emissions in, 321-322 patient history in, 318 physical assessment in, 318-319 pure-tone audiometry in, 319-320 radiographic testing in, 322

Hearing, examination of (Continued) speech audiometry in, 320 tympanometry in, 320 Hearing loss. See also Deafness. central, 330 conductive, 318, 329 acoustic reflex in, 321 causes of, 319-321 definition of, 329 hereditary, 329 noise-induced, 332 retinopathy/optic neuropathy associated with, 283 sensorineural, 318, 329-330 acoustic reflex in, 321 causes of, 332-333 in ulcerative colitis, 1514 sudden, 333 types of, 318 Heart disease, neurogenic, electrocardiography of, 1507, 1507f Heart Outcomes Prevention Evaluation (HOPE) study, 569 Heart Protection Study (HPS), 580 Heart rate, during pregnancy, 1491, 1492f Heat-shock protein 27 (HSP27), 1105 Heavy metals. See also specific metal. intoxication with, 1477-1481 complication and management of, 1478t toxic neuropathy due to, 1121-1122 Hebbian synapse, 45 Hemangioblastoma magnetic resonance imaging of, 1344, 1346f of spinal cord, 530 Hemangioma cavernous, radiation-induced, 1358, 1358f retinal, in von Hippel–Lindau disease, 306, 307f Hematoma epidural, 1389-1390, 1390f intracerebral, 1388-1389 subdural, 1389, 1389f cerebrospinal fluid leaks causing, 822 Hemi walker, 1429f Hemianesthesia, sensory neglect and, 73 Hemianopia bitemporal, due to craniopharyngioma, 265f incomplete, due to occipital lobe infarction, 264f progressive, brain tumors and, 1326 with neglect, 73 without neglect, 73 Hemiasomatognosia (personal neglect), 75. See also Neglect syndrome. examination of, 76-77 Hemicrania. See also Headache. paroxysmal clinical features of, 775t, 782-783, 783f diagnostic criteria for, 776t diagnostic workup for, 783 epidemiology of, 782 management of, 783-784 symptomatic, 783, 783t Hemicrania continua, 765t, 766 Hemidyschromatopsia, 62 Hemiparesis ataxia, 556t, 557 pure motor, 556, 556t Hemiplegia pure motor, 556, 556t spastic, in cerebral palsy, 1577 Hemiplegic migraine, familial, 344 Hemispatial neglect, 64, 64t screening for, 67t Hemodialysis, for urea cycle disorders, 1475

Hemodynamic changes, in pregnancy, 1491, 1492f Hemoglobinopathy(ies), 1527 Hemophilia, 1528 Hemorrhage cerebellar, 347 cerebral, reduced CSF absorption due to, 826 Duret, 103 in brain arteriovenous malformations, 600 treatment after, 601 in sickle cell anemia, 1527 in spinal cord arteriovenous malformations, 604-605 intracranial, 587-592. See also Intracranial hemorrhage. retinal, associated with subarachnoid hemorrhage, 309-310, 309f subarachnoid, 1390 headache secondary to, 796-797, 796t, 797f Hemorrhagic necrotizing leukoencephalitis, acute, 1059-1060 Hemorrhagic stroke. See also Stroke. during pregnancy pathophysiology of, 1496 treatment of, 1496 Hemostasis, excessive neurological consequences of, 610-611, 614f615f pathology of, 609-610, 612f, 613f Hemostatic system, 609, 610f, 611f disorders of, 609-619. See also specific disorder, e.g., Stroke. hypercoagulability in, 617-619, 617f vessel wall defects in, 611-613, 615t, 616f Virchow’s triad superimposed on, 609, 612f, 613f Henoch-Schönlein purpura, 1316 Heparin, prophylactic, for ischemic stroke, 576577 Heparin in Acute Embolic Stroke Trial (HAEST), 577 HEPARINISE mnemonic, 609 Heparinoids, prophylactic, for ischemic stroke, 576-577 Hepatic biopsy, for Wilson’s disease, 1449 Hepatic disease, 1517-1520 alcoholic, 1542 neuropathy associated with, 1116 Hepatic encephalopathy chronic, 1517-1518, 1517t minimal, 1517 Hepatic failure, fulminant, 1518-1519 Hepatic myelopathy, 509-510 Hepatic transplantation, for Wilson’s disease, 1450 Hepatitis C virus (HCV), infection with, 1136 Hepatocerebral degeneration, acquired, 15191520, 1519t Hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS), 309 Hereditary hemorrhagic telangiectasia, 598-599 Hereditary inclusion body myopathy, 1144t, 1145 definition of, 1158 etiology and pathophysiology of, 1159 phenotypic differentiation of, 1154t Hereditary lesions, in spinal cord arteriovenous malformations, 603 Hereditary neuropathy, with liability to pressure palsies, 1100 inheritance pattern in, 1101 Hereditary spastic paraparesis, vs. amyotrophic lateral sclerosis, 865 Hereditary spastic paraplegia, 508, 508t, 899906 autosomal dominant, 900t

index Hereditary spastic paraplegia (Continued) autosomal recessive, 900t-901t clinical classification of, uncomplicated and complicated, 899 diagnostic criteria for, 904-905 differential diagnosis of, 905 epidemiology of, 899 genetic classification of, 899, 900t-901t genetic counseling in, 905-906 laboratory studies of, 904 neurological examination of, 902-903 neuropathology of, 899, 901 pathogenesis of, emerging concepts in, 901902 prognosis of, 905 red flags in associated with, 905 symptoms of, 902 treatment of, 905 uncomplicated asymptomatic upper extremity involvement in, 903 axonal degeneration in, 899, 901 variability of, 903-904 Hereditary vitreoretinopathy(ies), 276-277, 277f Heredodegenerative disorders, dystonia in, 447, 448t Hering-Breuer reflex, 1571 Herniation syndromes (coning). See also specific syndrome, e.g., Chiari malformation. in comatose patient, 102-104, 102f, 103t, 104t of lumbar intervertebral disks, 524-525, 525t, 526f HERNS (hereditary endotheliopathy, retinopathy, nephropathy, and stroke), 309 Herpes simplex encephalitis, 51-53, 1250, 12521253, 1253f acyclovir for, 1256 Herpes simplex virus (HSV), 1136 meningitis due to, 1249 myelitis due to, 516-517 Herpetic infections, of retina, 300-301, 301-302, 301f HESX1 gene, in optic nerve hypoplasia, 278 Heterotopia periventricular genes associated with, 686t neuroimaging of, 665, 685f subcortical band genes associated with, 686t neuroimaging of, 664-665, 666f, 686f Heterotopic ossification, rehabilitation strategies for, 1431 n-Hexane, exposure to, 1481-1482, 1481t Hexosaminidase A deficiency, vs. amyotrophic lateral sclerosis, 863 Hiccups, 1573 Highly active antiretroviral therapy (HAART), 1261 for HIV–associated dementia, 1264-1266 survival prognosis with and without, 12641265 Hippocampus, lesions of, memory impairment associated with, 49-50, 50f Histoplasma capsulatum, 1289 Histoplasmosis, 1289-1290 Hitselberger’s sign, in evaluation of hearing, 319 HIV. See Human immunodeficiency virus (HIV) entries. HLA. See Human leukocyte antigen (HLA) entries. Hoffman sign, in amyotrophic lateral sclerosis, 860 Holmes tremor, 425-426 treatment of, 426

Holmes-Adie syndrome, pupillary responses in, 270, 270f Homeostasis disorders of, headache secondary to, 802-803, 802t of hormone systems, 1549 regulation of interaction of circadian regulation with, 182 of sleep and wakefulness, 181-182 Homocysteine, elevated levels of, in ischemic stroke, 580 Hormonal changes, in pregnancy, 1490-1491, 1491f Hormone(s). See also named hormone. adenohypophysial, 1551, 1552f classification of, 1545, 1546f concentration of, regulation of, 1548-1549 mechanism of action of, 1545-1548, 1547f, 1547t, 1548t neurohypophysial, 1551 pituitary, 1550t rhythms of, regulation of, 1549 steroid biosynthesis of, 1545, 1546f receptor signaling of, 1546, 1547f Hormone receptors, membrane-associated, 1548f Hormone replacement therapy, and ischemic stroke, 580 Hormone-secreting tumors, of hypothalamus and pituitary, headache secondary to, 801 Horner’s syndrome, pupillary responses in, 270, 270f Hospital admission, for traumatic brain injury, 1392-1393 HPRT1 gene, in Lesch-Nyhan disease, 1442 HSP27 (heat-shock protein 27), 1105 HSP27 gene, in inherited neuropathies, 1105 HSV. See Herpes simplex virus (HSV). HTLV-1 (human T-lymphotropic virus type 1), 1136-1137 Human chorionic gonadotropin (hCG), in pregnancy, 1490 Human immunodeficiency virus (HIV) peripheral nervous system complications associated with, 1132-1133, 1132t strains of, 1261 Human immunodeficiency virus (HIV)–associated dementia, 1261, 1264f clinical features of, 1264t HAART for, 1264-1266 limited efficacy of, 1266 progression of, 1265 radiological and neuropathological features of, 1265, 1265t, 1266f risk factors for, 1265, 1265t Human immunodeficiency virus (HIV)–associated encephalitis, pathological features of, 1263f Human immunodeficiency virus (HIV)–associated meningitis, 1250 Human immunodeficiency virus (HIV)–associated mononeuritis multiplex, 1132-1133, 1132t, 1268 Human immunodeficiency virus (HIV)–associated myelopathy, 1266-1267, 1267t Human immunodeficiency virus (HIV)–associated myopathy, 1269 Human immunodeficiency virus (HIV)–associated neuropathy, 1267-1269 entrapment, 1268 miscellaneous, 1268-1269 sensory, 1267-1268, 1267t

1601

Human immunodeficiency virus (HIV)–associated polyneuropathy distal symmetric, 1133 inflammatory and demyelinating, 1132, 1268 Human immunodeficiency virus (HIV) infection future perspectives on, 1269-1270 headache associated with, 1269 late stages of, 518 malignancies associated with, 302 neurocognitive syndromes in, 1264-1266, 1264t, 1265t, 1266f neurological disorders associated with, 12611270, 1262f retinal manifestations of, 301 seizure disorders associated with, 1269 syphilis in, 302 toxoplasmosis in, 302, 302f Human leukocyte antigen (HLA), in neurosarcoidosis, 1303 Human leukocyte antigen (HLA) gene complex, in multiple sclerosis, 999-1000, 999f, 1000t Human spastic ataxia, 891 Human T-lymphotropic virus type 1 (HTLV-1), 1136-1137 Humphrey field, in vision assessment, 262f Huntingtin mutant, in Huntington’s disease, 879, 880f Huntington’s disease, 879-884 autonomic dysfunction in, 881 clinical features of, 880 cognitive features of, 881 differential diagnosis of, 882, 883t evaluation of, 882, 882f genetic testing for, 882 genetics and molecular pathogenesis of, 879880, 880f, 881f historical aspects of, 879, 880f mania in, 239 motor features of, 880-881 pathophysiology of, 882, 882f prevalence of, 879 prognosis of, 884 psychiatric features of, 881 treatment options for, 882-884, 883t, 884f variants of, 881-882 Hydralazine hydrochloride, for supine hypertension, 360 Hydration therapy, for cerebrospinal fluid leaks, 822 Hydrocephalus, 825-830 adult-onset, clinical presentation of, 827 cerebrospinal fluid flow disturbance in, 825, 826f classification of, 825 etiology of, 825-826, 826f infantile, 827 medical treatment of, 830 neuroparasites causing, 1274t normal-pressure, 830-831 radiological investigations of, 827-828, 828f, 829f surgical treatment of, 828-830 drainage in, 828 endoscopic, 829-830 shunting in, 828 complications of, 828-829 Hydrocephalus ex vacuo, 828 Hydromyelia, 494 Hydroperoxidase, levels of, in substantia nigra in Parkinson’s disease, 935, 935t Hydrophobia, in rabies, 1254, 1254f 3-Hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors, for multiple sclerosis, 1048 17α-Hydroxyprogesterone, in pregnancy, 1490, 1491f

1602

Index

Hydroxytryptophan, for myoclonus, 442t Hyperalgesia, in migraine, 736 Hyperammonemia, 1470t, 1472, 1473f, 1474 Hyperargininemia (arginase deficiency), 1470t, 1474 Hyperbaric oxygen therapy, for carbon monoxide intoxication, 1484 Hypercapnia, in obstructive sleep apneahypopnea, 206 Hypercarbia, 1574 Hypercoagulability, 617-619 genetic causes of, 615t hereditary, 617-618, 617f Hypercoagulable states, 1531-1532 Hyperexplexia (startle syndrome), 437 Hyperglycemia, 1533 control of, in ischemic stroke, 569-570 nonketotic, seizures associated with, 704-705 Hyperkalemia, 1535 Hyperkalemic periodic paralysis, 1189 Hyperkinetic dysarthria, 158t, 159, 160 Hypernatremia, definition of, 1533 Hyperosmolality, 1533 treatment of, 1533-1534 Hyperoxia, 1574 Hyperreflexia, autonomic, rehabilitation strategies for, 1431 Hypersensitivity vasculitis, 1316 Hypersomnia idiopathic, 195 international classification of, 186t Hypertension headache secondary to, 802-803 idiopathic intracranial, 807-813. See also Intracranial hypertension, idiopathic. spontaneous intracranial hemorrhage due to, 590-591, 591t supine, management of, 359-360, 383, 384t, 385 step-wise approach in, 359t Hypertonicity, 1533 Hyperventilation, 100, 1574 central neurogenic, 1572 Hypervitaminosis A, idiopathic intracranial hypertension due to, 811 Hypervolemia, in pregnancy, 1491 Hypnogenic dyskinesia, paroxysmal, 453 Hypnotics, barbiturate, for migraine, 744 Hypocarbia, 1574 Hypoglossal nerve (XII), function of, in speech and swallowing, 155, 157f Hypoglycemia, 696 in alcoholics, 1542 Hypokalemia, 1535 Hypokalemic periodic paralysis, 1190-1191 secondary, 1191 Hypokinesia, 75 Hypokinetic dysarthria, 158t, 159, 160 Hypomyelinating neuropathy, congenital, 1101 Hyponatremia, 1534-1535 definition of, 1534 Hypoperfusive lesions, causing vascular dementia, 635 Hypopnea, definition of, 203 Hypoprothrombinemia, 1530 Hypotension intracranial, spontaneous, 817 orthostatic, 354-360. See also Orthostatic hypertension. Hypothalamic-pituitary unit, development and structure of, 1549-1550, 1550t, 1551f Hypothalamus development and structure of, 1549-1550, 1551f hormone-secreting tumors of, headache secondary to, 801

Hypothalamus (Continued) leptin targets in, 1553, 1554f Hypothermia chronic, in multiple sclerosis, 1022 induced, for ischemic stroke, 570 Hypovolemia, cerebrospinal fluid, 817 Hypoxia, 1573-1574 Hysteria, 250. See also Conversion syndrome. vs. factitious disorder and malingering, 250t Hysterical amnesia, 55

I I band, of sarcomere, 1096, 1096f Ibuprofen, for tension-type headache, 759t Idazoxan, for parkinsonism, in progressive supranuclear palsy, 972 Ideational apraxia, 13, 404-405, 407 definition of, 404 pathophysiology of, 409 Ideomotor apraxia, 13, 407-408 definition of, 407 Ifosfamide, neurological complications caused by, 1355 Illness acute, rehabilitation protocols for, 1423, 1425, 1425t longitudinal course of, 3 Immobility, after stroke, detraining effects of, 652-653 Immodulatory therapy, for relapsing-remitting neurosarcoidosis, 1309 Immune reconstitution inflammatory syndrome, after HAART, 1265 Immune response alterations of, in leprosy, 1130-1131 during pregnancy, 1493 Immune-mediated neuropathy(ies), acquired chronic, 1116-1117 Immunization diphtheria, 1487 measles, mumps, rubella, autism and, 133 rabies, encephalomyelitis after, 1059t tetanus, 1487 Immunocompromised patient, bacterial meningitis in, agents causing, 1237 Immunoglobulin(s) abnormalities of, in cerebrospinal fluid production, 1031-1032, 1032f intravenous for inflammatory myopathies, 1218 for multiple sclerosis, 1048, 1049 tetanus, 1487 Immunoglobulin G antigliadin antibodies, in gluten ataxia, 1512 Immunosuppressive agents in transplantation, adverse effects of, 1564t toxic neuropathy due to, 1120t, 1121 Inclusion body myositis autoantibodies in, 1217 clinical presentation of, 1212, 1212t diagnosis of, 1213-1217, 1214t immunopathogenesis in, 1216-1217 muscle biopsy in, 1215, 1215f prognosis of, 1219 treatment of, 1218, 1218t vs. amyotrophic lateral sclerosis, 864 Incomplete infarctions, in vascular dementia, 640, 640f, 641f, 642t Incontinence after stroke, management of, 649 in multiple system atrophy, management of, 967-968 Incontinentia pigmenti, 282

Indium-111 cisternography, of cerebrospinal fluid leaks, 818, 819f Individual cognitive domains, neuropsychological assessment of, 22 Indomethacin for orthostatic hypotension, 359t for paroxysmal hemicrania, 783 Infants. See also Children; Neonates. benign familial convulsions in, genetics of, 683-684, 683t brain arteriovenous malformations in, 600 epileptic syndromes in, 703 globoid leukodystrophy in, 1071 hydrocephalus in, 827 metachromatic leukodystrophy in, 1069 Refsum disease in, 281 severe myoclonic epilepsy in, 678 genetics of, 682-683, 683t vanishing white matter disease in, 1080 Infarction. See at specific anatomic site. Infection(s). See also specific infection. associated with parkinsonism, 934 in alcoholics, 1542 in illicit drug abusers, 1538 intracranial, headache secondary to, 802 of retina, 299-302, 300f-303f of spinal cord, 512, 515-522 opportunistic, after organ transplantation, 1565-1566 reduced CSF absorption due to, 826 shunt-induced, 828-829 Inferior genu stroke, 638-639 Infiltrative optic neuropathy, visual loss in, 291, 291f Inflammation ischemic stroke and, 619 of eye, 295 Inflammatory bowel disease, 1513-1515, 1513t. See also Crohn’s disease; Ulcerative colitis. central nervous system involvement in, 15141515, 1515t peripheral nervous system dysfunction in, 1513t peripheral nervous system involvement in, 1514 seizures and, 1515 vascular complications of, 1515 Inflammatory demyelinating polyneuropathy in systemic lupus erythematosus, 1564 vs. amyotrophic lateral sclerosis, 864 Inflammatory markers, in giant cell arteritis, 797-798 Inflammatory myopathy, 1211-1219. See also specific type, e.g., Dermatomyositis. clinical presentation of, 1211-1213, 1212t diagnosis of, 1213-1217, 1213f, 1214t, 1215f, 1216f differential diagnosis of, 1218-1219 prognosis of, 1219 treatment of, 1217-1218, 1218t Inflammatory polyneuropathy, HIV-associated, 1268 Inflammatory spondyloarthropathy, 1561 Informant history, in mental status assessment, 2-3 Infratentorial herniation, in comatose patient, 104 Inhalants, intoxication and withdrawal of, 1538 Inherited ataxia, 887-896 cerebellar autosomal dominant. See Autosomal dominant cerebellar ataxia. autosomal recessive. See Autosomal recessive cerebellar ataxia. mitochondrial, 891-892 X-linked, 891

index Inherited ataxia (Continued) clinical features of, 888-892 clinical trials for, 896t description of, 887, 888f diagnostic strategy for, 890t, 892, 893f, 894t differential diagnosis of, 894 epidemiology of, 887-888 future considerations in, 896, 896t laboratory tests and findings in, 892-893, 892t, 893t, 895f prognosis of, 896 risk factors for, 888 treatment of, 894-896, 896t long-term, 895-896 supportive care in, 895 Inherited myoclonus-dystonia syndrome, 437 Inhibition, 8 Iniencephaly, 495 Injection injury, to peripheral nerves, 1416 Inner ear, autoimmune disease of, 344-345 Innervation. See also Nerve entries. of intracranial vasculature, 793, 794f of muscles, tendons, and cutaneous reflexes, 514t Insecticides organochlorine, 1483t, 1484 organophosphate, 1483t, 1484-1485 Insight, assessment of, 8 Insomnia, 185, 187-189. See Sleep entries. adverse consequences of, 187 assessment of, 188 definition of, 185 in Lewy body dementia, treatment of, 922t, 923 international classification of, 186t medical conditions associated with, 188, 188t medications associated with, 193t pathophysiology of, 187-188, 187f prevalence of, epidemiology of, 185, 187 primary or secondary, 185 restless leg syndrome causing, 1525 treatment of, 188-189, 189f, 189t Inspiration, 1569. See also Respiration. Insulin, leptin signal transduction and, 1554, 1554f Insulin-like growth factor-1, for amyotrophic lateral sclerosis, 869 Intention tremor, 417 in Huntington’s disease, 881 in multiple sclerosis, 1022 treatment of, 1050 Interferon-α, for cerebral vasculitis, 1320 Interferon-α-2a, for Japanese encephalitis, 1256 Interferon-β for multiple sclerosis, 1046-1047, 1046t, 1049 side effects of, 1047 Interictal discharges, effect of sleep on, 193 International Classification of Epilepsies and Epileptic syndromes, 677, 677t International Classification of Seizures, 674, 674t International Classification of Sleep Disorders, 185, 186t-187t International Headache Society (IHS) diagnostic criteria for atypical facial pain, suggested modification of, 837, 837f for headache secondary to Chiari malformation, 800t for headache secondary to intracranial aneurysm, 796, 796t for sleep apnea headache, 802t International Restless Leg Syndrome Study Rating Scale, 476, 477f-479f International Stroke Trial (IST), 574

International Subarachnoid Aneurysm Trial (ISAT), 589 Internet Resources for amyotrophic lateral sclerosis, 859-860, 861t for frontotemporal dementia, 991t Intervertebral disk disease, lumbar, degenerative, 524-525, 525t, 526f Intoxication. See also Toxin(s). arsenic, 1122, 1477-1478, 1478t neuropathy due to, 1122 carbon monoxide, 1483-1484, 1483t Parkinson’s disease and, 933 ethanol, 1539, 1540t. See also Alcoholism. disorders associated with, 1541-1542 nonnutritional neurological complications of, 1542-1543 heavy metal, 1477-1481, 1478t illicit drug, 1537-1539 lead, 1122, 1478-1479, 1478t manganese, 1478t, 1479-1480 associated with Parkinson’s disease, 934 mercury, 1478t, 1480-1481 Intracarotid therapies, neurological complications caused by, 1355 Intracerebral hematoma, 1388-1389 Intracranial aneurysms. See Aneurysm, intracranial. Intracranial disorders. See also specific disorder. nonvascular, headache secondary to, 799-800, 800f, 800t Intracranial hemorrhage, 587-592 aneurysmal, 587-590 diagnosis of, 589 during pregnancy, management of, 1496 epidemiology of, 587 etiology of, 587-588, 588f manifestations of, 588-589 outcome of, 590 treatment of, 589-590 hypertensive, 590-591, 591t idiopathic, causes of, 591-592 spontaneous, 592 Intracranial hypertension, idiopathic, 807-813 clinical features of, 807-808, 808t definition of, 807 diagnostic testing for, 808, 809f, 810 epidemiology of, 807 in pregnancy, 812 pathophysiology of, 810-811 prognosis of, 813 secondary causes of, 810, 811t treatment of, 811-812 Intracranial hypertension syndrome, 624 Intracranial hypotension, spontaneous, 817 Intracranial infection, headache secondary to, 802 Intracranial pressure increased, in brain tumors, 1325-1326 monitoring of, in traumatic brain injury, 1393, 1394f raised, management of, 1393-1394 Intracranial vasculature, innervation of, 793, 794f Intracranial venous system, anatomy of, 621623 Intramedullary spinal cord abscess, 520 Intraneural ganglion, 1380 Intratumoral therapies, neurological complications caused by, 1355 Intrusions, saccadic, examination of, 272 Ion channels, adaptive changes of expression of, in demyelination, 1004-1005 Ipsilateral neglect, 76 Iron concentrations, in substantia nigra, with Parkinson’s disease, 934-935

1603

Iron deficiency, 1525 in restless leg syndrome, ferrous sulfate with vitamin C for, 476 Iron metabolism, in restless leg syndrome, 472 Iron replacement, for Ekbom’ s syndrome, 1525 Iron-binding globulin, low plasmal levels of, in Wilson’s disease, 1450 Isaac’s syndrome, 1225t, 1230-1231 Ischemic injury, to peripheral nerves, 1416-1417 Ischemic lesions, causing vascular dementia, 635 Ischemic mononeuropathies, 1114 Ischemic optic neuropathy arteritic, 289, 289f nonarteritic, 288-289, 288f perioperative, 289 Ischemic stroke. See also Stroke. imaging of brain parenchyma in, 565 in pregnancy, pathophysiology of, 1495-1496 secondary prevention of, 574-582 Isethionate, for African trypanosomiais, 1276t Isoniazid for tuberculous meningitis, 1244t toxic neuropathy due to, 1120

J Jackson-Freud-Luria model, of language disorders, 31 Japanese encephalitis, 1250 interferon-α-2a for, 1256 Jargonaphasia, 36 Jerks, myoclonic, 435 Jet lag, 196 Joubert syndrome, 283 Judgment, assessment of, 8 Juvenile myoclonic epilepsy, 678, 703. See also Epilepsy. genetics of, 681-682, 683t treatment of, 714 Juvenile pilocytic astrocytoma, pathology of, 1328, 1329f Juvenile retinoschisis, 277 Juvenile-onset Huntington’s disease, 881-882

K Karnofsky Performance Scale, 1335, 1349 Kawasaki disease (mucocutaneous lymph node syndrome), 1316 Kayser-Fleischer rings, in Wilson’s disease, 448, 449f, 1448, 1449 fading of, 1450 Kearns-Sayre syndrome, 282, 303, 1202-1203, 1205t Kennedy disease, vs. amyotrophic lateral sclerosis, 862 Kernig’s sign, 1238 Kernohan’s notch, 103 Kernohan’s sign, 103 Ketamine, for status epilepticus, 727 Ketoacidosis, alcoholic, 1542 Ketogenic diet, for epilepsy, 717 Ketoprofen, for tension-type headache, 759t Khachaturian criteria, for Alzheimer’s disease, 850 Kinesigenic dyskinesia, paroxysmal, 452 Kinetic tremor, 417 Kleine-Levin syndrome, 195 Klippel-Feil anomaly, 489-490, 489t, 490f Klippel-Trenaunay syndrome, 604 Knobloch syndrome, 276, 277

1604

Index

Kojewnikoff’s epilepsy. See Epilepsia partialis continua. Kokmen Short Test of Mental Status, for Alzheimer’s disease, 852, 854t Köllner’s rule, 260 Korsakoff syndrome, 1541. See also WernickeKorsakoff syndrome. Korsakoff’s psychosis, 50-51, 51t delirium in, 148 Kuf’s disease, 705 Kuru clinical features of, 1300 epidemiology of, 1298

L La Crosse virus encephalitis, 1250, 1254 Labyrinthine concussion, 346 Labyrinthine trauma, 345-346 Labyrinthitis, 342 Laceration(s), nerve, 1415 Lactate dehydrogenase deficiency, 1198 Lacunar infarcts, in vascular dementia, 640 Lacunar strokes, 553-554. See also Stroke. Lacunar syndromes, of ischemic stroke, 556557, 556t, 557f Lafora disease, 705 Lambert-Eaton myasthenic syndrome, 1225t, 1229-1230, 1370 postexercise fasciculations in, 867 vs. amyotrophic lateral sclerosis, 864 Laminectomy, for metastatic epidural spinal cord compression, 534 Laminin A/C (LMNA), 1105 Lamotrigine for generalized seizures, 711 for secondary SUNCT, 785 Language conceptualization of, 31 disorders of, 31-41. See also specific disorder. after stroke, management of, 651 history of, 31 rehabilitation strategies for, 1431 fluency of, 32-33, 32t formulation of, 31-32, 32t in Alzheimer’s disease, 851 neurocognitive assessment of, 4-5 neurocognitive examination of, 12, 13t production of, 31-33 LARGO study, of Parkinson’s disease, 944-945 Laryngeal dystonia, 446 Laryngospasm, in amyotrophic lateral sclerosis, management of, 872 Larynx, anatomy of, 165f Lassitude. See also Fatigue. in multiple sclerosis, 1017 Lateral medullary infarction (Wallenberg’s syndrome), 347 Lateral sinus, anatomy of, 622 Lathyrism, 1485-1486 Laughter (gelastic) seizures, 676. See also Seizure(s). Lazarus sign, 109 Lead intoxication, 1122 complications and management of, 1478t, 1479 inorganic, 1478-1479 organic, 1479 Learning, neurobiology of, 45-55. See also Memory. cellular mechanisms in, 45-46 Learning disabilities, celiac disease and, 1513 Leber’s congenital amaurosis, 275, 276f

Leber’s hereditary optic neuropathy, 1202-1203, 1205t visual loss in, 280, 280f, 289-290, 290f Leflunomide, toxic neuropathy due to, 1121 Legal definition, of brain death, 107 Leigh’s syndrome, 282, 1203, 1205t Lennox-Gastaut syndrome, treatment of, 714 Leprosy, 1127-1132 history of, 1127 immune response in, alterations of, 11301131 lepromatous, 1128-1129, 1129f, 1130f Mycobacterium leprae in, 1127, 1128 nerves commonly affected by, 1130, 1131f treatment of, 1131-1132 tuberculoid, 1128f, 1129f Leprosy reactions, 1130-1131 treatment of, 1132 Leptin, 1553-1554, 1554f signal transduction of, insulin and, 1554, 1554f Leptomeningeal anastomoses, 541, 542f Lesch-Nyhan disease, 1442 Leukodystrophy(ies), 1065-1083 Alexander’s disease, 1076-1078, 1077f. See also Alexander’s disease. Canavan’s disease, 1074-1076. See also Canavan’s disease. cerebrotendinous xanthomatosis, 1078-1079 definition of, 1065 disorders resembling, 1083, 1083t globoid, 1071-1073. See also Globoid leukodystrophy. megalencaphalic, with subcortical cysts, 1081-1082, 1081f membranous lipodystrophy, 1082 metachromatic, 1069-1071. See also Metachromatic leukodystrophy. Pelizaeus-Merzbacher disease, 1073-1074 ribose-5-phosphate isomerase deficiency in, 1082-1083 Sjögren-Larsson syndrome, 1079-1080 undefined genetic defects in, 1083, 1083t vanishing white matter disease, 1080-1081 X-linked adrenoleukodystrophy, 1065-1069. See also X-linked adrenoleukodystrophy. Leukoencephalitis, hemorrhagic necrotizing, acute, 1059-1060 Leukoencephalopathy associated with polyol metabolism disturbance, 1082-1083 progressive multifocal clinical features of, 1060 definition of, 1060 epidemiology of, 1060 pathology and pathogenesis of, 1060-1061, 1061f treatment of, 1061-1062 radiation-induced, dementia due to, 1357, 1358f spongiform, illicit drugs causing, 1539 Levetiracetam for generalized seizures, 711 for myoclonus, 442t Levodopa for manganese intoxication, 1480 for parkinsonism in corticobasal ganglionic degeneration, 975, 976 in multiple system atrophy, 967 in progressive supranuclear palsy, 972, 973 for Parkinson’s disease, 940-941, 941f for restless leg syndrome, 481 Levodopa test, for restless leg syndrome, 475476 Lewis-Sumner syndrome, 1118

Lewy body(ies) in Parkinson’s disease, 927-928, 928f α-synuclein in, 372, 929-930 Lewy body dementia, 3, 53-54, 377, 911-924 autonomic dysfunction in, 913t, 914 treatment of, 922t, 923 clinical features of, 911-914, 913t cognitive impairment in, 911-912, 913t treatment of, 386, 919-920, 921t diagnostic criteria for, 914, 914t, 915t diagnostic evaluation of, 914-918 autonomic testing in, 917, 920f blood/urine studies in, 914 cerebrospinal fluid analysis in, 915 electroencephalography in, 915 functional neuroimaging in, 916, 917f neuropsychological testing in, 915, 916f polysomnography in, 916-917, 918f-919f smell testing in, 918 structural neuroimaging in, 915-916, 917f epidemiology of, 911 historical aspects of, 911, 912f management of, 918-923 future directions in, 923-924 pharmacotherapy in, dosing schedules for, 921t-922t motor dysfunction in, 913, 913t treatment of, 383, 920, 922t, 923 neuropsychiatric features of, 912-913, 913t treatment of, 920, 921t-922t sleep disorders in, 913, 913t treatment of, 922t, 923 terminology in, 911 vs. Parkinson’s disease, 938 Lewy body syndromes autonomic failure in, 357, 373, 373f diffuse, psychosis in, 229 neuropathology of, 373, 373f Lexicology, 32t. See also Language. LH (luteinizing hormone), source and function of, 1550t Lhermitte’s symptom, in multiple sclerosis, 1021 Light, pupillary reaction to, 269 Lightheadedness, 322 Lignocaine, for cluster headache, 778 Limb(s), disordered motor control of, after stroke, management of, 649-650 Limb apraxia, 401-412. See also Apraxia, limb. Limb ataxia, in multiple system atrophy, 962, 963t Limb dystonia, task-specific, 445-446 Limb girdle muscular dystrophy, 1142, 1143t autosomal dominant, 1149, 1150t autosomal recessive, 1149, 1150f classification of, 1148-1149, 1149f, 1150f definition of, 1148 phenotypic differentiation of, 1151t-1153t Limbic encephalitis autoimmune, rare forms of, 705 immune system–mediated, 51, 52f nonparaneoplastic, 51, 52f paraneoplastic, 51, 52f, 1367, 1367f viral, 51-53 Limbic veins, anterior, anatomy of, 621 Limb-kinetic apraxia, 408 pathophysiology of, 410-411 Line bisection tests, for spatial neglect, 76, 76f Linezolid, toxic neuropathy due to, 1120 Linguistic concepts, 32t Lipid peroxidation and peroxynitrite inhibition, for spinal trauma, 1406 Lipodystrophy, membranous, 1082 Lipofibromatous hamartoma, 1380 Lipoma, intradural, in tethered cord syndrome, 499, 500f

index Lipoprotein metabolism disorders, retinopathy and optic neuropathy associated with, 280281 LIS1 gene, in Miller-Dieker syndrome, 1579 Lisinopril for chronic daily headache, 768t for migraine, 749 Lissenencephaly, genes associated with, 663, 686t Listeria infection, after organ transplantation, 1565 Listeria monocytogenes, in meningitis, 1237. See also Meningitis, bacterial. Lisuride, for restless leg syndrome, 482t Lithium, prophylactic, for cluster headache, 779-780 Liver. See Hepatic entries. Living situation, of Alzheimer’s patient, 855-856 LMNA gene, in inherited neuropathies, 1105 Locked-in syndrome, 118, 563 Locomotion, 455 control of, central generators in, 456 spatiotemporal features of, 456-457 LogMAR charts, 260 Logopenic progressive aphasia, 38 Long-chain L-3hydroxyacyl–coenzyme A dehydrogenase deficiency, 1200 Lorazepam for alcohol and drug withdrawal–related seizures, 714 for delirium tremens, 1540t for ethanol withdrawal symptoms, 1540t for REM sleep behavior disorder, 198 for seizures, 713 for status epilepticus, 723f, 724 Lorenzo’s oil, for X-linked adrenoleukodystrophy, 1069 Lou Gehrig’s disease. See Amyotrophic lateral sclerosis. Lower motor neuron lesions, speech disorders due to, 158, 158t LRRK2 (PARK8) gene, in Parkinson’s disease, 928t, 931-932 Lumbar puncture for coma, 105 for multiple sclerosis cell count in, 1031 cerebrospinal fluid immunoglobulin abnormalities in, 1031-1032, 1032f Lumbar spine degenerative disk disease of, 524-525, 525t, 526f injury to, 1400-1401, 1401f Lumbar stenosis, spondylitic, 524 Lumboperitoneal drainage, for gait disturbances, 468 Lumboperitoneal shunt, for hydrocephalus, 828 Lumbosacral agenesis, 504 Lumbosacral neuropathy, radiation-induced, 1359-1360 Lumbosacral polyradiculopathy, CMV-associated, 1133-1134 Luteinizing hormone (LH), source and function of, 1550t Lyme disease, 300, 1134-1135, 1134f Lyme meningitis, 1245-1246, 1246f Lymphocytic choriomeningitis, 1249 Lymphoma central nervous system, 1336 after organ transplantation, 1566 non-Hodgkin’s, in HIV infection, 302 ocular, 303-304, 304f spinal cord, 530 Lymphomatoid granulomatosis, 1317 Lysosomal storage diseases, retinopathy/optic neuropathy associated with, 281, 281f

M M band, of sarcomere, 1095 Machado-Joseph disease (spinocerebellar ataxia, type 3), 890-891 imaging of, 893, 895f vs. vitamin E deficiency, 1463, 1463f Macroglobulinemia, 1530 Macroplanning, in conceptualization of language, 31 Macula lutea, 295 Macular dystrophy age-related, Amsler grid defect due to, 269, 269f Best’s vitelliform, 277-278 Magnesium sulfate for neonatal seizures, 713 for preeclampsia-eclampsia, 1499 for toxemia of pregnancy, 717 Magnesium supplements, for restless leg syndrome, 476 Magnetic resonance angiography (MRA) of cerebral vasculitis, 1318 of ischemic stroke, 566-567 Magnetic resonance imaging (MRI) of arteriovenous malformations, 601 of bacterial meningitis, 1239, 1239f of brain death, 112 of brain in Alzheimer’s disease, 853, 854f of brain tumors, 1329f of cerebral palsy, 1579 of cerebral vasculitis, 1318 of cerebrospinal fluid leaks, 818, 820f, 820t abnormalities of, 820-821, 821f of Chiari malformation, 493, 494f, 498f of Creutzfeldt-Jakob disease, 1299, 1300, 1300f of herpes simplex encephalitis, 1252, 1253f of hydrocephalus, 827, 829f of internal auditory canal, 322 of ischemic stroke, 565 of Lyme disease, 1245, 1245f of malformations caused by abnormal cortical development, 664-666, 664f-667f of multiple sclerosis, 1035-1038 conventional protocols in, 1035-1036, 1035f, 1036f, 1036t fluid-attenuated inversion recovery, 1036, 1037f T1 hypointensities in, 1037-1038, 1038f of multiple system atrophy, 964, 965f, 966, 966f of neurosarcoidosis, 1304, 1305f, 1306f of peripheral nerve injury, 1414 of peripheral nerve tumors, 1375, 1376f of primary autonomic failure cerebral, 381 structural, 381-382 of progressive supranuclear palsy, 970-971, 971f of sacral agenesis, 505, 505f of spinal cord arteriovenous malformations, 606 of spinal cord disorders, 511-512 of spinal cord tumors, 527, 529f, 531f, 13441345, 1344f-1348f of spinocerebellar ataxia, type 3, 893, 895f of split cord malformation, 503, 504f of syrinx, 494, 495f of Taenia solium cysticercosis, 1277, 1278f1284f of traumatic brain injury, 1386 of tuberculous meningitis, 1244, 1244f of vegetative state, 123, 124f of Wernicke-Korsakoff syndrome, 1457, 1458f

1605

Magnetic resonance imaging (MRI) (Continued) of Wilson’s disease, 1448, 1448f, 1451f of women with eclampsia, 1498f Magnetic resonance spectroscopy, nuclear, of multiple sclerosis, 1039-1042, 1040f N-acetyl resonance in, 1040, 1042, 1042f trimethylamine resonance in, 1040, 1041f Malaria, falciparum clinical presentation of, 1279, 1283, 1283t diagnosis of, 1283 epidemiology of, 1279 pathophysiology of, 1279 treatment of, 1283, 1285 Malformations caused by abnormal cortical development (MCD), 662-670 animal studies of, 668 classification of, 662-663, 663t definition of, 662 electrophysiology of, 668-669 epilepsy caused by, genetics of, 685, 685f, 686f, 686t epilepsy surgery for, 669 prospects for improving outcome of, 669670, 670f genetic basis of, 663-664 human in vitro studies of, 668 human in vivo studies of, 668-669 mild, 663 neuroimaging of, 666 neoplastic, neuroimaging of, 664, 665f, 666f neurogenetics of, 663-664 neuroimaging of, 664-668 conventional magnetic resonance imaging in, 664-666, 664f-667f diffusion tensor imaging in, 667 functional imaging in, 666-667 metabolic imaging in, 667-668 morphometry in, 667 tractography in, 667 types of, 662. See also specific type, e.g., Focal cortical dysplasia. Malignant angioendothelioma, 1317 Malignant hypertension, headache associated with, 803 Malignant hyperthermia susceptibility, in central core disease, 1171 genetics of, 1171-1173 Malignant peripheral nerve sheath tumor, 1375, 1380-1381, 1381f biopsy of, 1375-1376 clinical features of, 1381 histological appearance of, 1381, 1382f imaging of, 1375, 1377f management of, 1382 Malingering, vs. conversion hysteria and factitious disorder, 250t Malondialdehyde, levels of, in Parkinson’s disease, 935, 935t Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic or Ischemic Stroke (MATCH) trial, 575-576 Manganese intoxication, 1479-1480 associated with Parkinson’s disease, 934 complications and management of, 1478t, 1480 Mania cerebral regions associated with, 239, 240f in cerebrovascular disease, 239 in extrapyramidal disorders, 239 in systemic lupus erythematosus, 1563 in traumatic brain injury, 241 neurological and psychotropic agents associated with, 240t neurological conditions associated with, 239, 240t

1606

Index

Mania (Continued) treatment of, 241, 241f Mannitol for cerebral edema, 1241 for normal-pressure hydrocephalus, 830 Manometric studies, of peristalsis, 166 Marchiafava-Bignami disease, in alcoholics, 1542 Marcus Gunn pupil, 1018, 1018f Marijuana, intoxication and withdrawal of, 1537 Maternal brain death, and live birth, 112-113 Maternal folic acid supplementation, in prevention of neural tube defects, 498 Maternal serum alpha-fetoprotein, in diagnosis of neural tube defects, 498 McArdle’s disease, 1197 MCD. See Malformations caused by abnormal cortical development (MCD). McGregor’s line, in basilar impression, 490 McRae’s line, in basilar impression, 491 Measles, mumps, rubella vaccination, autism and, 133 Mechanical ventilation, for amyotrophic lateral sclerosis, 215, 872f MECP2 gene, in encephalopathies, 1435 Medical history, in mental status assessment, 9 Medication overdose, chronic daily headache and, 767 treatment of, 767-768 Medium-chain acyl–coenzyme A dehydrogenase deficiency, 1200 Medulloblastoma, 1337 imaging, pathology, and histology of, 1332f Megalencaphalic leukodystrophy, with subcortical cysts, 1081-1082, 1081f synonyms for, 1081 Megaloblastic anemia, 1525-1527 Melanoma-associated retinopathy, 304-305 Melarsoprol, for African trypanosomiais, 1276t Melatonin for delayed sleep phase syndrome, 196 for REM sleep behavior disorder, 198 prophylactic, for cluster headache, 781 Melkersson-Rosenthal syndrome, inflammatory bowel disease and, 1514 Melting-brain syndrome, 600 Memantine, for Alzheimer’s disease, 854t Membranous lipodystrophy, 1082 Memory clinical assessment of, 47, 47f declarative (explicit), 43, 44t subdivision of, 43-44 definitions of, 43-45 disorders of, 48-55. See also specific disorder, e.g., Amnesia. fixed, 49-53 in psychiatric disorders, 55 progressive, 53-55 transient, 48-49 episodic, 43-44 in Alzheimer’s disease, 851 neurobiology of, 45-55 cellular mechanisms in, 45-46 neurocognitive assessment of, 5 neurocognitive examination of, 13-14, 14f, 14t neuropsychological assessment of, 47-48, 48t nondeclarative (implicit), 43, 44t semantic, 43-44 terminology associated with, 43-45 topography of, 46-47, 46f working (short-term), 45, 98 Meniere disease, 343, 343f treatment of, 349 Meningeal irritation, tests for, 1238-1239

Meningioma, 1337-1338 imaging, pathology, and histology of, 1332f of spinal cord, 531, 531f magnetic resonance imaging of, 1345, 1348f radiation-induced, 1358, 1358f Meningitis aseptic, in systemic lupus erythematosus, 1562 bacterial, 1236-1243 agents causing, 1236, 1237t according to route of infection, 1237, 1237t by patient age, 1236-1237, 1237t in immunocompromised patient, 1237 atypical presentations of, 1239 cerebral edema in, treatment of, 1241 clinical features of, 1238 complications of, treatment of, 1241-1242 diagnosis of, 1239-1240, 1239f, 1240t epidemiology of, 1236 Listeria monocytogenes in, 1237 Lyme, 1245-1246, 1246f meningeal irritation in, tests for, 12381239 pathology and pathogenesis of, 1237-1238 prognosis of, 1242-1243 Staphylococcus aureus in, 1237 syphilitic, 1245 treatment of, 1240-1242 antibiotics in, 1240-1241, 1241t, 1242t corticosteroids in, 1240-1241, 1241t, 1242t prophylactic, 1242, 1243t tuberculous, 1243-1245, 1244f, 1244t carcinomatous, headache associated with, 801 crptococcal, after organ transplantation, 1565 epilepsy due to, 698 HIV–associated, 1250 reduced CSF absorption due to, 826 spinal, 521-522 viral clinical syndromes associated with, 1252 diagnosis of, 1250, 1252 epidemiology of, 1249-1250 etiology and pathogenesis of, 1255 specific etiologies in, 1249-1250 treatment of, 1255-1256 Meningocele cranial, 495 definition of, 495, 496f Meningoencephalitis epilepsy due to, 698 neuroparasites causing, 1274t Meningomyelitis coxsackie virus–related, 516 echoviral, 516 mumps-related, 516 spinal, 521-522 Menkes disease, 1439 Mental status change in, brain tumors and, 1326 clinical assessment of, 2-17 abnormal behaviors in, 8-9 beyond bedside, 16 in unassessable patient, 16 neurobehavioral domains function in, 6-8 neurobehavioral rating scales in, 10, 10t neurocognitive domains function in, 4-6 neurocognitive examination in, 10-15. See also Neurocognitive examination. neurocognitive formulation in, 16, 17f neurocognitive history in, 2-3 neurocognitive “sketch” in, 3-4 relevant history in, 9-10

Mental status (Continued) standardized cognitive instruments in, 1516 Mentation, altered, illicit drug abuse causing, 1539 Mercury intoxication complications and management of, 1478t, 1480, 1481 inorganic, 1480 organic, 1480-1481 Mesenchymal scar, in spinal cord injury, 1402 Mesial temporal lobe epilepsy, 679, 704 Mesoderm, paraxial, division of, 488 Metabolic diseases, ophthalmological features of, in children, 310 Metabolic imaging, of malformations caused by abnormal cortical development, 667-668 Metabolic myopathy(ies), 1195-1207. See also specific myopathy. Metabolic regulation, of cerebral circulation, 546 Metachromatic leukodystrophy clinical manifestations of, 1069 diagnosis of, 1070 genetics of, 1070 neuroimaging of, 1069-1070 pathogenesis of, 1070-1071 pathology of, 1069 retinopathy/optic neuropathy associated with, 281 schizophrenia-like psychosis in, 229 synonyms for, 1069 treatment of, 1071 Metal intoxication, 1477-1481. See also specific metal. complications and management of, 1478t toxic neuropathy due to, 1121-1122 Metastasis brain, 1337 ocular, 303, 304f spinal cord, 530 epidural magnetic resonance imaging of, 1345, 1348f outcome for, 1350 intramedullary, magnetic resonance imaging of, 1344, 1347f Methotrexate for cerebral vasculitis, 1319 for inflammatory myopathies, 1218, 1218t for myasthenia gravis, 1230t for relapsing-remitting neurosarcoidosis, 1308 neurological complications caused by, 1355 Methsuximide, for generalized seizures, 712 Methyl alcohol, exposure to, 1481t, 1482 Methyl benzene (toluene), exposure to, 1481t, 1483 Methyl-N-butyl ketone, exposure to, 1481t, 1482 Methylprednisolone for cerebral vasculitis, 1319 for early-stage neurosarcoidosis, 1308 for ischemic optic neuropathy, 289 for myelitis, 1563 for optic neuritis, 287 for spinal trauma, 1405-1406 Methylxanthines, for central sleep apnea, 209 Methysergide for parkinsonism, in progressive supranuclear palsy, 972 prophylactic for cluster headache, 780 for migraine, 749 Metoprolol, for tremor, 419 Metronidazole, toxic neuropathy due to, 1120

index MFN2 gene, in inherited neuropathies, 11041105 MFN2 mitofusin 2, 1104-1105 Microglia, in spinal cord injury, 1402 Microglial activation, in amyotrophic lateral sclerosis, management of, 868-869 Microinfarcts, in vascular dementia, 640 Microphthalmia, 274 Microplanning, in conceptualization of language, 31 Microvascular decompression, for trigeminal neuralgia, 838, 840 Midazolam, 713 for status epilepticus, 723f, 725-726 Middle ear acute disorders of, 347 fluid or mass in, conductive hearing loss due to, 332 Midodrine, for orthostatic hypotension, 359t Migraine, 343-344, 739-750. See also Headache. analgesics in, 744, 744t celiac disease and, 1513 chronic, 763-764, 765t cluster, 773 diagnostic criteria of, 742, 742t epidemiology of, 739, 740f familial hemiplegic, 344, 737 genetics and, 737, 739, 740f headache phase of, 742 in pregnancy, 1493-1494, 1493t memory symptoms associated with, 49 pain of, 734-735 modulation of, 736-737 neurogenic inflammation during, 735-736, 735f pathophysiology of, 739-741 premonitory symptoms of, 741-742 resolution phase of, 742 sensitization in, 736 serotonin 5-HT receptors and, 741 stroke associated with, 555 transformed, 763-764, 765t treatment of, 743-750 analgesics in, 744, 744t angiotensin II receptor antagonists in, 749750 angiotensin-converting enzyme inhibitors in, 749 antiemetics in, 744 barbiturate hypnotics in, 744 botulinum toxin in, 750 corticosteroids in, 746 dihydroergotamine in, 744t, 746 during pregnancy, 1493-1494 ergotamine in, 744t, 746 neuroleptics in, 744, 744t nonspecific medication in, 744 NSAIDS in, 744, 744t opioids in, 744, 744t pharmacotherapy in, 743-746 indications for and contraindications to, 744t prophylactic, 746-750, 747t anticonvulsants as, 747t, 748-749 antidepressants as, 747-748, 747t beta-blockers as, 747, 747t calcium channel blockers as, 747t, 748 mechanism of action of, 747 natural products as, 749 serotonin antagonists as, 749 selective 5-HT1 agonists in, 745-746, 745t serotonin 5-HT receptors and, 741 setting priorities in, 750 specific medication in, 744-746 variants of, 743

Migraine (Continued) with aura, 343, 739-742, 742 cortical spreading depression in, 739-740, 740f vs. simple partial seizure, 696 Miliary aneurysm, 590 Miller-Dieker syndrome, 1579 Minimally conscious state, 117, 118 Minimally responsive state, 118 Mini-Mental State Examination (MMSE), 4, 15 modified, 15 Minor cognitive and motor deficit, as risk factor for HIV-associated dementia, 1265 Mirtazapine, prophylactic, for tension-type headache, 759, 759t Mitochondria dysfunction of hereditary spastic paraplegia due to, 902 in Parkinson’s disease, 935 genetic control of, 1201-1202, 1203f Mitochondrial disorders clinical features of, 1202-1204, 1204t, 1205t nuclear genetic, 1204 retinopathy/optic neuropathy associated with, 281f, 282, 282f Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), 282, 303 Mitochondrial gene, 1104-1105 Mitochondrial inherited cerebellar ataxia, 887, 888t, 891-892 Mitochondrial oxidative phosphorylation defects of, 1201-1207 clinical features of, 1202-1204, 1204t, 1205t diagnosis of, 1204, 1206f genetic analysis of, 1204-1206 treatment of, 1206-1207 mitochondrial genetics and, 1201-1202, 1202f, 1203f Mitochondrial respiratory chain disease, 12041207, 1206f Mitofusin 2 (MFN2), 1104-1105 Mitoxantrone, for multiple sclerosis, 1049 Mixed dysarthrias, 159 Mixed solvents, exposure to, 1481t, 1482-1483 Mixed transcortical aphasia, 38 MMSE (Mini-Mental State Examination), 4, 15 modified, 15 Mobility, impaired, rehabilitation strategies for, 1427 Modality-specific apraxia, 408 Molol, for tremor, 419 Monoamine oxidase-B (MAO-B) inhibitors, for Parkinson’s disease, 943-945, 944f, 948 initiation of, 945 Monoclonal antibodies, for multiple sclerosis, 1047-1048 Monoclonal gammopathy, vs. amyotrophic lateral sclerosis, 864 Mononeuritis multiplex HIV-associated, 1132-1133, 1132t, 1268 in Sjögren’s syndrome, 1558 Mononeuropathy in systemic lupus erythematosus, 1564 ischemic, 1114 Monro-Kellie hypothesis, of idiopathic intracranial hypertension, 810 Mood, 6, 235 Morphometry, of malformations caused by abnormal cortical development, 667 Mortality rates in multiple sclerosis, 1026, 1026t in status epilepticus, 722 Moschowitz’s disease, 1528

1607

Motility disorders, ocular, in multiple sclerosis, 1019, 1019f, 1020f Motor activities, in Alzheimer’s disease, 852 Motor chronic inflammatory demyelinating neuropathy, 1117 Motor components, in respiration lower, 1569, 1571 upper, 1571 Motor conduction, central, in multiple sclerosis, 1034 Motor control, impaired, rehabilitation strategies for, 1427 Motor dysfunction in HIV-associated dementia, 1265 in Lewy body dementia, 913, 913t treatment of, 383, 920, 922t, 923 in Parkinson’s disease, 936 Motor extinction, 75 Motor impersistence, 75 Motor neglect. See also Neglect syndrome. examination of, 77 Motor neuron(s) anatomy and physiology of, 1094, 1095f, 1095t fast-twitch, 1094 slow-twitch, 1094 Motor neuron disease, 859. See also specific disease, e.g., Amyotrophic lateral sclerosis. frontotemporal dementia with, 984 inflammatory bowel disease and, 1515 nomenclature in, 859, 860t Motor neuron syndrome, lower, radiationinduced, 1359 Motor neuropathy, multifocal, 1118, 1118f vs. amyotrophic lateral sclerosis, 863-864 Motor symptoms, in Parkinson’s disease, treatment of, 383 Motor system examination of, in comatose patient, 102 extrapyramidal, 396-398 pyramidal input from, subcortical regions receiving, 396-397, 397f regulation of, subcortical regions participating in, 398 pyramidal, 398-400 cortical and thalamic input to, 399 corticospinal outputs and origins of, 399400, 399f primary cortex of, 398 Motor unit potentials, nascent, 1414 Movement disorders. See also specific disorder. in systemic lupus erythematosus, 1562 neuro-ophthalmologic findings in, 305 psychogenic, in conversion syndrome, 251252, 252t sleep-related, international classification of, 187t Moyamoya disease, 1525 stroke associated with, 555-556, 556f MPZ (myelin protein zero), 1103 MPZ gene, in inherited neuropathies, 1103 MRA. See Magnetic resonance angiography (MRA). MRI. See Magnetic resonance imaging (MRI). MTM1 gene, in myotubular (centronuclear) myopathy, 1177-1178 MTMR2 (myotubularin-related protein 2), 1104 MTMR2 gene, in inherited neuropathies, 1104 Mucormycosis, 1290-1291 Multifactorial tests, of executive function, 86 Multifocal motor neuropathy, 1118, 1118f vs. amyotrophic lateral sclerosis, 863-864 Multifocal sensorimotor demyelinating neuropathy, 1118-1119 Multi-infarct dementia, 637, 639t

1608

Index

Multi-minicore disease clinical features of, 1173-1174 gene defects in, 1169t genetics of, 1174-1175 histopathology of, 1171f, 1173 Multiple myeloma, 1530, 1530f Multiple sclerosis acute malignant, 1016 adoption and half-sibling studies of, 998 affective symptoms in, treatment of, 1051 antiganglioside antibodies in, 1007 atrophy in, 1039 autonomic disturbances in, 1022 axonal degeneration in, disability and, 10071008, 1008f, 1009f axonal hyperexcitability in, 1005-1006 basal ganglionic features in, 1022 benign, 1016 bladder dysfunction in, 365 treatment of, 1051 blood tests for, 1031, 1032t brainstem auditory evoked potentials in, 1033-1034, 1034f breathing disturbance in, 1020 cerebellar features in, 1022 cerebral, 1016 childhood, 1016-1017 chronic cerebellar, 1016 clinical features of, 1017-1023, 1017t clinical phenotypes of, 1015-1017 cognitive impairment in, treatment of, 1051 computed tomography of, 1034, 1034f consciousness and cognition in, 1017 cortical lesions in, 1008 course of, during pregnancy, 1501 cranial nerve involvement in, 1018-1019 cytokines and, 1006-1007 deafness in, 1020 definition of, 1015 demyelinating plaques in disorientation/imbalance associated with, 348 impaired sleep-wake regulation due to, 191 demyelination in, 1002-1003, 1003f activity-dependent conduction block and, 1003, 1005f effects of temperature on, 1002-1003, 1004f ion channels in, adaptive changes of expression of, 1004-1005 depression in, 238 management of, 1051 diagnosis of, MR imaging in, 1040t, 1042 diffusion-weighted imaging of, 1038 disability in, 1024-1025 disease heterogeneity in, 996 dysarthria in, 1020 dysphagia in, 1020 evoked potentials in, 1032-1034, 1032f-1034f excessive daytime sleepiness due to, 191192 expanded disability status scale (EDSS) score in, 1024-1025 facial palsy in, 1019 familial aggregation studies in, 998, 998t fatigue in, 1017 treatment of, 1050 future directions in, 1000 genetic factors in, 997-998 geographic distribution of, 996-997, 997f glutamate excitotoxicity in, 1007-1008 headache in, 1017-1018 human leukocyte antigen gene complex in, 999-1000, 999f, 1000t imaging of computed tomographic, 1034, 1034f diagnostic, 1040t, 1042

Multiple sclerosis (Continued) magnetic resonance conventional protocols in, 1035-1038, 1035f-1038f, 1036t nuclear spectroscopy in, 1039-1042, 1040f-1042f research protocols in, 1038, 1039f inflammation in, role of, 1006-1007 Lhermitte’s symptom in, 1021 long-term outcome in, 1025-1026 lumbar puncture in, 1031-1032 magnetic resonance imaging of conventional protocols in, 1035-1038, 1035f-1038f, 1036t diagnostic, 1040t, 1042 nuclear spectroscopy in, 1039-1042, 1040f1042f magnetization transfer imaging of, 1038, 1039f mortality in, 1026, 1026t motor and sensory findings in, 1020-1021, 1021t trigeminal, 1019 muscle wasting in, 1022 natural progression of, 1023, 1023t neuronal loss in gray matter in, 1008 nitric oxide in, 1007 nonsphincteric autonomic problems in, 1022, 1023t nuclear magnetic resonance spectroscopy of, 1039-1042, 1040f-1042f ocular involvement in, 298-299, 299f ocular motility disorders in, 1019, 1019f, 1020f opticospinal (Devic’s disease), 1016 pain in, 1021, 1021t paroxysmal symptoms in, 1021 peripheral neuropathy in, 1022 plastic cortical changes in, 1005 population prevalence in, 996-998, 997f primary progressive, 1016 treatment of, 1049 prognosis of, predictors of, 1025-1026, 1025t progressive, 1023-1024, 1024t spinal, 1016 pseudo-relapse in, 1015, 1016t pupillary defects in, 1018, 1018f relapsing, 1015-1016, 1016t annual rates of, 1023t treatment of, 1045-1046 relapsing-remitting, 1015 treatment of, 1046-1048, 1046t remyelination in, 1003-1004 research protocols for, 1038, 1039f schizophrenia-like psychosis in, 229 secondary progressive, treatment of, 10481049 seizures in, 1017 sensory dysfunction in, treatment of, 10501051 sexual dysfunction in, 367, 1022 treatment of, 1051 sleep disturbances in, 1017 somatosensory evoked potentials in, 1033, 1033f spasticity in, 1022 treatment of, 1049-1050, 1050t susceptibility genes in, 998-999 treatment of corticosteroids in, 1048 course-modifying, 1046-1049, 1046t FDA-approved, 1046t for acute relapses, 1045-1046 for clinically isolated syndromes, 1048 glatiramer acetate in, 1047

Multiple sclerosis (Continued) 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors in, 1048 interferon-β in, 1046-1047, 1046t, 1049 intravenous immunoglobulins in, 1048, 1049 mitoxantrone in, 1049 natalizumab in, 1047-1048 symptomatic, 1049-1051, 1050t tremor in, treatment of, 1050 trigeminal neuralgia in, 836, 1021, 1021t twin studies of, 998 vertigo in, 1020 visual evoked potentials in, 1032-1033, 1032f visual loss in, 1018-1019, 1018t vs. transverse myelitis, 516 weakness in, 1021 treatment of, 1050 Multiple sulfatase deficiency, in metachromatic leukodystrophy, 1070 Multiple system atrophy, 961-968, 962f ancillary investigations in, 963 autonomic dysfunction in, 357-358, 373-374 management of, 967-968 autonomic function tests for, 963 bladder dysfunction in, 364-365, 964 cardiovascular dysfunction in, 964 clinical presentation, course, and prognosis of, 377-378, 961-962 diagnostic criteria in, 962, 963t epidemiology of, 961 excess daytime sleepiness due to, 192 genetic factors in, 962-963 magnetic resonance imaging of, 964, 965f, 966, 966f management of, principles of, 967-968 motor symptoms in, treatment of, 383 neuropathology of, 373-374 parkinsonism in, management of, 967 positron emission tomography of, 966 scintigraphy of, 967 single-photon emission computed tomography of, 966-967 sphincter electromyography of, 964 vs. Parkinson’s disease, 938 Multi-Society Task Force on Persistent Vegetative State, 118 Multivitamins. See also Vitamin(s). for ethanol withdrawal symptoms, 1540t for Wernicke-Korsakoff syndrome, 1541 Mumps, neurological manifestations of, 516 Mumps meningitis, 1249 Murcomycosis, ocular involvement in, 302 Muscle(s) segmental innervation of, 514t striated anatomy of, 1094-1095, 1096f effects of aging on, 1097 histology of, 1095-1096, 1096f injury to, common reaction to, 1097 physiology of Muscle biopsy in amyotrophic lateral sclerosis, 867 in hereditary spastic paraplegia, 904 in polymyositis, 1214, 1215f Muscle channelopathy(ies), 1187-1191, 1188f Andersen syndrome as, 1191 calcium channel disorders as, 1190-1191 chloride channel disorders as, 1187-1189, 1189f hypokalemic periodic paralysis as, 1191 sodium channel disorders as, 1189-1190 thyrotoxic periodic paralysis as, 1191 Muscle contractions, involuntary, dystonic patterns of, 446

index Muscle cramps, in amyotrophic lateral sclerosis, 860 management of, 871 Muscle enzymes, in inflammatory myopathies, 1214 Muscle fibers, 1096-1097 types of, 1096, 1096t Muscle pain, neuroparasites causing, 1274t Muscle spasms, in Wilson’s disease, 1447 Muscle spindles, 1095 Muscle strength grading, 1398t Muscle wasting, in multiple sclerosis, 1022 Muscle-eye-brain disease, 1144t, 1153t Muscle-specific receptor tyrosine kinase antibody–associated myasthenia gravis, 1227t, 1228 Muscular atrophy, spinal, 508-509, 508t Muscular dystrophy, 1142-1161 forms of, 1142, 1143t-1144t, 1145, 1145f, 1146f. See also specific type, e.g., Duchenne muscular dystrophy. phenotypic differentiation of, 1151t-1154t recommendations for, 1161 retinal involvement in, 305 treatment of, 1159-1161 gene therapy in, 1160 pharmacological, 1159-1160 stem cell therapy in, 1160 surgical, 1160 Mushroom toxins, 1486 Mutations metachromatic leukodystrophy–causing, 1070 null, in Pelizaeus-Merzbacher disease, 1074 Mutism, akinetic, 118 Myasthenia gravis, 1223-1229, 1224t, 1370 acetylcholine receptor/muscle-specific receptor tyrosine kinase antibody–negative, 1228 clinical features of, 1223-1224 diagnosis of, 1224, 1225t differential diagnosis of, 1225t early onset, 1226, 1227t epidemiology of, 1226, 1227f etiology and pathophysiology of, 1225-1226, 1226f generalized with acetylcholine receptor antibodies, 1226-1227 without acetylcholine receptor antibodies, 1228 in pregnancy, 1501 in systemic lupus erythematosus, 1564 late onset, 1227, 1227f, 1227t muscle-specific receptor tyrosine kinase antibody–associated, 1227t, 1228 neonatal, 1228 ocular, 1226, 1227t thymoma-associated, 1227-1228, 1227t treatment of, 1228-1229, 1229t, 1230t Myasthenic syndromes, congenital, 1225t, 1231, 1232t Mycobacterium leprae, in leprosy, 1127, 1128. See also Leprosy. Mycobacterium tuberculosis in meningitis, 1243, 1244. See also Tuberculous meningitis. in neurosarcoidosis, 1303 in spinal epidural abscess, 520 Mycophenolate mofetil for inflammatory myopathies, 1218, 1218t for myasthenia gravis, 1230t for relapsing-remitting neurosarcoidosis, 1308 Mycoplasma myelitis, 518 Mycoplasma pneumoniae, 1138

Myelin genes associated with transport through, 1103 primary disturbance of, hereditary spastic paraplegia due to, 902 Myelin inhibitors, for spinal trauma, neutralizing effects of, 1406 Myelin protein zero (MPZ), 1103 Myelin sheath, 1409, 1410f Myelitis acute, in systemic lupus erythematosus, 1562-1563 coxsackie virus–related, 516 cytomegalovirus-related, 518 Epstein-Barr virus–related, 518 herpes simplex virus–related, 516-517 Mycoplasma-related, 518 optic neuritis and, 1371 rare causes of, 518 transverse, 513, 515-516, 515t clinical features of, 515-516 diagnostic criteria for, 513 etiology of, 515 imaging of, 516 vs. multiple sclerosis, 516 varicella-zoster virus–related, 517-518 Myelography, CT of cerebrospinal fluid leaks, 818-819, 820f of peripheral nerve injury, 1414, 1414f of spinal cord tumors, 1343-1344 Myeloma, multiple, 1530, 1530f Myelomeningocele definition of, 495, 496f in tethered cord syndrome, 499 Myeloneuropathy, copper deficiency, 1464 Myelopathy(ies). See also specific type. acute, 507-508, 508t cervical excess daytime sleepiness due to, 192 spondylitic, 523-524, 523t, 524f chronic, 508-510, 508t HIV–associated, 1266-1267, 1267t in Sjögren’s syndrome, 1557 in systemic lupus erythematosus, 1562-1563 infectious and parainfectious, 513, 515-519 paraneoplastic, 509 radiation-induced delayed progressive, 1359 early delayed, 1359, 1359f Myeloproliferative disorders, 1527-1528 Myocardial cell death, 1506 Myocardial lesions, stress-induced, 1507 Myoclonic seizures, 675. See also Seizure(s). generalized, preserved consciousness in, 696697 treatment of, 710-712 Myoclonic status epilepticus. See also Status epilepticus. definition of, 719-720 Myoclonus, 435-442 classification of, 435, 437t clinical features of, 435-437, 436f, 438f cortical, 435, 437t definition of, 428 drug-induced, 438, 439f epileptic, 435 essential, 438 experimental model of, 441 in corticobasal ganglionic degeneration, management of, 976 in Huntington’s disease, 881 in Lewy body dementia, 913 laboratory tests of, 439-441, 440t negative, 435, 436 physiological mechanisms of, 438-439, 440f positive, 435, 436

1609

Myoclonus (Continued) spostanoxic, 437, 438t rhythmic, 428 treatment of, 441, 442t underlying diseases associated with, 437-438, 438t, 439f, 439t Myoclonus epilepsy, 435. See also Epilepsy. in infancy, 678 genetics of, 682-683, 683t juvenile, 678, 703 genetics of, 681-682, 683t progressive, 437, 438t, 439t, 706 genetics of, 685, 685t with ragged red fibers, 705 Myoclonus-dystonia syndrome, 446-447 inherited, 437 Myofibrils, muscle, 1095, 1096f Myokemia, radiation-induced, 1360 Myoneural junction disease, in inflammatory bowel disease, 1514 Myopathic ptosis, 271 Myopathy(ies) acute necrotizing, 1371 alcoholic, 1542 congenital, 1168-1178. See also specific type, e.g., Central core disease. clinical features of, 1168-1169 epidemiology of, 1168 investigations of, 1169 major gene defects in, 1169t management of, 1170 distal, 1142, 1144t, 1145 diagnosis of, 1158, 1159f etiology and pathophysiology of, 1158 phenotypic differentiation in, 1153t-1154t hereditary inclusion body, 1144t, 1145 definition of, 1158 etiology and pathophysiology of, 1159 phenotypic differentiation of, 1154t HIV-associated, 1266-1267, 1267t, 1269 inflammatory, 1211-1219. See also specific type, e.g., Dermatomyositis. clinical presentation of, 1211-1213, 1212t diagnosis of, 1213-1217, 1213f, 1214t, 1215f, 1216f differential diagnosis of, 1218-1219 in celiac disease, 1513 prognosis of, 1219 treatment of, 1217-1218, 1218t metabolic, 1195-1207. See also specific myopathy. Myophosphorylase deficiency, 1197 Myorhythmia(s), in Whipple’s disease, 1516 Myotome, 488 Myotonia fluctuans, 1190 Myotonic dystonia, 437 Myotonic dystrophy, cataracts and, 305 Myotonic dystrophy(ies), 1191-1193 clinical features of, 1192, 1192t epidemiology of, 1192 molecular pathogenesis of, 1192-1193 principles of care in, 1193 Myotubular (centronuclear) myopathy, 11761178 clinical features of, 1177 gene defects in, 1169t genetics of, 1177-1178 histopathology of, 1171f, 1177 Myotubularin-related protein 2 (MTMR2), 1104

N Nadol, for tremor, 419, 422t Nadroparin, for cerebral vein and sinus thrombosis, 628-629

1610

Index

NANA assay, for Canavan’s disease, 1075 Nanophthalmos, 274 Naratriptan for medication overdose–headache, 767 for migraine, 745-746, 745t Narcolepsy, 193-194, 194t, 195t treatment of, 194, 194t Narcosis, nitrogen-induced, 1574 Nasal continuous positive airway pressure for central sleep apnea, 210 for obstructive sleep apnea-hypopnea, 207, 208f Nasogastric tube feeding, for stroke patients, 653 Nasopharynx, anatomy of, 162f Natalizumab, for multiple sclerosis, 10471048 National Adult Reading Test, 4 National Institute on Aging–Ronald and Nancy Reagan Institute criteria, for Alzheimer’s disease, 850 Natural products, prophylactic for chronic daily headache, 768t for migraine, 749 NDRG1 gene, in inherited neuropathies, 1104 Near-falls, 457. See also Falls. Neary classification, of frontotemporal dementia, 983, 984t NEB gene, in nemaline myopathy, 1176 Neck, structural disorders of, headache secondary to, 801-802 Neck pain, in spinal cord disease, 511 Necrosis, radiation, 1357, 1357f Necrotizing myopathy, acute, 1371 NEEL gene, in inherited neuropathies, 1103 Neglect syndrome, 73-81 anatomy of, 77-78, 77f, 78f body image aspects of, 75 examination of, 76-77 components, separation of, 75 examination of, 75-77, 76f frequency of, 79-80 motor aspects of, 75 examination of, 77 pathophysiology of, 78-79, 78f, 79f sensory aspects of, 73-74 examination of, 75 spatial aspects of, 74-75, 74f examination of, 75-76, 76f terminology and phenomenology in, 73-75 treatment of, 80 unilateral, after stroke, 651 Nemaline myopathy clinical features of, 1175-1176 gene defects in, 1169t genetics of, 1176 histopathology of, 1171f, 1175 Neonates. See also Children; Infants. adrenoleukodystrophy in, 281 benign familial convulsions in, genetics of, 683, 683t, 684f brain arteriovenous malformations in, 600 brain death in, 112 epileptic syndromes in, 703 myasthenia gravis in, 1228 seizures in, treatment of, 713 vitamin K deficiency in, antiepileptic agents causing, 1500 Neoplasms. See also specific neoplasm, e.g., Lymphoma. associated with dermatomyositis, 1213 central nervous system, after organ transplantation, 1566 in paraneoplastic neurological disorders, demonstration of, 1364, 1364f

Neoplasms (Continued) intracranial, 1324-1338. See also Brain tumor(s); specific neoplasm. headache secondary to, 800-801 metastatic. See Metastasis. of external auditory canal, conductive hearing loss due to, 330 of spinal cord, 526-531 of vestibular system, 346-347 radiation-induced, 1358, 1358f thrombophilic state associated with, 619 Nephrotic syndrome, venous thrombosis in, 618-619 Nerve(s) anatomy of, 1094, 1095f commonly affected by leprosy, 1130, 1131f peripheral anatomy of, 1409, 1410f injury to, 1410-1420. See also Peripheral nerve injury. physiology of, 1410 physiology of, 1094, 1095t structure of, genes associated with, 11021103 Nerve biopsy, in amyotrophic lateral sclerosis, 867 Nerve compression, chronic, 1415 Nerve conduction studies, 1411-1413, 1412f, 1413f Nerve laceration, 1415 Nerve roots, compression of, clinical features associated with, 525t Nerve sheath tumors, 1375 classification of, 1376t magnetic resonance imaging of, 1344-1345, 1347f Nervous system. See also Autonomic nervous system; Central nervous system; Peripheral nervous system. immunological and inflammatory disorders of, 1314t involvement of, in respiration, 1569, 1570f, 1571 normal development of, 488, 489t paraneoplastic disorders of, 1361-1371. See also Paraneoplastic neurologic disorders. Neural Darwinism, 98 Neural processes, underlying limb apraxia, 408409 Neural reorganization, after stroke, 651-652 maladaptive or ineffective, 652 Neural tube closure of, 489t development of, 488 Neural tube defects, 489t, 494-499 classification of, 493f, 494-495, 496f, 497f clinical features of, 495-497 definition of, 494 epidemiology of, 495 etiology and pathophysiology of, 497-498 management of childhood, 499 lifelong, 499 perinatal surgical considerations in, 499 prenatal diagnosis and, 498-499, 498f prevention of, 498 prognosis of, 497 Neural tumors, classification of, 1376t Neuralgia geniculate, vs. trigeminal neuralgia, 837 glossopharyngeal, vs. trigeminal neuralgia, 836 postherpetic, definition of, 1136 trigeminal, 835-840. See also Trigeminal neuralgia. Neurapraxia, classification of, 1410, 1410f

Neuritis leprous, 1127-1132. See also Leprosy. optic. See Optic neuritis. vestibular, 342 Neurobehavioral Cognitive Status Examination (NCSE), 15 Neurobehavioral domains, function in, 6-8 Neurobehavioral history, integration of neurocognitive history and, 3 Neurobehavioral rating scales, 10, 10t Neuro-Behçet’s disease clinical features of, 1309 diagnostic approaches to, 1310 nonparenchymal (cerebrovascular) forms of, 1310 parenchymal (intra-axial) forms of, 1309-1310 treatment approaches to, 1310 Neurocardiac lesion, 1505-1506, 1506f Neurocognitive domains, function in, 4-6 Neurocognitive examination, 10-15 general observation in, 11 of attention and orientation, 12, 12t of cortical release signs, 15 of executive function, 14, 15t of language, 12, 13t of memory, 13-14, 14f, 14t of visuoperceptual/visuoconstructional function and calculation, 13, 13t quantitative vs. qualitative data in, 11, 11f setting for, 11 undertaking of, 10-11 Neurocognitive formulation, 16 case example of, 16, 17f Neurocognitive function, premorbid, 4 Neurocognitive history, 2-3 integration of neurobehavioral history and, 3 principles of, 2 Neurocognitive impairment, in HIV-associated dementia, 1265 Neurocognitive sequelae, in obstructive sleep apnea-hypopnea, 204-205 Neurocognitive “sketch” assessment trigger in, 3 baseline in, 4 evolution of symptoms in, 3 gross functional capacity in, 4, 4t Neurocognitive theories of attention-deficit hyperactivity disorder, 133-134 of autism, 132-133 Neurodegenerative diseases. See also specific disease, e.g., Huntington’s disease. retinopathy/optic neuropathy associated with, 282 Neurodevelopmental disorders. See specific disorder, e.g., Autism. Neuroendocrine testing, of primary autonomic failure, 380-381 Neuroepithelial tumors, dysembryonic, neuroimaging of, 664, 665f Neurofibrillary tangles, in Alzheimer’s disease, 849-850, 849f Neurofibroma, solitary, 1378-1379, 1379f Neurofibromatosis, 1380-1382 retinal changes associated with, 306 type 1, 1380t, 1381f malignant peripheral nerve sheath tumor in, 1380-1381, 1381f type 2, 1380t Neurofilament-light (NEEL), 1103 Neurogenic bladder, rehabilitation strategies for, 1430-1431 Neurogenic bowel, rehabilitation strategies for, 1430 Neurogenic dysphagia. See Dysphagia, neurogenic.

index Neurogenic hyperventilation, central, 1572 Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), 282, 282f Neurogenic ptosis, 271 Neurogenic regulation, of cerebral circulation, 545-546, 545t Neurogenic scoliosis, 492 Neurogenic shock, 1403 Neurohypophysial hormones, 1551 Neuroimaging. See also specific modality. of Alexander’s disease, 1076, 1077f of Alzheimer’s disease, 853, 854f, 855f of attention-deficit hyperactivity disorder, 134 of autism, 133 of Canavan’s disease, 1075 of epileptic syndromes, 701-702, 702f, 703f of frontotemporal dementia, 991 of globoid leukodystrophy, 1071-1072, 1072f of Lewy body dementia functional, 916, 917f structural, 915-916, 917f of malformations caused by abnormal cortical development, 664-668, 664f-667f of megalencaphalic leukodystrophy with subcortical cysts, 1081, 1081f of metachromatic leukodystrophy, 1069-1070 of X-linked adrenoleukodystrophy, 1066-1067 Neuroinflammation, in amyotrophic lateral sclerosis, management of, 868-869 Neuroleptic(s) for Gilles de la Tourette syndrome, 216 for migraine, 744, 744t for schizophrenia, side effects of, 227 sensitivity of, 920 Neuroleptic malignant syndrome, 227 Neurological deficits after stroke, management of, 649-652, 650f in brain arteriovenous malformations, 600 in celiac disease, 1511-1512, 1512t in spinal cord arteriovenous malformations, 605-606 progressive, in tethered cord syndrome, 500 Neurological disease abnormal respiration patterns in, 1571-1573, 1572t paraneoplastic, 1361-1371. See also Paraneoplastic neurological disorder(s). Neuroma, acoustic (vestibular schwannoma), 1338 Neuromatabolic disease, manifestations of, 1437t Neuromuscular junction disorders, 1223-1232, 1224t. See also specific disorder, e.g., Myasthenia gravis. vs. amyotrophic lateral sclerosis, 864 Neuromyelitis optica, 1016. See also Multiple sclerosis. Neuromyotonia, acquired, 1225t, 1230-1231 Neuron ceroid lipofuscinoses, 282 Neuronal injury, in status epilepticus, pathophysiology of, 722-723 Neuroparasites, clinical findings associated with, 1274t Neuropathy(ies) acute motor-sensory axonal, 1137 after organ transplantation, 1566-1567 autonomic, in systemic lupus erythematosus, 1564 brachial and lumbosacral, radiation-induced, 1359-1360 chemotherapy-induced, 1353, 1354t cranial in Lyme disease, 1135 radiation-induced, 1356-1357

Neuropathy(ies) (Continued) HIV-associated entrapment, 1268 miscellaneous, 1268-1269 peripheral, 1267-1269, 1267t iatrogenic and toxic, 1119-1123, 1120t, 1122t immune-mediated, 1116-1119, 1118f infective, 1127-1138. See also specific neuropathy, e.g., Leprosy. inherited, 1099-1108 classification of, 1101-1102, 1101t clinical diagnosis of, 1099 disease phenotypes in, 1099-1101 genetic counseling in, 1108 genetic factors in, 1102-1106, 1102f genetic testing for, 1106-1108, 1106f, 1106t, 1107f genotype-phenotype correlation in, 1100t management of, 1108 pattern of, 1101 metabolic, 1113-1116, 1114f, 1114t, 1116f, 1116t optic, 285-293. See also Optic neuropathy(ies). paraneoplastic, 1369-1370 peripheral HIV-associated, 1267-1269, 1267t in celiac disease, 1513 in inflammatory bowel disease, 1514 in multiple sclerosis, 1022 in rheumatoid arthritis, 1561 tremor syndromes in, 426-427 pyridoxine toxicity, 1464 sensory HIV-associated, 1267-1268, 1267t paraneoplastic, 1369, 1369f Neuroprotection, for Parkinson’s disease, 948950 Neuropsychiatric inventory, 10, 10t Neuropsychological assessment deficits and changes in, measurement of, 2728 of cognitive domains and neuropsychological tests, 22, 23f, 23t principles of, 22-29 strategies in, 28 Neuropsychological model(s), of executive function, 83-85 supervisory attentional system, 84-85, 84f working memory, 83-84, 84f Neuropsychological tests, for Lewy body dementia, 915, 916f Neuropsychology, optimal use of, 28-29 Neurorehabilitation. See Rehabilitation, for neurological injury. Neuroretinitis, 288, 299, 299f infectious causes of, 299-300, 300f Neurosarcoidosis, 1303-1309. See also Sarcoidosis. clinical features of, 1303, 1304t cranial neuropathy forms of, 1304, 1304t diagnostic approaches to, 1306-1307 early stages of, treatment of, 1308 encephalitic forms of, 1304-1305, 1304t, 1305f endocrine forms of, 1304t, 1305, 1306f epidemiology of, 1303 etiopathogenesis of, 1303 meningeal forms of, 1304, 1304t, 1305f myelopathic forms of, 1304t, 1306 myopathic forms of, 1304t, 1306 neuropathic forms of, 1304t, 1306 relapsing-remitting forms of, treatment of, 1308-1309

1611

Neurosarcoidosis (Continued) treatment of for acute forms, 1308 for relapsing-remitting forms, 1308-1309 Neurotmesis, classification of, 1410f, 1411 Neurotrophic growth factors, for amyotrophic lateral sclerosis, 869-870, 870t Neurulation, stages in, 488, 489t Neutralizing antibodies, to interferon-β, 1047 Niacin (nicotinic acid ), 1458-1459 deficiency of, polyneuropathy associated with, 1123 Nifedipine, for supine hypertension, 360 Night blindness, congenital stationary, 278 NINDS-rt-PA Stroke Study, 570, 571t NINDS-SPSP diagnostic criteria, for progressive supranuclear palsy, 969, 970t Nipah virus meningitis, 1249-1250, 1254 Nitrates, low doses of, for supine hypertension, 360 Nitrazepam, 713 Nitric oxide in cerebral circulation regulation, 547 in multiple sclerosis, 1007 in Parkinson’s disease, 935 Nitrofurantoin, toxic neuropathy due to, 1120 Nitrogen-induced narcosis, 1574 Nobarbital, for medication overdose–headache, 768 Nociceptive system, role of, in restless leg syndrome, 472-473 Nocturia impaired sleep due to, 191 in multiple system atrophy, management of, 968 Nocturnal frontal epilepsy. See also Epilepsy. autosomal dominant, 678 genetics of, 683t, 684 Nocturnal penile tumescence testing, 367 NOD2/CARD15 gene, in Crohn’s disease, 1513 Noise-induced hearing loss, 332. See also Hearing loss. Nonbacterial thrombotic endocarditis, 1531 Noncardioembolic stroke, 578-579. See also Stroke. Nonconvulsive status epilepticus. See also Status epilepticus. management of, 727 Nondeclarative (implicit) memory, 43, 44t Nonepileptic seizures. See also Seizure(s). psychogenic impaired consciousness in, 695-696 loss of consciousness in, 695 Nonfluent aphasia. See Aphasia, nonfluent. Nonfluent language, 32-33, 32t Nonglial tumors, of spinal cord, 530 Nonhereditary lesions, in spinal cord arteriovenous malformations, 603-604 Non-Hodgkin’s lymphoma, ocular, in HIV infection, 302 Non–24-hour circadian rhythm disturbance, 196 Nonidiopathic partial epilepsy, 703-704, 704f, 705. See also Epilepsy. Nonkinesigenic dyskinesia, paroxysmal, 452-453 Nonlinear testing, of balance, 323 Nonmotor features, of Parkinson’s disease, 936937, 937t Nonorganic disorders, of voice, 159 Nonparaneoplastic limbic encephalitis, 51, 52f Nonpharmacological therapy, for delirium, 148150 Non–rapid eye movement (NREM) sleep. See also Sleep entries. altered thermoregulation during, 181 breathing during, 181

1612

Index

Non–rapid eye movement (NREM) sleep (Continued) disorders of, 196-197 treatment of, 197-198 electrophysiology of, 180-181 parasympathetic activity during, 181 Nonsteroidal anti-inflammatory drugs, for migraine, 744, 744t Nontropical sprue, 1511-1512, 1512t Nonverbal memory, testing of, 13, 14f Norrie disease, 276, 277 North American Symptomatic Carotid Endarterectomy (NASCET) trial, 581 Nortriptyline, for migraine, 748 Notch3 gene in CADASIL, 639, 743 in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, 309 NR2E3 gene, in hereditary vitreoretinopathies, 276 NRG1 gene, in schizophrenia, 224 Nuclear magnetic resonance spectroscopy, of multiple sclerosis, 1039-1042, 1040f N-acetyl resonance in, 1040, 1042, 1042f trimethylamine resonance in, 1040, 1041f Nucleoside analogs, toxic neuropathy due to, 1120 Null alleles, in metachromatic leukodystrophy mutations, 1070 Null mutations, in Pelizaeus-Merzbacher disease, 1074 Nutritional disorder(s) associated with alcoholism, 1541 by symptom complex, 1457t copper deficiency myeloneuropathy as, 1464 postgastroplasty polyneuropathy as, 1464 pyridoxine toxicity neuropathy as, 1464 Strachan’s syndrome as, 1464-1465 vitamin deficiencies and. See Vitamin entries. Nutritional optic neuropathy, visual loss in, 292 Nystagmus, 323 gaze, 323, 325 gaze-evoked, 347 head-shaking, 323 in temporal bone fractures, 346 optokinetic, 325 in comatose patient, 102 positional, 344t spontaneous, 325

O Obesity, and obstructive sleep apnea-hypopnea, 206 Obsessions, 7 definition of, 217 Obsessive-compulsive disorder, 7 diagnosis of, 217 epidemiology of, 217-218 Gilles de la Tourette syndrome associated with, 216 management and prognosis of, 217 recommendations for, 217-218 Obstructive sleep apnea, 1573. See also Sleep apnea; Sleep apnea-hypopnea. headache secondary to, 802, 802t Occasional seizures, 704-705, 706. See also Seizure(s). Occipital lobe infarction, incomplete hemianopia due to, 264f Occipital nerve blockade, prophylactic, for cluster headache, 782 Occipital sinus, anatomy of, 623 Occipitalization, of atlas, 489t, 491

Ocular axis, deviation of, in comatose patient, 101 Ocular ischemic syndrome, 308 Ocular motility disorders, in multiple sclerosis, 1019, 1019f, 1020f Ocular myasthenia gravis, 1226, 1227t Oculo facial-skeletal myorhythmia, in Whipple’s disease, 1516 Oculocephalic reflex absent, in brain death, 108t in comatose patient, 101-102 Oculomasticatory myorhythmia, in Whipple’s disease, 1516 Oculomotor apraxia, 64, 64t Oculomotor disturbances, in progressive supranuclear palsy, management of, 938939 Oculomotor nerve paresis, in multiple sclerosis, 1019 Oculomotor system, examination of, 271-272 Oculomotor testing, of balance, 323, 324-325 Oculopharyngeal muscular dystrophy, 1142, 1143t clinical features of, 1157-1158, 1158f definition of, 1157 etiology and pathophysiology of, 1158 phenotypic differentiation of, 1151t Oculovestibular reflex, in comatose patient, 102 Odynophagia, 164 Office-based tests for olfactory disorders, 174, 174t of executive function, 86 Olfactory dysfunction, 171-175 anatomical sites of, 172t causes of, 172t clinical approach to, 171, 172t drug-induced, 172t history of, 171, 173-174, 173t in Parkinson’s disease, 936 investigation of, 174 management of, principles in, 174-175 office assessment of, 174, 174t Olfactory hallucinations, 676 Olfactory neurons, anatomy and physiology of, 171 Oligoastrocytoma, pathology of, 1327 Oligodendroglioma imaging, pathology, and histology of, 1332f vs. astrocytoma, 1330 Olivopontocerebellar phenotype, in X-linked adrenoleukodystrophy, 1066 Ondine’s curse, 1573 One-and-a-half syndrome, in multiple sclerosis, 1019, 1020f Opalski cells, in Wilson’s disease, 1449 Ophthalmoplegia, internuclear in comatose patient, 101 in multiple sclerosis, 1019, 1019f, 1020f Opioid(s) for medication overdose–headache, 768 for migraine, 744, 744t for restless leg syndrome, 481 intoxication and withdrawal of, 1537 Opioid antagonists, for spinal trauma, 1406 Opportunistic infections, after organ transplantation, 1565-1566 Opsoclonus-myoclonus, paraneoplastic, 1368 Optic ataxia, 64, 64t Optic disc, swelling of in idiopathic intracranial hypertension, 808, 809f insidious visual loss with or without, 290-292, 291f, 292f, 292t sudden visual loss with or without, 286-290, 287f-290f without visual loss, 285-286, 286f

Optic nerve atrophy autosomal dominant, 279-280, 279f X-linked, 280 Optic nerve diseases, blindness due to childhood and adulthood onset of, 279-280, 279f, 280f congenital, 278-279, 279f, 279t Optic nerve hypoplasia, congenital, 278, 279f Optic nerve sheath fenestration, for idiopathic intracranial hypertension, 812 Optic neuritis acute, visual loss in, 286-288, 287f, 288f in systemic lupus erythematosus, 1562 paraneoplastic, 1371 with retinitis, 305 risk of multiple sclerosis with, 1018 variant of, 288 Optic neuropathy(ies), 285-293 associated with dermatological, skeletal, ocular, and renal disease, 282-283 associated with systemic and neurodegenerative disease, 280-282, 281f compressive, 290-291, 291f infiltrative, 291, 291f ischemic, 288-289, 288f, 289f Leber’s hereditary. See Leber’s hereditary optic neuropathy. radiation-induced, 292-293, 293f toxic and deficiency, 291-292, 292f, 292t traumatic, 292 vitamin B12 deficiency causing, 1526 Optokinetic nystagmus, in comatose patient, 102 Oral appliances, for obstructive sleep apneahypopnea, 207 Orbitofrontal circuit, in executive function, 85 Organ procurement, after brain death, 114 Organ transplantation. See Transplantation. Organic aciduria, 1441 Organic solvents, exposure to, 1481-1483 complications of, 1481t Organochlorine insecticides, 1483t, 1484 Organophosphate insecticides, 1483t, 1484-1485 Orientation neurocognitive assessment of, 4 neurocognitive examination of, 12 Ornithine transcarbamylase deficiency, 1469, 1470t, 1473-1474 Ornithine translocase deficiency, 1470, 1472, 1473f, 1474 Orofacial dystonia, in multiple system atrophy, 962f Oromandibular dystonia, 445 Oropharyngeal weakness, in amyotrophic lateral sclerosis, aspiration due to, 861 Orthopedic deformities, progressive, in tethered cord syndrome, 500, 502f Orthopedic interventions, for gait disturbances, 468 Orthoses, type and application of, 1428t Orthostatic hypotension, 354-360 autonomic failure in, causes of, 357-358 conditions related to, management of, 359360 diagnosis of, 355 evaluation of, 355, 355t, 357, 357f in multiple system atrophy, 964. See also Multiple system atrophy. management of, 967-968 management of, 358-360, 383, 384t nonpharmacological, 358-359, 358f, 358t pharmacological, 359, 359t pathophysiology of, 354, 355f, 356f Oscillopsia bobbing, 341 definition of, 337

index Osmolality, measurement of, 1533 Ossification, heterotopic, rehabilitation strategies for, 1431 Osteomyelitis, vertebral, 521 Otitic barotrauma, 345-346 Otitis media conductive hearing loss due to, 331 definition of, 329 serous, 347 Otoacoustic emissions, 321-322 Otoconia, 337, 338f Otosclerosis, 331 Ototoxicity, sensorineural hearing loss due to, 333 Out-of-body experiences, 249 Oxafloxacin, prophylactic, for bacterial meningitis, 1243t Oxaliplatin, toxic neuropathy due to, 1121 Oxcarbazepaine, for partial and tonic-clonic seizures, 708-709 Oxidative phosphorylation, mitochondrial. See also Mitochondrial oxidative phosphorylation. Oxidative stress/damage, in Parkinson’s disease, 935, 935t Oxprenolol, for tremor, 419 Oxygen therapy for central sleep apnea, 209 for cluster headache, 778 hyperbaric, for carbon monoxide intoxication, 1484 Oxygenation, adequate, for ischemic stroke, 569 Oxytocin, 1551 source and function of, 1550t

P Pachymeningitis, in rheumatoid arthritis, 1561 Paclitaxel (Taxol) neurological complications caused by, 1355 toxic neuropathy due to, 1121 Paget’s disease, spinal cord compression due to, 534 PAH gene, in phenylketonuria, 1442 Pain after stroke, management of, 653 back and neck, in spinal cord disease, 511 facial. See also Trigeminal neuralgia. atypical, 837, 837f from spinal cord tumors, 1341-1342 head. See Headache; Migraine. impaired sleep due to, 191 in amyotrophic lateral sclerosis, management of, 873 in multiple sclerosis, 1021, 1021t in Parkinson’s disease, 937 in tethered cord syndrome, 500 Pain insensitivity, in leprosy, management of, 1132 Painful crises, in sickle cell anemia, 1527 Painful tonic spasm, in multiple sclerosis, 1021, 1021t Pain-relieving agents, for gait disturbances, 468 Palatal lifts, for speech disorders, 161 Palatal tremor syndromes, 426, 436-437 Palilalia, in Gilles de la Tourette syndrome, 214 Palipraxia, in Gilles de la Tourette syndrome, 214 Palliative procedures, for epilepsy, 718 Pallidotomy, for Parkinson’s disease, 947, 947t Palsy. See specific type, e.g., Cerebral palsy. Pandysautonomia, clinical presentation of, 374375 Panencephalitis, subacute sclerosing, ocular involvement in, 301

Panic attacks, 696 PANK2 gene in pantothenate kinase deficiency, 1442 in pantothenate kinase–associated neurodegeneration, 305 Pantomiming, action selection disruption of, in limb apraxia, 409 Pantothenate kinase deficiency, 1442 Pantothenate kinase–associated neurodegeneration, 305 Papilledema appearance of, 285-286, 286f bilateral, blind spots due to, 268f definition of, 285 double vision in, 285 in idiopathic intracranial hypertension, 808, 809f, 810f Papilledema grading system, of idiopathic intracranial hypertension, 808, 808t Papilloma, choroid plexus, overproduction of CSF due to, 827 Papillorenal syndrome, congenital, 278-279 Paragrammatism, 33 Paralysis hypokalemic periodic, 1190-1191 secondary, 1191 in conversion syndrome, 251 thyrotoxic periodic, 1191 tick, 1485 Paralysis agitans. See Parkinson’s disease. Paramyotonia congenita, 1189 Paraneoplastic antibodies, detection of, 13641366, 1365f, 1365t, 1366t Paraneoplastic neurological disorder(s), 13611371. See also specific disorder. associated cancer in, demonstration of, 1364, 1364f cerebellar degeneration as, 1365t, 1367-1368 dermatomyositis as, 1370-1371 diagnosis of approach to, 1363-1366 criteria in, 1366, 1366t differential diagnosis of, 1363t encephalomyelitis as, 1365t, 1366-1367, 1366f immune-mediated, 1361-1363 and effects on tumor, 1363 classification of, 1362t limbic encephalitis as, 51, 52f, 1367, 1367f myelopathy as, 509 neuropathy as, 1369-1370 opsoclonus-myoclonus as, 1368 paraneoplastic antibodies in, detection of, 1364-1366, 1365t, 1366t, 1414f sensory neuropathy as, 1369, 1369f specific syndromes as, 1366-1371 visual syndromes as, 304, 1371, 1371f Paraneoplastic optic neuritis, with retinitis, 305 Paraphrasia definition of, 33 features of, 32, 33t Paraplegia definition of, 1397 hereditary spastic, 508, 508t, 899-906. See also Hereditary spastic paraplegia. Paraproteinemia(s), 1530-1531, 1530f Paraquat herbicide, associated with Parkinson’s disease, 933 Parasitic infections of central nervous system, 1273-1289, 1274t. See also specific infection. of spinal cord, 521 Parasomnias, 196-198 international classification of, 186t-187t non-REM, 194t, 196-197 treatment of, 195t, 196-197

1613

Parasomnias (Continued) REM, 194t, 198 treatment of, 198 vs. nocturnal seizures, 696 Parent training, in management of autism, 135 Paretic/hypotonic gait, 464t Parietal vision-related cortex disorders, 63-64, 64t, 65f PARK1 (alpha-synuclein) gene, in Parkinson’s disease, 928t, 929-930 PARK2 (parkin) gene, in Parkinson’s disease, 928t, 930-931, 932 PARK5 (UCH-L1) gene, in Parkinson’s disease, 928t, 931 PARK6 (PINK1) gene, in Parkinson’s disease, 928t, 931 PARK7 (DJ-1) gene, in Parkinson’s disease, 928t, 931 PARK8 (LRRK2) gene, in Parkinson’s disease, 928t, 931-932 PARK9 gene, in Parkinson’s disease, 928t, 932 PARK10 gene, in Parkinson’s disease, 928t, 932 PARK11 gene, in Parkinson’s disease, 928t, 932 Parkes-Weber syndrome, 604 Parkin (PARK2) gene, in Parkinson’s disease, 928t, 930-931, 932 Parkinsonian syndromes apathy in, 243 depression in, 238 Parkinsonian tremor classic, definition of, 422-423 definition of, 422 treatment of, 423-424, 423t variant of, 423 Parkinsonism benign tremulous, definition of, 423 drug-induced, vs. Parkinson’s disease, 938 dystonia, rapid-onset, 447 frontotemporal dementia with, 983-984 genetic causes of, 932-933, 932t in corticobasal ganglionic degeneration, management of, 975 in Lewy body dementia, 913 in multiple system atrophy, 961-962 management of, 967 in progressive supranuclear palsy, 936t, 969 management of, 938 vascular, vs. Parkinson’s disease, 938 Parkinson’s disease, 927-950 and autonomic failure, clinical presentation of, 376-377 apathy in, 243 bladder dysfunction in, 364 Braak staging of, 928, 929f clinical features of, 936-937, 937t depression in, 238 differential diagnosis of, 937-938, 937t environmental factors associated with, 933934 epidemiology of, 927 etiology of, 928-934 excess daytime sleepiness due to, 192 genetic associations with, 932 genetic factors in, 928-932, 928t historical perspectives of, 927 imaging of, 938-939, 939f Lewy bodies in, 927-928, 928f mania in, 239 motor features of, 936 motor symptoms in, treatment of, 383 neuroprotection for, 948-950 coenzyme Q10 in, 949f, 950 dopamine agonists in, 948-950, 949f MAO-B inhibitors in, 948 nonmotor features of, 936-937, 937t pathogenesis of, 934-935, 935t

1614

Index

Parkinson’s disease (Continued) pathology of, 927-928, 928f, 929f psychotic symptoms in, 228-229 sexual dysfunction in, 367 substantia nigra in iron concentrations in, 934-935 mitochondrial dysfunction in, 935 oxidative stress and damage to, 935, 935t treatment of, 939-948, 940f amantadine in, 945 anticholinergics in, 945 catechol-O-methyl transferase inhibitors in, 941-942, 942f complications of, 946 dopamine agonists in, 942-943, 943f initiation of, 945, 945f levodopa in, 940-941, 941f maintenance of, 946 MAO-B inhibitors in, 943-945, 944f nonmotor complications of, management of, 946-947 slowing progression of neurodegeneration in, 948-950, 949f surgical, 947-948, 947t tremors in, treatment of, 423-424, 424t variant for, 423 Paroxysmal exercise-induced dyskinesia, 453 Paroxysmal hypnogenic dyskinesia, 453 Paroxysmal kinesigenic dyskinesia, 452 Paroxysmal nonkinesigenic dyskinesia, 452-453 Partial epilepsy. See also Epilepsy. nonidiopathic, 703-704, 704f, 705 Partial seizures. See also Seizure(s). complex, 676-677 impaired consciousness in, 695 generalized, 694 simple, 676 abnormal sensations with preserved consciousness in, 696 differential diagnosis of, 696-697 treatment of, 708-710 Parvovirus B19 infection, 1317 Patent foramen ovale, stroke associated with, 554, 579 PAX2 gene, in papillorenal syndrome, 279 PAX6 gene, in optic nerve hypoplasia, 278 PC gene, in pyruvate carboxylase deficiency, 1440 PDHA1 gene, in pyruvate dehydrogenase deficiency, 1440 Pearson’s syndrome, 1203, 1205t Pediatric Glasgow Coma Scale, 100, 100t Pedunculopontine nucleus, in locomotion, 456 Pelizaeus-Merzbacher disease, 1073-1074 classical, 1073 connatal, 1073 Pellagra (rough skin) in alcoholics, 1541-1542 niacin deficiency causing, 1458-1459 Penetrating trauma, gunshot, 1391 D-Penicillamine for lead intoxication, 1479 for Wilson’s disease, 1450 Penicillin G, for syphilitic meningitis, 1245 Penile tumescence testing, nocturnal, 367 Pentobarbital, for refractory status epilepticus, 723f, 725 Perception, assessment of, 7-8 Percutaneous balloon compression, for trigeminal neuralgia, 839 Percutaneous glycerol retrogasserian rhizotomy, for trigeminal neuralgia, 838-839 Pergolide, for restless leg syndrome, 482t Periaxin, 1104 Perimysium, of muscle, 1095, 1096f

Perindopril Protection Against Recurrent Stroke Study (PROGRESS), 569 Perineurium, 1409, 1410f Periodic limb movements disorder of, 189-190, 190f in restless leg syndrome, 471, 474 polysomnographic recordings of, 475 Peripatetic specialist stroke team, care delivered by, 648 Peripheral myelin protein 22 (PMP22), 11021103 Peripheral nerve injury, 1409-1420 anatomy and physiology of, 1409-1410, 1410f cause(s) of chronic compression as, 1415 cold-induced trauma as, 1417-1418 electrical trauma as, 1418 injection trauma as, 1416 ischemic trauma as, 1416-1417 nerve transection or laceration as, 1415 radiation trauma as, 1417, 1417f stretch trauma as, 1415-1416, 1416f classification of, 1410-1411, 1410t clinical evaluation of, 1411 electrophysiological evaluation of, 1411-1414, 1412f, 1413f imaging of, 1414, 1414f treatment of surgical, 1418-1420, 1419t symptomatic, 12 Peripheral nervous system immunological and inflammatory disorders of, 1314t involvement of in inflammatory bowel disease, 1514 in systemic lupus erythematosus, 15631564, 1563t paraneoplastic neurological disorders of, 1361-1362. See also Paraneoplastic neurological disorder(s). tumors of, 1375-1382. See also specific tumor. biopsy of, 1375-1376, 1377f Birch and Sinisi’s experience with, 1377t classification of, 1376t imaging of, 1375, 1376f vasculitis of, 1320-1321 primary, 1314-1315 Peristalsis, manometric studies of, 166 Periventricular heterotopia genes associated with, 686t neuroimaging of, 665, 685f Permanent vegetative state, 117. See also Vegetative state. Peroxisomal disorders, retinopathy/optic neuropathy associated with, 281-282 Persistent vegetative state, 117. See also Vegetative state. Personal neglect (hemiasomatognosia), 75. See also Neglect syndrome. examination of, 76-77 Personality changes in Alzheimer’s disease, 852 in Huntington’s disease, 881 in Wilson’s disease, 1448 Pes cavus, in hereditary spastic paraplegia, 903 Pesticides associated with Parkinson’s disease, 933-934 toxicity of, 1483-1485, 1483t PET. See Positron emission tomography (PET). Peter’s anomaly, 274 Petrosal sinuses, anatomy of, 622-623 Phantosomia, 174

Pharmacotherapy. See also specific drug and drug group. cognitive side effects of, 853t for Alzheimer’s disease, 854, 854t for amyotrophic lateral sclerosis, 868, 870t for autism, 135 for delirium, 150 for dystonia, 450-451, 451t for insomnia, 188-189, 189t for Lewy body dementia, dosing schedules in, 921t-922t for migraine, 743-746 indications for and contraindications to, 744t for muscular dystrophy, 1159-1160 for speech disorders, 161 for spinal trauma, 1405-1406 new agents in, 1406 for status epilepticus, 724-725 new drugs in, 726-727 for vestibular disorders, 349 Phencyclidine, intoxication and withdrawal of, 1538 Phenobarbital for delirium tremens, 1540t for medication overdose–headache, 768 for neonatal seizures, 713 for partial and tonic-clonic seizures, 710 for status epilepticus, 723f, 725 Phenylketonuria, 1442 Phenytoin for neonatal seizures, 713 for partial and tonic-clonic seizures, 709 for status epilepticus, 723f, 724, 725 for toxemia of pregnancy, 717 toxic neuropathy due to, 1120t, 1121 Phonemic (letter) fluency, 89 Phonemic paraphrasia, 33 Phonology, 32t. See also Language. Phosphofructokinase deficiency, 1197-1198 Phosphoglycerate kinase deficiency, 1198 Phosphoglycerate mutase deficiency, 1198 Phosphorylase β kinase, 1197 Photic cortical reflex myoclonus, 435 Photoreceptors, retinal, 295 Phototherapy, for delayed sleep phase syndrome, 196 Physical sequelae, of delirium, 143 Physiotherapy after stroke, 648 meta-analysis of, 650 for gait disturbances, 466, 467t for tension-type headache, 759-760 Pica behaviors, 1525 Pick’s disease, 983. See also Frontotemporal dementia. Pincer fracture, 1405f Pineal tumors, 1337 hydrocephalus secondary to, 826, 826f PINK1 (PARK6) gene, in Parkinson’s disease, 928t, 931 Piracetam, for myoclonus, 442t Pituitary development and structure of, 1550 hormone-secreting tumors of, headache secondary to, 801 Pituitary hormones, 1550t Pizotifen, prophylactic, for migraine, 749 Plant toxins, 1485-1486 Plaques in Alzheimer’s disease amyloid protein, 847-848, 848f nonamyloid component of, 850 senile, 849-850, 849f

index Plaques (Continued) in multiple sclerosis disorientation/imbalance associated with, 348 impaired sleep-wake regulation due to, 191 Plasmapheresis, for cryoglobulinemia, 1319 Platybasia, 490 Pleocytosis, cerebrospinal fluid, in multiple sclerosis, 1031 Plexopathy, in systemic lupus erythematosus, 1564 PMP22 (peripheral myelin protein 22), 11021103 PMP22 gene, in inherited neuropathies, 11021103, 1102f Pneumocephalus, 1390 Pneumocystis carinii, in choroiditis, 302 POEMS syndrome, 1117, 1531 Poiseuille’s equation, 544 Poison(s). See Toxin(s); specific poison. Poliomyelitis, 519 excess daytime sleepiness due to, 192 Poliomyelitis-like syndromes, 519 Polyangiitis, microscopic, 1315 Polyarteritis nodosa classical, 1315 ocular involvement in, 298 vasculitic neuropathy due to, 1119 Polycythemia, 618 Polycythemia vera, 1527-1528 Polymicrogyria genes associated with, 686t neuroimaging of, 665, 667f, 686f Polymyositis associated clinical manifestations of, 12121213 autoantibodies in, 1217 clinical presentation of, 1211-1212, 1212t diagnosis of, 1213-1217, 1214t differential diagnosis of, 1219 immunopathogenesis in, 1216, 1217f muscle biopsy in, 1214, 1215f paraneoplastic, 1370-1371 prognosis of, 1219 treatment of, 1218, 1218t Polyneuropathy(ies) alcoholic, 1541 associated with dietary states, 1123, 14561457 distal diabetic, 1113-1115, 1114f HIV-associated distal symmetric, 1133 inflammatory and demyelinating, 1132, 1268 in systemic lupus erythematosus, 1563-1564 postgastroplasty, 1464 Polyradiculoneuropathy, acute inflammatory demyelinating, 1137 Polyradiculopathy, lumbosacral, CMV-associated, 1133-1134 Polysomnography of Lewy body dementia, 916-917, 918f-919f of obstructive sleep apnea-hypopnea, 206, 207f Pompe’s disease, 1195 Pons, role of, in bladder control, 362 Pontomedullary respiratory generator, 1571 Posaconazole, for mucormycosis, 1291 Positional testing, of balance, 323-324, 325 Positioning testing, of balance, 325 Positive pressure ventilation for amyotrophic lateral sclerosis, 871 for central sleep apnea, 210 Positron emission tomography (PET) of brain in Alzheimer’s disease, 853, 855f of multiple system atrophy, 382, 966

Positron emission tomography (PET) (Continued) of Parkinson’s disease, 939 of progressive supranuclear palsy, 971-972 of Wilson’s disease, 1448 Postanoxic myoclonus, 437, 438t Postapoplectic dementia, 635 Postcoma responsiveness, 117 Posterior fossa tumors of, 347 veins of, 621-622 Postgastrectomy neuropathy, 1123 Postgastroplasty polyneuropathy, 1464 Postherpetic neuralgia, definition of, 1136 Postinfectious encephalitis, 1255 Postinfectious encephalomyelitis, 1057, 1059t Postpolio syndrome excess daytime sleepiness due to, 192 vs. amyotrophic lateral sclerosis, 863 Poststroke fatigue, 653 Posttraumatic epilepsy, 697-698. See also Epilepsy. Post-traumatic syndrome, 1395 Postural control, poor, rehabilitation strategies for, 1427 Postural control testing, of balance, 324 Postural instability, in normal-pressure hydrocephalus, 830 Postural tremor, 417 Posture tetanus, 355t Posturography, computerized dynamic, 326 Postvaccination encephalomyelitis, 1057, 1059t Potassium, in cerebral circulation regulation, 546 Powassan encephalitis, 1250 Practice effects, in repeated testing of executive function, 86 Pralidoxime, for organophosphate insecticide toxicity, 1485 Pramipexole for REM sleep behavior disorder, 198 for restless leg syndrome, 482t Praziquantel for gnathostomiasis, 1286 for schistosomiasis, 1288 Prednisolone for autoimmune inner ear disease, 345 for cerebral vasculitis, 1319 for giant cell arteritis, 1320 for myasthenia gravis, 1230t prophylactic, for cluster headache, 780-781 Prednisone for early-stage neurosarcoidosis, 1308 for giant cell arteritis, 798 for medication overdose–headache, 767 for schistosomiasis, 1288 for vasculitis, 1119 Preeclampsia-eclampsia, 1497-1499 clinical presentation of, 1499 diagnosis of, 1499 epidemiology of, 1497 management of, 1499 pathophysiology of, 1497, 1498f, 1499 Pre-emergency room management, of ischemic stroke, 569 Prefrontal circuit, dorsolateral, in executive function, 85 Pregabalin, for partial and tonic-clonic seizures, 709 Pregnancy arteriovenous malformations and, management of, 1496-1497 coagulability changes in, 1492, 1492t epilepsy in, 1499-1501 consequences of, 1499-1500 management of, 1500-1501

1615

Pregnancy (Continued) fluid, hemodynamic, cardiovascular, and endothelial changes in, 1491-1492, 1492f hormonal changes in, 1490-1491, 1491f idiopathic intracranial hypertension in, management of, 812 immune changes in, 1493 migraine in, 1493-1494, 1493t multiple sclerosis in, 1501 myasthenia gravis in, 1501 physiology of, 1490-1493 preeclampsia-eclampsia in, 1497-1499 clinical presentation of, 1499 diagnosis of, 1499 epidemiology of, 1497 management of, 1499 pathophysiology of, 1497, 1498f, 1499 risk of thrombosis in, 1531-1532 stroke in, 1494-1497 clinical presentation of, 1496 epidemiology of, 1494-1495 management of, 1496-1497 pathophysiology of, 1495-1496 prognosis of, 1497 toxemia of, 716-717 Prehospital management, of spinal trauma, 1404 Presbycusis, physiological mechanisms contributing to, 332 Pressure palsy hereditary neuropathy with liability to, 1100 inheritance pattern in, 1101 in multiple sclerosis, 1022 Pressure ulcers, rehabilitation strategies for, 1431 Pressure-flow relationships, in cerebral circulation, 543-544 PRESTO study, of Parkinson’s disease, 944 Presyncope states, vs. epileptic seizures, 696 Primary angiitis of central nervous system, 1314-1315 headache secondary to, 798-799 Primary progressive aphasia, 38 Primary torsion dystonia early-onset, 444, 445t focal, 444-446 Primidone for myoclonus, 442t for partial and tonic-clonic seizures, 710 for tremor, 421, 421t, 422t Prion diseases, 1297-1301. See also specific disease, e.g., Creutzfeldt-Jakob disease. characteristics of, 1298t clinical features of, 1299-1301 epidemiology of, 1297-1299 etiology and pathogenesis of, 1297 human and animal, 1298t treatment of, 1301 Prism adaptation therapy, for spatial neglect, 80, 81f PRNP gene in prion diseases, 1297, 1298 screening for, 1299 Progesterone, in pregnancy, 1490, 1491f Progressive aphasia, primary, 38, 983 Progressive multifocal leukoencephalopathy clinical features of, 1060 definition of, 1060 epidemiology of, 1060 pathology and pathogenesis of, 1060-1061, 1061f treatment of, 1061-1062 Progressive myoclonus epilepsy, 437, 438t, 439t, 706. See also Epilepsy. assessment of, 705 genetics of, 685, 685t

1616

Index

Progressive nonfluent aphasia, 38, 984t. See also Aphasia, nonfluent. case study of, 987, 989f Progressive prosopagnosia, case study of, 989991, 992f Progressive supranuclear palsy, 968-973, 968t ancillary investigations of, 969-970 cerebrospinal fluid studies in, 970 classification of, 970t clinical presentation, course, and prognosis of, 968-969, 969t, 970t cognitive disturbances in, management of, 939 diagnostic criteria for, 969, 970t epidemiology of, 968 functional imaging of, 971-972 genetic factors in, 969 magnetic resonance imaging of, 970-971, 971f management of practical, 939 principles of, 972-973 neurophysiology of, 972 oculomotor disturbances in, management of, 938-939 parkinsonism in, 936t, 969 management of, 938 vs. Parkinson’s disease, 938 Progressive systemic sclerosis, 1558-1559 Prolactin, 1552-1553 as marker of epileptic seizures, 697 source and function of, 1550t Prolactinoma, diagnosis of, 1552 Prolyse in Acute Cerebral Thromboembolism Trial (PROACT), 573 Propionibacterium acnes, in neurosarcoidosis, 1303 Propionibacterium granulosum, in neurosarcoidosis, 1303 Propofol, for status epilepticus, 726 Propranolol, for tremor, 419, 421, 421t, 422t Propriospinal myoclonus, 437, 437t Prosody, 159 Prosopagnosia, 13, 61, 61t, 62-63, 63f after infarction, 564 progressive, case study of, 989-991, 992f screening for, 67t Prosthesis, for speech disorders, 161 Prosthetic valves, embolization of, 578 Protein disorders, retinopathy and optic neuropathy associated with, 280-281 Protein mutations, in limb girdle muscular dystrophy, 1148 Protein S-100, serum astroglial, as marker in vegetative state, 123 Prothrombotic state, 609 Protriptyline, prophylactic, for migraine, 748 PRX gene, in inherited neuropathies, 1104 PSEN1 gene, in early-onset Alzheimer’s disease, 848t PSEN2 gene, in early-onset Alzheimer’s disease, 848t Pseudobulbar effect, in amyotrophic lateral sclerosis, 861 Pseudobulbar palsy, corticobulbar tract lesions and, 155-156, 158, 158t Pseudodeficiency genes, in metachromatic leukodystrophy, 1070 Psychiatric disorders after stroke, management of, 653 memory impairment in, 55 Psychiatric factors, in Alzheimer’s disease, 852 Psychiatric history, in mental status assessment, 9 Psychic paresis of gaze, 64 Psychogenic aphonia, 159

Psychogenic dystonia, 447-448 Psychogenic nonepileptic seizures. See also Seizure(s). impaired consciousness in, differential diagnosis of, 695-696 loss of consciousness in differential diagnosis of, 695 in conversion syndrome, 252, 252t Psychogenic spasmodic dysphonia, 159, 160f Psychogenic tremor, 427 Psychometrics basic principles of, 23-27 ceiling and floor effects in, 24, 25f decision theory in, 26, 27t practice effects in, 24, 25f symptom validity testing in, 24 test reliability in, 23 test validity in, 23-24 tests scores in, reporting of, 25-26, 26f Psychosis in Alzheimer’s disease, 852 in systemic lupus erythematosus, 1563 schizophrenia-like, 228-229 Psychostimulants for apathy, 243 for gait disturbances, 468 intoxication and withdrawal of, 1537 PTEN-induced kinase 1 (PINK1) gene, in Parkinson’s disease, 928t, 931 Ptosis aponeurotic, 271 myopathic, 271 neurogenic, 271 Pudendal evoked responses, in sexual function, 367 Pulfrich phenomenon, in multiple sclerosis, 1019 Punch drunk syndrome, 1388, 1395 Pupil(s) dilatation of, 269 examination of, in comatose patient, 101 Marcus Gunn, 1018, 1018f pharmacological testing of, 270, 270f, 271f reaction of, to light, 269 Pupillary defects in multiple sclerosis, 1018, 1018f relative afferent, 269-270 Pupillography, 270 Pure autonomic failure clinical presentation of, 375-376 differential diagnosis of, 376 Pure motor hemiparesis, 556, 556t Pure sensory stroke, 556-557, 556t Pure word deafness, 36 Pure-tone audiometry, 319-320 Pure-tone average, in hearing sensitivity, 320 Pyrazinamide, for tuberculous meningitis, 1244t Pyrethroid pesticides, associated with Parkinson’s disease, 933-934 Pyridoxine deficiency of, 1462 polyneuropathy associated with, 1123 for West’s syndrome, 713 for Wilson’s disease, 1450 Pyridoxine toxicity neuropathy, 1464 Pyruvate carboxylase deficiency, 1440 Pyruvate dehydrogenase deficiency, 1440

Q Quadrantinopia, upper, due to temporal infarction, 263f Qualia, 97 Quetiapine, for severe agitation, 856 Quinidine, for falciparum malaria, 1285

Quinine dihydrochloride, for falciparum malaria, 1285

R RAB7 gene, in inherited neuropathies, 1104 Rabies, encephalitic form of, 1254-1255, 1254f Rabies vaccination, encephalomyelitis after, 1059t Radiation injury, to peripheral nerves, 1417, 1417f Radiation necrosis, 1357, 1357f Radiation therapy cranial, neurological complications of, 13561358 early side effects in, 1356, 1356f late side effects in, 1356-1358, 1357f, 1358f for brain tumors, 1331-1332, 1332f for gliomas, 1335 for malignant glioma, 1335 for metastatic epidural spinal cord compression, 533-534 for spinal cord tumors, 1349 optic neuropathy due to, 292-293, 293f spinal cord/plexus, neurological complications of, 1359-1360, 1359f Radicular syndrome, 513t Radiculoneuritis, painful, in Lyme disease, 1135 Radiofrequency retrogasserian rhizotomy, for trigeminal neuralgia, 839 Radiography, of peripheral nerve tumors, 1375, 1376f Radioisotope cisternography, of cerebrospinal fluid leaks, 818, 819f Radiosurgery gamma knife, for trigeminal neuralgia, 838 stereotactic, for brain arteriovenous malformations, 602 R-alleles, in metachromatic leukodystrophy mutations, 1070 Ramipril, for blood pressure control, 569 Ramsay-Hunt syndrome, 342, 1136 Rankin scale, of stroke, 570, 570t Rapid eye movement (REM) behavior disorder, in Parkinson’s disease, 936 Rapid eye movement (REM) sleep. See also Sleep entries. altered thermoregulation during, 181 behavior disorder of, 198 clinical features of, 913t in Lewy body dementia, 913, 913t treatment of, 922t, 923 in Parkinson’s disease, 192 treatment of, 384t, 385-386 breathing during, 181 dysregulation of, in narcolepsy, 193-194 electrophysiology of, 179-180 sympathetic activity during, 181 Rasagiline, for Parkinson’s disease, 944 Rating scales in assessment of gait, 460 neurobehavioral, 10, 10t Reading comprehension, testing of, 12 Reading disorders, acquired, 39-40 REAL-PET ropinirole study, of Parkinson’s disease, 949-950 Recanalization strategies, for ischemic stroke, 570-574 Recent memory, testing of, 13, 14t Recombinant factor VIIa, reversal of anticoagulant effects with, 1391-1392 Recombinant tissue plasminogen activator. See also Thrombolysis. for stroke, 570, 571t

index Red fibers, of muscle, 1096 Reflex(es) absent, in brain death, 108, 108t, 109t acoustic, 320-321 Cushing’s, 99 cutaneous, 514t gag, 155 Hering-Breuer, 1571 ocular, in comatose patient, 101-102 primitive, in executive function assessment, 91 swallow, 164 vestibulo-ocular, 272, 323 Reflex seizures, 677. See also Seizure(s). Refractory status epilepticus. See also Status epilepticus. management of, 725-726 Refsum’s disease, 890 infantile, 281 Rehabilitation after stroke, 645-654 complex organizational interventions in, 645-649, 646f, 646t, 647f, 647t future developments in, 653-654 goals in, 645, 646t management of neurological impairments in, 649-652, 650f management of systemic complications in, 652-653 outpatient or domiciliary, 648-649 apraxia, approaches to, 412 for gait disturbances, 466, 467t for neurological injury, 1423-1432 activities of daily living and, 1426-1428 acute illness and, 1423, 1425, 1425t adaptive equipment in, 1428, 1428f-1430f, 1428t, 1430t assessment scales in, 1423, 1424f, 1425f, 1425t, 1426t balance, coordination, and neuromuscular reeducation in, 1427 common issue(s) in, 1429-1431 autonomic hyperreflexia as, 1431 communication as, 1431 dysphagia as, 1431 heterotopic ossification as, 1431 neurogenic bladder as, 1430-1431 neurogenic bowel as, 1430 pressure ulcers as, 1431 spasticity as, 1429, 1430t flexibility exercises in, 1425, 1427 fundamental interventions in, 1425, 14261428 gait improvement in, 1427 initial evaluation in, 1423, 1424t mobility improvement in, 1426 strengthening exercises in, 1426 framework for, in conversion syndrome, 255 vestibular, 349 Relative afferent pupillary defect, 269-370 grading of, 270 Release signs, in executive function assessment, 91 Relevant history, in mental status assessment, 9-10 Reliability coefficient, of tests, 23 Religious attitudes, toward brain death, 113 REM. See Rapid eye movement (REM) entries. Remote memory, testing of, 13-14, 14t Remyelination, in multiple sclerosis, 1003-1004 Renal disease retinopathy/optic neuropathy associated with, 283 venous thrombosis in, 618-619 Renal failure, illicit drugs causing, 1539 Renal-colomba syndrome, congenital, 278-279

REP-1 gene, in choroideremia, 278 Repetition, testing of, 12 Repetition conduction aphasia, 36 Representational neglect, 74-75. See also Neglect syndrome. Reproduction conduction aphasia, 36 Resective surgery, for epilepsy, 717-718 Reserpine, for Huntington’s disease, 884 Resolution phase, of migraine, 742 Respiration acid-base balance and, 1575 apneustic, 100, 1572 ataxic, 100, 1572 chemical regulation of, 1571 Cheyne-Stokes, 100, 1572 cluster, 100 lower motor components of, 1569, 1571 neural control of, 1569, 1570f, 1571 upper motor components of, 1571 Respiratory activity, during sleep states, 181 Respiratory chain disease, mitochondrial, 12041207, 1206f Respiratory disorders assorted, 1573 automatic, 1573 sleep-related. See also Sleep apnea entries. international classification of, 186t voluntary, 1573 Respiratory failure, 1571-1572, 1572t Respiratory impairment in amyotrophic lateral sclerosis, 861-862, 862t in congenital myopathy, 1169 in multiple sclerosis, 1020 in neurological disease, 1571-1573, 1572t Respiratory insufficiency, neurological consequences of, 1573-1575 Respiratory muscle weakness, in amyotrophic lateral sclerosis, 862t management of, 872t Respiratory patterns in comatose patient, 100 in sleep states and wakefulness, 181 Respiratory stimulants, for central sleep apnea, 209 Resting hand tremor, in Parkinson’s disease, 936 Resting tremor, 417 Restless leg syndrome, 471-482, 1525 clinical features of, 471 definition of, 471 diagnostic criteria for, 473-474, 473t differential diagnosis of, 476, 476t dopaminergic function in, 472 epidemiology of, 471-472 evaluation of blood tests in, 475 electrophysiological studies in, 475 levodopa test in, 475-476 medical history in, 474-475, 474t polysomnographic recordings in, 475 severity assessment in, 476, 477f-479f, 480f iron metabolism in, 472 location of dysfunction in, 473 pathophysiology of, 472-473 primary, 472 role of nociceptive system in, 472-473 secondary, 472 treatment of, 481-482, 482t Restless Leg Syndrome-6 Rating Scales, 476, 480f Reticular reflex myoclonus, 437, 437t Retina, anatomy of, 295 Retinal detachment, deposits associated with, 303, 304f

1617

Retinal disease, 295-310 blindness due to childhood and adulthood onset of, 277-278, 278f congenital, 275-277, 276f, 277f cerebrovascular, 307-310, 308f, 309f in movement disorders, 305, 305f in multiple sclerosis, 298-299, 299f in muscular dystrophy, 305-306 in neurofibromatosis, 306 in Sturge-Weber syndrome, 306 in tuberous sclerosis, 306, 306f in von Hippel–Lindau disease, 306, 307f in Wyburn-Mason syndrome, 307, 307f infectious, 299-302, 300f-303f inflammatory, 295 metabolic, 310 mitochondrial, 303, 303f neoplastic, 303-305, 304f rheumatologic, 297-298, 297f uveomeningeal, 295-297, 296f, 297f Retinal hemorrhage, associated with subarachnoid hemorrhage, 309-310, 309f Retinal vasculitis, and stroke, 308 Retinitis cytomegalovirus-associated, 298, 298f, 301 in HIV infection, 301 paraneoplastic optic neuritis with, 305 toxoplasmosis, 302, 302f Retinitis pigmentosa, 277, 303, 303f Retinopathy associated with dermatological, skeletal, ocular, and renal disease, 282-283 associated with systemic and neurodegenerative disease, 280-282, 281f carcinoma-associated, 304 melanoma-associated, 304-305, 1371 necrotizing herpetic, 301-302 pigmentary, 303 stroke-associated, 307 venous stasis, 308 Retinoschisis, juvenile, 277 Retrograde amnesia, 44, 44f Retropulsion test, of balance, 459 Retrosplenial cortex, lesions of, memory impairment associated with, 50, 50f Rhabdomyolysis, illicit drugs causing, 1539 Rheumatoid arthritis, 1559-1561 corneal and scleral changes associated with, 297, 297f Rheumatoid disease, seropositive, 1316 Rhizotomy percutaneous glycerol retrogasserian, for trigeminal neuralgia, 838-839 radiofrequency retrogasserian, for trigeminal neuralgia, 839 Rhodopsin gene in congenital stationary night blindness, 278 in retinitis pimentosa, 277 Rhythmic myoclonus, 428 Ribose-5-phosphate isomerase deficiency, 10821083 Rifampin for leprosy, 1132 for tuberculous meningitis, 1244t prophylactic, for bacterial meningitis, 1243t Rigidity in Parkinson’s disease, 936 in Wilson disease, 1447 Riluzole, for amyotrophic lateral sclerosis, 868 Rinne test, for hearing, 319 Risperidone for autism, 135 for Huntington’s disease, 883 Rivastigmine, for Alzheimer’s disease, 854t Rizatriptan, for migraine, 745t, 746

1618

Index

Rods, retinal, 295 Romberg test, of balance Ropinirole, for restless leg syndrome, 482t Rotational chair testing, of balance, 325-326 Rotenone pesticide, associated with Parkinson’s disease, 933 Rotigotine, for restless leg syndrome, 482t Roussy-Levy syndrome, 427, 1101 RYR1 gene in central core disease and malignant hyperthermia susceptibility, 1172-1173 in congenital myopathies, 1168, 1170 in multi-minicore disease, 1174

S Saccades, examination of, 272 Saccular aneurysm, 587 location of, 588 Sacral agenesis, 504-505, 505f definition of, 504 Sacral reflex testing, of sexual dysfunction, 367 Safety issues, in Alzheimer’s disease, 855-856 St. Louis encephalitis, 1250, 1254 St. Vitus’s Dance, 879. See also Huntington’s disease. Saposin B deficiency, in metachromatic leukodystrophy, 1070 Sarcoidosis nervous system involvement in, 1316 neurological involvement in. See also Neurosarcoidosis. assessment of, 1307 pathology of, 1307 retinal involvement in, 296, 296f spinal cord, 534 systemic, assessment of, 1307 treatment approaches to, 1307 Sarcolemma, 1095 Sarcomeres, 1095, 1096f Sarcopenia, 1097 SBF2 (sey binding factor 2), 1104 SBF2 gene, in inherited neuropathies, 1104 Schaltenbrand’s headache, 817 Schistosoma haematobium, 1286, 1287 Schistosoma japonica, 1286 Schistosoma mansoni, 1286, 1287 Schistosomiasis, 1286-1288, 1287f Schizencephaly genes associated with, 664, 686t neuroimaging of, 665-666, 667f Schizophrenia, 223-228 blunting of affect in, 6 clinical features of, 223 cognitive deficits in, 223-224 delusions in, 7 epidemiology of, 223 genetic studies of, 224, 225f neurochemistry of, 225-226 neuropathology of, 224-225, 226f pathophysiology of, 226-227 symptoms of, 224t treatment of drug, 227 psychological, 228 Schizophrenia-like psychosis, 228-229 Schwannoma benign, 1376-1378 clinical features of, 1378, 1379f of spinal cord, 531, 1347f pathology of, 1377, 1378f vestibular (acoustic neuroma), 1338 Schwannosis, in spinal cord injury, 1403

Scintigraphy of brain death, 111, 111f of multiple system atrophy, 967 Scleroderma (progressive systemic sclerosis), 1558-1559 Sclerotome, 488 SCN4A gene, in sodium channel disorders, 1190 Scoliosis, 489t, 492 spina bifida with, 493f spinal dysraphism with, 502f Scorpion toxins, 1485 Scotoma arcuate, due to glaucoma, 267f centrocaecal, due to toxic amblyopia, 266f Sedatives, intoxication and withdrawal of, 1538 Seddon’s classification, of nerve injury, 14101411, 1410t Segawa disease (dopa-responsive dystonia), 446, 1439-1440 Segmental spinal myoclonus, 437, 437t Seizure(s). See also Epilepsy. abnormal sensations with preserved consciousness in, 696-697 after organ transplantation, 1565, 1565t alcohol and drug withdrawal–related, treatment of, 714 and circadian rhythm, 193 autoimmune and endocrinological, 705-706 chemotherapy-induced, 1354 differential diagnosis of, 694-695 drug abuse causing, 1538 due to neurocysticercosis, antiepileptic treatment for, 1285f effect of, on sleep, 193, 193t epileptic, 675-677 absence, 675, 695 childhood, 703 atonic, 675-676, 694 biological markers of, 697 brain tumors and, 1326 clonic, 675, 694 definition of, 673 generalized, 675 in pregnancy consequences of, 1499-1500 effect of frequency of, 1499 management of, 1500-1501 myoclonic, 675 partial, 676-677. See also Partial seizures. reflex, 677 tonic, 675, 694 unclassified, 677 validating core features of, 692-693 ethanol-related, 1540 febrile, 678 complicated, 697 generalized epilepsy with, 679 genetics of, 682, 683t genetics of, 685, 687 impaired consciousness in, 695-696 in brain arteriovenous malformations, 600 treatment after, 601-602 in cerebral vein and sinus thrombosis, 624 in conversion syndrome, 252, 252t in HIV infection, 1269 in inflammatory bowel disease, 1515 in multiple sclerosis, 1017 in systemic lupus erythematosus, 1563 international classification of, 674, 674t loss of consciousness associated with, 694-695 neonatal, treatment of, 713 occasional, 704-705, 706 post-traumatic, 1394 precipitating factors in, search for, 692

Seizure(s) (Continued) psychogenic nonepileptic impaired consciousness in, 695-696 loss of consciousness in, 695 simulated, 695 types of, diagnosis of, 692-697 witness accounts of, 693-694 Seizure episodes, 692 classification of, 694 investigation of, 692 laboratory investigation of, 697 Selective serotonin reuptake inhibitors for autism, 135 for depression, 239 Selegiline, for Parkinson’s disease, 943-944 Semantic dementia, 38, 984t case study of, 987-989, 990f Semantic (category) fluency, 89 Semantic memory, 43-44 Senile plaques, in Alzheimer’s disease, 849-850, 849f Sensorimotor demyelinating neuropathy, multifocal, 1118-1119 Sensorimotor spinal tract syndrome, 513t Sensorimotor syndrome, stroke associated with, 556t, 557 Sensorineural hearing loss, 318. See also Hearing loss. acoustic reflex in, 321 causes of, 332-333 sudden, 333 Sensory chronic inflammatory demyelinating neuropathy, 1117 Sensory disturbances, in conversion syndrome, 252-253 Sensory extinction, 73-74 Sensory loss in multiple sclerosis, 1020 spinal cord tumors causing, 1342-1343 Sensory neglect, 73. See also Neglect syndrome. examination of, 75 pathophysiology of, 78-79, 78f, 79f Sensory neuropathy HIV-associated, 1267-1268, 1267t paraneoplastic, 1369, 1369f Sentence frames, 32 SEPN1 gene, in multi-minicore disease, 1174 Septal veins, anatomy of, 621 Serotonin (5-HT) agonists, selective, for migraine, 745-746, 745t Serotonin (5-HT) antagonists, prophylactic for chronic daily headache, 768t for migraine, 749 Serotonin (5-HT) receptors, for migraine therapy, 741 Serum astroglial S-100 protein, as marker in vegetative state, 123 Serum neuron-specific enolase, as marker in vegetative state, 123 Severe myoclonus epilepsy in infancy, 678. See also Epilepsy. genetics of, 682-683, 683t Sexual drive, assessment of, 8 Sexual dysfunction diagnostic testing of, 366-367, 367t in multiple sclerosis, 1022 treatment of, 1051 in Parkinson’s disease, 937 management of, 947 neurological diseases and, 367 treatment of, 367-368, 368t Sexual function, 366-368 neuroanatomy and neurophysiology of, 366 Sey binding factor 2 (SBF2), 1104 Shingles, complications of, 1317 Shock, neurogenic vs. spinal, 1403

index Short-chain 3-hydroxyacyl–coenzyme A dehydrogenase deficiency, 1200 Short-chain acyl–coenzyme A dehydrogenase deficiency, 1200 Short-chain thiolase deficiency, 1200 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) brain imaging of, 774, 775f in trigeminal automatic cephalgias, 784, 784t clinical features of, 775t diagnostic criteria for, 776t secondary, 784-785 vs. trigeminal neuralgia, 837 Short-term memory, 45, 98 Shunt(s) for gait disturbances, 468 for hydrocephalus, 828, 830f complications of, 828-829 normal-pressure, 831 for relapsing-remitting neurosarcoidosis, 1309 Sialidosis, 705 Sialorrhea, in amyotrophic lateral sclerosis, management of, 872 Sickle cell anemia, 1527 venous thrombosis associated with, 618 Sickle cell trait, 1527 Signaling, genes associated with, 1104 SIMPLE gene, in inherited neuropathies, 1104 Simple partial seizures, 676. See also Seizure(s). abnormal sensations with preserved consciousness in, 696 differential diagnosis of, 696-697 Simple partial status epilepticus, 720-721. See also Status epilepticus. Simulated seizures. See also Seizure(s). loss of consciousness in, 695 Simultanagnosia, 64, 64t Simvastatin, for hypercholesterolemia, 580 Single-photon emission computed tomography (SPECT) of multiple system atrophy, 382, 966-967 of Parkinson’s disease, 13f, 938-939 of progressive supranuclear palsy, 971-972 Sinus(es), dural, anatomy of, 622-623, 622f, 624f Sinus arrhythmia (SA) ratio, 355t Sinus headache, 801-802 Sinus thrombosis, cerebral venous, 621-630. See also Venous thrombosis, cerebral. Sjögren-Larsson syndrome, 1079-1080 Sjögren’s syndrome, primary, 1557-1558 Skeletal anomalies, retinopathy/optic neuropathy associated with, 282-283 Skeletal muscle. See Muscle(s), striated. Skull fracture, 1390, 1391f Sleep deprivation of, seizures associated with, 704 disorders of, 185-198. See also specific disorder, e.g., Insomnia. in Parkinson’s disease, 937 international classification of, 185, 186t187t drowsy, 180 effect of on interictal discharges, 193 on seizures, 193 nature of, 180-181 neurobiological control of, 182-183 non–rapid eye movement. See Non–rapid eye movement (NREM) sleep. periodic limb movements in, 189-190, 190f, 471, 474 physiologic function during, 181

Sleep (Continued) rapid eye movement. See Rapid eye movement (REM) sleep. regulation of, 181-182 slow-wave, 180 transitional, 180 Sleep apnea central, 207-210, 208f etiology and pathogenesis of, 208-209 morbidity and mortality in, 209 prevalence of, 209 treatment of, 209-210 obstructive, 1573 headache secondary to, 802, 802t Sleep apnea-hypopnea, obstructive, 203-207 clinical manifestations/sequelae of, 204-206, 207f diagnosis of, 206, 207f epidemiology of, 203 history of, 206 pathophysiology of, 203-204, 205f treatment of, 206-207, 208f Sleep disturbances in Alzheimer’s disease, 852 in amyotrophic lateral sclerosis, 862 management of, 871-872 in multiple sclerosis, 1017 in restless leg syndrome, 474 Sleep phase syndrome advanced, 196 delayed, 195-196 Sleep terrors, 197 treatment of, 198 Sleepiness, excessive daytime, 190-193. See also Daytime sleepiness, excessive. Sleeping sickness, 1273, 1275 treatment of, 1275, 1276t Sleep-wake regulation, impaired, multiple sclerosis plaques causing, 191 Sleepwalking, 197 treatment of, 198 Slit-ventricle syndrome, shunting causing, 828, 830f Slow channel syndrome, 1232t Small fiber neuropathy, 1115-1116, 1116f, 1116t Small-vessel vasculitis, 1316 Smell, disorders of, 171-175. See also Olfactory dysfunction. Smell tests, for Lewy body dementia, 918 Smith-Lemli-Opitz syndrome, 1442-1443 Smith’s disease, 887, 891 SMN1 gene, in encephalopathies, 1435 Snake toxins, 1485 Snellen chart, 260 Social disinhibition, 8 Social sequelae, of delirium, 143 Sodium channel disorders, 1189-1190 Sodium chloride, for orthostatic hypotension, 359t Sodium valproate, for myoclonus, 442t Somatogenesis, 488 Somatomotor seizures, 676. See also Seizure(s). Somatosensory evoked potentials in brain death, 111-112 in comatose patient, 106 in multiple sclerosis, 1033, 1033f in myoclonus, 440-441, 440t in vegetative state, 120, 122, 122f, 123f Somatosensory seizures, 676. See also seizure(s). Somatosensory status epilepticus, 721. See also Status epilepticus. Somatostatin receptor antagonists, for cluster headache, 778-779 Somnolence, excessive daytime. See Daytime sleepiness, excessive.

1619

Spasm(s) arterial, 615 muscle, in Wilson’s disease, 1447 Spasmodic dysphonia, 159 psychogenic, 159, 160f Spasmodic torticollis (cervical dystonia), 445 Spastic diplegia, in cerebral palsy, 1577 Spastic dysarthria, 158, 158t Spastic hemiplegia, in cerebral palsy, 1577 Spastic paraparesis, tropical, 518-519 Spastic paraplegia complicated, 1073 hereditary, 508, 508t, 899-906. See also Hereditary spastic paraplegia. pure, 1073 Spasticity after stroke, management of, 650 impaired sleep due to, 191 in amyotrophic lateral sclerosis, management of, 871 in multiple sclerosis, 1022 treatment of, 1049-1050, 1050t rehabilitation strategies for, 1429, 1430t Spatial neglect, 74, 74f. See also Neglect syndrome. examination of, 75-76, 76f treatment of, 80, 81f Spatial relations, impaired, 64, 64t screening for, 67t SPECT. See Single-photon emission computed tomography (SPECT). Speech anatomy associated with, 155-156 corticobulbar tract in, 155, 156f cranial nerves in, 155, 157f assessment of, 6 clinical assessment of, 159-160 empty, 33 Speech audiometry, 320 Speech detection threshold, 320 Speech discrimination score, 320 Speech disorder(s), 156-159 apraxia as, 156-157 cerebellar, 158-159 dysarthrias as, 157-158 mixed, 159 dysphonia as, 159 extrapyramidal, 159 lower motor neuron lesions causing, 158, 158t management of, 160-161 nonorganic, 159 psychogenic aphonia as, 159 rehabilitation strategies for, 1431 upper motor neuron lesions causing, 158, 158t Speech dyspraxia (aphemia), 34, 34t neuroanatomy of, 34 Speech reception threshold, 320 SPG genes, in hereditary spastic paraplegia, 899, 900t-901t SPG4 gene, genetic anticipation in, 903 Sphincter bradykinesia, in Parkinson’s disease, 364 Sphincter electromyography, of multiple system atrophy, 964 Spider venom, 1485 Spina bifida classification of, 495, 496f closed, 495 cutaneous manifestations of, 495-496 functional outcomes in, 496 late complications of, 497 management of, 498-499, 498f open, 495 orthopedic abnormalities in, 497

1620

Index

Spina bifida (Continued) prognosis of, 497 scoliosis in patient with, 493f urological abnormalities in, 496-497 Spina bifida aperta, 495 Spina bifida cystica, 495, 496f Spina bifida occulta, 495, 496f Spinal agenesis, distal, 504 Spinal cord anatomy of, 511, 512f arteriovenous malformations of, 602-607. See also Arteriovenous malformations, of spinal cord. blood supply to, 542-543 cross-section of, 1343f involvement of, in restless leg syndrome, 473 malformations of clinical features of, 503 definitions of, 502-503 management of, 503, 504f tethered. See Tethered cord syndrome. Spinal cord abscess, intramedullary, 520 Spinal cord angiography, of arteriovenous malformations, 606 Spinal cord compression metastatic epidural, 532-534 clinical features of, 532 epidemiology of, 532, 532t identification of, 532, 533f prognosis of, 534 radiotherapy for, 533-534 surgery for, 534 systemic corticosteroids for, 532 nonneoplastic, 534 Spinal cord disorders back and neck pain in, 511 degenerative, 522-525. See also specific disorder, e.g., Syringomyelia. developmental, 488, 489t, 492-505. See also specific disorder, e.g., Chiari malformation. imaging of, 511-512 red flag features indicative of, 513t vitamin B12 deficiency causing, 1526 Spinal cord infarction, in sickle cell anemia, 1527 Spinal cord infections, 512, 515-522, 515t. See also Myelitis. parasitic, 521 viral, 516-518 Spinal cord injury, 1397-1407 anatomy of, 1398-1401 ASIA classification of, 1423, 1424f ASIA impairment scale of, 1423, 1425f bladder dysfunction after, 365 cervical, 1398-1399, 1398f, 1399f coexisting traumatic brain injury and, 1392 histology of, 1401-1403 acute phase in, 1401-1402 immediate phase in, 1401 intermediate phase in, 1402 late phase in, 1402-1403 lumbar, 1400-1401, 1401f penetrating, 1403-1404 sexual dysfunction in, 367 thoracic, 1400, 1400f without radiographic abnormality, 1404 Spinal cord nerves, peripheral in bladder control, 362-363 in sexual function, 366 Spinal cord sarcoidosis, 534 Spinal cord syndromes, 513t, 1403-1404, 1403f. See also specific syndrome.

Spinal cord tumor(s), 526-531, 1341-1350. See also specific tumor, e.g., Astrocytoma. angiography of, 1345 cerebrospinal fluid studies in, 1345 clinical features of, 526-527, 1341-1343, 1343f computed tomography of, 1343-1344 diagnosis of, 1343-1345 differential diagnosis of, 1343, 1343t epidemiology of, 526, 1341, 1342f, 1342t extradural, 1341, 1342f, 1342t extramedullary, 526t, 530-531, 531f, 1341, 1342f, 1342t glial, 527-530, 528t, 529f imaging of, 527 intramedullary, 526t, 527-530, 1341, 1342f, 1342t, 1367 magnetic resonance imaging of, 1344-1345, 1344f-1348f management of, 527 chemotherapy in, 1349 radiation therapy in, 1349 surgical, 1345-1346, 1349 metastatic, 530 nonglial, 530 outcome for, 1349-1350 radiography of, 1343 Spinal dysgenesis, 504 Spinal dysraphism, 499 with scoliosis, 502f Spinal epidural abscess, 519-520, 520t, 521f Spinal meningitis, 521-522. See also Meningitis. Spinal meningomyelitis, 521-522 Spinal muscular atrophy, 508-509, 508t adult-onset, vs. amyotrophic lateral sclerosis, 862 Spinal myoclonus, 437, 437t Spinal osteomyelitis, 521 Spinal reflexes, after brainstem death, 109 Spinal shock, 1403 Spinal trauma, 1397-1407. See also Spinal cord injury; Spinal cord syndromes. bony level of injury in, 1397 definitions of, 1397, 1398t epidemiology of, 1397 incomplete of injury in, 1397 management of, 1404-1407 imaging in, 1404 in emergency department, 1404 pharmacological, 1405-1406 new agents in, 1406 prehospital, 1404 spine immobilization in, 1404 surgical, 1405, 1405f transplantation strategies in, 1406-1407 neurologic level of injury in, 1397, 1398t Spine cervical. See also Cervical entries. injury to, 1398-1399, 1398f, 1399f rheumatoid arthritis affecting, 1559-1561, 1560f deformities of, in congenital myopathy, 1169 developmental disorders of, 488, 489-492, 489t. See also specific disorder, e.g., Scoliosis. immobilization of, 1404 lumbar. See also Lumbar; Lumbo- entries. degenerative disk disease of, 524-525, 525t, 526f injury to, 1400-1401, 1401f thoracic, injury to, 1400, 1400f Spinobulbar neuronopathy, vs. amyotrophic lateral sclerosis, 862 Spinocerebellar ataxia imaging of, 893, 895f treatment of, 895

Spinocerebellar ataxia (Continued) types of, 890-891 vs. vitamin E deficiency, 1463, 1463f Spondyloarthropathy(ies), inflammatory, 1561 Spongiform leukoencephalopathy, illicit drugs causing, 1539 Spontaneous nystagmus, 325 Stabbing headache, idiopathic, vs. trigeminal neuralgia, 837 Stagardt disease, 277, 278f Standardized cognitive assessment instruments, 15-16 Staphylococcus aureus in meningitis, 1237. See also Meningitis, bacterial. in spinal epidural abscess, 519 Startle syndrome, 437 Stasis, venous, 615-616 Statins, toxic neuropathy due to, 1120 Status dystonicus, 452. See also Dystonia. Status epilepticus, 692. See also Epilepsy. classification of, 719-721, 720f, 721f definition of, 719 etiology of, 722 incidence of, 721-722 management of acute, 723-724, 723f new pharmacologic developments in, 726727 pharmacotherapy in, 724-725 mortality rate in, 722 neuronal injury in, pathophysiology of, 722723 nonconvulsive, management of, 727 physiological changes in, 722, 722t refractory, management of, 725-726 Statutory definition, of brain death, 107 Stem cell therapy for amyotrophic lateral sclerosis, 870 for muscular dystrophy, 1160 Stem cell transplantation embryonic and mature, for spinal trauma, 1406-1407 hematopoietic for globoid leukodystrophy, 1073 for X-linked adrenoleukodystrophy, 1068 Stenosis. See at specific anatomic site. Stent (stenting) prophylactic, for ischemic stroke, 581-582 venous, for idiopathic intracranial hypertension, 812 Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, 582 Stenting for Symptomatic Atherosclerotic Lesions in Vertebral and Intracranial Arteries (SSYLVIA) trial, 582 Step width, in locomotion, 457 Stereotactic radiosurgery, for brain arteriovenous malformations, 602 Stereotype(ies), assessment of, 9 Steroids. See also specific agent. for brain tumors, 1333-1334, 1334f for myasthenia gravis, 1228-1229, 1229t, 1230t for traumatic brain injury, 1394 for X-linked adrenoleukodystrophy, 1068 Stickler syndrome, 276, 277f Stiff gait, 464t Stiff-person syndrome, 1368, 1368f Stimulants, for autism, 135 Stop signal task, for attention-deficit hyperactivity disorder, 133 Storage disorders, glycogen clinical features, diagnosis, and management of, 1195-1198

index Storage disorders, glycogen (Continued) glycolytic pathway in, 1195, 1196f neurological features of, 1197t Strachan’s syndrome, 1123, 1464-1465 Straight sinus, anatomy of, 622 Strengthening exercises, in rehabilitation schemes, 1427 Streptococcal infections, Gilles de la Tourette syndrome and, 215 Streptomycin, for tuberculous meningitis, 1244t Stress/damage, oxidative, in Parkinson’s disease, 935, 935t Stretch injury, to peripheral nerves, 1415-1416, 1416f Stria vascularis atrophy, contributing to presbycusis, 332 Stride length, in locomotion, 456 Stride-to-stride fluctuations, of gait timing, 460461, 461f, 462f Stroke after organ transplantation, 1566 apathy in, 243 bladder dysfunction after, 364 chemotherapy-induced, 1354 complications after management of, 646t neurological, 649-652, 650f systemic, 652-653 depression in, 238 excess daytime sleepiness due to, 191 hemorrhagic, in pregnancy pathophysiology of, 1496 treatment of, 1496 in alcoholics, 1542 in drug abusers, 1538-1539 in pregnancy, 1494-1497 clinical presentation of, 1496 epidemiology of, 1494-1495 management of, 1496-1497 pathophysiology of, 1495-1496 prognosis of, 1497 in sickle cell anemia, 1527 in systemic lupus erythematosus, 1562 ischemic, 551-582 arterial, 610 associated with antiphospholipid antibodies, 579 associated with patent foramen ovale, 579 cardioembolic, 554 classification of, 552-556 clinical syndromes of, 556-565 cortical syndromes of, 557-565, 558t-559t anterior circulation in, 557, 558t, 559560 posterior circulation in, 559t, 561-565 cryptogenic, 554-555 definition of, 551 emergency room evaluation of, 569 evaluation of, 565-568 cardioembolic source workup in, 568 cerebral tissue perfusion assessment in, 567-568 CT angiography in, 566 duplex Doppler imaging in, 565-566, 566f laboratory, 568 MR angiography in, 566-567 parenchymal imaging in, 565 transcranial Doppler imaging in, 566, 566f, 567f vascular imaging in, 565 headache secondary to, 793-794 in pregnancy, pathophysiology of, 14951496 inflammation and, 619 lacunar syndromes of, 556-557, 556t

Stroke (Continued) large-artery atherosclerosis causing, 552553 noncardioembolic, 578-579 of other determined cause, 555-556, 555f, 556f pre-emergency room management of, 569 secondary prevention of, 574-582 angioplasty and stenting in, 581-582 anticoagulants in, 576-578 oral, 577-579 antiplatelet therapy in, 574-575 combination, 575-576 aspirin in, 574-575, 575f blood pressure control in, 579-580 carotid endarterectomy in, 581 cholesterol-reducing strategies in, 580 clopidogrel in, 575 aspirin with, 575-576 dipyridamole in, aspirin with, 576 heparin and heparinoids in, 576-577 risk factor control in, 580 small-artery atherosclerosis causing, 553554 subtypes of, 552-556 thromboembolism causing, 610-611, 614f615f tissue perfusion failure in, 552 treatment of, 569-574 adequate oxygenation in, 569 blood pressure management in, 569 combined intravenous and intra-arterial thrombolysis in, 573-574 glycemic control in, 569-570 intra-arterial thrombolysis in, 573, 574f intravenous thrombolysis in, 570-571, 570t, 571t, 572f beyond 3-hour period, 572 recanalization strategies in, 570-574 temperature control in, 570 thrombolysis in community in, 572-573 venous, 610 pure sensory, 556-557, 556t radiation-induced, 1357-1358 recovery after, mechanisms of, 645, 646t rehabilitation after, 645-654 complex organizational interventions in, 645-649, 646f, 646t, 647f, 647t future developments in, 653-654 goals in, 645, 646t management of neurological impairments in, 649-652, 650f management of systemic complications in, 652-653 outpatient or domiciliary, 648-649 retinal vasculitis and, 308 strategic, in vascular dementia, 637-639 Stroke care unit acute and rehabilitative components of, 646647, 647f aspects of care in, 647-648, 647t benefits of, 645-648 dimensions of care in, 647, 648t early discharge from, 648 high-dependency care in, 648 specialist team in, 648 Stroke volume, during pregnancy, 1491 Stroke-related syndrome, 624 Strongyloides infection, after organ transplantation, 1565-1566 Stroop color-word test for attention-deficit hyperactivity disorder, 133 for autism, 132 Stroop test, for executive function, 87, 87f

1621

Strumpell-Lorrain syndrome. See Hereditary spastic paraplegia. Stupor definition of, 97 recurrent, idiopathic, 195 Sturge-Weber syndrome, ocular involvement in, 306 Subacute sclerosing panencephalitis, ocular involvement in, 301 Subarachnoid hemorrhage, 1390 headache secondary to, 796-797, 796t, 797f retinal hemorrhage associated with, 309-310, 309f Subcortical band heterotopia genes associated with, 686t neuroimaging of, 664-665, 666f, 686f Subcortical cysts, megalencaphalic leukodystrophy with, 1081-1082, 1081f Subcortical ischemic vascular dementia, 639640 Subdural hematoma, 1389, 1389f cerebrospinal fluid leaks causing, 822 Subependymal veins, 621 Subfalcine herniation, in comatose patient, 104 Substance dependence alcohol in. See Alcoholism: Ethanol entries. definitions of, 1537 history of, in mental status assessment, 10 illicit, 1537-1539. See also named substance. intoxication and withdrawal of, 1537-1538 Substantia nigra, in Parkinson’s disease iron concentrations in, 934-935 mitochondrial dysfunction in, 935 oxidative stress and damage to, 935, 935t pathology of, 927 Subthalamotomy, for Parkinson’s disease, 947, 947t Sudden death mechanisms of, 1507 phenomenon of, 1507 situations predisposing to, 1505, 1506f Sumatriptan for cluster headache, 777 for migraine, 745, 745t SUNCT. See Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Sunderland’s classification, of nerve injury, 1410-1411, 1410t Superior canal dehiscence syndrome, conductive hearing loss due to, 332 Superoxide dismutase, levels of, in Parkinson’s disease, 935, 935t Supervisory attentional system model, of executive function, 84-85, 84f Supine hypertension, management of, 359-360, 383, 384t, 385 step-wise approach in, 359t Supratentorial herniation, in comatose patient, 102-104, 103t, 104t Suramin, for African trypanosomiais, 1276t Surgery. See also specific procedure. for brain tumors, indications for, 1330-1331 for dystonia, 451t, 452 for malignant glioma, 1335 for Parkinson’s disease, 947-948, 947t for spinal trauma, 1405, 1405f resective, for epilepsy, 717-718 Susac’s syndrome, 308-309, 309f Susceptibility genes, in schizophrenia, 224, 225f Swallow reflex, 164 Swallowing anatomy associated with, 155-156 corticobulbar tract in, 155, 156f cranial nerves in, 155, 157f

1622

Index

Swallowing (Continued) difficulty in. See Dysphagia. esophageal phase of, 163f, 164 neuromuscular control of, 161, 162f, 163f oral phase of, 161, 163f, 164 painful, 164 pharyngeal phase of, 163f, 164 Swallowing therapy, for dysphagia, 168 Symptom validity testing, 24 Symptomatic and supportive care, for amyotrophic lateral sclerosis, 870-871 Syncope, loss of consciousness in, 694-695 Syndrome of inappropriate ADH secretion, 1551 α-Synuclein protein, in Lewy bodies, 372, 929930 Syphilis in HIV infection, 302 retinal changes in, 300, 300f Syphilitic meningitis, 1245 Syringobulbia, 494 Syringomyelia, 494 Chiari malformation with, 493, 522 classification of, 522t clinical features of, 522-523, 523f in multiple sclerosis, 1022 pathogenesis of, 522 treatment of, 523 Syringomyelic cord syndrome, 513t Syrinx, 489t, 494, 495f definition of, 494 formation of, in spinal cord injury, 1402-1403 Systemic diseases, retinopathy/optic neuropathy associated with, 280-282, 281f Systemic lupus erythematosus, 1316, 1561-1564 central nervous system manifestations of, 1562-1563 classification of, 1562t cotton wool spots in, 297, 297f peripheral nervous system manifestations of, 1563-1564, 1563t Systemic sclerosis, progressive, 1558-1559

T T cell lymphoma, enteropathy-associated, celiac disease and, 1511 T cells. See also CD4 T cells; CD8 T cells. cytotoxic, in paraneoplastic neurological disorders, 1361, 1362f Tabes dorsalis, 518 Tacrolimus, toxic neuropathy due to, 1121 Tactile apraxia, 408 Taenia solium cysticercosis clinical presentation of, 1277 diagnosis of, 1277, 1278f-1284f epidemiology of, 1276-1277 treatment of, 1277, 1279, 1285f Tai Chi Quan techniques, for gait disturbances, 466 Takayasu’s arteritis, 1319 retinal involvement in, 298 “Talk and die” injuries, brain trauma and, 1392, 1393f Tamoxifen, neurological complications caused by, 1355 Tandem gait test Taste disorders of, 175-176, 176t. See also Gustatory disorders. loss of, in multiple sclerosis, 1019 Tau gene mutations, in frontotemporal dementia, 985-986, 986f clinical screening for, 987t Tau haploid, in frontotemporal dementia, 986 Tau protein deposits, 985t

Tauri’s disease, 1197-1198 Tay-Sachs disease, cherry-red spot in, 310 TDP1 (tyrosyl DNA phosphodiesterase 1), 1105 TDP1 gene, in inherited neuropathies, 1105 Telangiectasia, hereditary hemorrhagic, 598-599 Telencephalon, arteriovenous lesions of, 598 Temozolomide, for brain tumors, 1333 Temperature control of, in ischemic stroke, 570 effects of, on demyelinated axons, 1002-1003, 1004f TEMPO study, of Parkinson’s disease, 944f, 945, 948 Temporal arteritis, 1320 Temporal bone fractures, dizziness and nystagmus in, 346 Temporal lobe epilepsy. See also Epilepsy. familial lateral genetics of, 683t, 684-685 memory impairment associated with, 49 mesial, 679, 704 Temporal lobe infarction, upper quadrantinopia due to, 263f Temporal lobe lesions memory impairment associated with, 49-50, 50f seizures associated with, 1326 Temporal vision-related cortex disorders, 60-61, 61t Tendonitis, of superior oblique tendon (Brown’s syndrome), 1559 Tendons, segmental innervation of, 514t Tensilon test, for myasthenia gravis, 1224 Tension pneumocephalus, 1390 Tension-type headache, 757-760, 758t, 759t. See also Headache. Terminal care, for amyotrophic lateral sclerosis, 873 Terson’s syndrome, 309-310, 309f Test reliability, 23 Test scores, reporting of, 25-26, 26f Test validity, 23-24 Testis, in X-linked adrenoleukodystrophy, 1066 Test-retest reliability, 23 Tetanus, 1487 Tethered cord syndrome, 499-502 clinical features of, 499-501, 501f, 502f definition of, 499 etiology and pathophysiology of, 501-502 management of, 502 modes of presentation of, 499-500, 501f Tetrabenazine, for Huntington’s disease, 884 Tetraplegia, definition of, 1397 Thalamic dementia, 638 Thalamostriate veins, anatomy of, 621 Thalamotomy, for Parkinson’s disease, 947, 947t Thalamus, lesions of, vascular dementia due to, 638-639 Thalassemia, 1527, 1528f Thalidomide for leprosy reactions, 1132 toxic neuropathy due to, 1121 Thallium toxicity, 1122 Thermal regulations, during sleep states, 181 Thiamine active form of, 1455, 1456f. See also Vitamin B1. deficiency of. See Vitamin B1 deficiency. Thomsen myotonia congenita, 1187, 1188 Thoracic spine, injury to, 1400, 1400f Thoracolumbar junction, burst fracture of, 1400, 1400f Thought content, 7 Thought form, 7 Three-wheeled walker, 1429f

Thrombectomy, for cerebral vein and sinus thrombosis, 629 Thrombocytopenia, 1528 Thromboembolism, ischemic stroke due to, 610-611, 614f-615f Thrombolysis, for ischemic stroke in community, 572-573 intra-arterial, 573, 574f with intravenous thrombolysis, 573-574 intravenous, 570-571, 570t, 571t, 572f beyond 3-hour period, 572 with intra-arterial thrombolysis, 573-574 Thrombosis cavernous sinus, 624-625 pathology of, 609-610 pregnancy and, 1531-1532 venous. See Venous thrombosis. Thrombotic endocarditis, nonbacterial, 1531 Thrombotic thrombocytopenic purpura, 1528, 1529f Thunderclap headache, 796 differential diagnosis of, 796t Thymectomy, for myasthenia gravis, 1228 Thymoma-associated myasthenia gravis, 12271228, 1227t Thyroid-stimulating hormone (TSH), 1553 source and function of, 1550t Thyrotoxic periodic paralysis, 1191 Thyrotropin, 1553 Tic douloureux, 835 Tick paralysis, 1485 Tickborne encephalitis, 1254 Tics. See also Gilles de la Tourette syndrome. characteristics of, 214 differential diagnosis of, 214-215 epidemiology of, 215 etiology of, 215 Tigabine, for partial and tonic-clonic seizures, 709-710 Timed Up and Go (TUaG) test, in assessment of gait, 459-460 Tinnitus, pulsatile, in idiopathic intracranial hypertension, 808 Tissue biopsy, in neurosarcoidosis, 1307 Tissue damage, in vasculitis, mechanisms of, 1313-1314 Tissue plasminogen activator. See also Thrombolysis. for stroke, 570-571, 571t FDA approval of, 571 Titubation, in cerebellar disease, 424 TNNT1 gene, in nemaline myopathy, 1176 Tobacco smoke, atherosclerosis associated with, 619 α-Tocopherol. See Vitamin E. Toes, impaired vibration sensation of, in hereditary spastic paraplegia, 902-903 Tolcapone, for Parkinson’s disease, 942 Tolosa-Hunt syndrome, 625 Toluene (methyl benzene), exposure to, 1481t, 1483 Tonic pupil, pupillary responses in, 270, 270f Tonic seizures, 675, 694 Tonic-clonic seizures. See also Seizure(s). generalized, 694 treatment of, 708-710 Tonsillar herniation, 492. See also Chiari malformation. in comatose patient, 104 Topiramate for generalized seizures, 711 for status epilepticus, 727 for tremor, 421, 421t prophylactic for cluster headache, 781 for migraine, 747t, 748-749

index “Top-of-the-basilar” syndrome, 558t, 564, 564f Topography, of tremors, 417, 418t TORA1 gene, in dystonia, 444, 445t Torticollis, spasmodic (cervical dystonia), 445 Tourette syndrome. See Gilles de la Tourette syndrome. Tower of Hanoi Test, for autism, 132 Tower of London Test, of executive function, 89, 90f Toxemia of pregnancy, 716-717 Toxic neuropathy(ies), 1119-1123 alcohol-induced, 1122 heavy metals associated with, 1121-1122, 1122t medication(s) associated with, 1119, 1120t antibiotics as, 1120, 1120t cardiovascular agents as, 1120-1121, 1120t chemotherapy agents as, 1120t, 1121 colchicine as, 1120t, 1121 immunosuppressants as, 1120t, 1121 phenytoin as, 1120t, 1121 n-hexane and methyl-N-butyl ketone associated with, 1122 optic, visual loss in, 291-292, 292f, 292t pyridoxine associated with, 1464 Toxic tremor, 427-428 Toxin(s) botulinum. See Botulinum toxin. environmental, 1477-1487. See also specific toxin. animal, 1485 bacterial, 1486-1487 gaseous, 1483-1484, 1483t metals as, 1477-1481 organic solvents as, 1481-1483, 1481t pesticides as, 1484-1485 plant, 1485-1486 heavy metal, 1121-1122, 1122t Toxin-induced vasculitis, 1317 Toxoplasma gondii, 1288 Toxoplasmosis clinical presentation of, 1288, 1288t diagnosis of, 1288 epidemiology and pathophysiology of, 1288 retinal involvement in, 302, 302f treatment of, 1288-1289 TP53 gene, in brain tumors, 1325 TPM2 gene, in nemaline myopathy, 1176 TPM3 gene, in nemaline myopathy, 1176 Traction injury, to peripheral nerves, 1415-1416, 1416f Tractography, of malformations caused by abnormal cortical development, 667 Traffic accidents, sleep-related, 204-205 Trail making test, for executive function, 87-88 Transcortical motor aphasia, 35-36 Transcortical sensory aphasia, 37 Transient epileptic amnesia, 49 Transient global amnesia, 48 Transient ischemic attack, 551-552. See also Stroke. definition of, 551 large artery atherosclerosis–associated, 553 misdiagnosis of, 696 radiation-induced, 1357-1358 vertebrobasilar, 347 Transplantation, 1564-1567 bone marrow for globoid leukodystrophy, 1073 for metachromatic leukodystrophy, 1071 neuropathies after, 1566-1567 central nervous system neoplasms after, 1566 for spinal trauma, strategies in, 1406-1407 graft-versus-host disease after, 1567 immunosuppressive drugs in, adverse effects of, 1564t

Transplantation (Continued) liver, for Wilson’s disease, 1450 neuropathy after, 1566-1567 opportunistic infections after, 1565-1566 postoperative encephalopathy after, 1564-1565 seizures after, 1565, 1565t stem cell for globoid leukodystrophy, 1073 for spinal trauma, 1406-1407 for X-linked adrenoleukodystrophy, 1068 stroke after, 1566 Trauma. See also at anatomic site, e.g., Spinal cord injury; specific trauma, e.g., Fracture(s). amnesia associated with, 49 in alcoholics, 1542 in drug abusers, 1538 labyrinthine, 345-346 Trauma care systems, 1386 Traumatic optic neuropathy, visual loss in, 292 Tremor, 417-428 asymmetric intermittent resting, in Parkinson’s disease, 936 cerebellar, 424-425 treatment of, 425 clinical definitions of, 417 clinical presentation of, 418t cortical, 428, 435 differential diagnosis of, 419t drug-induced, 427-428 dystonic, 424 enhanced physiological, 417-419 differential diagnosis of, 419, 419t epidemiology of, 417-418 etiology of, 418-419 pathophysiology of, 418 treatment of, 419 essential, 419-422 differential diagnosis of, 419t, 421 etiology and epidemiology of, 420 pathophysiology of, 420 treatment of, 421-422, 421t, 422t vs. Parkinson’s disease, 938 Holmes, 425-426 treatment of, 426 in Lewy body dementia, 913 in peripheral neuropathy, 426-427 in Wilson disease, 428, 1447 intention, 417 in Huntington’s disease, 881 in multiple sclerosis, 1022 treatment of, 1050 orthostatic, 422 palatal, 426, 436-437 parkinsonian, 422-424 definition of, 422-423 epidemiology and etiology of, 423 pathophysiology of, 423 treatment of, 423-424, 423t psychogenic, 427 tardive, 428 toxic, 427-428 Treponema pallidum, 300 Trial of ORG 10172 in Acute Stroke Treatment (TOAST), 577 Triangle sign, in cerebral vein and sinus thrombosis, 625 Triazolam, for non-REM parasomnias, 198 Trichloroethylene, exposure to, 1481t, 1483 Trichothiodystrophy, 889, 890 Triethylene tetramine dihydrochloride, for Wilson’s disease, 1450 Trigeminal automatic cephalgias, 773-785 clinical features of, 775t cluster headaches as, 775-782. See also Headache, cluster.

1623

Trigeminal automatic cephalgias (Continued) differential diagnosis of, 774-775, 774t experimental studies of, 773 human studies of, 773-774 paroxysmal hemicranias as, 782-784. See also Hemicrania, paroxysmal. pathophysiology of, 773-774 short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing as, 784, 784t clinical features of, 775t diagnostic criteria for, 776t secondary, 784-785 treatment effects on, 777t trigeminal-parasympathetic activation in, 774, 774f, 775f Trigeminal nerve (V) divisions of, 734 function of, in speech and swallowing, 155, 157f Trigeminal neuralgia, 835-840 clinical syndrome of, 835-836 complications of, 840 differential diagnosis of, 836-837 in multiple sclerosis, 836, 1021, 1021t testing for, 836 treatment of medical, 837-838 surgical, 838-840 trigger zones in, 835 Trigeminal nucleus, 734 Trigger zones, in trigeminal neuralgia, 835 Triglycerides, circulating, atherosclerosis and, 611-612 Triptans for cluster headache, 777-778 for migraine, 745-746, 745t Trochlear nerve (IV), paresis of, in multiple sclerosis, 1019, 1019f Tropheryma whippelii, 300, 1516. See also Whipple’s disease. Trophic ulcer(s), in leprosy, management of, 1132 Tropical spastic paraparesis, 518-519 Troposomia, 173 Trunk apraxia, 412-413 Trunk control impairment, after stroke, management of, 649 Trypanosoma brucei, 1273 Trypanosomiasis, African, 1273, 1275 treatment of, 1275, 1276t TSH (thyroid-stimulating hormone), 1553 source and function of, 1550t Tuberculosis, ocular involvement in, 300, 300f Tuberculous meningitis, 1243-1245 clinical features of, 1243-1244 diagnosis of, 1244, 1244f pathogenesis of, 1243 prognosis of, 1244-1245 treatment of, 1244, 1244t Tuberous sclerosis cortical hamartoma, neuroimaging of, 664, 665f genes associated with, 686t retinal hamartomas in, 306, 306f Tulio phenomenon, 322 Tumors. See Neoplasms; specific tumor; at anotomic site. Tuning fork test, for hearing, 319 Twin studies, of multiple sclerosis, 998 Tympanic membrane, perforations of acoustic trauma causing, 346 conductive hearing loss due to, 331 Tympanometry, 320

1624

Index

Tympanosclerosis, conductive hearing loss due to, 331 Tyrosyl DNA phosphodiesterase 1 (TDP1), 1105

U UCH-L1 (PARK5) gene, in Parkinson’s disease, 928t, 931 Uhthoff’s phenomenon, in multiple sclerosis, 1018 Ulcer(s) pressure, rehabilitation strategies for, 1431 trophic, in leprosy, management of, 1132 Ulcerative colitis cerebrovascular events in, 1515 extraintestinal manifestations of, 1514 gastrointestinal features of, 1513t sensorineural hearing loss in, 1514 Ultradian rhythms, regulation of, hormones and, 1549 Ultrasonography duplex Doppler, of ischemic stroke, 565-566, 566f of brain death, 112 of head, for urea cycle disorders, 1472, 1472f of hydrocephalus, 827 of neural tube defects, 498, 498f of Parkinson’s disease, 939 of peripheral nerve injury, 1414 transcranial Doppler, of ischemic stroke, 566, 566f, 567f Uncal herniation, in comatose patient, 103-104, 104t Unclassified seizures, 677. See also Seizure(s). Undernutrition, in stroke patients, management of, 653 Uniform Determination of Death Act, 107 United Kingdom Glucose Insulin Trial (GISTUK), 569 United Kingdom guidelines, for brain death, 107-108, 108t United States guidelines, for brain death, 108, 109t Unresponsiveness, postcoma, 117 Unverricht-Lundborg disease, 705 Upper extremity, asymptomatic involvement of, in uncomplicated hereditary spastic paraplegia, 903 Upper motor neuron lesions, speech disorders due to, 158, 158t Urea cycle, steps in, 1469, 1470f Urea cycle disorders, 1441, 1469-1476, 1470t clinical features of, 1470-1472 cognitive deficits in, 1472 definition of, 1469, 1471f epidemiology of, 1469-1470 neuroimaging abnormalities in, 1472, 1472f neuropathology of, 1472, 1473f neurotoxicity in, 1471-1472 pathophysiology of, 1472-1474 treatment of, 1474-1476 acute management in, 1475 alternative pathway therapy in, 1475, 1475f dialysis in, 1475 dietary management in, 1476 long-term, 1476 Uremic neuropathy, 1116 Urinary urgency in hereditary spastic paraplegia, 902 in multiple sclerosis, 1022 in normal-pressure hydrocephalus, 830 Urine tests, for Lewy body dementia, 914 Urodynamic testing, of bladder function, 363 Urokinase, for cerebral vein and sinus thrombosis, 629

Useless hand syndrome, in multiple sclerosis, 1020-1021, 1021t Usher syndrome, 283 U-step walker, 1430f Utilization behavior, 9 Uveal melanocytic proliferation, bilateral diffuse, 305 Uveitis, 295 in multiple sclerosis, 299 Uveomeningeal syndromes, 295-297, 296f, 297f

V Vaccination. See Immunization. Vagus nerve (X), function of, in speech and swallowing, 155, 157f Validity, of tests, 23-24 Valproic acid (valproate) for generalized seizures, 710-711 for West’s syndrome, 714 intravenous, for status epilepticus, 726-727 prophylactic for cluster headache, 781 for migraine, 747t, 748 Valsalva ratio, 355t Valvular heart disease, and cardioembolic stroke, 578 Vanishing white matter disease, synonyms for, 1080 Varicella-zoster virus (VZV), 1136 myelitis due to, 517-518 Vascular dementia, 635-643 acute forms of, 637 apathy in, 243 clinical features of, 637-640, 638t definition of, 635 depression in, 238 diagnosis of, 640-641, 642t diagnostic criteria for, 635 epidemiology of, 635, 637 etiologies of, 635, 636t-637t incidence of, 637 multi-infarct, 637 pathology and pathophysiology of, 640, 640f, 641f, 642t prevalence of, 637 prevention of, 641, 642t, 643 risk factors for, 642t strategic strokes in, 637-639 subacute forms of, 639-640 treatment of, 641 Vascular parkinsonism, vs. Parkinson’s disease, 938 Vasculature, intracranial, innervation of, 793, 794f Vasculitic neuropathy, 1119 Vasculitis, 615 antineutrophil cytoplasmic antibody–related, 1313-1314 central nervous system (cerebral), 1317-1320 blood tests in, 1318 cerebrospinal fluid analysis in, 1318 clinical definition of, 1314 clinical features of, 1317 diagnosis of, 1317-1319, 1318t drug- and toxin-induced, 1317 histopathology of, 1319 primary, 1314 radiography of, 1318-1319 treatment of, 1319-1320 classification of, 1313, 1314t hypersensitivity, 1316 immune complex–mediated, 1313 infectious, 1316-1317 leukocytoclastic, 1317

Vasculitis (Continued) neurological, 1313-1321 causes of, 1314-1317 peripheral nervous system, 1320-1321 primary, 1314-1315 retinal, and stroke, 308 secondary, 1316 small-vessel, 1316 systemic, with neurological involvement, 1315-1316 tissue damage in, mechanisms of, 1313-1314 Vasoactive transmitters, in neurogenic regulation of cerebral blood flow, 545t Vasopressin, 1551 source and function of, 1550t Vasospasm, 615 cerebral, 589-590 Vegetative function, assessment of, 8 Vegetative state, 117-127 biochemical markers of, 123 criteria for, 117-118 diagnosis of, 119 electroencephalography of, 119-120, 120f-122f epidemiology of, 118 ethical considerations of, 127 imaging studies of, 123, 124f, 125f neurophysiological assessment of, 119-120 pathology of, 118-119 permanent, 117 persistent, 117 prognosis and management of, 123, 126-127, 126f salient features of, 117 somatosensory evoked potential studies in, 120, 122, 122f, 123f survivors of, incidence of, 118 Vehicular accidents Alzheimer’s disease and, 855 sleep-related, 204-205 Vein of Galen, 542, 543f anatomy of, 621 Velopharyngeal incompetence, surgical management of, 161 Venezuelan equine encephalitis, 1250, 1254 Venom, animal, 1485 Venous anastomoses, 623 Venous stasis, 615-616 Venous stasis retinopathy, 308 Venous stents, for idiopathic intracranial hypertension, 812 Venous thrombosis after stroke, management of, 652 cerebral, 621-630 clinical features of, 624-625 diagnosis of, 625-626, 626f disorders associated with, 618-619 epidemiology of, 623 headache secondary to, 797 pathophysiology of, 623-624 prognosis of, 629-630 risk factors for, 626-628, 628f, 628t, 629f treatment of, 628-629 Ventilation mechanical, for amyotrophic lateral sclerosis, 215, 872f positive pressure for amyotrophic lateral sclerosis, 871 for central sleep apnea, 210 Ventricles, cerebral, cerebrospinal fluid flow patterns in, 825, 826f Ventriculoperitoneal shunt for gait disturbances, 468 for hydrocephalus, 828, 830f Ventriculostomy, for relapsing-remitting neurosarcoidosis, 1309

index Verapamil, prophylactic for cluster headache, 779 for migraine, 747t, 748 Verbal fluency tests, of executive function, 89 Verbal paraphrasia, 33 Vertebral artery dissection of, stroke due to, 555 extracranial, embolic material in, 558t, 562 intracranial, embolic material in, 558t, 562 Vertebral bodies, development of, 488 Vertebrobasilar transient ischemic attack, 347 Vertical gaze impairment, in Whipple’s disease, 1516 Vertigo, 322. See also Dizziness. benign paroxysmal positional, 322, 344, 344t, 345f diagnostic characteristics of, 346t treatment of, 349 benign recurrent, 344 definition of, 337 diagnosis of, 342, 342f in multiple sclerosis, 348, 1020 migrainous, 343-344 episodic, 343 Very-long-chain acyl–coenzyme A dehydrogenase defect, 1200 Vessel wall defect(s), 611-613, 615-616 arteriosclerosis as, 613, 615 atherosclerosis as, 611-613, 615t, 616f. See also Atherosclerosis. dissection as, 615 inflammation as, 615 spasm as, 615 stasis as, 615-616 Vestibular deafferentation, unilateral acute, 340-341, 340f, 341f chronic, 341 compensation for, 340t consequences of, 340t Vestibular hypofunction, bilateral, 341 Vestibular neuritis, acute, 342 Vestibular schwannoma (acoustic neuroma), 1338 Vestibular stabilization agents, for gait disturbances, 468 Vestibular system, 337-340, 338f age-related changes of, 339-340 anatomy of, 337-338, 338f disorders of. See also specific disorder, e.g., Vertigo. causes of, 338t central, 347-348 definitions of, 337 diagnosis of, 342, 342f epidemiology of, 337 management of, 348-350, 348f, 348t general measures in, 348-349 pharmacological, 349 psychological intervention in, 349 rehabilitation in, 349 surgical, 349-350 peripheral, 340-342 bilateral, 341 common, 342-346 compensation/decompensation for, 341342, 341f unilateral, 340-341, 340f, 340t, 341f failure of, bilateral, 346-347 neoplasia of, 346-347 physiology of, 337-338, 339f Vestibulo-ocular reflex, 323 examination of, 272 Vibration sensation impairment, of toes, in hereditary spastic paraplegia, 902-903 Videofluoroscopic swallowing study, of dysphagia, 166, 166f

Vigabatrin, for partial and tonic-clonic seizures, 710 Vinca alkaloids, neurological complications caused by, 1354-1355 Vincristine, toxic neuropathy due to, 1121 Viral encephalitis. See Encephalitis, viral. Viral infections. See also specific infection, e.g., Human immunodeficiency virus (HIV) infection. exanthematous, acute disseminated encephalomyelitis associated with, 1058t of retina, 300-302, 301f of spinal cord, 516-518 Viral meningitis. See Meningitis, viral. Virchow-Robin space, 543 Virchow’s triad in hemostasis, 609, 612f pathological causes of, 609, 613f Vision-related cortex disorders parietal-occipital, 63-64, 64t, 65f temporo-occipital, 60-61, 61t Visual acuity, 260 in Leber’s hereditary optic neuropathy, 280, 280f Visual agnosia, 60-61, 61t apperceptive, 62 associative, 62-63, 63f compensatory techniques for, 68 screening for, 67t Visual attention deficits, remediation of, cognitive training for, 80 Visual dysfunction, in conversion syndrome, 253 Visual evoked potentials, in multiple sclerosis, 1032-1033, 1032f Visual field defects, in idiopathic intracranial hypertension, 808 examination of, 260-261, 261f-269f, 269 Visual loss. See also Blindness. in acute optic neuritis, 286-288, 287f, 288f in compressive optic neuropathy, 290-291, 291f in infiltrative optic neuropathy, 291, 291f in ischemic optic neuropathy, 288-289, 288f, 289f in Leber’s hereditary optic neuropathy, 280, 280f, 289-290, 290f in multiple sclerosis, 299, 1018-1019, 1018t in radiation-induced optic neuropathy, 292293, 293f in toxic and deficiency optic neuropathies, 291-292, 292f, 292t in traumatic optic neuropathy, 292 localization of, 275 optic disc swelling without, 285-286, 286f optic nerve–related insidious, 290-292, 291f, 292f sudden, 286-290, 287f-290f Visual processing pathways, dorsal and ventral, 60 Visual syndromes, paraneoplastic, 304, 1371, 1371f Visuoconstructional function, neurocognitive examination of, 13, 13t Visuoperceptual disorders, higher, 59-70. See also specific disorder. anatomy and physiology of, 60-64 diagnosis of, 65-66 assessment strategies in, 66, 68f-70f neuropsychological tests in, 66t pitfalls in, 66 screening battery for, 67t epidemiology of, 59 treatment of, 66-68 Visuoperceptual function, neurocognitive examination of, 13

1625

Visuospatial disorders, higher, anatomy and physiology of, 60-64 Visuospatial domain, in Alzheimer’s disease, 851 Visuospatial function higher, two-systems approach to, 60, 62f neurocognitive assessment of, 5 testing of, 13 Vital signs, in comatose patient, 101 Vitamin(s), 1455 deficiency of, 1455-1464. See also specific vitamin deficiency. therapy with, hereditary disorders responsive to, 1455, 1457t water-soluble, metabolic pathways of, 1456f Vitamin B1 for ethanol withdrawal symptoms, 1540t for hereditary disorders, 1457t for Wernicke-Korsakoff syndrome, 1541 recommended daily allowance of, 1456 Vitamin B1 deficiency, 1455-1457 disorders associated with, 1123, 1456-1457 epidemiology and risk factors for, 1456 evaluation of, 1457, 1458f management of, 1457 pathogenesis and pathophysiology of, 1455, 1457f Vitamin B6 for West’s syndrome, 713 for Wilson’s disease, 1450 Vitamin B6 deficiency, 1462 polyneuropathy associated with, 1123 Vitamin B9 deficiency, 1461-1462 Vitamin B12, recommended daily allowance of, 1460 Vitamin B12 deficiency anemia due to, 1525-1526 differential diagnosis of, 1460 disorders associated with, 1460, 1460t epidemiology and risk factors for, 1460 evaluation of, 1460-1461, 1461f management of, 1461 myelopathy associated with, 509 pathogenesis and pathophysiology of, 1459, 1459f polyneuropathy associated with, 1123 Vitamin B complex deficiency, 1458-1459 polyneuropathy associated with, 1123 Vitamin C ferrous sulfate with, for iron deficiency, in restless leg syndrome, 476 for amyotrophic lateral sclerosis, supplemental, 870t Vitamin E for amyotrophic lateral sclerosis, supplemental, 870t for blood pressure control, 569 high doses of, safety of, 869 recommended daily allowance of, 1462 Vitamin E deficiency, 1462-1464, 1462f, 1463f disorders associated with, 1462-1463, 1463t in autosomal recessive cerebellar ataxia, 889 neurological findings in, 1463, 1463t polyneuropathy associated with, 1123 α-tocopherol for, 1463 Vitamin Intervention for Stroke Prevention (VISP) trial, 580 Vitamin K, during pregnancy, 716 Vitamin K deficiency, in newborn, antiepileptic agents causing, 1500 Vitamins to Prevent Stroke (VITATOPS) study, 580 Vitreoretinopathy(ies), hereditary, 276-277, 277f Vitreous humor, 295 Vivid dreams, sleep disruption due to, 192 VMD2 gene, in Best’s vitelliform macular dystrophy, 277-278

1626

Index

Vocal cords abduction of, 159 adduction of, 159 Vogt-Koyanagi-Harada disease, retinal involvement in, 297, 297f Voice, nonorganic disorders of, 159 Voice amplifiers, for speech disorders, 161 Voice tremor, treatment of, 421-422, 421t, 422t Voluntary breathing, disorders of, 1573 Von Hippel–Lindau disease, retinal hemangioma in, 306, 307f “Voodoo” death, 1505 VZV. See Varicella-zoster virus (VZV).

W Wakefulness neurobiological control of, 182 periodic limb movements in, 471, 474 regulation of, 181-182 Walkers, 1428t, 1429f Walker-Warburg syndrome, 1144t, 1153t Walking. See also Gait entries. cognitive function and, 465 effects of dual-tasking on, 463, 464, 465f execution of, 456 Walking aids, for gait disturbances, 467 Wallenberg’s syndrome (lateral medullary infarction), 347 Wallerian degeneration, in spinal cord injury, 1402 Wandering, of Alzheimer’s patient, 855 Warfarin, contraindications to, during pregnancy, 1496 Warfarin Aspirin for Symptomatic Intracranial Disease (WASID) trial, 578 Water-soluble vitamins, metabolic pathways of, 1456f Weakness in multiple sclerosis, 1021 treatment of, 1050 muscle, neuroparasites causing, 1274t spinal cord tumors causing, 1342 vs. spasticity, in hereditary spastic paraplegia, 904 Weber test, for hearing, 319 Wechsler Test of Adult Reading, 4 Wegener’s granulomatosis, 1315 orbital involvement in, 298

Wernicke syndrome, 1541 Wernicke-Korsakoff syndrome, 51 clinical features of, 1456-1457 ethanol neurotoxicity contributing to, 1541 evaluation of, 1457, 1458f management of, 1457, 1541 pathogenesis and pathophysiology of, 1455, 1457f Wernicke-Lichtheim-Geschwind model, of language disorders, 31 Wernicke’s aphasia, 36 agraphia in, 40t alexia with, 40 Wernicke’s encephalopathy, delirium in, 148 West Nile encephalitis, 1250, 1251f, 1254 Western equine encephalitis, 1250 Westphal’s variant Huntington’s disease, 881 West’s syndrome, treatment of, 713-714 Wet beriberi, 1123 Whipple’s disease, 1515-1516 neurological features of, 1516t ocular involvement in, 300 systemic features of, 1516t Wilson’s disease, 1447-1451 biochemical anatomy of, 1450 clinical features of, 1447-1448, 1448t diagnosis of, 1449 epidemiology of, 1447 Kayser-Fleischer rings in, 448, 449f molecular genetics of, 1449-1450 neuroimaging of, 1448, 1448f pathological anatomy of, 1449 retinal changes in, 305 treatment of, 1450-1451, 1451f tremor in, 428 Wisconsin Card Sorting Test (WCST), 22 for autism, 132 of executive function, 88, 88f Withdrawal of ethanol, 1540-1541, 1540t of illicit drugs, 1538-1539 Wolfram disease, 280 Women’s Estrogen for Stroke Trial (WEST), 580 Women’s Health Initiative (WHI) study, 580 Working memory, 45, 98 testing of, 13, 14t Working memory model, of executive function, 83-84, 84f World Health Organization (WHO) classification, of brain tumors, 1328t

Writer’s cramp, 445-446 Wyburn-Mason syndrome, 599 retinal arteriovenous malformation in, 307, 307f

X Xanthomatosis, cerebrotendinous, 1078-1079 Xeroderma pigmentosum, 889 X-linked adrenoleukodystrophy, 281-282, 10651069 clinical features of, 1065-1066 diagnosis of, 1067 genetics of, 1067 neuroimaging of, 1066-1067 pathogenesis of, 1067-1068 pathology of, 1066 phenotypic, in male patients, 1065-1066 synonyms associated with, 1065 treatment of, 1068-1069 X-linked centronuclear myopathy, 1177 X-linked cerebellar ataxia, 887, 888t, 891 X-linked hereditary spastic paraplegia, 901t. See also Hereditary spastic paraplegia. X-linked optic atrophy, 280 Xp28 gene, in adrenomyeloneuropathy, 510

Y Yohimbine, for orthostatic hypotension, 359t

Z Z band, of sarcomere, 1096, 1096f Zellweger syndrome, 281 Zinc acetate, for Wilson’s disease, 1450 ZNF9 gene, in myotonic dystrophies, 1193 Zolmitriptan for cluster headache, 777-778 for migraine, 745, 745t Zolpidem, for oculomotor disturbances, in progressive supranuclear palsy, 972-973 Zonisamide, for generalized seizures, 711-712 Zoo map test, of executive function, 89 Zoster sine herpete syndrome, 1136